Allogeneic Hematopoietic Cell Transplantation for Adult Philadelphia-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors

Article Outline

• Abstract
• Introduction
  • Allogeneic HCT after Front-Line Imatinib in Ph+ ALL
  • Imatinib Facilitates allo-HCT in Patients with Relapsed or Refractory Ph+ ALL
  • Prophylactic Administration of Imatinib Post-allo-HCT
  • Imatinib plus Donor Lymphocyte Infusion (DLI)
  • MRD Post-allo-HCT: Is There a Role for Imatinib?
  • Other Tyrosine Kinase Inhibitors
    • Dasatinib
    • Feasibility of dasatinib as induction therapy
    • Nilotinib
  • TKIs in Elderly Patients with Ph+ ALL Not Candidates for allo-HCT
  • TKI in Patients Older Than 55 Years of Age
    • Imatinib monotherapy
    • Imatinib plus steroids for elderly patients with Ph+ ALL
    • Dasatinib plus prednisone as front-line therapy in elderly Ph+ ALL
• Summary
• References
• Copyright

Abstract 

Allogeneic hematopoietic cell transplantation in first complete remission (CR1) is considered the standard of care, and the only established therapy that offers a possibility of cure for patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Unfortunately, a number of patients, with suitable HLA-matched donors, are unable to receive an allograft because they fail to respond, or relapse shortly after induction chemotherapy. Incorporating imatinib during the induction/consolidation phase is facilitating a higher number of potentially curative allografts by improving both remission rates and/or the durability of responses in patients with Ph+ ALL. Imatinib and other tyrosine kinase inhibitors are also improving outcomes in elderly patients with Ph+ ALL, ineligible for allografting, when combined with glucocorticoids, and/or conventional chemotherapy. The addition of imatinib or other tyrosine kinase inhibitors to the therapeutic armamentarium of Ph+ ALL is reshaping the treatment algorithm and improving prognosis of this dreadful disease.

Key Words: Allogeneic hematopoietic cell transplantation, Imatinib, Philadelphia-positive acute lymphoblastic leukemia, Tyrosine kinase inhibitors

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Introduction 

Adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) have an extremely poor prognosis when treated with conventional chemotherapy alone, yielding a long-term disease-free survival (DFS) of <10% 1, 2, 3, 4, 5. Allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1) is considered the standard of care, and the only established approach that offers the possibility of cure in Ph+ ALL (Table 1) 6, 7, 8, 9, 10, 11, 12, 13, 14.

Table 1. Selected Studies Evaluating the Outcome of Ph+ ALL after allo-HCT (Pre-imatinib Era)

TRM indicates treatment-related mortality; RR, relapse rate; CR1, first complete remission; MRD, matched related donor; MUD, matched unrelated donor; DFS, disease-free survival; OS, overall survival.

The Philadelphia chromosome is among the first cancer-specific translocations identified in humans [15]. It is the product of a reciprocal translocation between the long arms of chromosomes 9 and 22 t(9;22) (q34;q11), which results in a hybrid BCR-ABL gene that is transcribed into a chimeric BCR-ABL mRNA 16, 17. Based on the breakpoint of the BCR region, 2 fusion transcripts products are identified: (1) a major BCR-ABL transcript that encodes the p210 oncoprotein, and (2) a minor BCR-ABL transcript that encodes the p190 oncoprotein, most commonly present in Ph+ ALL. The Philadelphia chromosome is seen in approximately 20% of cases of adult ALL [18], and up to 50% in patients above 50 years of age [4]. These oncoproteins play a key role in the pathogenesis of the disease by enhancing tyrosine kinase activity, among others, with a consequent effect on signal transduction pathways responsible for cellular proliferation [19].

Imatinib mesylate is a selective BCR-ABL tyrosine kinase inhibitor that is active against Ph+ ALL 20, 21, 22, 23. Incorporation of imatinib and other tyrosine kinase inhibitors (TKIs) into the therapeutic armamentarium of Ph+ ALL is reshaping the treatment algorithm of patients with Ph+ ALL. In this article we provide a comprehensive review of the published data of imatinib and other TKIs in the setting of allo-HCT for adult patients with Ph+ ALL. We also review the role of TKIs in the treatment of elderly patients with Ph+ALL, not otherwise candidates for allo-HCT.

