Publications by authors named "Betty Hamilton"

94 Publications

Chronic Graft-Versus-Host Disease, Non-Relapse Mortality and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A CIBMTR Analysis.

Transplant Cell Ther 2021 Oct 9. Epub 2021 Oct 9.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: The effect of chronic graft-versus-host disease (cGVHD) on the risk of non-relapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (≥60 years).

Methods: We included 4429 adults ≥40 years who received first HLA-matched peripheral blood alloHCT for acute myeloid leukemia or myelodysplastic syndrome between the years 2008-2017. We compared outcomes of 4 groups: older adults (≥60 years) and younger adults (40-59 years) with or without cGVHD to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse and overall survival (OS). We treated cGVHD as a time-dependent covariate. Severity of cGVHD was based on the CIBMTR clinical definitions.

Results: cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher among older versus younger adults. Adults who developed cGVHD as a group had longer OS, compared to age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild and moderate cGVHD were associated with longer OS.

Conclusions: Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse and longer OS. Older adults had a higher risk of NRM but the increased risk of NRM associated with cGVHD did not differ based on age. Development of mild-moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing relapses. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important.
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http://dx.doi.org/10.1016/j.jtct.2021.10.002DOI Listing
October 2021

Initial therapy of chronic graft vs. host disease: Analysis of practice variation and failure-free survival.

Blood Adv 2021 Sep 17. Epub 2021 Sep 17.

Fred Hutchinson Cancer Research Center, SEATTLE, Washington, United States.

Prior clinical trials largely considered prednisone 1mg/kg/day with or without calcineurin inhibitor as standard initial therapy for chronic graft vs. host disease (cGVHD) but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 cGVHD patients treated with initial systemic immune suppressive (IS) therapy from three prior Chronic GVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥ 0.4mg/kg/day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were non-prednisone IS therapies (n=137, 18%), prednisone alone (n=411, 55%), or prednisone plus other IS therapy (n=197, 26%). In multivariate analysis, initial therapy group was not associated with FFS (failure-free survival, a composite of death, relapse, new IS therapy), overall survival (OS) or non-relapse mortality (NRM). Among the prednisone-based approaches, steroid dose (mg/kg/day) was <0.25 (9%), 0.25-0.74 (36%), 0.75-1.25 (42%), or >1.25 (13%). Prednisone dose within the steroid-treated patients was not significantly associated with FFS, OS, or NRM. No significant interactions were detected between overall cGVHD severity and either initial therapy group or prednisone dose for the outcomes of FFS, OS, or NRM. These observational data document heterogeneity in more contemporary cGVHD initial treatment practices, including prednisone dose and use of non-steroid approaches. This variation was not associated with FFS, OS, or NRM. Prospective trials are needed to verify efficacy of reduced-dose prednisone or prednisone-free initial therapy approaches.
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http://dx.doi.org/10.1182/bloodadvances.2021005286DOI Listing
September 2021

Non-relapse mortality among patients diagnosed with chronic GVHD: An updated analysis from The Chronic GVHD Consortium.

Blood Adv 2021 Sep 14. Epub 2021 Sep 14.

Cleveland Clinic, Cleveland, Ohio, United States.

Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for non-relapse mortality (NRM), we analyzed patient, transplant, and chronic GVHD-related variables, risk factors, and causes of non-relapse deaths in an updated cohort of 937 subjects enrolled on two prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (0.1 months - 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years and increased over time with a projected 40% (95%CI, 30-50) at 12 years. Centers reported that chronic GVHD (37.8%) was the commonest cause of NRM and was associated with organ failure, infection, or additional cause not otherwise specified. The next most frequent causes without mention of chronic GVHD were infection (17%) and respiratory failure (10%). In multivariate analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, NIH skin score 2-3, NIH lung score 1-3, worse modified HAP adjusted activity score, and decreased distance on walk test. In conclusion, chronic GVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung chronic GVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options are needed that do not predispose patients to infections.
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http://dx.doi.org/10.1182/bloodadvances.2021004941DOI Listing
September 2021

Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2021: Looking Forward as the Network Celebrates its 20th Year.

Transplant Cell Ther 2021 Aug 27. Epub 2021 Aug 27.

Center for International Blood & Marrow Transplant Research, Minneapolis, Minnesota.

