Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Current Treatment and Future Perspectives Review Article

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Current Treatment and Future Perspectives Review Article

Review Article
Philadelphia Chromosome-Positive Acute
Lymphoblastic Leukemia
Current Treatment and Future Perspectives
Hun J. Lee, MD; James E. Thompson, MD; Eunice S. Wang, MD; and Meir Wetzler, MD
The Philadelphia chromosome (Ph) is the most common cytogenetic abnormality associated with adult acute lymphoblastic leukemia (ALL). Before the advent of tyrosine kinase inhibitors (TKIs), Ph-positive ALL carried a dismal
prognosis and was characterized by a poor response to most chemotherapy combinations, short remission durations,
and poor survival rates. Outcomes for patients with Ph-positive ALL improved substantially with the introduction of
TKIs, and the TKI imatinib induced complete remissions in >95% of patients with newly diagnosed Ph-positive ALL
when it was combined with chemotherapy. However, imatinib resistance remains a problem in a substantial proportion of patients with Ph-positive ALL, and multiple molecular mechanisms that contribute to imatinib resistance have
been identified. Second-generation TKIs (eg, dasatinib and nilotinib) have demonstrated promising efficacy in the
treatment of imatinib-resistant, Ph-positive ALL. Future strategies for Ph-positive ALL include novel, molecularly targeted treatment modalities and further evaluations of TKIs in combination with established antileukemic agents. For
this article, the authors reviewed past, current, and future treatment approaches for adult and elderly patients with
C 2010
Ph-positive ALL with a focus on TKIs and combined chemotherapeutic regimens. Cancer 2011;117:1583–94. V
American Cancer Society.
KEYWORDS: acute lymphoblastic leukemia, imatinib resistance, Philadelphia chromosome, tyrosine kinase inhibitors.
Age is an important determinant of prognosis and outcome for patients with acute lymphoblastic leukemia (ALL).
Long-term survival rates approach 80% in children aged <5 years but decrease to approximately 50% to 60% in adolescents and young adults, to approximately 30% in adults ages 45 to 54 years, and rarely exceed 15% in older adults.1-3
Prognostic changes that occur with increasing age may be attributable in part to age-dependent increases in unfavorable
cytogenetic abnormalities.4-6 The Philadelphia (Ph) chromosome is the most common cytogenetic abnormality associated
with adult ALL. Although Ph-positive ALL occurs in only approximately 5% of patients with ALL aged <20 years, the
incidence escalates to 33% in patients aged 40 years and is 49% in patients aged >40 years; the incidence decreases to
35% in patients aged >60 years.4,7 Until recently, Ph-positive ALL carried a dismal prognosis in both children and
adults.5,8-14 Patients with Ph-positive ALL who received conventional chemotherapy reportedly had long-term survival
rates of approximately 10%,5,12,14 and only allogeneic stem cell transplantation (alloSCT) extended long-term survival in
38% to 65% of patients.15-21
Outcomes for patients with Ph-positive ALL improved substantially with the introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate. Although imatinib monotherapy in previously treated patients with Ph-positive ALL
produced only a modest, short-lived response,22,23 imatinib combined with chemotherapeutic regimens has induced complete remissions (CRs) in almost every patient (95%) with newly diagnosed Ph-positive ALL.24-30 However, imatinib resistance develops in a substantial proportion of imatinib-treated patients with Ph-positive ALL. Second-generation TKIs
(eg, dasatinib and nilotinib) have demonstrated promising efficacy in the treatment of imatinib-resistant, Ph-positive
ALL.31-35 In this review, our objectives were to provide a historic perspective on treatment approaches to Ph-positive ALL
and to review current and future treatment options, focusing on TKIs and combined chemotherapeutic regimens.
Corresponding author: Meir Wetzler, MD, Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263;
Fax: (716) 845-2343; [email protected]
Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York
DOI: 10.1002/cncr.25690, Received: December 29, 2010; Revised: July 23, 2010; Accepted: August 30, 2010, Published online November 8, 2010 in Wiley Online
Library (wileyonlinelibrary.com)
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Table 1. Survival Data From Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic
Leukemia Who Were Treated on Intense Chemotherapy Regimens in the Era Before Imatinib
Trial/Regimen
Reference
No. of
Patients
CR Rate,
%
Survival
CALBG 8762
GMALL
VAD/CVAD
MRC-UKALL XA
LALA
CALGB
Hyper CVAD
GMALL
CALGB
Westbrook 19928
Gotz 19929
Preti 199410
Secker-Walker 199711
Thomas 199812
Wetzler 19995
Kantarjian 200013
Forman 198715
Setzler 20046
14
25
41
40
43
67
32
175
111
71
76
56
83
64
79a
91
68.4
74
Median OS, 11.2 mo
OS at 40 mo, 6%
Median OS, 11 mo
DFS at 3 y, 13%
Median OS, 9 mo
5-Y survival probability, 0.11
OS at 5 y, 7%
DFS at 3 y, 13%
OS at 3 y, 19%
CR indicates complete remission; CALGB, Cancer and Leukemia Group B; CR, complete remission; OS, overall survival;
GMALL, German Multicenter Trials of Adult Acute Lymphocytic Leukemia; VAD, combined vincristine, doxorubicin, and
dexamethasone; CVAD, combined cyclophosphamide, vincristine, doxorubicin, and dexamethasone; MRC-UKALL XA,
Medical Research Council-United Kingdom Acute Lymphoblastic Leukemia Trial XA; DFS, disease-free survival; LALA,
French Adult Lymphoblastic Leukemia Group.
