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Treatment of Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

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Treatment of Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia Treatment of Philadelphia chromosome positive acute lymphoblastic leukemia O.G. Ottmann ABSTRACT Patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) are now Department of Internal Medicine, routinely treated front-line with tyrosine kinase inhibitors (TKI), usually combined with chemotherapy, Hematology-Oncology, with unequivocal evidence of clinical benefit. The first-generation TKI imatinib induces hematologic Goethe University, Frankfurt am remissions in nearly all patients, but these are rarely maintained unless patients undergo allogeneic Main, Germany stem cell transplantation (alloSCT), the current gold standard of curative therapy. The more potent sec - ond- and third-generation TKI display greater clinical efficacy based on molecular response data and Correspondence: clinical outcome parameters. It is still uncertain whether they may obviate the need for alloSCT in Oliver G. Ottmann some adult patients who achieve a deep molecular response, whereas this appears to often be the case E-mail: [email protected] in pediatric patients. Which chemotherapy regimen is best suited in combination with the individual TKI in different subsets of patients is being explored in ongoing studies. Molecular analyses to measure MRD levels, detect BCR-ABL kinase domain mutations, or further subclassify patients according to Hematology Education: additional genomic aberrations has become increasingly important in clinical patient management. A the education program for the variety of novel targeted treatment approaches are in clinical development for patients with an unsat - annual congress of the European isfactory response to current therapy. Hematology Association Learning goals 2014;8:15-22 At the conclusion of this activity, participants should: - know about the efficacy of first- and second-generation tyrosine kinase inhibitors (TKI) in terms of inducing hematologic and molecular responses; - understand the role of chemotherapy intensity regarding efficacy and tolerability; - be able to identify the current treatment paradigm as TKI combined with chemotherapy, followed by allogeneic stem cell transplantation (alloSCT); - be able to identify BCR-ABL mutations as a principal cause of treatment failure; - understand the role of minimal residual disease assessment prior to and after SCT and the thera - peutic implications; - have some knowledge of the therapeutic options in relapsed or refractory patients. Introduction TKI-based treatment regimens on long-term survival of patients with Ph + ALL remains The BCR-ABL translocation in Philadelphia uncertain. This is due primarily to a paucity of chromosome positive (Ph +) acute lymphoblas - large prospective phase III trials, with clinical tic leukemia (ALL) defines a subpopulation research having focused on smaller phase II trials exploring specific treatment modalities among adult ALL that encompasses approxi - + mately 25% of patients and is amenable to within subgroups of Ph ALL patients. This article will review the current state of the art treatment with tyrosine kinase inhibitors (TKI) + that target the oncogenic BCR-ABL protein. and the evolving concepts in therapy for Ph The availability of now three generations of ALL, primarily of adult patients, will highlight ABL-directed TKI has fostered numerous unresolved clinical management issues, and clinical trials exploring different strategies of will look towards future novel therapeutic approaches. TKI-based therapy, and have unequivocally improved patient outcome. Moreover, the importance of molecular diagnostics not only for up-front identification of BCR-ABL posi - Role of tyrosine kinase inhibitors during tivity but for minimal residual disease (MRD)- induction therapy guided treatment decisions during therapy and detection of mutations in case of resistance Extensive data on first-line treatment for Ph + have become universally accepted. As a conse - ALL is available for the first-generation TKI quence, results of treatment for the very high- imatinib, and experience with second-genera - + risk subset of Ph ALL have now surpassed tion (dasatinib, nilotinib) and third-generation those of BCR-ABL negative high-risk ALL in (ponatinib) TKI is growing rapidly. Current the German Multicenter Adult ALL (GMALL) efforts to optimize utilization of these TKI in cooperative group trials. Despite these treatment algorithms for newly diagnosed Ph + achievements, the precise impact of different ALL are focusing on the advantages and limi - Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 15 | 19 th Congress of the European Hematology Association tations of the different TKIs and the intensity and type of er molecular response. chemotherapy used during induction and consolidation Several studies have investigated dasatinib in combina - cycles. It is widely accepted that TKI should be initiated tion with either low-intensity or aggressive chemotherapy as soon as the diagnosis of Ph + ALL is established, i.e. typ - regimens. The European Working Group for Adult ALL ically after pre-phase therapy. 