In 2021 the BMT CTN held the 4th State of the Science Symposium where the deliberations of 11 committees concerning major topics pertinent to a particular disease, modality, or complication of transplant, as well as two committees to consider clinical trial design and inclusion, diversity, and access as cross-cutting themes were reviewed. This article summarizes the individual committee reports and their recommendations on the highest priority questions in hematopoietic stem cell transplant and cell therapy to address in multicenter trials.
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http://dx.doi.org/10.1016/j.jtct.2021.08.016DOI Listing
August 2021

Personalized Prediction Model to Risk Stratify Patients With Myelodysplastic Syndromes.

J Clin Oncol 2021 Aug 18:JCO2002810. Epub 2021 Aug 18.

Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.

Purpose: Patients with myelodysplastic syndromes (MDS) have a survival that can range from months to decades. Prognostic systems that incorporate advanced analytics of clinical, pathologic, and molecular data have the potential to more accurately and dynamically predict survival in patients receiving various therapies.

Methods: A total of 1,471 MDS patients with comprehensively annotated clinical and molecular data were included in a training cohort and analyzed using machine learning techniques. A random survival algorithm was used to build a prognostic model, which was then validated in external cohorts. The accuracy of the proposed model, compared with other established models, was assessed using a concordance (c)index.

Results: The median age for the training cohort was 71 years. Commonly mutated genes included , , and . The algorithm identified chromosomal karyotype, platelet, hemoglobin levels, bone marrow blast percentage, age, other clinical variables, seven discrete gene mutations, and mutation number as having prognostic impact on overall and leukemia-free survivals. The model was validated in an independent external cohort of 465 patients, a cohort of patients with MDS treated in a prospective clinical trial, a cohort of patients with paired samples at different time points during the disease course, and a cohort of patients who underwent hematopoietic stem-cell transplantation.

Conclusion: A personalized prediction model on the basis of clinical and genomic data outperformed established prognostic models in MDS. The new model was dynamic, predicting survival and leukemia transformation probabilities at different time points that are unique for a given patient, and can upstage and downstage patients into more appropriate risk categories.
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http://dx.doi.org/10.1200/JCO.20.02810DOI Listing
August 2021

Post-Transplantation Cyclophosphamide: An Old Nemesis to a New Transplant Paradigm?

JACC CardioOncol 2021 Jun 15;3(2):260-262. Epub 2021 Jun 15.

Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

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http://dx.doi.org/10.1016/j.jaccao.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352273PMC
June 2021

Influence of Killer Immunoglobulin-Like Receptors and Somatic Mutations on Transplant Outcomes in Acute Myeloid Leukemia.

Transplant Cell Ther 2021 Aug 8. Epub 2021 Aug 8.

Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Natural killer (NK) cells are regulated by killer immunoglobulin-like receptor (KIR) interactions with human leukocyte antigen class I ligands. Various models of NK cell alloreactivity have been associated with outcomes after allogeneic hematopoietic cell transplant (alloHCT), but results have varied widely. We hypothesized that somatic mutations in acute myeloid leukemia (AML) in the context of KIR profiles may further refine their association with transplant outcomes. In this single-center, retrospective, observational study, 81 AML patients who underwent matched-related donor alloHCT were included. Post-HCT outcomes were assessed based on mutational status and KIR profiles with the Kaplan-Meier method and log-rank test. On multivariable analysis those with any somatic mutations and C1/C2 heterozygosity had less acute graft-versus-host disease (GvHD) (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14-0.75; P = .009), more relapse (HR, 3.02; 95% CI, 1.30-7.01; P = .010), inferior relapse-free survival (RFS; HR, 2.22; 95% CI, 1.17-4.20; P = .014), and overall survival (OS; HR, 2.21; 95% CI, 1.17-4.20; P = .015), whereas those with a missing KIR ligand had superior RFS (HR, 0.53; 95% CI, 0.30-0.94; P = .031). The presence of a somatic mutation and donor haplotype A was also associated with less acute GvHD (HR, 0.38; 95% CI, 0.16-0.92; P = .032), more relapse (HR, 2.72; 95% CI, 1.13-6.52; P = .025), inferior RFS (HR, 2.11; 95% CI, 1.07-4.14; P = .030), and OS (HR, 2.20; 95% CI, 1.11-4.38; P = .024). Enhanced NK cell alloreactivity from more KIR activating signals (donor B haplotype) and fewer inhibitory signals (recipient missing KIR ligand or C1 or C2 homozygosity) may help mitigate the adverse prognosis associated with some AML somatic mutations. These results may have implications for improving patient risk stratification prior to transplant and optimizing donor selection.
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http://dx.doi.org/10.1016/j.jtct.2021.08.002DOI Listing
August 2021

Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy.

