Publications by authors named "Ran Reshef"

85 Publications

Vitamin D deficiency after allogeneic hematopoietic cell transplantation promotes T-cell activation and is inversely associated with an EZH2-ID3 signature.

Transplant Cell Ther 2021 Sep 28. Epub 2021 Sep 28.

Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, New York. Electronic address:

Vitamin D promotes a shift from a proinflammatory to a more tolerogenic immune state in allogeneic hematopoietic cell transplant (HCT) recipients. The dominant mechanism responsible for this shift has not been elucidated. We took a multifaceted approach to evaluating the clinical and immunologic impact of low vitamin D levels in 53 HCT recipients. We used 28-plex flow cytometry for immunophenotyping, serum cytokine levels, T-cell cytokine production, and T-cell whole genome transcription. The median day-30 vitamin D level was 20 ng/mL, and deficiency was common in younger patients undergoing myeloablative transplantation. Low vitamin D levels were associated with a high CD8/Treg ratio, increased serum levels and T-cell production of proinflammatory cytokines, and a gene expression signature of unrestrained T-cell proliferation and epigenetic modulation through the PRC2/EZH2 complex. Immunophenotyping confirmed a strong association between high levels of vitamin D and an activated EZH2 signature, characterized by overexpression of ID3, which has a role in effector T-cell differentiation. Our findings demonstrate the critical role of vitamin D in modulating T-cell function in human GVHD and identify a previously undescribed interaction with EZH2 and ID3, which may impact effector differentiation and has implications to cell therapies and other forms of cancer immunotherapy. © 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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http://dx.doi.org/10.1016/j.jtct.2021.09.017DOI Listing
September 2021

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Blood Adv 2021 Sep 22. Epub 2021 Sep 22.

University of Texas Southwestern Medical Center, Dallas, Texas, United States.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease.
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http://dx.doi.org/10.1182/bloodadvances.2021004881DOI Listing
September 2021

Evaluation of Elafin as a Prognostic Biomarker in Acute Graft-versus-Host Disease.

Transplant Cell Ther 2021 Aug 30. Epub 2021 Aug 30.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3α in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3α were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3α or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P = .19). OS at 6 months (68% versus 68%; P > .99) and 4-week response (78% versus 78%; P = .98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3α. The addition of elafin to the other 2 biomarkers did not improve the AUC. Our data indicate that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD did not predict 6-month NRM, OS, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM, and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD.
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http://dx.doi.org/10.1016/j.jtct.2021.08.021DOI Listing
August 2021

Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improve Transplantation Outcomes in Older Patients with Myelodysplastic Syndromes.

Transplant Cell Ther 2021 Nov 14;27(11):921.e1-921.e10. Epub 2021 Aug 14.

Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤ .0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤ .0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.007DOI Listing
November 2021

HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis.

Blood 2021 07;138(3):273-282

Center for International Blood and Marrow Transplant Research (CIBMTR), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.

Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.
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http://dx.doi.org/10.1182/blood.2021011281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310426PMC
July 2021

Standardized Semistructured Psychosocial Evaluation Before Stem Cell Transplantation Predicts Delirium After Transplant.

J Acad Consult Liaison Psychiatry 2021 Jul-Aug;62(4):440-444. Epub 2020 Dec 16.

Department of Psychiatry, Division of Consultation-Liaison Psychiatry, Columbia University Irving Medical Center, New Year, NY.

Background: Delirium affects many patients undergoing stem cell transplantation (SCT). Delirium is treatable, but prevention is a better goal, making it desirable to identify patients at heightened risk for delirium. A standardized pretransplant psychosocial assessment rating scale, the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), has been demonstrated to predict outcomes in solid organ transplant recipients and nonadherence in patients with SCT.

Objectives: In this study, we aimed to evaluate the association of SIPAT score and post-SCT incident delirium.

Methods: We retrospectively reviewed records of SCT recipients who had SIPAT evaluations before SCT, for indications of delirium in the 6 months after transplant. We tested the association between SIPAT score and delirium by logistic regression, controlling for relevant covariates such as transplant type (allogeneic vs autologous).

