Infectious and immunological sequelae of daratumumab in multiple myeloma

Johnsrud, Andrew; Johnsrud, Joyce J; Susanibar, Sandra; Kamimoto, Jorge Jo; Kothari, Atul; Burgess, Mary Jo; Rhee, Frits van; Rico, Juan Carlos

doi:10.1111/bjh.15433

Cited by 39 publications

(26 citation statements)

References 10 publications

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“…These two cases argue to the potential of T-cell transfers after allo-HCT, although only selected patients will be in a situation where T-cell transfer is an option. Multiple myeloma (MM) patients treated with the anti-CD38 monoclonal antibody daratumumab (Dara) show an increased risk for infectious complications, potentially attributable to the depletion of NK cells [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes

et al. 2020

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Background: Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. Methods:To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. Results:Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. Conclusion:We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.

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Section: Introductionmentioning

confidence: 99%

Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes

et al. 2020

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“…The University of Arkansas Medical Sciences Group evaluated 171 patients who received daratumumab, and it reported that 36.5% encountered infectious complications during therapy. Interestingly, the absolute CD56+ lymphocytes (NK cells) were severely diminished among patients receiving daratumumab, and the median CD56+ lymphocytes were significantly lower among patients who had an infection in comparison with patients without an infection . Several other groups have reported similar findings of increased susceptibility to infectious complications of cytomegalovirus and fungal and parasitic infections among patients with myeloma receiving daratumumab.…”

Section: Managing Daratumumab‐related Toxicities and Practical Aspectsmentioning

confidence: 76%

“…Interestingly, the absolute CD56+ lymphocytes (NK cells) were severely diminished among patients receiving daratumumab, and the median CD56+ lymphocytes were significantly lower among patients who had an infection in comparison with patients without an infection . Several other groups have reported similar findings of increased susceptibility to infectious complications of cytomegalovirus and fungal and parasitic infections among patients with myeloma receiving daratumumab. A recently published meta‐analysis designed to determine the risks of upper respiratory tract infections and pneumonia in patients with myeloma reported a pooled risk ratio for an upper respiratory tract infection of 1.59 (95% CI, 1.33‐1.91; P = .00001) and a pooled risk ratio for pneumonia of 1.48 (95% CI, 1.14‐1.93; P = .002) among patients receiving daratumumab .…”

Section: Managing Daratumumab‐related Toxicities and Practical Aspectsmentioning

confidence: 76%

“…The majority of these occurred with the first infusion, were either grade 1 or 2, and did not require treatment discontinuation. The most common (25) Pneumonia (12) and thrombocytopenia (10) SIRIUS, 12 phase 2 (n = 106) Fatigue (40), anemia (33), nausea (29), and thrombocytopenia (25) Anemia (24), thrombocytopenia (19), and neutropenia (12) Daratumumab in combination with IMiDs GEN503, 14 DVd: thrombocytopenia (45), anemia (14), neutropenia (13), PN (5), fatigue (5), pneumonia (8), and HTN (7) Vd: thrombocytopenia (33), anemia (16), PN (7), and pneumonia (10) EQUULEUS, 22 phase 1b (n = 85) Thrombocytopenia (64), anemia (48), asthenia (38), nausea (34), dyspnea (29), insomnia (27), lymphopenia (26), diarrhea (26), neutropenia (25), and pyrexia (25) Thrombocytopenia (27), lymphopenia (24), anemia (20), neutropenia (19), asthenia (12), and hypertension (12) Daratumumab in newly diagnosed myeloma ALCYONE 23 (n = 706) D-VMP: neutropenia (50), thrombocytopenia (49), anemia (28), PN (28), and URTI Cancer July 15, 2019 hematologic and nonhematologic AEs are summarized in Table 2. On the basis of the findings in this study, an effective dose of daratumumab was determined to be 16 mg/kg.…”

Section: Early-stage Clinical Development Of Daratumumabmentioning

confidence: 99%

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Daratumumab in multiple myeloma

Nooka

Kaufman

Hofmeister

et al. 2019

Cancer

123

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The development of effective monoclonal antibodies for the treatment of myeloma has been a long journey of clinical and drug development. Identification of the right target antigen was a critical part of the process. CD38 as a target has been considered for some time, but clinically, daratumumab, a CD38 monoclonal antibody, was the first to be tested, and it has delivered the best clinical responses as a single agent to date. Its proven safety and efficacy in combination with other antimyeloma agents have led to several US Food and Drug Administration approvals for treating myeloma. Furthermore, the results of early trials in the induction therapy setting have demonstrated a beneficial role when it is added to the existing induction regimens. This review summarizes the importance of CD38 as a target and examines the clinical development of the CD38 monoclonal antibody daratumumab and its clinical significance in combination regimens in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma.

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“…Despite not reaching statistical significance often, the rates of infections (particularly those of viral etiology) have been frequently reported to be increased with the use of MoAb. Indeed, real-world data have registered infectious rates up to 39% in patients treated with daratumumab [119,120]. Long-term observation and future clinical trials should specifically address infection risk in MM patients receiving MoAbs, to develop appropriate guidelines for prophylactic and treatment procedures.…”

Section: Expert Opinionmentioning

confidence: 99%

Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses

Musto

Rocca

2020

Expert Review of Hematology

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Introduction: In the last few years, monoclonal antibodies have rapidly modified the therapeutic strategies for treating patients with multiple myeloma. Areas covered: In this review, the most recent literature data regarding indications for which monoclonal antibodies are currently or will be shortly approved as salvage therapies in relapsed/refractory myeloma are discussed. In particular, updated results until March 22, 2020 of antibodies directed against CD38 (daratumumab and isatuximab), SLAMF7 (elotuzumab), BCMA (GSK2857916/belantamab mafodotin), and PD-1/PD-1 L axis (nivolumab and pembrolizumab) will be analyzed in detail. Expert opinion: Monoclonal antibodies represent a new, very effective approach that will open novel and dynamic treatment scenarios for myeloma patients in the coming years. Optimal positioning and selection of different antibodies that are or will be soon available, appropriate combinations and careful evaluation of possible new toxicities should be considered in the future management of these patients.

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Infectious and immunological sequelae of daratumumab in multiple myeloma

Cited by 39 publications

References 10 publications

Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes

Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes

Daratumumab in multiple myeloma

Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses

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