Transplant Cell Ther 2021 08;27(8):642-649

West Virginia University, Morgantown, West Virginia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized.
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http://dx.doi.org/10.1016/j.jtct.2021.04.007DOI Listing
August 2021

Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation.

JCI Insight 2021 Jul 8;6(13). Epub 2021 Jul 8.

Translational Hematology and Oncology Research Program, Department of Hematology and Oncology, Cleveland Clinic, Cleveland, Ohio, USA.

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR Vβ sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.
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http://dx.doi.org/10.1172/jci.insight.149080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410023PMC
July 2021

Systematic Reviews in Hematopoietic Cell Transplantation and Cellular Therapy: Considerations and Guidance from the American Society for Transplantation and Cellular Therapy, European Society for Blood and Marrow Transplantation, and Center for International Blood and Marrow Transplant Research Late Effects and Quality of Life Working Committee.

Transplant Cell Ther 2021 05 28;27(5):380-388. Epub 2021 Jan 28.

Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin. Electronic address:

Systematic reviews apply rigorous methodologies to address a prespecified, clearly formulated clinical research question. The conclusion that results is often cited to more robustly inform decision making by clinicians, third-party payers, and managed care organizations about the clinical question of interest. Although systematic reviews provide a rigorous standard, they may be infeasible when the task is to create general disease-focused guidelines comprising multiple clinical practice questions versus a single major clinical practice question. Collaborating transplantation and cellular therapy society committees also recognize that the quantity and or quality of reference sources may be insufficient for a meaningful systematic review. As the conduct of systematic reviews has evolved over time in terms of grading systems, reporting requirements, and use of technology, here we provide current guidance on methodologies, resources for reviewers, and approaches to overcome challenges in conducting systematic reviews in transplantation and cellular therapy.
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http://dx.doi.org/10.1016/j.jtct.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415092PMC
May 2021

Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States.

Transplant Cell Ther 2021 08 22;27(8):679.e1-679.e8. Epub 2021 Apr 22.

Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, Minnesota.

Young adult (YA) survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk for late psychosocial challenges, including the inability to return to work post-HCT. Work-related outcomes in this population remain understudied, however. We conducted this study to assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YAs and to analyze the patient-, disease-, and HCT-related factors associated with their work status at 1 year post-HCT. Using Center for International Blood and Marrow Transplant Research data, we evaluated the post-HCT work status (full-time, part-time work, unemployed, or medical disability) of 1365 YA HCT survivors who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at 4 time points: 6 months, 1 year, 2 years, and 3 years post-HCT. Percentages of post-HCT work status categories at the 1-year time point were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. From 6 months to 3 years post-HCT, the percentage of survivors working full-time increased from 18.3% to 50.7% and the percentage working part-time increased from 6.9% to 10.5%. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1 year post-HCT. Female sex (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.40 to 0.77), HCT Comorbidity Index score ≥3 (OR, 0.57; 95% CI, 0.39 to 0.82), pre-HCT unemployment (OR, 0.37; 95% CI, 0.24 to 0.56), medical disability (OR, 0.44; 95% CI, 0.28 to 0.70), development of grade III-IV acute graft-versus-host disease (OR, 0.52; 95% CI, 0.34 to 0.80), and relapse within 1 year post-HCT (OR, 0.34; 95% CI, 0.21 to 0.56) were associated with a lower likelihood of employment at 1 year post-HCT. Compared with myeloablative conditioning (MAC) with total body irradiation (TBI), MAC without TBI (OR, 1.71; 95% CI, 1.16 to 2.53) was associated with a greater likelihood of employment at 1 year post-HCT. Graduate school-level education (OR, 2.47; 95% CI, 1.49 to 4.10) was also associated with a greater likelihood of employment at 1 year post-HCT. Although the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective interventions to support return to work in this population.
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http://dx.doi.org/10.1016/j.jtct.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425287PMC
August 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report.

