A Decade of Reduced-Intensity Conditioned Allogeneic Haematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes Following Conditioning with Fludarabine, Busulphan and Alemtuzumab.

Abstract 2266

Poster Board II-243

Reduced-intensity conditioning haematopoietic stem cell transplantation has dramatically improved the accessibility and safety of transplantation in groups of patients previously ineligible because of age or comorbidity. We report the long term results of allografting following reduced intensity conditioning with Fludarabine^® 30 mg/m² i.v. ( Day –9 to Day –5); busulphan 4mg/kg/day oral or 3.2mg/kg/day i.v. (Day –3 to Day –2) & alemtuzumab 20mg i.v. ( Day –8 to Day –4) in patients with myelodysplastic syndromes. Immunosuppression comprised cyclosporine 1.5 mg/kg iv 12 hourly from Day –1 titrated to plasma trough levels of 150-200 ng/l. Peripheral blood stem cells (PBSC) or bone marrow was infused on Day 0. Filgrastim 300 mcg iv/sc was administered from Day +7 to neutrophil engraftment (neutrophils ≥ 0.5×10⁹/l).

213 patients with Myelodysplastic Syndrome (RCMD-RS=5, RCMD=44, RAEB-1=19, RAEB-2=36, CMML=18, TLD-AML=91)(IPSS Low=7, Int-1=46, Int-2=39, High=12) received transplants from matched sibling donors (57) or volunteer unrelated donors (VUD)(156 ). The median age for sibling recipients was 56 years (38-72) and for VUD recipients 55 years (19-71). All had relative or absolute contraindications to receiving standard myeloablative conditioning allografts. 52 of 57 sibling HSCTs utilised PBSCs compared with 106 of 156 VUD HSCTs, with a median CD34 cell dose of 5.11×10⁶ (0.7-17.5) and 5.2×10⁶ (0.44-19.90) respectively. On high resolution typing 46 VUD grafts were mismatched. There was no difference in engraftment latency between sibling and VUDs, with the median time to neutrophil engraftment (>0.5×10⁹/l) of 14 days (9-57) and 13 days (8-31) and platelets(>20×10⁹/l), 14 days (7-120) and 15 days (3-120) respectively.

With a median follow-up of 2202 days (718-3709)(siblings) and 1693 days (29-3659)(VUD), the treatment related mortality (TRM) at Day100, 200 and 360 and 5 years was 4%, 9% 13% and 27% respectively for siblings; 8%, 17% and 25% and 28% for VUD (p=0.48). 12% of TRM deaths were due to CMV and 8% to PTLD. The Kaplan-Meier overall survival at 5 years was 46% for siblings and 41% for VUD(p=0.28), with a disease free survival (DFS) of 30% and 35% (p=0.94) respectively. The prognostic significance of some of the IPSS and diagnostic groups was preserved with a DFS of 46% in the “Low & Int-1” group at 5 years; 23% in “Int-2”; 0 % in “High”, 21% in CMML and 37% in TLD-AML. (p=ns, except Low-Int-1 vs. CMML(0.005), H (0.002) and Int-2(0.014)). The DFS was 80% in RCMD-RS, 49% in RCMD, 19% in RAEB-1 and 13% in RAEB-2.(p=ns except RCMD vs. CMML(0.015), RAEB-2(0.023)).

Patients with TLD-AML had received more pre-transplant chemotherapy (median 3 courses (1-6)) compared with IPSS-High (median 1(1-3)). Patients who did not require cytotoxic chemotherapy had a 5 year DFS of 60%(p=0.003). There was no statistical difference in 5 year DFS between patients requiring induction chemotherapy in CR1(29%), CR2 (25%), PR (20%), or with progressive/relapsed disease (22%). The median DFS for these groups were 410, 362, 158 and 271 days.

Lineage specific (CD3 & CD15) chimerism results were available on 133 patients. 40% achieved full donor T-cell chimerism (>95%) with 72% achieving full donor engraftment in unfractionated bone marrow by Day100, with a 24% cumulative incidence of Grade II to IV denovo aGvHD and 9% extensive cutaneous cGvHD.

83 patients (41(74%) sibling & 42(26%)VUD) received the first dose of incremental DLI at a median of 195 days (60-1323) post transplant. 53 received DLI for persistent mixed or declining donor chimerism, 11 for cytogenetic relapses and 19 morphological relapses. The desired effect was achieved in 67%, 45% and 42% respectively. A graft versus leukaemia effect was demonstrable. RIC allogeneic HSCT with fludarabine, busulphan and alemtuzumab appears to be potentially curative with a plateaux in DFS after 5 years. Further follow-up in patients with Low-Int-1 and Int-2 MDS and CMML is required to determine if there is a survival advantage for transplanted patients.