Abstract
Background: Related haploidentical bone marrow transplant (haplo-BMT) with posttransplant cyclophosphamide is a potentially curative treatment for patients with sickle cell disease (SCD) who traditionally have limited donor options. The presence of donor-specific, anti-human leukocyte antigens (HLA) antibodies or DSA has been associated with a significantly increased risk of graft failure following haploidentical stem-cell transplantation (Ciurea et al. Transplantation, 2009). Development of DSA is common in SCD secondary to sensitization through blood transfusion. We evaluated the efficacy of our desensitization strategy in patients with SCD with prohibitive DSA undergoing haplo-BMT.
Methods: The study was conducted as part of a multi-institutional Vanderbilt Haploidentical Learning Collaborative, which opened in October 2013, with institutional specific IRB and the primary objective of optimizing haplo-BMT for SCD. Patients and donors were high resolution HLA typed at the HLA-A, B, C, DRB1, DRB3-5, DQB1, and DPB1 loci. Patients' sera were tested for HLA-antibodies against the donor using solid-phase immunoassays on the Luminex platform using the LABScreen Single Antigen Kit (One Lambda, Canoga Park, CA, USA) at the time of initial evaluation and within 30 days prior to start of conditioning. The crossmatch techniques used were standard complement dependent cytotoxicity assays and/or flow cytometric crossmatch tests. A mean fluorescence intensity (MFI) of 3000 Units (U) was used as the cut-off for clinical relevance and considered moderate-to-severe DSA level for both anti-HLA class I and class II antibodies. Desensitization was initiated in patients with DSA MFI ≥3000 U and with no other donors identified. Each patient underwent desensitization based on modified Johns Hopkins approach (Gladstone et al. BBMT 2013), and common haplo-BMT conditioning (de la Fuente et al. BBMT 2019), figure 1. Desensitization included alternate-day, single-volume plasmapheresis (PP), performed using the COBE Spectra (TerumoBCT, Lakewood, CO), replacing 100% volume with 5% albumin, anti-CMV hyper-intravenous immune immunoglobulin (IVIg) (100 mg/kg), tacrolimus (1 mg, IV per day or 2 mg, po twice daily) and mycophenolate mofetil (1 g, twice daily) starting 1 to 2 weeks prior to start of haplo-BMT conditioning, with 1 additional treatment on the day before infusion of stem cells. Most patients also received a single dose of rituximab 375 mg/kg at least 1 week prior to start of PP/IVIg. HLA antibodies were measured on day 0 before the infusion of bone marrow and if the MFI had not decreased to <3000 U, two additional cycles of PP/IVIg were given on days +1 and day +2 post-transplant.
Results: Eight haploidentical patients had moderate-to-severe DSA levels (Table). All had DSA to HLA class I, patient #7 had DSA to two class I antigens, and patient #8 to 2 class I and 2 class II antigens. Donors were all first-degree relatives (4-maternal, 2-paternal and 2-sibling). Mean age of patients was 12.25 years (range 3-25), 5 patients were female. Patient #6 underwent a second haplo-BMT from paternal donor after a previous graft failure from a maternal haploidentical donor 18 months prior. A paired t-test showed a statistically significant difference between baseline DSA level (mean (M)= 14187.25, standard deviation (SD)= 6782.55) and day-0 DSA level (M= 3849.63, SD= 3704.21); [t(7) = 5.54, p=0.0008]. The 95% confidence interval of the difference between the means ranged from 5926.3 to 14749. Desensitization was well tolerated without serious adverse events in all patients. Four patients required additional cycles of PP/IVIg on days +1 and +2. DSA was undetectable or <1000 U in 3 of 4 patients who required PP/IVIg on D+1 and D+2. Median time to neutrophil engraftment was 20.5 days (range 15-28); all patients engrafted by day +28, though 4 patients had initial mixed chimerism in the T cell fraction. Patient #8 had persistent DSA to class II on Day +2, developed poor graft function despite having primary engraftment and died of pulmonary hemorrhage on Day + 45.
Conclusion: The combination of rituximab, PP/IVIg and pre-transplant immunosuppression is an effective desensitization strategy for patients with SCD and high DSA titer undergoing haplo-BMT. The risk of graft failure is reduced, enabling transplantation when no other donor exists. Larger prospective studies are needed to further validate this approach.
Disclosures
Gatwood:Kite Pharma: Speakers Bureau; sanofi: Speakers Bureau; AstraZeneca: Research Funding; Jazz Pharmaceuticals: Speakers Bureau. Dholaria:Angiocrine: Research Funding; Janssen: Research Funding; Poseida: Research Funding; BEAM Therapeutics: Consultancy; Jazz Pharmaceuticals: Consultancy; MJH Biosciences: Honoraria; MEI Pharma: Research Funding; BMS: Research Funding; Orca Bio: Research Funding; Takeda: Research Funding; Arivan: Consultancy; Pfizer: Research Funding; Molecular Templates: Research Funding; Wugen: Research Funding; Vanderbilt University Medical Center: Current Employment; Gamida Cell: Consultancy. Sengsayadeth:Amgen: Research Funding. Kitko:Horizon Therapeutics: Consultancy. Connelly:X4: Consultancy; Horizon: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. de la Fuente:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