Transplant Cell Ther 2021 06 2;27(6):452-466. Epub 2021 Mar 2.

Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Durham, North Carolina. Electronic address:

Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials.
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http://dx.doi.org/10.1016/j.jtct.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217141PMC
June 2021

Systematic reviews in hematopoietic cell transplantation and cellular therapy: considerations and guidance from the American Society for Transplantation and Cellular Therapy, European Society for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research late effects and quality of life working committee.

Bone Marrow Transplant 2021 04 29;56(4):786-797. Epub 2021 Jan 29.

Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA.

Systematic reviews apply rigorous methodologies to address a pre-specified, clearly formulated clinical research question. The conclusion that results is often cited to more robustly inform decision-making by clinicians, third-party payers and managed care organizations about the clinical question of interest. While systematic reviews provide a rigorous standard, they may be unfeasible when the task is to create general disease-focused guidelines comprised of multiple clinical practice questions versus a single major clinical practice question. Collaborating transplantation and cellular therapy societal committees also recognize that the quantity and or quality of reference sources may be insufficient for a meaningful systematic review. As the conduct of systematic reviews has evolved over time in terms of grading systems, reporting requirements and use of technology, here we provide current guidance in methodologies, resources for reviewers, and approaches to overcome challenges in conducting systematic reviews in transplantation and cellular therapy.
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http://dx.doi.org/10.1038/s41409-020-01199-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168056PMC
April 2021

Outcomes and factors impacting use of axicabtagene ciloleucel in patients with relapsed or refractory large B-cell lymphoma: results from an intention-to-treat analysis.

Leuk Lymphoma 2021 06 29;62(6):1344-1352. Epub 2020 Dec 29.

Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Data on real-world outcomes of axicabtagene ciloleucel (axi-cel) therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL) are limited. In this intent to treat (ITT) analysis, we reviewed records of 38 consecutive patients with R/R LBCL for whom axi-cel was intended. Twenty-seven (71%) patients received axi-cel and 11 (29%) did not. Patients in the non-axi-cel group had a higher hematopoietic cell transplantation comorbidity index (HCT-CI) (median 4 vs. 2,  = .04). Median overall survival for the ITT, axi-cel and non-axi-cel group was 10 (95% CI, 3.7 to 13), 13 (95% CI, 7.7 to N.R.) and 1 (95% CI, 0.4 to 3.7) month(s) respectively. Factors limiting axi-cel use were disease progression, sepsis, manufacturing failure and socioeconomic barrier in 6 (55%), 3 (27%), 1 (9%) and 1 (9%) patient(s) respectively. Additional strategies are needed to ensure all LBCL patients for whom chimeric antigen receptor (CAR) T-cell therapy is prescribed can receive this treatment.
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http://dx.doi.org/10.1080/10428194.2020.1864349DOI Listing
June 2021

Survival following relapse after allogeneic hematopoietic cell transplantation for acute leukemia and myelodysplastic syndromes in the contemporary era.

Hematol Oncol Stem Cell Ther 2020 Dec 5. Epub 2020 Dec 5.

Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Objective/background: Relapse is the most common cause of treatment failure after allogeneic hematopoietic cell transplantation (alloHCT). No standard of care exists, and a wide range of treatments are used for post-alloHCT relapse. In the recent era, several novel therapies including targeted agents are available for acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS).

Methods: We reviewed outcomes after alloHCT relapse, with or without use of these newer agents for ALL, AML, and MDS. In total, 115 adults with relapsed or refractory ALL (n = 17), AML (n = 67), and MDS (n = 31) at median 5 (range, 1-64) months after their first alloHCT in 2010-2018 were included.

Results: Median follow-up was 19 (range, 6-80) months after relapse from alloHCT. Targeted agents were given to 29 (25%) patients. In multivariable analysis, use of targeted agent at any time point after relapse was not associated with survival. Matched unrelated (vs. matched sibling; hazard ratio [HR] 1.70; p = .027) or haploidentical donor grafts (vs. matched sibling; HR 2.69; p = .003), presence of grade II-IV acute graft-versus-host disease before relapse (HR 2.46; p < .001), and less than 12 months from HCT to relapse (<6 vs. > 12 months; HR 6.34; p < .001; 6-12 vs. > 12 months; HR 3.16; p = .005) were adverse prognostic factors for post-relapse survival.

