Curr Hematol Malig Rep (2014) 9:144–147 DOI 10.1007/s11899-014-0204-7
ACUTE LEUKEMIAS (F RAVANDI, SECTION EDITOR)
Incorporating Tyrosine Kinase Inhibitors into Treatment Regimens for AML and ALL: Is There a Right or Wrong Way? Farhad Ravandi
Published online: 16 March 2014 # Springer Science+Business Media New York 2014
Abstract Although combination chemotherapy regimens have been clearly successful in treating a proportion of patients with acute leukemia, we are probably close to a ceiling of maximal benefit from such combinations. Identification of targets in the cellular signaling pathways and development of specific drugs against them have added to our armamentarium; our current challenge is how to best incorporate these agents into the currently available regimens.
Keywords Tyrosine kinase inhibitors . Acute leukemia . Monoclonal antibodies . Combination regimens . Toxicity
Introduction By signing the National Cancer Act of 1971, Richard Nixon declared the beginning of one of the costliest wars that America has embarked on and continues to undertake, that is the war on cancer [1]. At the beginning, the available armamentarium to conduct this war was very limited and the casualties, in all age groups, extensive [2]. The discovery of antimetabolites and various DNA-damaging agents as well as the potential role of radiation treatment were instrumental in some of the earlier successes in this war, such as the remarkable improvement in the outcome in children with various cancers and particularly acute lymphoblastic leukemia (ALL) [3•]. However, in the late 20th century it appeared that we were reaching a status of stalemate with the cytotoxic agents being able to reduce the size of tumors, achieve morphological remission, and perhaps cure some patients with more “chemosensitive” disease or less-advanced stages of disease, but not being universally successful in all patients [4]. F. Ravandi (*) MD Anderson Cancer Center, University of Texas, Houston, TX, USA e-mail: [email protected]
Over the last two decades, we have witnessed significant progress in understanding the biology of neoplastic transformation with increased insights into the cellular signaling pathways governing cellular proliferation, survival and apoptosis as well as major progress in identifying the genetic and molecular changes responsible for the disruptions in cellular function that lead to carcinogenesis [5, 6••]. More recently, progress has been made in identifying events that allow cancer cells to evade the body’s immunological surveillance mechanisms and ways to enhance these [7]. All in all, these advances have significantly increased the number and type of weapons and tools available to us to continue to fight hematological cancers and solid tumors. Even in the early years, it was evident to some of the more inspired researchers that drug combinations were more likely to provide meaningful responses and be effective in eradicating any residual disease, for example in patients with childhood ALL [3•]. This set the precedent for combination chemotherapy regimens to become the norm in treating virtually all neoplasms. This practice that has been carried forward in more recent years with the incorporation of kinase inhibitors, monoclonal antibodies and chromatin-modifying agents into the chemotherapy-based strategies that have become established for various leukemias. We explore here such combination strategies with particular emphasis on those that include kinase inhibitors, and discuss potential pitfalls and benefits of this approach.
What is the Current Role of Kinase Inhibitors in Treating Acute Leukemia? The identification and characterization of the role of cellular signaling pathways in leukemic cells has led to intense research towards the identification of specific targets that are amenable to drug development [5]. Since many of these pathways are characterized by a cascade of tyrosine and serine/threonine kinases as well as transcription factors that
Curr Hematol Malig Rep (2014) 9:144–147
transmit various aberrant signals into the nucleus, much of the recent research has centered on developing agents that can inhibit these kinases and interrupt the pathways. This research was significantly amplified by the success of imatinib and the next generation ABL kinase inhibitors in treating patients with chronic myeloid leukemia (CML) as well as other Philadelphia chromosome-positive (Ph+) leukemias [8–11]. It has become clearly established that a potent kinase inhibitor can change the natural history of a disease that is almost exclusively driven by a constitutively active, aberrant kinase [12]. This does not occur exclusively in patients with CML, and patients with other disorders such as hypereosinophilic syndrome and subtypes of chronic myelomonocytic leukemia driven by PDGFR fusions as well as solid tumors such as the gastrointestinal stromal tumors (GISTs) have derived significant benefit from the introduction of imatinib. Similarly, other kinase inhibitors are dramatically changing the landscape in other diseases such as the B-cell receptor inhibitors in lymphoid neoplasms, JAK kinase inhibitors in myeloproliferative neoplasms and a number of kinase inhibitors in melanoma, renal cell carcinoma and other solid tumors [13, 14]. The best example to date of an acute leukemia driven, at least partly, by a well-defined aberrant signaling pathway is Ph + ALL. Although earlier studies clearly demonstrated the immense benefit of incorporating tyrosine kinase inhibitors (TKIs) into the treatment strategies, it has become clear that such agents, even the more potent second and third generation TKIs, may not have sufficient activity as monotherapy to produce long-term responses and potential “cures” in the way we have become accustomed to in many patients with CML [15]. In an attempt to challenge this concept, a group in Italy treated patients with Ph + ALL solely with steroids, intrathecal chemotherapy and the potent second generation ABL kinase inhibitor, dasatinib [16]. Although there was a universal response and no early deaths due to the complete exclusion of cytotoxic chemotherapy, many patients relapsed during further follow-up, clearly demonstrating that monotherapy with TKIs may not be sufficient in patients with acute leukemia. This is further corroborated by earlier phase II studies of first and second generation TKIs in patients with relapsed disease in which, although the inhibitors proved to be highly effective and produced high response rates, these have not been durable [17, 18].
