Tyrosine Kinase Inhibitors Plus Intensive Chemotherapy Prolong Survival in Patients with Ph+ ALL

SAN DIEGO, CA—Prolonged use of tyrosine kinase inhibitors (TKIs) plus chemotherapy and stem cell transplantation (SCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), a disease of predominantly older persons, can achieve long-term survival, according to results of a study reported during the 53rd American Society of Hematology Annual Meeting and Exposition.

Taiichi Kyo, MD, and colleagues at the Hiroshima Red Cross and Atomic Bomb Survivals Hospital in Hiroshima, Japan, reported that the use of TKIs such as imatinib and dasatinib has significantly improved treatment outcome in patients with Ph+ ALL; however, when SCT is not performed, long-term survival rates are low. Dr. Kyo et al sought to determine whether an effective combination of a TKI and chemotherapy could extend long-term survival in patients with Ph+ ALL initially ineligible for SCT. Between June 2001 and February 2011, 43 consecutive patients (18 male and 25 female) with untreated Ph+ ALL had BCR-ABL fusion transcript levels measured and, if positive, were given imatinib 600mg/day. Median age was 57 years (range 13–84); 21 were ≥60 years. In the first 14 patients, a remission induction regimen commonly used in acute myeloblastic leukemia (AML) (idarubicin 12mg/m² Days 1, 3, 5 and 8, behenoyl-ara-C 350mg/m² Days 1–10, 6-merucaptopurine 70mg/m² Days 1–10, and oral prednisolone 20mg/day Days 1–10) was combined with imatinib 600mg. The subsequent 29 patients received another remission induction regimen often used in patients with ALL: vincristine 1.3mg/m² on Days 1, 8, 15, and 22, daunorubicin 60mg/m² on Days 1, 2, and 3, cyclophosphamide 1,200mg/m² on Day 2, L-asparaginase 3,000IU/m² on Days 9, 11, 13, 16, 18, and 20, oral prednisolone 100 mg, also combined with imatinib 600mg. Macrophage colony-stimulating factor was given for seven days from Day 11 and granulocyte colony-simulating factor from Day 18. Initially following remission, high-dose cytarabine 2g/m² twice daily for five days (1g/m² twice daily in patients ≥60 years) and mitoxantrone 7mg/m² × 3 were administered. Maintenance/consolidation therapy was given by alternating behenoyl-ara-C 350mg/m² × 4 plus aclarubicin at 20mg/body × 6 and behenoyl-ara-C 350mg/m² × 4 plus idarubicin 10mg/m² × 1 plus vincristine 1.3mg/m², each for 35 days. Imatinib 600mg/day was given daily simultaneously with post-remission therapy. Dasatinib 140mg/day was used in eight patients post-remission.

Both TKIs were given to patients for three years after completion of chemotherapy. Among the 43 patients treated, complete remission (CR) was achieved in 41 (95%), 13 of 14 (93%) treated with the AML induction regimen and 28 of 29 (97%) treated with the ALL induction regimen.

Following first CR, 10 of the 41 patients underwent SCT; median age was 37 years (range 25–56 years). The remaining 31 patients were assigned to the chemotherapy group; median age was 63 years (range 13–84 years). Median follow-up for those achieving CR was 24 months (range 5–128). For the 41 patients who achieved CR, 10-year overall survival (Kaplan-Meier) was 57%; for the 20 patients <60 years of age, OS was 66% and; for 21 patients ≥60 years, OS was 49%. For the 10 patients who underwent SCT, OS was 80% at first CR; for the 31 patients in the chemotherapy group, OS was 47%. For the chemotherapy group, 50% OS was 36 months. The 10-year event-free survival was 50% for patients who achieved CR, 80% for patients who underwent SCT at first CR, and 43% for the chemotherapy group. For the chemotherapy group, 50% event-free survival was 33 months.

A total of 16 patients relapsed; in 11 of 13 (85%), a new chromosomal aberration was observed at relapse. Two patients had central nervous system (CNS) relapse and three patients had relapses both in the bone marrow and in the CNS. Dr. Kyo noted that about two-thirds of patients aged 60 years and older who received chemotherapy experienced a relapse. Although not statistically significant, risk of relapse was higher for those with a white blood cell (WBC) count of ≥20×10⁹/L at the first visit (50%), vs those with a WBC <20×10⁹/L 30%).

Dr. Kyo said these results indicate that in patients with Ph+ ALL, SCT should be performed at first CR and be available for those up to 65 years of age and/or with a WBC ≥20×10⁹/L. An optimal chemotherapy for concomitant use with a TKI should be determined, the investigators concluded.