Conclusion: Outcomes after alloHCT relapse remain poor regardless of the novel agent use. Innovative treatment strategies are needed to improve outcomes after relapse post-alloHCT.
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http://dx.doi.org/10.1016/j.hemonc.2020.11.006DOI Listing
December 2020

Comparison of outcomes of HCT in blast phase of BCR-ABL1- MPN with de novo AML and with AML following MDS.

Blood Adv 2020 10;4(19):4748-4757

Department of Hematology and Oncology, Dokkyo Medical University, Tochigi, Japan.

Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1- myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation-based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.
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http://dx.doi.org/10.1182/bloodadvances.2020002621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556156PMC
October 2020

Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy.

Transplant Cell Ther 2021 01 20;27(1):6-20. Epub 2020 Sep 20.

EBMT Paris Study Office, Paris, France; Chaim Sheba Medical Center, Tel Hashomer, Israel.

The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.020DOI Listing
January 2021

A Personalized Prediction Model for Outcomes after Allogeneic Hematopoietic Cell Transplant in Patients with Myelodysplastic Syndromes.

Biol Blood Marrow Transplant 2020 11 8;26(11):2139-2146. Epub 2020 Aug 8.

Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Mortality after HCT is high, with deaths related to relapse or transplant-related complications. Thus, identifying patients who may or may not benefit from HCT is clinically important. We identified 1514 patients with MDS enrolled in the Center for International Blood and Marrow Transplant Research Registry and had their peripheral blood samples sequenced for the presence of 129 commonly mutated genes in myeloid malignancies. A random survival forest algorithm was used to build the model, and the accuracy of the proposed model was assessed by concordance index. The median age of the entire cohort was 59 years. The most commonly mutated genes were ASXL1(20%), TP53 (19%), DNMT3A (15%), and TET2 (12%). The algorithm identified the following variables prior to HCT that impacted overall survival: age, TP53 mutations, absolute neutrophils count, cytogenetics per International Prognostic Scoring System-Revised, Karnofsky performance status, conditioning regimen, donor age, WBC count, hemoglobin, diagnosis of therapy-related MDS, peripheral blast percentage, mutations in RAS pathway, JAK2 mutation, number of mutations/sample, ZRSR2, and CUX1 mutations. Different variables impacted the risk of relapse post-transplant. The new model can provide survival probability at different time points that are specific (personalized) for a given patient based on the clinical and mutational variables that are listed above. The outcomes' probability at different time points may aid physicians and patients in their decision regarding HCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609542PMC
November 2020

Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network.

Leukemia 2021 04 7;35(4):1023-1036. Epub 2020 Aug 7.

Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a deoxynucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). Here, upon serial analyses of DNMT1 levels in patients' bone marrows on-therapy, we found DNMT1 was not depleted at relapse. Showing why, bone marrows at relapse exhibited shifts in expression of key pyrimidine metabolism enzymes in directions adverse to pro-drug activation. Further investigation revealed the origin of these shifts. Pyrimidine metabolism is a network that senses and regulates deoxynucleotide amounts. Deoxynucleotide amounts were disturbed by single exposures to decitabine or 5-azacytidine, via off-target depletion of thymidylate synthase and ribonucleotide reductase respectively. Compensating pyrimidine metabolism shifts peaked 72-96 h later. Continuous pro-drug exposures stabilized these adaptive metabolic responses to thereby prevent DNMT1-depletion and permit exponential leukemia out-growth as soon as day 40. The consistency of the acute metabolic responses enabled exploitation: simple treatment modifications in xenotransplant models of chemorefractory leukemia extended noncytotoxic DNMT1-depletion and leukemia control by several months. In sum, resistance to decitabine and 5-azacytidine originates from adaptive responses of the pyrimidine metabolism network; these responses can be anticipated and thus exploited.
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http://dx.doi.org/10.1038/s41375-020-1003-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867667PMC
April 2021

Bone Health Management After Hematopoietic Cell Transplantation: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2020 10 9;26(10):1784-1802. Epub 2020 Jul 9.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington.

