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Nonmyeloablative Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia in the Imatinib Era
CML
Leukemia 2008 Proceedings
Nonmyeloablative Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia in the Imatinib Era Richard Champlin, Marcos de Lima, Partow Kebriaei, Gabriela Rondon, Tobi Fisher, Elias Jabbour, Jorge E. Cortés, Hagop Kantarjian, Paolo Anderlini, Amin Alousi, Chitra Hosing, Elizabeth Shpall, Uday Popat, Muzaffar Qazilbash, Borje Andersson, Sergio Giralt Abstract Allogeneic stem cell transplantation (ASCT) is a potentially curative treatment for patients with chronic myelogenous leukemia (CML) and was previously considered the preferred treatment for newly diagnosed CML. The success of imatinib has changed treatment recommendations, and allogeneic transplants are now reserved for imatinib treatment failures. Previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. It is unclear whether patients whose disease is considered to have failed imatinib should be referred immediately for ASCT or receive treatment with a second-generation tyrosine kinase inhibitors (TKI). Patients whose disease fails 2 TKIs should receive ASCT if possible. Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation treatment with TKIs and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions. Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 3, S261-S265, 2009; DOI: 10.3816/CLM.2009.s.021 Keywords: Busulfan, Chronic myeloid leukemia, Fludarabine, Graft-versus-host disease, Preparative regimen
Introduction The treatment of chronic myelogenous leukemia (CML) has rapidly evolved during the past decade. Allogeneic hematopoietic stem cell transplantation (ASCT; SCT) was previously considered by many as the treatment of choice, able to induce durable molecular complete remissions in an otherwise incurable disease.1-6 The role of hematopoietic transplantation as initial therapy was questioned with the introduction of interferon treatment.7-10 Most recently, imatinib and related tyrosine kinase inhibitors (TKIs) have revolutionized the treatment for this disease.11-17 A recent update of the IRIS (International Randomized IFN vs. ST1571) study demonDepartments of Stem Cell Transplantation and Cellular Therapy and Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX Submitted: May 8, 2009; Revised: Jul 9, 2009; Accepted: Jul 14, 2009 Address for correspondence: Richard Champlin, MD, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0423, Houston, TX 77030 Fax: 713-792-4346; e-mail: [email protected]
strated approximately 83% were event free and 93% were free of progression to accelerated or blast phase (AP; BP) at 6 years. An analysis by Hehlmann indicated superior survival in patients treated with interferon and imatinib compared with early treatment with SCT.18 Imatinib is now recommended as the international standard of care for initial therapy of CML.19,20,11 However, approximately 15% fail to achieve a cytogenetic remission or progress during the first 5 years, and a small fraction of patients will develop blast crisis while responding to imatinib treatment.21 In a recent follow-up of the IRIS study, approximately 30% of patients discontinued imatinib as a result of inadequate response or intolerance. Patients are typically considered for transplantation if they fail to have an adequate response to imatinib or progress after initial therapy. Baccarani et al summarized international consensus criteria for suboptimal response to imatinib; these criteria are used to select patients for studies of alternative therapies including hematopoietic transplantation.19 Allogeneic stem cell transplantation is a potentially curative treatment for CML, and remains the only effective treatment to produce durable complete remissions for patients resis-
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Nonmyeloablative AlloSCT for CML in the Imatinib Era Figure 1 Scheme for Nonmyeloablative Allogeneic Stem Cell Transplantation D
Preparative Regimen
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The preparative regimen uses well-tolerated, lower-dose chemotherapy or radiation designed to reduce preparative regimen toxicity. This is not expected to eradicate the malignancy, but it is sufficiently immunosuppressive to prevent graft rejection. This allows durable engraftment of the donor stem cells and immunocompetent cells with mixed chimerism (coexistence of donor and some recipient-derived hematopoietic cells). A natural graft-versus-hematopoietic effect occurs, which eliminates recipient-derived normal and malignant cells. This graft-versus-malignancy effect can be augmented by donor lymphocyte infusion if there is evidence of residual disease. When successful, the patient ultimately becomes a complete chimera (with only donor-derived hematopoiesis) and no residual leukemia.
tant to TKIs. Allogeneic stem cell transplantation is an expensive procedure, but its cost is less than a potential lifetime treatment with TKIs.
Antileukemia Effects of Allogeneic Stem Cell Transplantation Allogeneic stem cell transplantation remains the most effective “antileukemic” treatment in CML, with the majority of surviving patients achieving molecular complete remission with undetectable bcr-abl rearrangement by polymerase chain reaction (PCR) analysis; this represents superior cytoreduction of the leukemia than can be achieved by imatinib; however, this benefit has historically been offset by an unacceptably high risk of treatment-related morbidity and mortality related to the toxicity of the myeloablative preparative regimens, graft-versus-host disease (GVHD), and infections.