Strategies for Incorporating TKIs into Chemotherapy Regimens How best to incorporate these TKIs into the available regimens is a question that continues to be explored by clinical researchers. Early on, a number of centers were concerned
145
about the potential increased toxicity when TKIs were added to chemotherapy. For example, Wassmann et al. found that the outcome in a cohort of patients with Ph + ALL treated sequentially with imatinib was inferior to that in patients who received it concomitantly [19]. Levis et al. examined the best sequence of combining the FLT3 kinase inhibitor, leustartinib, with cytarabine and anthracycline-based chemotherapy and found that leustartinib given concomitantly or after chemotherapy was cytotoxic but if it was administered before chemotherapy it would be potentially antagonistic [20]. In early phase I studies, midastaurine, when administered concomitantly with cytarabine and daunorubicin, was associated with significant gastrointestinal toxicity, which resulted in changing the schedule to a more sequential approach [21]. More recent trials have suggested that continuous therapy with TKIs can be important and the total number of days of TKI treatment without interruption may influence the outcome. Schultz et al. found that prolonged administration of imatinib to children with Ph + ALL resulted in outcomes equivalent to those in patients receiving allogeneic stem cell transplantation in first complete remission (CR) [22]. In our clinical trial of dasatinib plus the hyperCVAD regimen in patients with Ph + ALL, we are now administering dasatinib on a continuous daily basis after the patient has achieved CR (typically after only the first cycle of treatment) [23]. Similarly, in trials in patients with FLT3-mutated acute myeloid leukemia (AML), we have advocated continuous TKI therapy, at least after achievement of CR [24]. In patients in whom the TKI may be the most potent agent against the leukemic cells (such as in Ph + ALL), we advocate reducing the dose or even omitting cytotoxic chemotherapy if drug interactions and toxicity would prohibit their combined full-dose administration (e.g. in maintenance courses in patients with Ph + ALL in whom we omit mercaptopurine and methotrexate) [23]. In general, the available data, though limited, suggest that continuous therapy with TKIs in acute leukemias, is as necessary as it is in chronic leukemias such as CML in which it has been demonstrated that full compliance with a daily dosing regimen is an important strategy to avoid the development of resistance to the TKIs and to achieve long-term eradication of the disease [25].
Can Targeted Agents Replace Chemotherapy in Acute Leukemias? Clearly the most important determinant of the response to this question is the efficacy of the targeted agent in achieving the eradication of disease. For example, arsenic trioxide was clearly demonstrated to be a highly potent (perhaps the most potent) agent against the leukemic cells in patients with acute promyelocytic leukemia in which, in the relapse setting, it produced complete remission including complete eradication of molecular evidence of the disease in about 85 % of patients
146
treated [26]. This led to a number of groups combining it with the other highly potent targeted agent in the disease, all-trans retinoic acid (ATRA) while eliminating chemotherapy [27]. This strategy has now been demonstrated to be superior to the combination of ATRA and chemotherapy demonstrating the feasibility of a “chemo-free” regimen in a specific subtype of AML [28••]. As indicated above, the author does not believe that any of the currently available TKIs used in treating acute leukemias (specifically, FLT3 kinase inhibitors in patients with FLT3mutated AML or ABL kinase inhibitors in Ph + ALL) are adequate as monotherapy to produce long-term cures. Even the more potent agent, quizartinib, that produces a remarkable 50 % clinical response in patients with relapsed FLT3-mutated AML, does not produce universally durable responses, and most patients with eventually relapse [29]. However, novel combinations that could allow prolonged administration of TKIs with other effective agents without undue toxicity may provide a feasible strategy for the future. We have recently demonstrated the high efficacy of combining the FLT3 kinase inhibitor, sorafenib, with the demethylating agent 5azacytidine in patients with multiply relapsed and refractory FLT3-mutated AML, with some patients maintaining prolonged responses [30]. Similar ongoing studies combining quizartinib and other kinase inhibitors with demethylating agents may provide a clearer answer as to the feasibility and efficacy of such a strategy. Alternatively, the identification of ever more potent targeted agents that are not associated with unacceptable toxicity as well as combinations of drugs against several pathways may eventually lead to the development of such “chemo-free” regimens for all leukemias (and for that matter, for all cancers).
