- Email: [email protected]
Dasatinib Combined with Interferon-alfa Induces a Complete Cytogenetic Response and Major Molecular Response in a Patient with Chronic Myelogenous Leukemia Harboring the T315I BCR-ABL1 Mutation
Chronic Myeloid Leukemia
Dasatinib Combined with Interferon-alfa Induces a Complete Cytogenetic Response and Major Molecular Response in a Patient with Chronic Myelogenous Leukemia Harboring the T315I BCR-ABL1 Mutation A. Megan Cornelison, Mary-Alma Welch, Charles Koller, Elias Jabbour Abstract Mutations of BCR-ABL1 are observed in 50% of patients with imatinib-resistant chronic myeloid leukemia (CML). The T315I mutation is resistant to imatinib and second-generation tyrosine kinase inhibitors (TKIs). We report the case of a 57-year-old man diagnosed with CML in 2003 in whom imatinib therapy failed after which he acquired the T315I mutation. He was treated sequentially with an anti-T315I–specific agent, KW-2449, that led to eradication of the mutation without any further improvement. Subsequent introduction of combination therapy that included dasatinib and pegylated interferon led to the achievement of a sustained complete cytogenetic and major molecular response (MMR). This case illustrates the benefit of combination therapy that includes a TKI and a second agent with a different mechanism of action, either sequentially (TKI followed by KW-2449) or concomitantly (TKI ⫹ interferon), in eradicating resistant disease with the T315I clone. Clinical Lymphoma, Myeloma & Leukemia, Vol. 11, No. S1, S111-3 © 2011 Elsevier Inc. All rights reserved. Keywords: Chronic myelogenous leukemia (CML), Combination, Kinase domain mutations, TKI resistance, T315I mutation
Introduction Tyrosine kinase inhibitors (TKIs) are standard therapy for patients with chronic myeloid leukemia (CML), with durable responses noted in most cases. However a subset of patients experience resistance to TKIs. Such resistance to TKIs such as imatinib is attributable to point mutations in the ABL kinase domain (KD) in about 50% of cases,1 with 10% to 15% of these being T315I mutations (called the gatekeeper mutation). This results in a substitution of isoleucine for threonine in position 315, causing a conformational change in the binding site occupied by all TKIs, and portends universal resistance to TKI therapy.2,3 Nilotinib and dasatinib, secondgeneration TKIs used in the treatment of CML, have shown activity
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX Submitted: Jan 19, 2011; Revised: Mar 2, 2011; Accepted: Mar 4, 2011 Address for correspondence: A. Megan Cornelison, MS, PA-C, Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 425, Houston, Texas 77030 Fax: 713-794-4297; e-mail contact: [email protected]
2152-2650/$ - see frontmatter © 2011 Elsevier Inc. All rights reserved. doi: 10.1016/j.clml.2011.03.032
against most of the KD mutations, with the notable exception of the T315I4-6 mutation. Drugs with different mechanisms of action are being explored in this setting. Older drugs are being revisited for their potential activity, including combinations of interferon-alfa and others.7,8 Homoharringtonine (HHT; also called omacetaxine, ChemGenex Pharmaceuticals, Victoria, Australia), a cephalotaxine ester and multitargeted protein synthase inhibitor, has shown activity in patients with T315I mutations after imatinib failure, with hematologic and cytogenetic response rates of 64% and 27%, respectively, in chronic phase; 100% and 25%, respectively, in accelerated phase; and hematologic response rates of 34% in blast phase.9 In 2003, O’Brien et al showed improved outcomes in patients with CML when triple therapy with interferon-alfa, cytarabine, and HHT was followed by imatinib monotherapy.10 Promising new therapies are also being explored in this setting of TKI failure, including new multikinase inhibitors, aurora kinase inhibitors, and histone deacetylase inhibitors. Among these new agents, several have shown clinical activity against the T315I mutation: among them, KW-244911 (a FLT3, ABL, FGFR1, and aurora kinase inhibitor1) and PHA-739538 (Nerviano Medical Sciences,
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Dasatinib and Interferon Combined is Active in Patient with T315I Mutation Figure 1 Serial Monitoring of Phⴙ Cells, T315I Cells, and BCR-ABL1/ABL1 Ratio
