Alemtuzumab for aplastic anemia and related immunemediated bone marrow failures: Long-term follow up of a pilot study

Background. Immunosuppression (IS) is a worthy treatment option for patients suffering from aplastic anemia (AA) or other lineage-specific immune-mediated marrow failure, such as pure red or white cell aplasias (PRCA and PWCA). Aims. We have previously described results from a pilot phase II prospective trial (NCT00895739) investigating the anti-CD52 monoclonal antibody alemtuzumab in combination with low-dose cyclosporine A (CyA; Risitano, BJH 2010;148:791). Here we report the long-term follow up of the study.Methods. Twentyeight patients were enrolled in the study: 13 SAA, 13 PRCA and 2 PWCA; 15 (6 SAA, 9 PRCA and 1 PWCA) had not received any previous IS. Median age was 51 years (range 25-87). The patients received alemtuzumab as subcutaneous injection of 3-10-30-30-(30) mg (total dose 103 mg for SAA, 73 mg for PRCA and PWCA), in consecutive days, followed by oral CyA 1 mg/kg). Given the major concerns about infectious risk, all patients received adequate prophylaxis, including valganciclovir (for 3 months) and bactrim. Results. All patients completed the treatment without serious adverse events; lymphocyte depletion was immediate and complete in all patients, with delayed immune reconstitution (especially for CD4+ T-cells). With a median follow up of 33 months, infectious events were infrequent and clinically mild, with exception of 1 fatal sepsis and 1 progressive multifocal leukoencephalopathy (PML, occurring in a PRCA patient relapsed with metastatic thymic carcinoma, during salvage chemotherapy). No CMV disease nor EBV-related disease or lymphoproliferative disorder was observed, even if 5 patients developed asymptomatic CMV reactivation (promptly cleared by pre-emptive valganciclovir). The response rates were 77% (38.5% CR) in AA and 84.5% (61.5% CR) in PRCA patients; both PWCA achieved long-lasting CR. Current stable remission were achieved in 38.5% of AA and 23% of PRCA; the majority of longterm responders have received an additional dose of alemtuzumab to sustain the hematological response. Long-term treatment failures were due to refractory relapses (15% for AA and 7.5% for PRCA) or to clonal evolution (15% for AA, both myelodysplastic syndromes with chromosome 7 abnormalities, and 23% for PRCA, with 2 acute megakaryoblastic leukemia and 1 5q- syndrome). Overall survival in AA was 72%, even due to effective salvage therapies; all deaths were due to refractory disease. Unexpectedly, overall survival was only 20% in PRCA; the causes of death were disease evolution (3 leukemias and 1 AA), PRCA-associated morbidities (1 thymoma complicated with PML, 1 refractory connective tissue disease) or unrelated cardiovascular comorbidities. Conclusions. Long-term follow up of patients treated with alemtuzumab confirms that this agent has a remarkable efficacy for the treatment of immune-mediated bone marrow failures, with response rates comparable to that of standard IS. Treatment-related long-term toxicity was acceptable, with a low risk of infectious complications; as with standard IS, late treatment failures were mainly due to relapse (alternative maintenance strategies might be considered) or clonal evolution. Even in consideration of the recent data showing the inferiority of rabbit ATG (Scheinberg, ASH 2010;116:LBA-4), our results suggest that alemtuzumab is a worthy alternative to standard IST by horse ATG, possibly deserving appropriate head-to-head comparison.