Conclusions Despite some of the impressive early successes in the war against leukemias attributable to cytotoxic chemotherapy regimens, progress in adult acute leukemias has halted in the past two decades. Multiple randomized and nonrandomized trials in adult ALL and AML have produced similar response rates and survivals despite some variations in the dose and type of some of the agents used. This suggests that we may have reached a ceiling of maximal benefit that may be gained from the cytotoxic drug combinations and perhaps we can simplistically divide patients with acute leukemias into those with chemosensitive disease (who achieve long-term success and “cure”) and those with chemoresistant disease who either do not achieve a response or inevitably relapse despite maximal available therapy. Clearly, new and novel strategies using TKIs and monoclonal antibodies are needed, particularly for the latter group. With the identification of a number of targets and the development of novel, highly potent agents, the
Curr Hematol Malig Rep (2014) 9:144–147
current challenge in clinical research in acute leukemia is to how best to incorporate these agents into current regimens. The introduction of more specific and potent agents will likely reduce our dependence on the traditional cytotoxic agents. Significant early success has demonstrated that this is likely to be a highly fruitful approach and a strategy that is likely to achieve the ultimate goal that is victory over leukemia and cancer. Compliance with Ethics Guidelines Conflict of Interest Dr. Farhad Ravandi is a section editor for Current Hematologic Malignancy Reports. Dr. Ravandi has received research funding and honoraria from Bristol Myers Squibb, Celgene, Novartis, and Bayer/Onyx. Human and Animal Rights and Informed Consent This article does not report on any studies with human or animal subjects performed by the author.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance Weinhouse S. National Cancer Act of 1971 – an editorial. Cancer Res. 1972;32(4):i–ii. 2. Freireich EJ, Frei 3rd E, Holland JF, et al. Evaluation of a new chemotherapeutic agent in patients with 'advanced refractory' acute leukemia. Studies of 6-azauracil. Blood. 1960;16:1268–78. 3.• Frei 3rd E, Karon M, Levin RH, et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood. 1965;26(5):642–56. Early study demonstrating the efficacy of combination therapy in childhood ALL. 4. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993;328(14): 1002–6. 5. Ravandi F, Talpaz M, Estrov Z. Modulation of cellular signaling pathways: prospects for targeted therapy in hematological malignancies. Clin Cancer Res. 2003;9(2):535–50. 6.•• Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. Important study clearly establishing the existence of recurring molecular events responsible for leukemogenesis and the availability of potential pathways for intervention. 7. Pardoll D, Allison J. Cancer immunotherapy: breaking the barriers to harvest the crop. Nat Med. 2004;10(9):887–92. 8. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031–7. 9. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344(14): 1038–42. 1.
Curr Hematol Malig Rep (2014) 9:144–147 10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinibresistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542–51. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075–88. Kantarjian H, O'Brien S, Cortes J, et al. Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years. Cancer. 2008;113(7 Suppl):1933–52. O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807. Ravandi F, Jorgensen JL, Thomas DA, et al. Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy. Blood. 2013;122(7):1214–21. Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118(25):6521–8. Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110(7):2309–15. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood. 2006;108(5):1469–77. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004;104(4):1145–50.
147 21.
22.
23.
24.
25.
26.
27.
28.••
29.
30.
Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061–8. Schultz KR, Bowman WP, Aledo A, et al. Improved early eventfree survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009;27(31):5175–81. Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116(12):2070–7. Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010;28(11): 1856–62. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28(14):2381–8. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19(18):3852–60. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27(4):504–10. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–21. Randomized trial demonstrating the superiority of a “chemo-free” regimen over chemotherapy in a specific acute leukemia. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681–7. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655–62.