Allogeneic HCT after Front-Line Imatinib in Ph+ ALL 

Incorporating imatinib during the induction/consolidation phase represents a logical approach that facilitates allo-HCT in a higher number of patients with Ph+ ALL by improving both remission rates and/or durability of responses. A prospective phase II study by Thomas et al. [24] evaluated a combination of hyper-CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone) plus imatinib 400 mg/day on days 1 through 14 of each chemotherapy cycle, followed by imatinib-based consolidation/maintenance in 20 patients with Ph+ ALL. Fifteen patients had persistent disease (de novo = 11; primary induction failure = 4) and 5 were in CR, after induction chemotherapy. All 15 (100%) patients treated with persistent disease achieved CR; but only 10 patients (de novo = 7, CR = 2, primary refractory = 1, at study entry) underwent allo-HCT at a median of 3.5 (1-8) months from starting therapy. Fifteen (75%) of the 20 patients remained alive and in CR at a median follow-up of 20 (4-24) months. Nine of 10 patients treated with hyper-CVAD plus imatinib, who underwent allo-HCT, were alive in CR after a median of 12 months. One patient in the allo-HCT group died in relapse during reinduction. A long-term follow-up of 54 patients was presented at the annual meeting of the American Society of Hematology (ASH) in 2007 [25]; only 16 of 54 patients had undergone allografting at a median of 5 (1-13) months from start of therapy. Allo-HCT did not appear to improve 2-year survival rates when compared to a group of 38 patients who received imatinib plus chemotherapy (63% versus 56%) [25]. However, these results should be interpreted with caution because of the nonrandomized nature of the study and the small sample size.

A prospective nonrandomized phase II trial by the Japan Adult Leukemia Study Group (JALSG ALL202) reported the interim results on 24 patients with newly diagnosed Ph+ ALL who received imatinib 600 mg/day in combination with chemotherapy [26]. Imatinib was prescribed concurrently with induction chemotherapy, and alternated with chemotherapy during consolidation. Allo-HCT was performed if an HLA-matched donor was available. Twenty-three (96%) achieved CR after 1 course of remission-induction chemotherapy plus imatinib. Eighteen (78%) of 23 patients achieved molecular remission (MR). Fifteen (63%) patients underwent allografting in CR1 (matched-related [MRD] = 6; matched-unrelated [MUD] = 7; cord blood = 2). At a median follow up of 1 year, event-free survival (EFS) and overall survival (OS) rates were reported at 68% and 89%, respectively. This study suggests that imatinib plus chemotherapy produces high and durable CR rates, allowing the necessary time to identify a suitable HLA-matched donor.

A single institution study by Lee et al. [27] evaluated the efficacy of first-line imatinib and allo-HCT in 29 adult patients with newly diagnosed Ph+ ALL. All patients enrolled had completed induction chemotherapy and were eligible to proceed with allo-HCT. Twenty-three of 29 patients, in CR1, received consolidation chemotherapy followed by imatinib 400-600 mg/day until allo-HCT. Twenty-two of 23 maintained CR until allografting, performed at a median of 3.5 (2-7) months from starting therapy. When compared to a historic control (chemotherapy without imatinib), the group treated with imatinib had lower relapse rates (4.3% versus 40.7%, P = .003). The remaining 6 patients, refractory to induction chemotherapy, received imatinib 600 mg/day plus a combination of high-dose cytarabine, mitoxantrone, and etoposide. Three of the 6 patients achieved CR and proceeded to transplant. Imatinib allowed a higher rate of allografting than historic approaches (86.2% versus 51.5%, P = .004). Twenty-eight (CR = 25; refractory = 3) of 29 patients underwent HLA-matched sibling (N = 22) or unrelated (N = 6) allo-HCT at a median of 138 (range: 56-217) days from induction therapy. Estimated probability of nonrelapse mortality (NRM) at 3 years was 18.7%. The 3-year estimated probabilities of both DFS and OS were 78.1% at a median follow-up of 25 months from allo-HCT. This study suggests that imatinib is a reasonable and effective postinduction maintenance therapy which results in sustained CR that ultimately facilitates allografting.