a
Data were from the unfavorable group, which included those with t(9;22), þ8, 7, and t(4;11).
Philadelphia Chromosome-Positive Acute
Lymphoblastic Leukemia
The Ph chromosome results from a reciprocal translocation (t) between chromosomes 9 and 22
(t[9,22][q34;q11])36,37 and produces a fusion gene on
chromosome 22, namely, the breakpoint cluster regionAbelson leukemia viral proto-oncogene (BCR-ABL).
BCR-ABL fusion proteins are constitutively active tyrosine kinases that can alter multiple signaling pathways,
contributing to tumor growth and proliferation. The
breakpoint may occur within 1 of 4 sites on the BCR gene
to produce 3 proteins of different sizes: p190, p210, and
p230.38 The p190 BCR-ABL fusion gene occurs in about
90% of children with Ph-positive ALL39 and between
50% and 80% of adults with Ph-positive ALL.40,41 The
p210 BCR-ABL gene constitutes the rest of the Ph-positive ALL population.40,41 The p230 BCR-ABL mutation
is associated with Ph-positive chronic neutrophilic
leukemia.38
Treatment of Philadelphia ChromosomePositive Acute Lymphoblastic Leukemia
Imatinib combined with chemotherapy generally is considered first-line treatment for Ph-positive ALL. The role
of alloSCT as the standard of care and the use of secondgeneration TKIs, both for imatinib failure and as frontline
treatment, are discussed below.
Standard chemotherapy and allogeneic stem cell
transplantation
Although CRs may occur in 70% to 90% of patients
with Ph-positive ALL who receive intensive chemotherapy
1584
alone, most patients relapse and die within 6 to 11 months
of treatment (Table 1).5,6,8-14 AlloSCT substantially
improves long-term survival rates (Table 2).15-21 In the
UK-ALL XII/Eastern Cooperative Oncology Group
E2993 trial, the 5-year relapse-free survival (RFS) rate in
the preimatinib era increased to 57% in patients who
underwent a sibling alloSCT and to 66% in patients
who underwent a matched unrelated donor (MUD)
alloSCT compared with 10% for patients who received
chemotherapy alone and 44% after autologous SCT
(autoSCT).19 Although the alloSCT group fared worse
initially because of high rates of transplantation-related
mortality, the lower relapse risk translated into a higher
5-year event-free survival (EFS) rate (41% for sibling donor alloSCT and 36% for MUD alloSCT) and a higher
5-year overall survival (OS) rate (44% for sibling donor
alloSCT and 36% for MUD alloSCT) compared with
chemotherapy alone (EFS, 9%; OS, 10%) and autoSCT
(EFS and OS, 29%). In 2003, that study was amended
to add imatinib after induction or after SCT for 2 years
or until patients developed a relapse; in 2005, imatinib
was added during phase 2 of induction. The 3-year OS
of the imatinib-treated group was 23% versus 26% in
patients who were treated in the preimatinib era, and the
alloSCT rates were similar between the 2 groups.42
Those investigators concluded that imatinib does not
appear to improve survival. This is a finding not supported by other studies, as described below. Furthermore, despite improvements in CR rates for Ph-positive
ALL with newer treatments, alloSCT still is considered
the mainstay of treatment for this patient subgroup.16
However, this notion is being challenged.
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40
Median, 19 mo
Treatment-related mortality, %
Survival
NA indicates not available; CR1, first complete remission; CTX, cyclophosphamide; TBI, total body irradiation; VP16, etoposide; , with or without.
a
C 2008
Adapted with permission: Barrett AJ, Horowitz MM, Ash RC, et al. Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 1992;79:3067-3070.16 V
Nature Publishing Group.
b
In this study, a donor versus no-donor analysis was possible.
c
Mixed remissions included those at CR1, beyond CR1, and active disease.
