Graft Failure in Patients With Hematological Malignancies: A Successful Salvage With a Second Transplantation From a Different Haploidentical Donor

Abstract

Graft failure (GF) is a fatal complication of allogeneic stem cell transplantation, especially after haploidentical transplantation. The mortality of GF is nearly 100% without an effective salvage method. A second transplantation is usually necessary to save the patient's life. However, there is no standardized regimen, and the outcome is usually disappointing. We report on a prospective single-center study using a reduced-intensity conditioning regimen with different haploidentical donors (HIDs). Patients with GF after the first transplantation were enrolled in a prospective single-arm clinical trial (ClinicalTrials.Gov ID: NCT03717545) at the Peking University Institute of Hematology. The conditioning regimen consisted of fludarabine (30 mg/m2) (days−6 to−2) and cyclophosphamide (1,000 mg/m2/day) (days−5 to−4). Patients underwent a second transplant from a different HID using a granulocyte colony-stimulating factor primed bone marrow and peripheral blood stem cells. The primary outcome was neutrophil engraftment at day 28. The secondary outcomes included platelet engraftment at day 100, transplant-related mortality (TRM) at day 30, TRM at day 100, and overall survival (OS) at 1 year. From March 2018 to June 2020, 13 patients were enrolled in this clinical trial. Of the 13 patients, five had acute myeloid leukemia, five had acute lymphoblastic leukemia, two had myelodysplastic syndromes, and one had a non-Hodgkin lymphoma. The median age at first transplantation was 38 years (range, 8–55 years). As for the first transplantation, 11 patients underwent haploidentical transplantations and two underwent unrelated donor transplantations. At the time of GF, three patients had complete donor chimerism, five had mixed chimerism, and five had complete recipient chimerism. The median time from the first transplantation to the second transplantation was 49 (range 35–120) days. The medians of infused cell doses were as follows: mononuclear cells 7.93 (5.95–12.51) × 108/kg and CD34 + cells 2.28 (0.75–5.57) × 106/kg. All 13 patients achieved neutrophil engraftment after the second transplantation, with a median engraftment time of 11 (range 10–20) days after transplantation. The platelet engraftment rate on day 100 after transplantation was 76.9%. The TRMs at day 30, day 100, and 1-year were 0, 0, and 23.1%, respectively. The OS and disease-free survival at 1-year were 56.6 and 48.4%, respectively. For patients with GF after first transplantation, a second transplantation using a fludarabine/cyclophosphamide regimen from a different HID was a promising salvage option. Further investigation is needed to confirm the suitability of this method.

Analysis of factors associated with hematopoietic stem-cell retransplantation: a case-control study

“…Graft failure and disease relapse are the main reasons that lead to retransplantation mentioned in a study (16) . Factors associated with graft failure include HLA incompatibility, underlying disease, type of conditioning regimen, source of CPH employed, low HPC dose, ex vivo T cell depletion, major ABO incompatibility, grafts from female donors to male recipients and disease status at the transplantation time, infection or sepsis and nonadherence to drug therapy with ursodeoxycholic acid and immunosuppressants in the post-HSCT period (17) . The latter two mentioned were pointed out by the results of this research as factors which increase the chances of retransplantation.…”

Análise dos fatores associados ao retransplante de células-tronco hematopoiéticas: estudo caso-controle

“…Graft failure and disease relapse are the main reasons that lead to retransplantation mentioned in a study 16 . Factors associated with graft failure include HLA incompatibility, underlying disease, type of conditioning regimen, source of CPH employed, low HPC dose, ex vivo T cell depletion, major ABO incompatibility, grafts from female donors to male recipients and disease status at the transplantation time, infection or sepsis and non-adherence to drug therapy with ursodeoxycholic acid and immunosuppressants in the post-HSCT period 17 . The latter two mentioned were pointed out by the results of this research as factors which increase the chances of retransplantation.…”

Salvage haploidentical or cord‐blood allogeneic stem cell transplantation after a prior alternative allograft in hematologic malignancies: A retrospective study from the SFGM‐TC

“…In the largest retrospective study published so far on alternative salvage transplantations in the context of graft failure (699 patients between 2007 and 2016), Harada et al 30 found a 45.1% TRM in haplo‐ and 49.8% in CB‐HSCT. A prospective clinical trial led by the Peking University Institute of Hematology 31 reported an experience of salvage haplo‐HSCT using a fludarabine/cyclophosphamide regimen with a promising 56.6% 1‐year OS and 23.1% 1‐year TRM. Finally, development of non‐transplant treatments (TKI in CML, anti‐CD19 therapies in ALL, etc.)…”