De Labarthe et al. [28] treated 45 patients with de novo Ph+ ALL with imatinib in combination with induction or consolidation chemotherapy. Fourteen patients (31%) were good early responders after corticosteroids and chemotherapy, and continued with standard induction chemotherapy, without imatinib, until achieving hematologic CR. Patients were subsequently treated with imatinib 600 mg/day plus consolidation chemotherapy until allo-HCT for a planned period of 90 days. Another cohort of 31 (69%) poor early responders were treated with imatinib 800 mg/day in combination with vincristine and dexamethazone (DIV), and imatinib was continued at the same dose until allo-HCT for a planned period of 90 days. Simultaneous administration of imatinib and chemotherapy was well tolerated. The overall CR rate was 96%, with 2 deaths occurring in the DIV group. Overall, the authors reported a BCR-ABL PCR negativity rate of 29%. In addition, 56% of patients achieved low PCR levels (defined as a BCR-ABL/ABL ratio between 10⁻⁵ and 10⁻⁴). Twenty-two (good early responder = 8; poor early responder = 14) of 39 patients in CR proceeded to allografting once a suitable HLA-matched donor was available (MRD = 15; MUD = 7), at a median of 92 (18-159) days from induction chemotherapy. Fourteen of 22 patients had achieved low PCR levels prior to allo-HCT. At 18 months, estimated cumulative incidence of relapse, DFS, and OS for allograft recipients were reported at 30%, 51%, and 65%, respectively. This study shows that combining imatinib and chemotherapy is a reasonable pre-allo-HCT strategy.

A prospective multicenter trial by Wassmann et al. [29] evaluated 2 different schedules of imatinib in 92 patients with Ph+ ALL who received uniform induction and consolidation chemotherapy. Forty-seven patients (cohort I) received imatinib alternating with chemotherapy, whereas 45 patients (cohort II) received imatinib concomitantly with chemotherapy until allo-HCT. Patients in cohort I received imatinib 400 mg/day. Twelve patients had the dose increased to 600 mg/day. Patients in cohort II received imatinib at 600 mg/day. A higher proportion of patients in cohort I had chemoresistant disease. PCR-negativity was superior in patients in cohort II (52% versus 19%); but grade III-IV cytopenias and transient hepatotoxicity, requiring treatment disruption, were also higher in this cohort (87% versus 53%). Seventy-seven percent of patients from each cohort proceeded to allo-HCT in CR1. Median survival of patients in cohorts I and II were 16.3 months and 19.6 months, respectively. The estimated 1-year and 2-year probability of survival, after diagnosis, for patients in cohort I were 72% and 36.2%, and in cohort II 61% and 43%, respectively (P = .97). This study shows that both schedules of imatinib facilitate allo-HCT in CR1 in a significant proportion of patients; but concurrent administration of imatinib and chemotherapy, albeit not statistically significant, appears to offer a better antileukemia effect.

The UKALLXII/ECOG2993 study originally intended to evaluate a preparative regimen of total body irradiation (TBI) and etoposide in 267 patients with Ph+ ALL in the pre-imatinib era [30]. Imatinib 600 mg/day was added following induction chemotherapy and for 2 years or until relapse/progression postallograft to a subsequent group of 153 patients (following first induction = 89; imatinib started with second induction = 64). The authors conclude that addition of imatinib during induction may result in higher CR rates, but did not appear to improve survival [30]. These studies are summarized in Table 2.

Table 2. Selected Trials of Imatinib Up-front with Induction/Consolidation in Patients with Ph+ ALL Prior to Allogeneic HCT

CHR indicates complete hematologic response; Mol. R, molecular response; DFS, disease-free survival; OS, overall survival; MUD, matched unrelated donor; MRD, matched related donor; CB, cord blood; EFS, event-free survival.

