Targeted Agents for Chronic Myelogenous Leukemia: Will That Be the End of Allogeneic Bone Marrow Transplantation for That Disease?

Transcription

1 Targeted Agents for Chronic Myelogenous Leukemia: Will That Be the End of Allogeneic Bone Marrow Transplantation for That Disease? Yuzhen Liang, 1 Yongrong Lai, 1 Paul Schwarzenberger, 2 Qiaochuan Li, 1 Jie Ma, 1 Jun Luo, 1 Rongrong Liu, 1 Lingling Shi, 1 Jicheng Zhou, 1 Zhigang Peng, 1 Jie Yang, 1 Donghong Deng, 1 Yizhen Zhou 1 Although the drug imatinib has been accepted as the treatment of choice for chronic myelogenous leukemia (CML) in chronic phase (CP) throughout the Western world, allogeneic stem cell transplantation (allo-sct) continues to remain a widely practiced first-line treatment in countries with limited health care budgets. The rationale is not scientific, but largely economically based. We analyzed a cohort of 46 CML patients who participated in a graft-versus-host disease (GVHD) prophylaxis clinical trial and underwent related HLAmatched allogeneic peripheral blood stem cell transplantation. The median time of follow-up in surviving patients was 43 months (range: 4-89 months). Risk stratification of the population was done by European Blood and Marrow Transplant (EBMT) criteria. The estimated probabilities of overall survival (OS) and leukemiafree survival (LFS) at 3 years in low EBMTrisk score (0-2) patients were both 91%, respectively. We conclude that in countries with restricted access to imatinib, allo-sct should be considered early on as front-line therapy. Continued research support for bone marrow transplantation will be needed to make a global impact on this disease. Biol Blood Marrow Transplant 16: (2010) Ó 2010 American Society for Blood and Marrow Transplantation KEY WORDS: Allogeneic peripheral blood SCT, CML, GVHD, Prophylaxis INTRODUCTION Chronic myelogenous leukemia (CML) is a myeloproliferative disorder, arising from a translocation t(9;22)(q34;q11) in hematopoietic precursors, known as the Philadelphia chromosome [1,2]. The fusion gene (Bcr-Abl) product initiates deregulated cellular proliferation, which adversely affects differentiation and blocks apoptosis. Collectively, this leads to malignant expansion of pluripotent stem cells in blood forming organs [3]. The annual incidence of CML is 1 to 2 cases per 100,000 adults [3]. The majority of patients (90%95%) are diagnosed in chronic phase (CP). If From the 1 The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People s Republic of China; and 2 University of South Alabama, Mobile, Alabama. Financial disclosure: See Acknowledgments on page 852. Correspondence and reprint requests: Yongrong Lai, MD, PhD, Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, No. 6, Binhu Road, Nanning, Guangxi , P.R. China ( laiyongrong@hotmail. com). Received July 21, 2009; accepted January 27, 2010 Ó 2010 American Society for Blood and Marrow Transplantation /$36.00 doi: /j.bbmt left untreated, after an average of approximately 3 to 5 years, the disease changes to an accelerated phase, which inevitably progresses to a fatal acute leukemia, also known as blast crisis (BC). The median survival at that point is less than 6 months [4]. Historically, arsenic, hydroxyurea, busulfan, radiation, interferon-a, and stem cell transplantation (SCT) had been developed as treatments [5]. Until the development of imatinib, treatment was largely palliative, and the only potentially curative treatment available was allogeneic SCT (allo-sct), which carried very high risks of morbidity and mortality [6,7]. Data of European Group for Blood and Marrow Transplantation (EBMT) showed that the outcome of transplantation has improved over time with a marked reduction in treatmentrelated mortality (TRM) [8]. Five-year event-free survival (EFS) after an HLA-identical sibling allo-sct in CML patients was 70%-80% (CP \1 year after diagnosis), 50%-60% (CP.1 year after diagnosis), 30%- 50% (accelerated phase), and 5%-10% (blastic phase), respectivly [9]. Imatinib mesylate is a specific tyrosine kinase inhibitor that blocks theenzymatic activity of the dysregulated Bcr-Abl oncoprotein. The introduction of this drug has revolutionized the treatment of CML. It has dramatically improved the overall outcomes of 848

