Graft-Versus-Host Disease in Multiple Myeloma Patients Treated With Daratumumab After Allogeneic Transplantation

Nikolaenko, Liana; Chhabra, Saurabh; Biran, Noa; Chowdhury, Arnab; Hari, Parameswaran; Krishnan, Amrita; Richter, Joshua

doi:10.1016/j.clml.2020.01.010

Cited by 10 publications

(6 citation statements)

References 65 publications

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“…Preliminary data have also shown promising responses after application of the CD38-antibody Daratumumab in MM-patients relapsed after allo-SCT with acceptable toxicity [ 95 , 96 ].…”

Section: Consolidation and Relapse Therapy After Transplantationmentioning

confidence: 99%

Allogeneic Stem Cell Transplantation in Multiple Myeloma

Greil

Engelhardt

Finke

et al. 2021

Cancers

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The development of new inhibitory and immunological agents and combination therapies significantly improved response rates and survival of patients diagnosed with multiple myeloma (MM) in the last decade, but the disease is still considered to be incurable by current standards and the prognosis is dismal especially in high-risk groups and in relapsed and/or refractory patients. Allogeneic hematopoietic stem cell transplantation (allo-SCT) may enable long-term survival and even cure for individual patients via an immune-mediated graft-versus-myeloma (GvM) effect, but remains controversial due to relevant transplant-related risks, particularly immunosuppression and graft-versus-host disease, and a substantial non-relapse mortality. The decreased risk of disease progression may outweigh this treatment-related toxicity for young, fit patients in high-risk constellations with otherwise often poor long-term prognosis. Here, allo-SCT should be considered within clinical trials in first-line as part of a tandem approach to separate myeloablation achieved by high-dose chemotherapy with autologous SCT, and following allo-SCT with a reduced-intensity conditioning to minimize treatment-related organ toxicities but allow GvM effect. Our review aims to better define the role of allo-SCT in myeloma treatment particularly in the context of new immunomodulatory approaches.

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“…Preliminary data have also shown promising responses after application of the CD38-antibody Daratumumab in MM-patients relapsed after allo-SCT with acceptable toxicity [ 95 , 96 ].…”

Section: Consolidation and Relapse Therapy After Transplantationmentioning

confidence: 99%

Allogeneic Stem Cell Transplantation in Multiple Myeloma

Greil

Engelhardt

Finke

et al. 2021

Cancers

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“…The inhibition of CD38 has therefore been proposed as an emerging therapeutic target in many autoimmune diseases, such as rheumatoid arthritis, systematic lupus erythematosus (7), asthma (14), neurodegeneration (15) and inflammatory bowel disease (16). Given its immunologically relevant functions, one published study evaluated the incidence of GVHD in 34 relapsed multiple myeloma patients treated with Dara after allo-HCT, in which the incidence of GVHD after Dara treatment was low, with only five patients (15%) developing aGVHD and no patient experiencing cGVHD (17). We questioned whether CD38 is a potential therapeutic target against alloreactive T cells in the GVHD pathological process.…”

Section: Introductionmentioning

confidence: 99%

Daratumumab Prevents Experimental Xenogeneic Graft-Versus-Host Disease by Skewing Proportions of T Cell Functional Subsets and Inhibiting T Cell Activation and Migration

Gao

Shan

et al. 2021

Front. Immunol.

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Graft-versus-host disease (GVHD) remains the major cause of mortality and morbidity in non-relapse patients after allogeneic hematopoietic cell transplantation (allo-HCT). As the number of patients undergoing allo-HCT increases, it will become imperative to determine safe and effective treatment options for patients with GVHD, especially those who become refractory to systemic steroid therapy. Daratumumab (Dara), a humanized IgG1 (ĸ subclass) monoclonal antibody targeting the CD38 epitope, is used for the treatment of multiple myeloma. CD38 is a multifunctional ectoenzyme that behaves either as an enzyme, a cell adhesion molecule or a cell surface receptor involved in cell signaling. CD38 is also expressed on various immune effector and suppressor cells. However, the role of CD38 in the immune response remains elusive. We questioned whether CD38 is a potential therapeutic target against alloreactive T cells in the GVHD pathological process. Here, we investigated the impact of Dara on xenogeneic GVHD (xeno-GVHD) and graft-versus-leukemia (GVL) effects in a humanized murine model of transplantation, where human peripheral blood mononuclear cells were adoptively transplanted into immunocompromised NOD.SCID.gc-null (NSG) mice. Mice receiving Dara treatment experienced less weight loss, longer survival and lower GVHD scores compared with those in the control group. Histological evaluations, flow cytometry, RNA-sequencing and RT-qPCR analysis revealed that Dara efficaciously mitigated GVHD through multiple mechanisms including inhibition of the proliferation, activation and differentiation of CD8+ cytotoxic T cells, reduced expression of cytotoxic effector molecules, pro-inflammatory cytokines, chemokines and chemoattractant receptors by T cells and promotion of immunosuppressive T cells. More importantly, Dara preserved the GVL effect in a humanized mouse model of leukemia by metabolic reprograming of T cells to promote the induction of Th17, Th1/17and Tc1/17 cells. Our findings indicate that Dara may be an attractive therapeutic option to separate GVHD from GVL effects in patients with hematopoietic malignancies receiving allo-HCT.

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“…Nikolaenko et al. ( 34 ) did not observe an increased development of cGVHD in 34 relapsed multiple myeloma patients treated with dara after allo-HCT. Moreover, patient 3 did not experience worsened cGVHD after dara treatment.…”

Section: Discussionmentioning

confidence: 92%

The role of daratumumab in relapsed/refractory CD38 positive acute leukemias—case report on three cases with a literature review

Prejzner,

Piekoś,

Bełdzińska

et al. 2023

Front. Oncol.

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Primary refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) and mixed phenotype myeloid/T-cell acute leukemia have dismal prognoses. New treatment approaches, preferably targeting specific leukemic aberrations to overcome resistance, are urgently needed. The bright expression of the CD38 antigen found in several cases of T-ALL led to an investigation into the role of anti-CD38 antibodies in the treatment of T-ALL. Here, we present three cases of resistant and relapsed T-ALL and myeloid/T-cell treated with daratumumab-based therapy, including venetoclax and bortezomib (Dara-Ven-Bor). All patients achieved complete remission, with minimal residual disease negativity within four weeks of treatment, allowing them to proceed to allogeneic hematopoietic cell transplantation. The toxicity of the triple schema was acceptable. Our patients and other cases reviewed here suggest that daratumumab combined with venetoclax and bortezomib may be a very effective and relatively safe salvage treatment, even in primary resistant T-ALL.

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Graft-Versus-Host Disease in Multiple Myeloma Patients Treated With Daratumumab After Allogeneic Transplantation

Cited by 10 publications

References 65 publications

Allogeneic Stem Cell Transplantation in Multiple Myeloma

Allogeneic Stem Cell Transplantation in Multiple Myeloma

Daratumumab Prevents Experimental Xenogeneic Graft-Versus-Host Disease by Skewing Proportions of T Cell Functional Subsets and Inhibiting T Cell Activation and Migration

The role of daratumumab in relapsed/refractory CD38 positive acute leukemias—case report on three cases with a literature review

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