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Keywords:

  • acute lymphoblastic leukemia;
  • imatinib resistance;
  • Philadelphia chromosome;
  • tyrosine kinase inhibitors

Abstract

  1. Top of page
  2. Abstract
  3. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  4. Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  5. Future Directions
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

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 Ph-positive ALL with a focus on TKIs and combined chemotherapeutic regimens. Cancer 2011. © 2010 American Cancer Society.

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.

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

  1. Top of page
  2. Abstract
  3. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  4. Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  5. Future Directions
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

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 region-Abelson 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 Chromosome-Positive Acute Lymphoblastic Leukemia

  1. Top of page
  2. Abstract
  3. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  4. Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  5. Future Directions
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

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 second-generation 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 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.

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/RegimenReferenceNo. of PatientsCR Rate, %Survival
  • 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), +8, −7, and t(4;11).

CALBG 8762Westbrook 199281471Median OS, 11.2 mo
GMALLGotz 199292576OS at 40 mo, 6%
VAD/CVADPreti 1994104156Median OS, 11 mo
MRC-UKALL XASecker-Walker 1997114083DFS at 3 y, 13%
LALAThomas 1998124364Median OS, 9 mo
CALGBWetzler 199956779a5-Y survival probability, 0.11
Hyper CVADKantarjian 2000133291OS at 5 y, 7%
GMALLForman 19871517568.4DFS at 3 y, 13%
CALGBSetzler 2004611174OS at 3 y, 19%
Table 2. The Role of Allogeneic Stem Cell Transplantation in the Era Before Imatiniba
VariableForman 198715Barrett 199216Chao 199517Snyder 199918Goldstone 2001101bDombret 200220bLaport 200821
  • NA indicates not available; CR1, first complete remission; CTX, cyclophosphamide; TBI, total body irradiation; VP16, etoposide; ±, with or without.

  • a

    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 © 2008 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.

Total no. of patients/total in study1067382372/20374/15467
Age (range), y28 (23-45)28 (5-49)NA30 (6-44)NA42 (17-56)36 (2-57)
Remission stance at time of transplantationMixedcMixedMixedCR1CR1CR1Mixed
Conditioning therapyCTX/TBI; VP16/TBICTX/TB1; other/ TBI; non -TBICTX±VP16 except for 2 patientsVP16/TBI except for 2 patientsVP16/TBINot specifiedVP16/TBI; CTX/VP16/TBI
Treatment-related mortality, %4041NA39402435
SurvivalMedian, 19 mo38% at 2 yCR1, 46% at 2 y65% at 3 y43% at 5 y35% at 3 yCR1, 54% at 10 y; >CR1, 29% at 10 y

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 BCR-ABL-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.47-50BCR-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 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 α-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 cell-cell contact, and stromal cell-derived factor 1α, 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 (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 V-yes-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 Ph-positive 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 BCR-ABL 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 325-fold 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 (imatinib-resistant 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 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 imatinib-resistant 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.

Table 3. The Effect of Combined Imatinib and Chemotherapy on Outcome in Philadelphia Chromosome-Positive Adult and Elderly Patients
Study: ReferenceNo. of PatientsMedian Age (Range), yInduction RegimenCR Rate, %DFS RateBenefit of AlloSCTSurvival 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 chromosome-negative); 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 = .2).

  • e

    In de novo patients aged ≤40 years, the 3-year OS rate was 90% with alloSCT (n = 10) versus 33% without alloSCT (n = 6; P = .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 = .16; alloSCT vs no SCT, P = .05; autoSCT vs no SCT, P = .008).

Adult patients
 JALSG ALL 202: Hatta 20092810345 (15-64)Imatinib, CTX, daunorubicin, VCR, PRED97.1NARelapses in 13% with alloSCT vs 90% without alloSCTa56.8% at 3 y
 Modified linker: Lee 20052419b37 (15-67)Imatinib, daunorubicin, ASNase, VCR, PRED95NA NA
 GMALL: Wassmann 20062547 Alternate; 45 concurrent43.5 (19-65)Concurrent or alternating imatinib with dexamethasone, VCR, daunorubicin, pegaspargase, CTX, Ara-C, 6-mercaptopurine, methotrexate, G-CSFNA; 9552% at 2 y; 61% at 2 yc 36% at 2 y; 43% at 2 y
 Hyper-CVAD: Thomas 20103054b51 (17-84)Imatinib, CTX, VCR, doxorubicin, dexamethasone9376% vs 63% at 3 yd3-y OS: 90% with alloSCT, 33% without alloSCTeNA
 GRAAPH-2003: Tanguy-Schmidt 200929f4545 (16-59)Daunorubicin, CTX, VCR, PRED, L-asparaginase, CTX, VCR, PRED, ASNase, triple intrathecalNA43% at 4 y4-y OS: 55% with alloSCT, 80% with auto-SCT, 25% without SCTg52% at 4 y
Elderly patients       
 GRALL AFR09: Delannoy 200626b29b65.8 (58-78)VCR, CTX, daunorubicin, PRED7258% at 1 y 66% at 1 y
 GIMEMA: Vignetti 20072729b69 (61-83)Imatinib, PRED10048% at 1 y 74% at 1 y
Concurrent administration

Administration of the fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating 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 = .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 BCR-ABL transcripts than the alternating schedule (52% versus 19%, respectively; P = .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 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 = 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 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 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

  1. Top of page
  2. Abstract
  3. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  4. Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  5. Future Directions
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

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, PHA-739358, and sorafenib. Both INNO-406 and bosutinib (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 (PHA-739358 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-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

  1. Top of page
  2. Abstract
  3. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  4. Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  5. Future Directions
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

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.

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  1. Top of page
  2. Abstract
  3. Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  4. Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
  5. Future Directions
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES
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