Autologous Stem Cell Transplantation (SCT) Following Sequential Chemotherapy and Imatinib for Adults with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) — CALGB Study 10001.

Imatinib, given sequentially or concomitantly with chemotherapy, now plays an important role in the frontline treatment of Ph+ ALL. Once in morphologic and cytogenetic remission, most patients are recommended to undergo allogeneic SCT. However, many patients lack an HLA-matched donor. No data have yet shown a benefit from autologous SCT in this disease. We hypothesized that sequential chemotherapy and imatinib would result in greater leukemia cell cytoreduction than previously achieved with chemotherapy alone, thereby allowing collection of large numbers of normal hematopoietic stem cells from the blood uncontaminated by residual Ph+ lymphoblasts. Thus, patients without matched sibling donors could undergo autologous SCT with a lower likelihood of relapse. Patients 15–59 years old with Ph+ ALL who had a CR or PR after one cycle of a 4 or 5-drug induction regimen were eligible. Imatinib 400 mg BID was then given for 4 weeks. Central nervous system prophylaxis was given with 3 weekly doses of high-dose systemic and intrathecal methotrexate, followed by another 4 weeks of imatinib. Patients with donors then received allogeneic SCT after 13.2 Gy fractionated total body irradiation (FTBI) and etoposide (60 mg/kg × 1). Those without donors received high-dose cytarabine (2 gm/m2 every 12 hours × 8), etoposide (10 mg/kg/day × 4), and G-CSF (10 mcg/kg) for stem cell mobilization and leukapheresis, followed by autologous SCT after 13.2 Gy FTBI, etoposide (60 mg/kg × 1) and cyclophosphamide (100 mg/kg × 1). Imatinib was held during the transplant period but resumed for maintenance until patients were RT-PCR negative for 12 months. To date, 35 patients have enrolled; 31 were in complete and 4 in partial morphologic remission following induction. Data are available on 16 patients who have completed their SCT so far. The median age at study entry was 41 years for the 8 allogeneic SCT patients (range, 27–54) and 47 years (range, 24–56) for the 8 autologous SCT patients. The time interval between achievement of remission and initiation of either an allogeneic SCT (109 days, range 99–132) or stem cell collection (119 days, range 98–158) was similar between the two groups. The median autologous CD34+ cell yield by leukapheresis was 67.1 × 10⁶/kg (range, 34.8 – 309.8). Peripheral blood stem cells have been assayed from 5 patients by RT-PCR with a sensitivity of 1:10⁵-10⁶; 4 were negative for BCR-ABL. Median time to autologous engraftment was 29 days (range, 28–35). Two patients have relapsed at 334 and 475 days, and 6 are in continuous major molecular remission (≥3 log reduction from pretreatment level) at a median of 487 days (range, 197 – 923). Sequential chemotherapy and imatinib yields RT-PCR negative CD34+ leukapheresis products, allowing autologous SCT for patients without donors. Engraftment is not compromised. Post-transplant imatinib is tolerable. Molecular data on minimal residual disease following induction and pre- and post-autologous SCT will be presented. As patients continue to be accrued, longer follow-up will allow comparison of outcomes between patients who underwent autologous versus allogeneic SCT for Ph+ ALL in first CR.