PS946 BLINATUMOMAB + PONATINIB FOR RELAPSED PH1‐POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA: THE FRENCH EXPERIENCE
Authors: M.‐A. Couturier, X. Thomas, E. Raffoux, F. Huguet, C. Berthon, C. Simand, M.‐P. Gallego‐Hernanz, Y. Hicheri, M. Hunault‐Berger, C. Saillard, T. Leguay, P. Chevallier
Journal: HemaSphere (2019)

Background: Despite the progress achieved with the combination of BCR‐ABL1 tyrosine kinase inhibitors (TKI) and chemotherapy, the prognosis of patients with a refractory/relapsed Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph1+ ALL) is still very dismal. However, new drugs have recently improved outcomes of these patients: ponatinib has shown some efficacy in this context and a recent study has reported very encouraging results of the anti‐CD3/CD19 monoclonal antibody blinatumomab as single‐agent. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce. Aims: Methods: This was a retrospective study in 12 French centers: 23 patients with a relapsed/refractory Ph1+ ALL have concomitantly received blinatumomab (28 mg/day by continuous infusion for 28 days every 6 weeks) and daily orally ponatinib. Results: There were 13 males and 10 females, with a median age of 58 years (range:17–72). All patients, but 3 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Seven cases (30.4%) had BCR‐ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n = 10) or a second or more (n = 11) cytologic relapse. There was one refractory patient. One patient received blina/pona in consolidation, after serious side effects from front‐line chemotherapy. Previous allograft and autograft has been performed in 9 and 4 patients, respectively. The majority of patients (n = 15) had previously received 3 2 or more lines of TKI. The median number of blinatumomab cycle administered per patient was 3 (range: 1–5) while ponatinib was administered continuously at an initial dose of 45 mg once daily in 17 pts (74%) and 30 mg in 6 pts (26%) during a median time of 5 months (range: 1–41) from first blinatumomab cycle. The toxicity profile was safe: blinatumomab was stopped in 48% of cases because of neurologic events in 4, infections in 4 and cytokine release syndrome in 3 patients; ponatinib was stopped in 22% of cases because of neurologic events in 3, hepatobiliary disorder in 1 and severe arteriopathy in 1 patient who had others vascular disease risk factors. All neurologic events resolved after stopping involved drug. All but one patient (95.6%) obtained a cytologic complete remission (CR), of whom 19/22 (86%) achieved a complete molecular response (CMR). However, 2 patients were documented with CNS relapse, treated with intrathecal infusion of chemotherapy. Then, 7 patients underwent allogeneic transplant (including 3 patients already allotransplanted before blina/pona). With a median follow‐up of 29 months (range: 17.5–66.7) for the alive patients (74%), median overall survival from first cycle of blina/pona was not reached and leukemia‐free survival was 18.2 months (range: 1.3–41). At last follow‐up (February 2019), 7 relapses had occurred at a median of 7 months (range: 1.3–41) from first blina/pona cycle and 1 patient had refractory disease. 6 patients (26%) had died of 2 bacterial infections, 2 fungal infections, 1 secondary cancer and 1 progressive refractory ALL. Among the 17 patients alive, one had relapsed and 16 are still in CMR, but 2 with CNS relapse. Twelve patients are still under ponatinib medication. Summary/Conclusion: The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients. It could replace chemotherapy salvage regimens and allow a brigde to allogeneic transplantation, or may be tested in first‐line therapy in the future. Our results have to be confirmed prospectively on a larger cohort of patients.