A Healthcare Reform: Cost- Hematologic Drug Pipeline Containment Not Very Likely

Transcription

AHDB_ASH_012010_ASCO Highlights Tabloid 2/16/10 1:12 PM Page c1
THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™
FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS
FEBRUARY 2010 I VOL 3, NO 1 I SPECIAL ISSUE
ASH 2009: PAYER’S PERSPECTIVES
THE AMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS
Hematologic Drug Pipeline
Healthcare Reform: CostContainment Not Very Likely Diverse and Promising
By Caroline Helwick
By Wayne Kuznar
A
Paul B. Ginsburg, PhD
S
ome degree of healthcare reform
seems likely to be enacted, but
what is shaping up as reform will
likely be a failure in terms of “serious
cost-containment,” suggested Paul B.
Ginsburg, PhD, President of the
Center for Studying Health System
Change, a “think tank” that analyzes
changes in financing and the delivery
of healthcare (www.hschange.org). Dr
Ginsburg was the main speaker at the
session on Healthcare Costs and
Reform at the 2009 annual meeting of
the American Society of Hematology.
Continued on page 4
The Costs of Multiple Myeloma
Treatment Vary Widely
By Caroline Helwick
T
he costs of treating multiple
myeloma (MM) can present as
much of a burden on the patient
and/or payers as on the disease itself.
In a recent cost analysis, investigators
compared the cost of treatment for
MM with bortezomib (Velcade), an
injectable drug, and with the oral medications lenalidomide (Revlimid) and
thalidomide (Thalomid).
Continued on page 5
host of investigational drugs
in the pipeline for the treatment of hematologic disorders
were featured in many oral and poster
presentations at ASH. The following
is a sampling of agents that show
particular promise.
Perhaps the 2 drugs that had the
biggest reception were dabigatran
etexilate and rivaroxaban, which
showed impressive success for the
prevention of recurrent venous thromboembolic events (see article, page 21).
Omacetaxine mepesuccinate is
being studied for the treatment of
chronic myelogenous leukemia (CML)
that is resistant to imatinib because of
the development of the BCR-ABL
T315I genetic mutation. In an ongoing
phase 2/3 study of 81 patients with
CML (49 in chronic-phase CML, 17 in
the accelerated phase, and 15 in the
blast phase), omacetaxine produced
durable hematologic and cytogenetic
responses, reported Jorge E. Cortes,
MD, Deputy Chair and Professor of
Medicine, Department of Leukemia,
University of Texas M.D. Anderson
Cancer Center.
“Omacetaxine works by a completely different mechanism, inhibiting the
synthesis of certain oncoproteins
instead of directly attacking BCRABL,” Dr Cortes said.
Previous imatinib therapy had
failed in all the patients, and ≥2
previous tyrosine kinase inhibitors
failed in 79%. A baseline BCR-ABL
T315I gene mutation was confirmed
in all patients.
In chronic-phase CML patients,
complete hematologic responses occurred in 86% (median response duration, 9 months) and the total cytogenetic response rate was 41%, with a
major cytogenetic response in 27%.
Continued on page 21
New Regimen Challenges Standard
Treatment of Indolent Lymphoma
By Wayne Kuznar
B
endamustine (Treanda) plus
rituximab (Rituxan) (B/R) was
more effective and better tolerated than the standard first-line regimen
of CHOP-R—cyclophosphamide (Cytoxan), hydroxydaunorubicin (Adriamycin), vincristine (Oncovin), and
prednisone (Deltasone), plus rituximab—for indolent lymphoma and
mantle-cell lymphoma (MCL), according to a phase 3 German trial in which
B/R reduced the risk of tumor progression by 43%. The study was highlighted at a special press conference
during ASH.
“Bendamustine
plus rituximab has
the potential to
become a treatment
of first choice in
these disease entities,” said Mathias
J. Rummel, MD,
of the University
Hospital in Giessen,
Mathias J.
Rummel, MD
Germany.
“I think there will be a great deal of
interest in this study. The findings are
Continued on page 8
INSIDE
HEALTH ECONOMICS
LYMPHOMA
©2010 Engage Healthcare Communications, LLC
4
8
LEUKEMIA
12
MULTIPLE MYELOMA
17
OTHER ASH HIGHLIGHTS 21
AHDB_ASH_012010_ASCO Highlights Tabloid 2/16/10 12:58 PM Page c2
For more information, visit www.cllinformation.com
*
Refractory to fludarabine and alemtuzumab
© 2009 The GlaxoSmithKline Group of Companies All Rights reserved. AZA140R0 October 2009
11:12:39 AM
AHDB_ASH_012010_ASCO Highlights Tabloid 2/16/10 12:58 PM Page 3
ASH 2009: PAYER’S PERSPECTIVES
THE AMERICAN SOCIETY OF HEMATOLOGY HIGHLIGHTS
CONTENTS
Publisher
Nicholas Englezos
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732-992-1884
Associate Publisher
Maurice Nogueira
[email protected]
732-992-1895
HEALTH ECONOMICS
LEUKEMIA
4
5
12 First Head-to-Head Comparison of Targeted TKIs
13 Intermittent Dosing of Dasatinib May Cut Toxicity,
6
Editorial Director
Dalia Buffery
[email protected]
732-992-1889
Associate Editor
Lara J. Reiman
[email protected]
732-992-1892
Senior Production Manager
Robyn Jacobs
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9
10
12
Indolent Lymphoma
In Challenging B-Cell Lymphoma, Aggressive
Chemotherapy plus Rituximab Show Best Outcomes
Treatment Is Beneficial in Older Patients with
Advanced Lymphoma
Hodgkin’s Lymphoma: No Changes in Standard of Care,
but Emerging Therapies Are Promising
Adding Rituximab to Standard Therapy in Hodgkin’s
Lymphoma Improves Outcomes
Novel Agent Shows Impressive Outcomes in Aggressive
NHL
How Much Rituximab Is Necessary in Advanced NHL?
Long-Term Survival Achieved with Tositumomab/I-131
Emerging Strategies for Mantle-Cell Lymphoma
Contact Information:
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EDITORIAL BOARD
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CLINICAL EDITOR
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Chief Clinical Officer
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American Health & Drug Benefits, ISSN 1942-2962
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VOL. 3
NO. 1
SPECIAL ISSUE
14
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8 New Regimen Challenges Standard Treatment of
Editor-in-Chief
Robert E. Henry
[email protected]
732-992-1885
This publication provides benefit design decision
makers the integrated industry information they
require to devise formularies and benefit designs that
stand up to today’s special healthcare delivery and
business needs.
Healthcare Reform: Cost-Containment Not Very Likely
The Costs of Multiple Myeloma Treatment Vary Widely
Pegfilgrastim with Transplant: Upfront Cost
May Be Offset
For MDS Treatment, Azacitidine Enhances
Cost-Effectiveness Compared with Decitabine
Bortezomib Cost-Effective for Newly Diagnosed
Patients with Multiple Myeloma
Alemtuzumab Contributes 39% to Treatment Costs
in CLL
LYMPHOMA
Business Manager
Blanche Marchitto
Mission Statement
American Health & Drug Benefits is founded on the
concept that health and drug benefits have undergone
a transformation: the econometric value of a drug is of
equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies
and benefit designs. Benefit designs are greatly affected by clinical, business, and policy conditions.
FEBRUARY 2010 I VOL 3, NO 1 I SPECIAL ISSUE
Arthur F. Shinn, PharmD, FASCP
President, Managed Pharmacy
Consultants, Lake Worth, FL
GOVERNMENT EDITOR
Kevin B. “Kip” Piper, MA, FACHE
President, Health Results Group
Sr. Counselor, Fleishman-Hillard
Washington, DC
F. Randy Vogenberg, RPh, PhD
Chief Strategy Officer
Employer-based Pharmaceutical
Strategies
Senior Scholar, Department of Health
Policy, Thomas Jefferson University
ACTUARY
David Williams
Milliman Health Consultant
Windsor, CT
EPIDEMIOLOGY RESEARCH
Joshua N. Liberman, PhD
Vice President, Strategic Research
CVS Caremark, Hunt Valley, MD
CANCER RESEARCH
Al B. Benson, III, MD, FACP
Professor of Medicine
Associate Director for Clinical
Investigations
Robert H. Lurie Comprehensive
Cancer Center, Northwestern
University
Chair, Board of Directors, NCCN
Nirav R. Shah, MD, MPH
Assistant Professor of Medicine
NYU School of Medicine, NYC
Senior Investigator, Geisinger Health
System, Danville, PA
Samuel M. Silver, MD, PhD, FACP
Professor, Internal Medicine
Director, Cancer Center Network
Division of Hematology/Oncology
Assistant Dean for Research
University of Michigan Health
Systems
CARDIOLOGY RESEARCH
Michael A. Weber, MD
Professor of Medicine
Department of Medicine (Cardiology)
State University of New York
ENDOCRINOLOGY RESEARCH
James V. Felicetta, MD
Chairman, Dept. of Medicine
Carl T. Hayden Veterans Affairs
Medical Center, Phoenix, AZ
EMPLOYERS
Alberto M. Colombi, MD, MPH
Corporate Medical Director
PPG Industries, Pittsburgh, PA
Wayne M. Lednar, MD, PhD
Global Chief Medical Officer
Director, Integrated Health Services
DuPont, Wilmington, DE
HEALTH INFORMATION TECHNOLOGY
J.B. Jones, PhD, MBA
Research Associate, Geisinger
Health System, Danville, PA
HEALTH OUTCOMES RESEARCH
Gordon M. Cummins, MS
Director, IntegriChain
Kavita V. Nair, PhD
Associate Professor, School of
Pharmacy
University of Colorado at Denver
Gary M. Owens, MD
President, Gary Owens Associates
Glen Mills, PA
Timothy S. Regan, BPharm, RPh
Executive Director, Xcenda
Palm Harbor, FL
MANAGED CARE & GOVERNMENT
AFFAIRS
Sharad Mansukani, MD
Chief Strategic Officer, Nations Health
Senior Advisor, Texas Pacific Group, FL
MANAGED MARKETS
Jeffrey A. Bourret, MS, RPh, FASHP
Senior Director, Customer Marketing
& Innovation, US Specialty Customers
Pfizer Specialty Business Unit, PA
Allow Continued Treatment in CML
Bendamustine-Rituximab Combo an Effective First-Line
Therapy for CLL
Statins Delay Treatment in CLL
Second-Generation TKIs Effective, Safe for Relapsed ALL
Advances in Treating MDS
Adding Alemtuzumab to Fludarabine Doubles PFS in
Relapsed CLL
Antifungal Prophylaxis in AML Patients Receiving
Induction Chemotherapy
MULTIPLE MYELOMA
17 Maintenance Therapy an Emerging Theme in Myeloma
20
High-Risk Smoldering Myeloma Responds to Treatment
Multiple Myeloma Management in 2010
Weekly Bortezomib Effective, Less Toxic
OTHER ASH HIGHLIGHTS
21 Hematologic Drug Pipeline Diverse and Promising
22
Investigational Alternatives to Warfarin Prevent VTE
Events
Stem-Cell Mobilization Strategies: What Works,
What Doesn’t
Positive Long-Term Data for 2 ITP Treatments
POLICY & PUBLIC HEALTH
Joseph R. Antos, PhD
Wilson H. Taylor Scholar in Health
Care Retirement Policy
American Enterprise Institute
Charles E. Collins, Jr, MS, MBA
Associate Director, Managed Markets
Marketing, Boehringer-Ingelheim
Ridgefield, CT
PATIENT ADVOCACY
William E. Fassett, BSPharm, MBA,
PhD
Professor of Pharmacy Law & Ethics
Vice Chair, Dept. of
Pharmacotherapy
College of Pharmacy,
Washington State University
Spokane, WA
PERSONALIZED MEDICINE
Wayne A. Rosenkrans, Jr, PhD
Chairman and President, Personalized
Medicine Coalition, Distinguished
Fellow, MIT Center for Biomedical
Innovation
PHARMACOECONOMICS
Jeff Jianfei Guo, BPharm, MS, PhD
Associate Professor of
Pharmacoeconomics
& Pharmacoepidemiology, College of
Pharmacy, University of Cincinnati
Medical Center, OH
Jack E. Fincham, PhD, RPh
Professor of Pharmacy, School of
Pharmacy University of Missouri,
Kansas City
Alex Hathaway, MD, MPH,
FACPM
Senior Medical Policy Advisor
Government Programs
GlaxoSmithKline, Philadelphia, PA
J. Warren Salmon, PhD
Professor of Health Policy &
Administration
School of Public Health
University of Illinois at Chicago
REIMBURSEMENT POLICY
Grant D. Lawless, BSPharm, MD,
FACP
Executive Director for Payor Relations
Corporate Account
Amgen, Thousand Oaks, CA
Michael Schaffer, PharmD, MBA
Director, Pharmacy Programs
Sanovia Corp., Philadelphia, PA
PHARMACY BENEFIT DESIGN
Joel V. Brill, MD
Chief Medical Officer, Predictive
Health, Phoenix, AZ
Leslie S. Fish, PharmD
Sr. Director of Pharmacy Services
Fallon Community Health Plan, MA
RESEARCH & DEVELOPMENT
Michael F. Murphy, MD, PhD
Chief Medical Officer and Scientific
Officer
Worldwide Clinical Trials
Faculty, Center for Experimental
Pharmacology and Therapeutics,
Harvard-MIT Division of Health
Sciences and Technology,
Cambridge, MA
Paul Anthony Polansky, BSPharm,
MBA
Executive VP and Chief Pharmacy
Officer
Sanovia Corp., Philadelphia, PA
SPECIALTY PHARMACY
Atheer A. Kaddis, PharmD
Vice President, Managed Markets
Diplomat Specialty Pharmacy
Swartz Creek, MI
Scott R. Taylor, RPh, MBA
Associate Director, Industry Relations
Geisinger Health System
Danville, PA
James T. Kenney, RPh, MBA
Pharmacy Operations Manager
Harvard Pilgrim Health Care
Wellesley, MA
William J. Cardarelli, PharmD
Director of Pharmacy
Atrius Health
Harvard Vanguard Medical Associates
Boston, MA
www.AHDBonline.com
3
Health Economics
Healthcare Reform: Cost-Containment...
“A single approach to containing
costs is unlikely to be sufficiently successful,” he advised. “We need to pursue many distinct but consistent ap proaches to offset risks that some
approaches will not succeed.”
Rising Healthcare Costs
On the national level, rising costs are
undermining the mechanisms that
finance healthcare and are a key factor
in the country’s “dire public fiscal outlook,” Dr Ginsburg noted. On the individual level, private insurance is
increasingly unaffordable and the
affordability problem now affects the
middle class, he said.
The costs of Medicare, Medicaid,
and tax expenditures for private health
insurance are all growing faster than
the gross domestic product (GDP), and
the result is that other priorities are
neglected, taxes are higher, and the
deficit is growing.
An international comparison provides the evidence of undue high costs
in the United States. Healthcare
accounts for 16% of the GDP in this
country, compared with about 11% in
many other countries, including France,
Germany, Switzerland, and Canada.
“Adjusting for income, the United
States spends an extra $477 billion per
year on healthcare” compared with
many other countries, said Dr
Ginsburg. Evidence of rising costs
comes from a comparison of cost and
income trends. “There has been a 37%
increase in earnings to support a 120%
increase in premiums,” he said. “This
gap explains three fourths of the longterm decline in the percent of the
insured population.”
Dr Ginsburg. Additional drivers include the poorly functioning medical
liability system and state insurance
mandates.
At least one third of the trend in
spending stems from technological
“advances.” While new treatments are
more effective—yielding better outcomes with lower risks—there is a
tendency to overuse them to the point
of limited or negative gains, he pointed out. Marginally effective, ineffective, or harmful treatments also add to
rising costs, and there is little funding
for effectiveness research to weed
these out.
Unhealthy lifestyles create more
health problems. Obesity alone is estimated to account for 12% of spending
growth in recent years. Declines in
smoking have held down cost trends,
but the killer habit still contributes to
spending growth, Dr Ginsburg said.
The prosperity of the economy
largely derives from gains in productivity, but this is true only for certain
industries, such as banking and airlines. “There is much less productivity
in healthcare,” he noted.