Results: Of 85 patients (median age of 49 years, range 18-74), 56 (66%) were men, and 43 (50.5%) were autologous SCT recipients. The median pretransplant SIPAT score was 8, range 0-40. There were 15 cases (17.6%) of delirium in the 6 months following transplant.  In univariate analyses, transplant type was significantly associated with incident delirium. In multivariate analyses, SIPAT score was significantly associated with incident delirium (odds ratio, 1.090; P = 0.021).

Conclusions: Psychosocial risk as quantified by the SIPAT is associated with development of delirium in SCT recipients. This scale can therefore be integrated into medical risk models to anticipate which patients are at higher risk for delirium in their hospital course, enabling preventative measures tailored to the needs of the individual patient.
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http://dx.doi.org/10.1016/j.jaclp.2020.12.004DOI Listing
November 2021

TGM4: an immunogenic prostate-restricted antigen.

J Immunother Cancer 2021 06;9(6)

Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, New York, USA

Background: Prostate cancer is the second leading cause of cancer-related death in men in the USA; death occurs when patients progress to metastatic castration-resistant prostate cancer (CRPC). Although immunotherapy with the Food and Drug Administration-approved vaccine sipuleucel-T, which targets prostatic acid phosphatase (PAP), extends survival for 2-4 months, the identification of new immunogenic tumor-associated antigens (TAAs) continues to be an unmet need.

Methods: We evaluated the differential expression profile of castration-resistant prostate epithelial cells that give rise to CRPC from mice following an androgen deprivation/repletion cycle. The expression levels of a set of androgen-responsive genes were further evaluated in prostate, brain, colon, liver, lung, skin, kidney, and salivary gland from murine and human databases. The expression of a novel prostate-restricted TAA was then validated by immunostaining of mouse tissues and analyzed in primary tumors across all human cancer types in The Cancer Genome Atlas. Finally, the immunogenicity of this TAA was evaluated in vitro and in vivo using autologous coculture assays with cells from healthy donors as well as by measuring antigen-specific antibodies in sera from patients with prostate cancer (PCa) from a neoadjuvant clinical trial.

Results: We identified a set of androgen-responsive genes that could serve as potential TAAs for PCa. In particular, we found transglutaminase 4 (Tgm4) to be highly expressed in prostate tumors that originate from luminal epithelial cells and only expressed at low levels in most extraprostatic tissues evaluated. Furthermore, elevated levels of expression in primary PCa tumors correlated with unfavorable prognosis in patients. In vitro and in vivo assays confirmed the immunogenicity of TGM4. We found that activated proinflammatory effector memory CD8 and CD4 T cells were expanded by monocyte-derived dendritic cell (moDCs) pulsed with TGM4 to a greater extent than moDCs pulsed with either PAP or prostate-specific antigen (PSA), and T cells primed with TGM4-pulsed moDCs produce functional cytokines following a prime/boost regiment or in vitro stimulation. An IgG antibody response to TGM4 was detected in 30% of vaccinated patients, while fewer than 8% of vaccinated patients developed antibody responses to PSA or prostate-specific membrane antigen (PSMA).

Conclusions: These results suggest that TGM4 is an immunogenic, prostate-restricted antigen with the potential for further development as an immunotherapy target.
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http://dx.doi.org/10.1136/jitc-2020-001649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246381PMC
June 2021

Current and Future Role of Medical Imaging in Guiding the Management of Patients With Relapsed and Refractory Non-Hodgkin Lymphoma Treated With CAR T-Cell Therapy.

Front Oncol 2021 28;11:664688. Epub 2021 May 28.

Department of Radiology, New York Presbyterian, Columbia University Irving Medical Center, New York City, NY, United States.

