SAA is a life-threatening hematopoietic stem cell disorder that is treated with either bone marrow transplantation (BMT) or immunosuppressive therapy (IST). BMT is the treatment of choice for young patients with a matched sibling donor. Those with acquired SAA lacking a matched sibling donor and older adults (> 40yrs) generally receive IST because of the high toxicity of BMT in these patients. Roughly two-thirds will respond but up to 40% of patients eventually relapse or acquire a secondary clonal disease such as paroxysmal nocturnal hemoglobinuria (PNH) or myelodysplastic syndromes. Thus, a major challenge in treating SAA is the management of patients who are have relapsed after or are refractory to IST or who have acquired a secondary clonal disorder. BMT is the only curative therapy for patients with inherited SAA but problems with graft failure, graft-versus-host disease (GVHD), and lack of matched unrelated donors especially for ethnic minorities have limited the success of alternative donor BMT, especially for adult patients. PTCy after HLA-haplo BMT has been shown to facilitate engraftment and yield rates of GVHD comparable to those of matched sibling BMT in hematologic malignancies. We hypothesized that PTCy would improve outcomes for patients with refractory SAA by reducing the risk of GVHD and expanding the donor pool to include haplo related and mismatched unrelated donors (URD).

Patients received an allogeneic BMT (alloBMT) for relapsed or refractory SAA. Relapsed/ refractory disease was defined as having failed previous course of IST. In the majority of the cohort, haplo donors were used due to lack of availability of suitable and timely URDs. Nine patients underwent haploBMT. A mismatched URD was used in one case of no suitably available haplo donor given the inherited nature of her disorder. The nonmyeloablative preparatory regimen included antithymocyte globulin (0.5 mg/kg day-9 and 2 mg/kg on days -8,-7), fludarabine (30mg/m2/day on days - to -2), low dose CY (14.5 mg/kg on days -4, -5 ) and total body irradiation (200cGy day -1). After the unmanipulated marrow graft was infused on day 0, cyclophosphamide 50mg/kg/day IV on days +3,+4 post-transplant was administered. All patients received tacrolimus and mycophenolate mofetil (MMF) beginning day+5 through 35 (MMF) and day +5 through 1 year (tacrolimus) for additional graft versus host disease (GVHD) prophylaxis. Neutrophil engraftment was defined as an ANC >1.0 x109/L measured for three consecutive measurements on different days. Red cell engraftment was defined as days from last red blood cell transfusion. Platelet engraftment was defined as a platelet count >50,000 for 7 days without transfusion.

Ten patients were treated according to this IRB approved protocol. Eight patients had documented acquired disease and received grafts from 5/10 related donors. Six had failed ATG-containing regimens previously and two relapsed after high dose cyclophosphamide as IST. Two patients had inherited syndromes: one with Diamond Blackfan who received a graft from 5/10 related donor and one with telomeres less than the first percentile in length with a presumed familial syndrome who received a 9/10 unrelated graft. Median follow-up time is 17.5 months (range 5-49). The median age was 34 years (range 17-54) with 6 patients greater than age 30 years, and 50% were males. Median time to neutrophil engraftment was 18 days (range 16-24). Median time to red cell engraftment was 25 days (range 16-48). Median time to platelet engraftment was 27.5 days (range 22-108). At the time of BMT, six patients had PNH clones, and all were eliminated. All patients are alive and well, fully engrafted with 100% donor chimerism in blood and marrow. Two patients had grade 1-2 skin acute GVHD. These two also had mild chronic GVHD of the skin/mouth requiring systemic steroids. One patient was able to come off all immunosuppression by 15 months and the other by 17 months.

Nonmyeloablative alloBMT with PTCy appears promising in patients with refractory acquired and inherited SAA with acceptable rates of engraftment, eradication of pre-existing clonal diseases, and expansion of the donor pool. Given these promising results, this approach is being utilized in the next BMTCTN national trial for acquired refractory SAA. We believe this approach could also be considered as upfront therapy for SAA, and such a trial is in development at Hopkins


Brodsky:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Author notes


Asterisk with author names denotes non-ASH members.