1 Major conceptual differ - (EWALL) conducted a prospective single-arm phase II ences regarding induction strategies concern the intensity trial in elderly Ph + ALL patients in whom dasatinib was of treatment, which may rely on TKI only in combination combined with mild induction chemotherapy (vincristine, with corticosteroids, 2-4 on their combination with reduced dexamethasone and intrathecal prophylaxis), followed by 18 intensity chemotherapy, e.g. vincristine plus steroids, 5,6 or more intensive consolidation cycles. Median age of combination with intensive multi-agent induction patients was 69 years (58-83 years). Despite this low- chemotherapy. 7-10 intensity approach, the initial protocol was amended to Imatinib further reduce toxicity in patients older than 75 years of age, by decreasing the dasatinib dose from 140 mg once daily (QD) to 100 mg QD, and the dexamethasone dose The use of imatinib during induction has been most from 40 mg to 20 mg. Hospitalization rather than outpa - extensively studied over the past decade, and more than tient treatment was recommended for the early initial 90% of patients can expect to achieve complete remission, treatment phase to prevent or adequately treat tumor lysis irrespective of whether imatinib is given alone or in com - 1,3,9,11-15 and compromised renal function. In this multicenter trial, bination with chemotherapy. Concurrent adminis - the complete remission (CR) rate was 94% and early mor - tration with cytotoxic drugs commonly used for induction tality 5%. Major toxicities included sepsis, hemorrhage (anthracyclines, cytarabine, cyclophosphamide, vin - and renal function impairment. Molecular response rate cristine, 6-mercaptopurine) has proven to be feasible and after induction was approximately 25% and 50% based on reasonably well tolerated, but induction mortality may 3 log and 4.5 log reduction of BCR-ABL transcripts, reach approximately 10% even in younger patients. respectively. Primary hematologic resistance is distinctly uncommon in Dasatinib in conjunction with intensive chemotherapy previously untreated patients, in contrast to the relapse set - 16 according to the hyper-CVAD regimen was similarly ting. One of the primary goals of combining imatinib effective in terms of inducing remissions, with a CR rate only with steroids is the avoidance of induction mortality, of 94% and 6% induction mortality. 19 Septicemia and and this has been evaluated in elderly as well as young hemorrhage were the major toxicities leading to death. patients. The rate of induction deaths is indeed exceeding - SRC inhibition by dasatinib may have contributed to the ly low using such an approach, with studies reporting no 3 higher rate of clinically significant hemorrhagic events induction deaths with imatinib and steroids. The principal due to its effect on platelet function. With short (14 drawback of this approach appears to be an unsatisfactory months) median follow up, estimated 2-year survival was depth of response by MRD analysis based on quantitative 64%. To date, the results of only 2 clinical trials examining RT-PCR measurement of BCR-ABL transcripts. For nilotinib as first-line therapy for Ph + ALL have been example, only 4% molecular remissions after induction reported. 20,21 This paucity of clinical trials is possibly relat - were reported for the GIMEMA LAL0201-B protocol. ed to the poor clinical activity against p-loop mutations Concern that a poor molecular response is associated with that was observed in early phase I and II trials of nilotinib early disease recurrence and a high relapse rate is borne for relapsed or refractory Ph + ALL, and the preponderance out by clinical trials particularly, but not exclusively, in of these mutations in imatinib failure. 22 As front-line treat - elderly Ph + ALL patients who do not undergo allogeneic 2,3,7,17 ment, nilotinib proved effective and tolerable in conjunc - stem cell transplantation (alloSCT). tion with chemotherapy: the CR rate was 90%, with medi - Second-generation tyrosine kinase inhibitors an time to CR of 27 days. 20 Already at the time of CR, 55% of patients had undetectable BCR-ABL transcripts, with The greater potency of second-generation TKI and their further improvement over time, leading to a cumulative activity against a broader spectrum of BCR-ABL kinase complete molecular response rate
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