Nerviano, Italy), an aurora kinase inhibitor.12 Both are being explored in combination with imatinib in patients with T315I mutations.13 Ponatinib (AP24534) is a multikinase inhibitor designed using a structure-based approach to avoid the hindrance of the isoleucine mutation at position 315 and fits into the adenosine triphosphate binding pocket of BCR-ABL. The in vitro inhibitory profile of ponatinib is very broad across BCR-ABL variants, and mutagenic work shows that no mutations emerge on exposure to this particular drug, which has shown promising activity in early clinical trials.14 Another agent, DCC-2036, is highly selective for ABL, FLT3, TIE2, and Src family kinases and, when dosed at 100 mg/kg/day, significantly prolonged the survival of mice with CML-like myeloproliferative disease induced by retroviral expression of BCR-ABL/WT and T315I in bone marrow.15 This agent is being explored in phase I clinical trials. Thus resistance could be due to several clones, among them some harboring the T315I mutation. Therefore overcoming this multifactorial resistance could be achieved by targeting different clones with drugs having different mechanisms of action. Herein we present a case of highly resistant disease involving the T315I mutation that responded to strategies that included combination and sequential therapy.
Case Report We report the case of a 57-year-old man with a medical history significant for poorly controlled diabetes who was diagnosed with CML in 2003. The patient received initial therapy with standarddose imatinib at 400 mg daily that was subsequently increased to 800 mg daily. He achieved a complete cytogenetic response (CCyR) 9 months after dose escalation. He was followed by serial real-time polymerase chain reaction (RT-PCR) for BCR-ABL1. In May 2007, the patient’s BCR-ABL1/ABL1 ratio increased from 9.05% to
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16.38%, but the patient remained in CCyR. BCR-ABL1 sequencing revealed the T315I mutation in 100% of cells (Figure 1). One month later, the patient lost CCyR (major cytogenetic response [MCyR]; 5% Philadelphia-positive [Ph⫹] cells) and the BCR-ABL1/ABL1 ratio was 5.08. He was started on the T315I-specific inhibitor KW2449 (100 mg orally twice daily for 14 days, every 3 weeks). Over 3 months, the patient had a progressive decline in the percentage of cells with the T315I mutation (Figure 1); however, he had a simultaneous increase in the percentage of Ph⫹ cells. In September 2007, 3 months after starting therapy with KW-2449, the patient lost his cytogenetic response (80% Ph⫹ cells, PCR for BCR-ABL1 ratio ⬎ 100), and the T315I mutation was undetectable. At that time, ABL1 sequencing revealed the F359I mutation. The patient was maintained on KW-2449 for the next 6 months without recurrence of the T315I mutated clone but without significant improvement in cytogenetic response or in the BCR-ABL1/ABL1 ratio. In February 2008, he lost hematologic response with an elevated white blood cell count of 22 x 109/L. The F359I mutation was still present. Therapy with KW-2449 was stopped, and the patient started dasatinib 50 mg twice daily and interferon-alfa 3 million U daily with titration up to the full dose of 9 million U daily. Four months later, the patient achieved CCyR and major molecular response (MMR; as defined by BCRABL1/ABL1 ratio ⬍ 0.1) with a BCR-ABL1/ABL1 ratio of 0.05. Sixteen months after the start of the combination of dasatinib and interferon-alfa, the patient was maintaining CCyR and MMR; however, grade 2 pleural effusions developed, necessitating treatment interruption and a 50% dose reduction of dasatinib. The episodes of pleural effusions were not associated with peripheral blood lymphocytosis or neutropenia. At the last follow-up, 23 months after initiation of this combination therapy, he maintained his CCyR and his
A. Megan Cornelison et al MMR with a BCR-ABL1/ABL1 ratio of ⬍ 0.01, and a white blood cell count and absolute neutrophil count within normal range (12 ⫻ 109 – 7 ⫻ 109 and 7 ⫻ 109 – 4 ⫻ 109, respectively) but bilateral buttock wounds developed at the interferon-alfa injection sites, which cultured positive for multidrug-resistant Escherichia coli. He died thereafter, in remission, presumably of complications of this infection in the setting of poorly controlled diabetes. The infectious complications that led to his death were deemed to be associated with his comorbidities. At no point in the patient’s treatment did he experience ⬎ grade 1 neutropenia or any treatment-related myelosuppression.