Graft-Versus-Leukemia and Nonmyeloablative Stem Cell Transplantation The curative effect of ASCT in CML is largely derived from the immune graft-versus-leukemia (GVL) effect mediated by alloreactive donor T cells reacting against residual host malignant cells.22-26 Simple infusion of donor lymphocytes (donor lymphocyte infusion [DLI]) can produce durable molecular complete remissions in patients with hematologic relapse after bone marrow transplantation without the need for any additional cytoreductive therapy.27,28 This observation led ourselves and subsequently others to explore the use of nonablative or reduced-intensity conditioning to reduce treatment-related toxicities. The preparative regimen using lower dose, relatively nontoxic chemotherapy or radiation is not expected to eradicate the malignancy, but it is sufficiently immunosuppressive to prevent graft rejection. This allows durable engraftment of the donor immunocompetent cells which mediate the GVL effect.24,29-32 The lower level of tissue damage associated with nonmyeloablative regimens results in a lower incidence and sever-
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CML Cell Mass
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Figure 2 Sequential Therapy Protocol Timeline
Initial Treatment
Imatinib
Donor Lymphocyte Infusion
Residual Disease
No mCR
> 3 months
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Patients initially receive a reduced-intensity preparative regimen involving fludarabine 40 mg/m2 × 4 days, busulfan 130 mg/m2 × 2 days, and antithymocyte globulin 2.5 mg/kg daily × 3 days followed by allogeneic stem cell transplantation from an HLA-identical or 1-antigen mismatched related or unrelated donor. Patients with residual disease after 3 months by quantitative polymerase chain reaction analysis for Bcr-Abl receive imatinib. Patients who did not achieve molecular complete response with imatinib treatment receive escalating doses of donor lymphocyte infusion.
ity of GVHD and a lower rate of treatment-related mortality. This general approach is summarized in Figure 1. We have demonstrated that nonmyeloablative ASCT reduces treatment-related mortality and allows allogeneic transplantation to be successfully performed in older and medically debilitated patients who could not tolerate myeloablative regimens. This is important because the median age of patients with CML is > 60 years of age and many have coexisting medical problems. Donor lymphocyte infusion is an effective treatment for patients with CML with persistent or recurrent disease after allogeneic hematopoietic transplantation; approximately 70% of patients with molecular or cytogenetic relapse will respond and achieve a molecular complete remission.33-40 Use of repeated escalating doses from 106 to 107 T-cells/kg have produced less GVHD and comparable remission rates compared with single large doses approximately 108/kg.41,42 The major risk of ASCT is GVH disease, and a major goal is to develop strategies to eliminate GVHD while retaining the benefit of GVL. We and others report success with this strategy in patients with CML.43-45 Kebriaei et al recently reported the long-term results of our initial studies of nonmyeloablative allogeneic transplantation in high-risk patients with CML.46 Patients were selected for a reduced-intensity conditioning regimen because of older age or comorbidities which would preclude the use of myeloablative preparative regimen. Patients with CML with AP disease (80% beyond first chronic phase [CP]) were treated with fludarabine-based, reduced-intensity preparative regimens. Donor type was matched related (n = 30), 1 antigen mismatched related (n = 4), or matched unrelated (n = 30). With median follow-up of 7 years, overall- and progression-free survival (OS; PFS) were 33% and 20%, respectively, at 5 years. The incidence of treatment-related mortality was 33%, 39%, and 48% at 100 days, 2 years, and 5 years after hematopoietic stem cell transplantation in this high-risk patient population. In multivariate analysis, only disease stage at time of ASCT was significantly predictive for survival and PFS. Patients with late CP had better results than patients with AP disease.
Richard Champlin et al
Response Molecular to Prep Molecular Alive/cCR CR to Regimen CR to DLI mCR/Relapse Imatinib at 3 Months N = 33 16 Early
Cyto CR 16mCR 5
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The initial response after the reduced-intensity preparative regimen is assessed at 3 months. Patients with molecular evidence of residual disease receive imatinib treatment and are assessed after 3 months. Patients with residual disease after imatinib treatment receive donor lymphocyte infusion. The final column summarizes the current status of patients, number alive, complete cytogenetic remission (cCR), molecular complete remission (mCR), and number with hematologic relapse and progression of disease.
