Haploidentical Transplantation Using High Dose Post-Transplant Cyclophosphamide for Patients with Aplastic Anemia : The European Group for Blood and Marrow Transplantation Experience

The outcome of patients with severe aplastic anemia (SAA) has greatly improved in recent years but is still poor for patients who failed or relapsed after immunosuppressive therapy (IST) and don't have a matched donor. Recent use of eltrombopag shows blood count improvements in 40% of cases, but most patients refractory to immunosuppressive therapy, are also unresponsive to eltrombopag. In this situation, hematopoietic stem cell transplantation (HSCT) using alternative donor sources (mismatched unrelated donors, cord blood, and haploidentical family donors) may be curative but are also associated with a high risk of morbidity and mortality. Moreover, ethnic minorities have limited access to an alternative donor, especially in the adult population. Haploidentical transplantation using post-transplant cyclophosphamide (Haplo-PTCy) has been shown to facilitate engraftment and shows GvHD rates comparable to those of matched sibling HSCT in hematologic malignancies. However, few papers have been published on Haplo-PTCy in the context of aplastic anemia.

We conducted a retrospective analysis of 36 patients (72% male), who received an haplo-PTCy for aplastic anemia in 22 EBMT centers from June 2010 to March 2017. Haplo-PTCy was the first transplantation for 81% patients (second, 11%; third, 8%). The non-myeloablative preparatory regimen included anti-thymocyte globulin in 33% of patients and low dose TBI in 58% of patients. Donors were father (n=12, 35%), mother (n=12, 35%), brother (n=5, 15%), sister (n=3, 9%), cousin (n=1, 3%) and daughter (n=1, 3%). The stem cell source was mainly bone marrow (55%). All patients received cyclophosphamide 50mg/kg/day IV on days +3, and +4 post-transplant and 75% received tacrolimus or cyclosporine plus mycophenolic acid. The primary endpoint was the probability of OS. Secondary study endpoints included probability of neutrophil recovery (ANC 500/ μL for at least 3 consecutive days), platelet recovery (platelets 20 000/ μL for at least 3 consecutive days, and 7 days after the last transfusion), cumulative incidences of acute and chronic GVHD and relapse-free survival without Grade III-IV acute GvHD and without extensive chronic (GRFS).

Thirty-two patients were diagnosed with moderate (7%), severe (52%) or very severe idiopathic aplastic anemia (41%), while 4 patients were transplanted for congenital aplastic anemia (3 Fanconi Anemia and 1 Diamond Blackfan). The median age was 19.4 years (range 2.5-45.4 years; 58% adults). Median disease duration before haplo-PTCy was 11.3 months (1.9-201.2). Thirty patients (83%) received pretreatment (77% anti-thymocyte globulin plus cyclosporine, 12% eltrombopag, and 1 patient (3%) received androgens). Cumulative incidence (CI) of neutrophil recovery at day 60 was 78% (64-91) with a median time of 21 days (18-26). Cumulative incidence (CI) of platelet recovery at day 60 was 60% (44-76) with a median time of 31 days (22-185). The CI of grade II-IV acute GvHD was 26% (12-41%) (grade II 19% (7-32%), grade III 6% (0-13%) and no grade IV). CI of chronic GvHD was 17% (5-30) at 1 year (6% (0-13%) extensive) and a CI of 22% (7-37) at 2 years (only limited, there was no new case of extensive cGvHD after one year). With a median follow-up of 24.6 months (15.9 - 38.2), the estimated probability of overall survival (OS) was 78% (64-91) at 1 year and 74% (60-89) at 2 years. Of note, among the 4 patients with inherited disorders, 2 died [1 infection (Diamond Blackfan) and 1 aGvHD (Fanconi Anemia)] and 2 are alive at month 12 and month 15 of follow-up, respectively. Nine patients died during the study. The main cause of death was infection (n=6, 67%). Finally, the GRFS (alive, full donor chimerism, without previous grade III-IV GvHD and without extensive cGvHD) was 58% (41-75) at 2 years.

In conclusion, with a median follow-up of 2 years, Haplo-PTCy leads to 74% overall survival in 36 patients with aplastic anemia, with almost 60% of the patients being free from GvHD complication. In a population with no other therapeutic options, our data suggests haplo-PTCY is a feasible option. However, prospective well-designed trials are urgently needed before the inclusion of Haplo-PTCy in the treatment strategy of aplastic anemia.