2 Biol Blood Marrow Transplant 16: , 2010 Targeted Agents for CML 849 CML patients and is generally reasonably well tolerated [10,11]. Recently, updated results from a randomized clinical trial compared imatinib with interferon-a as a first-line treatment for chronic phase CML (IRIS study) [12,13]. At 7 years, the estimated overall survival (OS) and EFS were 86% and 81%, respectively [14]. The clinical practice guidelines of the National Comprehensive Cancer Network (NCCN) (2008) recommends imatinib to be used as first-line treatment for patients with newly diagnosed CML. It recommends allo-sct as second-line treatment after imatinib failure, except for high-risk disease and for very low transplantation risk, patients preference, or for economic reasons. Published results comparing historic data from allo-sct for CML clearly favor use of imatinib over front-line transplant in patients with CP [15,16]. Either form of treatment is very expensive and poses a major burden on health care systems. However, given the drug cost for imatinib, in poorer nations or nations with a limited health care budget, the use of imatinib can be prohibitive. For instance, the annual cost for imatinib in China is in U.S. $41,000. Socially disadvantaged patients may be eligible to receiving financial help from a government controlled foundation; however, those patients still will be responsible for $10,300 per annum. Considering that in 2008, in China, the annual income in urban households was approximately $2310 and $700 in rural households, this is a classic catch 22, because patients who would be eligible for the foundation money would not be able to come up with the residual balance. In contrast, relative to the United States, the average cost for a related donor allo-sct is much cheaper in economically less developed countries because all such services are rendered within the system at less cost. In China, the costs for the procedure are between U.S. $20,000. and 30,000, which includes follow-up visits and graft-versus-host dieases (GVHD) medications. That means that the drug cost for only 1 year of imatinib already substantially exceeds the allo-sct costs plus follow-up treatments. For that reason, in China as well as in many other non-western countries whose health care system cannot afford the use of imatinib, allo-sct is considered more cost effective than life-long therapy with imatinib [17,18]. Therefore, exclusively for economic reasons, in China and likely also in other nations, for transplant-eligible patients allo-sct remains the standard first-line treatment of choice for all CML risk group patients. As part of a larger prospective cohort study designed to investigate a new GVHD prophylaxis regimen in patients with related HLA-matched and single antigen mismatched allogeneic peripheral blood stem cell transplantation (PBSCT), we treated a cohort of 46 CML patients between June of 2001 and September 2008 [19]. We subanalyzed this cohort and compared the outcomes to that of the IRIS study. DESIGN AND METHODS Patients and transplantation characteristics are summarized in Table 1. The data were collected and analyzed through December 31, The median time of follow-up in surviving patients was 43 months (range: 4-89 months). Risk score was defined following the EBMT risk score system [20].The patients were divided into 2 groups: low EBMT risk scores (0-2) and high EBMT risk scores ($3) patients. Forty-three patients received cyclophosphamide (Cy, 60 mg/kg/day 2 days) and busulfan (Bu) as conditioning regimen. Bu was given either orally (4 mg/ kg/day on days 1-4) or intravenously (3.2 mg/kg/day on days 1-4). Three patients in blastic phase received cyclophosphamide (Cy, 60 mg/kg/day 2 days) and total body irradiation (TBI 5.0 Gy/day 2 days) as conditioning regimen. Patients were infused with granulocyte-colony stimulating factor (G-CSF) mobilized donor allogeneic mobilized stem cells. The median numbers of mononuclear cells (MNC) and CD 34 1 cells infused were 9.26 ( ) 10 8 / kg and 5.79 ( ) 10 6 /kg, respectively. GVHD