Figure 3 Survival in Early (First Chronic Phase or Clonal Evolution) Versus Advanced Chronic Myelogenous Leukemia (Accelerated Phase or Second Chronic Phase) 100
Cumulative Proportion Surviving, %
Table 1 Responses After Sequential Therapy Protocol
90 80 70 60 50 40 30 20 10 0
Busulfan is a highly effective drug for the treatment of CML. It targets normal and malignant stem cells, and high doses can only be administered with stem cell transplantation to restore hematopoiesis. The oral formulation is erratically absorbed. Several centers have used pharmacokinetic monitoring to ensure achievement of optimal drug levels.47 A major advance has been the development of intravenous (I.V.) formulation of busulfan. Andersson et al demonstrated that the pharmacokinetics of busulfan predicted for toxicity, the rate of GVHD, and outcome in patients with CML.48 We evaluated the 100-day mortality rates associated with busulfan-based myeloablative conditioning regimens based on data from the Center for International Blood & Marrow Transplant Research (CIBMTR) analyzing patients with CML who underwent allogeneic blood or marrow transplantation for CML during the same period; we found improved results with the busulfan I.V. preparation.49
Use of Imatinib After Stem Cell Transplantation We also evaluated the use of imatinib within the first hundred days after SCT for high-risk patients with advanced CML or Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL). We demonstrated that imatinib can be safely administered to patients early after SCT, that reversible myelosuppression was the limiting toxicity, and that tacrolimus serum levels increased from 25% to 33%. Close monitoring for hematologic toxicity was required.50 Kantarjian et al demonstrated that imatinib was effective treatment for CML relapsing after transplantation, achieving complete molecular remission in many patients.51
Allogeneic Stem Cell Transplantation After Treatment With Tyrosine Kinase Inhibitors Patients undergoing allogeneic hematopoietic stem cell transplantation for CML are increasingly likely to have received a second-generation TKI (dasatinib and nilotinib) after failing imatinib. It is unknown whether the use of these agents might effect transplantation-related toxicity and the outcome of SCT. Jabbour et al analyzed outcome of 12 patients, most with advanced CML (1 in CP, 6 AP, and 5 BP) who had received dasatinib, nilotinib, or both before ASCT. The preparative
Early Phase, 82% Advanced Phase, 54% 10
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regimen was ablative in 8 patients and nonablative in 4. All patients engrafted promptly. There was no significant early transplantationrelated toxicity. One patient developed secondary graft failure and required a second transplantation. Acute and chronic GVHD was observed in 7 and 6 patients, respectively. Nine patients achieved a molecular response (complete response, 4; major response, 5 [quantitative reverse-transcriptase PCR < 0.05%]). After a median follow-up of 10 months, 7 patients were alive with molecular response and 5 patients had died, 4 from disease progression. We concluded that previous treatment with a TKI did not increase transplantation-related toxicity, and outcomes were similar to historic patients with advanced CML before the imatinib era.52 This conclusion has subsequently been confirmed by analyses by other centers53 and the CIBMTR.54
Allogeneic Stem Cell Transplantation for Patients With Chronic Myelogenous Leukemia With Bcr-Abl Mutations Allogeneic stem cell transplantation is now considered primarily in patients with resistance or suboptimal responses to imatinib or other TKIs. Resistance to imatinib is often associated with point mutations in the Bcr-Abl kinase domain. The effect of these mutations on the outcome of ASCT is unknown. Ten imatinib-resistant patients with Bcr-Abl kinase mutations received a transplant: 9 had CML (3 in CP, 4 in AP, and 2 in BP) and 1 had Ph+ ALL. Patients harbored 9 different protein kinase mutations, including the T315I mutation (which results in resistance to all available TKIs) in 2. Preparative regimens were ablative (n = 7) and nonablative (n = 3). All patients were engrafted; there were no treatment-related deaths. Disease response was complete molecular (CMR; n = 7), major molecular (n = 2), and no response (n = 1). Three patients (mutations Q252H, E255K, and T315I) died of relapse after ASCT. Seven patients are alive (6 in CMR) for a median of 19 months. We concluded that ASCT remains an important salvage option for patients who develop imatinib resistance through Bcr-Abl mutations. Further study in larger numbers of patients is required.55
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Nonmyeloablative AlloSCT for CML in the Imatinib Era Figure 4 When to Perform Allogeneic Stem Cell Transplantation in Chronic Myelogenous Leukemia Diagnosis
First Failure
Risk of transplantation outweighs benefit vs. TKIs
Considerations: Patient age, PS, goal, disease stage, prognostic factors, mutations, donor availability, efficacy of alternative treatment
Second Failure
AP/Blast Crisis BMT least likely to be successful, poor PS, disease resistant
Two early patients achieved molecular CR. Of 6 advanced patients receiving DLI, 2 have a molecular CR, and 4 still have detectable disease by quantitative PCR. Twenty-five patients are alive, including 15 of 16 with early disease (94%), all currently in cytogenetic CR, and 10 in molecular CR. Of the 17 patients with advanced disease, 10 are alive (58%), 8 in cytogenetic CR, and 5 in molecular CR. Six advanced patients succumbed to blast crisis. We concluded that sequential therapy including nonmyeloablative allotransplantation, posttransplantation imatinib, and DLI was well tolerated and capable of prolonged cytogenetic remissions and survival.
Conclusion Allogeneic stem cell transplantation (ASCT) is not recommended as initial therapy; recent studies indicate improved survival with imatinib or alternative tyrosine kinase inhibitor (TKI)–based initial treatment. Patients should be considered for ASCT at initial failure of imatinib or after failure of a second TKI. Patients receiving ASCT after transformation to accelerated phase or blast crisis have relatively poor results.