35
CR1, 54% at 10 y;
>CR1, 29% at 10 y
24
35% at 3 y
40
43% at 5 y
VP16/TBI; CTX/VP16/TBI
Not specified
VP16/TBI
CTX/TB1; other/
TBI; non -TBI
41
38% at 2 y
CTX/TBI; VP16/TBI
CTXVP16 except
for 2 patients
NA
CR1, 46% at 2 y
VP16/TBI except
for 2 patients
39
65% at 3 y
67
36 (2-57)
Mixed
74/154
42 (17-56)
CR1
72/203
NA
CR1
23
30 (6-44)
CR1
38
NA
Mixed
67
28 (5-49)
Mixed
Total no. of patients/total in study
Age (range), y
Remission stance at time of
transplantation
Conditioning therapy
10
28 (23-45)
Mixedc
Chao
199517
Barrett
199216
Forman
198715
Variable
Table 2. The Role of Allogeneic Stem Cell Transplantation in the Era Before Imatiniba
Dombret
200220b
Goldstone
2001101b
Snyder
199918
Laport
200821
Philadelphia Chromosome-Positive ALL/Lee et al
Several factors influence the outcome of patients
who undergo alloSCT. Patients who underwent alloSCT
during first CR had substantially better outcomes (Table
2) than patients who underwent alloSCT in second or
later CR.43 Other favorable factors include younger age,
total body irradiation conditioning, the use of a human
leukocyte antigen-identical sibling donor, and the occurrence of acute graft-versus-host disease.20,44,45 The widespread use of alloSCT often is hindered by donor
availability. This limitation has been overcome in part by
the use of unrelated donors, nonmyeloablative conditioning regimens to facilitate the extension of eligibility for
SCT, and harvesting stem cells from umbilical cord
blood.43 Nevertheless, approximately 30% of patients
who undergo SCT relapse, and treatment-related mortality (up to 40%) is a frequent cause of failure.19,43 The role
of TKIs after alloSCT is discussed below. In summary,
improved therapies for patients with Ph-positive ALL are
still needed.
Tyrosine kinase inhibitors
Imatinib mesylate.
The first BCR-ABL inhibitor to gain clinical approval was imatinib mesylate, which partially blocks the
adenosine triphosphate (ATP) binding site of BCR-ABL,
preventing a conformational switch of the oncogenic protein to the activated form.46 Early studies demonstrated
that many patients with previously treated, Ph-positive
ALL initially responded to imatinib monotherapy (400
mg or 600 mg daily22,23) with CR rates of 20% then but
quickly relapsed after a median treatment duration of 58
days. Thus, although imatinib was well tolerated and produced a modest response in patients with previously
treated, Ph-positive ALL when it was used as single-agent
therapy, responses were short-lived, and relapses were
common.22,23
Imatinib resistance.
Imatinib resistance has been attributed to BCRABL-dependent and BCR-ABL-independent mechanisms. BCR-ABL-dependent mechanisms include amplification of the BCR-ABL gene and mutations within ABL
that reactivate BCR-ABL and disrupt binding to the drug
target.47-50 BCR-ABL point mutations are most common
in the ATP-binding pocket (P-loop), the contact site (eg,
threonine at codon 315 [T315] and phenylalanine at
codon 317 [F317]), the Src homology 2 (SH2) binding
site (eg, methionine at codon 351 [M351]), and the
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Review Article
A-loop. Detecting mutations before imatinib therapy is
controversial; even when mutations are detected, they do
not seem to affect the achievement of CR.51,52 A common
mutation that occurs frequently after imatinib therapy in
Ph-positive ALL patients is the glutamic acid to lysine
mutation at codon 255 (E255K).50 P-loop mutations are
70-fold to 200-fold less sensitive to imatinib compared
with native BCR-ABL,53 and studies indicate that patients
with these mutations have a worse prognosis.54,55 Gatekeeper mutations (eg, the threonine to isoleucine mutation at codon 315 [T315I] and the phenylalanine to
leucine mutation at codon 317 [F317L]) impede contact
between imatinib and BCR-ABL and, thus, contribute to
imatinib resistance and resistance to other second-generation TKIs.53
BCR-ABL-independent mechanisms include chromosomal abnormalities in addition to the Ph chromosome abnormalities (clonal evolution), disruptions in
drug uptake and efflux, and activation of alternative signaling pathways that cause proliferation or promote cell
survival. Maintaining effective intracellular drug concentrations also is a major hurdle to imatinib efficacy. Imatinib is a substrate of the drug efflux permeability
glycoprotein (PgP), and increased PgP expression can
decrease intracellular concentrations of imatinib to confer
drug resistance in vitro.56-58 Similarly, imatinib uptake
