Commentary on D-ALBA Study

Dr Ng Chin Hin,
Senior Consultant Haematologist, CFCH
Former Head of Adult Leukaemia Service, National University Cancer Institute, Singapore
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Do we see the arrival of chemotherapy-free treatment for Philadelphia positive acute lymphoblastic leukaemia?
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Philadelphia positive acute lymphoblastic leukaemia (Ph+ALL) has been conventionally regarded as a form of poor risk ALL that requires intensive chemotherapy and allogeneic stem cell transplant (alloSCT). In the pre-TKI (tyrosine kinase inhibitor) era, the overall survival at five years was between 30-40% with alloSCT1.
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The introduction of TKI, i.e. Imatinib, Dasatinib and Ponatinib into standard intensive chemotherapy, has improved the outcomes Ph+ALL with or without alloSCT. For example, the 5-year overall survival for imatinib, Dasatinib and ponatinib with HyperCVAD regimen is 43%, 46% and 71% respectively 2-4. Treatment of elderly Ph+ALL remains a significant challenge as most of these patients are unfit for intensive chemotherapy and ineligible for alloSCT. Elderly Ph+ALL who receive Dasatinib with low-intensity chemotherapy may attain up to a 36% long term survival5. However, in clinical practice, many of the older Ph+ALL are unable to tolerate even low-intensity chemotherapy.
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Blinatumomab is a bi-specific monoclonal antibody that targets both CD3 (normal T-cells) and CD19 (the B-lymphoblasts). It activates T-cells and brings them near the B-lymphoblasts resulting in the killing of leukemic cells.
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The GIMEMA group designed a chemotherapy-free treatment strategy for newly diagnosed Ph+ALL, incorporating Dasatinib with Blinatumomab. Patients received Dasatinib plus steroid during the induction phase (85 days) followed by consolidation phase with five cycles of Blinatumomab.
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Dasatinib was also continued during and after the consolidation phase. A total of 63 patients were recruited with a median age of 54 years (range: 24-82). At the end of the induction phase, 98% of those who completed the induction achieved complete haematologic remission. At the end of cycle 4 of Blinatumomab, 81% achieved a molecular response. With a median follow-up of 18 months, the overall survival was 95% while the disease-free survival was 88%. The cumulative incidence of relapse was 8%. Blinatumomab effectively cleared seven patients who developed mutations (6 T315I, 1 E255K) during the induction phase during the consolidation phase.
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The combination therapy appeared to be well tolerated with no early death reported. Twenty-four patients eventually underwent alloSCT. Impressively, only one transplant-related mortality (TRM) reported (4%). The authors believed that a prior chemotherapy-free regimen could have contributed to a low TRM.
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Though this was a phase 2 single-arm study, the results were overwhelmingly impressive. This could be a new standard of care, especially for older Ph+ALL. A phase 3 randomised study comparing this to the standard TKI plus intensive chemotherapy is eagerly awaited and the results, if positive, could set a new standard of care for Ph+ALL.
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Reference:

1. 1. Preti HA, O’Brien S, Giralt S, Beran M, Pierce S, Kantarjian HM. Philadelphia-chromosome-positive adult acute lymphocytic leukaemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med. 1994 Jul;97(1):60-5
   2. Daver N, Thomas D, Ravandi F et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia. Haematologica. 2015 May;100(5):653-61.
   3. Ravandi F, O’Brien SM, Cortes JE et al. Long-term follow-up of a phase 2 study of chemotherapy plus Dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia. Cancer. 2015 Dec 1;121(23):4158-64.
   4. 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 Dec;5(12):e618-e627
   5. Rousselot P, Coudé MM, Gokbuget N et al. European Working Group on Adult ALL (EWALL) group. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood. 2016 Aug 11;128(6):774-82
      Foà R, Bassan R, Vitale A, et al. GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623
      

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