Browsing by Author "Gasparetto, Cristina"

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    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, 2021-05-12) Bohannon, Lauren; Tang, Helen; Page, Kristin; Ren, Yi; Jung, Sin-Ho; Artica, Alexandra; Britt, Anne; Islam, Prioty; Siamakpour-Reihani, Sharareh; Giri, Vinay; Lew, Meagan; Kelly, Matthew; Choi, Taewoong; Gasparetto, Cristina; Long, Gwynn; Lopez, Richard; Rizzieri, David; Sarantopoulos, Stefanie; Chao, Nelson; Horwitz, Mitchell; Sung, Anthony
    BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies, but is associated with significant morbidity and mortality. While deaths during the first year after transplant 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 GVHD, and lower relapse rates. OBJECTIVES: Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplant vs. matched related donor (MRD) and matched unrelated donor (MUD) transplant in patients with hematologic malignancies over a 20-year period. STUDY DESIGN: 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 (ABMT) 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 post-HCT; received an allogeneic HCT for a disease other than a hematologic malignancy; or received cells from a haploidentical or mismatched adult donor. RESULTS: UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank p=0.03, Figure 1, median OS: 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 (HR: 0.69, 95% CI: 0.47-0.99, p=0.049). 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 non-relapse 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. CONCLUSIONS: 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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    Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial.
    (Nature medicine, 2023-10) Bahlis, Nizar J; Costello, Caitlin L; Raje, Noopur S; Levy, Moshe Y; Dholaria, Bhagirathbhai; Solh, Melhem; Tomasson, Michael H; Damore, Michael A; Jiang, Sibo; Basu, Cynthia; Skoura, Athanasia; Chan, Edward M; Trudel, Suzanne; Jakubowiak, Andrzej; Gasparetto, Cristina; Chu, Michael P; Dalovisio, Andrew; Sebag, Michael; Lesokhin, Alexander M
    Multiple myeloma (MM) is a plasma cell malignancy expressing B cell maturation antigen (BCMA). Elranatamab, a bispecific antibody, engages BCMA on MM and CD3 on T cells. The MagnetisMM-1 trial evaluated its safety, pharmacokinetics and efficacy. Primary endpoints, including the incidence of dose-limiting toxicities as well as objective response rate (ORR) and duration of response (DOR), were met. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Eighty-eight patients with relapsed or refractory MM received elranatamab monotherapy, and 55 patients received elranatamab at efficacious doses. Patients had received a median of five prior regimens; 90.9% were triple-class refractory, 29.1% had high cytogenetic risk and 23.6% received prior BCMA-directed therapy. No dose-limiting toxicities were observed during dose escalation. Adverse events included cytopenias and cytokine release syndrome. Exposure was dose proportional. With a median follow-up of 12.0 months, the ORR was 63.6% and 38.2% of patients achieving complete response or better. For responders, the median DOR was 17.1 months. All 13 patients evaluable for minimal residual disease achieved negativity. Even after prior BCMA-directed therapy, 53.8% achieved response. For all 55 patients, median PFS was 11.8 months, and median OS was 21.2 months. Elranatamab achieved durable responses, manageable safety and promising survival for patients with MM. ClinicalTrials.gov Identifier: NCT03269136 .
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    Morphologic leukemia-free state in acute myeloid leukemia is sufficient for successful allogeneic hematopoietic stem cell transplant.
    (Blood cancer journal, 2021-05-16) Pabon, Cindy M; Li, Zhiguo; Hennig, Therese; de Castro, Carlos; Neff, Jadee L; Horwitz, Mitchell E; LeBlanc, Thomas W; Long, Gwynn D; Lopez, Richard D; Sung, Anthony D; Chao, Nelson; Gasparetto, Cristina; Sarantopoulos, Stefanie; Adams, Donna B; Erba, Harry; Rizzieri, David A
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    Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.
    (J Hematol Oncol, 2018-03-04) Green, Michael MB; Chao, Nelson; Chhabra, Saurabh; Corbet, Kelly; Gasparetto, Cristina; Horwitz, Ari; Li, Zhiguo; Venkata, Jagadish Kummetha; Long, Gwynn; Mims, Alice; Rizzieri, David; Sarantopoulos, Stefanie; Stuart, Robert; Sung, Anthony D; Sullivan, Keith M; Costa, Luciano; Horwitz, Mitchell; Kang, Yubin
    BACKGROUND: The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation. METHODS: We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. RESULTS: Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls. CONCLUSIONS: Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280955.
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    Selinexor-based regimens in patients with multiple myeloma after prior anti-B-cell maturation antigen treatment.
    (EJHaem, 2022-11) Baljevic, Muhamed; Gasparetto, Cristina; Schiller, Gary J; Tuchman, Sascha A; Callander, Natalie S; Lentzsch, Suzanne; Monge, Jorge; Kotb, Rami; Bahlis, Nizar J; White, Darrell; Chen, Christine I; Sutherland, Heather J; Madan, Sumit; LeBlanc, Richard; Sebag, Michael; Venner, Christopher P; Bensinger, William I; Biran, Noa; DeCastro, Andrew; Van Domelen, Dane R; Zhang, Chris; Shah, Jatin J; Shacham, Sharon; Kauffman, Michael G; Bentur, Ohad S; Lipe, Brea
    There is a lack of consensus on therapy sequencing in previously treated multiple myeloma, particularly after anti-B-cell maturation antigen (BCMA) therapy. Earlier reports on selinexor (X) regimens demonstrated considerable efficacy in early treatment, and after anti-BCMA-targeted chimeric antigen receptor-T cell therapy. Here, we present data from 11 heavily pretreated patients who predominantly received BCMA-antibody-drug conjugate therapy. We observe that X-containing regimens are potent and achieve durable responses with numerically higher overall response and clinical benefit rates, as well as median progression free survival compared to patients' prior anti-BCMA therapies, despite being used later in the treatment course. In an area of evolving unmet need, these data reaffirm the efficacy of X-based regimens following broader anti-BCMA therapy.
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    Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.
    (The Journal of clinical investigation, 2014-07) Horwitz, Mitchell E; Chao, Nelson J; Rizzieri, David A; Long, Gwynn D; Sullivan, Keith M; Gasparetto, Cristina; Chute, John P; Morris, Ashley; McDonald, Carolyn; Waters-Pick, Barbara; Stiff, Patrick; Wease, Steven; Peled, Amnon; Snyder, David; Cohen, Einat Galamidi; Shoham, Hadas; Landau, Efrat; Friend, Etty; Peleg, Iddo; Aschengrau, Dorit; Yackoubov, Dima; Kurtzberg, Joanne; Peled, Tony

    Background

    Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.

    Methods

    In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.

    Results

    No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.

    Conclusion

    UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.

    Trial registration

    Clinicaltrials.gov NCT01221857.

    Funding

    Gamida Cell Ltd.