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.

Figure 1

EWALL-PH-01 treatment strategy. ★, PCR analysis; ASP, asparaginase; IDAC, intermediate-dose cytarabine; Cons., consolidation; Dasa, dasatinib; DEXA, dexamethasone; IDMTX, intermediate-dose methotrexate; IT, intrathecal (triple IT, 15 mg MTX, 40 mg AraC, and 40 mg prednisone); 6MP, 6-mercaptopurine; MTX, methotrexate; mo, month; P, prephase with dexamethasone; QD, once a day; VCR, vincristine.

Figure 2

Consort diagram. CR1, complete remission 1; CR2, complete remission 2; TRM, treatment-related mortality; pts, patients.

Figure 3

Survival analysis. Overall survival (A, n = 71), event-free survival (B, n = 71), relapse-free survival (C, n = 67), and relapse-free survival according to MRD2 at the level of 0.1% (D, n = 49).

Figure 4

Cumulative incidence of dasatinib discontinuation. Deaths or relapses were considered as competing risks for dasatinib discontinuation.

Figure 5

Relapse analysis. Cumulative incidence of relapse in all 67 patients in CR (A) and in patients with BCR-ABL1^T315I >0.05% compared with other patients (B) (P < .001).

Figure 6

Distribution of BCR-ABL1 tyrosine kinase domain mutations in 36 patients in first relapse.

Figure 7

Follow-up of 10 patients positive for BCR-ABL1^T315I by ASO PCR at inclusion. A systematic screening for presence of the T315I mutation at diagnosis was performed by ASO qRT-PCR in 43 patients and the T315I mutation was detected in 10 of them (23%). The kinetic of detection of the T315I mutation before relapse is indicated. Solid black circle, BCR-ABL1^T315I detected by ASO PCR; open gray circle, BCR-ABL1^T315I not detected by ASO PCR during follow-up. Allo, allogeneic; Post M, postmaintenance; R, relapse associated with BCR-ABL1^T315I detected by ASO PCR and Sanger sequencing.