Dasatinib for CML Blast Phase after Imatinib Failure
Abstract & commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Options for CML blast phase after imatinib failure have been very limited. This trial combined results of two parallel studies evaluating dasatinib, a second-generation tyrosine kinase inhibitor, for imatinib-resistant or -intolerant CML in blast phase. Among the 157 patients, 109 had myeloid blast phase (MBP) and 48 had lymphoid blast phase (LBP). Major hematologic responses occurred in 34% for MBP and 35% for LBP, and cytogenetic responses occurred in 33% of MBP and 52% of LBP. The median overall survival was 11.8 months and 5.3 months for MBP and LBP, respectively. Cytopenias were frequent with pleural effusion being the primary non-hematologic toxicity. Dasatinib shows considerable activity in imatinib-resistant or -intolerant blast phase of CML.
Source: Cortes J, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 2008;22:2176-2183.
Chronic myelogenous leukemia (CML) is typically considered a triphasic disease. It often presents in chronic phase and, without treatment, progresses to accelerated and/or blast phase. The blast phase can be immunophenotypically characterized as myeloid in approximately 70% of cases and lymphoid in around 30%. The prognosis for blast-phase CML remains very poor, with a median survival of around eight months.1
Imatinib (originally known as STI-571) inhibits the aberrant tyrosine kinase activity of the Bcr-Abl fusion protein found in CML. Single-agent imatinib has considerable activity and excellent long-term results in chronic-phase CML.2,3 Unfortunately, for blast-phase CML, imatinib has reasonable activity but minimal long-term benefit.4 Several second-generation tyrosine kinase inhibitors, namely nilotinib and dasatinib, have activity in imatinib-resistant CML and Philadelphia chromosome-positive ALL. Dasatinib is an oral multi-kinase inhibitor of BCR-ABL and SRC. Initially Cortes et al reported early results of 74 imatinib-resistant or -intolerant CML blast-phase patients.5 Now, Cortes et al report on the complete series of 157 patients and extended follow-up.
These results represent pooled data from two parallel phase II open-label, single-arm international studies (START-A, START-L) using dasatinib for imatinib-resistant or intolerant CML in either myeloid blast phase (MBP) or lymphoid blast phase (LBP). The dasatinib starting dose was 70 mg twice daily. Among the 157 patients, 69% had MBP and 31% had LBP. Imatinib resistance, as opposed to intolerance, was present in 90% of subjects. Over half of these patients had received chemotherapy (not including imatinib). Nineteen patients underwent stem cell transplantation, and they were censored at the time of transplantation.
A hematologic response of at least four weeks was achieved in 50% of MBP and 40% of LBP. A complete hematologic response was achieved in 25% and 29% of MBP and LBP, respectively. Response rates were similar for those who previously received stem cell transplantation. Median progression-free survival was 6.7 months and 3.0 months in MBP and LBP, respectively. Median overall survival was 11.8 months (95% CI 7.1 no upper bound) for MBP and 5.3 (95% CI 4-11.4 months) for LBP.
Cytopenias were a common and expected toxicity. Among the non-hematologic toxicities, pleural effusions were frequent. Grade 3 to 4 pleural effusions occurred in 15% of MPB and 6% of LBP. The median time to occurrence was 2.4 to 3.0 months.
Commentary
The management of blast-phase CML is particularly difficult. Chemotherapy alone has high toxicity with relatively poor response rates.6 Imatinib has emerged as a front-line option for blast-phase CML. Imatinib induced a 52% response rate and 16% complete cytogenetic response for blast-phase disease.7 Nevertheless, complete hematologic responses are infrequent, and median survival approximates that in the pre-imatinib era.4 Combining imatinib with chemotherapy for MBP may improve response rates,8 but long-term results remain dismal due to primary resistance and short-remission durations. Further, in the modern era, many patients in blast phase have progressed on prior imatinib therapy. Allogeneic transplantation remains the only viable option for disease eradication, but transplantation in blast phase only offers 10%-15% long-term survival.
This study of dasatinib for imatinib-resistant or -intolerant CML in blast phase shows a reasonable response rate and favorable toxicity profile. Specifically, response rates were around one-third, with complete cytogenetic responses in one-third of MBP and half of LBP. A major benefit to responses derived from dasatinib may be to allow the opportunity for patients to proceed to transplantation, assuming they were transplant candidates and a donor could be identified. Unfortunately, most patients will not be transplant candidates, and the median progression-free survival of 6.7 months for MBP and 3.0 months for LBP illustrate the poor long-term outcomes.
Preliminary data also suggest nilotinib has activity in imatinib-resistant CML.9 There are insufficient data to guide which drug may be preferential. While dasatinib has the adverse toxicity of pleural effusions, dasatinib has the beneficial property of crossing the blood-brain barrier and even inducing responses in Philadelphia chromosome-positive disease in the CNS.10
Several drawbacks are worth noting. In addition to the frequent complication of cytopenias in the first several months of therapy, the unusual toxicity of pleural effusion was fairly common. The biologic underpinning for pleural effusions using dasatinib has been postulated to relate to inhibition of platelet-derived growth factor (PDGF)-Beta inhibition. Also, while only 10% of the patients had imatinib intolerance, Cortes et al do not provide the response rate for imatinib resistance alone. It is conceivable that all of the imatinib-intolerant patients responded; in which case, the response rate for imatinib-resistant CML in blast phase is slightly lower. More difficult to decide will be whether to extrapolate these findings to employ dasatinib as initial therapy, with or without chemotherapy, for initial treatment of imatinib-naïve CML blast phase.
The data suggest dasatinib or nilotinib could be considered as initial therapy for CML in blast phase. However, until comparative studies are performed, the standard remains imatinib initially with or without chemotherapy for CML in blast phase. Future studies will explore not only the option of dasatinib as initial therapy for all phases of CML, but also combining dasatinib with chemotherapy for CML in blast phase.
References
1. Wadhwa J, et al. Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia. Blood. 2002;99:2304-2309.
2. Druker BJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.
3. O'Brien SG, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348:994-1004.
4. Sawyers CL, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530-3539.
5. Cortes J, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109:3207-3213.
6. Sacchi S, et al. Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer. 1999;86:2632-2641.
7. Kantarjian HM, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002;99: 3547-3553.
8. Fruehauf S, et al. Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer. 2007;109:1543-1549.
9. Kantarjian H, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542-2451.
10. Porkka K, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112:1005-1012.