prophylaxis consisted of cyclosporine (CsA), methothexate (MTX), and mycophenolate mofetil (MMF). Intravenous CsA (3 mg mg/kg/day) given on days 1-30, thereafter orally (6 mg mg/kg/day), with target trough levels at ng/ml. MTX was administered intravenously at doses of 15 mg/m 2 on day 11 and 10 mg/m 2 on days 13, 16, and 111. MMF was given orally at a dose of 250 mg twice daily until day 20 and tapered to a maintenance dose of 250 mg to day 130. Dose adjustments and supportive care were administered following standard practice guidelines. Statistical Analysis Both OS and leukemia-free survival (LFS) were calculated by using the Kaplan-Meier method provided through the statistical software program SPSS version 13.0 (SPSS, Chicago, IL, USA). TRM and mortality rates from disease progression (MDP) were calculated using the cumulative incidence method provided through the statistical software program NCSS 2007 (Number Cruncher Statistical System, Kaysville, UT, USA). RESULTS The outcomes and the cost of transplantation in 46 patients are summarized in Tables 2 and 3,

3 850 Y. Liang et al. Biol Blood Marrow Transplant 16: , 2010 Table 1. Patients and Transplantation Characteristics Characteristic n % Patients 46 Adult Pediatric Male/Female 36/ /21.7 Median age, years (range) 33 (10-49) Disease status CP AP BC Risk score $ HLA status Identical antigen mismatched ABO blood group status Matched Mismatched Conditioning regimen TBI + Cy Bu + Cy CML indicates chronic myelogenous leukemia; CP, chronic phase; AP, accelerated phase; BC, blast crisis; HLA, human leukocyte antigen; TBI, total body irradiation; Cy, cyclophosphamide; Bu, busulfan; Risk score, EBMT risk score. respectively. All patients with the exception of 1 high EBMT risk scores patient achieved engraftment. Only 7 of 46 patients developed acute GVHD (agvhd), 1 of whom developed grade III disease. No fatality was recorded. The cumulative incidence of agvhd was 15.2% (95% confidence interval [CI] 7.7%-30.1%). The cumulative incidence of grade I agvhd was 6.5% (95% CI 2.2%-19.5%).The cumulative incidence of grade II-IV agvhd was 8.7% (95% CI 3.4%-22.2%). The cumulative incidence of grade III-IV agvhd was 2.2% (95% CI 0.3%-15.1%). There was no difference in the overall incidence between low and high EBMT risk score groups. Sixteen patients (cumulative incidence 35.7%) developed chronic GVHD (cgvhd) with 8 patients (17.9%) having limited and 8 patients (17.9%) having extensive cgvhd. Here again, no detectable difference in cgvhd was found between risk groups. Five patients died free of disease (4 died from infection and 1 died from graft failure). The cumulative rates of TRM at 3 years in low EBMT risk score patients and high EBMT risk score patients were 6.1% (95% CI 1.6%-23.3%) and 20.0% (95% CI 5.8%- 69.1%) (P ), respectively. All patients who engrafted (n 5 45) achieved a complete remission (CR). The cumulative rates of MDP at 3 years in low EBMT risk score and high EBMT risk scores patients were 3.3% (95% CI 0.5%-22.9%) and 57.8% (95% CI 33.1%-100.0%) (P \.0001),respectively. One patient who relapsed in CP achieved another long-lasting (29 months) CR after stopping the GVHD prophylaxis and subsequent initiation of imatinib therapy. Three patients who relapsed or progressed to BC failed rescue with imatinib as well as donor lymphocyte infusion (DLI) therapy. With a median time of follow-up of 43 months (range: 4-89 months), 34 of 46 patients were alive without disease. The estimated probabilities of OS at 3 years in low EBMT risk score patients and high EBMT risk score patients were 90.8% (95% CI 80.7%-100.0%) and 21.2% (95% CI 0 %-47.0%) (P \.0001), respectively (Figure 1 A). The estimated probabilities of LFS at 3 years in low EBMT risk scores patients and high EBMT risk scores patients were 90.8% (95% CI 80.7%-100.0%) and 18.2% (95% CI 0 %-40.9%) (P \.0001), respectively (Figure 1B). DISCUSSION In light of the available imatinib data, recommending allo-sct for patients with newly diagnosed CML in CP is an ethical challenge for physicians practicing in countries that are on a restricted health care budget. Historically, the only definitive curative