Successful treatment with daratumumab for post‐HSCT refractory hemolytic anemia

Even‐Or, Ehud; NaserEddin, Adeeb; Shadur, Bella; Schejter, Yael Dinur; Najajreh, Mohammad; Zelig, Orly; Zaidman, Irina; Stepensky, Polina

doi:10.1002/pbc.28010

Cited by 36 publications

(30 citation statements)

References 16 publications

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“…This is consistent with a previous case report where daratumumab achieved a sustained remission in an infant with both AIHA and ITP who had previously failed multiple lines of therapy. 33,[38][39][40][41][42] Although reports agree that there is efficient periph-…”

Section: Discussionmentioning

confidence: 99%

“…3,4 AICs tend to have a protracted course and can be resistant to multiple therapies. 5,6 Prior studies have identified several risk factors for AIC development including nonmalignant transplant indications, chemotherapy naivety, unrelated donors, cord blood stem cell source, graft-vs-host disease (GVHD), reduced-intensity preparative regimens, serotherapy, and cytomegalovirus (CMV) reactivation. [7][8][9][10] Corticosteroids and rituximab are the most common first-line therapies for AICs.…”

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confidence: 99%

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Autoimmune cytopenias following allogeneic hematopoietic stem cell transplant in pediatric patients: Response to therapy and late effects

Koo

Giller

Quinones

et al. 2020

Pediatric Blood & Cancer

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Background Autoimmune cytopenias (AICs) are rare, but serious complications of allogeneic hematopoietic cell transplantation (allo‐HSCT). Procedure We performed a case‐control study using 20 pediatric AIC cases and 40 controls, matched by stem cell source and primary indication comparing clinical and transplant characteristics, treatment, outcomes, and late effects. Results Cases were more likely to be human leukocyte antigen mismatched (P = 0.04). There was no difference in conditioning regimen, serotherapy use, graft‐versus‐host disease (GVHD) prophylaxis, incidence of acute or chronic GVHD, ABO compatibility, infections, and donor engraftment. The median time to AIC onset was 219 days (range, 97‐1205 days) and AIC resolution was 365 days (range, 10 days to 2737.5 days). First‐line therapies for AIC patients most commonly included corticosteroids (75%) and rituximab (55%). Only 25% of patients responded to first‐line treatment. At a median of 611.5 days from last rituximab dose, 82.5% patients were still receiving intravenous immune globulin for hypogammaglobulinemia compared with 2.5% of controls (P < 0.0001). Iron overload was higher in AIC patients (P = 0.0004), as was avascular necrosis (P = 0.04). There was no difference in overall survival at one year after HSCT (85% vs 82.5%). Two patients with refractory autoimmune hemolytic anemia responded to daratumumab and had resolution of B‐cell aplasia. Conclusions In this study, we find poor initial responses to AIC‐directed therapies and significant late effects.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Autoimmune cytopenias following allogeneic hematopoietic stem cell transplant in pediatric patients: Response to therapy and late effects

Koo

Giller

Quinones

et al. 2020

Pediatric Blood & Cancer

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“…In a retrospective study, bortezomib (the first registered proteasome inhibitor) together with other drugs elicited a positive response in patients with refractory wAIHA [111,112]. Daratumumab (anti CD38 monoclonal antibody) has shown a rapid and sustained response in the treatment of refractory AIHA after HSCT in children [113] and in adults [114]. Proliferation disorder and apoptosis of pathological B lymphocytes is obtained by means of bruton tyrosine kinase (BTKs) inhibitors and antibodies directed against CD20 or CD52.…”

Section: Future Prospects Of Aiha Therapymentioning

confidence: 99%

Autoimmune hemolytic anemia: current knowledge and perspectives

et al. 2020

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Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases which includes warm AIHA, cold agglutinin disease (CAD), mixed AIHA, paroxysmal cold hemoglobinuria and atypical AIHA. Currently CAD is defined as a chronic, clonal lymphoproliferative disorder, while the presence of cold agglutinins underlying other diseases is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies directed against red blood cells (RBCs) causing premature erythrocyte destruction. The pathogenesis of AIHA is complex and still not fully understood. Recent studies indicate the involvement of T and B cell dysregulation, reduced CD4+ and CD25+ Tregs, increased clonal expansions of CD8 + T cells, imbalance of Th17/Tregs and Tfh/Tfr, and impaired lymphocyte apoptosis. Changes in some RBC membrane structures, under the influence of mechanical stimuli or oxidative stress, may promote autohemolysis. The clinical presentation and treatment of AIHA are influenced by many factors, including the type of AIHA, degree of hemolysis, underlying diseases, presence of concomitant comorbidities, bone marrow compensatory abilities and the presence of fibrosis and dyserthropoiesis. The main treatment for AIHA is based on the inhibition of autoantibody production by mono- or combination therapy using GKS and/or rituximab and, rarely, immunosuppressive drugs or immunomodulators. Reduction of erythrocyte destruction via splenectomy is currently the third line of treatment for warm AIHA. Supportive treatment including vitamin supplementation, recombinant erythropoietin, thrombosis prophylaxis and the prevention and treatment of infections is essential. New groups of drugs that inhibit immune responses at various levels are being developed intensively, including inhibition of antibody-mediated RBCs phagocytosis, inhibition of B cell and plasma cell frequency and activity, inhibition of IgG recycling, immunomodulation of T lymphocytes function, and complement cascade inhibition. Recent studies have brought about changes in classification and progress in understanding the pathogenesis and treatment of AIHA, although there are still many issues to be resolved, particularly concerning the impact of age-associated changes to immunity.

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“…The activity of DARA has been noted in the treatment of post-transplant autoimmune hemolytic anemia, mostly in pediatric patients [ 65 , 66 , 67 ]. In such setting, DARA showed encouraging results also as a rescue therapy in pre-treated patients refractory to common drugs such as rituximab, alemtuzumab, bortezomib, mycophenolate mofetil (MMF), sirolimus, and ibrutinib [ 68 ].…”

Section: Clinical Applications Outside MMmentioning

confidence: 99%

The Circular Life of Human CD38: From Basic Science to Clinics and Back

et al. 2020

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Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

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Successful treatment with daratumumab for post‐HSCT refractory hemolytic anemia

Cited by 36 publications

References 16 publications

Autoimmune cytopenias following allogeneic hematopoietic stem cell transplant in pediatric patients: Response to therapy and late effects

Autoimmune cytopenias following allogeneic hematopoietic stem cell transplant in pediatric patients: Response to therapy and late effects

Autoimmune hemolytic anemia: current knowledge and perspectives

The Circular Life of Human CD38: From Basic Science to Clinics and Back

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