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

Abstract

Prognosis of Philadelphia-positive (Ph(+)) 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 age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (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, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions 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 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 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-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 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-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.

• Authors: Philippe Rousselot, Marie Magdelaine Coudé, Nicola Gokbuget, Carlo Gambacorti Passerini, Sandrine Hayette, Jean-Michel Cayuela, Françoise Huguet, Thibaut Leguay, Patrice Chevallier, 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, Oliver G Ottmann, European Working Group on Adult ALL (EWALL) group
• Journal: Blood (Blood) Vol. 128 Issue 6 Pg. 774-82 (08 11 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 27121472 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents
• BCR-ABL1 fusion protein, human
• Protein Kinase Inhibitors
• Fusion Proteins, bcr-abl
• Dasatinib

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, therapeutic use)
• Dasatinib (adverse effects, therapeutic use)
• Female
• Fusion Proteins, bcr-abl (genetics)
• Humans
• Male
• Middle Aged
• Mutation
• Philadelphia Chromosome (drug effects)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (diagnosis, drug therapy, genetics)
• Prognosis
• Prospective Studies
• Protein Kinase Inhibitors (adverse effects, therapeutic use)