Increased incidence of hematologic malignancies in SCD after HCT in adults with graft failure and mixed chimerism.
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ABSTRACT:
SUBMITTER: Lawal RA
PROVIDER: S-EPMC9837433 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
Publications
Increased incidence of hematologic malignancies in SCD after HCT in adults with graft failure and mixed chimerism.
Lawal Rialnat A RA Mukherjee Devdeep D Limerick Emily M EM Coles Wynona W Hsieh Matthew M MM Dillon Laura W LW Hourigan Christopher S CS Fitzhugh Courtney D CD
Blood 20221201 23
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Project description:Non-myeloablative hematopoietic cell transplantation (HCT) is a curative option for individuals with sickle cell disease (SCD). Our traditional goal with this approach has been to achieve a state of mixed donor/recipient chimerism. Recently, we reported an increased risk of hematologic malignancies (HMs) in adults with SCD following graft failure or mixed chimerism. To evaluate the origin of HMs, we performed chimerism analyses of 5 patients with SCD who developed HMs after non-myeloablative HCT. DNA was extracted from sorted peripheral blood or bone marrow cells representing mature cell lineages or leukemic blasts and subjected to chimerism analysis by PCR amplification of polymorphic short tandem repeats. Unlike mature cell lineages in patients with mixed chimerism, which still showed a donor-derived fraction of cells, leukemic blast cells were found to be 99-100% recipient-derived in all patients. Non-myeloablative conditioning allows for the survival of patients' cells that might harbor pre-leukemic clones that possess the capacity to evolve under genotoxic or environmental stress into malignancies; therefore, we have modified our HCT protocols with the goal of full donor chimerism to mitigate the risk of HM development.
| S-EPMC11759619 | biostudies-literature
Project description:Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared with bone marrow grafts (2.5 vs 7.3%; P<0.001). A fourfold increase of PGF was observed in myeloproliferative disorders compared with acute leukemia (P<0.001). Other risk factors for PGF included recipient age <30, HLA mismatch, male recipients of female donor grafts, ABO incompatibility, busulfan/cyclophosphamide conditioning and cryopreservation. In bone marrow transplants, total nucleated cell doses ⩽2.4 × 10(8) per kg were associated with PGF (odds ratio 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post transplant may provide the rationale for an early request for additional hematopoietic stem cells.
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Project description:In humans receiving intestinal transplantation (ITx), long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early after transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without causing GVHD. Consistently, donor-derived T cells, including GvH clones, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were simultaneously detected in the recipients' BM more than 100 days after transplant. Individual GvH clones appeared in ileal mucosa or PBMCs before detection in recipient BM, consistent with an intestinal mucosal origin, where donor GvH-reactive T cells expanded early upon entry of recipient APCs into the graft. These results, combined with cytotoxic single-cell transcriptional profiles of donor T cells in recipient BM, suggest that tissue-resident GvH-reactive donor T cells migrated into the recipient circulation and BM, where they destroyed recipient hematopoietic cells through cytolytic effector functions and promoted engraftment of graft-derived HSPCs that maintain chimerism. These mechanisms suggest an approach to achieving intestinal allograft tolerance.
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Project description:Allogeneic hematopoietic cell transplantation is a curative procedure for hematologic malignancies but is associated with a significant risk of non-relapse mortality (NRM). The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) is a prognostic tool that discriminates this risk in all age groups. A recent survey of transplant physicians demonstrated that 79% of pediatric providers used the HCT-CI infrequently, and most reported concerns about its applicability in the younger population. We conducted a retrospective study using the Center for International Blood and Marrow Transplant Research database to examine the impact of expanded HCT-CI definitions on NRM in pediatric and young adult patients with hematologic malignancies. We included 5790 patients <40 years old receiving allogeneic transplants between 2008 and 2017 to examine broader definitions of comorbidities in the HCT-CI, including history of mechanical ventilation and fungal infection, estimated glomerular filtration rate, and body mass index (BMI) percentiles. Multivariable Fine-Gray models were created to determine the effect of each HCT-CI defining comorbidity and its modification on NRM and were used to develop 2 novel risk scores. We next developed the expanded HCT-CI for children and young adults (youth with malignancies; expanded ymHCT-CI), where 23% patients had an increased comorbidity score, compared to the HCT-CI. Comorbidities with hazard ratio < 1.2 were then removed to create the simplified HCT-CI for children and young adults (youth with malignancies; simplified ymHCT-CI), which demonstrated higher scores corresponded to a greater risk of NRM (P < .001). These novel comorbidity indexes with broader definitions are more relevant to pediatric and young adult patients, and prospective studies are needed to validate these in the younger patient population. It remains to be seen whether the development of these pediatric-specific and practical risk indexes increases their use by the pediatric transplant community.
