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Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL

Philippe Rousselot, Marie Magdelaine Coudé, Nicola Gokbuget, Carlo Gambacorti Passerini, Sandrine Hayette, Jean-Michel Cayuela, Françoise Huguet, Thibaut Leguay, Celia Salanoubat, Caroline Bonmati, Magda Alexis, Mathilde Hunault, Sylvie Glaisner, Philippe Agape, Christian Berthou, Eric Jourdan, José Fernandes, Laurent Sutton, Anne Banos, Oumedaly Reman, Bruno Lioure, Xavier Thomas, Norbert Ifrah, Marina Lafage-Pochitaloff, Anne Bornand, Laure Morisset, Valérie Robin, Heike Pfeifer, Andre Delannoy, Josep Ribera, Renato Bassan, Marc Delord, Dieter Hoelzer, Herve Dombret and Oliver G. Ottmann

Key points

  • Dasatinib, a potent TKI, combined with low-intensity chemotherapy gave 36% 5-year OS in Ph+ ALL patients over the age of 55 years.

  • Prospective monitoring of mutations may be useful to personalize therapy in Ph+ ALL patients not eligible for intensive therapies.

Abstract

Prognosis of Philadelphia-positive acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than 55 years were included in the EWALL-PH-01 international study and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, reduced doses of sequential cytarabine and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone re-inductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled, 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3log reduction in BCR-ABL1 transcript levels during consolidation. Only seven patients underwent allogeneic hematopoietic stem cell transplantation. At 5-years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing and 75% were T315I-positive. BCR-ABL1T315I was tested by ASO RT-QPCR in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and eight relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well tolerated and gave long-term survival in 36% of elderly patients with Ph+ ALL. Monitoring of BCR-ABL1T315I from diagnosis identified patients with at high risk of early relapse and may help to switch therapy.

  • Submitted February 22, 2016.
  • Accepted April 13, 2016.