Successful treatment of thrombocytopenia with daratumumab after allogeneic transplant: a case report and literature review

Migdady, Yazan; Ediriwickrema, Asiri; Jackson, Ryan P.; Kadi, Wendy; Gupta, Rahul; Socola, Francisco; Arai, Sally; Martin, Beth A.

doi:10.1182/bloodadvances.2019001215

Cited by 32 publications

(21 citation statements)

References 12 publications

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“…The intravenous anti-CD38 monoclonal IgG 1 antibody daratumumab has proven its capability to deplete clonal plasma cells in myeloma [ 95 ]. Short series have reported on its potential efficiency in post-allogeneic-transplantation-associated thrombocytopenia [ 96 ]. Due to its mechanism of action, one concern is the emergence of severe hypogammaglobulinemia and infectious complications.…”

Section: New Therapeutic Perspectivesmentioning

confidence: 99%

Emerging Therapies in Immune Thrombocytopenia

Audia

Bonnotte

2021

JCM

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Immune thrombocytopenia (ITP) is a rare autoimmune disorder caused by peripheral platelet destruction and inappropriate bone marrow production. The management of ITP is based on the utilization of steroids, intravenous immunoglobulins, rituximab, thrombopoietin receptor agonists (TPO-RAs), immunosuppressants and splenectomy. Recent advances in the understanding of its pathogenesis have opened new fields of therapeutic interventions. The phagocytosis of platelets by splenic macrophages could be inhibited by spleen tyrosine kinase (Syk) or Bruton tyrosine kinase (BTK) inhibitors. The clearance of antiplatelet antibodies could be accelerated by blocking the neonatal Fc receptor (FcRn), while new strategies targeting B cells and/or plasma cells could improve the reduction of pathogenic autoantibodies. The inhibition of the classical complement pathway that participates in platelet destruction also represents a new target. Platelet desialylation has emerged as a new mechanism of platelet destruction in ITP, and the inhibition of neuraminidase could dampen this phenomenon. T cells that support the autoimmune B cell response also represent an interesting target. Beyond the inhibition of the autoimmune response, new TPO-RAs that stimulate platelet production have been developed. The upcoming challenges will be the determination of predictive factors of response to treatments at a patient scale to optimize their management.

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Section: New Therapeutic Perspectivesmentioning

confidence: 99%

Emerging Therapies in Immune Thrombocytopenia

Audia

Bonnotte

2021

JCM

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“…Finally, anti-CD38 treatment ameliorated autoimmune disease in an animal model of cynomolgus monkeys ( 32 ). As regards clinical reports, few and heterogeneous conditions are described, including two post-HSCT cytopenias (pure red cell aplasia and ITP) ( 27 , 28 ), 2 SLE ( 29 ), and 2 autoimmune encephalitis ( 30 , 31 ). All patients were adult and heavily pre-treated.…”

Section: Resultsmentioning

confidence: 99%

The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

et al. 2021

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Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

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“…Of note, cyclosporine-, and calcineurin-based immunosuppression and incomplete lymphodepletion are associated with AICs after both solid organ transplantation (SOT) ( 41 , 43 – 46 ) and non-malignancy HSCT and could point to shared biological mechanisms. Supporting this notion is the observation in the AHSCT AIC where withdrawal of CSA followed by anti-B cell directed therapy with rituximab or anti-CD38 resulted in clinical responses ( 11 , 47 ). Finally, decades ago cyclosporine was shown to induce autologous GvHD-like reaction purportedly via disruption of peripheral tolerance ( 48 ).…”

Section: Hematopoietic Autoimmune Manifestations Following Ahsctmentioning

confidence: 93%

“…Also, AHSCT associated AIHA appears to be more treatment refractory ( 9 ) compared to non-AHSCT associated cases with the latter having ∼80% of response rate to corticosteroids within 3 weeks, splenectomy having a 70% response rate, and rituximab having a 60% response rate. Several recalcitrant cases of post-AHSCT AIC, including AIHA, have been recently reported to respond to daratumumab ( 47 , 50 , 51 ), which targets CD38 that is expressed on plasmablasts and plasma cells.…”

Section: Hematopoietic Autoimmune Manifestations Following Ahsctmentioning

confidence: 99%

“…Passive transfer of donor ITP has been described in the adult AHSCT literature ( 31 , 52 ), but not in the pediatric setting. For post-AHSCT ITP and Evans syndrome, systemic corticosteroids and IVIG were the typical first line treatment, with a majority of the patients eventually receiving multiple lines of therapy, including rituximab, which resulted in a few complete responses ( 30 , 31 ), daratumumab ( 47 , 51 ), vincristine, cyclophosphamide, azathioprine, 6-mercaptopurine, alemtuzumab, plasma exchange, stem cell boost, splenectomy, rapamycin, romiplostim, and eltrombopag ( 28 ). It appears that ITP after AHSCT is often chronic, recalcitrant to treatment, and can result in mortality ( 15 , 28 , 31 , 55 ).…”

Section: Hematopoietic Autoimmune Manifestations Following Ahsctmentioning

confidence: 99%

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Autoimmunity Following Allogeneic Hematopoietic Stem Cell Transplantation

Buxbaum

Pavletić

2020

Front. Immunol.

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Autoimmune manifestations after allogeneic hematopoietic stem cell transplantation (AHSCT) are rare and poorly understood due to the complex interplay between the reconstituting immune system and transplant-associated factors. While autoimmune manifestations following AHSCT have been observed in children with graft-versus-host disease (GvHD), an alloimmune process, they are distinct from the latter in that they are generally restricted to the hematopoietic compartment, i.e., autoimmune hemolytic anemia, thrombocytopenia, and/or neutropenia. Autoimmune cytopenias in the setting of ASHCT represent a donor against donor immune reaction. Non-hematologic autoimmune conditions in the post-AHSCT setting have been described and do not currently fall under the GvHD diagnostic criteria, but could represent alloimmunity since they arise from the donor immune attack on the antigens that are shared by the donor and host in the thyroid, peripheral and central nervous systems, integument, liver, and kidney. As in the non-transplant setting, autoimmune conditions are primarily antibody mediated. In this article we review the incidence, risk factors, potential pathophysiology, treatment, and prognosis of hematologic and non-hematologic autoimmune manifestations in children after AHSCT.

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Successful treatment of thrombocytopenia with daratumumab after allogeneic transplant: a case report and literature review

Abstract: Key Points A source of treatment refractoriness in immune cytopenias appears to be residual CD138/38-positive lymphocyte populations. A short course of daratumumab is a novel treatment of refractory thrombocytopenia after failure of standard treatment options.

Cited by 32 publications

References 12 publications

Emerging Therapies in Immune Thrombocytopenia

Emerging Therapies in Immune Thrombocytopenia

The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

Autoimmunity Following Allogeneic Hematopoietic Stem Cell Transplantation

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