therapy for CML was and remains allo-sct. Initial outcomes with allo-sct in CML was associated with significant mortality and morbidity, which may have been related to older techniques as well as transplantations that were performed predominantly in high-risk patients as a rescue setting or in patients who already had been treated conservatively for longer periods. Although much work still needs to be done, during the past decade, all aspects of SCT have continuously improved. Specifically, progress has been made in HLA typing, management of infections, supportive care, conditioning regimens, GVHD prophylaxis, and new salvage approaches for disease relapse post transplant [20-24]. Our group previously reported a new GVHD prophylaxis regimen that effectively decreased the risk of developing agvhd. Our data were compared to international historic data as well Table 2. Outcomes at 3 Years in 46 Patients with CML N 5 46 OS (%) LFS (%) TRM (%) MDP (%) EBMT risk score $ CML indicates chronic myelogenous leukemia; OS, overall survival; LFS, leukemia-free survival; TRM, treatment-related mortality; MDP, mortality from disease progression.

4 Biol Blood Marrow Transplant 16: , 2010 Targeted Agents for CML 851 Table 3. The Median Allogeneic Transplantation Costs per CML Patient at a Chinese Institution (n 5 46) Category Costs ($)* The costs of hospitalizations Pharmacy 13,101 (4,370-25,386) therapy 2108 (1, ) Nursing 294 ( ) Laboratory 1018 ( ) Blood bank 1017 ( ) Other 2469 ( ) The costs of outpatient visits 6539 ( ,698) and drug treatment Total costs 26,432 (18,770-62,039) CML indicates chronic myelogenous leukemia. *1 USD56.83 CNY. Includes the costs for transplant-related rehospitalizations. as data within the Chinese registries [19]. In our series of 100 patients, the cumulative incidence of grade II- IV agvhd was 9.5% [19]. In previously published studies, GVHD prophylaxis typically consisted of a combination of CsA and MTX, with cumulative incidence of grade II-IV agvhd ranging between 37.4% and 65% [25-29]. In comparable settings within Chinese registries, the incidence of grade II- IV agvhd ranged between 21.6% and 40.0% [30-32]. In a series of 131 CML patients treated with allo-sct during first CP using a targeted Bu/Cy preparative regimen reported by Radich et al. [23], the OS and disease-free survival (DFS) at 3 years were 86% and 78%, respectively. The outcome of transplantation is highly dependent on the presence or absence of certain risk factors, and patient selection for transplantation is critical for the success of the procedure. Gratwohl et al. [8,20] determined for the EBMT favorable risk factors: availability of a sibling donor, younger age of the recipient, female recipient/female donor, transplantation at first CP, and the time frame being less than 12 months from the time of diagnosis to transplant. Patients with EBMT risk scores of 0-2 are expected to have a 85% OS at 5 years [20]. In our study, the estimated probability of OS at 3 years for low EBMT risk scores (0-2) patients was 91%, the LFS was also 91%. The 3 year results are also not far from the published 7 year IRIS data achieved with imatinib. Combining the evidence from the EBMT data [22], Radich s et al. study [23], the Mexico experience [17], as well as the data from our study, a reasonable argument could be made for considering front-line allo-sct for situations where imatinib is not an option. Ruiz-Argüelles et al. [17] recently reported the outcomes of 72 CML patients in first CP (22 patients received a reduced-intensity allo-sct, 50 patients received a tyrosine kinase inhibitor (TKI), mainly imatinib). The 6-year OS in allo- SCT and TKI patients were 77% and 84%, respectively (P, NS). Given the global economic crisis, it is unlikely that the treatment decision tree for CML in China or other countries with limited health care Figure 1. Estimated probabilities of overall survival (OS) (A) and leukemia-free survival (LFS) (B) at 3 years in low EBMT risk score (0-2) and high EBMTrisk score ($3) CML patients following allogeneic peripheral blood SCT (PBSCT) and CsA/MTX/MMF GVHD prophylaxis. budgets will change anytime soon. It