Different Donors and Conditioning Regimens in Hematopoietic Stem Cell Transplantation for Inherited Bone Marrow Failure Syndromes: A Tale of Custom-Made Suits
Authors: Lopez Hernandez Gerardo , Olaya Vargas Alberto , Ramírez Uribe Rosa Maria Nidesha , Salazar Rosales Haydeé del Pilar , Maldonado Silva Karla , Martínez Talavera Isabel , Salazar Bailón José Luis 
Published: December 2024

Background
Hematopoietic stem cell transplant (HSCT) continues to stand for the only curative option for patients with inherited bone marrow failure syndromes (IBMFS). Transplant-related mortality (TRM) especially opportunistic infections is likely to increase among patients as is engraftment failure, therefore, specific conditioning regimen based on each disease are essential to achieve long-term survival.
Objective
To present results of patients with IBMFS underwent HSCT with conditioning regimens according to their main condition.
Methods
Between January 2014 to December 2022, 31 patients with IBMFS underwent HSCT from matched related donor (MRD), matched unrelated donor (MURD), haploidentical with post-transplant cyclophosphamide (haplo-PTCy), haploidentical with CliniMACS ex vivo depletion or umbilical cord blood (UCB), in the National Institute of Pediatrics in Mexico City.
Disease-specific conditioning regimen and prophylaxis against graft vs host disease (GVHD)
Fanconi anemia (FA) patients and MSD were conditioning with fludarabine (FLU) 150 mg/m2, cyclophosphamide (Cy) 20 mg/kg, and anti-thymocyte globulin [rabbit] (ATG) 20 mg/kg. In haplo-PTCy, ATG 15 mg/kg, FLU 150 mg/m2, Cy 20 mg/kg and in CliniMACS total body irradiation (TBI) 2 Gy was added. Patients with Dyskeratosis congenita (DC) were administered TBI 2 Gy, FLU 120 mg/m2, Cy 1200 mg/m2, ATG 10 mg/kg. Diamond-Blackfan anemia (DBA) and Shwachman-Diamond Syndrome (SD) patients, intravenous busulfan (Bu) dose according to weight, Cy 120 mg/kg and ATG 15 mg/kg. GVHD prophylaxis in MSD was cyclosporine (CsA) and methotrexate. PTCy was administered at 25 mg/kg on +3 and +4, also with mycophenolate mofetil 30 mg/kg and tacrolimus 0.06 mg/kg. Cy dose for haplo-PTCy group was changed after the first two FA patients developed gastrointestinal grade IV GVDH; thus, the rest of patients received 50 mg/kg per day. In CliniMACS only in case of a log5 lymphocyte in the graft CsA would be started.
Results
Twenty women and eleven men with a median age of 8 (range 2 to 17) years underwent HSCT. The diagnoses corresponded to FA n= 20, DBA n=8, CD n=2, SD n=1. Diagnoses was made according to published consensus criteria.
Donors, graft source and engraftment
MSD (n=17) to which it corresponds FA=13, DBA= 4; haplo-PTCy (n=7), to whom FA= 4, DBA= 2, SD=1 (originally planned for a transplant from a MURD, the sudden start of the lockdown due to the COVID19 pandemic one day before donor´s bone marrow harvest, urgently forced to switch to patient´s father as donor); CliniMACS FA=2, CD= 2; MURD FA=1, DBA= 1, and UCB (n=1).
Source, other than UCB of hematopoietic progenitors was bone marrow (n=26) and peripheral blood (n=4), the last corresponds to patients in cliniMACS group. Grafts had a median TNC of 5.33x108/kg, and CD34+= 6.7x106/kg. Median time to neutrophil recovery was 12 (range 10-19) days.
Clinical outcomes in MSD and MURD groups
Skin grade II acute GVHD developed in three FA patients. Two of them evolved to oral mucosal disease and upper intestinal severe chronic GVHD. Two FA patients died secondary to infectious complications before engraftment. A FA patient in MURD group died because of sudden acute kidney failure secondary to dimethyl sulfoxide (HSCT was performed for the time of COVD19 pandemic, when it was recommended to cryopreserve grafts). The rest of patients remains alive and well, with full donor chimerism.
Clinical outcomes in haplo groups
In haplo-PTCy group, three patients developed grade II-IV acute-GVHD, two of which died. Two DB in the haplo-PTCy group presented primary graft failure. Both FA and one of CD patients in cliniMACS group died consequence of invasive fungal and CMV disease. All DBA in PTCy group presented primary graft failure, same result in remaining CD patient in cliniMACS group; all these patients remain alive at the time of this report.
Clinical outcome in umbilical cord patients.
DB patient transplanted with UCB remains alive and well, with full chimerism.
Discussion and Conclusions
Our HSCT outcomes in pediatric patients with IBMFS differ among specific diseases. This review was conducted to evaluate the outcomes of HSCT using specific conditioning regimens in IBMFS. Our data show an encouraging 65% EFS and 75% OS after transplantation, suggesting that adequacy of the conditioning regimen based on disease can achieve successful HSCT. Ongoing follow up is needed to evaluate the long-term success.