17th Annual International Congress on Hematologic Malignancies : Focus on Leukemias, Lymphomas,

17th Annual International Congress
on Hematologic Malignancies®:
Focus on Leukemias, Lymphomas,
and Myeloma
Meeting in a Box
MULTIPLE MYELOMA
What Can We Learn From Multiple
Myeloma Genomic Analysis?
Nikhil Munshi, MD
Genomic Analysis Takeaways
•
Methods of genomic analysis
– Established techniques: cytogenetics, FISH
– Emerging techniques: RNA- and DNA-based arrays, transcriptprocessing arrays, genomic sequencing, and proteomics
•
Current goals of genomic analysis in myeloma
– Understand the biology of myeloma
– Identify risk categories to improve prognostication
– Identify and validate novel targets
– Develop biologic agents that target the myeloma cell
– Ultimately, develop personalized therapy
•
Currently, gene expression profiling has prognostic value, predicting
survival of patients with different genomic signatures, but it cannot yet
predict response to therapy.
High-Risk Smoldering Myeloma –
Should We Intervene Early?
Ola Landgren, MD, PhD
Smoldering Myeloma
•
Definition of smoldering myeloma1
– Serum monoclonal IgG or IgA ≥ 3 g/dL and/or clonal bone marrow
plasma cells ≥ 10% AND
– Absence of end-organ damage (ie, hypercalcemia, renal
insufficiency, anemia, or bone lesions attributed to plasma cell
proliferative disorder)
•
Overall risk of progression2
– 10% per year in years 0-5
– 3% per year in years 6-10
– 1% per year in years 11-20
•
Risk stratification
– Mayo Clinic analysis3 stratifies patients according to their 5-yr risk of
progression into 3 groups: 25% risk, 51% risk, and 76% risk
– PETHEMA Study Group analysis4 stratifies patients according to
their 5-yr risk of progression into 3 groups: 4% risk, 46% risk, and
1Kyle RA, et al. Leukemia. 2010;24:1121-7.
72% risk
2
e
Kyle RA, et al. N Engl J Med. 2007;356:2582-90.
3Dispenzieri A, et al. Blood. 2008;111:785-9.
4Perez-Persona E, et al. Blood. 2007;110:2586-92.
First Randomized Phase III Trial
for Smoldering Myeloma
Randomization of high-risk smoldering MM patients:
Lenalidomide 25 mg/day,
D1-21
Dexamethasone
20 mg D1-D4 and D12-D15
Lenalidomide 10 mg/day,
D1-21 every 2 months
Induction:
Nine 28-day cycles
Therapeutic abstention
Maintenance:
Until progression
Therapeutic abstention
Primary endpoint: time to progression to symptomatic MM
Secondary endpoints: ORR, DOR, PFS, OS, and safety and tolerability
Median time to symptomatic progression
Len/dex: not yet reached
Observation: 21 months
HR = 5.67; P < .0001
4-year overall survival
Len/dex: 94%
Observation: 85%
HR = 3.5; P < .01
Mateos MV, et al. ASH 2011. Abstract 991.
Smoldering Myeloma Takeaways
•
Current clinical recommendation for smoldering myeloma: no treatment
unless part of a clinical trial1
•
Better understanding of pathogenesis from MGUS to myeloma needed:
– To develop better biological markers
– To predict a patient’s risk of progression
– To develop early intervention strategies
1Kyle
R, et al. Int’l Myeloma Working Group. Leukemia 2010.
Current Trends:
Treatment Strategies for Newly
Diagnosed Elderly Patients With Myeloma
James Berenson, MD
Dexamethasone ± Lenalidomide
SWOG S0232
Len + Dex (n = 97)
Dexamethasone (n = 95)
Len: 25 mg/day, D1-28
Placebo: 25 mg/day, D1-28
Dex: 40 mg/day, D1-4, 9-12, 17-20
Dex: 40 mg/day, D1-4, 9-12, 17-20
Three 35-day cycles
Three 35-day cycles
Disease
progression
Responding/stable
disease
Len + Dex
Dexamethasone
Unblinded Treatment
Len: 25 mg/day, D1-21
Placebo: 25 mg/day, D1-21
Len: 25 mg/day, D1-28
Dex: 40 mg/day, D1-4 and 15-18
Dex: 40 mg/day, D1-21
Dex: 40 mg/day, D1-4, 9-12, 17-20
28-day cycles until progression
28-day cycles until progression
Three 35-day cycles
Objective: to determine the efficacy and safety of Len + Dex
as induction therapy in NDMM patients
Unblinded Len + Dex
Primary endpoint: PFS
Dex: 40 mg/day, D1-4 and 15-18
Len: 25 mg/day, D1-21
Zonder JA, et al. Blood. 2010;116:5838-41.
Dexamethasone ± Lenalidomide
SWOG S0232
90
80
Patients (%)
70
ORR = 78%
15
ORR, P < .0001
VGPR, P < .001
PR
60
ORR = 48%
50
37
VGPR
CR
40
32
30
20
10
26
4
0
Len + dex
•
12
Placebo + dex
1-yr PFS was significantly improved with the addition of lenalidomide
(78% vs 53%; P = .002)
Zonder JA, et al. Blood. 2010;116:5838-41.
Lenalidomide + High-Dose Dex vs
Lenalidomide + Low-Dose Dex: ECOG E4A03
Lenalidomide + High-Dose Dexamethasone (RD)a
Len: 25 mg/day, days 1-21
Transplant-eligible
patients can
proceed to SCT
Dex: 40 mg/day, days 1-4, 9-12, 17-20
(n = 223)
Four 28-day cycles
Lenalidomide + Low-Dose Dexamethasone (Rd)
Len: 25 mg/day, days 1-21
Continue therapy until
disease progression
Dex: 40 mg/day, days 1, 8, 15, 22
(n = 222)
Objective: to assess if a reduced dose of dex decreases toxicity while maintaining efficacy
Primary endpoint: ORR after first 4 cycles
aBased
on the superiority of the Rd regimen, the study was stopped at a median
follow-up of 12.5 months and patients in the RD arm crossed over to Rd therapy.
Arm
1-yr OS
2-yr OS
RD (high-dose)
87%
75%
Rd (low-dose)
96%
87%
Survival significantly improved
with Rd (low-dose) regimen (P =
.0002 at 1 year)
Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
MP ± Bortezomib: VISTA
► Endpoints: Primary: TTP; Secondary: CR, ORR, TTR, DOR, PFS, TNT, OS, QoL
Previously untreated patients;
not candidates for transplant
► Study Schema:
ARM A (VMP)
R
A
N
D
O
M
I
Z
E
VMP: Four 6-week cycles: Cycles 1-4
Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22, 25, 29, 32;
Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4
– 682 patients randomized
Followed by five 6-week cycles: Cycles 5-9
Bortezomib 1.3mg/m2 days 1, 8, 22, 29; Melphalan 9mg/m2 and
prednisone 60mg/m2 once daily on days 1–4
Max of 9 cycles (total 54 weeks) in both arms
151 centers

22 countries worldwide
– IDMC recommended study stop in
September 2007 based on protocolspecified interim analysis
– VMP was significantly superior for all
efficacy endpoints
ARM B (MP)
MP: Nine 6-week cycles: Cycles 1-9
Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4
Efficacy Parameter

Lenalidomide
Placebo
HR
P Value
Median TTP, months
24.0
16.6
0.483
< .000001
Median OS, months
NR
NR
0.61
.008
•
3-yr OS: 72% in VMP arm vs 69.5% in MP arm
San Miguel J, et al. N Engl J Med. 2008;359:906-17.
Mateos MV, et al. J Clin Oncol. 2010;28:2259-66.
Phase II Studies for Newly Diagnosed
Multiple Myeloma
Regimen
Drugs
ORR
CR
Cybor-D1
cyclophosphamide + bortezomib + dex
93%
39%
DVD2
bortezomib + pegylated liposomal doxorubicin + dex
86%
20%
VRD3
bortezomib + lenalidomide + dex
100%
37%
BAM4
bortezomib + ascorbic acid + melphalan →
maintenance bortezomib
74%
13%
BiRD5,6
clarithromycin + lenalidomide + high-dose dex
90%
39%
CRd7
carfilzomib 27 mg/m2 + lenalidomide + dex
100%
85%
CYCLONE8
carfilzomib + cyclophosphamide + thalidomide + dex
96%
29%
CMP9
carfilzomib + melphalan + prednisone
89%
3%
1Reeder
CB, et al. ASCO 2008. Abstract 8517.
JR, et al. Br J Haematol. 2011;155:580-7.
3Richardson PG, et al. Blood. 2009;114:501-2.
4Berenson JR, et al. Eur J Haematol. 2009;82:433-9.
5Niesvizky R, et al. Blood. 2008;111:1101-9.
6Rossi A, et al. ASCO 2011. Abstract 8008.
7Jakubowiak AJ, et al. Blood. 2012;120:1801-9.
8Mikhael J, et al. ASCO 2012. Abstract 8010.
9Kolb B, et al. ASCO 2012. Abstract 8009.
2Berenson
Novel Combinations and New Drugs
for Elderly Patients With Myeloma
•
•
Approved drugs
‒
Novel combinations
‒
Modifications of dose and schedule