Imatinib Facilitates allo-HCT in Patients with Relapsed or Refractory Ph+ ALL 

Achieving a CR before initiation of the myeloablative preparative chemotherapy (or chemoradiotherapy) is a determinant for improved outcomes in patients with Ph+ ALL after allografting [31]. Wassmann et al. [23] evaluated the efficacy of imatinib as a salvage strategy in 46 patients, median age of 43.5 (17-57) years, with relapsed or refractory Ph+ ALL who had not received a previous transplant. Imatinib was administered at 600 mg/day. Ten patients achieved CR (hematologic or bone marrow) prior to proceeding with allo-HCT. Twenty-two (73%) of 30 eligible patients underwent allo-HCT, and 18 (82%) attained CR, 1 patient had refractory disease, and 3 died prior to response assessment. Seven (32%) maintained a CR after a median follow-up of 9.4 (1.7-23.8) months, whereas 7 (32%) relapsed after a median of 5.2 months post-allografting. Treatment-related mortality (TRM) was 36%. Estimates of 1-year DFS and OS for all patients were 25.5% and 44.8%, respectively. The probability of 1-year DFS was superior when allo-HCT was performed in CR compared to persistent (relapsed or refractory) disease (51.4% versus 8.3%, P = .006). This study shows that imatinib is effective salvage therapy prior to allo-HCT in patients with Ph+ ALL; but allo-HCT must be performed promptly before disease progression ensues. Also, it confirms that remission status at time of allo-HCT is an important determinant of outcome. This and other studies using TKIs in a similar manner are summarized in Table 3 20, 23, 32, 33.

Table 3. Selected Studies Evaluating Imatinib in Relapsed or Refractory Ph+ ALL

CHR indicates complete hematologic response; CMR, complete marrow response; PMR, partial marrow response; TTP, time to progression; OS, overall survival; DFS, disease-free survival; PFS, progression-free survival; LyBC, CML-lymphoid blast crisis; MyBC, CML-myeloid blast crisis; MR, marrow response; RR, relapse rate.

Prophylactic Administration of Imatinib Post-allo-HCT 

Carpenter et al. [34] provided safety data on postallografting imatinib therapy in 15 high-risk Ph+ ALL patients (children and adults). Adults were given imatinib at a dose of 400 mg/day after hematologic engraftment until 1 year from allo-HCT [34]. Fourteen patients had received imatinib prior to allo-HCT. Grade I-III nonhematologic toxicities were reported in 66.6%. Administering imatinib early after allografting is feasible; however, efficacy of this approach and its ultimate effect on minimal residual disease (MRD) post allo-HCT is not known.

Imatinib plus Donor Lymphocyte Infusion (DLI) 

Patients with Ph+ ALL relapsing after allo-HCT have a poor prognosis. There is anecdotal experience using imatinib in combination with DLI in patients with Ph+ ALL relapsing after an allograft. Shimoni et al. [22] reported on 2 patients with relapsed Ph+ ALL, after allo-HCT, where imatinib induced hematologic CR and BCR-ABL negativity (by FISH) prior to administering DLI of 1 × 10⁸ CD3⁺ cells/kg within 2 weeks from imatinib [22]. Acute graft-versus-host disease (aGVHD) occurred 2 weeks following DLI in both cases. One patient who received imatinib maintenance after DLI remained alive in CR at 4.5 months, whereas the second patient died of relapsed disease 4 months after DLI.

Wassmann et al. reported a series of 5 patients receiving DLI for relapsed Ph+ ALL either prior to imatinib (N = 1), concomitantly with imatinib (N = 1), or following imatinib (N = 3) [35]. Administration of imatinib was feasible but did not appear to offer a survival benefit because all patients eventually relapsed. Using imatinib before DLI is feasible; however, larger clinical trials are needed to determine the precise benefit of imatinib in this setting.

MRD Post-allo-HCT: Is There a Role for Imatinib? 

One-third of patients with Ph+ ALL transplanted in CR1 ultimately relapse and die from their disease [20]. Persistence of molecular disease after allo-HCT predicts for a higher risk of relapse [36]. A prospective study by Wassmann et al. [35] assessed the efficacy of imatinib 400 mg/day in 27 patients with Ph+ ALL with evidence of persistent molecular disease after allo-HCT (N = 24) or auto-HCT (N = 3). BCR-ABL became undetectable in 52% of these patients after a median of 1.5 (0.9-3.7) months; and MR were sustained while on imatinib treatment. However, 3 patients relapsed after discontinuation of imatinib. Interestingly, 12 (92%) of 13 patients who failed to achieve PCR negativity, within 2 to 3 months after starting imatinib, relapsed at a median of 3 months.

Other Tyrosine Kinase Inhibitors 

Dasatinib (N-(2-chloro-6-methylphenyl)-2[6-[4-(2-hydroxylethyl)-1-piperazinyl]-2-methyl-4-pyrimadinlyl]amino]-5-thiazolecarboxamide, monohydrate) is a multityrosine kinase inhibitor that targets BCR-ABL, various SRC family of kinases (FYN, LCK, SRC, and YES), c-KIT, EPHA2, and platelet-derived growth factor receptor-β (PDGFR-β) at very low concentrations 37, 38, 39. It is approved by the United States Food and Drug Administration (U.S. FDA) for patients with chronic myelogenous leukemia (CML) and Ph+ ALL resistant or intolerant to imatinib [40]. Dasatinib differs from imatinib by its ability to bind to both the active and inactive conformations of the ABL kinase domain [41].