Bone health disturbances commonly occur after hematopoietic cell transplantation (HCT) with loss of bone mineral density (BMD) and avascular necrosis (AVN) foremost among them. BMD loss is related to pretransplantation chemotherapy and radiation exposure and immunosuppressive therapy for graft-versus-host-disease (GVHD) and results from deficiencies in growth or gonadal hormones, disturbances in calcium and vitamin D homeostasis, as well as osteoblast and osteoclast dysfunction. Although the pathophysiology of AVN remains unclear, high-dose glucocorticoid exposure is the most frequent association. Various societal treatment guidelines for osteoporosis exist, but the focus is mainly on menopausal-associated osteoporosis. HCT survivors comprise a distinct population with unique comorbidities, making general approaches to bone health management inappropriate in some cases. To address a core set of 16 frequently asked questions (FAQs) relevant to bone health in HCT, the American Society of Transplant and Cellular Therapy Committee on Practice Guidelines convened a panel of experts in HCT, adult and pediatric endocrinology, orthopedics, and oral medicine. Owing to a lack of relevant prospective controlled clinical trials that specifically address bone health in HCT, the answers to the FAQs rely on evidence derived from retrospective HCT studies, results extrapolated from prospective studies in non-HCT settings, relevant societal guidelines, and expert panel opinion. Given the heterogenous comorbidities and needs of individual HCT recipients, answers to FAQs in this article should be considered general recommendations, with good medical practice and judgment ultimately dictating care of individual patients. Readers are referred to the Supplementary Material for answers to additional FAQs that did not make the core set.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.001DOI Listing
October 2020

Ixazomib for Treatment of Refractory Chronic Graft-versus-Host Disease: A Chronic GVHD Consortium Phase II Trial.

Biol Blood Marrow Transplant 2020 09 25;26(9):1612-1619. Epub 2020 May 25.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

New interventions are needed in advanced chronic graft-versus-host disease (GVHD). In a phase II, single-arm, multicenter trial, we examined the efficacy of ixazomib in patients with chronic GVHD who had progressed after at least 1 previous line of systemic immunosuppressive (IS) therapy. Ixazomib was given as a 4 mg oral dose weekly on days 1, 8, and 15 of a 28-day cycle for up to 6 total cycles. The primary endpoint was 6-month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic IS therapy. A total of 50 subjects were enrolled at 6 institutions. The median time from the onset of chronic GVHD to enrollment was 2.8 years (interquartile range, 1.5 to 4.3 years). The degree of chronic GVHD at enrollment was National Institutes of Health (NIH)-defined moderate (16%) or severe (84%), predominantly classic (80% versus 20% overlap), with 52% of patients having involvement of 4 or more organs. The patients were heavily pretreated, with 39 (78%) receiving 3 or more previous lines of systemic therapy for chronic GVHD. Of the 50 patients treated, 26 completed 6 months of planned therapy. The 6-month treatment failure rate was significantly lower than the historical benchmark (28% versus 44%; P = .01) previously established in second-line therapy for chronic GVHD. No patient, transplantation, or chronic GVHD variables were significantly associated with 6-month treatment failure. NIH-defined overall response rate was 40% at 6 months. Overall survival was 92% at 6 months and 90% at 12 months. Ixazomib met the primary endpoint of low treatment failure at 6 months in the setting of advanced chronic GVHD. At 6 months, the NIH-defined rate of complete/partial response was 40%, and 52% of patients remained on ixazomib therapy, suggesting that the low treatment failure rate was due in part due to prevention of progressive disease that would have required additional treatment.
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http://dx.doi.org/10.1016/j.bbmt.2020.05.015DOI Listing
September 2020

Quality-of-Life Trajectories in Adolescent and Young Adult versus Older Adult Allogeneic Hematopoietic Cell Transplantation Recipients.

Biol Blood Marrow Transplant 2020 08 19;26(8):1505-1510. Epub 2020 May 19.