Discussion Resistance to TKI therapy is multifactorial and includes both BCRABL– dependent and –independent mechanisms1. KD mutations represent a clinically relevant subset of resistant disease. Strategies for eradicating KD mutations, such as T315I, that portend poor prognosis and nearly universal resistance to monotherapy, should include sequential and combination therapies with drugs with different mechanisms of actions such as HHT and interferon-alfa and the new multikinase inhibitors. The sequential and concomitant combinations of imatinib and pegylated interferon have led to an improvement of molecular responses and conversion of patients with minimal residual disease to complete molecular remission.16,17 Moreover, French investigators have recently reported that the addition of pegylated interferon alfa-2a to imatinib therapy resulted in significantly higher rates of molecular response in patients with chronic-phase CML. This could be due to the effect of interferon-alfa stimulating the turnover and proliferation of hematopoietic stem cells in vivo. Therefore the recruitment of dormant CML stem cells into the cell cycle by pegylated interferon-alfa may increase the efficacy of TKIs.18 Our patient died in remission, without lymphocytosis, due to sepsis and multiple comorbidities. Recent data has shown no increase in the rate of opportunistic infections in patients treated with dasatinib.19 There is no evidence suggesting that the patient described in this article died because of therapy-related immunosuppression. Therefore a longer follow-up on a larger number of patients is needed. This case illustrates the benefit of combination therapy, particularly when delivered sequentially, targeting multiple clones leading to disease demonstrating resistance to TKIs. The reintroduction of dasatinib was successful after the eradication of theT315I clone after treatment with KW-2449. In addition, the combination with interferon-alfa might have been successful in consolidating and sustaining the remission. New agents like ponatinib and HHT have shown promising activity in the setting of TKI resistance and the T315I mutation. Looking to the future, more trials exploring drug combinations with different biologic targets and mechanisms of action may lead to greater success in treating highly resistant disease involving the T315I mutation, preventing resistance, and eradicating all CML clones with the cure of the disease as an endpoint. Future trials exploring second-
generation TKIs in a front-line setting combined sequentially with other drugs with different mechanisms of action, such as ponatinib, are needed.
Disclosure All authors report that they have no relevant relationships to disclose.
References 1. Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 2006; 20:1767-73. 2. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8:1018-29. 3. Quintas-Cardama A, Kantarjian HM, Cortes JE. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia. Cancer Control 2009; 16:1222-31. 4. Jabbour E, Kantarjian H, Jones D, et al. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 2008; 112:53-5. 5. Weisberg E, Manley PQ, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-abl. Cancer Cell 2005; 7:129-41. 6. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med 2006; 354:2531-41. 7. Kantarjian HM, O’Brien S, Smith TL, et al. Treatment of Philadelphia chromosome–positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. J Clin Oncol 1999; 17:284-92. 8. Kantarjian HM, O’Brien S, Cortes JE, et al. Complete cytogenetic and molecular responses to interferon-alpha– based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 2003; 97:1033-41. 9. Cortes JE, Khoury HJ, Corm S, et al. Multicenter open label study of subcutaneous (SC) omacetaxine (OMA) in imatinib (IM)-resistant chronic myeloid leukemia (CML) in patients (Pts) with the T315I mutation [abstract]. J Clin Oncol 2008; 26:7021. 