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Transplant vs Imatinib for Accelerated Phase CML
Abstract & Commentary
By Andrew S. Artz, MD, MS, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Artz reports no relationships relevant to this field of study.
Synopsis: Limited data are available to guide the decision between up-front allogeneic hematopoietic cell transplantation (HCT) or imatinib on long-term outcomes for accelerated phase chronic myelogenous leukemia (CML). Outcomes of CML accelerated phase patients likely transplant-eligible based on age under 60 years and good health were analyzed. Of these, 87 patients elected to receive long-term imatinib and 45 patients decided on initial HCT. HCT patients typically received imatinib or other therapy for 3 months in preparation for HCT. Overall survival (OS) was superior for HCT (P = 0.023). A CML risk score was generated based on CML duration 12 months or more, hemoglobin < 10.0 g/dL, and 5% or more peripheral blasts. For low-risk patients, event-free survival (EFS) and OS for both cohorts exceeded 80%. For intermediate risk patients, higher EFS and OS for HCT were not statistically different compared to imatinib. For higher-risk patients, EFS and OS favored HCT. Specifically, five-year survival for HCT was 100% vs 17.7% with imatinib (P = 0.008). These data support early HCT for high-risk accelerated phase CML and warrant consideration for intermediate risk patients.
Source: Jiang Q, et al. Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 2011;117:3025-3031.
Chronic myelogenous leukemia (CML) has classically been described as a triphasic disease with patients presenting in chronic phase, progressing to accelerated phase, and eventually terminating in blasts crisis. Around 10%-15% initially will present past chronic phase. The curative potential of allogeneic hematopoietic cell transplantation (HCT) and the lack of other effective therapies placed HCT as the recommended treatment for eligible patients. A particular potent graft-versus-leukemia occurs in CML promoting long-term disease control.1 The short- and long-term morbidity and mortality of HCT raises concerns even for transplant-eligible patients. The advent of imatinib mesylate (Gleevec), an oral inhibitor of BCR/ABL tyrosine kinase activity, revolutionized treatment by enabling cytogenetic remissions in around 80% of patients in chronic phase with excellent tolerance.2 Response rates and response durability decline markedly for more advanced disease phases. Imatinib at 600 mg daily induces initial hematologic control in 80% but cytogenetic remissions occur in around 20% for accelerated disease and suboptimal survival of 37 months.3,4 For HCT candidates, the optimal timing to proceed remains uncertain. Early HCT allows definitive therapy prior to drug resistance but delayed transplant permits highly responsive patients to avoid early transplant-related morbidity and mortality.
In this retrospective review, investigators summarized records of 132 patients diagnosed with accelerated phase CML, good performance status, and age < 60 years at Peking University in Beijing, China, from 2001 to 2008. Patients were treated either with imatinib (n = 87) or HCT (n = 45) based on physician and personal choice. Imatinib dosing was 400 mg to 600 mg initially.
For the 87 imatinib-treated patients, 85% achieved a complete hematologic remission and 47% achieved a complete cytogenetic remission. The 6-year overall survival rate was 51.4% and median overall survival was 80 months. Seven patients eventually crossed over to HCT and another seven received one of the second-generation tyrosine kinase inhibitors of nilotinib or dasatinib.
HCT patients received 3 months or less of imatinib 400 mg daily in 71% or hydoxyurea combined with interferon if imatinib was unavailable. The median age of imatinib patients was 44 years, one decade older than HCT patients. The median duration of disease was considerably shorter for HCT patients at 2 months vs 17 months, suggesting HCT patients may have evolved more quickly. Transplant donors included HLA-matched siblings in 42% and 51% with HLA mismatched or haploidentical donors.