Sequential Therapy With Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia We recently evaluated a novel strategy to provide a safe, nontoxic approach for ASCT in patients with CP CML who have not responded optimally to imatinib. We studied sequential therapy using a nonmyeloablative preparative regimen, designed to reduce the risks of the preparative regimen. We hypothesized that patients might be cured by receiving a series of treatments designed to minimize toxicity and achieve molecular remission. Patients initially received a nonmyeloablative transplantation designed to minimize toxicity, GVHD, and treatment-related mortality. Those with residual disease received posttransplantation imatinib, and those who did not achieve a molecular remission received donor lymphocyte infusion for those still with residual or recurrent disease after 6 months (Figure 2).56 Patients received a reduced-intensity preparative regimen involving fludarabine 40 mg/m2 × 4 days, busulfan 130 mg/m2 × 2 days, and antithymocyte globulin 2.5 mg/kg daily × 3 days followed by ASCT from an HLA identical or 1 antigen mismatched related or unrelated donor. The regimen was designed to achieve engraftment with a low rate of GVHD and treatment-related mortality. Patients with residual disease after 3 months by quantitative PCR analysis for BcrAbl received imatinib, and those who did not achieve molecular CR within 3 months received escalating doses of DLI. Thirty-eight patients were entered, and 33 have > 6 months of follow-up and are evaluable. Median age was 41 years (range, 22-69 years). All were previously treated with imatinib, 11 were in cytogenetic CR, and 32 had detectable disease by PCR. Sixteen had early disease (in CP or with isolated clonal evolution), and 17 had advanced disease (with previous AP or in second CP after blast crisis). Results are summarized in Table 1 and Figure 3. Median follow up time is 2.4 years (range, 0.3-4.2 years). The regimen was well tolerated. One patient required a second transplant for rejection. Seven patients (21%) developed reversible grade 2-3 acute GVHD. None died within 100 days after transplantation. At 3 months, all 16 early patients and 12 of the 17 advanced patients achieved cytogenetic CR, and 4 early and 2 advanced had molecular CR, respectively. Eighteen patients with residual or recurrent molecular residual disease after 3 months received treatment with imatinib; molecular CR was achieved in 8 of 9 early patients and 2 of 9 with advanced CML. Eight patients subsequently received DLI.
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Allogeneic stem cell transplantation remains an important, potentially curative treatment for patients with CML. Preliminary analysis indicates that previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. Allogeneic stem cell transplantation should be considered for patients with failure to treatment with imatinib. The criteria for failure described by Baccarani et al include no hematologic response in 3 months of imatinib treatment, less than complete hematologic response or no cytogenetic response (Ph+ cells > 95%) at 6 months, Ph+ cells > 35% at ≤ 12 months or less than complete cytogenetic response at 18 months, loss of response or acquisition of mutation or intolerance to TKI-based therapy.19 Patients with imatinib failure have a high rate of response to second-generation TKIs, but only short-term follow-up is available. It is unclear whether patients with imatinib failure should receive ASCT immediately or receive a trial of treatment with a secondgeneration TKI; this issue should be addressed in prospective clinical trials. Patients failing treatment with 2 TKIs should receive ASCT if possible (Figure 4). Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation immunomodulatory therapy and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions in patients failing to respond optimally to imatinib.
Acknowledgement This work was supported by grant CA49639 from the National Cancer Institute and a grant from Genzyme Corporation.
Disclosures Dr. Richard Champlin has received research funding from Genzyme Corporation. Dr. Sirgio Giralt has served on a Speaker’s Bureau for Celgene Corporation, Millenium Pharmaceuticals, Inc., Ortho Biotech Products, L.P., and has served on an advisory board for Celgene Corporation, Millenium Pharmaceuticals, Inc., and Kyphon. Dr. Uday Popat has served on a Speaker’s Bureau for and received Honorarium from Novartis Pharmaceuticals Corporation. Dr. Amin Alousi has received research support from Celgene Corporation and THERAKOS, Inc. Dr. Elias Jabbour has served on a Speaker’s Bureau for Bristol-Myers Squibb Company and Novartis Pharmaceuticals Corporation. Dr. Jorge E. Cortés has received research support from Bristol-Myers Squibb Company, ChemGenex Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Wyeth Pharmaceuticals. Dr. Hagop M. Kantarjian has received research support from Bristol-Myers Squibb Company,
Richard Champlin et al Genzyme Corporation, MGI PHARMA, and Novartis Pharmaceuticals Corporation. Dr. Hosing has received honoraria from. has served as a paid consultant or been on an Advisory Board for, and is a member of the Speaker’s Bureau for Genzyme, Inc. and Schering Plough.