Improve efficacy

Better tolerability
Drugs in development
‒
‒
Similar targets

Proteasome inhibitors - carfilzomib (FDA-approved!), ixazomib

IMiDs - pomalidomide (FDA-approved!)
New classes of agents

Monoclonal antibodies - anti-CS-1 (elotuzumab), anti-CD40
(dacetuzumab), anti-CD38

mTOR inhibitors - temsirolimus

PI3K inhibitors - perifosine

HDAC inhibitors - vorinostat, romidepsin, panobinostat
Maintenance Therapy –
Is It for Everyone?
Nikhil Munshi, MD
Maintenance Therapy for Multiple Myeloma
•
Maintenance therapy:
– Purpose is to prolong remission duration and life expectancy
– Requires periodic follow-up to monitor toxicity and response
•
Patient must have:
– Disease that is in remission (undetectable or at a low level)
– Recovered from all previous toxicities
•
Maintenance agent must have:
– Minimal toxicity or at least not overlapping with the toxicity of the
induction regimen
– Convenient dosing
– Convenient route of administration
Lenalidomide Maintenance After
Transplant: CALGB 100104
Restaging
Days 90–100
Registration
D-S Stage 1-3, < 70 years
> 2 cycles of induction
Attained SD or better
 1 yr from start of therapy
> 2 x 106 CD34 cells/kg
Efficacy Parameter
Median TTP, months
3-yr OS
Randomization
Placebo
Mel 200
ASCT
CR
PR
SD
Lenalidomide
10 mg/d with
↑↓ (5–15 mg)
Lenalidomide
Placebo
HR
P Value
46
27
--
< .0001
88%
80%
0.62
.027
McCarthy PL, et al. N Engl J Med. 2012;366:1770-81.
Lenalidomide Maintenance Following
Lenalidomide Consolidation: IFM 2005-02
Phase III randomized, placebo-controlled trial
N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008
Patients age < 65 years, with nonprogressive disease, ≤ 6 months after ASCT in first line
Randomization: stratified according to Beta-2m, del13, VGPR
Consolidation:
Lenalidomide alone 25 mg/day po
days 1-21 of every 28 days for 2 months
Arm A = Placebo
(N=307)
until relapse
Arm B = Lenalidomide
(N=307)
10-15 mg/d until relapse
Primary endpoint: PFS
Secondary endpoints: CR rate, TTP, OS, feasibility of long-term lenalidomide…
•
PFS significantly prolonged with lenalidomide maintenance compared with
placebo (41 vs 24 months; P < 10-9)
•
OS not significantly different between groups (P = .79)
Attal M, et al. Proc International Myeloma Workshop 2011.
McCarthy P, et al. Proc International Myeloma Workshop 2011.
Lenalidomide Maintenance in Patients
Ineligible for Transplant: MM-015
Open-Label
Extension Phase
Double-Blind Treatment Phase
RANDOMIZATION
Cycles (28 day) 1-9
MPR-R
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
MPR
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
MP
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
PBO: days 1 -21
•
•
Cycles 10+
Maintenance
Lenalidomide
10 mg/day
days 1 -21
Placebo
Disease
Progression
Lenalidomide
(25 mg/day)
+/Dexamethasone
Placebo
PFS significantly prolonged with the addition of lenalidomide
maintenance following MPR induction therapy (HR = 0.349; P < .001)
PFS benefit maintained across patient subgroups
Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
Maintenance Lenalidomide and
Second Primary Malignancies
•
Both CALGB 100104 and IFM 2005-002 showed increased risk of
second primary malignancies compared with placebo (23 vs 6 and 18
vs 4, respectively)1,2
•
MM-015 also showed increase in frequency of second primary
malignancies with lenalidomide use (n=12, MPR-R; n=10, MPR;
n=4, MP)
1Attal
2McCarthy
M, et al. Proc International Myeloma Workshop 2011.
P, et al. Proc International Myeloma Workshop 2011.
3Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
PAD + Bortezomib Maintenance vs VAD +
Thalidomide Maintenance: HOVON Trial
MM Stage II or III, Age 18–65
Randomization
3 x PAD
3 x VAD
CAD + GCSF
MEL 200 + PBSCT
Doxorubicin
9 mg/m2
Dexameth
40 mg
MEL 200 + PBSCT
Allogeneic
Tx
In GMMG 2nd
MEL 200 + PBSCT
Bortezomib maintenance
1.3 mg/m2/2 weeks for 2 yrs
Thalidomide maintenance
50 mg/day for 2 yrs
Efficacy Parameter
1.3 mg/m2 IV
CAD + GCSF
MEL 200 + PBSCT
In GMMG 2nd
Bortezomib
PAD → bortezomib
VAD → thalidomide
P Value
3-yr PFS
48%
42%
.005
3-yr OS
78%
71%
.02
Sonneveld P, et al. ASH 2010. Abstract 40.
Bortezomib + Thalidomide vs Bortezomib +
Prednisone as Maintenance: GEM2005MAS65
Series of 260 elderly untreated MM patients included in the GEM2005 Spanish trial
Bort/Mel/Pred
(VMP)
Induction
(6 cycles)
Maintenance
vs
Bort/Thal/Pred
(VTP)
Bort/Thal
Bort/Pred
Bort/Thal
Bort/Pred
(VT)
(VP)
(VT)
(VP)
No significant differences between VMP and VTP in ORR
(80% and 81%) and CR rate (20% and 27%)
Arm
ORR
CR
Median PFS
VT maintenance
95%
46%
39 months
VP maintenance
97%
39%
32 months
Mateos MV, et al. Lancet Oncol. 2010;10:934-41.
Conclusions About Maintenance Therapy
for Multiple Myeloma
•
Maintenance therapy prolongs PFS.
•
Low-dose oral agents preferable for maintenance therapy.
•
Both bortezomib and lenalidomide are useful maintenance agents and
may need to be combined for patients with high-risk disease.
•
Slight increase in incidence of secondary malignancy after lenalidomide
maintenance.
•
Overall, everyone who meets prerequisites for maintenance therapy
should be considered candidates for treatment.
How to Best Use New Proteasome
Inhibitors and IMiDs in Myeloma
Sundar Jagannath, MD
Pivotal Trial of Immunomodulatory Agent
Pomalidomide: MM-002
Randomization
• Primary endpoint: PFS
• Secondary endpoints: ORR, DOR, OS, and safety
POM (4 mg days 1–21
of 28-day cycles)
Progressive
disease
POM (4 mg days 1–21 of
28-day cycles) +
LoDEXa (40 mg/week)
Aspirin (80–100 mg) or equivalent mandated for all patients.
aPatients aged > 75 yrs had starting DEX dose of 20 mg/week.
Option to add
LoDEXa
(40 mg/week)
Progressive
disease
Progressive
disease
Discontinue
and followup for
survival and
subsequent
treatment
MM-002: Response Rates
•
Median number of cycles received = 5 (range, 1-28)
•
Disease control rate = 81% overall
POM + LoDEX
(n=113)
POM
(n=108)
ORR (%)
34
15
CR (%)
3
1
PR (%)
31
14
MR (%)
12
16
SD (%)
37
48
PD (%)
6
10
Median time to ORR, months
1.9
3.7
Median duration of response,
months
8.3
8.8
Response
Jagannath S, et al. ASH 2012. Abstract 450.
MM-002: PFS, OS, and Safety
Efficacy Parameter
POM + LoDEX
POM
HR
P Value
Median PFS, months
4.6
2.6
0.67
.002
Median OS, months
16.5
13.6
0.92
.609
Age ≤ 65 years
Age > 65 years
Grade 3/4 AEs ≥ 20%
POM + LoDEX
(n=61)
POM
(n=68)
POM + LoDEX
(n=51)
POM
(n=39)
Hematologic
Neutropenia
Anemia
Thrombocytopenia
46
26
18
40
24
24
35
18
20
59
26
21
Nonhematologic
Pneumonia
Dyspnea
16
7
10
7
29
20
21
8
•
Other AEs of clinical relevance in POM +/- LoDEX:
– Febrile neutropenia: 3%
– Peripheral neuropathy (grade1/2): 13% (none > grade 2)
– DVT: 2%
Jagannath S, et al. ASH 2012. Abstract 450.
Pomalidomide + Low-Dose DEX vs
High-Dose DEX: MM-003
28-day cycles
RANDOMIZATION 2:1
(n = 302)
POM:
4 mg/day D1-21 +
LoDEX:
40 mg (≤ 75 yrs)
20 mg (> 75 yrs)
D1, 8, 15, 22
PD* or
intolerable AE
(n = 153)
HiDEX:
40 mg (≤ 75 yrs)
20 mg (> 75 yrs)
D1-4, 9-12, 17-20
PD*
Follow-up for OS
and SPM until
5 years post
enrollment
Companion trial
MM-003C
POM 21/28 days
Thromboprophylaxis indicated for those receiving POM or with DVT history
Stratification
•
•
•
Age (≤ 75 vs > 75 yrs)
Number of prior Tx ( 2 vs > 2)
Disease population
*Progression of disease independently adjudicated in real-time
MM-003: PFS and OS
POM + LoDEX
n = 302
HiDEX
n=153
HR
P Value
Median PFS, months
ITT population
Refractory to bortezomib
Refractory to lenalidomide
Refractory to both
3.6
3.6
3.7
3.2
1.8
1.8
1.8
1.7
0.45
0.47
0.38
0.48
< .001
< .001
< .001
< .001
Median OS, months
ITT population
Refractory to bortezomib
Refractory to lenalidomide
Refractory to both
NR
NR
NR
NR
7.8
8.1
8.6
7.4
0.53
0.56
0.39
0.56
< .001
.037
.003
.003
Arm
Dimopoulos MA, et al. ASH 2012. Abstract LBA-6.