HCT treated patients had superior event-free survival (P = 0.008) and overall survival (P = 0.023) compared to imatinib. In a multivariate model, treatment choice did not significantly influence survival. Treatment choice was then stratified by three prognostic groups (using prognostic factors of disease duration of 12 months, hemoglobin < 10.0 g/dL, and peripheral blasts of 5% or more). For low-risk patients (no risk factors), treatment did not influence event-free or overall survival. For intermediate-risk patients, imatinib achieved 61% long-term survival compared to 81% for HCT but was not statistically different. For high-risk patients, overall survival was 17.7% for imatinib-treated patients and 100% for HCT (P = 0.008).
The broadening availability of therapies for CML presents an embarrassment of riches for devising treatment strategies. Advances in HCT, the historical gold-standard, continually push the age and health limits of HCT-eligible patients upward. In addition to imatinib, two second-generation tyrosine kinase inhibitors (nilotinib and dasatinib) are clinically available, with many more under study. This study on a large cohort of patients presenting with or developing accelerated phase disease prior to TKI exposure provides insights into treatment recommendations.
Patients reportedly selected the preference for imatinib or HCT, with transplant patients typically receiving a three-month course of imatinib or initial chemotherapy, presumably while donors were procured and pre-transplant testing occurred. Overall, HCT enabled superior event-free and overall survival. Specifically, imatinib-treated patients had 6-year event-free and overall survival of 39.2% and 51.4% compared to 71.8% and 83.3% for HCT in this group of transplant-eligible patients based on age 60 years or less and good performance status. Adjusted analysis provided a more mixed picture. Multivariate analysis did not show imatinib treatment choice was inferior to HCT whereas in stratified analysis, patients with high-risk disease features at the time of transplant fared considerably better with HCT, with 5-year overall survival of 100% vs 17.7% for imatinib. Intermediate risk disease showed an absolute benefit of 20% on survival but this was not statistically significant.
The major limitation in this analysis rests with retrospective nature of the study. Patients were not randomized and bias clearly may exist in either direction with HCT patients being younger and healthier (median age 10 years less) but also having worse disease features (more with short interval of CML before developing accelerated phase). The authors adjusted using a prognostic score and multivariate model but ultimately the sample size prevented robust estimates in subgroups. Another issue relates to the surprisingly good outcomes for HCT that may inflate the benefit of HCT, at least relative to registry data. We might anticipate better results since this series exclusively covered the imatinib period that permits both pre-transplant disease reduction and lower toxicity post-HCT therapy for relapse. However, 50% of patients received allografts from non-matched donors that typically drive inferior outcomes related to graft failure and high rates of graft-versus-host-disease and infection. The decision making for transplant also was only described as personal choice but other factors, such as donor availability and physician preference, affect decisions as well. A more practical limitation these days is that most accelerated phase patients have progressed from chronic phase while on imatinib therapy. Such imatinib failures with advancing disease represent a much higher risk patient for whom HCT would generally be advised. This series primarily consisted of about 80% progressing from chronic phase but who had not received imatinib therapy.
The authors ultimately propose an individualized algorithm to offer HCT to higher-risk patients. For clinical practice, one should initiate tyrosine kinase inhibitors for CML-accelerated patients. Promising data for nilotinib and dasatinib as front-line therapy for CML chronic phase will prompt more oncologists to employ these agents over imiatinib for initial therapy for accelerated phase.5,6 For any HCT-eligible patient, a donor search should be offered or referral to a transplant center to start the donor search. For lower-risk patients based on achieving a complete hematologic response, complete cytogenetic remission, long-term outcomes have been quite good with imatinib alone.4 For higher risk based on suboptimal response or baseline prognostic factors of anemia or other models, HCT should be entertained. Younger adults may still want to consider definitive therapy early as HCT persists as a proven modality for long-term survival and usually achieves similar results to imatinib over a 5- to 8-year period.
1. Kolb HJ, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990;76:2462-2465.
2. Druker BJ, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-2417.
3. Talpaz M, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood 2002;99:1928-1937.
4. Palandri F, et al. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: The GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica 2009;94:205-212.
5. Guilhot F, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007;109:4143-4150.
6. Kantarjian H, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542-2551.