10. O’Brien S, Giles F, Talpaz M, et al. Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in early chronic phase. Cancer 2003; 98:888-93. 11. Cortes J, Roboz GJ, Kantarjian H, et al. A phase I dose escalation study of KW2449, an oral multikinase inhibitor against FLT3, Abl,FGFR1, and Aurora in patients with relapsed/refractory AML, treatment resistant/intolerant CML, ALL, and MDS [abstract]. Blood 2007; 110:909. 12. Gontarewicz A, Balabanov S, Keller G, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood 2008; 111:4355-64. 13. Paquette RL, Shah NP, Sawyers CL, et al. PHA-739538, an aurora kinase inhibitor, induces clinical responses in chronic myeloid leukemia harboring T315I mutations of BCR-ABL [abstract]. Blood 2007: 110:907. 14. Cortes J, Talpaz M, Deininger M, et al. A phase 1 trial of oral AP24534 in patients with refractory chronic myeloid leukemia and other hematologic malignancies: first results of safety and clinical activity against T315I and resistant mutations [abstract]. Blood 2009; 114:643. 15. Van Etten RA, Chan WW, Zaleskas VM, et al. Switch pocket inhibitors of the ABL tyrosine kinase: distinct kinome inhibition profiles and in vivo efficacy in mouse models of CML and B-lymphoblastic leukemia induced by BCR-ABL T315I [abstract]. Blood 2008; 112:576. 16. Guilhot F, Preudhomme C, Guilhot J, et al. Significantly higher rates of undetectable molecular residual disease and molecular responses with pegylated form of interferon a2a in combination with imatinib (IM) for the treatment of newly diagnosed chronic phase (CP) chronic myeloid leukaemia (CML) patients (pts): confirmatory results at 18 months of part 1 of the Spirit Phase III randomized trial of the French CML Group (FI LMC) [abstract]. Blood 2009; 114; 340. 17. Burchert A, Muller MC, Kostrewa P, et al. Interferon alpha 2a (IFN) maintenance therapy after imatinib plus IFN induction therapy in chronic myeloid leukemia (CML) induces stable long-term molecular remissions and is associated with increased proteinase 3 (PR3) expression and the presence of PR1-specific T-cells [abstract]. Blood 2009; 114:647. 18. Peudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010; 363:2511-21. 19. Al-Ameri A, Kantarjian H, Borthakur G, et al. Opportunistic infections are uncommon with dasatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) [abstract]. Blood 2009; 114: 1120.
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Dasatinib Combined with Interferon-alfa Induces a Complete Cytogenetic Response and Major Molecular Response in a Patient with Chronic Myelogenous Leukemia Harboring the T315I BCR-ABL1 Mutation A. Megan Cornelison, Mary-Alma Welch, Charles Koller, Elias Jabbour Abstract Mutations of BCR-ABL1 are observed in 50% of patients with imatinib-resistant chronic myeloid leukemia (CML). The T315I mutation is resistant to imatinib and second-generation tyrosine kinase inhibitors (TKIs). We report the case of a 57-year-old man diagnosed with CML in 2003 in whom imatinib therapy failed after which he acquired the T315I mutation. He was treated sequentially with an anti-T315I–specific agent, KW-2449, that led to eradication of the mutation without any further improvement. Subsequent introduction of combination therapy that included dasatinib and pegylated interferon led to the achievement of a sustained complete cytogenetic and major molecular response (MMR). This case illustrates the benefit of combination therapy that includes a TKI and a second agent with a different mechanism of action, either sequentially (TKI followed by KW-2449) or concomitantly (TKI ⫹ interferon), in eradicating resistant disease with the T315I clone. Clinical Lymphoma, Myeloma & Leukemia, Vol. 11, No. S1, S111-3 © 2011 Elsevier Inc. All rights reserved. Keywords: Chronic myelogenous leukemia (CML), Combination, Kinase domain mutations, TKI resistance, T315I mutation