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Long-term follow-up of allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning for patients with chronic myeloid leukemia. Blood 2007; 110:3456-62. 47. Radich JP, Gooley T, Bensinger W, et al. HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood 2003; 102:31-5. 48. Andersson B, Thall PF, Madden T, et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft-vs.-host diesase; defining a therapetuic window for IV BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant 2002; 8:477-85. 49. Thall PF, Champlin RE, Andersson BS. Comparison of 100-day mortality rates associated with iv busulfan and cyclophosphamide vs other preparative regimens in allogeneic bone marrow transplantation for chronic myelogenous leukemia: Bayesian sensitivity analyses of confounded treatment and center effects. Bone Marrow Transplant 2004; 33:1191-9. 50. Anderlini P, Sheth S, Hicks K, et al. Re: Imatinib mesylate administration in the first 100 days after stem cell transplantation. Biol Blood Marrow Transplant 2004; 10:883-4. 51. Kantarjian HM, O’Brien S, Cortes JE, et al. Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 2002; 100:1590-5. 52. Jabbour E, Cortes J, Kantarjian H, et al. Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity. Cancer 2007; 110:340-4. 53. Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood 2007; 109:1782-9. 54. Lee SJ, Kukreja M, Wang T, et al. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood; 2008. 55. Jabbour E, Cortes J, Kantarjian HM, et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 2006; 108:1421-3. 56. Champlin RE, Giralt S, Shpall E, et al. Nonmyeloablative allogeneic transplantation in the imatinib era: three chances to achieve molecular remission in CML. Blood 2007; 110:1028a.
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Nonmyeloablative Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia in the Imatinib Era Richard Champlin, Marcos de Lima, Partow Kebriaei, Gabriela Rondon, Tobi Fisher, Elias Jabbour, Jorge E. Cortés, Hagop Kantarjian, Paolo Anderlini, Amin Alousi, Chitra Hosing, Elizabeth Shpall, Uday Popat, Muzaffar Qazilbash, Borje Andersson, Sergio Giralt Abstract Allogeneic stem cell transplantation (ASCT) is a potentially curative treatment for patients with chronic myelogenous leukemia (CML) and was previously considered the preferred treatment for newly diagnosed CML. The success of imatinib has changed treatment recommendations, and allogeneic transplants are now reserved for imatinib treatment failures. Previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. It is unclear whether patients whose disease is considered to have failed imatinib should be referred immediately for ASCT or receive treatment with a second-generation tyrosine kinase inhibitors (TKI). Patients whose disease fails 2 TKIs should receive ASCT if possible. Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation treatment with TKIs and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions. Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 3, S261-S265, 2009; DOI: 10.3816/CLM.2009.s.021 Keywords: Busulfan, Chronic myeloid leukemia, Fludarabine, Graft-versus-host disease, Preparative regimen
Introduction The treatment of chronic myelogenous leukemia (CML) has rapidly evolved during the past decade. Allogeneic hematopoietic stem cell transplantation (ASCT; SCT) was previously considered by many as the treatment of choice, able to induce durable molecular complete remissions in an otherwise incurable disease.1-6 The role of hematopoietic transplantation as initial therapy was questioned with the introduction of interferon treatment.7-10 Most recently, imatinib and related tyrosine kinase inhibitors (TKIs) have revolutionized the treatment for this disease.11-17 A recent update of the IRIS (International Randomized IFN vs. ST1571) study demonDepartments of Stem Cell Transplantation and Cellular Therapy and Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX Submitted: May 8, 2009; Revised: Jul 9, 2009; Accepted: Jul 14, 2009 Address for correspondence: Richard Champlin, MD, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0423, Houston, TX 77030 Fax: 713-792-4346; e-mail: [email protected]
strated approximately 83% were event free and 93% were free of progression to accelerated or blast phase (AP; BP) at 6 years. An analysis by Hehlmann indicated superior survival in patients treated with interferon and imatinib compared with early treatment with SCT.18 Imatinib is now recommended as the international standard of care for initial therapy of CML.19,20,11 However, approximately 15% fail to achieve a cytogenetic remission or progress during the first 5 years, and a small fraction of patients will develop blast crisis while responding to imatinib treatment.21 In a recent follow-up of the IRIS study, approximately 30% of patients discontinued imatinib as a result of inadequate response or intolerance. Patients are typically considered for transplantation if they fail to have an adequate response to imatinib or progress after initial therapy. Baccarani et al summarized international consensus criteria for suboptimal response to imatinib; these criteria are used to select patients for studies of alternative therapies including hematopoietic transplantation.19 Allogeneic stem cell transplantation is a potentially curative treatment for CML, and remains the only effective treatment to produce durable complete remissions for patients resis-
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Nonmyeloablative AlloSCT for CML in the Imatinib Era Figure 1 Scheme for Nonmyeloablative Allogeneic Stem Cell Transplantation D
Preparative Regimen
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The preparative regimen uses well-tolerated, lower-dose chemotherapy or radiation designed to reduce preparative regimen toxicity. This is not expected to eradicate the malignancy, but it is sufficiently immunosuppressive to prevent graft rejection. This allows durable engraftment of the donor stem cells and immunocompetent cells with mixed chimerism (coexistence of donor and some recipient-derived hematopoietic cells). A natural graft-versus-hematopoietic effect occurs, which eliminates recipient-derived normal and malignant cells. This graft-versus-malignancy effect can be augmented by donor lymphocyte infusion if there is evidence of residual disease. When successful, the patient ultimately becomes a complete chimera (with only donor-derived hematopoiesis) and no residual leukemia.
tant to TKIs. Allogeneic stem cell transplantation is an expensive procedure, but its cost is less than a potential lifetime treatment with TKIs.