One reason for this is the lack of
the right incentives for healthcare
providers. There are few incentives to
produce episodes of treatment or to
help improve a patient’s health more
efficiently, he noted. And there is wide
variation in the efficiency of the care
that is delivered.
“New patterns of competition”
refers to the “entrepreneurial delivery
system” of today or to the expansion
of services that are profitable but may
not add true value. A failure of
Medicare and private insurers to set
“A single approach to containing costs is
unlikely to be sufficiently successful….We need
to pursue many distinct but consistent
approaches to offset risks that some
approaches will not succeed.” —Paul Ginsburg, PhD
Key Cost Drivers
The key drivers of rising costs in the
United States are:
• Higher incomes (more money is
available to spend on healthcare)
• Developments in medical technology
• Less-healthy lifestyles
• Small gains in productivity related
to the delivery of health services
• New patterns of competition in
healthcare
• And to a lesser degree than is
often assumed, the aging of the US
population.
Aging contributes just ≤0.5% to the
annual spending trend, according to
payment rates to appropriately reflect
relative cost of services has led hospitals to expand services that are profitable, such as cardiac procedures, and
special facilities, such as “heart hospitals.” It is possible that expansions of
capacity are actually creating a demand for services, Dr Ginsburg noted.
Tied to this is an increase in physician self-referrals, for example, an
increase in referrals to magnetic resonance imaging occurs when physicians use their own imaging centers.
“With ownership of facilities the scope
of physician self-referral is wider, and
this is worrisome to me,” he said.
Continued from page 1
will increase healthcare spending.”
The public plan option is also faulty.
“Only the robust version can impact
costs through lower provider payment
rates,” he noted. “The version in the
current bills has little potential to
reduce costs.” Increased competition
in insurance markets has limited
potential.
Cost-savings through increased wellness and prevention is another fallacy.
“The evidence on the lack of potential
for savings is very strong. Many in
Congress are unwilling to accept the
evidence, but the Congressional
Budget Office analysis found that prevention will not reduce federal outlays,” Dr Ginsburg said.
“Politicians claim there will
be large savings through
reducing waste. It’s a terrific
idea, but it won’t solve the
cost problem.”
—Paul Ginsburg, PhD
Why Are Costs So Hard
to Contain?
Cost-containment is complex and,
for various reasons, is viewed by many
sectors as threatening. “All spending
pertains to someone’s income, and
there is an increasingly effective lobby
to protect incomes,” Dr Ginsburg
observed.
Our political leaders are also “falling
down on the job,” by fostering the
notion that costs can be contained
without sacrifice. “The concept of cutting waste, fraud, and abuse goes way
back,” he said. “Politicians claim there
will be large savings through reducing
waste. It’s a terrific idea, but it won’t
solve the cost problem.”
It is uncertain that such “painless
solutions” will contain costs, he maintained. The other current proposals
include the promotion of quality
reporting and payment for quality, the
advancement and adoption of health
information technology, and the application of comparative effectiveness
research.
“Red Herrings” of Current Reform
The current motivator for healthcare
reform is the expansion of insurance
coverage; however, coverage expansion
will exacerbate, not alleviate, the cost
problem, according to Dr Ginsburg.
“Uninsured people spend less,” he
pointed out. “More comprehensive in surance leads to higher spending. Bringing the uninsured up to insured status
Which Approaches May Work?
A single approach will not be the
sole solution to cost-containment, and
there are advantages and disadvantages to most of the strategies being
discussed.
Increased patient cost-sharing (benefits “buydowns,” consumer-directed
health plans, and health savings
accounts) is part of a demand-side
approach to cost-containment and is
not favored by political liberals. In fact,
patient cost-sharing does a fairly poor
job of addressing spending trends, Dr
Ginsburg added, because most spending is concentrated within a relatively
small population of patients. “The burden of healthcare falls more on the sick
and the poor.”
In contrast, patient financial incentives “clearly work,” but will not
accomplish much, because healthcare
use is not particularly sensitive to
patient incentives. To be effective, the
tools for patient incentives need refinement, he said.
One proposal is a value-based benefits design, which will vary costsharing by service type and patient
condition—with low barriers to the
management of chronic disease and
higher barriers for elective services.
This approach would promote the
choice of more efficient providers,
because consumers would reap savings when they choose less-costly
providers, and less-efficient providers
would have incentives to improve
care. Another tool is the excise tax on
“Cadillac plans.”
Also part of the demand-side
approach is more research on price
and quality, which in theory is favored
by all but providers but in practice
may be less useful, because its impact
would not be felt for years. The government’s role would be centered on
data gathering rather than price setting; the latter would fall to insurers to
customize and simplify.
Continued on page 5
4
AMERICAN HEALTH & DRUG BENEFITS
February 2010
VOL. 3
NO. 1
SPECIAL ISSUE
Health Economics
The Costs of Multiple Myeloma Treatment...
Results showed that bortezomib was
associated with less out-of-pocket
(OOP) cost than the 2 oral medications.
Bortezomib is a proteasome inhibitor,
and lenalidomide and thalidomide are
immunomodulatory drugs. These
medications are sometimes combined
with other agents into 1 regimen.
“Multiple myeloma is a complex disease. Improved outcomes have been
achieved with these novel agents; however, few studies have reported the
economic burden on patients,” said
Brett W. Pinsky, MPH, Senior Researcher at i3 Innovus, Eden Prairie, MN.
“Direct out-of-pocket costs
were significantly higher for
patients treated with the oral
drugs thalidomide and
lenalidomide compared with
bortezomib for injection.”
—Brett W. Pinsky, MPH
The investigators drew from a claims
database of a large national, commercial health plan with 14 million members. Treatment episodes, defined as
each course of therapy, were identified
from claims records for each patient.
Patient OOP costs and patient visit
data were examined for 1 year from the
beginning of each treatment episode.
Descriptive analyses were supple-
mented with multivariate regression
analyses to control for patient characteristics, comorbidities, and line of
treatment. A total of 2642 treatment
episodes were identified for the 1900
patients. The majority of episodes were
classified as “other chemotherapy or
radiation therapy” (66.6%), followed
by thalidomide (20.8%), bortezomib
(9.2%), and lenalidomide (3.4%).
Ambulatory visits accounted for
much of the patient visit burden.
As expected, patients treated with
bortezomib for injection had more visits
than those treated with oral lenalidomide, but the difference was not significant after adjusting for patient characteristics, line of treatment, and comorbidities by a multivariate analysis.
A significant number of outpatient
hospital visits occurred with all these
agents but most frequently with
thalidomide. Because patients must
visit doctors to receive bortezomib
injections more often than for the oral
medications, it is often assumed that
bortezomib injection is a more expensive treatment. The data, however, do
not support that assumption, Mr
Pinsky said.
Patient Out-of-Pocket Costs
“Direct out-of-pocket costs were significantly higher for patients treated
with the oral drugs thalidomide and
lenalidomide compared with bortezomib for injection,” said Mr Pinsky.
The total adjusted patient OOP costs
Healthcare Reform... Continued from page 4
Finally, many today believe that programs aimed at wellness and prevention will help contain costs, but the
effect of prevention has not been
proved, Dr Ginsburg cautions.
Improved Payment Structure
As a supply-side approach, the
crafting of a more accurate payment
structure is widely proposed, based on
the unintended wide variation in profitability by service. Medicare is wellpositioned to make structures more
accurate (and private insurers and
Medicaid programs will follow), but
Medicare needs to apply more political
and financial resources to this, which
is problematic, because many hold a
negative view of Medicare governance, Dr Ginsburg noted.
The supply-side approach also in cludes broader payment units (BPUs)
as a means of reducing the role of
fee-for-service, which is faulted by
having incentives for service volume
and lacking motivations or rewards for
coordinated services. BPUs introduce
elements of capitation in the form of
accountable care organizations. The
strategy can incorporate episodebased payments in which actual perepisode payments can be made to a
joint entity or by fee-for-service, with
incentives for all involved.
But Dr Ginsburg questions whether
BPUs will be implemented, and
whether the idea will succeed. “BPUs
have opportunities for physicians—
rewards for reducing spending on
hospital care, pharmaceuticals, and
devices. They can save money by
reducing hospitalizations, choice of
drugs, and so forth and not just
by reducing the physician’s own
services. They can capture rewards
from this.”
Although the debate once focused
on “competition versus regulation,”
Dr Ginsburg pointed out that the
country proved unwilling to embrace
either. He concluded that the search
for a solution is geared toward “pragmatism that recognizes the need to
build on present institutions.” ■
Table Adjusted Patient OOP Cost 1 Year after Treatment Initiation
Patient OOP Cost
Patient type
Bortezomib
Thalidomide
Lenalidomide
Non-Medicare
$3504
$4443
$4766
Medicare Advantage
$4395
$8824
$12,568
OOP indicates out-of-pocket.
for the year after treatment initiation
are shown in the Table. These costs,
and the differences between treatment
type, were even greater for Medicare
Advantage patients (Table). For the
Medicare group, treatment with bortezomib amounted to less than half the
cost of oral drug therapy with either
drug, he said.
The OOP cost discrepancy was magnified in the Medicare population likely because of the coverage gap, known
as the doughnut hole in Medicare Part
D, noted Henry Henk, PhD, also of i3
Innovus. “For the Medicare Advantage
group, there is the doughnut hole
effect that is causing a huge spike in
the cost of the oral drugs,” Dr Henk
pointed out.
The investigators concluded that
because patients with MM require a
great deal of care and resources, the
majority of patients will not see a significant difference in the number of
healthcare visits, regardless of the type
of treatment, but they may feel the
pinch of higher OOP costs with the
oral drugs. ■
Pegfilgrastim with Transplant:
Upfront Cost May Be Offset
By Caroline Helwick
H
igh-dose chemotherapy followed by autologous stem-cell
transplantation (ASCT) is the
standard of care for subgroups of
patients with multiple myeloma or
lymphoma. Granulocyte colony-stimulating factors (G-CSFs) are used to
enhance neutrophil engraftment in
these patients. Compared with no
growth factors, this reduces the number of days with fever, antibiotic use,
and duration of hospitalization. Randomized trials have shown that further cost reduction can be obtained by
delaying the start of G-CSF therapy
from day 1 to days 5 to 7 after transplant, without significantly changing
the time to neutrophil recovery.
Although the G-CSF agent pegfilgrastim (Neulasta) costs approximately 25% more up front than filgrastim
(Neupogen), the cost is offset by a
faster neutrophil engraftment, shorter
time on antibiotics, and a tendency to
shorter hospitalization time compared
with filgrastim, according to several
studies presented at ASH.
G-CSFs are regularly used after
ASCT to accelerate neutrophil engraftment. Swiss investigators evaluated
the safety and efficacy of pegfilgrastim, a long-acting form of filgrastim
given as a single, fixed dose, in 40
patients with multiple myeloma,
Hodgkin’s lymphoma, and nonHodgkin’s lymphoma.
“This is a more patient-friendly
approach, and since the drug is given
in a single shot, there is no need to
delay the therapy to decrease treatment costs,” said Luciano Wannesson,
MD, of the Oncology Institute of
Southern Switzerland, Bellinzona.
“This is a more patient-friendly
approach, and since
the drug is given in a
single shot, there is no need
to delay the therapy to
decrease treatment costs.”
—Luciano Wannesson, MD
Pegfilgrastim 6 mg was given on
transplant day 1. Results were compared with a matched historical control group of 40 patients who received
filgrastim 5 μg/kg daily starting on an
average of 7 days after transplant.
The median time to achieve a neutrophil count >500 μL (ie, neutrophil
engraftment) was 9.5 days for the
pegfilgrastim group versus 11.3 days
for the filgrastim control group, which
was a highly significant difference
(P <.001).
Median duration of neutropenia
was 5.8 days versus 7.4 days (P = .001),
median duration of intravenous
antibiotic therapy was 4.2 days versus
6.5 days (P = .007), and median hospitalization duration was 14.0 days versus 14.8 days (P = .018). These differences were most pronounced among
Continued on page 6
VOL. 3
NO. 1
SPECIAL ISSUE
www.AHDBonline.com
5
Health Economics
For MDS Treatment, Azacitidine Enhances Cost-Effectiveness
Compared with Decitabine
By Caroline Helwick
I
n a cost-effectiveness analysis for
the treatment of myelodysplastic
syndrome (MDS), azacitidine (Vidaza) was shown to be cost-saving or
cost-effective compared with decitabine (Dacogen). The analysis, funded
by Celgene, was presented by Risha
Gidwani, DrPH, lead health economist at Abt Bio-Pharma Solutions,
Lexington, MA.
The National Comprehensive
Cancer Network 2010 guidelines recommend the 2 agents, azacitidine and
decitabine, for the treatment of MDS,
with azacitidine being the preferred
Category 1 treatment for intermediateor high-risk patients ineligible for
transplant.
“Although the clinical benefits of
azacitidine have been shown, this is
the first study to evaluate its cost-effectiveness relative to decitabine,” Dr
Gidwani said.
Investigators developed a decisionanalytic Markov model with 1-month
cycles, which was run alternatively for
12- and 36-month periods. Patients in
the model replicated the demographics of subjects enrolled in phase 3 trials
for the drugs; based on these data, the
patients modeled in the decitabine
arm had lower MDS severity than
those in the azacitidine arm.
During each cycle of the model,
patients could remain in or transition
among 4 health states, including MDS
and transfusion independence, MDS
and transfusion dependence, progression to acute myeloid leukemia
(AML), or death. Therefore, in any
given model cycle a patient could be
found stable, become healthier,
become sicker, or die. The analysis
used model parameters derived from
published studies, product labels, clinical trial data and drug pricing, and
medical services cost databases.
“Despite a higher-risk profile in the
underlying data for azacitidine, treatment of MDS with azacitidine was
either cost-saving—meaning that it
cost less and conferred greater clinical
benefit—or was cost-effective compared with decitabine,” Dr Gidwani
reported.
“Azacitidine changed from dominating decitabine in the 12-month scenario to being cost-effective in the 36month scenario due to the survival
advantage for azacitidine-treated
Table Comparisons for Azacitidine and Decitabine
Parameter
Azacitidine
Decitabine
Total costs per patient: 12 months
$53,518
$62,760
Total costs per patient: 36 months
$154,112
$142,578
QALYs gained: 12 months
0.579
0.526
QALYs gained: 36 months
1.446
1.175
QALYs indicates quality-adjusted life-years.
“Azacitidine changed from dominating decitabine in the 12month scenario to being cost-effective in the 36-month scenario
due to the survival advantage for azacitidine-treated patients.”
—Risha Gidwani, DrPH
patients. Patients treated with azacitidine live longer, and therefore have
more opportunity to incur treatment
costs,” she explained.
In the 12-month and 36-month
scenarios, azacitidine-treated patients
had a greater number of life-years and
quality-adjusted life-years (QALYs),
attained a greater number of transfusion-independent months, and were
more likely to avoid progression
to AML.
In the 12-month scenario, the use of
azacitidine resulted in $9242 saved per
patient. In the 36-month scenario,
azacitidine treatment cost $11,534
more than treatment with decitabine
but conferred a clinical benefit of
0.2707 additional QALYs gained. The
incremental cost-effectiveness ratio
of $42,615 per QALY is considered
cost-effective, Dr Gidwani noted. The
total costs per patient and QALY
gained at 12 and 36 months are shown
in the Table. ■
SEE ALSO Advances in
Treating MDS, page 16.
Pegfilgrastim with Transplant... Continued from page 5
patients with lymphoma.
Median time to platelet engraftment
and median duration of fever were
similar, and the 2 groups received an
equal number of red blood cell and
platelet transfusions.
“Starting pegfilgrastim on day 1 and
filgrastim on days 5 to 7 posttransplant
may have contributed to the accelerated engraftment, in line with the results
of studies comparing early versus late
filgrastim that showed a trend to better
outcomes with early filgrastim,” Dr
Wannesson said.
Pegfilgrastim Frees Up Beds
In a study from the United King dom, investigators assessed the
impact on pegfilgrastim on bed availability. “Busy hematology centers
6
have severe pressure on bed availability, which can limit their ability to
deliver multiple cycles of intensive
chemotherapy on time,” said Neil
Phillips, MD, of the Heart of England
NHS Trust, Birmingham, UK.
“G-CSF use in ASCT
has been shown to hasten
neutrophil engraftment
and to shorten the
number of days of
febrile neutropenia.”
