IntroductionPre-transfusion tests, essential for the release of blood components, may be affected by drugs. Monoclonal antibodies represent a class of medications increasingly used in the clinical practice, with anti-CD38 monoclonal antibodies (daratumumab) being a promising resource in the treatment of refractory myeloma. This monoclonal antibody recognizes CD38 in myeloma cells and interferes with pre-transfusion tests by causing panreactivity in indirect antiglobulin tests thereby clinically masking alloantibodies. Dithiothreitol is a reagent that breaks disulfide bonds and effectively destroys antigenic sites for CD38 on red blood cells. This study reports the immunohematological findings of pre-transfusion tests of patients with multiple myeloma receiving daratumumab and on solutions to prevent the interference of this monoclonal antibody.MethodsSerum samples from five patients on anti-CD38 monoclonal antibody treatment were evaluated. Tests performed included ABO/RhD typing, indirect antiglobulin test, direct antiglobulin test and eluate test. A daily evaluation was performed to determine the shelf life of dithiothreitol-treated red blood cells when stored in Alsever's solution.ResultsNo interference in the ABO/RhD typing results was noted but in all samples, a panreactivity was observed in indirect antiglobulin tests. Regarding the direct antiglobulin test, two samples presented positive results but negative eluates. In all samples, treatment of reagent red blood cells with 0.2 M dithiothreitol offset interference by anti-CD38 monoclonal antibodies. Dithiothreitol-treated red blood cells stored in Alsever's solution were stable for up to 15 days.ConclusionTreatment of reagent red blood cells with dithiothreitol can be efficient and accessible to offset the interference of the anti-CD38 drug in pre-transfusion tests. The number of costly serological workups can be reduced by having stored dithiothreitol red blood cells with this proving to be a useful reagent for investigating anti-CD38.
Introduction: The treatment of human hematologic malignancies has rapidly advanced through the application of genomic platforms that have identified drug-able targets and companion diagnostics (e.g. BCR-ABL, IDH-1) and added new classes of targeted agents to the established compendium of cytotoxics. Despite these advances, the complexity, redundancy and promiscuity of cellular transformation remain incompletely understood at the molecular level. This has led to a renewed interest in whole cell experimental models for drug discovery. Laboratory platforms that measure cellular response to cytotoxic insult at the phenotypic level have been shown to correlate significantly with clinical response, and have the capacity to provide insights into chemotherapy selection and drug development. The Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) uses metabolic and morphologic features of drug induced cell death to measure both cytotoxic and targeted drug effects in human primary cultures. We applied EVA/PCD in 20 heavily pre-treated, drug refractory patients from the Hospital Israelita Albert Einstein (HIAE) in Sao Paulo - Brazil. Methods: Peripheral blood, node biopsy or bone marrow aspirates were submitted by overnight courier. Cells isolated by density centrifugation were evaluated by dose response curves that were interpolated to provide LC50 values for comparison with our databases by Z-score. Patients with Acute Lymphoblastic Leukemia (ALL, N=5) , Acute Myeloid Leukemia (AML, N=6), Non-Hodgkin Lymphoma (NHL, N=4) or Multiple Myeloma (MM, N=4) had received a mean of 5, median of 4 (range 1-8) prior therapies, 7 with prior bone marrow transplantation (BMT). Results: of 20 specimens, 16 (80%) provided viable tumor for EVA/PCD. A mean of 8, median of 7(range 3-22) cytotoxics and a mean 7, median of 5(range 1-20) targeted agents were evaluated. Findings were reported by day 7. Nine of 16 patients were treatment candidates, with 5 lost to follow up, 3 dying of sepsis before evaluation and 1 achieving complete remission (CR) with radiation plus Rituximab. Of 7 patients who received assay directed therapy there were 3 CR (43%), 2 partial responses (PR: 28%) and 2 progressive disease (PD: 29%) for an overall response rate of 71%. Conclusion: These results establish the feasibility of laboratory directed therapy in heavily pre-treated patients, with 80% of submitted samples providing actionable results. Although the extremely advanced state of these patients limited the capacity to undergo treatment in some cases, the achievement of CR's and PR's in this drug refractory cohort is of interest. Clinical responses by disease, treatment history and drugs received will be reported. Studies correlating molecular profiles with phenotypic analyses are currently under development. Disclosures Evans: Rational Therapeutics: Employment. Nagourney:Rational Therapeutics: Employment.
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