ACUTE LEUKEMIAS (F RAVANDI, SECTION EDITOR)
Incorporating Tyrosine Kinase Inhibitors into Treatment Regimens for AML and ALL: Is There a Right or Wrong Way? Farhad Ravandi
Published online: 16 March 2014 # Springer Science+Business Media New York 2014
Abstract Although combination chemotherapy regimens have been clearly successful in treating a proportion of patients with acute leukemia, we are probably close to a ceiling of maximal benefit from such combinations. Identification of targets in the cellular signaling pathways and development of specific drugs against them have added to our armamentarium; our current challenge is how to best incorporate these agents into the currently available regimens.
Keywords Tyrosine kinase inhibitors . Acute leukemia . Monoclonal antibodies . Combination regimens . Toxicity
Introduction By signing the National Cancer Act of 1971, Richard Nixon declared the beginning of one of the costliest wars that America has embarked on and continues to undertake, that is the war on cancer [1]. At the beginning, the available armamentarium to conduct this war was very limited and the casualties, in all age groups, extensive [2]. The discovery of antimetabolites and various DNA-damaging agents as well as the potential role of radiation treatment were instrumental in some of the earlier successes in this war, such as the remarkable improvement in the outcome in children with various cancers and particularly acute lymphoblastic leukemia (ALL) [3•]. However, in the late 20th century it appeared that we were reaching a status of stalemate with the cytotoxic agents being able to reduce the size of tumors, achieve morphological remission, and perhaps cure some patients with more “chemosensitive” disease or less-advanced stages of disease, but not being universally successful in all patients [4]. F. Ravandi (*) MD Anderson Cancer Center, University of Texas, Houston, TX, USA e-mail: [email protected]
Over the last two decades, we have witnessed significant progress in understanding the biology of neoplastic transformation with increased insights into the cellular signaling pathways governing cellular proliferation, survival and apoptosis as well as major progress in identifying the genetic and molecular changes responsible for the disruptions in cellular function that lead to carcinogenesis [5, 6••]. More recently, progress has been made in identifying events that allow cancer cells to evade the body’s immunological surveillance mechanisms and ways to enhance these [7]. All in all, these advances have significantly increased the number and type of weapons and tools available to us to continue to fight hematological cancers and solid tumors. Even in the early years, it was evident to some of the more inspired researchers that drug combinations were more likely to provide meaningful responses and be effective in eradicating any residual disease, for example in patients with childhood ALL [3•]. This set the precedent for combination chemotherapy regimens to become the norm in treating virtually all neoplasms. This practice that has been carried forward in more recent years with the incorporation of kinase inhibitors, monoclonal antibodies and chromatin-modifying agents into the chemotherapy-based strategies that have become established for various leukemias. We explore here such combination strategies with particular emphasis on those that include kinase inhibitors, and discuss potential pitfalls and benefits of this approach.
What is the Current Role of Kinase Inhibitors in Treating Acute Leukemia? The identification and characterization of the role of cellular signaling pathways in leukemic cells has led to intense research towards the identification of specific targets that are amenable to drug development [5]. Since many of these pathways are characterized by a cascade of tyrosine and serine/threonine kinases as well as transcription factors that
Curr Hematol Malig Rep (2014) 9:144–147
transmit various aberrant signals into the nucleus, much of the recent research has centered on developing agents that can inhibit these kinases and interrupt the pathways. This research was significantly amplified by the success of imatinib and the next generation ABL kinase inhibitors in treating patients with chronic myeloid leukemia (CML) as well as other Philadelphia chromosome-positive (Ph+) leukemias [8–11]. It has become clearly established that a potent kinase inhibitor can change the natural history of a disease that is almost exclusively driven by a constitutively active, aberrant kinase [12]. This does not occur exclusively in patients with CML, and patients with other disorders such as hypereosinophilic syndrome and subtypes of chronic myelomonocytic leukemia driven by PDGFR fusions as well as solid tumors such as the gastrointestinal stromal tumors (GISTs) have derived significant benefit from the introduction of imatinib. Similarly, other kinase inhibitors are dramatically changing the landscape in other diseases such as the B-cell receptor inhibitors in lymphoid neoplasms, JAK kinase inhibitors in myeloproliferative neoplasms and a number of kinase inhibitors in melanoma, renal cell carcinoma and other solid tumors [13, 14]. The best example to date of an acute leukemia driven, at least partly, by a well-defined aberrant signaling pathway is Ph + ALL. Although earlier studies clearly demonstrated the immense benefit of incorporating tyrosine kinase inhibitors (TKIs) into the treatment strategies, it has become clear that such agents, even the more potent second and third generation TKIs, may not have sufficient activity as monotherapy to produce long-term responses and potential “cures” in the way we have become accustomed to in many patients with CML [15]. In an attempt to challenge this concept, a group in Italy treated patients with Ph + ALL solely with steroids, intrathecal chemotherapy and the potent second generation ABL kinase inhibitor, dasatinib [16]. Although there was a universal response and no early deaths due to the complete exclusion of cytotoxic chemotherapy, many patients relapsed during further follow-up, clearly demonstrating that monotherapy with TKIs may not be sufficient in patients with acute leukemia. This is further corroborated by earlier phase II studies of first and second generation TKIs in patients with relapsed disease in which, although the inhibitors proved to be highly effective and produced high response rates, these have not been durable [17, 18].