Antileukemia Effects of Allogeneic Stem Cell Transplantation Allogeneic stem cell transplantation remains the most effective “antileukemic” treatment in CML, with the majority of surviving patients achieving molecular complete remission with undetectable bcr-abl rearrangement by polymerase chain reaction (PCR) analysis; this represents superior cytoreduction of the leukemia than can be achieved by imatinib; however, this benefit has historically been offset by an unacceptably high risk of treatment-related morbidity and mortality related to the toxicity of the myeloablative preparative regimens, graft-versus-host disease (GVHD), and infections.
Graft-Versus-Leukemia and Nonmyeloablative Stem Cell Transplantation The curative effect of ASCT in CML is largely derived from the immune graft-versus-leukemia (GVL) effect mediated by alloreactive donor T cells reacting against residual host malignant cells.22-26 Simple infusion of donor lymphocytes (donor lymphocyte infusion [DLI]) can produce durable molecular complete remissions in patients with hematologic relapse after bone marrow transplantation without the need for any additional cytoreductive therapy.27,28 This observation led ourselves and subsequently others to explore the use of nonablative or reduced-intensity conditioning to reduce treatment-related toxicities. The preparative regimen using lower dose, relatively nontoxic chemotherapy or radiation is not expected to eradicate the malignancy, but it is sufficiently immunosuppressive to prevent graft rejection. This allows durable engraftment of the donor immunocompetent cells which mediate the GVL effect.24,29-32 The lower level of tissue damage associated with nonmyeloablative regimens results in a lower incidence and sever-
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CML Cell Mass
D
Figure 2 Sequential Therapy Protocol Timeline
Initial Treatment
Imatinib
Donor Lymphocyte Infusion
Residual Disease
No mCR
> 3 months
> 3 months later
Patients initially receive a reduced-intensity preparative regimen involving fludarabine 40 mg/m2 × 4 days, busulfan 130 mg/m2 × 2 days, and antithymocyte globulin 2.5 mg/kg daily × 3 days followed by allogeneic stem cell transplantation from an HLA-identical or 1-antigen mismatched related or unrelated donor. Patients with residual disease after 3 months by quantitative polymerase chain reaction analysis for Bcr-Abl receive imatinib. Patients who did not achieve molecular complete response with imatinib treatment receive escalating doses of donor lymphocyte infusion.
ity of GVHD and a lower rate of treatment-related mortality. This general approach is summarized in Figure 1. We have demonstrated that nonmyeloablative ASCT reduces treatment-related mortality and allows allogeneic transplantation to be successfully performed in older and medically debilitated patients who could not tolerate myeloablative regimens. This is important because the median age of patients with CML is > 60 years of age and many have coexisting medical problems. Donor lymphocyte infusion is an effective treatment for patients with CML with persistent or recurrent disease after allogeneic hematopoietic transplantation; approximately 70% of patients with molecular or cytogenetic relapse will respond and achieve a molecular complete remission.33-40 Use of repeated escalating doses from 106 to 107 T-cells/kg have produced less GVHD and comparable remission rates compared with single large doses approximately 108/kg.41,42 The major risk of ASCT is GVH disease, and a major goal is to develop strategies to eliminate GVHD while retaining the benefit of GVL. We and others report success with this strategy in patients with CML.43-45 Kebriaei et al recently reported the long-term results of our initial studies of nonmyeloablative allogeneic transplantation in high-risk patients with CML.46 Patients were selected for a reduced-intensity conditioning regimen because of older age or comorbidities which would preclude the use of myeloablative preparative regimen. Patients with CML with AP disease (80% beyond first chronic phase [CP]) were treated with fludarabine-based, reduced-intensity preparative regimens. Donor type was matched related (n = 30), 1 antigen mismatched related (n = 4), or matched unrelated (n = 30). With median follow-up of 7 years, overall- and progression-free survival (OS; PFS) were 33% and 20%, respectively, at 5 years. The incidence of treatment-related mortality was 33%, 39%, and 48% at 100 days, 2 years, and 5 years after hematopoietic stem cell transplantation in this high-risk patient population. In multivariate analysis, only disease stage at time of ASCT was significantly predictive for survival and PFS. Patients with late CP had better results than patients with AP disease.
Richard Champlin et al
Response Molecular to Prep Molecular Alive/cCR CR to Regimen CR to DLI mCR/Relapse Imatinib at 3 Months N = 33 16 Early
Cyto CR 16mCR 5
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Cyto CR 15mCR 1
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The initial response after the reduced-intensity preparative regimen is assessed at 3 months. Patients with molecular evidence of residual disease receive imatinib treatment and are assessed after 3 months. Patients with residual disease after imatinib treatment receive donor lymphocyte infusion. The final column summarizes the current status of patients, number alive, complete cytogenetic remission (cCR), molecular complete remission (mCR), and number with hematologic relapse and progression of disease.
