Publications by authors named "D A Rizzieri"

215 Publications

Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.

Transplant Cell Ther 2021 May 12. Epub 2021 May 12.

Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina. Electronic address:

Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies but is associated with significant morbidity and mortality. Although deaths during the first year after transplantation are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased graft-versus-host disease, and lower relapse rates. Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplantation versus matched related donor (MRD) and matched unrelated donor (MUD) transplantation in patients with hematologic malignancies over a 20-year period. In this single-center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant program from January 1, 1996, to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 after HCT, received an allogeneic HCT for a disease other than a hematologic malignancy, or received cells from a haploidentical or mismatched adult donor. UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank P = .03, median overall survival: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (hazard ratio, 0.69; 95% confidence interval, 0.47-0.99; P = .049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and nonrelapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.05.002DOI Listing
May 2021

A phase 1 study of the pan-bromodomain and extraterminal inhibitor mivebresib (ABBV-075) alone or in combination with venetoclax in patients with relapsed/refractory acute myeloid leukemia.

Cancer 2021 May 2. Epub 2021 May 2.

Division of Hematology and Oncology, Department of Internal Medicine, University of California-Davis School of Medicine, Sacramento, California.

Background: Acute myeloid leukemia (AML) is a heterogenous malignancy driven by genetic and epigenetic factors. Inhibition of bromodomain and extraterminal (BET) proteins, epigenetic readers that play pivotal roles in the regulation of genes relevant to cancer pathogenesis, constitutes a novel AML treatment approach.

Methods: In this first-in-human study of the pan-BET inhibitor mivebresib as monotherapy (MIV-mono) or in combination with venetoclax (MIV-Ven), the safety profile, efficacy, and pharmacodynamics of mivebresib were determined in patients with relapsed/refractory AML (ClinicalTrials.gov identifier NCT02391480). Mivebresib was administered at 3 monotherapy dose levels (1.5, 2.0, or 2.5 mg) or in combination with venetoclax (400 or 800 mg).

Results: Forty-four patients started treatment: of 19 who started MIV-mono, 5 went on to receive MIV-Ven combination therapy after disease progression and a washout period. Twenty-five patients started MIV-Ven, resulting in a total of 30 patients treated with the combination. The most common mivebresib-related treatment-emergent adverse events were dysgeusia (74%), decreased appetite (42%), and diarrhea (42%) in the MIV-mono group and decreased appetite (44%), vomiting (44%), and nausea (40%) in the MIV-Ven group. Serious adverse events occurred in 14 patients (74%) who received MIV-mono and in 22 patients (88%) who received MIV-Ven. In the MIV-mono group, responses were complete remission with incomplete blood count recovery in 1 patient and resistant disease in 15 patients. In the MIV-Ven group, responses were complete remission in 2 patients, partial remission in 2 patients, morphologic leukemia-free state in 2 patients, resistant disease in 12 patients, and aplasia in 1 patient. The pharmacodynamic effects of mivebresib were proportional to dose and drug exposure.

Conclusions: Mivebresib was tolerated and showed antileukemic effects as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML.

Lay Summary: Mivebresib is a novel drug that influences the way cancer cells read genetic information. Mivebresib was tested together with venetoclax in patients with acute myeloid leukemia after standard medicines failed and the disease returned, or when standard medicine was unavailable. Adverse effects were described for different drug doses, and the dose that is tolerable was determined. In some patients, their leukemia improved for some time. More studies are necessary to determine whether mivebresib can be used to treat acute myeloid leukemia.
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http://dx.doi.org/10.1002/cncr.33590DOI Listing
May 2021