This month, Wendy Stock, MD, discusses best options for an older patient with Philadelphia chromosome (Ph)–positive B-cell acute lymphocytic leukemia (ALL).
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I have a 66-year-old female patient recently diagnosed with Ph-positive B-cell ALL. Conventional cytogenetics showed hyperdiploid karyotype plus FISH/PCR positive for BCR-ABL. After four cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) plus dasatinib, PCR is negative. Bone marrow aspirate is also negative for ALL. Should she be considered for allogeneic hematopoietic cell transplantation (alloHCT)?
I believe that there is potential equipoise about the optimal post-remission treatment approach in 2019. While the general recommendation from most studies in Ph-positive ALL is to perform an alloHCT in first complete remission (CR1) if the patient is a candidate, there are pros and cons to this approach.
A landmark analysis performed at 175 days from the time of CR/CRi demonstrated a statistically superior advantage for both relapse-free survival (RFS) and overall survival (OS) for patients who received a transplant in CR1 after an induction with hyper-CVAD plus dasatinib, much like the patient in question.1 However, the maximum age of patients enrolled in this study was 60 years. Furthermore, there were no data on the impact of minimal residual disease (MRD) on RFS and OS in patients who did/did not receive transplant in this study. Interestingly, MD Anderson also published data on the impact of MRD status after hyper-CVAD plus dasatinib. A 2016 study demonstrated that patients with Ph-positive ALL treated with hyper-CVAD plus a tyrosine kinase inhibitor (TKI) achieved a complete molecular response at three months (which appears to be the case in your patient), and their survival was excellent, even without alloHCT.2
My approach for older adults with Ph-positive ALL involves a much less intensive induction/consolidation with TKI-based therapy with or without transplant depending on response, patient suitability, and desire for transplant – as per the CALGB 10701 trial.3 However, additional data are beginning to affect my approach to the older adult with Ph-positive ALL in CR1. Both blinatumomab and inotuzumab ozogamicin have been approved for relapsed Ph-positive ALL, and blinatumomab has been approved to treat MRD-positive Ph-positive ALL and can result in long-term disease-free survival even without transplant.4,5 The use of the third-generation TKI ponatinib also may be even more effective in achievement of complete molecular remissions and appears to result in improved event-free survival compared with historical controls in a single institution study, also without transplantation.6 There are still no studies that carefully examine the optimal duration of TKI therapy with or without transplant, although prolonged therapy appears beneficial, even after transplant. Prospective cooperative group or multicenter studies will be useful to test some of these exciting approaches to achieve MRD negativity in Ph-positive ALL, which can improve quality and duration of life for our patients.
- Ravandi F, Othus M, O’Brien SM, et al. US Intergroup Study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1:250-9.
- Short NJ, Jabbour E, Sasaki K, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia. Blood. 2016;128:504-7.
- Wieduwilt MJ, Yin J, Wetzler M, et al. A phase II study of dasatinib and dexamethasone as primary therapy followed by transplantation for adults with newly diagnosed Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph+ ALL): final results of Alliance/CALGB Study 10701. Abstract #309. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA.
- Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836-47.
- Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740-53.
- Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol. 2018;5:e618-27.
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NEXT MONTH'S CLINICAL DILEMMA
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