Figure 3 Survival in Early (First Chronic Phase or Clonal Evolution) Versus Advanced Chronic Myelogenous Leukemia (Accelerated Phase or Second Chronic Phase) 100
Cumulative Proportion Surviving, %
Table 1 Responses After Sequential Therapy Protocol
90 80 70 60 50 40 30 20 10 0
Busulfan is a highly effective drug for the treatment of CML. It targets normal and malignant stem cells, and high doses can only be administered with stem cell transplantation to restore hematopoiesis. The oral formulation is erratically absorbed. Several centers have used pharmacokinetic monitoring to ensure achievement of optimal drug levels.47 A major advance has been the development of intravenous (I.V.) formulation of busulfan. Andersson et al demonstrated that the pharmacokinetics of busulfan predicted for toxicity, the rate of GVHD, and outcome in patients with CML.48 We evaluated the 100-day mortality rates associated with busulfan-based myeloablative conditioning regimens based on data from the Center for International Blood & Marrow Transplant Research (CIBMTR) analyzing patients with CML who underwent allogeneic blood or marrow transplantation for CML during the same period; we found improved results with the busulfan I.V. preparation.49
Use of Imatinib After Stem Cell Transplantation We also evaluated the use of imatinib within the first hundred days after SCT for high-risk patients with advanced CML or Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL). We demonstrated that imatinib can be safely administered to patients early after SCT, that reversible myelosuppression was the limiting toxicity, and that tacrolimus serum levels increased from 25% to 33%. Close monitoring for hematologic toxicity was required.50 Kantarjian et al demonstrated that imatinib was effective treatment for CML relapsing after transplantation, achieving complete molecular remission in many patients.51
Allogeneic Stem Cell Transplantation After Treatment With Tyrosine Kinase Inhibitors Patients undergoing allogeneic hematopoietic stem cell transplantation for CML are increasingly likely to have received a second-generation TKI (dasatinib and nilotinib) after failing imatinib. It is unknown whether the use of these agents might effect transplantation-related toxicity and the outcome of SCT. Jabbour et al analyzed outcome of 12 patients, most with advanced CML (1 in CP, 6 AP, and 5 BP) who had received dasatinib, nilotinib, or both before ASCT. The preparative
Early Phase, 82% Advanced Phase, 54% 10
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regimen was ablative in 8 patients and nonablative in 4. All patients engrafted promptly. There was no significant early transplantationrelated toxicity. One patient developed secondary graft failure and required a second transplantation. Acute and chronic GVHD was observed in 7 and 6 patients, respectively. Nine patients achieved a molecular response (complete response, 4; major response, 5 [quantitative reverse-transcriptase PCR < 0.05%]). After a median follow-up of 10 months, 7 patients were alive with molecular response and 5 patients had died, 4 from disease progression. We concluded that previous treatment with a TKI did not increase transplantation-related toxicity, and outcomes were similar to historic patients with advanced CML before the imatinib era.52 This conclusion has subsequently been confirmed by analyses by other centers53 and the CIBMTR.54
Allogeneic Stem Cell Transplantation for Patients With Chronic Myelogenous Leukemia With Bcr-Abl Mutations Allogeneic stem cell transplantation is now considered primarily in patients with resistance or suboptimal responses to imatinib or other TKIs. Resistance to imatinib is often associated with point mutations in the Bcr-Abl kinase domain. The effect of these mutations on the outcome of ASCT is unknown. Ten imatinib-resistant patients with Bcr-Abl kinase mutations received a transplant: 9 had CML (3 in CP, 4 in AP, and 2 in BP) and 1 had Ph+ ALL. Patients harbored 9 different protein kinase mutations, including the T315I mutation (which results in resistance to all available TKIs) in 2. Preparative regimens were ablative (n = 7) and nonablative (n = 3). All patients were engrafted; there were no treatment-related deaths. Disease response was complete molecular (CMR; n = 7), major molecular (n = 2), and no response (n = 1). Three patients (mutations Q252H, E255K, and T315I) died of relapse after ASCT. Seven patients are alive (6 in CMR) for a median of 19 months. We concluded that ASCT remains an important salvage option for patients who develop imatinib resistance through Bcr-Abl mutations. Further study in larger numbers of patients is required.55
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Nonmyeloablative AlloSCT for CML in the Imatinib Era Figure 4 When to Perform Allogeneic Stem Cell Transplantation in Chronic Myelogenous Leukemia Diagnosis
First Failure
Risk of transplantation outweighs benefit vs. TKIs
Considerations: Patient age, PS, goal, disease stage, prognostic factors, mutations, donor availability, efficacy of alternative treatment
Second Failure
AP/Blast Crisis BMT least likely to be successful, poor PS, disease resistant
Two early patients achieved molecular CR. Of 6 advanced patients receiving DLI, 2 have a molecular CR, and 4 still have detectable disease by quantitative PCR. Twenty-five patients are alive, including 15 of 16 with early disease (94%), all currently in cytogenetic CR, and 10 in molecular CR. Of the 17 patients with advanced disease, 10 are alive (58%), 8 in cytogenetic CR, and 5 in molecular CR. Six advanced patients succumbed to blast crisis. We concluded that sequential therapy including nonmyeloablative allotransplantation, posttransplantation imatinib, and DLI was well tolerated and capable of prolonged cytogenetic remissions and survival.