—Neil Phillips, MD
“G-CSF use in ASCT has been shown
to hasten neutrophil engraftment and
to shorten the number of days of febrile
February 2010
neutropenia,” Dr Phillips added.
This retrospective study explored
the effect of a single injection of pegfilgrastim 6 mg on engraftment and
inpatient stay of 55 patients undergoing ASCT for the treatment of multiple
myeloma, comparing those who
received the drug with those not
receiving it. The use of pegfilgrastim
was associated with shorter duration
to neutrophil engraftment (P = .06),
less need for antibiotics (P = .04), and
reduced hospital stay (P = .004).
“This is very useful, considering the
pressure on the bed availability in the
tertiary referral centers,” Dr Phillips
said. “Cost-effectiveness due to reduced inpatient stay may lead to the
use of this agent post-ASCT as a
standard practice.” ■
“There’s nothing to laugh about
but I laugh all the time.”
VOL. 3
NO. 1
SPECIAL ISSUE
Health Economics
Bortezomib Cost-Effective for Newly Diagnosed Patients
with Multiple Myeloma
By Caroline Helwick
T
he bortezomib (Velcade)-based
regimen with melphalan (Alkeran) and prednisone (Deltasone)—the VMP regimen—is cost-effective despite greater upfront costs.
“Our study showed that while
adding bortezomib to melphalan and
prednisone increases cost a good bit, it
is actually cost-effective in patients
with myeloma,” said Si-Tien Wang,
MSc, of the Analysis Group, Boston,
MA, a consulting firm specializing
in health economics and outcomes
research. The study’s senior author
was Louis Garrison, PhD, Professor
of Pharmacy at the University of
Washington, Seattle.
Phase 3 trials have shown a survival
advantage with the MPT regimen—
thalidomide (Thalomid) plus melphalan and prednisone—over melphalan
and prednisone (MP) alone, and the
phase 3 VISTA trial showed the clinical
superiority of VMP over MP for frontline treatment in elderly patients who
were not eligible for transplantation.
Results of a survival analysis of the
VISTA trial after a median of more
than 3 years were presented at ASH,
confirming the benefits of the VMP
regimen compared with MP alone.
Overall survival rates in patients with
high-risk cytogenetics were 74.5%
with VMP versus 55.5% with MP.
The incremental cost-effectiveness
of VMP over MP and MPT as initial
treatment, however, had not been
assessed; that was the aim of this
cost-effectiveness analysis.
The primary data sources were
patient-level data from VISTA after 26
months of follow-up. The source of
data for VMP versus MPT was the
phase 3 IFM 99-06 trial, with a median
follow-up of 51 months. Cost data were
obtained from published studies/
sources. The cost analyses, adjusted to
2009 dollars, included per-protocol
drug and medical costs, treatmentrelated adverse event costs, second-line
treatment costs, and resource utilization during treatment-free intervals
and progressive disease states.
Compared with MPT, the
drug cost of VMP was
lower by $13,277, and the
cost of managing
treatment-related adverse
events was $10,213 lower.
Health outcomes were expressed in
life-years and quality-adjusted lifeyears (QALYs). Cost/health outcomes
were discounted at 3%. Incremental
cost-effectiveness ratios were calculated for VMP versus MP, and VMP versus MPT, over a lifetime horizon.
A Markov model, with a 20-year
lifetime horizon, was developed from
a US payers’ perspective. Patients
entered the model in the stable disease/minimal disease (SD/MD) state.
In subsequent monthly cycles, patients
moved to their best response state or
remained in SD/MD until they discon-
Table Cost-Effectiveness of VMP vs MP and VMP vs MPT over a Lifetime
VMP
MP
MPT
Cost
$110,870-$57,864
$129,902
$129,902
Life-years
4.187
2.864
4.140
QALYs
2.994
2.049
2.951
$40,051
$56,109
VMP dominant
VMP dominant
ICER (vs VMP)
Per life-year
Per QALY
ICER indicates incremental cost-effectiveness ratio; MP, melphalan and prednisone; MPT, thalidomide,
melphalan, and prednisone; QALY, quality-adjusted life-year; VMP, bortezomib, melphalan, and
prednisone.
tinued treatment, progressed, or died.
Patients in the second-line therapy
state received a maximum of 6 months
of treatment.
Compared with MP and MPT, VMP
was associated with more time on treatment in complete response, a longer
treatment-free interval, and less time
in a progressive disease state or death.
Overall survival was estimated to be
longest with VMP and MPT versus MP.
Lifetime direct medical costs were
highest for MPT, followed by VMP;
they were much lower for MP (Table).
“While adding bortezomib to melphalan and prednisone
increases cost a good bit, it is actually
cost-effective in patients with myeloma.”
—Si-Tien Wang, MSc
“The incremental cost-effectiveness
of VMP versus MP, however, was
found to be within the generally accept-
Alemtuzumab Contributes 39% to Treatment
Costs in CLL
By Wayne Kuznar
T
he cost of alemtuzumab
(Campath) contributes 39% of
total healthcare costs once it is
initiated for the treatment of chronic
lymphocytic leukemia (CLL). Other
cost drivers in this setting include
oncology services and medical
resources for cytopenia, infection, and
cardiac dysfunction, said MarieHélène Lafeuille, MA, of Groupe
d’analyse, Ltée, Montreal.
Her study used electronic claims
data of Medicare Part A and Part B
services to quantify the incremental
costs associated with alemtuzumab, by
calculating costs within 6 months after
alemtuzumab initiation versus 6
months before its initiation.
VOL. 3
NO. 1
SPECIAL ISSUE
The study assessed costs for 81
patients with CLL. After alemtuzumab
initiation, mean total healthcare costs
increased from $4272 to $10,385
per-patient per-month (PPPM) in the
next 6 months, a $6113 increase. The
mean cost for alemtuzumab in the
post–alemtuzumab initiation period
was $4006 PPPM, representing 39% of
total costs.
The cost for oncology-related services
(ie, office visits, hospitalizations, home
healthcare) jumped from $3759 to
$9602 PPPM from the prealemtuzumab to postalemtuzumab periods, an
increase of $5842.
In the prealemtuzumab period, the
cost associated with a diagnosis
of cytopenia was $1658 PPPM compared with $4441 postalemtuzumab—
ed cost-effectiveness range of $50,000 to
$100,000 per QALY, suggesting that
VMP is cost-effective compared with
MP,” Ms Wang said. “And compared
with MPT, the VMP regimen was dominant in the model, meaning it was costsaving and had better outcomes, costing 17.7% less and providing slightly
more QALYs on average.”
Compared with MPT, the drug cost
of VMP was lower by $13,277, and the
cost of managing treatment-related
adverse events was $10,213 lower. This
drove much of the dominance. A
After alemtuzumab
initiation, mean total
healthcare costs increased
from $4272 to $10,385
per-patient per-month.
a $2456 difference.
Costs associated with medical
resources for diagnoses of infection
and cardiac dysfunction increased by
$734 and $926, respectively, in the 6
months after alemtuzumab initiation
compared with prealemtuzumab. ■
SEE ALSO Adding Alemtuzumab
to Fludarabine Doubles PFS
in Relapsed CLL, page 16.
1-way sensitivity analysis of VMP versus MP pointed to the general robustness of the findings, with the key driver being the VMP versus MP hazard
ratio for the transition from secondline treatment to death.
The results may actually be conservative for the VMP regimen, said Ms
Wang, because the study populations
were not completely comparable. The
IFM 99-06 population was younger
and had less-advanced disease than
the VISTA population.
She acknowledged several limitations of the study—the indirect comparison of VMP to MPT (no head-tohead trials were available); the use of
just 1 of 5 phase 3 trials comparing
MPT with MP (only 1 provided necessary results); and the different baseline
characteristics of VISTA and IFM 99-06.
The researchers concluded that
adding bortezomib to the standard MP
regimen improves long-term outcomes with a survival benefit, while
remaining cost-effective. ■
SEE ALSO Weekly Bortezomib
Effective, Less Toxic, page 20.
www.AHDBonline.com
7
Lymphoma
New Regimen Challenges...
potentially practice changing,” concurred press briefing moderator
Richard Van Etten, MD, of Tufts
University. “I would like to see an
overall survival benefit, and the study
needs longer follow-up, but I don’t
think we need to wait for this.”
Large Randomized Study
Population
The trial by the German Study
Group on Indolent Lymphoma included 549 symptomatic patients
enrolled at 82 centers. Patients were
randomized to B/R or CHOP-R.
Approximately 50% of patients in
each arm had follicular lymphoma;
the remainder had other indolent lymphoma or MCL.
B/R caused significantly less hematologic toxicity, although just 4% of the
patients in this arm received growth
factors compared with 20% in the
CHOP-R arm.
As for side effects, alopecia did not
occur with B/R but was frequent with
CHOP-R. Paresthesia, stomatitis, infectious complications, and sepsis were
“Bendamustine plus rituximab has the potential to become
a treatment of first choice in these disease entities….There was
a 20-month gain with bendamustine. This was clearly a
surprise. It was not just noninferior, but was statistically
significantly better than CHOP-R and better tolerated.”
—Mathias J. Rummel, MD
less frequent with B/R. Skin rashes
and allergic reactions, however, were
more common with B/R than with
CHOP-R, Dr Rummel reported.
Overall response rates were similar
In Challenging B-Cell Lymphoma,
Aggressive Chemotherapy plus
Rituximab Show Best Outcomes
By Caroline Helwick
T
he addition of rituximab to
either conventional or highdose chemotherapy for B-cell
lymphoma yielded “unexpectedly
high efficacy,” particularly in untreated, young, high-risk patients with
aggressive disease, according to investigators from the MegaCHOEP Trial
of the German High-Grade NonHodgkin’s Lymphoma Study Group.
“The 3-year event-free and
overall survivals are the best
ever reported for this
group of patients.”
—Norbert Schmitz, MD
“The 3-year event-free and overall
survivals are the best ever reported for
this group of patients,” said Norbert
Schmitz, MD, of the Asklepios Kliniken
St. Georg, Hamburg, Germany.
This was an interim analysis of 216
patients in the phase 3 study that
included young (18-60 years old),
high-risk patients with aggressive
B-cell lymphoma. The study compared
8 cycles of CHOEP-14 (cyclophosphamide [Cytoxan], doxorubicin
8
[Adriamycin], vincristine [Oncovin],
and prednisone [Deltasone] plus etoposide [Eposin] given every 2 weeks) with
high-dose MegaCHOEP, which used
higher doses of the same drug given
every 21 days, followed by stem-cell
transplantation. Half of the patients
also received rituximab (Rituxan).
After a median follow-up of 29
months, the estimated 3-year overall
survival was 84% with the CHOEP
plus rituximab regimen and 75% with
MegaCHOEP plus rituximab; progression-free survival rates were 76%
and 64%, respectively. These survival
rates were significantly higher than in
the treatment arms that did not receive
rituximab; therefore, the arms not
including rituximab were discontinued, Dr Schmitz noted.
“Eight cycles of CHOEP-14 plus 6
cycles of rituximab gave excellent
results in young, high-risk patients
with untreated aggressive B-cell lymphoma. Because of higher toxicity and
inferior survival, the MegaCHOEP
arm was discontinued. High-dose
therapy and transplant has no role to
play as part of first-line therapy for
these patients if rituximab is combined
with aggressive conventional chemo therapy,” he said. ■
February 2010
between the 2 regimens—92.7% with
B/R and 91% with CHOP-R—but
patients receiving B/R were more like-
ly to have a complete response (39.6%
vs 30%, respectively).
Improved complete response rates
were translated into better progression-free survival with B/R—54.9
months (median) versus 34.8 months
for CHOP-R—a significant difference
(P = .001).
“There was a 20-month gain with
bendamustine. This was clearly a surprise. It was not just noninferior, but
was statistically significantly better
than CHOP-R and better tolerated,”
Dr Rummel commented.
He added that the dose of
bendamustine used (90 mg/m2) was
lower than the dose of 120 mg/m2
currently approved in the United
States for lymphoma. The lower dose
did not compromise efficacy but did
improve tolerability, he said.
Dr Rummel said the B/R regimen
would be economical, because it is
associated with fewer complications
and reduced use of growth factor
support. ■
Treatment Is Beneficial in Older
Patients with Advanced Lymphoma
I
n older patients with advanced follicular lymphoma, a brief course of
chemotherapy followed by maintenance therapy with rituximab
(Rituxan) led to high response rates,
including complete remissions, and
was well-tolerated in an Italian study
presented at ASH.
immunotherapy—with fludarabine
(Fludara), mitoxantrone (Novantrone),
and dexamethasone (Decadron)—plus
rituximab. Patients who achieved a
complete response or partial response
were randomized to 4 consolidation
doses of rituximab at months 9, 11, 13,
and 15, or to observation.
These findings show that
chemotherapy is beneficial in this
older patient population, and
withholding treatments because of
age is therefore inappropriate.
—Umberto Vitolo, MD
Umberto Vitolo, MD, of the
University of Torino, Italy, noted that
in elderly patients, “the goal is to
reduce the chemotherapy that patients
sometimes don’t tolerate and in the
meantime, to maintain the efficacy of
the treatment.” He added that, based
on his study’s findings that
chemotherapy is beneficial, it is not
appropriate to withhold treatments
only because of age.
Investigators at 33 Italian centers
enrolled 242 patients aged 61 to 75
years with advanced or aggressive
non-Hodgkin’s lymphoma that had not
been treated. The regimen consisted of
4 weekly administrations of chemo-
The 4 cycles of chemoimmunotherapy led to complete responses in 55% of
patients, and partial responses in 37%.
After rituximab consolidation therapy,
69% of patients achieved complete responses and 18% of patients achieved
partial responses. At the 22-month
follow-up, 2-year survival was 92%,
and 2-year progression-free survival
was 75%.
The data, however, are not mature
enough to assess the value of maintenance versus observation over
time. The most common toxicity in
patients was neutropenia (65%), but it
was severe in only 25% of those
patients.—CH ■
VOL. 3
NO. 1
SPECIAL ISSUE
Lymphoma
Hodgkin’s Lymphoma: No Changes in Standard of Care,
but Emerging Therapies Are Promising
By Caroline Helwick
H
odgkin’s lymphoma is a very
curable malignancy, because
the majority of patients present
with localized disease. But advanced
Hodgkin’s lymphoma is associated
with failure rates of 30% to 40% in
response to anthracycline-based polychemotherapy. Current clinical trials
are focusing on improving this outcome with the use of multiple first-line
agents, said John Kuruvilla, MD, of the
University of Toronto, who presented
an update on the treatment of
Hodgkin’s lymphoma at ASH 2009.
For advanced Hodgkin’s lymphoma, the initial gold-standard
regimen is ABVD—doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban), and dacarbazine
(DTIC). Many groups have developed
alternate regimens based on doseintensive or dose-dense chemotherapy, or by using a similar approach that
dose-intensifies certain drugs while
minimizing leukemogenic or gonadotoxic drugs.
The results from clinical trials applying these approaches indicate that
dose-intensifying chemotherapy improves disease control, but at the cost
of acute toxicity and possibly delaying
toxicity. The BEACOPP regimen—
bleomycin, etoposide (Eposin), doxorubicin, cyclophosphamide (Endoxan), procarbazine (Matulane),
vincristine (Oncovin), prednisone
(Meticorten)—largely used in Europe,
One interesting approach
being evaluated is the
use of novel, risk-adapted
strategies using FDG-PET
imaging to identify patients
who are deemed at risk
for treatment failure after 2
cycles of ABVD.
is the only regimen that has shown an
overall survival advantage over the
ABVD regimen.
An alternative strategy to altering
the primary chemotherapy for
Hodgkin’s lymphoma is to attempt to
“consolidate” the response, using
high-dose chemotherapy, autologous
stem-cell transplantation (ASCT), or
radiation, but clinical trial results show
no role for consolidation in advanced
Hodgkin’s lymphoma.
One interesting approach being
evaluated is the use of novel, riskadapted strategies using FDG-PET
imaging to identify patients who are
deemed at risk for treatment failure
after 2 cycles of ABVD and who may
need more intensive treatment, Dr
Kuruvilla said.
Treatment of Relapsed or
Refractory Hodgkin’s Lymphoma
Relapsed or refractory HL is another
common problem associated with
treatment of the disease. Second-line
(ie, salvage) chemotherapy followed
by ASCT is the standard of care, but
there is a lack of consensus about the
type of salvage chemotherapy to use
before the transplant. ASCT carries
significant toxicity and may be limited
in application, because of the patient’s
age and medical fitness.
Several interesting approaches are
currently being evaluated, including
high-dose sequential therapy and tandem ASCT approaches. But few large
or prospective series are studying
strategies that are not based on transplantation, Dr Kuruvilla pointed out.
bendamustine as front-line therapy is
very interesting. At ASH, we heard
many presentations on this agent. It’s
a very active drug and one that will be
widely used in lymphoma,” he stated.
“This is just one of many therapies
we now have for indolent lymphoma,
including a number of new biologics
and new immune-based therapies.
Among the emerging drugs of interest
are new fully humanized monoclonal
anti-CD20 antibodies that aim to
improve upon the activity of rituximab [Rituxan],” he pointed out.
“We are also hearing about some new
antibody/toxin conjugates, and some
completely new approaches, such
“In clinical care, the use of bendamustine as front-line therapy
is very interesting. At ASH, we heard many presentations
on this agent….Among the emerging drugs of interest
are new fully humanized monoclonal anti-CD20
antibodies…some new antibody/toxin conjugates,
and some completely new approaches.”
—Lawrence Kaplan, MD
Emerging Trends in Lymphoma
Lawrence Kaplan, MD, Director of
the Lymphoma Program at the
University of California, San Francisco, mentioned the importance of
emerging trends in the treatment of
lymphoma, such as bendamustine
(Treanda). “In clinical care, the use of
as the bidirectional antibody blinatumomab [MT103]. How all these
new approaches will impact the
long-term outcome is not known,
but with advances in treatment, our
lymphoma patients are now able to
survive for many years,” Dr Kaplan
concluded. ■
Adding Rituximab to Standard Therapy in
Hodgkin’s Lymphoma Improves Outcomes
T
he addition of rituximab (Rituxan) to the standard ABVD
regimen (R-ABVD) of doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban), and
dacarbazine (DTIC) for Hodgkin’s
lymphoma can improve outcomes,
according to the final report of a
phase 2 study in newly diagnosed
patients with advanced-stage Hodgkin’s lymphoma.
The large, multicenter US study
compared outcomes of patients treated
with R-ABVD with those of institutional historical controls and found
that R-ABVD yielded a higher 5-year
event-free survival rate in every category of the International Prognostic
Score (IPS), an indication of disease
severity (Table), according to lead
VOL. 3
NO. 1
SPECIAL ISSUE
investigator Amanda R. Copeland,
MS, of the University of Texas M.D.
Anderson Cancer Center, Houston.
With a median follow-up of 5 years,
the projected event-free survival for RABVD was 87% overall, “which is significantly better than institutional re-
sults with ABVD,” Ms Copeland noted.
The findings form the rationale
for a multicenter randomized comparison of ABVD with R-ABVD, which
is currently enrolling patients with
stage II bulky, stage III, or stage
IV disease.—CH ■
Table 5-Year Event-Free Survival by IPS and Treatment
IPS group
Institutional ABVD, %
R-ABVD, %
All patients
66
87
0-1
>1–<2
>2–<3
>3
73
62
55
47
96
79
79
65
ABVD indicates doxorubicin, bleomycin, vinblastine, and dacarbazine; IPS, International Prognostic
Score; R-ABVD, rituximab, doxorubicin, bleomycin, vinblastine, and dacarbazine.
With a median follow-up of 5
years, the projected event-free
survival for R-ABVD was 87%
overall, “which is significantly
better than institutional
results with ABVD.”
—Amanda R. Copeland, MS
www.AHDBonline.com
9
Lymphoma
Novel Agent Shows Impressive How Much Rituximab Is
Outcomes in Aggressive NHL Necessary in Advanced NHL?
By Caroline Helwick
T
reatment with the investigational anthracycline pixantrone
achieved significant increases in
complete and overall response rates
and a trend toward improved survival,
compared with current agents, in
patients with relapsed or refractory
non Hodgkin’s lymphoma (NHL) in
the phase 3 randomized open-label
EXTEND trial.
Pixantrone is an analogue of mitoxantrone that has reduced cardiotoxicity. “An anthracycline with reduced
cardiotoxicity that can be used for salvage therapy of aggressive NHL meets
a significant unmet medical need,”
noted lead researcher Ruth Pettengell,
MD, of St George’s Hospital, London.
EXTEND enrolled 140 patients who
had previous treatment for relapsed
aggressive NHL. They were randomized to pixantrone for up to 6 cycles or
to a single-agent comparator at the
treating physician’s discretion. In the
United States, the only comparators
permitted were gemcitabine (Gemzar)
and rituximab (Rituxan). The patients
were followed up to 18 months after
treatment completion.
“An anthracycline with
reduced cardiotoxicity that
can be used for salvage
therapy of aggressive NHL
meets a significant unmet
medical need.”
—Ruth Pettengell, MD
The Table shows results after at least
9 months of follow-up. A trend for
improved survival at 9 months was
shown with pixantrone, at 10.2
months, compared with 6.9 months for
the comparators; 1-year survival
was 45% for pixantrone and 35%
for the comparators, Dr Pettengell
reported. ■
Table Pixantrone vs Single-Agent Comparators: 9-Month Follow-Up
Response rate
Pixantrone
Comparators
Complete/unconfirmed
complete response
25.7%
7%
Overall response
40%
14.3%
Median progression-free
survival
5.6 months
2.6 months
All P <.001.
First Comparison of Fewer Courses of Therapy than
Current Standard
F
or the treatment of advanced nonHodgkin’s lymphoma (NHL),
there was no advantage of giving
multiple courses of rituximab (Rituxan) compared with just 1 course, in
a multicenter German study.
“The addition of rituximab to standard chemotherapy has substantially
improved the prognosis of NHL.
Over the past few years, a trend
toward intensified protocols with
multiple applications of rituximab
has been observed,” said Fabienne
McClanahan, MD, of the University
of Heidelberg, Germany. “We are able
to report a unique cohort that has also
been treated with only 1 or 3 courses
within a prospective randomized
phase 2 trial, contrasting with the current standard procedure.”
This study may be the first to randomize patients to fewer courses than
are currently applied in standard protocols. Included were 126 patients
with stage III or IV cluster of differentiation (CD) 20+ follicular lymphoma.
Patients were classified as low risk
(22%), intermediate risk (39%), or high
risk (39%).
Patients were randomized to receive
1 of 3 treatment options: 1 course
(arm A), 3 courses (arm B), or 6 courses
(arm C) of rituximab, along with
6 courses of standard CHOP—cyclophosphamide (Cytoxan), hydroxydaunorubicin (Adriamycin), vincristine
(Oncovin), and prednisone (Deltasone)—chemotherapy. In addition,
Long-Term Survival Achieved with
Tositumomab/I-131 Regimen
P
atients with indolent lymphoma
that progresses after treatment
with rituximab (Rituxan) can
achieve long-term survival after
switching to tositumomab and iodine
(I)-131 tositumomab (Bexxar regimen),
based on results from a multicenter
phase 2 study of the Eastern Cooper ative Oncology Group.
This treatment is already approved
for certain groups of patients with
relapsed or refractory low-grade, follicular or transformed, non-Hodgkin’s
lymphoma. The regimen pairs the targeting ability of a monoclonal antibody with the therapeutic potential of
radiation. Combined, these agents
form a radiolabeled monoclonal antibody regimen that binds to the target
10
antigen CD20 found on B-cells and
delivers the radiation.
In this study, median overall survival was 6.7 years for patients who
received the Bexxar regimen after
relapsing. Response rates to the regimen were high and durable, said
Sandra Horning, MD, of Stanford
University, CA.
The study included 40 patients
with indolent, follicular large-cell or
transformed B-cell lymphoma that
had progressed while using a median
of 4 previous therapies. Patients
received a therapeutic dose of the
I-131 tositumomab based on totalbody dosimetry.
Responses were seen in 72% of
patients, 38% of which were complete
February 2010
responses. Median response duration
was nearly 19 months; 40% of patients
responded for 5 years.
“Across 10 years, we are
seeing a consistent
result and effect on survival
by treating patients with
this approach.”
—Mark Kaminski, MD
Consistent Responses in
Treatment-Naïve Patients
In another phase 2 study of I-131
tositumomab in 79 untreated patients
60% of the patients also received
radiotherapy. Patients were followed
for a median of 60 months, after which
94% of patients in each arm had
achieved at least a partial response.
“We are able to report
a unique cohort that
has also been treated
with only 1 or 3
courses...contrasting
with the current standard.”
—Fabienne McClanahan, MD
There were no significant differences
in remission rates, remission duration,
progression-free survival, or overall
survival according to the number of
courses the patients received. Relapses
occurred in 36 patients, with no difference in remission duration among the 3
arms. Six-year progression-free survival rates were 45% in arm A, 60% in
arm B, and 65% in arm C, and 6-year
overall survival rates were 72%, 82%,
and 80%, respectively.
“More-frequent applications did
not differ from less-frequent applications, and a noninferiority of fewer
applications of rituximab could not
be detected,” Dr McClanahan said.
“The advantage of multiple courses
of rituximab, therefore, remains
uncertain.”—CH ■
with indolent lymphoma, the 10-year
survival rate was 83% and the 10-year
progression-free survival rate was
38%. Responses were observed in 97%
of patients, and 75% had complete
responses with a median duration of
response of 9 years.
“Across 10 years, we are seeing a
consistent result and effect on survival
by treating patients with this
approach,” said Mark Kaminski, MD,
Director of the Leukemia/Lymphoma
Program at the University of
Michigan, Ann Arbor. “Rarely are
there data to show a treatment can
produce a durable response over a
decade, and what is most exciting is
that these results were achieved after a
single treatment.”—CH ■
Lymphoma continued on page 12
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Lymphoma
Emerging Strategies for Mantle-Cell Lymphoma
By Caroline Helwick
M
antle-cell lymphoma (MCL) is
a unique subtype of B-cell
non-Hodgkin’s lymphoma
characterized by a certain chromosomal translocation and nuclear cyclin
D1 overexpression. Most patients present with advanced-stage disease and
undergo an aggressive clinical course.
Recent improvement has been achieved
with the use of monoclonal antibodies
and dose-intensified approaches, including autologous stem-cell transplantation (ASCT) strategies.
Allogeneic hematopoietic stem cell
transplantation remains the only curative option for patients with advanced
MCL. Recent improvement has been
seen with the introduction of reducedintensity conditioning, offering a 50%
chance of being disease-free at 5 years.
With the exception of this approach,
advanced disease is not curable; most
patients have a delayed but continuous decline, with average survival of
4 to 6 years, although a subset of
patients (15%) may have a more indolent course and long-term survival. In
these asymptomatic patients, close
monitoring is recommended, with
treatment initiated if symptoms or
progression occur, said Martin
Dreyling, MD, of Ludwig-Maximilians
University, Munich, Germany, in an
update of the disease.
Emerging strategies, such as proteasome inhibitors, immunomodulating
drugs, and mTOR inhibitors, are based
on the dysregulated control of cell
cycle machinery and impaired apoptotic pathways. Monotherapy with
these compounds achieves efficacy
comparable with conventional chemotherapy in relapsed MCL. Combination strategies are being studied,
although their introduction into clinical practice remains a challenge, Dr
Dreyling pointed out.
Various regimens are being
evaluated as consolidation
after transplant to further
improve outcomes.
Radioimmunotherapy is
also promising.
Based on its favorable toxicity profile, rituximab (Rituxan) remains a
valuable treatment option in combination with standard chemotherapy
or with bendamustine (Ribomustin,
Treanda), which is better tolerated. In
younger patients, dose-intensified
schemes in combination with rituximab are the standard of care. Various
regimens are being evaluated as consolidation after transplant to further
improve outcomes. Radioimmunotherapy is also promising.
Molecular-targeted approaches that
capitalize on the underlying biology
of MCL are very encouraging. Bortezomib (Velcade) in combination with
conventional chemotherapy has
shown encouraging results in re lapsed or refractory disease. Thalidomide (Thalomid) and lenalidomide
(Revlimid) have produced high
response rates. The mTOR inhibitors
temsirolimus and everolimus are
being evaluated as well, as are
flavopiridol, inhibitors of the Bcl-2
family, antisense approaches, and
approaches that directly target apoptosis (programmed cell death). ■
Leukemia
First Head-to-Head Comparison of Targeted TKIs
Nilotinib Potential First-Line Option for Chronic-Phase CML
By Wayne Kuznar
I
n the first head-to-head comparison
of targeted oral tyrosine kinase
inhibitors (TKIs) as initial treatment
for early-stage chronic myeloid
leukemia (CML), molecular and cytogenetic remissions were more common with nilotinib (Tasigna) than with
imatinib (Gleevec), the previous standard for treating early-stage CML, said
lead study investigator Giuseppe
Saglio, MD, of the University of Turin,
Italy, at ASH.
New Standard of Care?
This finding could elevate nilotinib
to first-line treatment for early CML.
Nilotinib is currently approved for the
treatment of patients with Philadelphia
chromosome-positive (Ph+) CML in
the chronic phase and accelerated
phase in patients who are resistant to
previous therapy, including imatinib.
“The superior efficacy and favorable
tolerability profile of nilotinib compared with imatinib suggests that
nilotinib may become the standard of
care in newly diagnosed CML,” said
Dr Saglio. In the open-label study, 846
patients with newly diagnosed Ph+
CML in chronic phase were randomized to receive either 400 mg of imatinib once daily, or 300 mg or 400 mg of
nilotinib twice daily. Follow-up lasted
about 5 years.
nilotinib groups compared with the
imatinib group.
Dr Saglio noted that molecular monitoring is the most sensitive measure of
CML disease burden. “Major molecular response is associated with an
extremely low rate of disease progression,” he said. Of the patients who
experienced progression of disease in
this study, none achieved a major
molecular response.
Complete cytogenetic responses at
12 months were also significantly better with nilotinib.
“The superior efficacy and
favorable tolerability profile of
nilotinib compared with
imatinib suggests that nilotinib
may become the standard of
care in newly diagnosed CML.”
—Giuseppe Saglio, MD
At 12 months, the rates of major
molecular response (the primary end
point) were 44% with 300 mg of nilotinib twice daily, 43% with 400 mg of
nilotinib twice daily, and 22% with 400
mg of imatinib once daily. The median
time to a major molecular response
was faster by about 2.5 months in the
Disease Progression
Rates of progression to accelerated
phase or blast crisis were 3.9% in the
imatinib group compared with less
than 0.7% and 0.4% in the patients
treated with 300 mg and 400 mg of
nilotinib, respectively.
The difference between nilotinib
and imatinib in progression to accelerated phase or blast crisis is the most
meaningful finding of the study,
“because people who go into accelerated phase or blast phase don’t really
have the opportunity for second-line
therapy,” according to Bayard L.
Powell, MD, Head of Hematology and
Oncology, Wake Forest University,
Winston-Salem, NC.
The importance of progression to
accelerated phase or progression to
blast phase is not questioned, Dr
Powell said. “Survival is negatively influenced by progression. It was accomplished with no additional toxicity.”
Nilotinib was superior to imatinib
on efficacy end points across all risk
groups of patients based on their Sokal
score (a risk index based on 6 criteria).
Molecular and cytogenetic
remissions were more
common with nilotinib than
with imatinib.
Side Effects
Both drugs were well tolerated. In
each group, 7% to 11% of patients discontinued their study drug because of
adverse events or abnormalities in
laboratory values, with no significant
differences between groups. In the
imatinib group, 4% of patients discontinued because of treatment failure, 4%
discontinued because of disease
progression, and 2% discontinued
because of suboptimal response.
Edema and weight gain occurred more
often with imatinib therapy. Grade 3 or
4 toxicities were rare in any group.
In commenting on the study, Rick
12
February 2010
VOL. 3
NO. 1
SPECIAL ISSUE
Leukemia
Intermittent Dosing of Dasatinib May Cut Toxicity, Allow
Continued Treatment in CML
By Wayne Kuznar
I
ntermittent dosing of dasatinib
may reduce toxicity, while allowing
patients with chronic myelogenous
leukemia (CML) to continue treatment, according to Paul La Rosée, MD,
Professor, Division of Hematology/
Oncology, Universitätsklinikum Jena,
Germany.
Dasatinib (Sprycel) is approved for
second-line treatment of CML after
imatinib (Gleevec) failure. Dose reduction beyond the labeled reduced continuous dosing is mandated in select
patients with chronic-phase CML who
experience dasatinib-induced toxicity.
In a retrospective analysis, treatment response was assessed in 33
patients with CML who were intolerant/resistant to imatinib and who
received a weekly on/off regimen
(3-5 days on/2-4 days off) of dasatinib.
The median weekly intermittent dose
was 500 mg.
Patients were followed by routine
hematologic and cytogenetic assess-
ment and molecular monitoring for a
median of 23 months. Resistant
patients were regularly screened for
BCR-ABL mutations. Of those evalu-
“This retrospective analysis in patients resistant or intolerant
to imatinib…suggests good, and in many cases even
improved, efficacy of interval treatment compared
with continuous dosing.”
—Paul La Rosée, MD
able for response, 18 of 31 patients
(58%) showed either maintenance of
or an improved response to dasatinib
with the intermittent-dosing schedule.
Of the 18 patients, 14 achieved or
maintained a major molecular response; 5 patients repeatedly tested
negative by polymerase chain reaction. The other 4 patients achieved a
complete cytogenetic remission.
Bendamustine-Rituximab
Combo an Effective
First-Line Therapy for CLL
A
new study presented at ASH
examined the use of bendamustine HCl (Treanda) in
combination with rituximab (Rituxan)
as first-line therapy in 117 patients
with newly diagnosed, advanced
chronic lymphocytic leukemia (CLL).
One third of the patients achieved
complete responses with this combination therapy, and another 56% of the
patients had partial responses, said
lead investigator Kirsten Fischer, MD,
Center of Integrated Oncology, University of Cologne, Germany. Of the
117 patients, 48% had Binet stage C
disease and 41% had Binet stage B.
Bendamustine had already been
shown to have considerable activity as
monotherapy in CLL and other
lymphoid cancers, and in combination
with rituximab in patients with
relapsed/refractory CLL.
In this study, rituximab was given
as four 6-week cycles, with 2 doses of
bendamustine with each cycle. Some
72% of patients in the study were
treated with all 6 cycles.
The median observation time was
15.4 months. Overall response rate
was 90.9%. A complete response was
observed in 32.7% of patients, and a
partial response in 55.5%. All other
VOL. 3
NO. 1
SPECIAL ISSUE
“Of note, 10 of 12 patients with
improved response have been treated
for a minimum of 6 months with continuous dosing dasatinib regimens,
without having achieved the response
level observed after allowing drug hol-
patients (9.1%) had stable disease;
none had progressive disease.
With up to 26 months of follow-up,
75.8% of the patients were still in
remission; the median progressionfree survival has not been reached.
Objective response rates of approximately 90% were achieved among the
different genetic subgroups, except
those with chromosome 17p deletion,
a high-risk subgroup whose partial
response rate was 42.9%.
Complete responses occurred most
often in patients with unmutated IGHV
gene, about 25%. The overall response
rate in this group was 88.9%.
Hematologic toxicities were grade
3/4 anemia (4.9%), grade 3/4
leukopenia (14.6%), and grade 3/4
neutropenia and thrombocytopenia
(6.5% and 6.1% of all given courses,
respectively). Twenty-nine episodes of
Common Toxicity Criteria grade >3
infections were documented (5.1%).
There were 2 treatment-related deaths
during the study.
The group is now conducting a
phase 3 trial in which the efficacy
of bendamustine-rituximab is being
compared with fludarabine-based
immunochemotherapy for the firstline treatment of CLL.—WK ■
iday,” said Dr La Rosée. “This retrospective analysis in patients resistant
or intolerant to imatinib with up to 5
preceding treatment modalities suggests good, and in many cases even
improved, efficacy of interval treatment compared with continuous dosing. These data mandate the initiation
of clinical trials to investigate alternative intermittent targeting regimens.”
Increasing Imatinib Dose
May Induce Response in
CML Failures
In another study of patients with
chronic-phase CML who had suboptimal response or failure with 400 mg of
imatinib, dose escalation achieved a
major molecular response, according
to Katia B.B. Pagnano, MD, PhD,
Hematology and Hemotherapy Center, Faculdade de Ciências MédicasUniversity of Campinas, Brazil.
This study evaluated the efficacy of
imatinib dose increase in 120 patients
who were treated with 400 mg of imatinib between March 2002 and
December 2008. Imatinib was escalated to between 600 mg and 800 mg in
cases of suboptimal response.
The dose was escalated in 55
patients because of unsatisfactory
response after 36 months of imatinib
treatment. Twenty-eight of the 55
patients (51%) were treated with imatinib as first-line therapy and 28
patients (51%) had previously taken
interferon. Median time between diagnosis and start of imatinib therapy was
5.0 months.
After the dose was increased, 31
patients (56%) responded, and 58% of
the patients with previous suboptimal
molecular response achieved major
molecular response, said Dr Pagnano.
“Most of the patients with hematologic failure did not respond to dose
escalation,” implying a change to a
second-line agent, such as nilotinib
(Tasigna) or dasatinib (Sprycel), was
needed, Dr Pagnano pointed out.
Patients who do not achieve major
molecular response may also be candidates for second-line treatment. ■
First Head-to-Head Comparison...
Van Etten, MD, PhD, Director of the
Tufts Medical Center Cancer Center in
Boston, agreed that the finding “could
be used to argue for nilotinib as firstline therapy.”
Potent Agents Show Impressive
Complete Cytogenetic Responses
Additional studies of nilotinib and
dasatinib, another oral TKI that is
several times as potent as imatinib,
show favorable efficacy on major
molecular response in patients with
newly diagnosed CML. The sets of
data were reported by Jorge E. Cortes,
MD, Deputy Chair and Professor of
Medicine, Department of Leukemia, at
the University of Texas M.D. Anderson
Cancer Center. The 2 studies he presented were identical in the nature of
their design.
In the open-label, single-agent trials,
the efficacy of either nilotinib 400 mg
twice daily or dasatinib 100 mg/day
(50 mg twice daily or 100 mg once
daily) were investigated as first-line
therapy in chronic-phase CML.
In the nilotinib study, 32 of 51
Jorge E. Cortes, MD
patients (63%) who were followed for
at least 3 months achieved a complete
molecular response, and 98% achieved
a complete cytogenetic response.
In the dasatinib study, major molecular response was achieved in 70% of
the 50 patients who were followed for
at least 3 months, and a complete cytogenetic response was achieved in 98%
of the 50 patients.
Dr Cortes noted that the cytogenetic response rates with nilotinib and
dasatinib in these studies compare
favorably with that observed in imatinib-treated patients. ■
www.AHDBonline.com
13
Leukemia
Statins Delay Treatment in CLL
By Wayne Kuznar
P
atients who take statins at the
time they are diagnosed with
chronic lymphocytic leukemia
(CLL) are less likely to have their disease progress to the point of requiring
therapy, said Daphne Friedman, MD,
Division of Medical Oncology, Department of Medicine, Duke University,
Durham, NC.
Of 355 patients in the Duke
University/Durham Veterans Affairs
Medical Center’s CLL database (1999present), statin use/lack of use at the
time of CLL diagnosis was known in
254 patients—65 statin users, 189
nonusers.
In these patients, CLL therapy was
not required in 132 (52%) patients; 122
(48%) patients received at least 1 treatment. Indications for therapy were
recorded in 117 of the 122 patients, and
included increasing lymphocyte count
in 49 patients, anemia in 14 patients,
thrombocytopenia in 8 patients, splenomegaly in 8 patients, and lymphadenopathy in 49 patients.
Follow-up ranged from 0.05 years
to 25 years from diagnosis, with a
shorter follow-up time in the patients
who were taking a statin at the time of
diagnosis.
Patients taking a statin at the time
of diagnosis were significantly less
likely to require therapy; this applied
primarily to women and patients
with low-risk (CD38-negative) CLL.
“Notably, even though patients taking a statin at the time of diagnosis
were less likely to ever require therapy,
CLL treatment was not significantly
associated with progression or time to
progression.
“Even though patients taking a statin at the time of
diagnosis were less likely to ever require therapy, statin
use was not associated with a significant
improvement in overall or treatment-free survival.”
—Daphne Friedman, MD
statin use was not associated with a significant improvement in overall or
treatment-free survival,” said Dr
Friedman.
In addition, statin use at time of first
There was no significant correlation
between lipid levels at diagnosis and
the need for CLL treatment. But data
for this lipid analysis were only available for 26 patients. ■
Second-Generation TKIs Effective, Safe for Relapsed ALL
T
he use of second- and thirdgeneration tyrosine kinase
inhibitors (TKIs) is a valid and
safe approach to treating relapsed
Philadelphia chromosome-positive
(Ph+) acute lymphoblastic leukemia
(ALL) in adult and elderly patients,
said Cristina Papayannidis, MD,
Department of Hematology and Medical Oncology, Institute L. and A.
Seràgnoli, University of Bologna, Italy.
About 30% of patients with ALL
have Ph+. “The prognosis of this
subset of patients treated with standard therapies, including multiagent
chemotherapy, imatinib [Gleevec], and
allogeneic stem-cell transplantation is
still dismal, due to a high risk of
relapse,” she said.
Dasatinib (Sprycel) and nilotinib
(Tasigna) are second-generation TKIs
that were developed to overcome
resistance to imatinib in patients with
Ph+ ALL.
This retrospective analysis evaluated the use of second-generation and
experimental third-generation TKIs in
29 adult patients (median age at diagnosis, 49 years) with relapsed Ph+
ALL. Of these patients, 14 were in first
relapse, 11 were in second relapse, and
4 were in third relapse.
All the patients were previously
treated with imatinib; 10 patients had
also received allogeneic bone marrow
transplantation. Of the 29 patients, 13
reached a hematologic response—11
patients with dasatinib, 1 patient with
nilotinib, and 1 patient with a thirdgeneration experimental TKI. Ten
patients also obtained a cytogenetic
response and 9 patients obtained a
molecular response.
With a median follow-up of 10.8
months, the median durations of
hematologic response, cytogenetic
response, and molecular response
were each 5.5 months.
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The median overall survival was
25.8 months, and progression-free survival was 5.5 months.
In the near future,
combination treatment—
including novel agents (ie,
aurora kinase inhibitors)—
with standard TKIs may
reduce the risk of relapse.
Although these TKIs proved effective, “relapse is unavoidable due to the
emergence of additional ABL mutations,” Dr Papayannidis said.
In the near future, combination
treatment— including novel agents (ie,
aurora kinase inhibitors)— with standard TKIs may reduce the risk of
relapse and overcome the genomic
instability of Ph+ ALL, she speculated.—WK ■
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Leukemia
Advances in Treating MDS
By Caroline Helwick
M
yelodysplastic
syndromes
(MDS), formerly known as
preleukemia, is a diverse collection of hematologic conditions united by the ineffective production or
abnormality of bone marrow cells and
the risk of transformation to acute lymphocytic leukemia (AML). Although
many patients with MDS have an indolent disease, approximately one third
eventually progress to AML.
Significant advances have been
made in the understanding of the disease. For example, several new molecular abnormalities have been identified, including loss of function
mutations in TET2. For patients with
bone marrow failure syndromes who
do not meet the World Health
Organization 2008 criteria for MDS,
and who also do not meet any other
disease classification, a category of
idiopathic cytopenias of undeter-
mined significance has been proposed.
Currently, 3 drugs are approved by
the Food and Drug Administration for
MDS—azacitidine (Vidaza), lenalidomide (Revlimid), and decitabine
(Dacogen). In addition, clinicians are
using multiple hematopoietic growth
factors, immunosuppressants, and
cytotoxic agents for MDS. Investigative
agents include thrombopoietin agonists
that stimulate platelet production,
other drugs that target novel pathways
in MDS, and drugs that show promise
for combination approaches, said
Mikkael Sekeres, MD, of the Cleveland
Clinic Taussig Cancer Institute.
Heather Leitch, MD, from the
University of British Columbia,
Vancouver, presented data suggesting
that iron overload is a factor in MDS.
Since humans lack a physiologic
mechanism for excreting excess iron,
the accumulation of iron can occur
from repeated red blood cell transfusions and can contribute to morbidity
and even mortality of patients with
MDS. There is the potential, therefore,
to derive iron-lowering benefits from
iron chelation therapy, which has
helped in similar conditions, she said,
but this requires more study.
Important findings on novel treatments for MDS were reported at the
ASH meeting:
• Lenalidomide, currently used in
low-risk MDS patients with certain
cytogenetic features, was evaluated
in high-risk patients in a phase 2
European study. Used as a single
agent, but in doses higher than are
used in low-risk patients, lenalidomide produced a 30% response rate.
• Alemtuzumab (Campath), an antiCD52 antibody, produced a very high
response rate in patients with intermediate-risk disease, with transfusion independence and normalization of blood counts and cytogenetic
remissions in a high proportion.
• An oral formulation of azacitidine
was active and well tolerated, with a
manageable side effect profile, in
patients with MDS.
• An oral formulation of clofarabine
(Clolar), a deoxyadenosine nucleoside analog, produced responses in
46% of patients with high-risk MDS.
• Compared with the 5-day intravenous schedule used in high-risk
MDS, decitabine given subcutaneously in a very low dose daily or
weekly was safe and active, with significantly less myelotoxicity in a
phase 2 study of patients with lower
risk disease.
• In trisomy 8 MDS patients refractory to other treatments, experimental
treatment with the styryl sulfone
ON 01910 (which decreases cyclin
D1 accumulation in bone marrow)
improved blood counts and in some
cases led to transfusion independence and long-term remission. ■
Adding Alemtuzumab to Fludarabine Antifungal Prophylaxis in AML
Patients Receiving Induction
Doubles PFS in Relapsed CLL
Chemotherapy
By Wayne Kuznar
A
dual regimen of alemtuzumab
(Campath) and fludarabine
phosphate (Fludara) reduces
the risk of disease progression or death
compared with single-agent fludarabine as second-line therapy for patients
with chronic lymphocytic leukemia
(CLL), according to Andreas Engert,
MD, Professor of Internal Medicine,
Hematology and Oncology, University
Hospital of Cologne, Germany.
Dr Engert is principal investigator of
a phase 3 study that compared the 2
regimens in 335 patients with relapsed
or refractory CLL.
Progression-free survival (PFS) was
the end point of the study; PFS more
than doubled with the alemtuzumabfludarabine combination compared
with fludarabine alone. As a result,
Genzyme indicated that it would seek
a new indication for alemtuzumab for
use in this combination regimen.
Until this study, there was no clear
standard of care for second-line therapy for CLL, said Dr Engert. To be eligible for the study, patients must not
have had an active infection within the
3 months before randomization.
Patients were randomized to alemtuzumab in escalating doses followed
by up to 6 cycles of fludarabine, or up
to 6 cycles of fludarabine alone.
A similar number of patients in each
group completed all 6 cycles of fludarabine, and the percentage of
patients who discontinued the study
drugs because of adverse events was
16
similar—23% with alemtuzumab/fludarabine and 22% with fludarabine
alone. The trial’s data safety monitoring panel recommended that the study
be closed early as a result of these data.
With a median of 17 months followup at the time of the second interim
analysis, the median PFS was 29.6
months with alemtuzumab/fludarabine compared with 20.7 with fludarabine alone—a 39% risk reduction of
disease progression. In the subgroup
of patients with advanced CLL, the
median PFS was 26.1 months with the
combination regimen and 12.1 months
with fludarabine only.
PFS more than doubled with
the alemtuzumab-fludarabine
combination compared with
fludarabine alone.
“The alemtuzumab/fludarabin safety profile compared with fludarabine
monotherapy resulted in no difference
in the number of deaths and a similar
frequency of grade 3/4 infectious complications,” noted Dr Engert.
Infection-related adverse events occurred in 47.0% of patients assigned to
alemtuzumab/fludarabine and 35.2%
in patients assigned to fludarabine
alone. ■
SEE ALSO Alemtuzumab Contributes
39% to Treatment Costs in CLL, page 7.
February 2010
I
nvasive fungal infections remain a
significant threat to patients with
acute myelogenous leukemia (AML)
and myelodysplastic syndromes (MDS)
who undergo induction chemotherapy.
New evidence with voriconazole
(Vfend) and posaconazole (Noxafil)
supports the benefit of antifungal prophylaxis in this setting.
In a retrospective study of patients
with AML or high-risk MDS, voriconazole was superior to 7 other regimens
as antifungal prophylaxis, reported
Gloria Mattiuzzi, MD, Assistant
Professor, Department of Leukemia,
University of Texas M.D. Anderson
Cancer Center.
“An ideal antifungal prophylaxis
regimen should be effective, safe, and
uncomplicated for the patients….We
have explored several options, including different type of drugs and various delivery schedules,” Dr Mattiuzzi
said.
M.D. Anderson’s experience with
antifungal prophylaxis for intensive
chemotherapy from 1997 to 2009
included 730 patients with AML or
high-risk MDS patients.
The regimens involved various
delivery methods and schedules
of amphotericin B lipid complex
(Abelcet), liposomal amphotericin B
(Ambisome), fluconazole (Diflucan),
itraconazole (Sporanox), caspofungin
(Cancidas), and voriconazole.
The percentage of documented
invasive fungal infections—0.7% (1
case of 137 patients treated) was lowest among patients treated with
voriconazole, 400 mg intravenously
(IV) twice daily followed by either 300
mg IV twice daily or 400-mg tablets
twice daily for 1 day, then 200-mg
tablets twice daily. Documented invasive fungal infections occurred at a
rate of 4% to 12% with the other regimens. The rates of possible or probable
invasive fungal infections were similar
between the regimens.
A significant difference was seen in
side effects among the 8 regimens,
with caspofungin and voriconazole
the least toxic. Oral voriconazole was
significantly less toxic than IV
voriconazole.
In a separate analysis, investigators
at the H. Lee Moffitt Cancer Center
and Research Institute in Tampa,
FL, looked at 195 patients receiving
AML/MDS induction chemotherapy
who received primary antifungal prophylaxis with voriconazole, 400 mg
orally twice daily for 1 day followed
by 200 mg orally twice daily, or
posaconazole, 200 mg orally 3 times
daily with meals. The median time on
prophylaxis was about 2 weeks in
each group.
Proved or probable invasive fungal
infection occurred in 7% of the
voriconazole group and 6.1% of the
posaconazole group. The rates of serious adverse events were 6% in the
voriconazole group and 7.5% in the
posaconazole group.—WK ■
VOL. 3
NO. 1
SPECIAL ISSUE
Multiple Myeloma
Maintenance Therapy an Emerging Theme in Myeloma
By Caroline Helwick
he duration of treatment for
multiple myeloma may be
lengthening, according to several studies that showed maintenance
therapy with lenalidomide (Revlimid)
or bortezomib (Velcade) improves
outcomes.
T
mens of limited duration,” said
Antonio Palumbo, MD, of the
University of Torino, Italy. “MPR-R
can be considered a new standard of
initial therapy for patients older than
65,” he pointed out.
Maintenance with MPR Followed
by Lenalidomide
In a 10-month interim analysis of a
phase 3 study that garnered attention
at ASH, investigators reported good
results with maintenance lenalidomide
in newly diagnosed, elderly patients.
Upfront induction therapy with
MPR (melphalan [Alkeran], prednisone [Deltasone], and lenalidomide)
versus MP (melphalan and prednisone) alone produced more responses and less toxicity; however, the 3drug combination did not improve the
rate of relapse. Until the study
matures, this comparison is likely to be
a topic of debate, experts noted.
The most interest was focused on
the maintenance approach with MPR
followed by lenalidomide (MPR-R),
which outperformed MPR without
maintenance. MPR-R reduced the risk
of disease progression by 47% compared with MPR. Median progressionfree survival (PFS) has not been
reached for MPR-R, and was 13.2
months with MPR.
“The study showed that continuous
lenalidomide was superior to regi-
“VMPT followed by
maintenance with bortezomib
and thalidomide was superior
to VMP for response rates
and progression-free
survival.”—Antonio Palumbo, MD
Of the 469 patients, overall response
rates were 77% for MPR-R, 67% for
MPR, and 49% for MP; complete
responses were 18%, 13%, and 5%,
respectively. In the first 3 months of
treatment, partial response rate
was 60% for the MPR-R arm and
30% for MP.
Very good partial responses (VGPR)
or better were still being observed at
17 months, suggesting that continued
improvement is possible with continued therapy.
4 Drugs plus bortezomib/
thalidomide Maintenance Better
than 3
In another phase 3 study of 511 elderly patients, Dr Palumbo reported
that maintenance therapy after a 4-
High-Risk Smoldering Myeloma
Responds to Treatment
H
igh interest was shown in a
study of the best approach to
managing patients with “smoldering” myeloma who were deemed
to be at risk for progressing to symptomatic disease. This phase 3 clinical
trial concluded that lenalidomide
(Revlimid) plus dexamethasone (Decadron) is a promising treatment
regimen compared with the usual
approach of surveillance without treatment intervention.
All 94 patients had elevations in
serum M-component and bone marrow plasma cells but no end-organ disease. Such patients typically develop
symptomatic myeloma in slightly >2
years. The patients were randomized
to nine 4-week induction cycles of
lenalidomide plus dexamethasone followed by maintenance therapy with
lenalidomide, or no treatment.
Results showed a significant benefit
to treating high-risk smoldering
patients, because 81% responded and
VOL. 3
NO. 1
SPECIAL ISSUE
14% achieved a “stringent” complete
response or complete response after 4
cycles. After 9 cycles, response rates
were 91% and 21%, respectively. At
follow-up, patients in the no-treatment
arm had a 19-month mean time to disease progression. In contrast, just 2
patients in the lenalidomide plus dexamethasone arm had progressed,
reported Maria-Victoria Mateos, MD,
of the University of Salamanca, Spain.
Lenalidomide plus
dexamethasone is a promising
treatment regimen compared
with the usual approach.
Despite treatment, patients maintained a good quality of life, with
few serious side effects, Dr Mateos
added. The analysis, however, did
not yet show an improvement in
survival.—CH ■
drug regimen that included thalidomide was superior to the same
regimen without thalidomide or maintenance. Patients were randomized to
bortezomib, melphalan, and prednisone (VMP) without maintenance, or
to VMP plus thalidomide (VMPT) followed by bortezomib and low-dose
thalidomide for maintenance.
VMPT plus maintenance therapy
was superior to VMP alone, with complete responses achieved by 34% and
21% of patients, respectively. The
achievement of a complete response
significantly delayed relapses in both
regimens, but was most pronounced in
the VMPT arm; 2-year survival was
similar (89%) for both arms.
The study began with twice-weekly
bortezomib, but was amended to a
once-weekly dosage. This resulted in a
“dramatic drop” in the incidence of
peripheral neuropathy without affecting the outcome, he said.
Grade 3 to 4 neuropathy occurred in
just 4% of patients given bortezomib
weekly versus 18% of patients given
bortezomib twice-weekly in the VMPT
arm, and in 2% and 13% of patients,
respectively, in the VMP arm. The
4-drug regimen was associated with
significantly more grade 3 to 4 neutropenia and cardiotoxicity, but other
toxicities were similar for both arms.
“VMPT followed by maintenance
with bortezomib and thalidomide was
superior to VMP for response rates
and progression-free survival,” Dr
Palumbo concluded.
Bortezomib, then Lenalidomide
Posttransplant
Improved outcomes were also
reported with a sequential approach
using bortezomib for induction and
lenalidomide as posttransplant consolidation maintenance. The investigators
said that bortezomib induction before
autologous stem-cell transplantation
(ASCT) has shown efficacy in newly
diagnosed patients, and lenalidomide
might be a less-toxic alternative to
thalidomide for follow-up consolidation-maintenance.
“This is the first phase 2 study of this
approach in newly diagnosed patients
aged 65 to 75 years old,” said Francesca
Gay, MD, of the University of Torino.
“We found that treatment was correlated with an increase in response rate
and in the depth of response, and was
generally well tolerated.”
This multicenter phase 2 trial
included 102 newly diagnosed patients (age 65-75 years). Induction
included 4 cycles of bortezomib,
pegylated liposomal doxorubicin
(Doxil), and dexamethasone (Deca-
dron), which was followed by ASCT,
then consolidation with 4 cycles of
lenalidomide plus prednisone, and
finally with lenalidomide for maintenance until relapse.
VGPR or better was 58% in patients
after induction, which increased to
>80% after consolidation and maintenance. Relapse-free rates were 88%
after 1 year and 69% at 2 years; 93%
and 75%, respectively, were still alive.
Patients achieving a complete response had better outcomes.
“Consolidation-maintenance was
well tolerated,” Dr Gay noted. “Only
4% of patients required growth factor
support, and no patient required
platelet transfusions. Skin toxicity was
easily manageable with dose reductions and supportive therapy.”
“This is the first phase 2 study
of this approach in newly
diagnosed patients aged 65 to
75 years old.”
—Francesca Gay, MD
Sequential VTD Maintenance
Approach
In another phase 2 study of sequential therapy, investigators from the
City of Hope Cancer Center, Duarte,
CA, evaluated the role of initiating
bortezomib and dexamethasone for
maintenance, followed by a second
maintenance phase with thalidomide
(VTD) after ASCT.
Several studies have shown improved PFS, and possibly improved
overall survival, with thalidomide
(Thalomid) alone or in combination
with steroids and chemotherapy as
maintenance-consolidation therapy
after ASCT. This study of 28 patients
evaluated efficacy and toxicity with a
prolonged course of sequential VTD
maintenance.
After ASCT, patients received weekly bortezomib and dexamethasone
monthly for 6 months. A second maintenance phase included thalidomide
and dexamethasone monthly for an
additional 6 months. Single-agent
thalidomide was then continued until
disease progression.
After 5-month follow-up, only 1
patient had died. Complete response
rates were boosted after each sequence,
and several patients remained in
complete remission after the second
maintenance phase. Toxicities were
manageable: 10 patients had peripheral neuropathy at baseline; 3 developed
it with bortezomib. ■
Multiple Myeloma continued on page 20
www.AHDBonline.com
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Multiple Myeloma
Multiple Myeloma Management in 2010
By Caroline Helwick
T
he survival rates of patients
with multiple myeloma (MM)
have increased substantially
over the past decade, as a result of
high-dose chemotherapy followed by
autologous stem-cell transplantation
(ASCT) in young patients, and the
new, highly efficient rescue treatments
in young and elderly patients, said
experts in a special update on this
malignancy at ASH.
The gold standard induction treatment, given before ASCT, is VAD
(vincristine [Oncovin], doxorubicin
[Adriamycin], and dexamethasone
[Decadron]), but novel drug combinations are being evaluated for their ability to prolong remission. New strategies
are based on thalidomide (Thalomid),
lenalidomide (Revlimid), and bortezomib (Velcade) in combination with
established antimyeloma agents.
Bortezomib/dexamethasone, with
or without thalidomide, has proved to
be very effective for debulking tumors,
and is superior to VAD. Similar efficacy is expected for bortezomib plus
lenalidomide and dexamethasone,
said Jesus F. San-Miguel, MD, Uni-
versity Hospital of Salamanca, Spain.
Based on the number of studies evaluating maintenance strategies, this is
an emerging concept that may become
established (see article, page 17).
Although thalidomide has been
effective for maintenance therapy, the
more favorable toxicity profile of lenalidomide makes it an ideal maintenance
agent. Other new studies are achieving good results, including higher response rates, with bortezomib.
Current investigations are showing
that bortezomib can overcome the
adverse prognosis of patients in the
high-risk category based on cytogenetics or other factors. To a lesser degree,
this is seen with lenalidomide as well.
Treatment of Elderly Patients
Patients with MM aged ≥65 years
have traditionally received an oral regimen of MP (melphalan [Alkeran] and
prednisone [Deltasone]). The introduction of thalidomide, lenalidomide, and
bortezomib has substantially changed
this treatment paradigm, said Antonio
Palumbo, MD, and Francesca Gay,
MD, of the University of Torino, Italy.
With these novel agents on board for
induction or consolidation after transplant, reduced-intensity transplantation is also now an option in some elderly patients. The choice of treatment
(and level of aggressiveness) is tailored
according to the patient’s biological
age, comorbidities, and the expected
toxicity profile of the regimen. When
cost is a concern, MP plus thalidomide
may be the best option, they said.
The introduction of
thalidomide, lenalidomide,
and bortezomib has
substantially changed this
treatment paradigm.
In elderly patients newly diagnosed
with MM who are ineligible for transplantation, analysis of the VISTA trial
showed that that the VMP regimen—
bortezomib, melphalan, and prednisone—was superior to MP alone.
The 3-year overall survival rate with
VMP was 68.5% compared with 54.0%
for MP (see also article, page 7).
Weekly Bortezomib Effective, Less Toxic
U
sing bortezomib weekly rather
than twice weekly appears to
have comparable efficacy but
less toxicity than the more-intensive
regimen, according to presentations at a
plenary session. Good results were
reported with the less-intensive regimen in newly diagnosed older patients.
“We were trying to optimize the treatment of elderly patients, so we tried a
less-intensive weekly administration
for induction, followed by maintenance
doses given every 3 months,” said lead
investigator Maria-Victoria Mateos,
MD, PhD, from University Hospital,
Salamanca, Spain.
The 260 elderly patients (aged >65
years) were treated in 6 cycles with
either VMP (bortezomib [Velcade],
melphalan [Alkeran], and prednisone
[Deltasone]) or VTP (bortezomib,
thalidomide [Thalomid], and prednisone). In the first cycle, patients
received bortezomib twice weekly,
and once weekly in subsequent cycles.
For maintenance, patients received
bortezomib plus thalidomide or prednisone for up to 3 years.
Both induction approaches were
very effective, with response rates
of about 80%; as maintenance, they
increased complete responses from
23% to 42%.
A clear difference, however, was
seen in the toxicity profiles of the
20
induction regimens: VMP was associated with more grade 3 neutropenia infections. VTP was associated
with more serious cardiovascular
events and more severe peripheral
neuropathy.
“We found that melphalan is
probably the best partner for
bortezomib in elderly
untreated myeloma patients.”
—Maria-Victoria Mateos, MD, PhD
“We found that melphalan is probably the best partner for bortezomib in
elderly untreated myeloma patients,
because the efficacy is similar to VTP,
but the toxicity profile is different,” Dr
Mateos said.
“We asked whether we could
achieve similar efficacy with a less
intensive bortezomib regimen, and the
answer is that clearly we can,” Dr
Mateos said. Perhaps the most important finding was that the poor prognosis of high-risk elderly patients could
be overcome with either regimen.
Comparing Regimens for Induction
Two prominent abstracts compared
TD (thalidomide [Thalomid] and dexamethasone [Decadron]) with VTD
February 2010
(TD plus bortezomib [Velcade]) as
induction therapy before autologous
stem-cell transplantation (ASCT). Both
were large randomized trials designed
to assess the effect of using bortezomib
in newly diagnosed patients.
The study from the Italian Myeloma
Network, presented by Michele Cavo,
MD, of the University of Bologna,
showed significantly improved response rates with VTD. At all assessment points, patients receiving VTD
had better outcomes, and VTD conferred improved progression-free survival—76% at 30 months compared
with 58% in the TD arm.
The addition of bortezomib added
little toxicity, except for more grade 3
rash (16% vs 2%) and peripheral neuropathy (10% vs 2%). Few patients discontinued VTD and 94% received all
the doses.
In a similar phase 3 trial of 299
patients, the Spanish Myeloma Group
reported that VTD resulted in higher
complete response rates before and
after ASCT, as well as lower rates of
progression compared with TD, particularly in patients with high-risk cytogenetics or soft-tissue extramedullary
plasmacytomas. Based on these and
other findings, VTD appears to be
emerging as a new standard for
younger myeloma patients who are
candidates for ASCT.—CH ■
Novel Therapies for Relapse
Despite extended periods of remission after treatment with bortezomib
and the immunomodulators thalidomide and lenalidomide, most patients
develop drug resistance and eventually relapse. Treatment for relapse
should be individualized to reflect
prior drug exposure, prior drug toxicities, responsiveness, age, tempo of
relapse, and genetic risk.
The frequent occurrence of relapse
and potential for intolerable adverse
effects from current drugs make
the development of newer agents
with novel mechanisms of action,
improved efficacy, and better tolerability a pressing need, said A. Keith
Steward, MD, of the Mayo Clinic
Arizona, Scottsdale.