Pivotal Trial of Proteasome Inhibitor
Carfilzomib: 003-A1
MM: Progressive disease
> 2 prior therapy lines
including bortezomib, thalidomide
or lenalidomide,
an alkylating agent,
and anthracycline alone or in
combination
003-A0
003-A1
Carfilzomib
Carfilzomib
20 mg/m2 days 1, 2, 8, 9, 15, 16
every 28 days
N = 46
Dose escalation to 27 mg/m2
after cycle 1 up to 12 cycles
N = 266
Primary Endpoint: ORR
Secondary Endpoints: clinical benefit rate (≥ minimal response), DOR, PFS,
OS, and safety
Single-Agent Carfilzomib Pivotal Trial:
Efficacy
Response
Carfilzomib
(N=257)
ORR
24%
Clinical benefit rate
34%
Duration of response
8.3 months
Median PFS
3.7 months
Median OS
15.6 months
Siegel DS, et al. Blood. 2012;120:2817-25.
Single-Agent Carfilzomib Pivotal Trial:
Safety
Adverse Event
•
Grade 3/4 AEs
N =266
Hematologic
Anemia
Thrombocytopenia
Lymphopenia
Neutropenia
24%
29%
20%
11%
Nonhematologic
Fatigue
Dyspnea
Upper respiratory tract infection
Headache
7.5%
3.4%
4.5%
1.9%
Other
Febrile neutropenia
Peripheral neuropathy
0.8%
1.1%
Other AEs (any grade) of clinical relevance:
– Dyspnea in 34%; 17% due to carfilzomib
– CHF in 3.8%; myocardial infarction or cardiac arrest in 2.3%
Siegel DS, et al. Blood. 2012;120:2817-25.
Multiple Myeloma Takeaways
•
Genomic analysis is an important area of research that is expanding
rapidly, but to date it has had limited use in the myeloma clinic, restricted
to its ability to predict survival on the basis of gene expression profiling.
•
Active monitoring remains optimal approach for smoldering myeloma,
although this may change in the future with further examination of
lenalidomide/dexamethasone treatment.
•
Elderly patients with newly diagnosed multiple myeloma can be treated
with a number of distinct regimens, depending on their comorbidities and
performance status. These include lenalidomide/low-dose dexamethasone
and VMP (bortezomib, melphalan, and prednisone).
•
Maintenance therapy with a convenient, low-toxicity regimen is suggested
for all myeloma patients meeting the following criteria: achievement of
remission and no ongoing toxicity.
•
Proteasome inhibitor carfilzomib and IMiD pomalidomide recently granted
accelerated approval by FDA for treatment of relapsed/refractory
myeloma, on the basis of promising response rates, and PFS and OS
results in this heavily pretreated population.
LYMPHOMA
Initial Management of Peripheral T-Cell
Lymphoma: If CHOP Is No Good, What Is?
Steven M. Horwitz, MD
Peripheral T-Cell Lymphoma Summary
•
With PTCL, first-line CHOP produces ORR of 60-80+%, CR of 30-60+%,
and durable remissions <20-30%. For most patients, CHOP is inadequate.
•
Adding therapy to a CHOP backbone is feasible but: (1) benefit not
equivalent in all subtypes,1 and (2) toxicity soon outweighs benefit
because regimen operating near MTD.2,3
•
ASCT has shown promise in some upfront trials with PTCL.4,5
•
Potential approaches to explore:
‒ CHOP + etoposide
‒ CHOP + novel agent (ie, brentuximab data very encouraging)
‒ CHOP → maintenance therapy
‒ ASCT
‒ Entirely new regimen
•
Current standard of care should be clinical trial, whenever possible.
1Kim
2Kim
SJ. Eur J Cancer. 2012;48:3223-31.
JG, et al. Cancer Chemother Pharmacol. 2007;60:129-34.
3Gallamini A, et al. Blood. 2007;110:2316-23.
4Reimer P, et al. J Clin Oncol. 2009;27:106-13.
5d’Amore F, et al. J Clin Oncol. 2012;30:3093-9.
Management of Cutaneous T-Cell
Lymphoma
Lauren Pinter-Brown, MD, FACP
•
Treatment and Supportive Care of
Cutaneous T-Cell Lymphoma
Treatment of mycosis fungoides and Sezary’s syndrome generally involves
skin-directed therapy for early-stage (IA-IIA) and systemic therapy for later
stages (≥IIB) or when skin-directed therapy fails.
‒ Skin-directed therapies: topical agents (corticosteroids, imiquimod,
chemotherapy, retinoids), phototherapy, radiation therapy
‒ Systemic therapies: extracorporeal photochemotherapy, retinoids,
interferon-alpha or gamma, alemtuzumab, denileukin diftitox (not
currently available), HDAC inhibitors, chemotherapy
•
Treatment considerations: stage, route (oral vs topical vs systemic), rapidity
of response, availability (geographically or due to cost), and comorbidities
•
Supportive care:
‒ Pruritus: distinguish generalized from localized; treat with moisturizers,
emollients, and barrier protection, as well as topical steroids,
camphor/menthol, others
‒ Infection: crucial to avoid central lines and maintain skin barrier.
Consider bleach baths.
Treatment of
CD30+ Lymphoproliferative Disorders
• Lymphomatoid papulosis:
‒ Treatment options: watch and wait (most cases), methotrexate,
phototherapy, interferon
‒ Rapid relapse off treatment, so maintenance therapy necessary
‒ 10%-20% of these cases associated with Hodgkin lymphoma,
mycosis fungoides, or ALCL, so follow-up required
• Primary cutaneous ALCL:
‒ Treatment options: skin-directed therapy, surgical resection, XRT,
chemotherapy only with extracutaneous involvement (CHOP not
recommended), retinoids, interferon, thalidomide, steroids, excimer
laser.
‒ 90% 5-year overall survival
‒ Spontaneous remission possible
How I Manage Early-Stage
Diffuse Large B-Cell Lymphoma
Daniel O. Persky, MD
Current Treatment Paradigm
for Early-Stage DLBCL
• Early-stage DLBCL is curable malignancy, with >50% cure rate and
a 70%-90% 5-year OS.1
‒ Differences in outcomes arise from variations in radiation therapy quality
and patient selection
‒ Early-stage disease has pattern of late relapses
• Addition of rituximab to chemotherapy modestly improved PFS
outcomes in early-stage disease, but has not improved OS.2,3
• Another option for early-stage DLBCL is R-CHOP x 3-4 (short
course) → IFRT, which showed favorable results in a retrospective
comparison to standard R-CHOP.4
Regimen
3-yr PFS
3-yr OS
R-CHOP x 3-4 → IFRT
90%
96%
R-CHOP x 6-8
74%
86%
1Miller
TP. J Clin Oncol. 2004;22:2982-4.
N, et al. Ann Oncol. 2013;24:1032-7.
3Pfreundschuh M, et al. Lancet Oncol. 2011;12:1013-22.
4Terada Y, et al. ASH 2012. Abstract 1628.
2Ketterer
Novel Approaches for Early-Stage DLBCL
•
Radioimmunotherapy consolidation:
‒ SWOG 0313:1 CHOP x 3 + IFRT → ibritumomab: 4-yr est. PFS = 84%
‒ E3402:2 R-CHOP → ibritumomab → IFRT (if PET+): 4-yr PFS = 88%,
OS = 98%
•
PET risk-adapted therapy – mid-treatment PET prognostically significant
in DLBCL3,4
‒ BCCA experience:5 R-CHOP x 3 → PET. If PET+, go on to IFRT. If PET‒,
receive R-CHOP x 1
PET –
n=103
PET +
n=30
P Value
3-yr TTP
92%
60%
.09
3-yr OS
96%
83%
.1
Result
‒ Ongoing phase II trial, S1001, will test this PET risk-adapted approach in
early-stage DLBCL, with PET+ population receiving R-CHOP x 3 → IFRT
1Miller TP, et al. ASH 2008. Abstract 3598.
→ ibritumomab
2
Witzig T, et al. ASH 2012. Abstract 2687.
C, et al. Blood. 2005;106:1376-81.
4Spaepen K, et al. Ann Oncol. 2002;13:1356-63.
5Sehn et al, Lugano 2008. Abstract 052; Sehn LH, et al. Lugano 2011. Abstract 028.
3Haioun
Biology of Early-Stage DLBCL
• DLBCL molecularly heterogeneous with different 5-year survivals:1
‒ Primary mediastinal:
64%
‒ Germinal center B-cell-like (GCB):
59%
‒ Activated B-cell-like (ABC):
30%
• GCB appears more prevalent in early-stage disease2 and with
superior survival3 after R-CHOP compared with ABC
• Bottom line: Biology of early-stage DLBCL needs further
exploration.
1Rosenwald
A, et al. J Exp Med. 2003;198:851-62.
G, et al. N Engl J Med. 2008;359:2313-23.
3Lenz G, et al. N Engl J Med. 2010;362:1417-29.
2Lenz
Advanced-Stage DLBCL
Craig Moskowitz, MD
R-CHOP Regimens for
Advanced-Stage DLBCL
• R-CHOP21 vs R-CHOP14 phase III studies
‒ GELA:1 3-yr EFS similar (60% vs 56%; HR = 1.04; P = .76)
‒ UK:2 2-yr OS similar (81% vs 83%; HR = 0.95; P = .70)
• Current strategy: R-CHOP21 x 6-8 cycles → 2nd-line treatment if
< CR3
‒ MSKCC:4 R-CHOP → ibritumomab