into cells depends on the organic cation transporter-1
(OCT-1),58 and low OCT-1 activity was documented in
a majority of patients with chronic myeloid leukemia
(CML) who had suboptimal responses to imatinib.59
Similar studies in Ph-positive ALL are ongoing. In vitro
studies also have indicated a role for plasma protein a-1
acid glycoprotein overexpression in imatinib resistance.60
Imatinib resistance in CML also involves up-regulation of chemokine (C-X-C motif) receptor 4 (CXCR4),
which plays a critical role in guiding normal hematopoietic and acute myeloid leukemia CD34-positive cells to
the bone marrow microenvironment.61 BCR-ABL overexpression down-regulates CXCR4 expression, causing
defective adhesion of CML cells to bone marrow stroma
in vitro.62 Stromal support also has been proposed as a
mechanism of resistance to TKIs in Ph-positive ALL.63
One study reported that murine P190 BCR-ABL ALL
cells with low BCR-ABL expression were able to grow in
the presence of stroma.63 This effect did not require cellcell contact, and stromal cell-derived factor 1a, a CXCR4
ligand, could substitute for the presence of the stromal
cells. Future treatments that interfere with stroma-lymphoblast interactions, eg, the CXCR4 inhibitor plerixafor
1586
(AMD3100), could be of benefit in eradicating TKI-resistant Ph-positive ALL cells.
Another recently identified mechanism of TKI resistance involves the expression of spliced isoforms of
IKAROS family zinc finger 1 (Ikaros) (IKZF1), a critical
regulator of normal lymphocyte development.64 The Ik6
isoform, which lacks all 4 N-terminal zinc fingers responsible for DNA-binding, was detected in 43 of 47 (91%)
Ph-positive ALL patients who were resistant to imatinib
or dasatinib. Expression levels of Ik6 were correlated with
BCR-ABL transcript levels. Restoring IKZF1 function
may provide another approach to combating TKI resistance in the future.
Constitutive activation of downstream signaling
molecules that results in pathway activation, regardless of
BCR-ABL inhibition, represents another mechanism of
imatinib resistance. Of relevance are the SRC family kinases (SFKs); the SFKs Lyn (which is encoded by the Vyes-1 Yamaguchi sarcoma viral-related oncogene homolog
[LYN]), Hck (which is encoded by the hematopoietic cell
kinase [HCK] gene), and Fgr (which is encoded by the
Gardner-Rasheed feline sarcoma viral [v-fgr] oncogene
homolog [FGR]) were required for the induction of Phpositive ALL, but not CML, in a murine model.65 Lyn
and Hck overexpression has been documented in imatinib-resistant CML cell lines with BCR-ABL-independent
imatinib resistance, and it has been demonstrated that
coinhibition of SFKs and BCR-ABL induces an enhanced
apoptotic response.65,66 The use of dual SFKs and BCRABL inhibitors holds promise for the treatment of
patients with imatinib-resistant leukemia.
Second-generation tyrosine kinase inhibitors
Dasatinib
Dasatinib, a dual SRC and ABL inhibitor, has 325fold greater potency than imatinib in cells transduced
with unmutated BCR-ABL and is active against many of
the BCR-ABL mutations, conferring imatinib resistance.67
Furthermore, the cellular uptake of dasatinib is not dependent on OCT-1 activity,68 although, like imatinib, it
is a substrate for efflux proteins.69
The SRC/ABL Tyrosine Kinase Inhibition Activity
Research Trials of Dasatinib (START)-L trial (imatinibresistant or imatinib-intolerant lymphoid blast crisis and
ALL) results indicated that dasatinib (70 mg twice daily)
was tolerated relatively well and produced a major hematologic response (MHR) in 41% of patients and major
cytogenetic response (MCyR) in 57% of patients after a
minimum follow-up of 12 months.34 The discrepancy
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Philadelphia Chromosome-Positive ALL/Lee et al
between hematologic and cytogenetic responses in that
trial probably stems from the high incidence of cytopenias
induced by dasatinib. The median OS was 8 months. After 1 year of treatment, 22% of patients remained alive
and progression free.34 A high proportion of patients with
P-loop and A-loop mutations of the ABL domain
achieved an MHR or an MCyR.32 However, patients who
had the T315I and F317L gatekeeper mutations did not
respond to dasatinib.32,70 Dasatinib is approved in the
United States for patients with Ph-positive ALL who have
failed to respond to imatinib, and clinical trials evaluating
its efficacy in patients with newly diagnosed Ph-positive
ALL are ongoing.