A phase II opened-label multicenter international trial (START-L) evaluated the efficacy and safety of dasatinib 70 mg twice daily in patients with Ph+ ALL who were imatinib-resistant or imatinib-intolerant [42]. A total of 36 patients (imatinib-resistant = 34; imatinib-intolerant = 2 patients) were evaluated. Over 50% of patients had received imatinib for over a year, and 15 (42%) had failed a prior HCT. Hematologic toxicities, including neutropenia (72%), anemia (47%), and thrombocytopenia (78%), ocurred in a majority of these patients. Grade III-IV nonhematologic toxicities consisted of febrile neutropenia (11%), diarrhea (8%), asthenia (8%), and pleural effusions (3%), among others. Overall hematologic response was 50%; major hematologic response (MaHR) were reported in 15 (42%) of 36 patients at a median of 1.8 months. Ten (67%) patients with an MaHR did not progress after 8 months of follow-up. Major cytogenetic responses were reported in 21 (58%) patients. The authors conclude that dasatinib is effective in patients with imatinib-resistant or imatinib-intolerant Ph+ ALL. A 2-year follow-up of the START-L, updated at ASH 2007, showed a median OS of 8.0 months and 1-year progression-free survival (PFS) of 22% after dasatinib initiation [43]. Dasatinib is capable of inducing hematologic and cytogenetic responses on most mutational genotypes of BCR-ABL except T315I 41, 42, 44, 45.

Ravandi et al. [46] reported results of a phase II trial for patients with newly diagnosed or relapsed Ph+ ALL or LY-BP CML who received dasatinib 50 mg twice daily for the first 14 days of each of 8 cycles of alternating hyper-CVAD and high-dose cytarabine and methotrexate (MTX). Patients achieving CR continued to receive maintenance dasatinib 50 mg twice daily, and vincristine and prednisone every month for 2 years followed by dasatinib treatment indefinitely. Outcomes were evaluated in different cohorts of patients: cohort I included 15 previously untreated Ph+ ALL patients with a median age of 55 (23-79) years; and cohort II included 4 patients with relapsed Ph+ ALL or LY-BP CML with a median age of 43 (26-69) years. Patients in both cohorts had received a median of 4 (1-8) cycles. At the time the authors presented at ASH 2007, 14 patients in cohort I and 3 patients in cohort II were evaluable for response to induction therapy. Thirteen (93%) patients in cohort I and 3 (100%) patients in cohort II achieved CR after 1 treatment cycle. Ten (91%) of 11 patients in cohort I and 3 (75%) of 4 patients in cohort II achieved cytogenetic CR after 1 cycle. Six patients achieved complete MR after the first cycle. Median time to neutrophil and platelet recovery was 18 and 25 days, respectively, for patients in cohort I, and 19 and 31 days, respectively, for patients in cohort II. Grade III-IV toxicity consisted of 7 episodes of GI bleeding as well as infections, diarrhea, hypophosphatemia, hypocalcemia, and elevated liver enzymes. One (7%) patient in cohort I died from infections. The authors conclude that dasatinib is feasible to administer in combination with hyper-CVAD, and could result in early MR in Ph+ ALL and LY-BP CML; but none of the patients had received an allo-HCT when the study was reported [46].

Nilotinib is an aminopyrimidine-derivative TKI that is active against imatinib-resistant CML and is more potent, in vitro, than imatinib 44, 47, 48. In 2007, the U.S. FDA granted accelerated approval to nilotinib for the treatment of chronic and accelerated phase CML in adult patients resistant or intolerant to prior therapy that included imatinib. Nilotinib, similar to imatinib, can only bind the inactive conformation of the ABL kinase domain, but with a 25-fold greater affinity that imatinib. A phase I dose escalation study by Kantarjian et al. [49] evaluated nilotinib in 119 patients with imatinib-resistant CML or Ph+ ALL. Thirteen patients with Ph+ ALL (hematologic relapse = 10; persistent molecular disease = 3) were included in the study. Only 1 (10%) of 10 patients with hematologic relapse achieved a partial hematologic response and 1 of 3 patients with persistent molecular disease achieved a complete MR. These findings suggest that nilotinib may have a role in Ph+ ALL; however, the nature of the study design (ie, phase I) and the small sample size limit the ability to draw conclusions about its efficacy in Ph+ ALL.