Department of Pediatric Hematology Oncology and Bone Marrow Transplant, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address:

Hematopoietic cell transplantation (HCT) is physically and psychologically challenging, potentially exposing patients to quality-of-life (QoL) impairments. Adolescent and young adults (AYAs, aged 15 to 39 years) are a vulnerable cohort facing multiple hurdles due to dynamic changes in several aspects of their lives. The AYA population may be particularly prone to QoL issues during HCT. We hypothesized that due to the unique psychosocial challenges faced by AYAs, they would have an inferior quality of life. We studied QoL differences between AYA (aged 15 to 39 years) and older adult (aged 40 to 60 years) allogeneic HCT recipients before and after HCT. Additionally, we determined if pre-HCT QoL for AYA transplant recipients changed over time. QoL data were collected prospectively before and after transplant on 431 recipients aged 15 to 60 years from June 2003 through December 2017 using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) questionnaire. Repeated-measures analysis of variance was used to assess differences among age groups. Pearson correlation (r) was used to determine if baseline QoL had improved after HCT from June 2003 through December 2017 in the AYA cohort. QoL did not differ among younger AYAs, older AYAs, or older adults at any time in the first year after allogeneic HCT. At 1 year post-HCT, total FACT-BMT score and all FACT-BMT domains except physical well-being improved from pre-HCT in all age groups. From 2003 to 2017, AYA allogeneic recipients experienced modest improvement in additional concerns (r = 0.26, P = .003), trial outcome index (r = 0.23, P = .008), and total FACT-BMT score (r = 0.19, P = .031), although no improvements were seen in physical, social, emotional, or functional well-being. Contrary to our hypothesis, we found that QoL in the AYA population is similar to that of older adults before and after HCT. Improvements in QoL of AYA allogeneic patients since 2003 were driven by the additional concerns domain, which addresses multiple psychosocial aspects such as vocation, hobbies, and acceptance of illness. Continued efforts to tailor treatment and support for AYA HCT recipients is critical to improving QoL outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371542PMC
August 2020

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Biol Blood Marrow Transplant 2020 08 17;26(8):1459-1468. Epub 2020 May 17.

(7)Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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http://dx.doi.org/10.1016/j.bbmt.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391266PMC
August 2020

To D or not to D: vitamin D in hematopoietic cell transplantation.

Bone Marrow Transplant 2020 11 25;55(11):2060-2070. Epub 2020 Apr 25.

Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Vitamin D plays an essential role in bone health, immune tolerance, and immune modulation. Autologous and allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk of vitamin D deficiency, which may increase risks of bone loss and fracture, graft-versus-host disease (GVHD), and relapse, and can delay hematologic and immune recovery following HCT. Growing evidence indicates that vitamin D may have a role as an immunomodulator, and supplementation during HCT may decrease the risk of GVHD, infection, relapse, and mortality. In this paper, we review the role of vitamin D and its association with HCT outcomes and discuss prevention and treatment of vitamin D deficiency after HCT in adult recipients. We review the role of monitoring of vitamin D levels pre- and post-HCT and its supplementation in appropriate patients. We also review the use of bone densitometry prior to HCT and in long-term follow-up and the treatment of osteoporosis in this high-risk population.
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http://dx.doi.org/10.1038/s41409-020-0904-7DOI Listing
November 2020

Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia.

Blood Adv 2020 03;4(6):983-992

Department of Haematology and Oncology, Dokkyo Medical University, Tochigi, Japan.

There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.
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http://dx.doi.org/10.1182/bloodadvances.2019001126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094022PMC
March 2020

Patient-reported outcomes in acute graft-versus-host disease: optimizing patient care and clinical trial endpoints.

Bone Marrow Transplant 2020 08 10;55(8):1533-1539. Epub 2020 Mar 10.

Blood and Marrow Transplant Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.

Patient-reported outcomes (PROs) refer to patient perceived and reported health-related quality of life (HRQOL), functional status, and symptom burden. PROs have become an important measure in oncologic care to identify the impact of the disease and its treatment on a patient's health status. Hematopoietic cell transplantation (HCT) is an aggressive and potentially curative therapy for patients with high-risk hematologic malignancies. A common complication of HCT is graft-versus-host disease (GVHD), which can be a significant contributor to morbidity and mortality, as well as a wide spectrum of physical and psychosocial effects. Quality of life and symptom burden have been shown to be important measures in the study of posttransplant complications, including chronic GVHD. We review the need for a novel tool in acute GVHD to capture disease symptoms and HRQOL to better understand patient symptoms, disease trajectory and outcome.
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http://dx.doi.org/10.1038/s41409-020-0850-4DOI Listing
August 2020
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