Feasibility and Toxicity of Nonmyeloablative Hematopoietic Cell Transplantation (HCT) with or without Imatinib for Philadelphia Chromosome (Ph+) Acute Lymphoblastic Leukemia (ALL).

Background: Ph+ is a risk factor for adult ALL and represents an indication for conventional allogeneic HCT.

Purpose: To determine whether safety and efficacy of allogeneic HCT can be improved with non-myeloablative conditioning with or without imatinib therapy after HCT for high-risk Ph+ ALL pts ineligible for conventional HCT.

Pts and Method: Between 6/2001 to 5/2004, 11 pts [median age of 51 (38–63) years] who had Ph+ ALL received HCT after nonmyeloablative conditioning consisting of fludarabine (30mg/m2/day x 3 days) and 2 Gy TBI followed by mycophenolate mofetil and cyclosporin. Median time from dx to HCT was 13 (range, 6–60) months. PBSC(n=10) or bone marrow (n=1) was infused from 10/10 HLA allele matched (n=9) or mismatched (n=2) unrelated (n=10) or related donors (n=1). Pts were divided into two groups. Group A (n=5): pts did not receive imatinib after HCT. Group B (n=6): pts were entered on a protocol that tested the safety and efficacy of imatinib 600 mg po qd for cytoreduction (<15% marrow blasts) before HCT and beyond 14 days after HCT for disease suppression until GVT effects could occur. All 5 group A pts were in CR by flow cytometry and conventional cytogenetic evaluation (one pt was FISH positive) at HCT, and four had detectable bcr-abl transcripts by PCR. All group B pts had relapsed after induction therapy and had measurable disease at HCT including abnormal cytogenetic (n=2), PCR (n=1) and persistent morphologic (n=1) or flow cytometric (n=2) disease. Disease responses were monitored by morphology, flow cytometry, FISH and PCR, while engraftment was assessed by variable number tandem repeat (VNTR) or FISH.

Results: All but one pt, who rejected a marrow graft, had sustained engraftment. Median time of neutrophil recovery (ANC>500) in group A was 18.5 (range, 18–19) days vs 21.6 (range, 20–23) days in group B. Two pts in group B and none in group A required platelet transfusions. Median levels of day 28 donor CD3 and CD33 chimerism were 90% and 90% in group A, respectively vs 81% and 96% in group B. Incidences of grades II-IV GVHD were 40% in group A and 100% in group B while incidences of grade III-IV acute GVHD were 20% and 17%, respectively. One pt (20%) in group A and 3 in group B (50%) developed chronic GVHD. Grade III-IV toxicities in group A pts were 4.0 vs 3.5 events/pt in group B. Three pts in group A (including the pt who rejected the marrow graft) relapsed at days 120, 198 and 365 after HCT, respectively. A fourth group A pt who achieved molecular remission committed suicide at day 90 and the fifth pt is in molecular remission at 6 months after HCT. Of the group B pts, 4 are alive: 2 in molecular remissions at 1 year after HCT, 1 in morphologic and cytogenetic CR but with bcr-abl expression at 1 year; and 1 too early to evaluate. Two group B pts died: one (with pretransplant liver cirrhosis) at day 58 from decompensated liver failure, acute GVHD and disseminated aspergillosis after achieving cytogenetic remission and another from relapse at day 100 after imatinib was discontinued due to presumed skin toxicity.

Conclusion: Nonmyeloablative HCT for pts with advanced Ph+ ALL appeared to be feasible and the addition of imatinib after HCT did not appear to increase hematopoietic or other organ toxicity.