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Twenty-year Follow-up of Histocompatibility Leukocyte Antigen-matched Kidney and Bone Marrow Cotransplantation for Multiple Myeloma With End-stage Renal Disease: Lessons Learned.

ABSTRACT: BACKGROUND:Specific immune tolerance of transplanted organs in association with either transient or sustained lymphohematopoietic chimerism has been demonstrated in several preclinical animal models and clinically in patients who are full donor chimeras after hematopoietic stem cell transplantation and subsequently received kidney transplants from the same donor. Most recently, tolerance induction has been extended to patients in whom chimerism was intentionally induced at the time of kidney transplantation. METHODS:Twenty years ago, we reported the first successful histocompatibility leukocyte antigen-matched sibling donor bone marrow and kidney transplant following nonmyeloablative conditioning in a patient with multiple myeloma and end-stage renal disease (ESRD). After 2 decades, she has normal renal function in the absence of ongoing systemic immunosuppressive therapy. Nine patients have subsequently undergone similar treatment for multiple myeloma with ESRD. RESULTS:In the initial patient, hematopoietic chimerism was detectable for only 105 days after the transplant. In subsequent patients, chimerism detection ranged from 49 days to >14 years. Nevertheless, a long remission of the myeloma and long-term immunosuppression-free survival of the kidney allograft were achieved in 7 of the 10 patients, 5 of whom currently survive. CONCLUSIONS:This initial patient demonstrated the feasibility of performing combined histocompatibility leukocyte antigen-matched, sibling donor bone marrow and kidney transplantation for ESRD due to multiple myeloma. This experience paved the way for extending the initial trial to 9 additional patients with multiple myeloma and ESRD and, more recently, to tolerance induction strategies involving combined bone marrow and kidney transplantation for patients with and without an underlying malignancy.

SUBMITTER: Spitzer TR

PROVIDER: S-EPMC6690803 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent studies have suggested that plasma-derived proteins may be potential biomarkers relevant for graft-versus-host disease and/or non-relapse mortality occurring after allogeneic blood or marrow transplantation. However, none of these putative biomarkers have been assessed in patients treated either with human leukocyte antigen-haploidentical blood or marrow transplantation or with post-transplantation cyclophosphamide, which has been repeatedly associated with low rates of severe acute graft-versus-host disease, chronic graft-versus-host disease, and non-relapse mortality. We explored whether seven of these plasma-derived proteins, as measured by enzyme-linked immunosorbent assays, were predictive of clinical outcomes in post-transplantation cyclophosphamide-treated patients using plasma samples collected at serial predetermined timepoints from patients treated on prospective clinical studies of human leukocyte antigen-haploidentical (n=58; clinicaltrials.gov Identifier: 00796562) or human leukocyte antigen-matched-related or -unrelated (n=100; clinicaltrials.gov Identifiers: 00134017 and 00809276) T-cell-replete bone marrow transplantation. Day 30 levels of interleukin-2 receptor ?, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-? all had high areas under the curve of 0.74-0.97 for predicting non-relapse mortality occurrence by 3 months post-transplant in both the human leukocyte antigen-matched and human leukocyte antigen-haploidentical cohorts. In both cohorts, all four of these proteins were also predictive of subsequent non-relapse mortality occurring by 6, 9, or 12 months post-transplant and were significantly associated with non-relapse mortality in univariable analyses. Furthermore, day 30 elevations of interleukin-2 receptor ? were associated with grade II-IV and III-IV acute graft-versus-host disease occurring after day 30 in both cohorts. These data confirm that plasma-derived proteins previously assessed in other transplantation platforms appear to retain prognostic and predictive utility in patients treated with post-transplantation cyclophosphamide.