| S-EPMC9911376 | biostudies-literature
Project description:IntroductionIn a phase III clinical trial (NCT02730299), omidubicel-onlv, a nicotinamide-modified allogeneic hematopoietic progenitor cell therapy, showed rapid hematopoietic and immune recovery compared with standard umbilical cord blood (UCB) transplant across all racial/ethnic groups.MethodsA decision-tree model was used to project the effect of omidubicel-onlv availability on addressing health disparities in allogeneic hematopoietic cell transplantation (allo-HCT) access and outcomes for patients with hematologic malignancies. The model used a hypothetical population of 10,000 allo-HCT-eligible US adults, for whom matched related donors were not available. Patients received matched or mismatched unrelated donor, haploidentical, UCB transplant, or no transplant. Scenarios with omidubicel-onlv use of 0% (status quo), 10%, 15%, 20%, and 30% were modeled on the basis of proportional reductions in other allo-HCT sources or no transplant by racial/ethnic group.ResultsIncreased omidubicel-onlv use was associated with a higher proportion of patients undergoing allo-HCT, decreased time to allo-HCT, decreased 1-year non-relapse mortality, and increased 1-year overall survival, particularly among racial minorities. In the scenario modeling 20% omidubicel-onlv use, the proportion of Black patients receiving allo-HCT increased by 129%; increases were also observed in Asian (64%), Hispanic (45%), and other (42%) patient groups. Modeled time to allo-HCT improved among transplanted patients (23%) from 11.4 weeks to 8.8 weeks. One-year OS in the overall population increased by 3%, with improvements ranging from 3% for White patients to 5% for Black patients.ConclusionThis study demonstrates that broad access to omidubicel-onlv could increase access to allo-HCT and improve outcomes for patients, with the greatest benefits seen among racial/ethnic minority groups.
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Project description:BackgroundCancer and cardiovascular diseases are the two leading causes of death in industrialized countries. Optimal management of life-threatening presentations of both of their diseases can pose significant challenges. The current study aimed to address the incidence, management, and outcome of acute coronary syndromes (ACS) in patients with active hematological malignancies.MethodsThis retrospective registry-based cohort study included adults with active leukemia or lymphoma who were hospitalized at Mayo Clinic Rochester from 01/01/2004 to 12/31/2014. The diagnosis of ST-segment elevation MI (STEMI) or non-ST-segment elevation MI (NSTEMI) was made based on the 3rd Universal Definition for MI, or of unstable angina (UA) in the absence of cardiac troponin elevation. Main outcome measures included all-cause, cardiac, and non-cardiac death in-hospital and at one year.ResultsOf 5300 adult patients with active hematological malignancies, 73 (1.4%) were diagnosed with an ACS (78.1% NSTEMI and 13.7% STEMI). 17.5% and 40% of NSTEMI and STEMI patients underwent coronary angiography, with percutaneous coronary intervention in 5.3% and 30%, respectively. While >80% of patients received β-blocker therapy, only half of all and <50% of patients managed "medically" received antiplatelet, anticoagulant, and/or statin therapy. The in-hospital and 1-year mortality was 21.9% and 58.9%, respectively, of which 25% and 15% were cardiac in etiology. Aspirin, beta-blocker, statins, and angiotensin-converting enzyme inhibitor/angiotensin-II receptor blocker were associated with better mortality outcomes.ConclusionsIn a large, contemporary study of adults with active hematologic malignancies, ACS was uncommon, but commonly managed not in keeping with societal guideline recommendations.
