Reduced Intensity Conditioning for Haploidentical Transplantation Using Double Source of Hematopoietic Stem Cells and Post-Transplant Cyclophosphamide for Severe Aplastic Anemia

Significant improvements in haploidentical stem cell transplantation (haplo-SCT) have confirmed its therapeutic role in severe aplastic anemia (SAA) and led to the evolution of treatment algorithms. However, the optimal conditioning regimen for haplo-SCT for SAA remains undefined. A recent review demonstrated haplo-SCT using NMA and RIC, engraftment between 75 to100% and OS one year of 75-100%. In our Institutions we started a double source since Jan 2017 using a RIC protocol that is the objective of this presentation.

There were nine haplo-SCT in eight patients in two Brazilian centers, Hospital Santa Marcelina (n=5) and Hospital São Paulo (n=3). All patients were male, median age 26 years old (14-39), nocturnal paroxysmal hemoglobinuria clonality in five (62,5%); treated with Cyclosporine, Thymoglobulin (n=4), Eltrombopag (n=1), Eculizumab (n=2) and/or Alemtuzumab (n=1). Median time disease to transplant was 15,7 months (3.8-192). All patients submitted more than 20 RBC transfusions, and median of ferritin was 2,283 ng/mL (753-3,486). One patient had carbapenem-resistant gram-negative bacilli (CRNGB: Escherichia coli, Klebsiella pneumoniae and/or Pseudomonas aeruginosa). Panel reactive antibody was negative in all patients.

The donor was a sibling in 44% (n=4), father and mother 22% each (n=2) and one patient received cells from his cousin after an early failure of engraftment from mother first transplant. The cause of this failure was a JC virus and adenovirus acute infections. The second haplo-SCT conditioning was Fludarabine, Cyclophosphamide and 600 cGy TLI.

There were seven male donors. RIC was consisted of Fludarabine, Cyclophosphamide and total body irradiation (TBI) 200 cGy. The source was G-CSF primed bone marrow (G-BM) grafts in combination with PBSC no ex-vivo T cells depleted, and Cyclophosphamide 50 mg/Kg/day IV on days +3 and +4 post-transplant (PTCy), as well as graft versus host disease (GvHD) prophylaxis. The median of G-BM MNCs was 5.4 x 10⁸/Kg (2.3-8.7), and PBSC was 10 x 10⁶CD34+/Kg (4-18.7).

One (11%) patient died for sepsis at day +13, he was the only with a confirmed CRGNB colonization before transplant. The ANC recovery was at day +17 (13-24). No one had Sinusoidal Obstructive Syndrome. Acute GvHD grade II and moderate chronic GvHD was observed in two patients (25%). Two patients had engrafting failure: the first at day +30 and received a successfully new haplo-SCT; the second at day +60, with a partial donor reconstitution without dependence of transfusion after immunosuppressive therapy. These two patients had female donors. The OS and DFS at two years were 87.5% and 75%, respectively.

In conclusion, with a median follow-up of 30 months, haplo-SCT, PTCy with double source keep the 87.5% overall survival, with no one severe chronic GvHD. Our data suggests an excellent results for haplo-SCT, PTCy, RIC, double source in the SAA treatment. However, prospective well-designed trials need to confirm these results.