Bortezomib, the first proteasome
inhibitor to be approved for myeloma,
elicits responses in about 50% of
patients at the time of relapse. New
proteasome inhibitors are being developed that differ somewhat from each
other in chemistry and in specificity
for the proteasome target, such as
carfilzomib, which has shown promise
in early trials. New immunomodulators are also entering trials, including
pomalidomide (Actimid). The alkylating agent bendamustine (Treanda) is
also being tested in combination with
other active agents in MM.
A review of the medical literature
reveals more than 180 different drugs
in which preclinical results give rationale to proceed to clinical testing, with
special interest in the AKT inhibitors,
heat-shock protein inhibitors, and
histone deacetylase inhibitors. It is
probable that the therapeutic arsenal
for MM will soon expand to help
improve patient outcomes, Dr Steward
predicted.
Questions Remain
Bart Barlogie, MD, PhD, Director of
the Myeloma Institute for Research
and Therapy, University of Arkansas
for Medical Sciences, Little Rock, said
that more radical questions need to be
answered about the future of MM,
saying that we need “more decisive
questioning, at the end of which we
have crucially important information.”
“One such question would be
whether to do transplant or not in the
low-risk myeloma patient. Some
would say they don’t need transplant,
although personally I disagree. The
downside is that once the patient has
a recurrence, we may have lost the
cure potential. Also, we need to use
more gene arrays in research. If this
were part and parcel of all evaluations of new agents, we could discover in 2 to 3 years an approach that
really works. ■
VOL. 3
NO. 1
SPECIAL ISSUE
Other Highlights
Hematologic Drug Pipeline...
The overall hematologic response was
35% (median duration, 7 months) in
accelerated-phase patients, and 47%
(median duration, 2 months) in blastphase patients.
A new cancer vaccine GRNVAC1,
which targets telomerase, an enzyme
whose activity is increased in acute
myelogenous leukemia (AML) and
other cancers, has produced immune
responses in more than half of vaccinated AML patients. Complete clinical
remission has been maintained in 14 of
20 vaccine recipients with AML in
ongoing complete remission or early
relapse. The median duration of clinical remission, including the patients
who have relapsed, is 12 months. The
vaccine was well tolerated, with the
exception of 1 patient who developed
immune thrombocytopenic purpura.
Elotuzumab, given with lenalidomide and low-dose dexamethasone,
showed clinical activity in a study of
28 patients with relapsed multiple
myeloma (MM). In the study, 23
patients (82%) had an objective
response. In 22 patients who had not
previously received lenalidomide, 21
patients (95%) achieved an objective
response. No dose-limiting toxicities
were reported up to the highest dose
level of 20 mg/kg, and a maximum
tolerated dose was not established.
Tositumomab and iodine I-131
tositumomab looked promising in 2
phase 2 studies, one in patients with
untreated follicular lymphoma, and the
other in patients with non-Hodgkin’s
lymphoma who no longer responded
to rituximab (see article, page 10).
Less far along in the pipeline, but
very promising, are the bifunctional
T-cell–engaging BiTE monoclonal antibodies, such as blinatumomab. In 50
heavily pretreated patients with
relapsed NHL, blinatumomab, given
for 4 to 8 weeks by continuous intravenous infusion via port with a
associated with a preliminary median
overall survival (OS) of 7.8 months
and a remission rate of 31%. The median OS in first relapsed or refractory
AML patients receiving currently
available chemotherapies ranges from
3.4 months to 5.9 months.
In a trial of single-agent voreloxin in
113 previously untreated elderly AML
“Omacetaxine works by a completely
different mechanism, inhibiting the
synthesis of certain oncoproteins
instead of directly attacking BCR-ABL.”
—Jorge E. Cortes, MD
portable pump produced responses in
all 12 (100%) evaluable patients. The
duration of responses extended to 20
months; response is ongoing in 7
patients. Neurologic toxicity was a
concern, but this is being mitigated by
slowing the infusion and using stepwise dosing.
Voreloxin has a strong efficacy and
safety profile when used as a single
agent or in combination with chemotherapy in patients with difficult-totreat AML, according to Jeffrey Lancet,
MD, Associate Member and Chief,
Leukemia Section, Department of
Hematologic Malignancies, H. Lee
Moffitt Cancer Center and Research
Institute, Tampa, FL.
In 64 evaluable patients with first
relapsed or refractory AML, voreloxin
in combination with cytarabine was
patients (median age, 74 years), 3 dosing schedules were tested: once weekly for 3 weeks (schedule A); once
weekly for 2 weeks (schedule B); and
on days 1 and 4 at either 72 mg/m2 or
90 mg/m2 (schedule C).
Median survival was 8.7 months in
schedule A; 5.8 months in schedule B;
and 7.3 months (preliminary) in schedule C (72 mg/m2 on days 1 and 4). The
median duration of remission was 10.7
months, and 1-year survival was 38%
for schedule A. For the other schedules, median duration of remission has
not been reached, and 1-year survival
is too early to evaluate.
INCB018424, an investigational oral
inhibitor of the Janus-activated kinase
(JAK) 1 and 2 enzymes, can reduce
spleen size and improve quality of life
and symptoms associated with myelo-
fibrosis, according to Srdan Verstovsek,
MD, PhD, Associate Professor, Department of Leukemia, University of
Texas M.D. Anderson Cancer Center.
Recent evidence indicates that exaggerated JAK signaling plays an important role in the pathogenesis of
myelofibrosis. Average life expectancy
for patients is 5 to 7 years. In 155
patients with the disease, INCB018424
treatment resulted in a rapid reduction
in spleen volume, which was evident
as early as 1 month into therapy and
lasted beyond 6 months of therapy.
Some 48% of patients had spleen volume reduction ≥35% after 6 months of
treatment. An improvement was also
observed in the 6-minute walk test.
Carfilzomib, the second-generation
proteasome inhibitor, is showing noteworthy response rates and low levels
of adverse effects in patients with MM,
according to updated data from a 17center study.
Carfilzomib induced a response in
45% of 51 evaluable patients with relapsed or resistant MM who received
1 to 3 previous therapies (but not
bortezomib, the original proteasome
inhibitor). The response rate is considered noteworthy for a single agent in
patients with tumor progression
despite previous therapy, said lead
investigator Michael Wang, MD,
Associate Professor, Department of
Lymphoma/Myeloma, M.D. Anderson. He said 37% of the patients experienced neuropathy from previous
treatments, which was reduced to 12%
with carfilzomib. ■
Investigational Alternatives to Warfarin Prevent VTE Events
By Wayne Kuznar
M
ore convenient options to
warfarin (Coumadin) for the
prevention of venous thromboembolism (VTE) events are a step
closer, as suggested by encouraging
results of 2 phase 3 clinical trials presented at ASH.
Dabigatran for VTE Prophylaxis
Two oral fixed-dose anticoagulants—
both inhibitors of factor Xa—showed
efficacy in the prevention of VTE
events, with acceptable bleeding rates.
In the RE-COVER trial, dabigatran
etexilate (Pradaxa) proved to be as
effective as warfarin in preventing
recurrent VTE in patients with acute
VTE. Current guidelines for the treatment of clinically documented VTE
recommend a parenteral heparin
preparation for at least 5 days, followed by oral anticoagulation with a
vitamin K antagonist, such as warfarin.
“In North America, 2 million people
are on warfarin at any time point,”
noted Sam Schulman, MD, lead investigator of RE-COVER and Director of the
Clinical Thromboembolism Program,
Hamilton General Hospital, Ontario,
Canada. “Patients on warfarin have to
go for blood tests, called an international normalized ratio [INR], every 2 to 3
weeks, and adjust the dose….Warfarin
has been around for 60 years and has
not really had any contester.”
“There’s probably no more dangerous drug on the market than warfarin,”
noted Bradford Schwartz, MD, Dean,
University of Illinois College of Med icine, Urbana-Champaign. “Warfarin is
a direct competitor to vitamin K, so
anything you do that varies the amount
of vitamin K you take in is going to
affect how much warfarin is there to
have an effect.” Many concomitant
drugs can also affect blood levels of
warfarin. Unlike warfarin, dabigatran
is not a vitamin K antagonist.
RE-COVER was an international
phase 3 study of 2539 patients with
acute VTE who were randomized to 6
months of therapy with oral dabigatran, 150 mg twice daily, or warfarin,
after initial treatment with a parenteral anticoagulant approved for this
indication.
The warfarin dosage was adjusted
to maintain a 2.0 to 3.0 INR, which
required a blood test about every 11
days; those randomized to dabigatran
received a sham blood test as part
of the double-blind, double-dummy
design of the study.
At 6 months, dabigatran was “noninferior” to warfarin on the primary
end point—the 6-month incidence
of recurrent symptomatic VTE/death.
This end point occurred in 2.4%
(30 patients) of the dabigatran
group and 2.2% (27 patients) of the
warfarin group.
The incidence of major/clinically
relevant bleeding was 37% lower with
dabigatran than with warfarin (207 vs
280 events, respectively); the major
“Patients on warfarin have to
go for blood tests…every 2 to 3
weeks and adjust the dose.
Warfarin has been around for 60
years and has not really had any
contester.” —Sam Schulman, MD
bleeding incidence was similar
between the 2 groups (1.6% vs 1.9%,
respectively).
VOL. 3
NO. 1
SPECIAL ISSUE
www.AHDBonline.com
21
Other Highlights
Stem-Cell Mobilization Strategies: What Works, What Doesn’t
By Caroline Helwick
I
n mobilizing hematopoietic stem
cells (HSCs) before proceeding to
autotransplant, especially in challenging cases, the conventional approach of intensifying cytokine-based
(growth factor) strategies was found to
be futile. No advantage was seen for
dose-escalated granulocyte colonystimulating factors (G-CSFs) or the
combination of G-CSFs plus granulocyte macrophage colony-stimulating
factor in mobilizing HSCs.
The strategies were evaluated as a
means of boosting HSC in patients
deemed hard to mobilize based on prior
therapy. “Unlike what is seen with normal donors, there was no benefit to dose
escalation of mobilization cytokines or
the use of 2 versus 1 cytokine in heavily
pretreated patients,” said Elizabeth
Berger, BA, of Loyola University, IL.
“Given the cost of these cytokines,
we conclude that standard-dose GCSF is the optimal method of stemcell mobilization for hard-to-mobilize
patients,” she said. “Alternative approaches, such as the combination of
plerixafor plus standard-dose G-CSF,
might be the preferred method of initial HSC mobilization.”
Plerixafor plus G-CSF
Several studies have shown that
plerixafor (a CXCR4 receptor inhibitor
that prevents the binding of the stem
cell to the stroma in the bone marrow)
plus G-CSF mobilizes more CD34+
cells in fewer apheresis days than
G-CSF alone in patients with myeloma
and lymphoma.
Two prospective, randomized, double-blind, placebo-controlled phase
3 trials compared plerixafor plus
G-CSF with placebo plus G-CSF for
“The addition of plerixafor to G-CSF
predictably allows significantly more
patients to achieve the target cell
collection within 1 day of apheresis.”
—Brian J. Bolwell, MD
Investigational Alternatives... Continued from page 21
Adverse events leading to medication discontinuation occurred in 115
patients (9.0%) taking dabigatran and
86 patients (6.8%) using warfarin.
Death, myocardial infarctions, and
abnormalities in liver function tests
were infrequent in both groups.
Dabigatran is also being studied for
the primary prevention of VTE in
patients undergoing elective total hip
and knee replacement surgeries, for
the prevention of atherothrombotic
events in patients with acute coronary
syndrome, and for stroke prevention
in atrial fibrillation.
Rivaroxaban for Recurrent VTE
In a second study, rivaroxaban
(Xarelto), the other direct oral factor
Xa inhibitor, was compared with
placebo in 1197 patients who had
completed 6 to 12 months of anticoagulant treatment for acute VTE. They
were randomized to rivaroxaban, 20
mg/day, or placebo for an additional
12 months.
Recurrent VTE event rates were
1.3% with rivaroxaban and 7.1% with
placebo—an 82% relative risk reduction. After the study medication was
stopped, 6 symptomatic recurrent VTE
events occurred in each group during
a 1-month observational period.
“There’s
probably
no more
dangerous drug
on the market
than warfarin.”
Bradford Schwartz, MD
Harry Büller, MD, lead investigator
and Professor of Medicine, Academic
Medical Center in Amsterdam, the
Netherlands, said that the ideal duration of VTE-related anticoagulation
event is still unknown. “The classical
way is 3 to 6 months,” he said.
Four patients treated with rivaroxaban and none receiving placebo had a
major bleeding episode, none of which
were fatal or in a critical site. Nonmajor
bleeding, such as nose bleeds, skin
hematoma, or blood in the urine,
occurred in 5.4% of the rivaroxaban
group and 1.2% of the placebo group.
Liver toxicity did not occur with
rivaroxaban. Continued study of a
previous factor Xa inhibitor, ximelagatran (Exanta), was halted after it was
found to be associated with significant
liver toxicity. ■
mobilization of HSC.
“The addition of plerixafor to G-CSF
predictably allows significantly more
patients to achieve the target cell collection within 1 day of apheresis compared with G-CSF alone,” said Brian J.
Bolwell, MD, of the Cleveland Clinic.
In a trial of patients with nonHodgkin’s lymphoma (NHL), 59.3% of
the patients in the plerixafor group collected sufficient CD34+ cells on day 1
of apheresis compared with 30.2% in
the placebo group. In a trial of patients
with myeloma, these percentages were
85.8% versus 58.5%, respectively. All
differences were very significant.
Ivana N. Micallef, MD, of the Mayo
Clinic, Rochester, MN, reported results
from patients in the plerixafor compassionate use program who failed/predicted to fail stem-cell collection with
any mobilization regimen, stratified
according to the presence or absence of
thrombocytopenia.
“We need to have a drug like this.
It’s a very good drug, and it reduces
the number of mobilization failures,”
said Dr Micallef. “We have shown that
50% of patients needed this drug, and
it has reduced our failure rate from
22% to about 5%.”
“It’s a very good drug…and it
has reduced our failure rate
from 22% to about 5%.”
—Ivana N. Micallef, MD
In another study, the cost of using
plerixafor was compared for patients
with NHL or Hodgkin’s lymphoma in
the expanded-access program versus
matched historical controls receiving
chemotherapy (cyclophosphamide)
plus G-CSF. The median cost of plerixafor plus G-CSF mobilization was not
higher than that of G-CSF plus
chemotherapy for HSC mobilization:
$19,644 versus $18,831. ■
Positive Long-Term Data for 2
ITP Treatments
By Wayne Kuznar
N
ew long-term data were presented at ASH for 2 new drugs
for the treatment of immune
thrombocytopenic purpura (ITP).
Romiplostim
Long-term follow-up of patients
with chronic ITP treated with romiplostim (Nplate), a peptibody protein
that increases platelet production,
shows maintenance of platelet counts
within the target range (50-200
103/µL) in an open-label study.
“This is the longest running ITP
extension study for a thrombopoietin
mimetic agent by far, with up to 5
years of continued romiplostim treatment,” said James Bussel, MD,
Professor, Platelet Disorders Center,
Division of Pediatric HematologyOncology, Weill Cornell Medical
College, New York City.
As of May 2009, 291 adults had been
treated with romiplostim for a median
of 2 years; 30 patients have been followed for >4 years. “The platelet
counts in general were very stable,”
said Dr Bussel. “The great majority of
patients maintained their dose, either
at their most frequent dose or within
2 µg/kg of their most frequent dose.”
Many patients receiving concurrent
ITP medications were able to taper the
doses or discontinue those other medications. “Rescue medication use was
less than 15% in most of the 12-week
periods during the study. This would
mean, on average…a rescue treatment
about once a year,” Dr Bussel said.
Most common adverse events were
headache (32%), nasopharyngitis (30%),
and confusion and fatigue (each 28%).
Twenty-six patients had venous or
arterial thrombotic events, with no correlation to the platelet count level. Two
of the 13 deaths in the study were possibly treatment-related, from unstable
angina or myocardial infarction.
In a European phase 3b study, romiplostim was compared with medical
standard of care (SOC). Romiplostim
reduced the rate of bleeding-related
episodes (BREs) and the need for intravenous immunoglobulin rescue in
nonsplenectomized adults with ITP.