Nilotinib
This highly specific BCR-ABL inhibitor is approximately 30-fold more potent than imatinib and is active in
vitro against 32 of 33 BCR-ABL mutations.71 It is a substrate for both OCT-1 and efflux proteins.72 A phase 1
study of nilotinib in patients with imatinib-resistant
CML and Ph-positive ALL indicated that nilotinib had a
relatively favorable safety profile, and responses were
noted in a subset of adult patients with imatinib-resistant,
Ph-positive ALL.31 Specifically, 10% of patients who had
hematologic relapses achieved a partial hematologic
response, and 33% of patients with persistent molecular
signs of ALL achieved complete molecular remission after
nilotinib therapy. A subsequent phase 2 study of nilotinib
(400 mg twice daily) in relapsed or refractory Ph-positive
ALL reported that 24% patients attained a complete hematologic response (CHR).33 Data from studies in
patients with CML indicate that BCR-ABL P-loop mutations (eg, tyrosine to phenylalanine or histidine mutation
at codon 253 [Y253F/H] or glutamic acid to methionine
or valine mutation at codon 255 [E255K/V]) are resistant
to nilotinib.73 Nilotinib is approved only for imatinibresistant or imatinib-intolerant chronic-phase and accelerated-phase CML.
Combination therapy
Combining imatinib with conventional chemotherapy revolutionized the treatment of Ph-positive ALL; CR
rates now approach 95%, and 3-year OS rates can exceed
50% (Table 3).24-30 Imatinib may be administered either
concurrently or sequentially with chemotherapy.
Concurrent administration
Administration of the fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alter-
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April 15, 2011
nating with methotrexate and high-dose cytarabine
(hyper-CVAD) regimen concurrently with imatinib in
patients with de novo or minimally treated Ph-positive
ALL yielded a CR rate of 93%, and 52% of patients
obtained molecular negativity for BCR-ABL transcripts.30
Three-year DFS rates were significantly higher with
hyper-CVAD and imatinib treatment compared with
hyper-CVAD alone (68% vs 25%; P < .001).74 No unexpected toxicities related to the addition of imatinib were
observed.
Imatinib (600 mg daily) initiated after the first week
of induction therapy, coadministered during standard
induction, and then alternated with high-dose methotrexate and cytarabine during consolidation in patients with
de novo, Ph-positive ALL in the Japanese Adult Leukemia
Study Group resulted in a CR rate of 96% (median time
to CR, 28 days), a 71% molecular response rate with prolonged therapy, and improved long-term survival (Table
3).28 Although adding imatinib did not significantly
prolong survival durations in patients who underwent
alloSCT, outcomes were significantly better (P ¼ .0006)
for patients who did not undergo SCT but received the
imatinib-combined chemotherapy regimen versus chemotherapy alone. The profile and incidence of severe toxicity
did not differ from those associated with the chemotherapy-alone regimen.75
A similar high CR rate of 95% and a median survival
of 2.4 years were reported from the concurrent administration of imatinib (600 mg) with chemotherapy based on
the Linker regimen (Table 3).24 All patients in that trial
experienced grade 3 or 4 neutropenia, which was treated
with antibiotics. Four patients (20%) developed grade 3
or 4 hyperbilirubinemia during induction, which was
resolved by interrupting L-asparaginase and imatinib.
