Reduced Intensity Conditioning (RIC) Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Background: RIC regimens are less myelosuppressive, but remain adequately immunosuppressive, allowing for successful engraftment with acceptable treatment-related mortality (TRM) in older or more frail patients (pts) who otherwise would not be suitable candidates for HSCT. This is particularly relevant in ALL, since pts often sustain toxicity from dose-intense upfront regimens or may be diagnosed in advanced age. The antitumor effect of this approach is not well-established in ALL.

Methods: We evaluated outcomes of 30 advanced ALL pts (19 M/11 F) treated from August 1996 to May 2008 with FM140 (fludarabine 120 mg/m², melphalan 140 mg/m²) and unmanipulated stem cells. Graft vs. host disease (GVHD) prophylaxis consisted of tacrolimus and mini-dose methotrexate in all but 1 pt who received cyclosporine. Anti-thymocyte-globulin was added to matched unrelated pts.

Results: The median age was 44 years (range 23–64). ECOG performance status at time of HSCT was 0 (n=16), 1 (n=10) or 2 (n=4) with median co-morbidity score of 3 (range 0–7) by Charlson Comorbidity Index (CCI). Twenty-four pts had B-lineage and 6 had T-lineage disease. Cytogenetic data were available for 26 pts; 19 had high-risk cytogenetics, including 9 with Ph+ disease. Disease stage at time of study entry was CR1 (n=5), ≥CR1 (n=12), or primary or refractory relapse (n=13), with median 2 prior chemotherapy regimens (range 1–4); five pts had a prior allogeneic HSCT. Donor type was matched related (n=13) or matched unrelated (n=17) and stem cell source was bone marrow (n=14) or peripheral blood (n=16). The median total nucleated cell dose and CD34+ cell dose were 3.80 × 10⁸ cells (range 0.68–17.16) and 4.15 × 10⁶ cells (range 1.78–12.03), respectively. Median time to ANC 0.5 × 10⁹/L was 13 days (range 10–24). Median time to platelet count 20 × 10⁹/L was 18 days (range 10–57). Eight pts were alive at a median follow up of 12 months from HSCT (range 3–59). OS and DFS were 32% and 29%, respectively, at 1 year. Of note, only 1 among 5 pts in CR1 had disease progression, compared to 8 among 13 with refractory disease at time of HSCT. The cumulative incidence of acute GVHD, grades II–IV and III–IV were 40% and 13%, respectively, and chronic GVHD was 22% (7% for extensive). The cumulative incidence of TRM at 100 days and 1 year were 17% and 33%, respectively. Among 22 deaths, 14 were related to disease recurrence, 4 related to infection and 4 related to GVHD.

Conclusion: RIC HSCT can provide disease control in patients with ALL, and merits further evaluation. Alternative treatment strategies need to be explored in pts with advanced disease. The observed TRM rate is comparable to what has been previously reported for this regimen in heavily pretreated leukemia patients.