Addition of Thiotepa to Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Reduces Secondary Graft Failure in Allogeneic HSCT for Inborn Errors of Immunity

Introduction Alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimen is associated with a high incidence of mixed chimerism and secondary graft failure in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for inborn errors of immunity (IEI). We hypothesized that addition of thiotepa to this regimen would reduce secondary graft failure without increasing toxicity in children and young adults undergoing allogenic HSCT for IEI. Methods We retrospectively reviewed charts of patients undergoing allogenic HSCT for IEI who received alemtuzumab (starting on day -14), fludarabine (150 mg/m2 or 5 mg/kg over days -8 to -4), and melphalan (140 mg/m2 or 4.7 mg/kg on day -3) containing RIC regimen with the addition of thiotepa (200 mg/m2 on day -2). Mixed chimerism and low-level mixed chimerism were defined as whole blood donor chimerism <95% and <50%, respectively, on two consecutive measures within a 2-week period. Results Thirty-one patients underwent allogeneic HSCT at a median age of 1.7 years (0.3-21 yrs). Patient demographics are outlined in Table 1. All patients engrafted at a median of 12 days (range, 8-17 days). The incidence of mixed chimerism was 0% (0/31), 20% (5/25), and 46% (7/15) upon engraftment at day +100 and one-year post-HSCT, respectively. Incidence of low-level mixed chimerism was 0% (0/25) and 6.6% (1/15) at day +100 and one-year post-HSCT, respectively. Three (9.6%) patients required a secondary intervention (2 CD34 selected boost and 1 second HSCT). Two (6.4%) patients developed sinusoidal obstruction syndrome, and 11 (35%) patients developed thrombotic microangiopathy. Six (19%) patients developed grade I-II skin GVHD, with none developing grade III-IV GVHD. One (3.2%) patient developed limited chronic GVHD. Thirteen of 31 (42%) patients had viral reactivation requiring treatment, with CMV (54%), EBV (54%), and adenovirus (15%) being the most common. Twenty-six (84%) patients are surviving at median follow-up of 10 months (range 2m-4y 2m) post-HSCT. Table 1.Patient demographics (n = 31).Median age at transplant (range)1y 8m (4m-21y 11m)Median Follow up (range)10 m (2m-4y 2m)GenderMale19 (61%)Female12 (39%)DiagnosisHLH19 (61%)sJIA5 (16%)XLP1 (3.2%)XIAP1 (3.2%)LRBA deficiency1 (3.2%)XMEN1 (3.2%)SCID1 (3.2%)Griscelli1 (3.2%)Early onset IBD1 (3.2%)Donor RelationshipRelated21 (68%)Unrelated10 (32%)HLA Match10/1021 (68%)9/106 (19%)7/101 (3%)6/103 (10%)Stem cell sourceBM23 (74%)PBSCs, CD34 selected5 (16%)PBSCs, alpha beta depleted3 (10%)GVHD prophylaxisCSA/MMF11 (35.5%)CSA/MMF/Abatacept10 (32%)CD34 selection5 (16%)Alpha-beta T cell depletion3 (10%)CSA/MMF/PT-Cy2 (6.5%) Conclusion Addition of thiotepa to a RIC regimen containing fludarabine, alemtuzumab, and melphalan reduces secondary graft failure without increasing toxicity in children and young adults undergoing allogenic HSCT for IEI. Longer duration of follow-up is needed to assess durability of donor chimerism.