Haploidentical Donor Transplantations with TLI, Fludarabine, Cyclophosphamide, and ATG Are Safe and Effective Treatment for Graft Failure

Graft failure is a well described complication of allogeneic hematopoietic cell transplantation (HCT). The likelihood of graft failure is greater when an HLA-mismatched donor (such as umbilical cord blood or haploidentical donor) is utilized. Salvage transplantations are associated with high mortality because of common concurrent infections and poor tolerance to reconditioning. We describe the use of a novel reduced-intensity regimen that combines four potent immunosuppressive but well tolerated agents with non-overlapping toxicities.

Patients received 8 Gy TLI divided 2 Gy per fraction (once daily on days -10, -9, and twice daily on day -8). Fludarabine at 40mg/m2/day on the following 3 days (-7, -6, and -5). Cyclophosphamide at 50mg/kg/day over 3 days (-4, -3, -2). Rabbit ATG at 1mg/kg on day -3, and then 3mg/kg/day on days -2 and -1. Patients then received a CliniMacs T-cell depleted peripheral blood stem cell graft from a haploidentical donor. The patients were typically heavily pretreated, had prolonged neutropenia, and many had identified infections.

In total, 7 patients experienced graft failure after haploidentical donor HCT (3 had primary graft failure; 4 had brief engraftment with subsequent rejection). They received salvage HCT at a median of 37 days (range 31 – 78 days) following the first HCT (with the same haploidentical donor in 5 and an alternative haploidentical donor in 2 recipients). Patient 7 required modification of the regimen (no cyclophosphamide given) due to ongoing mechanical ventilation and pressor support. Six of the 7 patients (86%) experienced durable engraftment beginning at a median of 12 days (range 10 – 27 days). All 6 were successfully discharged from the hospital post-engraftment including Patient 7. The remaining patient had rapidly progressive disease and never had signs of engraftment before death at day 101 after the salvage HCT. No other patient has relapsed. Patient 7 ultimately expired due to CMV pneumonitis at 103 days after salvage HCT. The remaining five patients are alive at a median of 846 days after salvage HCT (range 131 to 2569 days). Two patients had acute and 3 had chronic GvHD; all resolved.

Our results indicate that this novel immunosuppressive regimen is tolerable and effective in this heavily pretreated patient population. High success rate in reengraftment was observed despite the use of T-cell depleted haploidentical grafts, including those from the same donor whose graft was previously rejected.

Patient	Age at   1st HCT	Diagnosis	1st Donor	Graft Failure	Time to 2nd HCT (days)	2nd Donor	Time to Neutrophil Engraftment (days)	Outcome
1	1yr 5mo	AML	Mother	1°	78	Mother	27	Alive
2	9mo	ALL	Mother	1°	65	Mother	11	Alive
3	1yr 9mo	ALL	Mother	1°	35	Mother	na	Expired (ALL)
4	18yr 2mo	MDS	Mother	2°	65	Mother	11	Alive
5	10y 10mo	MDS	Father	2°	37	Mother	14	Alive
6	16yr 7mo	CML	Sister	2°	31	Father	10	Alive
7	3yr 7mo	SAA	Father	2°	34	Father	13	Expired (CMV)