A Phase II Trial of Sequential Treatment with Cytoreductive Therapy and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukaemia, High-Risk MDS and Other High Risk Myeoid Malignancies: An Interim Report.

Outcomes for patients with refractory or relapsed acute myeloid leukaemia (AML) are extremely poor and allogeneic haemopoietic stem cell transplantation (HSCT) provides the best hope for prolonged disease free survival. Ablative HSCT combines high dose, anti-leukaemic chemoradiotherapy and the graft versus leukaemia (GVL) effect, but is associated with significant toxicity and mortality and these risks rise exponentially with advancing age. Several factors mitigate against an attempt to transplant patients after relapsed disease, including a low probability of achieving second remission, high re-induction mortality, prolonged cytopenias and opportunistic infections and prolonged hospitalization. Based on promising results [1], we undertook a phase II study of sequential chemotherapy immediately followed by reduced intensity conditioning (RIC)-Allo with the aim of increasing the safety and applicability of AlloHSCT, while maintaining its antileukaemic efficacy.

All eligible patients received treatment with Daunorubicin 45mg/m2 OD IV D-15 to D-13 and AraC 1.5g/m2 BD IV D-15 to D-10, a three day rest period, and conditioning with Fludarabine 25mg/m2 D-6 to D-2 and Cyclophosphamide 1g/m2 D-3 and -2 before receiving HSCT. Graft versus Host Disease (GVHD) prophylaxis was with Cyclosporine and Methotrexate. To date 33 patients were enrolled (table 1), of whom 31 patients underwent transplant.

28/31 (90.3%) patients engrafted (neutrophils ≥0.5 and platelets ≥ 20) at a median of 33.5 days (15-49), while 3 died between d21-51 due to sepsis. The median d30, d60 and d100 whole blood chimerism was 96% (range 4–100), 80% (range 5–100), and 76% (range 0–100) respectively. 6/31 (19.4%) developed acute GVHD; 5 grade 1–2, 1 grade 4. Chronic GVHD was documented in 8 patients, extensive GVHD in 4/8. 7 patients had CMV re-activation (no CMV disease) and 1 non-specified pneumonitis. Median time of hospitalization was 37 days (30-61). No patient has required DLI to date. 18 pts (56.25%) achieved complete remission (CR) as assessed by day 30 bone marrow (BM). 2 had <5% blasts BM, 4 refractory disease, 4 died before evaluation, and 3 did not have a BM examination. 7 (6 previously documented CR in BM) of the 33 patients (21.2%) relapsed. Median time to relapse was 162 days (59–408). 18 /33 (54.5%) have died; 6 (33.4%) of sepsis, 5 (27.8%) of relapsed leukaemia, 4 (22.2%) of GVHD, and 3 (16.7%) of refractory leukaemia. D100 treatment related mortality (TRM) was 18.2% (n=6) and overall TRM is 30.3% (n=10). Median time of TRM was 84 days (range 21–519). 15 of the 33 patients (45.5 %) are alive, 12 of whom (36.4%) are disease free with a median follow up of 13 months (range 2–31 months). For these patients, the underlying diagnosis was relapsed AML in 7 (50 %), refractory AML in 5 (28.6 %), high risk MDS in 2 (14.3%) and other in 1 (7.1 %). 2 patients with relapsed and 1 with refractory AML subsequently relapsed after having achieved remission. Overall survival for the 31 patients is 45.2% with disease-free survival of 38.7%.

Sequential treatment with cytoreductive therapy and immediate RIC Allo is associated with good engraftment rates with a TRM acceptable for this high risk group. Our preliminary data indicate a favourable survival outcome for these patients with a particularly poor prognosis.

1. Schmid C, Scheuning M, Schwerdtfeger et al. Long-term survival in refractory acute myeloid leukemia afetr sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108:1092-1099.

Gribben:Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.