For those receiving RIT, 2-yr PFS = 79%, 2-yr OS = 84%
‒ Led to current US phase III trial:

R-CHOP → ibritumomab consolidation in elderly DLBCL
1Delarue
R, et al. Lancet Oncol. 2013;14:525-33.
D, et al. ASCO 2011. Abstract 8000.
3NCCN NHL guidelines. 2013.
4Hamlin PA, et al. ASH 2010. Abstract 1793.
2Cunningham
Risk-Adapted Therapy
for Advanced-Stage DLBCL
• MSKCC 01-142:
R-C1000HOuncappedP-14 x 4
+
Repeat Bx
Results showed no difference in
PFS among:1
• PET-negative
• PET-positive/biopsy-negative
• PET-positive/biopsy-positive
-
PET
Bx -
Bx +
ICE x 2
RICE x 1
HDT/ASCT
• MSKCC 08-026:
ICE x 3
followed by
observation
Results showed 4-yr OS > 80%
and 4-yr PFS > 70%
R-R-C1000HOuncappedP-14 x 3
C1000HOuncappedP-21 x 1
+
Repeat Bx
Bx +
Augmented
RICE x 2
followed by
HDT/ASCT
-
PET
Bx ≥80%
Ki-67
Augmented
RICE x 2
followed by
observation
<80%
ICE x 3
followed by
observation
1Moskowitz
et al. Lancet Oncol. 2010;28:1896-903.
Dose-Adjusted EPOCH-R
for Advanced-Stage DLBCL
• CALGB phase II study1
‒ Excellent 5-yr results in overall population

OS = 84%

PFS = 81%

EFS = 75%
‒ However, high-risk disease associated with worse outcomes than
other subgroups

IPI high-risk group, OS = 43%

ABC OS inferior to GCB (P = .04)

Ki67 < 60% OS inferior to ≥ 60% (P = .05)
• Ongoing phase III CALGB 50303: dose-adjusted EPOCH-R vs
R-CHOP21
1Wilson
WH, et al. Haematologica. 2012;97:758-65.
Relapsed DLBCL in the Rituximab Era
Anas Younes, MD
Salvage Phase III Trials in Relapsed DLBCL:
R-ICE + BEAM/ASCT Remains Standard
•
CORAL:1 Randomized patients who relapsed after CHOP ±R to R-ICE or RDHAP. Those achieving CR or PR then received BEAM ASCT.
‒ No difference between salvage therapies in OS (P = .49) or PFS (P = .44).
‒ Among those who relapsed within 12 months after diagnosis, prior
rituximab associated with poor EFS (P = .001).
‒ Among those who relapsed more than 12 months after diagnosis, prior
rituximab status had no impact on EFS (P = .11).
•
Bio-CORAL:2 subset of patients from CORAL trial with histologic material
available. Tumors classified as GCB or ABC.
‒ Among those receiving R-ICE, histologic type did not impact PFS (P = .82)
or OS (P = .96).
‒ Among those receiving R-DHAP, patients with GCB tumors had
significantly better PFS (P = .005) and potentially better OS (P = .06)
compared with patients with ABC tumors.
1Gisselbrecht,
2Thieblemont
et al. J Clin Oncol. 2010;28:4184-90.
et al. J Clin Oncol. 2011;29:4079-87.
Relapsed DLBCL Summary
•
As frontline therapy is changing based on tumor oncogenic properties, the
same should be done for salvage therapy and conditioning regimens.
‒ To achieve higher ORRs with salvage therapy and better ASCT outcome,
patients should be pre-selected based on predictive biomarkers.
‒ Randomized biomarker-driven salvage dynamic combination regimens will
need to be examined using innovative trial designs, such as shown below.
Lymphoma
PI3K/AKT/mTOR
JAK/STAT
BCR
P-PRAS40 +
pSTAT3 +
P-CD19 +
RCHOP
RCHOP +
Drug A
RCHOP
RCHOP +
Drug C
RCHOP
Biomarker -
RCHOP +
Drug D
RCHOP
New Directions in Follicular Lymphoma
Bruce D. Cheson, MD
Antibodies in Follicular Lymphoma
•
GA101: Anti-CD20 antibody
Trial
GAUGIN1
(BO20999)
GAUSS2
•
Treatment
n (FL)
ORR
GA101 low-dose
14
36%
GA101 high-dose
20
60%
GA101
74
43%
rituximab
75
39%
Antibody-drug conjugates
‒
DCDT2980S: anti-CD22 linked to MMAE. Showed CR in 2 of 3 patients with
DLBCL and 1 PR in patient with FL in phase I testing3
‒
DCDT4501A: anti-CD79b linked to MMAE. Showed responses in 5 of 8 patients
at first assessment in phase I testing4
‒
Ongoing randomized crossover trial:
Arm A: R (d1) +
DCDT2980S (d2)
Q 21 days
Response
PD
Arm B: R (d1) +
DCDT4501A (d2)
Q 21 days
Response
1Salles
GA, et al. ASH 2011. Abstract 268.
LH, et al. ASH 2011. Abstract 269.
3Advani R, et al. ASH 2012. Abstract 59.
4Palanca-Wessels MC, et al. ASH 2012. Abstract 56.
2Sehn
Small-Molecule Inhibitors
in Follicular Lymphoma
•
Ibrutinib (PCI-32765): BTK inhibitor produced 54% ORR in overall B-cell
malignancy population and 38% in FL.1
‒
•
Duration of response impressive, particularly in FL, where multiple patients
continue to receive ibrutinib after ≥2 years
Idelalisib (GS-1101): PI3K delta inhibitor
Decreased
Adenopathy
ORR
1-yr PFS
Idelalisib + rituximab
97%
77%
82%
Idelalisib + bendamustine
97%
85%
90%
Idelalisib + bendamustine/rituximab
100%
77%
78%
Phase I Treatment2
•
IPI-145: PI3K delta and gamma inhibitor
‒
In phase I testing, IPI-145 showed early signs of clinical activity across multiple
heme malignancies.3
1Advani
RH, et al. J Clin Oncol. 2013;31:88-94.
NH, et al. ASH 2012. Abstract 3645.
3Kahl B, et al. Lugano 2013. Abstract 066.
2Fowler
Apoptosis-Inducing Agents and IMiDs
in Follicular Lymphoma
•
•
ABT-199:1 apoptosis-inducing agent
Population
N
ORR
SD
Gr 3/4 Treatment-Related
AEs in >2 Patients
Overall (R/R NHL)
23
48%
30%
10% anemia
FL
8
12%
88%
NR
Lenalidomide:2 IMiD tested in combination with rituximab for untreated
indolent lymphoma in phase II study:
Population
•
N
ORR
SD
2-yr PFS
Overall
(untreated indolent NHL)
103
90%
8%
83%
FL
46
98%
2%
89%
Results led to ongoing RELEVANCE phase III trial:
1st line
FL
N=1000
R2
R2 maintenance
R+
chemo
Rituximab maintenance
R
R2 = rituximab + lenalidomide
1Davids
2Fowler
MS, et al. ASH 2012. Abstract 304.
NH, et al. ASH 2012. Abstract 901.
Management of Hodgkin Lymphoma
in the Elderly
Paul A. Hamlin, MD
Hodgkin Lymphoma:
Differences in the Elderly Subset
•
Approximately 20% of all HL patients are > 60 years old, but few are enrolled
in clinical trials.
•
HL biological factors in the older patient:
‒
Advanced stage1
‒
More aggressive histology1
‒
B symptoms1
‒
EBV positivity associated with worse disease-specific survival and OS2
•
Bleomycin produces high incidence of toxicity in elderly.3
•
Elderly outcomes:
‒
Elderly patients have worse outcomes in clinical trials than younger patients.4
‒
A study in Scotland of 674 patients with HL who were ≥ 60 years old reported a
5-year survival of only 35%.5
1Word,
et al. ASH 2011. Abstract 3648.
et al. Blood. 2005;106:2444-51.
3Evens AM. ASCO Post. 2012;3.
4Proctor SJ, et. al. Crit Rev Oncol Hematol. 2009;71:222-32.
5Proctor SJ, et al. Eur J Haematol. 2005;(suppl 66):63-7.
2Jarrett,
Reduced-Intensity Therapy
for Hodgkin Lymphoma
•
•
Reduced-intensity regimens:
‒
CVP/CEB
‒
VBM
‒
VEPEMB
‒
ChIVPP
Less-toxic regimens produce more relapses.
‒
•
CVP/CEB produces 73% remission rate and is well tolerated (4% toxic death),
but relapses are high (5-yr RFS 47%)1
Phase II SHIELD study used VEPEMB2
Population Receiving VEPEMB
N
CR
3-yr OS
3-yr PFS
Patients with early-stage disease
31
74%
81%
74%
Patients with advanced-stage disease
72
61%
66%
58%
1Levis
A, et al. Haematologica 1996;81:450-6.
SJ, et al. Blood. 2012;119:6005-15.
2Proctor
Anthracycline-Containing Therapy
in Hodgkin Lymphoma
•
•
Anthracycline-containing therapy:
‒
ChIVPP/ABV
‒
COPP/ABVD
‒
ABVD
‒
Stanford V
‒
BEACOPP
GHSD10 and 11: ABVD1
‒
•
In patients age ≥ 60, ABVD associated with 14% dose reductions and delays,
68% grade 3/4 toxicity, and 5% treatment-related mortality.
NLSG: ChIVPP vs ChIVPP/ABV2
‒
Retrospective analysis
‒
In patients age ≥ 60, those receiving ChIVPP/ABV had better 5-yr OS than those
receiving ChIVPP (67% vs 30%; P = .0086).
‒
Both OS (39% vs 87%) and EFS (31% vs 75%) worse in patients age ≥ 60
compared with patients age < 60.
1Boll
2Weekes
B, et al. J Clin Oncol. 2013;31:1522-9.
CD, et al. J Clin Oncol. 2002;20:1087-93.
Anthracycline-Containing Therapy
in Hodgkin Lymphoma
•
•
ABVD vs Stanford V1
‒
Analysis of patients age ≥ 60 treated on randomized E2496 trial (n=44)
‒
Among older patients, no survival difference between ABVD and Stanford V
‒
Compared with younger patients, older patients had worse treatment-related
mortality (9% vs 0.3%), 5-yr OS (58% vs 90%), and 5-yr FFS (48% vs 74%).
GHSD HD9elderly: COPP/ABVD vs BEACOPP2
‒
‒
Analysis of patients age 66-75 years from randomized HD9 clinical trial
Treatment
N
CR
5-yr OS
5-yr FFTF
Death due to acute toxicity
COPP-ABVD
26
77%
50%
46%
8%
BEACOPP
42
76%
50%
46%
21%
BEACOPP associated with lower relapse rate (12% vs 23%), but at cost of
increased toxicity
1Evens
AM, et al. Br J Haematol. 2013;161:76-86.
V, et al. Ann Oncol. 2005;16:124-31.
2Ballova
Relapsed and Refractory HL:
Will We Be Able to Avoid Transplant?
Craig Moskowitz, MD
Transplantation for Relapsed/Refractory
Hodgkin Lymphoma
•
Current status of transplantation for relapsed/refractory HL:
‒ Toxicity and cost markedly decreased, but relapse rate remains
relatively constant
‒ Standard conditioning regimens remain the same (CBV or BEAM)
‒ PFS = 30%-50%
‒ Adding more chemotherapy agents or escalating the dose has had
minimal value
‒ Adverse prognostic factors in patients with relapsed/refractory disease
(MSKCC model):1

B symptoms (night sweats, weight loss, fever without infection)

Extranodal disease

Complete remission duration < 1 year
1Moskowitz
CH, et al. Blood. 2001;97:616-23.
FDG-PET to Identify Patients Needing
Additional Salvage Therapy
•
Normalization of PET prior to transplant is predictive of survival1 and
identifies patients with excellent outcomes
•
MSKCC Protocol 04-047 for relapsed/refractory HL:
Repeat biopsy, determine risk factors
Staging evaluation: FDG PET, diagnostic CT CAP, BM Bx
Arm A = 0 or 1 risk factors
Standard ICE x 1
Augmented ICE x 1
PBPC collection
Arm B = 2 risk factors
Augmented ICE x 2
PBPCInduction:
collection
Nine 28-day cycles
Restaging: FDG-PET, CT CAP
PET negative
PET positive
Results showed
patients transplanted
after standard or
GVD salvage
chemotherapy had
POD on ICE EFS > 80%,
compared with 29%
EFS for patients with
PET positivity.2
GVD x 4
Restaging
Radiotherapy, if applicable
HDT/ASCT
CR, PR, MR
POD
off study
1Moskowitz
2Moskowitz
AJ, et al. Blood. 2010;116:4394-7.
CH et al. Blood. 2012;119:1665-70.
FDG-PET to De-escalate Salvage Therapy
in Hodgkin Lymphoma
•
Pre-transplant FDG-PET highly predictive of post-transplant outcome, so
perhaps PET can be used to identify patients appropriate for de-escalated
salvage therapy.
•
Brentuximab vedotin (SGN-35):
‒ Antibody directed against CD30 (antigen highly expressed on HL
surface) conjugated to MMAE, an anti-tubulin agent.
‒ Well tolerated and highly active in HL following transplant failure

ORR = 75% and CR = 34% in phase II study of q3w dosing in
relapsed/refractory HL1

Also being studied with qw dosing (3 wk on, 1wk off)
1Chen
RW, et al. ASCO 2011. Abstract 8031.
Current/Proposed Brentuximab Clinical Trials
in Relapsed/Refractory HL
MSKCC 11-142 ongoing trial
Proposed international trial adding RT
First treatment following upfront therapy
Nodal-only relapse, RT-naïve patients
Weekly SGN-35 x 2
+
PET
Weekly SGN-35 x 2
-
-
PET
-
Platinum-based
salvage x 2
Augmented ICE x 2
PET
+
HDT/ASCT
PET
+
+
Further treatment
according to
treating physician
Further treatment
according to
treating physician
RT alone
randomize
-
HDT/ASCT
New Directions in Hematologic
Malignancies
Jonathan W. Freidberg, MD (Aurora kinase inhibition)
Jennifer R. Brown, MD, PhD (Kinase inhibitors in lymphoma)
Anas Younes, MD (JAK inhibition in lymphoma)
Andre Goy, MD (IMiDs in lymphoma)
Aurora Kinase Inhibition With Alisertib
•
Aurora kinase
‒ Key to the cell cycle, regulating mitotic entry/progression, centrosome
maturation/separation, G2/M transition, chromosome alignment, and
cytokinesis
‒ Present in aggressive T and B cell NHL
•
Alisertib is an Aurora A kinase small-molecule inhibitor.
•
Alisertib clinical development in T-cell lymphoma:
‒ Showed 57% ORR (4/7) in T-cell lymphomas in phase II NHL testing1
‒ Ongoing SWOG 1108, a phase II study in relapsed/refractory PTCL
‒ Ongoing phase III study in PTCL: alisertib vs investigator’s choice
•
Alisertib clinical development in B-cell lymphoma:
‒ Because of preclinical synergy with vincristine, a phase I/II study is
ongoing, testing alisertib, vincristine, and rituximab in patients with
relapsed/refractory aggressive B-cell lymphomas.
1Friedberg
J, et al. ASH 2011. Abstract 95.
Kinase Inhibitors in Lymphoma
•
Ibrutinib
‒ Bruton’s tyrosine kinase (BTK) small-molecule irreversible inhibitor
‒ Efficacy in FL: 55% ORR and 12.3 months DOR1
‒ Efficacy in ABC DLBCL: 41% ORR (compared with 5% ORR for GCB)2
‒ Efficacy in phase II relapsed or refractory MCL: 66.1% ORR3
•
Idelalisib (GS-1101, CAL-101)
‒ PI3Kδ small-molecule inhibitor
‒ Efficacy in MCL and indolent lymphoma: 62% ORR for each4
‒ Efficacy in MCL in combination with everolimus, bortezomib, or
bendamustine/rituximab: 46% ORR5
1Fowler
NH, et al. ASH 2012. Abstract 156.
WH, et al. ASH 2012. Abstract 686.
3Wang M, et al. ASH 2012. Abstract 904.
4Kahl B, et al. ASH 2010. Abstract 1777.
5Wagner-Johnston N, et al. ASCO 2013. Abstract 8501.
2Wilson
JAK and STAT Inhibitors
•
JAK/STAT signaling
‒ Janus kinase 2 (JAK2) and Signal Transducers and Activators of
Transcription (STAT) pathways important to pathogenesis of
hematologic malignancies
‒ JAK2, STAT3, and STAT6 frequently overexpressed in HL and NHL
‒ JAK2 inhibition in vitro associated with reduced proliferation in
numerous lymphoma cell lines
•
SB1518 is a JAK2 small-molecule inhibitor.
‒ Phase I study of daily SB1518 in 35 patients with relapsed lymphoma
provided proof of principle of therapeutic value of inhibiting the
JAK/STAT pathway in lymphoma.1
•
Ongoing phase II study of ruxolitinib (JAK inhibitor already approved for the
treatment of myelofibrosis) will provide additional information on potential
value of targeting these pathways in DLBCL and PTCL.
1Younes
A, et al. Lugano 2011. Abstract 157.
IMiDs in Lymphoma
•
Lenalidomide is an immunomodulatory agent with pleiotropic effects not
completely understood. Effects include increases in T-cell activation, NKmediated killing, immune synapse formation, and APC function in B cells.
•
Currently approved for use in multiple myeloma, MDS, and MCL and has
activity across broad range of lymphomas
‒ Received approval in June 2013 for MCL based on MCL-001, a phase II
study showing a 28% ORR and a median DOR of 16.6 months in heavily
pretreated patients
‒ In 46 FL patients, lenalidomide + rituximab produced a 98% ORR1
‒ RELEVANCE: ongoing phase III trial of 1000 patients with untreated FL
R-chemo → maint R (2 yrs) vs R + Len → maint R (2 yrs) + Len (1 yr)
‒ Len monotherapy activity in DLBCL appears to be concentrated within
non-GCB population of relapsed/refractory patients (ORR, 53% vs 9%)2
‒ R2-CHOP (RCHOP + R and Len maint) produced a 100% ORR and 77%
CR in DLBCL3
‒ Len-RICE shows promise (8/13 CR) as salvage therapy in DLBCL4
1Fowler
NH, et al. ASH 2012. Abstract 901.
et al. Cancer. 2011;117(22):5058-66.
3Reddy NM, et al. ASH 2012. Abstract 3668.
4Feldman et al. ASH 2012. Abstract 3710.
2Hernandez-Ilizaliturri,
Lymphoma Takeaways
•
Strategies being tested to replace CHOP for PTCL, including ASCT and
CHOP + novel agents. Treatment of CTCL continues to involve skin-directed
therapy for early-stage disease and systemic therapy for later stages.
•
Novel approaches for early-stage DLBCL include radioimmunotherapy
consolidation and PET risk-adapted therapy. PET risk-adapted therapy also
being studied for advanced-stage DLBCL, as is dose-adjusted EPOCH-R.
Randomized biomarker-driven combination regimens need to be examined for
relapsed DLBCL using innovative trial designs.
•
New agents under investigation for follicular lymphoma include GA101, IPI145, Ibrutinib, idelalisib, ABT-199, and ADCs DCDT2980S and DCDT4501A.
•
Reduced-intensity therapies being examined in the elderly HL population.
Strategies to improve ASCT in relapsed/refractory HL include pre-transplant
PET imaging and inclusion of brentuximab vedotin into salvage therapy.
•
Many promising agents under investigation for treatment of hematologic
malignancies, including radioimmunoconjugates, antibody-drug conjugates,
aurora kinase inhibitors, BTK inhibitors, PI3K inhibitors, JAK inhibitors, and
IMiDs.
LEUKEMIA &
MYELOPROLIFERATIVE
NEOPLASMS
Debate: What Is the Optimal First-Line
Treatment for CML in Chronic Phase?
Imatinib
Harry P. Erba, MD, PhD
Optimal First-Line CML Therapy:
Cure Rate and OS Improvement
•
When choosing an optimal therapy for CML, there are several considerations:
Can it provide a cure?
•
Nearly 40% of patients from STIM trial who discontinued imatinib after
sustained complete molecular response (CMR) of ≥ 2 years maintained
CMR,1 but trial had short median follow-up of only 30 months, so
premature to call those patients cured.
Can it improve overall survival (OS)?
• Randomized TKI trials likely never be able to show survival advantage
because of crossover, inherent to all of these trials.
‒ IRIS trial: no OS improvement of imatinib vs IFN/Ara-C2 because of
the frequency of crossover from IFN/Ara-C to imatinib
‒ ENESTnd: no difference in OS of imatinib vs nilotinib (300 mg) after
3 years (94% vs 95%; P = .44)3
‒ DASISION: no difference in OS of imatinib vs dasatinib (95% vs 95%;
1Mahon FX, et al. ASH 2011. Abstract 603.
data still immature)4
2Druker
BJ, et al. N Engl J Med. 2006;355:2408-17.
HM, et al. ASH 2012. Abstract 1676.
4Kantarjian HM, et al. Blood. 2012;119:1123-9.
3Kantarjian
Optimal First-Line CML Therapy:
Achievement of Remission and Tolerability
Can it improve remission rate?
Experimental
TKI
MMR at 12 Months
vs Imatinib
MMR at 24 Months
vs Imatinib
P Value at
24 Months
DASISION1
dasatinib
46% vs 28%
64% vs 46%
< .0001
ENESTnd2
nilotinib 300 mg
55% vs 27%
73% vs 53%
< .0001
Trial
‒ Although major molecular response (MMR) at 24 months is inferior with imatinib,
MMR offers no advantage over CCyR in defining long-term outcomes.3
Experimental
TKI
CCyR at 12 Months
vs Imatinib
CCyR at 24 Months
vs Imatinib
P Value at
24 Months
DASISION1
dasatinib
85% vs 73%
85% vs 82%
NS
ENESTnd4
nilotinib 300 mg
80% vs 65%
87% vs 77%
.0018
Trial
‒ Shown above, no/modest differences in complete cytogenetic response (CCyR)
present at 24 months between imatinib and 2nd-generation TKIs
Can it improve tolerability?
‒ No clear tolerability advantage of 2nd-generation TKIs over imatinib.
Safety profiles different but overall AE incidences similar1,2
‒ Imatinib has no known late complications, unlike dasatinib
and nilotinib
1
Kantarjian HM, et al. Blood. 2012;119:1123-9.
2Saglio G, et al. ASH 2011. Abstract 452.
3Jabbour E, et al. J Clin Oncol. 2011;29:4260-5.
4Kantarjian HM, et al. Lancet Oncol. 2011;12:841-51.
Optimal First-Line CML Therapy:
Prevention of Progression and Cost of Therapy
Can it prevent progression?
‒ Imatinib may permit more progressions to accelerated-phase/blastphase (AP/BP) than dasatinib or nilotinib.
Experimental
TKI
Progression to AP/BP
vs Imatinib
P Value
DASISION1
dasatinib
3.5% vs 5.8%
NR
ENESTnd2
nilotinib 300 mg
3.2% vs 6.7%
.0496
Trial
Does it have an acceptable cost?
‒ Imatinib will be generic in 2015.
‒ Guidelines suggest that if BCR-ABL/ABL ratio > 10% at 3 months, then
switch therapy to 2nd-generation agent,3 showing that patients who
have suboptimal response to imatinib can then switch to a 2ndgeneration TKI.
1Kantarjian
HM, et al. Blood. 2012;119:1123-9.
G, et al. ASH 2011. Abstract 452.
3NCCN CML guidelines. Version 4. 2013.
2Saglio
Imatinib as First-Line CML Therapy:
Summary
• Cytogenetic and molecular response rates higher with
2nd-generation TKIs compared with imatinib for first-line
treatment of adults with CML in chronic phase (CML-CP)
at early time points, but advantage may disappear at later
time points.
• Imatinib remains standard of care for the initial therapy of adults
with CML-CP based on long-term follow-up data, OS, PFS, and
tolerability.
Debate: What Is the Optimal First-Line
Treatment for CML in Chronic Phase?
Second-Generation TKIs
Michael J. Mauro, MD
Prediction of Outcome Based on
Early Response to Therapy
•
Initially discovered that early reduction in BCR-ABL/ABL transcript levels
correlates with later achievement of MMR:1
Time Point
Early Response
MMR %
P Value
3 months
> 2-log reduction
100%
< .001
0- to 2-log reduction
54%
> 2-log reduction
86%
0- to 2-log reduction
0%
6 months
•
More recently discovered that early reduction in BCR-ABL/ABL transcript
levels correlates with survival:2
Time Point
3 months
•
< .001
Early BCR-ABL/ ABL Level
8-yr OS
P Value
< 9.84%
93%
< .001
> 9.84%
57%
NCCN guidelines now recommend switching TKIs if BCR-ABL transcript levels
> 10% at 3 months.3
1Branford
S, et al. Leukemia. 2003;17:2401-9.
D, et al. J Clin Oncol. 2012;30:232-8.
3NCCN CML guidelines. Version 4. 2013.
2Marin
Is Early Response to Therapy Really Important?
•
•
YES! Patients who don’t achieve CCyR after 12 months of treatment have
greater risk of an event (loss of response, disease progression, or death) than
those who don’t achieve CCyR after 3 months.1
Months on Treatment
Patients Not in CCyR
(n)
Event (%)
3
109
23
6
47
34
12
26
38
YES! Patients who don’t achieve MMR after 12 months of treatment have
greater risk of progression to AP/BP than those who do achieve MMR.2
MMR After 12 Months
AP/BP (%)
Yes
1
No
10
P Value
.0004
1Quintas-Cardama A,
2Hughes
et al. Blood. 2009;113:6315-21.
T, et al. Blood. 2010;116:3758-65.
Why Dasatinib and Nilotinib
for First-Line Therapy?
•
Both dasatinib and nilotinib produce more favorable early responses than
imatinib.1-4
Efficacy Measure
at 12 Months
•
•
Nilotinib
Imatinib
P Value
Dasatinib
Imatinib
P Value
CCyR
80%
65%
< .001
85%
73%
.0002
MMR
55%
27%
< .001
46%
28%
< .0001
CMR
11%
1%
< .001
~5%
~5%
NS
Both dasatinib and nilotinib associated with less transformation to AP/BP than
imatinib.5,6
Trial
Experimental TKI
Transformation to AP/BP (%)
vs Imatinib
DASISION
dasatinib
2.3% vs 5%
NS
ENESTnd
nilotinib 300 mg
0.7% vs 6.0%
.0003
P Value
Currently no prognostic tool validated to determine who needs additional
1Saglio G, et al. N Engl J Med. 2010;362:2251-9.
therapy.
2Kantarjian HM, et al. Blood. 2012;119:1123-9.
3Kantarjian
HM, et al. Lancet Oncol. 2011;12:841-51.
et al. EHA 2011. Abstract 484.
5Kantarjian HM, et al. ASCO 2011. Abstract 6510.
6Larson RA, et al. ASCO 2011. Abstract 6511.
4Hochhaus A,
Dasatinib and Nilotinib for First-Line Therapy:
Remaining Questions and Summary
•
Safety of long-term use of dasatinib and nilotinib needs further study.
‒ Imatinib has no known late effects of chronic use.1,2
‒ Dasatinib and nilotinib safety data less mature, but dasatinib associated
with pulmonary arterial hypertension3 and nilotinib associated with
peripheral arterial disease.4
•
TKI discontinuation holds promise. Of 25 patients who discontinued dasatinib
or nilotinib, 73% maintained MMR after 6 months.5
•
Final thoughts:
‒ Perhaps rather than managing treatment failures, may be preferable to
focus on prevention of treatment failure.
1Gambacorti-Passerini
C, et al. JNCI. 2011;103:553-61.
C, et al. ASH 2011. Abstract 3766.
3Montani D, et al. Circulation. 2012;125:2128-37.
4Le Coutre P, et al. JNCI. 2011;103:1347-8.
5Rea D, et al. ASH 2011. Abstract 604.
2Gambacorti-Passerini
Treatment for Elderly Chronic Lymphocytic
Leukemia:
Is There a Standard?
Alessandra Ferrajoli, MD
Considerations in the Treatment of
Elderly Patients With CLL
•
Nearly 80% of patients with CLL are ≥ 65 years old at diagnosis.1
•
Survival for patients aged 65-74 years with CLL is poorer than with
age-matched controls.2
•
Number of comorbidities increases with age in patients with CLL.3
•
CIRS (Cumulative Illness Rating Scale), a measure of chronic illness burden,
can be used to divide elderly patients into 3 categories:
– No go: use supportive therapy only
– Slow go: use reduced-intensity therapy
– Go go: use standard therapy
•
Physically fit patients with no significant comorbidities and excellent renal
function can receive standard FCR therapy, as shown by the CLL8 study
in which addition of rituximab to FC produced a doubling of the CR rate
(44% vs 22%; P < .0001).4
1SEER
cancer statistics 1975-2007.
T, et al. Cancer. 2010;116:4777-87.
3Cramer P, et al. ASH 2006. Abstract 2840.
4Hallek M, et al. Lancet. 2010;376:1164-74.
2Shanafelt
•
First-Line Treatment of Elderly Patients
With Comorbidities
CLL208: R-chlorambucil
– Phase II trial of 100 patients showed 80% ORR and 12% CR.1
– Median PFS 23.9 months; median OS not reached.1
•
Rituximab + GM-CSF
– Trial of patients ≥ age 70 years showed 68% ORR and 6% CR.2
– R + GM-CSF well tolerated, with 2% grade 3/4 neutropenia the only
grade 3/4 AE.2
•
CLL11: chlorambucil vs R-chlorambucil vs GA101-chlorambucil3
Efficacy Measure
•
GA101 +
Chlor vs Chlor P Value
R + Chlor
vs Chlor
P Value
ORR, %
75.5 vs 30.2
NR
65.9 vs 30.0
NR
Median PFS, months
23.0 vs 10.9
< .0001
15.7 vs 10.9
< .0001
Lenalidomide
– Phase II study of 60 patients age ≥ 65 years produced 65% ORR and
15% CR. CR rate increased over time to 38%.4
– Median PFS = 52 months; median OS not reached.1 4
Hillmen P, et al. ASH 2010. Abstract 697.
2Ferrajoli A, et al. Paper submitted.
3Goede V, et al. ASCO 2013. Abstract 7004.
4Badoux XC, et al. Blood. 2011;118:3489-98.
Targeted Therapy for CLL:
Focusing on the B Cell Receptor Pathway
Jennifer R. Brown, MD, PhD
Therapies Targeting BCR Pathway: Idelalisib
•
PI3Kδ inhibitor; BID dosing.
•
Unique response pattern: causes simultaneous decline in lymphadenopathy
(sustained over treatment) and increase in lymphocytosis (transient).
•
Single-agent idelalisib produced 56% ORR, 81% nodal response, and median
PFS of 17 months in relapsed/refractory CLL.1
•
Phase Ib study of idelalisib in combination with rituximab and/or bendamustine
in relapsed/refractory CLL:
– Patients from each group achieved nodal responses and ORR ≥ 78%.2
– Approximately 35% of patients relapsed in irst 12 months, after which a
plateau through 28 months.2
•
Ongoing phase III idelalisib trial in CLL:
– Idelalisib + BR vs placebo + BR in previously treated CLL
1Brown
2Barrientos
JR, et al. ASCO 2013. Abstract 7003.
JC, et al. ASCO 2013. Abstract 7017.
Therapies Targeting BCR Pathway: Ibrutinib
•
BTK inhibitor; QD dosing.
•
Phase II monotherapy study (N=116) of 3 groups of patients: treatment-naïve
≥ age 65 years, relapsed/refractory, and high-risk relapsed/refractory1
– Most grade 3/4 AEs ≤ 5% incidence; neutropenia ~20% and infection
~40% in RR group. One death due to pneumonia in R/R group.
– Sustained improvements observed in hemoglobin and platelets for most
relapsed patients with cytopenias.
– 68% ORR in treatment-naïve patients and 71% in R/R patients. Even
patients with bulky disease or del17p had good responses.
– Lymphocytosis occurred in most patients but normalized by 12 months.
•
R/R
Efficacy
at 26 Months
TN
Overall
del17p
del11q
No del
IgVH Mut
IGVH Unmut
Est. PFS
96%
75%
57%
73%
93%
83%
72%
Est. OS
96%
83%
70%
85%
93%
83%
82%
Ongoing phase III ibrutinib trials in CLL:
– BR ± ibrutinib in R/R CLL and ibrutinib vs chlorambucil in elderly CLL.
1Byrd
JC, et al. ASH 2012. Abstract 189.
IMiDs and Combinations:
How to Integrate Into Standard CLL Therapy
Alessandra Ferrajoli, MD
Lenalidomide Monotherapy in CLL
•
Properties of lenalidomide treatment
– Normalization of peripheral blood lymphocytes and T cells1,2
– Improvement in serum Igs2
•
Single-agent lenalidomide as salvage therapy:
RPCI3
n = 45
MDACC1
n = 44
CLL-014
n = 52
ORR
47%
32%
12%
CR
9%
7%
0%
SD
18%
25%
58%
Response
•
Lenalidomide monotherapy as frontline therapy for CLL (n = 25):5
– PR = 56%
– Tumor flare = 88%
– Grade 3/4 neutropenia = 72%
1Ferrajoli
A, et al. Blood. 2008;111:5291-7.
XC, et al. Blood. 2011;118:3489-98.
3Chanan-Khan AA, et al. J Clin Oncol. 2006;24:5343-9.
4Wendtner CM, et al. Leuk Lymphoma. 2012;53:417-23.
5Chen CI, et al. J Clin Oncol. 2011;29:1175-81.
2Badoux
Lenalidomide Combination Therapy in CLL
•
Lenalidomide + fludarabine + rituximab in untreated CLL
– Phase !/II study: ORR = 56%, but combination too toxic, with
myelosuppression and idiosyncratic drug reaction as DLTs.1
– REVLIRIT: Combination followed by lenalidomide and rituximab
maintenance therapy. Dosages more tolerable; ORR = 87%,
49%, MRDneg = 29%.2
•
CR =
Lenalidomide + rituximab in frontline CLL3
– Phase II study of 69 patients, divided by age (65 years) into 2 groups:
•
Group
N
ORR
CR
Age < 65 years
40
95%
20%
Age ≥ 65 years
29
78%
7%