Conclusion Allogeneic stem cell transplantation (ASCT) is not recommended as initial therapy; recent studies indicate improved survival with imatinib or alternative tyrosine kinase inhibitor (TKI)–based initial treatment. Patients should be considered for ASCT at initial failure of imatinib or after failure of a second TKI. Patients receiving ASCT after transformation to accelerated phase or blast crisis have relatively poor results.
Sequential Therapy With Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia We recently evaluated a novel strategy to provide a safe, nontoxic approach for ASCT in patients with CP CML who have not responded optimally to imatinib. We studied sequential therapy using a nonmyeloablative preparative regimen, designed to reduce the risks of the preparative regimen. We hypothesized that patients might be cured by receiving a series of treatments designed to minimize toxicity and achieve molecular remission. Patients initially received a nonmyeloablative transplantation designed to minimize toxicity, GVHD, and treatment-related mortality. Those with residual disease received posttransplantation imatinib, and those who did not achieve a molecular remission received donor lymphocyte infusion for those still with residual or recurrent disease after 6 months (Figure 2).56 Patients received a reduced-intensity preparative regimen involving fludarabine 40 mg/m2 × 4 days, busulfan 130 mg/m2 × 2 days, and antithymocyte globulin 2.5 mg/kg daily × 3 days followed by ASCT from an HLA identical or 1 antigen mismatched related or unrelated donor. The regimen was designed to achieve engraftment with a low rate of GVHD and treatment-related mortality. Patients with residual disease after 3 months by quantitative PCR analysis for BcrAbl received imatinib, and those who did not achieve molecular CR within 3 months received escalating doses of DLI. Thirty-eight patients were entered, and 33 have > 6 months of follow-up and are evaluable. Median age was 41 years (range, 22-69 years). All were previously treated with imatinib, 11 were in cytogenetic CR, and 32 had detectable disease by PCR. Sixteen had early disease (in CP or with isolated clonal evolution), and 17 had advanced disease (with previous AP or in second CP after blast crisis). Results are summarized in Table 1 and Figure 3. Median follow up time is 2.4 years (range, 0.3-4.2 years). The regimen was well tolerated. One patient required a second transplant for rejection. Seven patients (21%) developed reversible grade 2-3 acute GVHD. None died within 100 days after transplantation. At 3 months, all 16 early patients and 12 of the 17 advanced patients achieved cytogenetic CR, and 4 early and 2 advanced had molecular CR, respectively. Eighteen patients with residual or recurrent molecular residual disease after 3 months received treatment with imatinib; molecular CR was achieved in 8 of 9 early patients and 2 of 9 with advanced CML. Eight patients subsequently received DLI.
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Allogeneic stem cell transplantation remains an important, potentially curative treatment for patients with CML. Preliminary analysis indicates that previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. Allogeneic stem cell transplantation should be considered for patients with failure to treatment with imatinib. The criteria for failure described by Baccarani et al include no hematologic response in 3 months of imatinib treatment, less than complete hematologic response or no cytogenetic response (Ph+ cells > 95%) at 6 months, Ph+ cells > 35% at ≤ 12 months or less than complete cytogenetic response at 18 months, loss of response or acquisition of mutation or intolerance to TKI-based therapy.19 Patients with imatinib failure have a high rate of response to second-generation TKIs, but only short-term follow-up is available. It is unclear whether patients with imatinib failure should receive ASCT immediately or receive a trial of treatment with a secondgeneration TKI; this issue should be addressed in prospective clinical trials. Patients failing treatment with 2 TKIs should receive ASCT if possible (Figure 4). Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation immunomodulatory therapy and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions in patients failing to respond optimally to imatinib.
Acknowledgement This work was supported by grant CA49639 from the National Cancer Institute and a grant from Genzyme Corporation.
Disclosures Dr. Richard Champlin has received research funding from Genzyme Corporation. Dr. Sirgio Giralt has served on a Speaker’s Bureau for Celgene Corporation, Millenium Pharmaceuticals, Inc., Ortho Biotech Products, L.P., and has served on an advisory board for Celgene Corporation, Millenium Pharmaceuticals, Inc., and Kyphon. Dr. Uday Popat has served on a Speaker’s Bureau for and received Honorarium from Novartis Pharmaceuticals Corporation. Dr. Amin Alousi has received research support from Celgene Corporation and THERAKOS, Inc. Dr. Elias Jabbour has served on a Speaker’s Bureau for Bristol-Myers Squibb Company and Novartis Pharmaceuticals Corporation. Dr. Jorge E. Cortés has received research support from Bristol-Myers Squibb Company, ChemGenex Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Wyeth Pharmaceuticals. Dr. Hagop M. Kantarjian has received research support from Bristol-Myers Squibb Company,
Richard Champlin et al Genzyme Corporation, MGI PHARMA, and Novartis Pharmaceuticals Corporation. Dr. Hosing has received honoraria from. has served as a paid consultant or been on an Advisory Board for, and is a member of the Speaker’s Bureau for Genzyme, Inc. and Schering Plough.
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Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009
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