also appears that at least some patients who relapse after transplant can still be salvaged with imatinib and use of this drug would likely be rationed for such cases [33,34]. In health care settings with rationed resources, limiting the use of imatinib to such rescue settings would certainly be more cost effective, but only justifiable if short and long-term toxicities of GVHD can be better controlled. In a perfect system, the physician would have the discretion to sequence treatment modalities based on data rather than economics. The estimated probabilities of OS and LFS at 3 years in our high EBMT risk scores ($3) patients were 21.2% and 18.2%, respectively. We feel this was mainly because transplantation was performed at advanced stages of their disease. Although the outcomes are disappointing for high risk patients, allo-sct maintains a pivotal role for the treatment

5 852 Y. Liang et al. Biol Blood Marrow Transplant 16: , 2010 of patients at the advanced stage of CML [35]. Other strategies to improve transplantation outcomes for advanced stage or high risk CML are being investigated, and all eligible patients should take advantage of participating in innovative clinical trials. Examples are pretransplant treatment with TKIs [36,37], novel conditioning regimens, or biologic response modification pre- or posttransplant [23,38-40]. Close monitoring of minimal residual disease (MRD) followed by early intervention [41] as well as treatment of relapse posttransplant with donor lymphocyte infusions or TKIs may also extend OS [42-44]. To date, pretransplant imatinib treatment has not been shown to have a negative influence on the outcomes of allo- SCT [45,46]. There continues to be a substantial need for basic and clinical research to further improve allo-sct outcomes, specifically the management of GVHD. Most of this research is conducted in industrialized nations with a larger R&D budget. There is growing concern in other nations that the field of transplantation will receive less attention because the indications, at least in the Western world are shrinking, whereas at the same time in other countries the indications actually are expanding. Although allo-sct remains the standard treatment of choice for newly diagnosed CML patients in many developing countries, continuous research efforts will be vital to improve outcomes of this disease worldwide. ACKNOWLEDGMENTS Financial disclosure: The authors express their gratitude to Drs. Xiaodong Zhu, Dang Wang, Rensheng Wang, and all other faculty members who have participated and contributed to this study. REFERENCES 1. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulo-cytic leukemia. Science. 1960;132: Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243: Hehlmann R, Hochhaus A, Baccarani M. European Leukemia Net. Chronic myeloid leukaemia. Lancet. 2007;370: Sawyers C. Chronic myeloid leukaemia. N Engl J Med. 1999; 340: Druker BJ. Translation of the Philadelphia chromosome into therapy for CML. Blood. 2008;112: Passweg JR, Walker I, Sobocinski KA, et al. Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants. Br J Haematol. 2004;125: Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European Leukemia Net. Blood. 2006;108: Gratwohl A, Brand R, Apperley J, et al. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2006;91: Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354: Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2: 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: O Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348: Druker BJ, Guilhot F, O Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355: O Brien SG, Guilhot F, Gathmann I, et al. International randomized study of interferon versus ST1571(IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM). Blood. 2008;112: Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloidleukemia. Blood. 2007;109: Bittencourt H, Funke V, Fogliatto L, et al. Imatinib mesylate versus allogeneic BMT for patients with chronic myeloid leukemia in first chronic phase. Bone Marrow Transplant. 