Sequential administration
Several trials have evaluated the safety and efficacy
of alternately administering chemotherapy and imatinib
(Table 3). The German Multicenter Acute Lymphoblastic
Leukemia trial sequentially compared alternating blocks
of chemotherapy with single-agent imatinib versus a concurrent treatment regimen in 2 cohorts of patients with
newly diagnosed, Ph-positive ALL.25 The simultaneous
treatment schedule induced greater reductions in BCRABL transcripts than the alternating schedule (52% versus
19%, respectively; P ¼ .01). However, these did not translate into significant improvements in survival compared
with the alternating regimen. Both schedules had acceptable toxicity and enabled a high percentage of patients to
1587
1588
65.8 (58-78)
69 (61-83)
29b
VCR, CTX, daunorubicin,
PRED
Imatinib, PRED
Daunorubicin, CTX, VCR,
PRED, L-asparaginase,
CTX, VCR, PRED, ASNase,
triple intrathecal
Imatinib, daunorubicin,
ASNase, VCR, PRED
Concurrent or alternating imatinib with dexamethasone,
VCR, daunorubicin, pegaspargase, CTX, Ara-C, 6mercaptopurine, methotrexate, G-CSF
Imatinib, CTX, VCR, doxorubicin, dexamethasone
Imatinib, CTX, daunorubicin,
VCR, PRED
Induction
Regimen
100
72
NA
93
NA; 95
95
97.1
CR
Rate, %
48% at 1 y
58% at 1 y
43% at 4 y
76% vs 63%
at 3 yd
52% at 2 y;
61% at 2 yc
NA
NA
DFS
Rate
3-y OS: 90% with
alloSCT, 33%
without
alloSCTe
4-y OS: 55% with
alloSCT, 80%
with auto-SCT,
25% without
SCTg
Relapses in 13%
with alloSCT vs
90% without
alloSCTa
Benefit of
AlloSCT
74% at 1 y
66% at 1 y
52% at 4 y
NA
36% at 2 y;
43% at 2 y
NA
56.8% at 3 y
Survival
Rate
CR indicates complete remission; DFS, disease-free survival; alloSCT, allogeneic stem cell transplantation; JALSG, Japan Adult Leukemia Study Group; ALL, acute lymphoblastic leukemia; CTX, cyclophosphamide; VCR, vincristine; PRED, prednisone; NA, not available; ASNase, asparaginase; GMALL, German Multicenter Trials of Adult Acute Lymphoblastic Leukemia; Ara-C, cytosine arabinoside; G-CSF,
granulocyte-colony-stimulating factor; hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; OS, overall survival; GRAAPH, Group for Research on Adult Acute
Lymphoblastic Leukemia (Philadelphia chromosome-positive); autoSCT, autologous stem cell transplantation; GRALL, Group for Research in Adult Acute Lymphoblastic Leukemia (Philadelphia chromosomenegative); GIMEMA, Italian Adult Hematologic Malignancy Group.
a
Relapses developed in 18 of 20 patients (90%) who did not undergo alloSCT in CR1 but in only 7 of 54 patients (13%) who underwent alloSCT in CR1.
b
Values are shown for evaluable patients.
c
Values shown are the estimated probability of remission.
d
The 3-year CR rate was 76% for 13 patients who achieved a major molecular response before alloSCT compared with 63% for 31 patients who did not (P ¼ .2).
e
In de novo patients aged 40 years, the 3-year OS rate was 90% with alloSCT (n ¼ 10) versus 33% without alloSCT (n ¼ 6; P ¼ .005).
f
Patients received imatinib during consolidation therapy.
g
The 4-year OS rates in the alloSCT, autoSCT, and no-SCT groups were 55%, 80% and 25%, respectively (alloSCT vs autoSCT, P ¼ .16; alloSCT vs no SCT, P ¼ .05; autoSCT vs no SCT, P ¼ .008).
GRALL AFR09:
Delannoy 200626b
GIMEMA: Vignetti
200727
29b
45 (16-59)
45
GRAAPH-2003:
Tanguy-Schmidt
200929f
Elderly patients
51 (17-84)
54b
Hyper-CVAD:
Thomas 201030
43.5 (19-65)
37 (15-67)
19b
Modified linker:
Lee 200524
GMALL:
Wassmann
200625
47 Alternate;
45 concurrent
45 (15-64)
Median Age
(Range), y
103
No. of
Patients
JALSG ALL 202:
Hatta 200928
Adult patients
Study: Reference
Table 3. The Effect of Combined Imatinib and Chemotherapy on Outcome in Philadelphia Chromosome-Positive Adult and Elderly Patients
Review Article
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Philadelphia Chromosome-Positive ALL/Lee et al
undergo SCT. However, transient grade 3 or 4 liver toxicity developed frequently during the concurrent regimen
and was attributed to the use of pegylated L-asparaginase
and/or 6-mercaptopurine.76,77 A sequential imatinib protocol in which treatment with imatinib was stratified by
patient response to 2 weeks of chemotherapy resulted in a
significantly higher overall CR rate of 96% (P < .001)
compared with the historic CR rate of 71% reported in
the Adult ALL-94 trial, which did not include imatinib.
All patients who achieved CR and had an available donor
(n ¼ 22) underwent alloSCT in first CR; at 18 months,
the estimated DFS and OS rates were 51% and 65%,
respectively.78
Combination chemotherapy with dasatinib
Dasatinib combined with conventional chemotherapy is also efficacious and safe in patients with Ph-positive
ALL. Combining hyper-CVAD with dasatinib (50 mg
twice daily for the first 14 days of each cycle) led to CR in
93% of patients; after a median follow-up of 10 months,
75% of patients were alive, and 64% remained in CR. A
high incidence of T315I ABL mutation was noted among
relapsed patients.79 The AFR07 trial evaluated dasatinib
in combination with the European Working Group on
Adult ALL chemotherapy protocols for the treatment of
patients aged 55 years with Ph-positive ALL.80 Dasatinib was administered with vincristine and dexamethasone
during induction; sequentially with methotrexate and
L-asparaginase alternating with cytarabine during consolidation; and with 6-mercaptopurine, methotrexate, and
dexamethasone/vincristine during maintenance. A 95.2%
CHR rate was observed, and the rate of serious adverse
events was 40%, as expected in this population. Responses
appeared to be durable; the level of minimal residual disease (MRD) has continued to decrease with prolonged
therapy.
Synergy between chemotherapeutic agents used
in combination therapy
The success of multiagent combination chemotherapy is based on several factors. The drugs typically have
different mechanisms of action with minimal overlap of
toxicities and low cross-resistance. The drugs usually are
complementary; ie, they are additive or synergistic interaction and have minimal or no antagonistic effects.81 In
vitro studies have demonstrated clearly that imatinib
exerts a synergistic effect in combination with vincristine;
an additive effect with daunorubicin, cyclophosphamide,
cytarabine, and etoposide; and an antagonistic effect with
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methotrexate.81,82 However, imatinib and most of the
chemotherapeutic agents that are used in ALL therapy
may have overlapping toxicities.83 Examples are the hepatotoxicity of imatinib and L-asparaginase25,76 and the cardiotoxicity of imatinib and doxorubicin, although the
cardiotoxicity of imatinib is controversial.
Tyrosine kinase inhibitors with steroids alone
The treatment of elderly patients with Ph-positive
ALL has been limited by their intolerance to chemotherapy, the inability to undergo alloSCT because of comorbidities, and biologic characteristics of the disease.84
Several approaches to using TKI-based therapy have been
explored in these patients, including a chemotherapy-free
treatment based only on a TKI and steroids. In 1 study
from the Italian Adult Hematologic Malignancy Group
(GIMEMA), patients ages 61 to 83 years with Ph-positive
ALL received a 7-day steroid pretreatment followed by a
45-day induction of imatinib (800 mg daily) plus prednisone (40 mg/m2 daily).27 Therapy was well tolerated, and
no major toxicities were reported. All 29 assessable
patients (100%) experienced a CHR; and, at 12 months,
the OS and DFS probabilities were 74% and 48%, respectively. The GIMEMA prospective study LAL1205 has
evaluated a similar regimen using dasatinib (70 mg) in
adult patients with Ph-positive ALL (median age, 54
years).85 All 34 evaluable patients (100%) on that trial
who received this regimen achieved a CHR, and the OS
rate at 10 months was 80.7%. Adding mixed-agent chemotherapy to TKI-steroid treatments does not appear to
substantially increase 1-year OS or to decrease relapse
rates in elderly patients with Ph-positive ALL. The Group
for Research in Adult Acute Lymphoblastic Leukemia
AFR09 study, which combined standard induction therapy with imatinib and prednisone, reported 1-year relapse
and OS rates of 58% and 66%, respectively.26 Although
these values were significantly improved from historic
controls who received chemotherapy without imatinib,26
they appear to be at par with chemotherapy-free regimens
that included only TKIs and steroids.27,85 It would be
interesting to combine TKIs and steroids with other established nonmyelotoxic agents (eg, vincristine) in elderly
patients with Ph-positive ALL.
Allogeneic stem cell transplantation in the
tyrosine kinase inhibitor era
AlloSCT in first CR remains the standard of care for
Ph-positive ALL and is the only established therapy that
offers the possibility of cure.43 However, previous
1589
Review Article
treatment with TKIs can increase the feasibility of SCT in
a greater proportion of patients with Ph-positive ALL by
increasing remission rates and extending remission durations.43,84 In addition, TKIs have increased the proportion of patients who experience sustained remissions and
have provided additional time to identify a suitable donor.
Reducing BCR-ABL transcript levels after imatinib-based
therapy also has resulted in a lower pre-SCT tumor burden.84 Finally, 3 studies28-30 have demonstrated a clear
benefit for alloSCT over chemotherapy alone (Table 3).
Additional data with longer follow-up are needed to
determine whether alloSCT still may be necessary in
patients with Ph-positive ALL who receive TKI-combination chemotherapy regimens.
