Daratumumab therapy for post-HSCT immune-mediated cytopenia: experiences from two pediatric cases and review of literature

Abstract

Background Immune-mediated cytopenias (AIC) are challenging complications following allogeneic hematopoietic stem cell transplantation (HSCT). While broad-acting immunosuppressive agents like corticosteroids are often standard of care, several novel therapies which target specific immunological pathways have recently been developed and provide hope for patients with steroid-refractory courses and may limit long-term toxicity. The successful off-label use of the plasma cell depleting anti-CD38 antibody daratumumab was published in several case reports, suggesting efficacy, i.e., in patients with antibody-mediated AIC refractory to previous B cell depletion. We want to share our experience with two children, whom we treated with daratumumab, including one fatal course with uncontrolled disease. Given the absence of substantial data from HSCT registries or prospective trials, we furthermore provide a critical review of the literature on daratumumab treatment of AIC. Case presentations Patient 1 (P1), an 11-year-old girl with lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency who developed immune-mediated thrombocytopenia (AIT) from day +58 after HSCT, showed a complete response to daratumumab after the fourth of six total daratumumab doses. She remains transfusion independent for over a year of follow-up. Previously, her thrombocytopenia was refractory to corticosteroids, rituximab, intravenous immunoglobulins (IVIG), eltrombopag, cyclosporine A, and sirolimus. Patient 2 (P2), a 6-year-old boy with CD40 ligand (CD40L) deficiency, developed both AIT and hemolytic anemia (AIHA) after HSCT on days +58 and +83, respectively, and was also treated with daratumumab after being previously refractory to prednisolone, rituximab, and IVIG. Yet, he did neither respond to daratumumab nor the concomitantly administered methyprednisolone pulse, plasmapheresis, and eculizumab and succumbed due to refractory disease. Conclusion Reviewing the literature on the use of daratumumab for refractory AIC post-HSCT, we consider daratumumab a promising agent for this life-threatening disorder: ten of the twelve patients reached transfusion independency in the literature. However, treatment failures are likely to be underreported. Thus, controlled trials are needed to explore the safety and efficacy of daratumumab in this rare post-HSCT complication.

High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura

“…In this context, targeting ASCs with anti-CD38 appeared to be a very promising option. This work reports anti-CD38 daratumumab off-label use in 3 patients with refractory chronic ITP, a treatment that has been proposed for autoimmune cytopenia following bone marrow transplantation ( 40 , 41 ). Similar to our results, daratumumab therapy gave drastically different clinical outcomes, from complete remission to failure of therapy ( 41 ).…”

“…This work reports anti-CD38 daratumumab off-label use in 3 patients with refractory chronic ITP, a treatment that has been proposed for autoimmune cytopenia following bone marrow transplantation ( 40 , 41 ). Similar to our results, daratumumab therapy gave drastically different clinical outcomes, from complete remission to failure of therapy ( 41 ). The bone marrow is probably responsible for immediate failures of splenectomy by harboring sufficient autoreactive ASCs for effective platelet destruction.…”

Autoimmune Cytopenias Post Hematopoietic Stem Cell Transplantation in Pediatric Patients With Osteopetrosis and Other Nonmalignant Diseases

“…In our cohort, two patients received bortezomib, with no response. Daratumumab, an anti-CD38 monoclonal antibody developed to target malignant plasma cells in multiple myeloma, was also reported to effectively treat refractory post-HSCT AIC in several recent case reports (16). In our cohort, four patients received daratumumab, and in one of the patients (patient #4), a dramatic recovery from a refractory AIHA following the failure of several other treatments was observed (17).…”

Case report: Daratumumab treatment in pre-transplant alloimmunization and severe hemolytic anemia

“…In published literature so far, DARA has been used successfully for the treatment of post-allogenic hematopoietic stem cell transplantation (HSCT) associated autoimmune cytopenias (AIC) and pure red cell aplasia, refractory autoimmune hemolytic anemias (AIHA) and autoimmune thrombocytopenia (AIT), antibody-mediated rejection of transplanted kidney, antiphospholipid syndrome, systemic lupus erythematosus, and proliferative glomerulonephritis (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).…”