Successfull Engraftment and Clearance of Donor Specific Antibodies after Haploidentical Related Stem Cell Transplantation for an Adult Patient with Sickle Cell Disease
Authors: FÜrst Sabine , Bernit Emmanuelle , El Cheikh Jean , Granata Angela , Harbi Samia , Mohty Bilal , Caymaris Laurence , Lemarie Claude , Calmels Boris , Chabannon Christian , Picard Christophe , Mokart Djamel , Andersson Borje , Blaise Didier 
Published: October 2019

Introduction: Sickle cell disease (SCD) is one of the most common genetic disorders in the world and despite advances in best supportive care it remains a disease with high risk of morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative treatment modality. Reports of adults are limited because of the lack of suitable matched donors and the high treatment related toxicity (TRT) after conventional myeloablative conditioning regimen resulting from the accumulated disease specific end organ damage. Initial reports of non myeloablative conditioning regimen showed disappointing results because of the high risk of graft failure (GF) and disease recurrence. Recently, the development of reduced toxicity conditioning regimen (RTC) with lower TRT and the use of haploidentical family donors has widened the applicability of alloHSCT. Since SCD patients (pt) are highly alloimmunosized, donor HLA-specific antibodies (DSA) are often detectable and might compromise engraftment in HLA mismatched transplants.

Material and Methods: We report a twenty two year old male pt with severe sickle cell-ß thalassemia and chronic blood transfusion related alloimmunization who received a family donor bone marrow alloHSCT from his haploidentical father. To reduce the risk of graft rejection, the preparative regimen consisted in a prephase-conditioning sequential immunoablation using two courses of a four day immunosuppressive treatment with fludarabine 40 mg/m2/d and dexamethasone 40 mg/d, six and three weeks before the start of the RIT conditioning regimen consisting of antithymocyte globuline (ATG, rabbit) 1.5 mg/kg from days -12 to -10; thiotepa 5 mg/kg on day -9; fludarabine 40 mg/m2 and intravenous busulfan 100 mg/kg from days -6 to -3. Graft versus host disease (GVHD) prophylaxis was provided by posttransplantation cyclophosphamide 50 mg/kg on day +3 and +4; cyclosporine and mycofenolate mofetil were started at day +5. The transplant work-up program included routine HLA antibody screening and prophylactic desensitization treatment with Rituxan combined with high dose immunoglobulin infusions after each cycle of immunoablation; additionally, plasmapheresis were performed at day -13 and -1, as well as one cycle of red blood cell exchange before the start of the RIT. Disease response was weekly measured by HbS levels using hemoglobin electrophoresis. Chimerism studies were done monthly by peripheral blood isolated CD3+ cells PCR analysis of variable number of nucleotide tandem repeats. DSA were examined using the luminex-based single antigen assay and MFI>=1000 were considered positive.

Results: The time to neutrophil recovery over 500 x 103/mm3 and platelet recovery over 50 x 103/mm3 were 29 and 43 days respectively; transfusion independency was reached at day +36. No GF occurred with predominantly donor mixed chimerism (82%) at last follow-up. HbS levels (baseline 68%) continuously decreased after the start of the preparative regimen to < 1% at day +77. DSA were substantially reduced after desensitization treatment and importantly dropped down further after alloHSCT to undetectable levels. Of note, no increase of DSA posttransplantation was observed. With a follow up of 140 days, the pt developed no GVHD or early TRT.

Conclusions: We presume that our preparative regimen approach in association with posttransplantation cyclophosphamide provides sufficient T-cell depletion and tolerance induction to enhance durable donor engraftment. The presence of DSA should not be a barrier to HLA haploidentical related alloHSCT.

Disclosures

No relevant conflicts of interest to declare.