Outcomes of Allogeneic Hematopoietic Cell Transplantation In Aplastic Anemia Using Intermediate Dose Alemtuzumab Based-Conditioning

Unlike in hematologic malignancies, graft versus host disease (GVHD) has no therapeutic benefit in aplastic anemia (AA) and its prevention is highly desirable. Using conventional GVHD prophylaxis in AA, 30–40% of patients develop acute and chronic GVHD resulting in significant mortality and morbidity with long-term health issues and poor quality of life. Previous studies reported the favorable effect of alemtuzumab on acute GVHD in related and unrelated donor hematopoietic cell transplantation (HCT) for AA (Gupta et al, BBMT 2004; Gupta et al, BMT 2005). In these studies, a higher dose of alemtuzumab (75-100 mg) close to stem cell infusion was used. We subsequently designed a conditioning strategy using an intermediate dose of alemtuzumab (50-60 mg), and report our institutional experience at Princess Margaret Cancer Centre, Toronto, Canada using this strategy.

Between January 2005 and June 2013, 40 patients underwent HCT for AA at our centre. The median age at HCT was 35 years (range 17-59). The etiology of AA was idiopathic in 70%. Fifteen (38%) were positive for paroxysmal nocturnal haemoglobinurea (PNH) clones and 2 patients had symptomatic hemolytic PNH prior to HCT. Upfront HCT was used in 17 (42%) patients, and 23 (58%) had failed one or two courses of ATG-based immunosuppressive therapy (IST). Donors were HLA-identical matched siblings in 28 (70%) and matched unrelated donors (MUD) in 12 (30%). As the preferred source of hematopoietic cells was bone marrow, 34 (85%) received BM grafts and 6 (15%) received peripheral blood grafts. Twenty four (60%) patients were CMV seropositive. Conditioning regimens included: High-dose cyclophosphamide (50 mg/kg x 4 days from days -5 to -2) with alemtuzumab 50 mg (10, 20, 20 mg on days -8, -7 and -6 respectively) in 9 (23%) patients; fludarabine (30 mg/m² x 4 days from days -5 to -2) with low-dose cyclophosphamide (10 mg/kg x 4 days from days -5 to -2) and alemtuzumab 60 mg (30 mg x 2 days on days -7 and -6) in 28 (70%) patients. In 3 (7%) patients busulphan was used instead of low-dose cyclophosphamide because of symptomatic PNH or presence of monosomy 7. In the first 10 (25%) patients, alemtuzumab was used as an IV infusion; the subsequent 30 (75%) patients received subcutaneous alemtuzumab. Cyclosporine was also used for GVHD prophylaxis starting on day -1 and slowly tapered in the absence of GVHD at 6 months.

The median follow up time of survivors was 3.6 years (range 0.2-7.9). The median neutrophil (≥0.5 x10⁹/l) and platelet (≥20 x10⁹/l) engraftment times were 18 days (range 11-112) and 12 (range 2-395) respectively. Four patients had graft failure (2 primary and 2 secondary). Two of these patients died and two are long-term survivors (one after second HCT and the other had autologous recovery). The cumulative incidences of acute and chronic GVHD were 27.7% (95% CI 13.5-41.8) and 21.3% (95% CI 7.9-34.7) respectively. No patients developed grade 3-4 acute GVHD or severe chronic GVHD (NIH criteria). Viral complications were seen frequently: CMV reactivation (79%); HSV (18%); VZV (25%) and BK hemorrhagic cystitis (8%). None developed CMV disease. Three patients developed an EBV-related lymphoproliferative disorder. All three patients were heavily treated with ≥2 courses of ATG- IST prior to HCT.

The 3-year estimated overall survival was 85% (95% CI 74-97). The majority of patients had no significant long-term health issues. Of the 18 women of childbearing age (16-45 years), 6 patients conceived. An asymptomatic drop in FEV1 ≥20% was seen in only 4 of 21 patients who had survived >2 years. Two patients developed secondary malignancies (1 smouldering myeloma and 1 squamous cell carcinoma).

In conclusion, this intermediate dose alemtuzemab based conditioning in AA is a simplified approach that results in excellent survival and has a favorable impact on GVHD, and long-term health issues. Nevertheless, close monitoring for viral complications such as CMV reactivation, and EBV monitoring particularly in patients who fail IST prior to HCT is important.