Strategies for Incorporating TKIs into Chemotherapy Regimens How best to incorporate these TKIs into the available regimens is a question that continues to be explored by clinical researchers. Early on, a number of centers were concerned
145
about the potential increased toxicity when TKIs were added to chemotherapy. For example, Wassmann et al. found that the outcome in a cohort of patients with Ph + ALL treated sequentially with imatinib was inferior to that in patients who received it concomitantly [19]. Levis et al. examined the best sequence of combining the FLT3 kinase inhibitor, leustartinib, with cytarabine and anthracycline-based chemotherapy and found that leustartinib given concomitantly or after chemotherapy was cytotoxic but if it was administered before chemotherapy it would be potentially antagonistic [20]. In early phase I studies, midastaurine, when administered concomitantly with cytarabine and daunorubicin, was associated with significant gastrointestinal toxicity, which resulted in changing the schedule to a more sequential approach [21]. More recent trials have suggested that continuous therapy with TKIs can be important and the total number of days of TKI treatment without interruption may influence the outcome. Schultz et al. found that prolonged administration of imatinib to children with Ph + ALL resulted in outcomes equivalent to those in patients receiving allogeneic stem cell transplantation in first complete remission (CR) [22]. In our clinical trial of dasatinib plus the hyperCVAD regimen in patients with Ph + ALL, we are now administering dasatinib on a continuous daily basis after the patient has achieved CR (typically after only the first cycle of treatment) [23]. Similarly, in trials in patients with FLT3-mutated acute myeloid leukemia (AML), we have advocated continuous TKI therapy, at least after achievement of CR [24]. In patients in whom the TKI may be the most potent agent against the leukemic cells (such as in Ph + ALL), we advocate reducing the dose or even omitting cytotoxic chemotherapy if drug interactions and toxicity would prohibit their combined full-dose administration (e.g. in maintenance courses in patients with Ph + ALL in whom we omit mercaptopurine and methotrexate) [23]. In general, the available data, though limited, suggest that continuous therapy with TKIs in acute leukemias, is as necessary as it is in chronic leukemias such as CML in which it has been demonstrated that full compliance with a daily dosing regimen is an important strategy to avoid the development of resistance to the TKIs and to achieve long-term eradication of the disease [25].
Can Targeted Agents Replace Chemotherapy in Acute Leukemias? Clearly the most important determinant of the response to this question is the efficacy of the targeted agent in achieving the eradication of disease. For example, arsenic trioxide was clearly demonstrated to be a highly potent (perhaps the most potent) agent against the leukemic cells in patients with acute promyelocytic leukemia in which, in the relapse setting, it produced complete remission including complete eradication of molecular evidence of the disease in about 85 % of patients
146
treated [26]. This led to a number of groups combining it with the other highly potent targeted agent in the disease, all-trans retinoic acid (ATRA) while eliminating chemotherapy [27]. This strategy has now been demonstrated to be superior to the combination of ATRA and chemotherapy demonstrating the feasibility of a “chemo-free” regimen in a specific subtype of AML [28••]. As indicated above, the author does not believe that any of the currently available TKIs used in treating acute leukemias (specifically, FLT3 kinase inhibitors in patients with FLT3mutated AML or ABL kinase inhibitors in Ph + ALL) are adequate as monotherapy to produce long-term cures. Even the more potent agent, quizartinib, that produces a remarkable 50 % clinical response in patients with relapsed FLT3-mutated AML, does not produce universally durable responses, and most patients with eventually relapse [29]. However, novel combinations that could allow prolonged administration of TKIs with other effective agents without undue toxicity may provide a feasible strategy for the future. We have recently demonstrated the high efficacy of combining the FLT3 kinase inhibitor, sorafenib, with the demethylating agent 5azacytidine in patients with multiply relapsed and refractory FLT3-mutated AML, with some patients maintaining prolonged responses [30]. Similar ongoing studies combining quizartinib and other kinase inhibitors with demethylating agents may provide a clearer answer as to the feasibility and efficacy of such a strategy. Alternatively, the identification of ever more potent targeted agents that are not associated with unacceptable toxicity as well as combinations of drugs against several pathways may eventually lead to the development of such “chemo-free” regimens for all leukemias (and for that matter, for all cancers).