A phase II opened-label study evaluated the safety and efficacy of nilotinib in 41 patients, median age of 46 (18-75) years, with relapsed (N = 38) or refractory (N = 3) Ph+ ALL [50]. Nilotinib was administered for a median of 53 (1-563) days and a median dose of 800 mg/day. Responses were as follow: CHR = 24%; hematologic improvement = 2%; stable disease (SD) = 22%; progressive disease (PD) = 34%. The authors suggest that nilotinib appears to be active in patients with relapsed or refractory Ph+ ALL and propose future trials combining nilotinib with conventional chemotherapy.

Hematologic toxicicties are commonly seen with the various TKIs discussed herein. Nonhematologic toxicities including fluid retention and gastrointestinal side effects, among others, are common with TKIs. However, pleural effusions appear to be more commonly seen with dasatinib (grade I-IV = 19% [7/36 patients]; grade III-IV = 3% [1/36 patients] when using a dose of 70 mg twice daily) [43], whereas elevation of serum lipase (grade III-IV = 28% [9/32 patients] when using a dose of 400 mg twice daily) [50] and elevation of unconjugated bilirubin (grade I-I = 19% [6/32 patients] and grade III-IV = 9% [3/32 patients] when using a dose of 400 mg twice daily) [49] are more commonly seen with nilotinib.

TKIs in Elderly Patients with Ph+ ALL Not Candidates for allo-HCT 

The incidence of Ph+ ALL increases with age, achieving 50% in patients older than 50 years 4, 51. Elderly patients with Ph+ ALL have a poor prognosis because of low CR rates, short remissions, and high TRM. Imatinib and dasatinib have been evaluated, as monotherapy or in combination with chemotherapy, in older patients with Ph+ ALL.

TKI in Patients Older Than 55 Years of Age 

Ottmann et al. [52] prospectively compared imatinib (N = 28) to age-adapted multiagent chemotherapy (N = 27) in patients over 55 years of age with Ph+ ALL ineligible for allo-HCT. The median ages for patients randomized to receive either imatinib or multiagent chemotherapy were 66 (54-79) years or 68 (58-78) years, respectively. Imatinib 600 mg/day was administered in 4-week cycles. Crossover was permitted if there was no reduction of blasts after 2 weeks of assigned treatment. CNS prophylaxis was identical in all patients. Responses to induction were superior with imatinib (overall CR [CR with recovery of peripheral blood counts + CRi, CR without complete recovery of peripheral blood counts] = 96.3% versus 50%, P = .0001) (Table 4). Also, imatinib was associated with a significantly lower incidence of nonhematologic severe adverse events, both in the number of patients (39% versus 86%, P = .005) or number of serious adverse events (N = 12 versus N = 46, P = .0001). The estimated 2-year OS for all patients was 42% (±8%), with no significant difference between the 2 groups. The authors conclude that imatinib results in significantly higher CR rates in elderly patients with de novo Ph+ ALL with low toxicity compared to induction chemotherapy.

Table 4. Selected Trials of Tyrosine Kinase Inhibitors in Elderly Patients with Ph+ ALL Not Candidates for Allogeneic HCT

CHR indicates complete hematologic responses; DFS, disease-free survival; OS, overall survival. RFS, relapse-free survival.

The Group for Research on Adult Acute Lymphocytic Leukemia (GRAALL) evaluated imatinib 600 mg/day plus methylprednisolone alternating with chemotherapy in 30 patients, 55 years or older, with previously untreated Ph+ ALL (GRAALL AFR09) [53]. All patients were treated with methylprednisolone for 7 days, followed by chemotherapy-based induction and subsequent consolidation with imatinib and glucocorticoids for 2 months. Patients in CR, after consolidation, received 10 cycles of alternating chemotherapy, including 2 additional 2-month cycles of imatinib. Twenty-one (72%) of 29 evaluable patients achieved CR after induction therapy, and 5 additional patients achieved CRs after salvage with imatinib. The 1-year relapse-free survival (RFS) and OS were 58% and 66%, respectively. The authors compared these results to a historic cohort of 21 patients, who did not receive imatinib, demonstrating better CR rates (72% versus 29%, P = .003), 1-year RFS (58% versus 11%, P = .0003), and 1-year OS (66% versus 43%, P = .005) with imatinib. These findings albeit encouraging are limited by the relatively small sample size; there are also several unanswered questions including long-term outcomes beyond 1 year and the optimal dose and duration of imatinib therapy needed. Improvement in outcome of elderly patients with Ph+ ALL after introduction of imantinib has been reported by other groups [54].