“The risk of having a BRE was half as
likely in patients receiving romiplostim than in patients receiving the
SOC,” said Roberto Stasi, MD, of St
George’s Hospital, London. “Patients
22
February 2010
VOL. 3
NO. 1
SPECIAL ISSUE
AHDB_ASH_012010_ASCO Highlights Tabloid 2/16/10 1:57 PM Page C3
Other Highlights
Positive Long-Term Data...
receiving romiplostim spent more time
with platelet levels ≥50103/µL than
those receiving the SOC,” said Dr Stasi.
Eltrombopag
Long-term follow-up data were
also presented for ITP therapy with
eltrombopag (Promacta), an oral
thrombopoietin receptor agonist that
increases platelet production by increasing megakaryocyte proliferation.
The study included 299 patients who
were treated with eltrombopag.
Eltrombopag was started at 50
mg/day and adjusted to maintain
platelet counts within normal range.
The follow-up period extended to
104 weeks.
Overall, 86% of the patients achieved a platelet count of ≥50
103/µL. Response was similar between
splenectomized and nonsplenectomized patients.
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Median platelet counts increased to
≥50103/µL by week 2; 30% of the
patients were able to stop concomitant
ITP therapies. No treatment-related
deaths occurred.
“At this point, we have 2 very
promising drugs,” said Joel Anne
Chasis, MD, from the Lawrence
Berkeley National Laboratory, Berkeley, CA. “We can say that these drugs
are very effective in raising platelet
counts and maintaining these platelet
RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. postmarketing reports, the mean time to documented gastrointestinal perforation was 6
(range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and
WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS),
institute appropriate treatment for complaints of abdominal pain, especially early in the
SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL
course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of
LEUKOENCEPHALOPATHY (PML)
immunization with live viral vaccines following Rituxan therapy has not been studied and
Infusion Reactions: Rituxan administration can result in serious, including
vaccination with live virus vaccines is not recommended. Laboratory Monitoring
fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have
Because Rituxan binds to all CD20-positive B lymphocytes (malignant and nonoccurred. Approximately 80% of fatal infusion reactions occurred in
malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals
association with the first infusion. Carefully monitor patients during
during Rituxan therapy and more frequently in patients who develop cytopenias [see
infusions. Discontinue Rituxan infusion and provide medical treatment for
Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months
Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse
beyond the treatment period. ADVERSE REACTIONS The most common adverse
Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring
dialysis with instances of fatal outcome can occur in the setting of TLS reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion
following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious
[see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome,
Reactions: Severe, including fatal, mucocutaneous reactions can occur in mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other
patients receiving Rituxan [see Warnings and Precautions, Adverse viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation.
Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are
infection resulting in PML and death can occur in patients receiving Rituxan conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another
[see Warnings and Precautions, Adverse Reactions].
drug and may not reflect the rates observed in practice. The data described below reflect
®
INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan (rituximab) is exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up
indicated for the treatment of patients with: Relapsed or refractory, low-grade or to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n =
follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or
CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non–progressing DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion,
(including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after given as a single agent weekly for up to 8 doses, in combination with chemotherapy for
first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the
NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea,
WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting,
including fatal, infusion reactions. Severe reactions typically occurred during the first myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion
infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and reactions typically occurred within 30 to 120 minutes of beginning the first infusion and
sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, resolved with slowing or interruption of the Rituxan infusion and with supportive care
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion
ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate reactions was highest during the first infusion (77%) and decreased with each
patients with an antihistamine and acetaminophen prior to dosing. Institute medical subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections
management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than
reactions as needed. Depending on the severity of the infusion reaction and the required 5% of patients with NHL in the single-arm studies. The overall incidence of infections
interventions, consider resumption of the infusion at a minimum 50% reduction in rate was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and
after symptoms have resolved. Closely monitor the following patients: those with pre- Precautions.] In randomized, controlled studies where Rituxan was administered
existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary following chemotherapy for the treatment of follicular or low-grade NHL, the rate of
adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/ infection was higher among patients who received Rituxan. In diffuse large B-cell
mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor lymphoma patients, viral infections occurred more frequently in those who received
Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving
hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of
12–24 hours after the first infusion. Fatal TLS cases have occurred after administration patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%),
of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was
confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A
high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences
administer supportive care, including dialysis as indicated. [See Boxed Warning.] of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In
Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of
outcome, can occur in patients treated with Rituxan. These reactions include patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these
paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients
vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in
has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan
who experience a severe mucocutaneous reaction. The safety of readministration of 375 mg/m2 weekly for 4 doses.
Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Table 1
Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, Low-Grade
(PML) JC virus infection resulting in PML and death can occur in Rituxan-treated or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b
patients with hematologic malignancies or with autoimmune diseases. The majority of
All Grades (%) Grade 3 and 4 (%)
All Grades (%) Grade 3 and 4 (%)
patients with hematologic malignancies diagnosed with PML received Rituxan in Any Adverse Events
99
57
Respiratory System
38
4
Body as a Whole
86
10
Increased Cough
13
1
combination with chemotherapy or as part of a hematopoietic stem cell transplant. The
Fever
53
1
Rhinitis
12
1
Chills
33
3
Bronchospasm
8
1
patients with autoimmune diseases had prior or concurrent immunosuppressive therapy.
Infection
31
4
Dyspnea
7
1
Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan.
Asthenia
26
1
Sinusitis
6
0
Headache
19
1
Metabolic and Nutritional
Consider the diagnosis of PML in any patient presenting with new-onset neurologic
Abdominal Pain
14
1
Disorders
38
3
Pain
12
1
Angioedema
11
1
manifestations. Discontinue Rituxan and consider discontinuation or reduction of any
Back Pain
10
1
Hyperglycemia
9
1
concomitant chemotherapy or immunosuppressive therapy in patients who develop
Throat Irritation
9
0
Peripheral Edema
8
0
Flushing
5
0
LDH Increase
7
0
PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Heme and Lymphatic System 67
48
Digestive System
37
2
Lymphopenia
48
40
Nausea
23
1
Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death
Leukopenia
14
4
Diarrhea
10
1
can occur in patients with hematologic malignancies treated with Rituxan. The median
Neutropenia
14
6
Vomiting
10
1
Thrombocytopenia
12
2
Nervous System
32
1
time to the diagnosis of hepatitis was approximately 4 months after the initiation of
Anemia
8
3
Dizziness
10
1
44
2
Anxiety
5
1
Rituxan and approximately one month after the last dose. Screen patients at high risk of Skin and Appendages
Night Sweats
15
1
Musculoskeletal System
26
3
HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for
Rash
15
1
Myalgia
10
1
Pruritus
14
1
Arthralgia
10
1
clinical and laboratory signs of active HBV infection for several months following Rituxan
Urticaria
8
1
Cardiovascular System
25
3
therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who
Hypotension
10
1
Hypertension
6
1
develop viral hepatitis, and institute appropriate treatment including antiviral therapy.
Insufficient data exist regarding the safety of resuming Rituxan in patients who develop aAdverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by
hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Infections Rituxan is NCI-CTC criteria.
not recommended for treatment of patients with severe active infections. The following In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to
additional serious viral infections, either new, reactivated, or exacerbated, have been 6 months after Rituxan infusion. Rituxan in Combination With Chemotherapy
identified in clinical studies or postmarketing reports. The majority of patients received Adverse reactions information below is based on 1250 patients who received Rituxan in
Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell combination with chemotherapy or following chemotherapy. Rituxan in Combination
transplant. These viral infections included cytomegalovirus, herpes simplex virus, With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm
parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, experienced a higher incidence of infusional toxicity and neutropenia compared to
the viral infections occurred as late as one year following discontinuation of Rituxan and patients in the CVP arm. The following adverse reactions occurred more frequently
have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough
for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%),
and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following
or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, adverse reactions were reported more frequently (≥5%) in patients receiving Rituxan
including fatal, renal toxicity can occur after Rituxan administration in patients with following CVP compared to patients who received no further therapy: fatigue (39% vs.
hematologic malignancies. Renal toxicity has occurred in patients with high numbers of 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections
circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%),
lysis syndrome and in patients with NHL administered concomitant cisplatin therapy rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs.
during clinical trials. The combination of cisplatin and Rituxan is not an approved 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more
treatment regimen. Use extreme caution if this non-approved combination is used in frequently (≥2%) in the Rituxan arm compared with those who received no further
clinical trials and monitor closely for signs of renal failure. Consider discontinuation of therapy (4% vs. 1%). Rituxan in Combination With Chemotherapy for DLBCL In
Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Studies 6 and 7, the following adverse reactions, regardless of severity, were reported
Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to
to death, can occur in patients receiving Rituxan in combination with chemotherapy. In CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder
counts. The questions that still remain
are—what about thrombosis, what
about the development of reticulin
in the marrow, and what about
the development of hematologic
malignancies.” ■
(29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies
was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions.
In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or
tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP
vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more
frequently among patients in the R-CHOP arm compared with those in the CHOP arm:
thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4
adverse reactions occurring more frequently among patients receiving
R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study
8). Immunogenicity As with all therapeutic proteins, there is a potential for
immunogenicity. The observed incidence of antibody (including neutralizing antibody)
positivity in an assay is highly dependent on several factors including assay sensitivity
and specificity, assay methodology, sample handling, timing of sample collection,
concomitant medications, and underlying disease. For these reasons, comparison of the
incidence of antibodies to Rituxan with the incidence of antibodies to other products may
be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was
detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving singleagent Rituxan. Three of the four patients had an objective clinical response. The clinical
relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing
Experience The following adverse reactions have been identified during post-approval
use of Rituxan in hematologic malignancies. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to drug exposure. Decisions to
include these reactions in labeling are typically based on one or more of the following
factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of
causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia,
and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s
macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis,
optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness,
polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including
progressive multifocal leukoencephalopathy (PML), increase in fatal infections in
HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4
infections in patients with previously treated lymphoma without known HIV infection.
Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous
reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal
bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis).
DRUG INTERACTIONS Formal drug interaction studies have not been performed with
Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no
adequate and well-controlled studies of rituximab in pregnant women. Postmarketing
data indicate that B-cell lymphocytopenia generally lasting less than six months can
occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the
serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that
requires treatment. Rituximab should be used during pregnancy only if the potential
benefit to the mother justifies the potential risk to the fetus. Reproduction studies in
cynomolgus monkeys at maternal exposures similar to human therapeutic exposures
showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced
in the offspring of treated dams. The B-cell counts returned to normal levels, and
immunologic function was restored within 6 months of birth. Nursing Mothers It is not
known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the
milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published
data suggest that antibodies in breast milk do not enter the neonatal and infant
circulations in substantial amounts. The unknown risks to the infant from oral ingestion
of Rituxan should be weighed against the known benefits of breastfeeding. Pediatric
Use The safety and effectiveness of Rituxan in pediatric patients have not been
established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL
evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in
combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123
(13%) were age 75 or greater. No overall differences in effectiveness were observed
between these patients and younger patients. Cardiac adverse reactions, mostly
supraventricular arrhythmias, occurred more frequently among elderly patients. Serious
pulmonary adverse reactions were also more common among the elderly, including
pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma
Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not
include sufficient numbers of patients aged 65 and over to determine whether they
respond differently from younger subjects. OVERDOSAGE There has been no experience
with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been
given in dose-escalation clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis,
Mutagenesis, Impairment of Fertility No long-term animal studies have been
performed to establish the carcinogenic or mutagenic potential of Rituxan, or to
determine potential effects on fertility in males or females. PATIENT COUNSELING
INFORMATION Patients should be provided the Rituxan Medication Guide and provided
an opportunity to read prior to each treatment session. Because caution should be
exercised in administering Rituxan to patients with active infections, it is important that
the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and
any questions resulting from the patient’s reading of the Medication Guide be discussed.
Rituxan is detectable in serum for up to six months following completion of therapy.
Individuals of childbearing potential should use effective contraception during treatment
and for 12 months after Rituxan therapy.
Revised 10/2009 (4851501)
Jointly Marketed by:
Biogen Idec Inc. 5200 Research Place San Diego, CA 92122
Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990
©2009 Biogen Idec Inc. and Genentech, Inc. 7140918 November 2009
www.AHDBonline.com
23
11:27:51 PM
AHDB_ASH_012010_ASCO Highlights Tabloid 2/17/10 1:26 PM Page C4
Across approved NHL indications
DRIVING BETTER
OUTCOMES IN NHL
PROVEN OUTCOMES ACROSS MULTIPLE ENDPOINTS1-3
In the GELA trial1‡
In the Marcus trial 1
In the E1496 trial 1
At 5 years, OS
increased from
46% with CHOP
alone to 58%
with R-CHOP
At 1.5-year median
follow-up, there was
a 71% improvement
in median PFS
(2.4 years R-CVP vs
1.4 years CVP alone)
At 2.3-year median
follow-up, there was a
51% reduction in the risk
of relapse, progression,
or death with CVP→R
vs CVP alone (p≤0.05)
Indications
RITUXAN® (Rituximab) is indicated for the treatment of patients with:
Relapsed or refractory, low-grade or follicular, CD20-positive,
B-cell NHL as a single agent
Weekly ×4
Weekly ×8
Bulky disease
Retreatment
Previously untreated follicular, CD20-positive, B-cell NHL in
combination with CVP chemotherapy
Across DLBCL trials in patients ≥60 years of age, the following
Grade 3 or 4 adverse reactions were reported more frequently among
patients in the R-CHOP arm compared with those in the CHOP arm:
thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other
Grade 3 or 4 adverse reactions reported more frequently among
patients receiving R-CHOP were viral infection and neutropenia. In
the Marcus trial of first-line follicular NHL, patients in the R-CVP
arm had higher incidences of infusional toxicity (71% vs 51%) and
Grade 3–4 neutropenia (24% vs 14%) as compared with those in the
CVP arm. In the E1496 trial of low-grade NHL, neutropenia was the
only Grade 3 or 4 adverse event that occurred more frequently (≥2%)
in the RITUXAN arm compared with those who received no further
therapy (4% vs 1%).
BOXED WARNINGS and
Additional Important Safety Information
The most important serious adverse reactions of RITUXAN are
fatal infusion reactions, tumor lysis syndrome (TLS),
severe mucocutaneous reactions, progressive multifocal
leukoencephalopathy (PML), hepatitis B reactivation with fulminant
hepatitis, other viral infections, cardiovascular events, renal toxicity,
and bowel obstruction and perforation. The most common adverse
©2009 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved.
10021800
Non-progressing (including stable disease), low-grade,
CD20-positive B-cell NHL, as a single agent, after first-line CVP
chemotherapy
Previously untreated diffuse large B-cell, CD20-positive
NHL in combination with CHOP or other anthracycline-based
chemotherapy regimens
reactions of RITUXAN (incidence ≥25%) observed in patients with NHL
are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.
For additional safety information, please see following page for
brief summary of prescribing information, including BOXED
WARNINGS and Medication Guide.
Attention Healthcare Provider: Provide Medication Guide to
patient prior to RITUXAN infusion.
*In the ECOG 4494 and MInT DLBCL trials, 2-year OS was R-CHOP 74% vs CHOP
63% (p<0.05) and R-CHEMO 95% vs CHEMO 86% (p<0.05), respectively.1
†
Improvement in overall PFS was calculated using the formula (1–HR)/HR.
‡
R-CHOP improved the primary endpoint of median event-free survival by 164%
(2.9 years vs 1.1 years) vs CHOP alone.1
NHL=non-Hodgkin’s lymphoma; DLBCL=diffuse large B-cell lymphoma; R=RITUXAN;
CHOP=cyclophosphamide, doxorubicin, vincristine, and prednisone; OS=overall survival;
GELA=Groupe d’Etude des Lymphomes de l’Adulte; CVP=cyclophosphamide, vincristine, and
prednisone; PFS=progression-free survival; HR=hazard ratio; ECOG=Eastern Cooperative
Oncology Group; MInT=MabThera® (Rituximab) International Trial; CHEMO=CHOP, CHOEP
(CHOP+etoposide), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine,
prednisone, and bleomycin) biweekly, or PMitCEBO (prednisolone, mitoxantrone,
cyclophosphamide, etoposide, bleomycin, and vincristine) biweekly.
References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2009. 2. Coiffier B,
Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP
chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk
patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 3. Marcus R, Imrie K, Solal-Céligny P,
et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in
patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008;26:4579-4586.
December 2009

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