Conclusions Despite some of the impressive early successes in the war against leukemias attributable to cytotoxic chemotherapy regimens, progress in adult acute leukemias has halted in the past two decades. Multiple randomized and nonrandomized trials in adult ALL and AML have produced similar response rates and survivals despite some variations in the dose and type of some of the agents used. This suggests that we may have reached a ceiling of maximal benefit that may be gained from the cytotoxic drug combinations and perhaps we can simplistically divide patients with acute leukemias into those with chemosensitive disease (who achieve long-term success and “cure”) and those with chemoresistant disease who either do not achieve a response or inevitably relapse despite maximal available therapy. Clearly, new and novel strategies using TKIs and monoclonal antibodies are needed, particularly for the latter group. With the identification of a number of targets and the development of novel, highly potent agents, the
Curr Hematol Malig Rep (2014) 9:144–147
current challenge in clinical research in acute leukemia is to how best to incorporate these agents into current regimens. The introduction of more specific and potent agents will likely reduce our dependence on the traditional cytotoxic agents. Significant early success has demonstrated that this is likely to be a highly fruitful approach and a strategy that is likely to achieve the ultimate goal that is victory over leukemia and cancer. Compliance with Ethics Guidelines Conflict of Interest Dr. Farhad Ravandi is a section editor for Current Hematologic Malignancy Reports. Dr. Ravandi has received research funding and honoraria from Bristol Myers Squibb, Celgene, Novartis, and Bayer/Onyx. Human and Animal Rights and Informed Consent This article does not report on any studies with human or animal subjects performed by the author.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance Weinhouse S. National Cancer Act of 1971 – an editorial. Cancer Res. 1972;32(4):i–ii. 2. Freireich EJ, Frei 3rd E, Holland JF, et al. Evaluation of a new chemotherapeutic agent in patients with 'advanced refractory' acute leukemia. Studies of 6-azauracil. Blood. 1960;16:1268–78. 3.• Frei 3rd E, Karon M, Levin RH, et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood. 1965;26(5):642–56. Early study demonstrating the efficacy of combination therapy in childhood ALL. 4. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993;328(14): 1002–6. 5. Ravandi F, Talpaz M, Estrov Z. Modulation of cellular signaling pathways: prospects for targeted therapy in hematological malignancies. Clin Cancer Res. 2003;9(2):535–50. 6.•• Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. Important study clearly establishing the existence of recurring molecular events responsible for leukemogenesis and the availability of potential pathways for intervention. 7. Pardoll D, Allison J. Cancer immunotherapy: breaking the barriers to harvest the crop. Nat Med. 2004;10(9):887–92. 8. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031–7. 9. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344(14): 1038–42. 1.
Curr Hematol Malig Rep (2014) 9:144–147 10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinibresistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542–51. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075–88. Kantarjian H, O'Brien S, Cortes J, et al. Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years. Cancer. 2008;113(7 Suppl):1933–52. O'Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807. Ravandi F, Jorgensen JL, Thomas DA, et al. Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy. Blood. 2013;122(7):1214–21. Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011;118(25):6521–8. Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110(7):2309–15. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood. 2006;108(5):1469–77. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004;104(4):1145–50.
147 21.
22.
23.
24.
25.
26.
27.
28.••
29.
30.
Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061–8. Schultz KR, Bowman WP, Aledo A, et al. Improved early eventfree survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009;27(31):5175–81. Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116(12):2070–7. Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010;28(11): 1856–62. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28(14):2381–8. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19(18):3852–60. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27(4):504–10. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–21. Randomized trial demonstrating the superiority of a “chemo-free” regimen over chemotherapy in a specific acute leukemia. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681–7. Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655–62.