2008;42: Ruiz-Arguelles GJ, Tarin-Arzaga LC, Gonzalez-Carrillo ML, et al. Therapeutic choices in patients with Ph-positive CML living in Mexico in the tyrosine kinase inhibitor era:sct or TKIs? Bone Marrow Transplant. 2008;42: GajewskiJL Robinson P. Do affluent societies have the only options for the best therapy? Leukemia. 2007;21: Lai Y, Ma J, Schwarzenberger P, et al. Combination of CsA, MTX and low-dose, short-course mycophenolate mofetil for GVHD prophylaxis. Bone Marrow Transplant. 2009;43: Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 1998;352: Mughal TI, Yong A, Szydlo R, et al. The probability of longterm leukaemia free survival for patients in molecular remission 5years after allogeneic stem cell transplantation for chronic myeloid leukaemia in chronic phase. Br J Haematol. 2001;115: Gratwohl A, Brand R, Frassoni F, et al. Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant. 2005;36: 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: Or R, Shapira MY, Resnick I, et al. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood. 2003;101: Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med. 2001;344: Couban S, Simpson DR, Barnett MJ, et al. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood. 2002;100:

6 Biol Blood Marrow Transplant 16: , 2010 Targeted Agents for CML Schmitz N, Beksac M, Hasenclever D, et al. Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia. Blood. 2002;100: Tanimoto TE, Yamaguchi T, Tanaka Y, et al. Comparative analysis of clinical outcomes after allogeneic bone marrow transplantation versus peripheral blood stem cell transplantation from a related donor in Japanese patients. Br J Haematol. 2004; 125: Stem Cell Trialists Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005;23: Liu QF, Sun J, Zhang Y, et al. Hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia. Chin J Cancer. 2004;23: (Chinese). 31. He Y, Feng SZ, Wang M, et al. HLA-identical sibling allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia in first chronic phase. Analysis of 51 cases. Chin J Hematol. 2005;26: (Chinese). 32. Liu D, Guo N, Zhang Y. Allogeneic bone marrow transplantation for chronic myeloid leukemia: 118 cases analysis. Chin J Hematol. 1999;20: (Chinese). 33. 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: DeAngelo DJ, Hochberg EP, Alyea EP, et al. Extended followup of patients treated with imatinib mesylate (gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res. 2004;10: 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 mutationrelated imatinib failure. Blood. 2006;108: Weisser M, Schleuning M, Haferlach C, et al. Allogeneic stemcell transplantation provides excellent results in dvanced stage chronic myeloid leukemia with major cytogenetic response to pre-transplant imatinib therapy. Leuk Lymphoma. 2007;48: Carpenter PA, Snyder DS, Flowers MED, et al. Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood. 2007;109: Poire X, Artz A, Larson RA, et al. Allogeneic stem cell transplantation with alemtuzumab-based conditioning for patients with advanced chronic myelogenous leukemia. Leuk Lymphoma. 2009;50: Steegmann JL, Casado LF, Tomas JF, et al. Interferon alpha for chronic myeloid leukemia relapsing after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1999;23: Posthuma EF, Marijt EW, Barge RM, et al. Alpha-interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease. Biol Blood Marrow Transplant. 2004;10: Kaeda J, O Shea D, Szydlo RM, et al. Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood. 2006;107: Guglielmi C, Arcese W, Hermans J, et al. Risk assessment in patients with Ph1 chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis. The Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2000;95: Olavarria E, Ottmann OG, Deininger M, et al. Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myloid leukemia. Leukemia. 2003;17: Weisser M, Tischer J, Schnittger S, et al. A comparison of donor lymphocyte infusion or imatinib mesylate for patients with chronic mylogenous leukemia who have relapsed after allogeneic stem cell transplantation. Haematologica. 2006;91: Deininger M, Schleuning M, Greinix H, et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica. 2006;91: 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;112: