Improved Outcome of Haploidentical Peripheral Blood Stem Cell Transplant Treating Severe Aplastic Anemia

Severe aplastic anemia (SAA) is one of the most common aggressive hematological disorders with a high mortality rate. For the past several decades, HLA-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been established as an effective treatment strategy for patients with SAA. However, available donor resources, graft rejection, transplant-related complications, and cost-effective concerns temper this medical achievement, and remain as harsh obstacles to benefit more patients with SAA.

We have developed a practical strategy using haploidentical PBSCT to treat patients with SAA and enrolled 22 patients. The conditioning regimen included semustine (300mg/m2, day -8), fludarabine (30mg/m2; day -7 to day -2) and cyclophosphamide (0.6g/m2; day -7 to day -2). The hematopoietic stem cells from peripheral blood were directly re-infused into the recipient immediately after a median yield of 10-14*10⁸/L mononuclear cells were obtained. We had a refined approach of GVHD prophylaxis without compromising the engraftment in addition to taking the health economy burden into consideration. The detailed GVHD prophylaxis regimen included cyclophosphamide (1.8g/m2; day +3 to day +4), ATG (2mg/kg; day +5 to day +6), cyclosporin A (0.5-1mg/kg with a monitoring of blood drug level at 100-300ng/ml; day +5 to day +100 then started to taper down with withdrawal at day 180); and Mycophenolate sodium (10mg/kg; day +5 to day +34). The engraftment rate was 100%.

The A median time of ANC >0.5*10⁹/L and platelet count >20*10⁹/L were 15 d (range: 10-16 d) and 13 d (range: 11-15 d), respectively. In this cohort, all of our patients (22/22; 100%) showed complete hematological reconstitution of donor origin by chimerism analysis both on day +30 and day +90. Three patients indicated mixed chimerism during the monitoring period, and one of them had late graft failure and quit further treatment due to financial reasons. The other two maintained stability, mixed chimerism with donor origin accounting for 60% and 65%. Durable engraftment resulted in sustained disease remission. All remission patients have become transfusion independent for both platelets and RBCs.

All the patients developed febrile neutropenia that was responsive to antibiotics, including seven patients who developed documented bacterial infections. Nine patients were diagnosed with invasive fungal infection after transplant, and five patients survived. Acute GVHD was the major transplant-related toxicity. The cumulative occurrence of acute grade II-IV GHVD was 32% (7/22) and grade III GVHD was 9% (2/22). There was no grade IV GVHD observed. In total, there were 10 patients (10/22; 45%) who were diagnosed with chronic GVHD. All the GVHD cases responded to GVHD intervention.

Regardless of the occurrence of acute GVHD, the survival rate was excellent. With a median follow-up time of 39 months, 17 of the 22 patients survived disease-free (Kaplan-Meier probability of overall survival 77%). The major mortality causes were infection (4/22) and late graft failure (1/22). Additional follow-up will be necessary to determine if chronic GVHD might contribute to late mortality and adversely impact long-term outcomes. Our results indicate a practical protocol with improved donor option, strong immunosuppressive effect and high engraftment rate, and more cost-effective regimens in countries like China with social-economic inequality in SAA treatment.