Treatment of minimal residual disease
The presence of p190 BCR-ABL transcripts after
alloSCT in the preimatinib era was indicative of MRD
and predicted a relapse in patients with Ph-positive
ALL.86 Prophylactic imatinib given after transplantation,
immediately after engraftment, may improve outcomes
by preventing a resurgence of the leukemia clone. Two
small series have demonstrated that this approach is tolerated well and is accompanied mainly by transient elevations in hepatic transaminases, which usually respond to
dose interruptions or modifications.87,88 One multicenter
trial evaluated imatinib (400 mg daily) as post-SCT treatment for patients with MRD-positive, Ph-positive ALL to
prevent relapse and reported the eradication of molecular
disease in 52% of treated patients after 1.5 months of
treatment.89 The failure to achieve molecular negativity
shortly after starting imatinib was predictive of relapse;
the 1-year DFS rate among patients who achieved an early
molecular CR was 91%, versus 8% in patients who had
MRD (P < .001). Therefore, additional or alternative
antileukemic treatment should be initiated in patients
who remain positive for BCR-ABL transcripts 2 to 3
months after starting imatinib therapy post-SCT.
Future Directions
Given the superior results of imatinib combined with
chemotherapy versus imatinib alone, future clinical studies should focus on how imatinib and other TKIs can be
incorporated most effectively into integrative chemotherapeutic regimens. Optimal combination schedules, dosages, and the role of alloSCT need to be determined. New
agents that are in development include INNO-406, bosutinib, XL228, FTY720, AP24534, DCC-2036, PHA739358, and sorafenib. Both INNO-406 and bosutinib
1590
(SKI-606) are orally available dual SRC/ABL inhibitors
that have demonstrated activity against most imatinib-resistant BCR-ABL mutants.90,91 However, neither has
demonstrated activity against the T315I mutant, and
bosutinib is inactive against the V299L mutant.90-94
Phase 1 trials indicate that both are well tolerated in imatinib-resistant leukemia patients, and phase 2 trials evaluating drug efficacy are ongoing.90,91
All of the other novel agents are active against all
mutations including, T315I. XL228, another dual SRC/
ABL inhibitor, may be a potent inhibitor of the T315I
mutant and is in phase 1 trials. The immunosuppressant
FTY720 (fingolimod) may offer an alternative approach
to controlling BCR-ABL-mediated leukemogenesis.95
FTY720 activates protein phosphatase 2A (PP2A) and
was developed to prevent organ transplantation rejection.
BCR-ABL-mediated inhibition of PP2A is essential to
BCR-ABL-mediated leukemogenesis, and FTY720 can
impair clonogenicity of imatinib/dasatinib-sensitive and
imatinib/dasatinib-resistant p190/p210 BCR-ABL myeloid and lymphoid cell lines. AP24534 is a pan-BCR-ABL
inhibitor that inhibits the T315I mutant and overcomes
imatinib-based resistance.96 DCC-2036 inhibits ABL by
a non-ATP-competitive mechanism and, thus, avoids the
steric clash with T315I.97 Finally, the last 2 agents (PHA739358 and sorafenib) are not ABL-specific inhibitors.
PHA-739358 (danusertib) is an aurora kinase inhibitor
that also is active against T315I,98 and sorafenib is an
RAF kinase inhibitor that exerts its effect on BCR-ABL
through the down-regulation of down-stream targets.99,100 Currently, all of these agents are being evaluated in clinical trials.
In conclusion, imatinib revolutionized the outcome
of patients with Ph-positive ALL and is a crucial element
of Ph-positive ALL therapy. However, when it is used as a
single agent in previously treated patients, imatinib
responses are not durable, and clinical resistance develops
rapidly. Its use as part of an integrative chemotherapeutic
regimen appears to elicit improved response rates and better long-term outcomes. Newer TKIs, such as dasatinib
and nilotinib, appear to be safe and efficacious in patients
with Ph-positive ALL who have imatinib resistance. Combining TKIs with established antileukemic agents is
promising and may substantially improve remission duration and the prognosis for patients with Ph-positive ALL.
Side-effect profiles must be evaluated with combination
regimens, and optimal dosages must be determined, to
minimize treatment-related toxicity and evaluate the efficacy and safety of these regimens in patients with Ph-
Cancer
April 15, 2011
Philadelphia Chromosome-Positive ALL/Lee et al
positive ALL. Finally, it will be interesting to observe how
the addition of monoclonal antibodies, eg, rituximab,
into the armamentarium of ALL will change the treatment
of Ph-positive ALL.
CONFLICT OF INTEREST DISCLOSURES
This research was supported in part by grants from the National
Cancer Institute (Grant CA16056; H.J.L., J.E.T., E.S.W., and
M.W.); the Szefel Foundation, Roswell Park Cancer Institute
(E.S.W.); and the Heidi Leukemia Research Fund, Buffalo, New
York (M.W.). Dr. Wetzler is receiving honoraria from Novartis,
Bristol Myers-Squibb, and Enzon. Editorial support was provided in part by Piyali Dhar Chowdhury, PhD (Phase 5 Communications Inc., NY) with financial support from Enzon
Pharmaceuticals, Inc.
12.
13.
14.
15.
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