Introduction Tyrosine kinase inhibitors (TKIs) are standard therapy for patients with chronic myeloid leukemia (CML), with durable responses noted in most cases. However a subset of patients experience resistance to TKIs. Such resistance to TKIs such as imatinib is attributable to point mutations in the ABL kinase domain (KD) in about 50% of cases,1 with 10% to 15% of these being T315I mutations (called the gatekeeper mutation). This results in a substitution of isoleucine for threonine in position 315, causing a conformational change in the binding site occupied by all TKIs, and portends universal resistance to TKI therapy.2,3 Nilotinib and dasatinib, secondgeneration TKIs used in the treatment of CML, have shown activity
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX Submitted: Jan 19, 2011; Revised: Mar 2, 2011; Accepted: Mar 4, 2011 Address for correspondence: A. Megan Cornelison, MS, PA-C, Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 425, Houston, Texas 77030 Fax: 713-794-4297; e-mail contact: [email protected]
2152-2650/$ - see frontmatter © 2011 Elsevier Inc. All rights reserved. doi: 10.1016/j.clml.2011.03.032
against most of the KD mutations, with the notable exception of the T315I4-6 mutation. Drugs with different mechanisms of action are being explored in this setting. Older drugs are being revisited for their potential activity, including combinations of interferon-alfa and others.7,8 Homoharringtonine (HHT; also called omacetaxine, ChemGenex Pharmaceuticals, Victoria, Australia), a cephalotaxine ester and multitargeted protein synthase inhibitor, has shown activity in patients with T315I mutations after imatinib failure, with hematologic and cytogenetic response rates of 64% and 27%, respectively, in chronic phase; 100% and 25%, respectively, in accelerated phase; and hematologic response rates of 34% in blast phase.9 In 2003, O’Brien et al showed improved outcomes in patients with CML when triple therapy with interferon-alfa, cytarabine, and HHT was followed by imatinib monotherapy.10 Promising new therapies are also being explored in this setting of TKI failure, including new multikinase inhibitors, aurora kinase inhibitors, and histone deacetylase inhibitors. Among these new agents, several have shown clinical activity against the T315I mutation: among them, KW-244911 (a FLT3, ABL, FGFR1, and aurora kinase inhibitor1) and PHA-739538 (Nerviano Medical Sciences,
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Dasatinib and Interferon Combined is Active in Patient with T315I Mutation Figure 1 Serial Monitoring of Phⴙ Cells, T315I Cells, and BCR-ABL1/ABL1 Ratio
Nerviano, Italy), an aurora kinase inhibitor.12 Both are being explored in combination with imatinib in patients with T315I mutations.13 Ponatinib (AP24534) is a multikinase inhibitor designed using a structure-based approach to avoid the hindrance of the isoleucine mutation at position 315 and fits into the adenosine triphosphate binding pocket of BCR-ABL. The in vitro inhibitory profile of ponatinib is very broad across BCR-ABL variants, and mutagenic work shows that no mutations emerge on exposure to this particular drug, which has shown promising activity in early clinical trials.14 Another agent, DCC-2036, is highly selective for ABL, FLT3, TIE2, and Src family kinases and, when dosed at 100 mg/kg/day, significantly prolonged the survival of mice with CML-like myeloproliferative disease induced by retroviral expression of BCR-ABL/WT and T315I in bone marrow.15 This agent is being explored in phase I clinical trials. Thus resistance could be due to several clones, among them some harboring the T315I mutation. Therefore overcoming this multifactorial resistance could be achieved by targeting different clones with drugs having different mechanisms of action. Herein we present a case of highly resistant disease involving the T315I mutation that responded to strategies that included combination and sequential therapy.
Case Report We report the case of a 57-year-old man with a medical history significant for poorly controlled diabetes who was diagnosed with CML in 2003. The patient received initial therapy with standarddose imatinib at 400 mg daily that was subsequently increased to 800 mg daily. He achieved a complete cytogenetic response (CCyR) 9 months after dose escalation. He was followed by serial real-time polymerase chain reaction (RT-PCR) for BCR-ABL1. In May 2007, the patient’s BCR-ABL1/ABL1 ratio increased from 9.05% to
S112
Clinical Lymphoma, Myeloma & Leukemia June 2011
16.38%, but the patient remained in CCyR. BCR-ABL1 sequencing revealed the T315I mutation in 100% of cells (Figure 1). One month later, the patient lost CCyR (major cytogenetic response [MCyR]; 5% Philadelphia-positive [Ph⫹] cells) and the BCR-ABL1/ABL1 ratio was 5.08. He was started on the T315I-specific inhibitor KW2449 (100 mg orally twice daily for 14 days, every 3 weeks). Over 3 months, the patient had a progressive decline in the percentage of cells with the T315I mutation (Figure 1); however, he had a simultaneous increase in the percentage of Ph⫹ cells. In September 2007, 3 months after starting therapy with KW-2449, the patient lost his cytogenetic response (80% Ph⫹ cells, PCR for BCR-ABL1 ratio ⬎ 100), and the T315I mutation was undetectable. At that time, ABL1 sequencing revealed the F359I mutation. The patient was maintained on KW-2449 for the next 6 months without recurrence of the T315I mutated clone but without significant improvement in cytogenetic response or in the BCR-ABL1/ABL1 ratio. In February 2008, he lost hematologic response with an elevated white blood cell count of 22 x 109/L. The F359I mutation was still present. Therapy with KW-2449 was stopped, and the patient started dasatinib 50 mg twice daily and interferon-alfa 3 million U daily with titration up to the full dose of 9 million U daily. Four months later, the patient achieved CCyR and major molecular response (MMR; as defined by BCRABL1/ABL1 ratio ⬍ 0.1) with a BCR-ABL1/ABL1 ratio of 0.05. Sixteen months after the start of the combination of dasatinib and interferon-alfa, the patient was maintaining CCyR and MMR; however, grade 2 pleural effusions developed, necessitating treatment interruption and a 50% dose reduction of dasatinib. The episodes of pleural effusions were not associated with peripheral blood lymphocytosis or neutropenia. At the last follow-up, 23 months after initiation of this combination therapy, he maintained his CCyR and his
A. Megan Cornelison et al MMR with a BCR-ABL1/ABL1 ratio of ⬍ 0.01, and a white blood cell count and absolute neutrophil count within normal range (12 ⫻ 109 – 7 ⫻ 109 and 7 ⫻ 109 – 4 ⫻ 109, respectively) but bilateral buttock wounds developed at the interferon-alfa injection sites, which cultured positive for multidrug-resistant Escherichia coli. He died thereafter, in remission, presumably of complications of this infection in the setting of poorly controlled diabetes. The infectious complications that led to his death were deemed to be associated with his comorbidities. At no point in the patient’s treatment did he experience ⬎ grade 1 neutropenia or any treatment-related myelosuppression.
Discussion Resistance to TKI therapy is multifactorial and includes both BCRABL– dependent and –independent mechanisms1. KD mutations represent a clinically relevant subset of resistant disease. Strategies for eradicating KD mutations, such as T315I, that portend poor prognosis and nearly universal resistance to monotherapy, should include sequential and combination therapies with drugs with different mechanisms of actions such as HHT and interferon-alfa and the new multikinase inhibitors. The sequential and concomitant combinations of imatinib and pegylated interferon have led to an improvement of molecular responses and conversion of patients with minimal residual disease to complete molecular remission.16,17 Moreover, French investigators have recently reported that the addition of pegylated interferon alfa-2a to imatinib therapy resulted in significantly higher rates of molecular response in patients with chronic-phase CML. This could be due to the effect of interferon-alfa stimulating the turnover and proliferation of hematopoietic stem cells in vivo. Therefore the recruitment of dormant CML stem cells into the cell cycle by pegylated interferon-alfa may increase the efficacy of TKIs.18 Our patient died in remission, without lymphocytosis, due to sepsis and multiple comorbidities. Recent data has shown no increase in the rate of opportunistic infections in patients treated with dasatinib.19 There is no evidence suggesting that the patient described in this article died because of therapy-related immunosuppression. Therefore a longer follow-up on a larger number of patients is needed. This case illustrates the benefit of combination therapy, particularly when delivered sequentially, targeting multiple clones leading to disease demonstrating resistance to TKIs. The reintroduction of dasatinib was successful after the eradication of theT315I clone after treatment with KW-2449. In addition, the combination with interferon-alfa might have been successful in consolidating and sustaining the remission. New agents like ponatinib and HHT have shown promising activity in the setting of TKI resistance and the T315I mutation. Looking to the future, more trials exploring drug combinations with different biologic targets and mechanisms of action may lead to greater success in treating highly resistant disease involving the T315I mutation, preventing resistance, and eradicating all CML clones with the cure of the disease as an endpoint. Future trials exploring second-
generation TKIs in a front-line setting combined sequentially with other drugs with different mechanisms of action, such as ponatinib, are needed.
Disclosure All authors report that they have no relevant relationships to disclose.
References 1. Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 2006; 20:1767-73. 2. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8:1018-29. 3. Quintas-Cardama A, Kantarjian HM, Cortes JE. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia. Cancer Control 2009; 16:1222-31. 4. Jabbour E, Kantarjian H, Jones D, et al. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood 2008; 112:53-5. 5. Weisberg E, Manley PQ, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-abl. Cancer Cell 2005; 7:129-41. 6. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med 2006; 354:2531-41. 7. Kantarjian HM, O’Brien S, Smith TL, et al. Treatment of Philadelphia chromosome–positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. J Clin Oncol 1999; 17:284-92. 8. Kantarjian HM, O’Brien S, Cortes JE, et al. Complete cytogenetic and molecular responses to interferon-alpha– based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 2003; 97:1033-41. 9. Cortes JE, Khoury HJ, Corm S, et al. Multicenter open label study of subcutaneous (SC) omacetaxine (OMA) in imatinib (IM)-resistant chronic myeloid leukemia (CML) in patients (Pts) with the T315I mutation [abstract]. J Clin Oncol 2008; 26:7021. 10. O’Brien S, Giles F, Talpaz M, et al. Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in early chronic phase. Cancer 2003; 98:888-93. 11. Cortes J, Roboz GJ, Kantarjian H, et al. A phase I dose escalation study of KW2449, an oral multikinase inhibitor against FLT3, Abl,FGFR1, and Aurora in patients with relapsed/refractory AML, treatment resistant/intolerant CML, ALL, and MDS [abstract]. Blood 2007; 110:909. 12. Gontarewicz A, Balabanov S, Keller G, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood 2008; 111:4355-64. 13. Paquette RL, Shah NP, Sawyers CL, et al. PHA-739538, an aurora kinase inhibitor, induces clinical responses in chronic myeloid leukemia harboring T315I mutations of BCR-ABL [abstract]. Blood 2007: 110:907. 14. Cortes J, Talpaz M, Deininger M, et al. A phase 1 trial of oral AP24534 in patients with refractory chronic myeloid leukemia and other hematologic malignancies: first results of safety and clinical activity against T315I and resistant mutations [abstract]. Blood 2009; 114:643. 15. Van Etten RA, Chan WW, Zaleskas VM, et al. Switch pocket inhibitors of the ABL tyrosine kinase: distinct kinome inhibition profiles and in vivo efficacy in mouse models of CML and B-lymphoblastic leukemia induced by BCR-ABL T315I [abstract]. Blood 2008; 112:576. 16. Guilhot F, Preudhomme C, Guilhot J, et al. Significantly higher rates of undetectable molecular residual disease and molecular responses with pegylated form of interferon a2a in combination with imatinib (IM) for the treatment of newly diagnosed chronic phase (CP) chronic myeloid leukaemia (CML) patients (pts): confirmatory results at 18 months of part 1 of the Spirit Phase III randomized trial of the French CML Group (FI LMC) [abstract]. Blood 2009; 114; 340. 17. Burchert A, Muller MC, Kostrewa P, et al. Interferon alpha 2a (IFN) maintenance therapy after imatinib plus IFN induction therapy in chronic myeloid leukemia (CML) induces stable long-term molecular remissions and is associated with increased proteinase 3 (PR3) expression and the presence of PR1-specific T-cells [abstract]. Blood 2009; 114:647. 18. Peudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 2010; 363:2511-21. 19. Al-Ameri A, Kantarjian H, Borthakur G, et al. Opportunistic infections are uncommon with dasatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) [abstract]. Blood 2009; 114: 1120.
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