Overall
69
88%
15%
Ongoing phase III lenalidomide trials in CLL:
– Lenalidomide vs chlorambucil as frontline therapy.
– Lenalidomide as maintenance (1 after 1st-line and 1 after 2nd-line).
1Brown
JR, et al. Leukemia. 2010;24:1972-5.
A, et al. ASH 2011. Abstract 292.
3James DF, et al. ASH 2011. Abstract 291.
2Egle
Lenalidomide Combination Therapy in CLL
•
Lenalidomide + rituximab in relapsed CLL1
– Phase II study of 59 patients who received prior purine analog therapy
– Median 2 prior regimens; 93% prior FCR, PCR, CFAR, or OFAR
– No grade 3/4 tumor flare; combination well tolerated
Treatment
ORR
CR
Median TTF
3-yr OS
Lenalidomide + rituximab
66%
12%
17.4 months
71%
 Deletion status did not impact PFS outcomes.
 Fludarabine-refractory patients had inferior PFS compared with patients
not refractory to fludarabine (P = .019).
•
Lenalidomide + ofatumumab in relapsed CLL2
– Phase II trial of 34 patients who received prior purine analog therapy
(100% received FCR).
Treatment
ORR
CR
Median PFS
2-yr OS
Lenalidomide + ofatumumab
68%
24%
16 months
73%
1Badoux
XC, et al. J Clin Oncol. 2013;31:584-91.
A, et al. ASH 2012. Abstract 720.
2Ferrajoli
Management of Patients With MDS
Refractory to Hypomethylating Agents
David Steensma, MD
Hypomethylating Agents for MDS:
Response to Treatment
•
Treatment with hypomethylating agents (HMAs; azacitidine and decitabine):
– Improves survival by 9 months in high-risk patients1
– Delays progression to AML by 4-6 months2
– Improves quality of life3
– Has low early treatment-related mortality4
•
However, it also:
– Produces low CR rate5,6
– Produces hematologic responses in only 30%-60% of patients7,8
– Has variable duration of response9
– Is associated with poor survival –
< 6 months – after HMA failure10
1Fenaux
P, et al. Lancet Oncol. 2009;10:223-32.
H, et al. Cancer. 2006;106:1794-803.
3Kornblith AB, et al. J Clin Oncol. 2002;20:2441-52.
4Santos FP, et al. Expert Rev Anticancer Ther. 2010;10:9-22.
5Itzykson R, et al. Blood. 2011;117:403-11.
6Lubbert M, et al. J Clin Oncol. 2011;29:1987-96.
7Lee JH, et al. Haematologica. 2011;96:1441-7.
8Lyons RM, et al. J Clin Oncol. 2009;27:1850-6.
9Steensma DP, et al. J Clin Oncol. 2009;27:3842-8.
10Prebet T, et al. J Clin Oncol. 2013;29:3322-7.
2Kantarjian
Hypomethylating Agents for MDS:
Outcomes After HMA Failure
•
Common reasons for azacitidine failure:1
– Primary failure (progression or stable disease): 55%
– Secondary failure (initial response, then progression or stable disease): 36%
– Intolerance: 9%
•
Outcomes after HMA failure:
HMA
Median OS
1-yr OS
Azacitidine
High risk1
Intermediate-1 risk2
Low risk2
5.6 months
15 months
46 months
29%
NR
NR
Decitabine
Intermediate-1 to high risk3
4.3 months
28%
1Prebet
T, et al. J Clin Oncol. 2013;29:3322-7.
A, et al. ASH 2012. Abstract 2815.
3Jabbour E, et al. Cancer. 2010;116:3830-4.
2Mishra
Hypomethylating Agents for MDS:
Treatment Options After HMA Failure
Treatment Option After HMA Failure
•
Median OS, months1
Allogeneic transplant
19.5
Clinical trial with investigational agent
13.2
Intensive cytotoxic chemotherapy
8.9
Low-dose chemotherapy
7.3
Supportive care
4.1
Rigosertib is a multikinase inhibitor that inhibits PI3K/Akt/ERK pathway that is
in phase III testing for MDS patients who have progressed after or did not
respond to an HMA.
Randomize
2:1
Rigosertib 1800 mg/24h as 72h continuous infusion
days 1, 2, and 3 of a 2-week cycle
Best supportive care or low-dose cytarabine
Primary endpoint: OS
Secondary endpoints: IWG 2006 response, AEs
1Prebet
T, et al. J Clin Oncol. 2011;29:3322-7.
BiTE Antibodies for Treatment of ALL
Daniel J. DeAngelo, MD, PhD
Bispecific T-Cell Engager (BiTE) Antibodies
•
BiTE antibodies are bispecific antibodies that harness patient’s
immune system by engaging T cells with tumor cells via variable
region from a T-cell-specific antibody linked to variable region from
a tumor-specific antibody.
•
Blinatumomab is a BiTE antibody with variable regions of anti-CD3
antibody and anti-CD19 antibody linked together.
Blinatumomab for Treatment of
ALL in Hematologic CR
•
Blinatumomab phase II study of 21 patients with ALL in hematologic complete
remission with either molecular failure or relapse after ≥ 3 cycles of
chemotherapy.1
– Patients received single-agent blinatumomab 15 µg/m2/d continuous
infusions 4 wk on/2 wk off.
Treatment
Blinatumomab
Molecular
CR
DFS After
Median 15 Months FU
80%
60%
– Responses were rapid, occurring within first cycle of treatment.
– Median DFS not yet reached.
•
E1910: phase III study of blinatumomab in patients with newly diagnosed
BCR-ABL-negative ALL. Will be followed by consolidation and maintenance
chemotherapy for both groups.
1Topp
MS, et al. J Clin Oncol. 2011;29:2493-8.
Blinatumomab for Treatment of
Relapsed/Refractory ALL
•
MT103-206 study design:
•
Cohort 1
15
µg/m2/d
Safety evaluation
Screening & enrollment
Dose-finding run-in phase
Cohort 2a
5-15 µg/m2/d
N=36
Cohort 2b
5-15-30 µg/m2/d
Primary endpoint: CR and CRh* rate
within 2 cycles
Cohort 3
extension phase
5-15 µg/m2/d
Cohort 2 was selected as dosage for
extension phase because it had lowest
incidence of treatment-emergent AEs.
Most common AEs were pyrexia, fatigue, headache, tremor, and leukopenia.
Medically important AEs were cytokine release syndrome (n=3), reversible
CNS AEs (n=6), and infection (n=1 death due to fungal encephalitis).
Treatment
CR
Molecular Remission
in Pts with CR/CRh*
Blinatumomab
69%
88%
Median RFS
Median OS
7.6 months
9.8 months
*CRh = CR with only partial hematologic recovery
A Critical Evaluation of the Role of JAK2
Inhibitors for Myeloproliferative Neoplasms
Ruben Mesa, MD
JAK2 Inhibitors and Myelofibrosis
•
Ruxolitinib – approved by FDA in 2011 for myelofibrosis
– COMFORT I and II – phase III trials of ruxolitinib vs placebo showed ruxolitinib
produced dramatic reduction in splenomegaly (both P < .001), reduced overall and
individual symptoms (P < .001), and improved OS (HR = 0.50 and 0.58; P ≤ .04).1,2
•
SAR302503 – in phase III testing (JAKARTA)
– Phase II data from 31 patients showed mean spleen volume reduction of
42% in patients receiving the highest dose (500 mg daily). Also evidence
of symptom improvement in majority of patients.3
•
Pacritinib – in phase III testing
– In a phase II study of 34 patients, pacritinib reduced splenomegaly by
≥ 25% in one-third of patients.4
•
CYT387 – in phase II testing
– Phase II study of 166 patients demonstrated rapid and sustained
reductions in splenomegaly, marked improvement to complete resolution of
constitutional symptoms by majority of patients, and increased transfusion
independence.5
1
Verstovsek S, et al. N Engl J Med. 2012;366:799-807.
2Harrison C, et al. N Engl J Med. 2012;366:787-98.
3Talpaz M, et al. ASH 2012. Abstract 2837.
4Komrokji RS, et al. ASH 2011. Abstract 282.
5Pardanani A, et al. ASH 2012. Abstract 178.
Ruxolitinib for Polycythemia Vera and
Essential Thrombocythemia
•
Polycythemia vera (PV)
– Hydroxyurea and IFN are frontline therapies. Ongoing trial will determine
standard of care for PV.
– Ruxolitinib examined in open-label phase II study of patients with PV refractory
or intolerant to hydroxyurea.
• Nearly three-quarters of patients remained on-study and phlebotomy-free
for ≥ 144 weeks.1
• Clinically meaningful improvements in pruritus, night sweats, and bone
pain sustained through week 1441
• In phase III testing (RESPONSE and RELIEF)
•
Essential thrombocythemia
– Of 39 patients, 79% achieved ≥ 50% reduction in platelets during ruxolitinib
use.2
– Ruxolitinib in phase III testing (RELIEF)
1Verstovsek
2Verstovsek
S, et al. ASH 2012. Abstract 804.
S, et al. ASH 2010. Abstract 313.
Leukemia and MPN Takeaways
•
Ongoing debate regarding best TKI for frontline treatment of CML-CP:
imatinib or 2nd-generation agents dasatinib and nilotinib. Imatinib has
excellent long-term safety, but 2nd-generation TKIs produce more early
cytogenetic and molecular responses.
•
A number of novel regimens being tested in elderly patients with CLL,
including rituximab + GM-CSF, GA101 + chlorambucil, and lenalidomide.
•
Ibrutinib and idelalisib have shown promising efficacy and safety in CLL and
are currently in late-stage development for treatment of this disease.
Lenalidomide, alone or in combination with other agents (primarily anti-CD20
antibodies), is currently under investigation for several CLL indications.
•
Treatment options limited for MDS after failure of hypomethylating agents.
Rigosertib is a targeted agent in phase III testing for this indication.
•
Blinatumomab is a BiTE antibody that has demonstrated encouraging efficacy
and safety for treatment of ALL and is undergoing phase III evaluation.
•
JAK2 inhibitor ruxolitinib approved for treatment of myelofibrosis and under
investigation in polycythemia vera and essential thrombocythemia. Several
other JAK2 inhibitors in development for myelofibrosis.