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Project description:T cell cancer neoantigens are created from peptides derived from cancer-specific aberrant proteins, such as mutated and fusion proteins, presented in complex with human leukocyte antigens on the cancer cell surface. Because expression of the aberrant target protein is exclusive to malignant cells, immunotherapy directed against neoantigens should avoid "on-target, off-tumor" toxicity. The efficacy of neoantigen vaccines in melanoma and glioblastoma and of adoptive transfer of neoantigen-specific T cells in epithelial tumors indicates that neoantigens are valid therapeutic targets. Improvements in sequencing technology and innovations in antigen discovery approaches have facilitated the identification of neoantigens. In comparison to many solid tumors, hematologic malignancies have few mutations and thus fewer potential neoantigens. Despite this, neoantigens have been identified in a wide variety of hematologic malignancies. These include mutated nucleophosmin1 and PML-RARA in acute myeloid leukemia, ETV6-RUNX1 fusions and other mutated proteins in acute lymphoblastic leukemia, BCR-ABL1 fusions in chronic myeloid leukemia, driver mutations in myeloproliferative neoplasms, immunoglobulins in lymphomas, and proteins derived from patient-specific mutations in chronic lymphoid leukemias. We will review advances in the field of neoantigen discovery, describe the spectrum of identified neoantigens in hematologic malignancies, and discuss the potential of these neoantigens for clinical translation.
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Project description:Hematopoietic stem cell transplant (HSCT) is potentially curative for a wide variety of malignant diseases, including acute and leukemias, lymphoma, and myelodysplasia. Choice of a stem cell donor is dependent on donor availability, donor compatibility and health, recipient disease type, and recipient condition. Current sources of stem cell donation for HSCT are matched sibling donors (MSDs), matched unrelated donors (MUDs), 1-antigen mismatched unrelated donors (MMUDs), haploidentical donors (haplo), and umbilical cord blood (UCB) units. Historically, preferred donors for HSCT have been human leukocyte antigen (HLA)-matched sibling donors; however, only about 30% of U.S. patients will have a MSD available. The majority of patients referred for HSCT will require an alternative donor graft: MUD, MMUD, UCB, or haplo. The likelihood of finding a MUD varies depending on the ethnicity of the recipient. White Caucasians of European descent have the greatest chance of finding a MUD. Chances of finding a MUD are significantly less for African-American or Hispanic recipients due to HLA polymorphisms. Therefore, MMUD, UCB, and haplo donor graft sources expand the donor pool for recipients who do not have a MSD or MUD available. Given the variety of different donor stem cell sources available today, nearly every patient who needs an allogeneic HSCT has a potential donor in 2017. All transplant-eligible patients with hematologic malignancies should be evaluated by a transplant center to determine if HSCT is a viable treatment option for their underlying disease process.Implications for practiceThe goal of this review is to increase the awareness of oncology practitioners to the availability of alternative donor stem cell transplants for patients with hematologic malignancies. Despite new agents, stem cell transplant remains the only curative therapy for many patients with acute and chronic leukemia, myelodysplasia, and lymphoma. Given the variety of different donor stem cell sources available today, nearly every patient who needs an allogeneic stem cell transplant will have a donor.
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Project description:Recurrent Glycogen synthase kinase-3 (GSK-3) phosphorylates multiple splicing factors, including SRSF2, and regulates the splicing of a broad range of mRNAs in human cells. Inhibition of GSK-3 disrupts splicing and promotes cell death in hematopoietic cells with heterozygous mutations in SRSF2 and not in cells with wild-type splicing factors. To characterize how GSK-3 inhibition alters the cellular proteome in SRSF2-P95H/+ cells, we have performed quantitative mass spectrometry (qMS) on K562 cells with SRSF2P95H/+ knocked into the endogenous locus (PMID 30799057) and parental K562 cells, treated with the GSK-3 inhibitor CHIR99021. We focused on the mitochondrial proteome using human proteome (UniprotKB) and mitochondrial (MitoCarta 3.0) databases for protein identification, identifying 163 mitochondrial proteins whose levels are affected by SRSF2 mutation.
2024-06-22 | PXD043213 | Pride
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