The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) evaluated a chemotherapy-free regimen (LAL0201-B protocol) that combined imatinib 800 mg/day preceded by increasing doses of prednisone (10-40 mg/m²/day) for 7 days and additional prednisone (40 mg/m²/day) for 45 days, in 30 patients, median age of 69 (61-83) years, with Ph+ ALL [55]. Seven (23%) required dose reduction or temporary discontinuation of imatinib because of nonhematologic toxicity. A CHR was reported in all 29 (100%) evaluable patients, and a complete MR in 1 (3%) patient. The median survival and the median duration of hematologic responses in 29 patients were 20 months and 8 months, respectively. Thirteen (45%) patients were alive and in continuous remission at a median of 10 (1-32) months; 14 (48%) patients relapsed after a median of 4 (3-28) months, and 2 patients died in CR at 5 and 15 months. The 1-year probability of OS and DFS was 74% and 48%, respectively. This study supports a role for imatinib in combination with prednisone; but whether additional benefit could be derived from a longer maintenance remains unknown.

The GIMEMA group presented their first interim analysis of LAL1205, which evaluates the safety and efficacy of dasatinib and prednisone as induction treatment in 23 patients, median age of 57 (30-74) years, with Ph+ ALL [56]. The regimen consisted of dasatinib 70 mg twice daily and prednisone up to 60 mg/m²/day started 1 week prior to dasatinib and continued until day 31. Intrathecal MTX infusions were administered on days 22 and 43. Dasatinib was administered for a total of 84 days. CHR was 100% after 3 weeks. This interim analysis suggests that the combination of dasatinib plus prednisone is well tolerated and capable of inducing rapid and impressive hematologic responses. A longer follow-up is needed to determine durability of reponses and, more important, the impact of dasatinib on OS. This and other studies are summarized in Table 4.

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Summary 

Imatinib and other TKIs are becoming an integral component of modern treatment algorithms for patients across different stages of Ph+ ALL. Aforementioned studies show that incorporation of imatinib as a pretransplant strategy facilitates a higher rate of allo-HCT by improving both quality and durability of responses prior to allografting without significant increase in toxicity. Using imatinib early during induction, and continuing through consolidation, results in higher and durable CR rates. Achieving CR, moreover an MR, at the time of allo-HCT has a beneficial impact on outcomes.

Imatinib is also a reasonable and promising strategy in the posttransplant setting to consolidate and maintain molecular responses that may ultimately improve survival for patients with Ph+ ALL. Available data shows that imatinib is relatively well tolerated in this setting. However, the optimal duration of therapy posttransplant, particularly in patients with sustained MR remains to be determined.

Newer generation of TKIs such as dasatinib, among others, are already showing encouraging responses in patients with relapsed Ph+ ALL after transplantation. Decisions as to which TKI is better in this setting will require large randomized, multicenter trials.

Combining imatinib with conventional chemotherapy is feasible and results in better EFS and OS compared to historic controls of adult patients with newly diagnosed Ph+ ALL treated with conventional chemotherapy alone, albeit the follow-up is relatively short 24, 57. Nevertheless, in the absence of large prospective randomized trials comparing imatinib-chemotherapy regimens versus allo-HCT as a consolidative strategy, allo-HCT remains the best therapeutic approach that offers a possibility of cure in Ph+ ALL.

Imatinib or other TKIs are also improving outcomes in elderly patients with Ph+ ALL, ineligible for allografting, when combined with glucocorticoids, with or without chemotherapy. Future clinical trials should continue to evaluate the optimal way of combining imatinib with conventional chemotherapy in patients unable to tolerate allografting and to determine the optimal duration of therapy once a MR has been obtained. TKIs are improving the overall prognosis of Ph+ ALL.

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