Alternative Bone Marrow Transplantation with Post-Transplant Cyclophosphamide (PTCy) As Initial Therapy for Acquired Severe Aplastic Anemia (SAA)

Immunosuppressive therapy (IST) is standard front-line treatment for SAA, except for patients aged <20 years with a suitable HLA-matched sibling donor (MSD) for BMT. The hematopoietic response after IST, even with the addition of eltrombopag, is ~ 70%-80% and 5-year survival is 60% to 85%. Failure-free survival (alive and in remission without clonal disease) beyond 10 years after IST is ~50%. In contrast, long-term survival after BMT is ~90% in patients aged < 20 years, and 75% in older patients. Currently, BMT with an unrelated or HLA-haploidentical (haplo) donor is reserved for failure of IST because of morbidity and mortality concerns. PTCy improves the safety and efficacy of haplo BMT by facilitating engraftment and decreasing graft-vs-host disease (GVHD), with survival comparable to MSD BMT. Here we review the outcomes of alternative donor BMT and PTCy in treatment-naïve (TN) SAA patients.

Eligible patients met criteria for SAA and were TN. Fanconi anemia and telomere biology disorder patients were excluded. Non-myeloablative (NM) conditioning included rabbit antithymocyte globulin (0.5 mg/kg day-9 and 2 mg/kg on days -8,-7), fludarabine (30mg/m²/day on days -6 to -2), low dose CY (14.5 mg/kg on days -6, -5) and total body irradiation (TBI) (200cGy or 400 cGy day -1). After the marrow graft was infused on day 0, cyclophosphamide 50 mg/kg/day IV was administered on days 3 and 4 post-transplant. All received mycophenolate mofetil (MMF) from day 5-35 and tacrolimus from day 5 through 1 year. Neutrophil recovery was defined as occurring on the first of three consecutive days of an ANC >1.0 x10⁹/L. Red cell recovery was defined as days from transplant to the last red blood cell transfusion. Platelet recovery was defined as the first day of a platelet count >50,000 without transfusion in the preceding 7 days.

Thirty-two eligible patients were treated at Johns Hopkins between 9/2016 and 5/2022. Median follow-up for all patients is 40 months (range 2-78). Table 1 shows demographics. The median age was 25 years (range 3-63) with 24 patients age >20 years, and 56% were males. Median time to neutrophil recovery was 20 days (range 14-88). Median time to red cell recovery was 25 days with 90% transfusion independence by day 60. Median time to platelet recovery was 25 days with 90% transfusion independence by day 100. TBI dose was increased from 200 to 400 cGy to reduce graft failure after graft loss in 3 of the first 7 patients; 2 of these 3 died (from infection and graft failure) and one has been re-transplanted and is now 100% donor. Overall survival at 3 years post-transplant is 93%. (Figure 1) All 24 consecutive patients who received 400 cGy are alive and well with engraftment. CMV reactivated in 13 patients, and 6 required therapy. Rates of acute and chronic GVHD were both 7%, none developed grade 3-4 acute or extensive chronic GVHD, and all patients beyond day 365 are off treatment for GVHD. No secondary malignancies have been observed.

NM BMT with PTCy, using mostly haplo donors, can cure SAA. Increasing TBI dose from 200 to 400 cGy improves engraftment. Rates of infection and mortality are not increased compared to standard upfront IST. Historical data show that >50% of patients in this age range require transplantation subsequent to IST. Upfront BMT, as described here, allows patients to come off immunosuppression by 6-12 months post-BMT, prevents the morbidity of prolonged IST, and may reduce healthcare costs. Most patients receiving 200 cGy TBI maintain fertility; we are monitoring fertility rates after 400cGy. This approach forms the basis for the upcoming Bone Marrow Transplant Clinical Trials Network multicenter study in TN acquired SAA.

DeZern:Bristol Myers Squibb: Consultancy, Honoraria; GERON: Other: DSMB; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Syntrix Pharmaceuticals: Research Funding; CTI BioPharma: Consultancy, Honoraria. Cooke:jazz pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brodsky:Alexion: Honoraria.