Project description:BackgroundThe COVID-19 pandemic, caused by SARS-CoV-2 virus, has resulted in over 100,000 deaths in the USA. Our institution has treated over 2000 COVID-19 patients during the pandemic in New York City. The pandemic directly impacted cancer patients and the organization of cancer care. Mount Sinai Hospital has a large and diverse multiple myeloma (MM) population. Herein, we report the characteristics of COVID-19 infection and serological response in MM patients in a large tertiary care institution in New York.MethodsWe performed a retrospective study on a cohort of 58 patients with a plasma-cell disorder (54 MM, 4 smoldering MM) who developed COVID-19 between March 1, 2020, and April 30, 2020. We report epidemiological, clinical, and laboratory characteristics including the persistence of viral detection by polymerase chain reaction (PCR) and anti-SARS-CoV-2 antibody testing, treatments initiated, and outcomes.ResultsOf the 58 patients diagnosed with COVID-19, 36 were hospitalized and 22 were managed at home. The median age was 67 years; 52% of patients were male and 63% were non-White. Hypertension (64%), hyperlipidemia (62%), obesity (37%), diabetes mellitus (28%), chronic kidney disease (24%), and lung disease (21%) were the most common comorbidities. In the total cohort, 14 patients (24%) died. Older age (> 70 years), male sex, cardiovascular risk, and patients not in complete remission (CR) or stringent CR were significantly (p < 0.05) associated with hospitalization. Among hospitalized patients, laboratory findings demonstrated elevation of traditional inflammatory markers (CRP, ferritin, D-dimer) and a significant (p < 0.05) association between elevated inflammatory markers, severe hypogammaglobulinemia, non-White race, and mortality. Ninety-six percent (22/23) of patients developed antibodies to SARS-CoV-2 at a median of 32 days after initial diagnosis. The median time to PCR negativity was 43 (range 19-68) days from initial positive PCR.ConclusionsDrug exposure and MM disease status at the time of contracting COVID-19 had no bearing on mortality. Mounting a severe inflammatory response to SARS-CoV-2 and severe hypogammaglobulinemia was associated with higher mortality. The majority of patients mounted an antibody response to SARS-CoV-2. These findings pave a path to the identification of vulnerable MM patients who need early intervention to improve outcomes in future outbreaks of COVID-19.

Project description:The COVID-19 pandemic, caused by SARS-CoV-2 virus, has resulted in over 100,000 deaths in the United States. Our institution has treated over 2,000 COVID-19 patients during the pandemic in New York City. The pandemic directly impacted cancer patients and the organization of cancer care. Mount Sinai Hospital has a large and diverse multiple myeloma (MM) population. Herein, we report the characteristics of COVID-19 infection and serological response in MM patients in a large tertiary care institution in New York. We performed a retrospective study on a cohort of 58 patients with a plasma-cell disorder (54 MM, 4 smoldering MM) who developed COVID-19 between March 1, 2020 and April 30, 2020. We report epidemiological, clinical and laboratory characteristics including persistence of viral detection by polymerase chain reaction (PCR) and anti-SARS-CoV-2 antibody testing, treatments initiated, and outcomes. Of the 58 patients diagnosed with COVID-19, 36 were hospitalized and 22 were managed at home. The median age was 67 years; 52% of patients were male and 63% were non-white. Hypertension (64%), hyperlipidemia (62%), obesity (37%), diabetes mellitus (28%), chronic kidney disease (24%) and lung disease (21%) were the most common comorbidities. In the total cohort, 14 patients (24%) died. Older age (>70 years), male sex, cardiovascular risk, and patients not in complete remission (CR) or stringent CR were significantly (p<0.05) associated with hospitalization. Among hospitalized patients, laboratory findings demonstrated elevation of traditional inflammatory markers (CRP, ferritin, D-dimer) and a significant (p<0.05) association between elevated inflammatory markers, severe hypogammaglobulinemia, non-white race, and mortality. Ninety-six percent (22/23) of patients developed antibodies to SARS-CoV-2 at a median of 32 days after initial diagnosis. Median time to PCR negativity was 43 (range 19-68) days from initial positive PCR. Drug exposure and MM disease status at the time of contracting COVID-19 had no bearing on mortality. Mounting a severe inflammatory response to SARS-CoV-2 and severe hypogammaglobulinemia were associated with higher mortality. The majority of patients mounted an antibody response to SARS-CoV-2. These findings pave a path to identification of vulnerable MM patients who need early intervention to improve outcome in future outbreaks of COVID-19.

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Twenty-year Follow-up of Histocompatibility Leukocyte Antigen-matched Kidney and Bone Marrow Cotransplantation for Multiple Myeloma With End-stage Renal Disease: Lessons Learned.

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