Chimeric antigen receptor (CAR) T-cells are a novel immunotherapy available for patients with refractory/relapsed non-Hodgkin lymphoma. In this indication, clinical trials have demonstrated that CAR T-cells achieve high rates of response, complete response, and long-term response (up to 80%, 60%, and 40%, respectively). Nonetheless, the majority of patients ultimately relapsed. This review provides an overview about the current and future role of medical imaging in guiding the management of non-Hodgkin lymphoma patients treated with CAR T-cells. It discusses the value of predictive and prognostic biomarkers to better stratify the risk of relapse, and provide a patient-tailored therapeutic strategy. At baseline, high tumor volume (assessed on CT-scan or on [18F]-FDG PET/CT) is a prognostic factor associated with treatment failure. Response assessment has not been studied extensively yet. Available data suggests that current response assessment developed on CT-scan or on [18F]-FDG PET/CT for cytotoxic systemic therapies remains relevant to estimate lymphoma response to CAR T-cell therapy. Nonetheless, atypical patterns of response and progression have been observed and should be further analyzed. The potential advantages as well as limitations of artificial intelligence and radiomics as tools providing high throughput quantitative imaging features is described.
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http://dx.doi.org/10.3389/fonc.2021.664688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195284PMC
May 2021

Cellular Immunotherapy-Highlights from TCT 2021.

Transplant Cell Ther 2021 07 26;27(7):527-532. Epub 2021 Apr 26.

Division of Hematology, Oncology, and Transplantation, University of Minnesota Cancer Center, Minneapolis, Minnesota.

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http://dx.doi.org/10.1016/j.jtct.2021.04.015DOI Listing
July 2021

Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation.

J Clin Oncol 2021 07 9;39(21):2397-2409. Epub 2021 Apr 9.

Anthony Nolan Research Institute, Royal Free Hospital, London, UK.

Purpose: Ultrahigh resolution (UHR) HLA matching is reported to result in better outcomes following unrelated donor hematopoietic cell transplantation, improving survival and reducing post-transplant complications. However, most studies included relatively small numbers of patients. Here we report the findings from a large, multicenter validation study.

Methods: UHR HLA typing was available on 5,140 conventionally 10 out of 10 HLA-matched patients with malignant disease transplanted between 2008 and 2017.

Results: After UHR HLA typing, 82% of pairs remained 10 out of 10 UHR-matched; 12.3% of patients were 12 out of 12 UHR HLA-matched. Compared with 12 out of 12 UHR-matched patients, probabilities of grade 2-4 acute graft-versus-host disease (aGVHD) were significantly increased with UHR mismatches (overall = .0019) and in those patients who were HLA-DPB1 T-cell epitope permissively mismatched or nonpermissively mismatched (overall = .0011). In the T-cell-depleted subset, the degree of UHR HLA mismatch was only associated with increased transplant-related mortality (TRM) (overall = .0068). In the T-cell-replete subset, UHR HLA matching was associated with a lower probability of aGVHD (overall = .0020); 12 out of 12 UHR matching was associated with reduced TRM risk when compared with HLA-DPB1 T-cell epitope permissively mismatched patients, whereas nonpermissive mismatching resulted in a greater risk (overall = .0003).

Conclusion: This study did not confirm that UHR 12 out of 12 HLA matching increases the probability of overall survival but does demonstrate that aGVHD risk, and in certain settings TRM, is lowest in UHR HLA-matched pairs and thus warrants consideration when multiple 10 out of 10 HLA-matched donors of equivalent age are available.
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http://dx.doi.org/10.1200/JCO.20.03643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280068PMC
July 2021

What about tocilizumab? A retrospective study from a NYC Hospital during the COVID-19 outbreak.

PLoS One 2021 8;16(4):e0249349. Epub 2021 Apr 8.

Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.

Background: Tocilizumab, an interleukin-6 receptor blocker, has been used in the inflammatory phase of COVID-19, but its impact independent of corticosteroids remains unclear in patients with severe disease.

Methods: In this retrospective analysis of patients with COVID-19 admitted between March 2 and April 14, 2020 to a large academic medical center in New York City, we describe outcomes associated with tocilizumab 400 mg (without methylprednisolone) compared to a propensity-matched control. The primary endpoints were change in a 7-point ordinal scale of oxygenation and ventilator free survival, both at days 14 and 28. Secondary endpoints include incidence of bacterial superinfections and gastrointestinal perforation. Primary outcomes were evaluated using t-test.

Results: We identified 33 patients who received tocilizumab and matched 74 controls based on demographics and health measures upon admission. After adjusting for illness severity and baseline ordinal scale, we failed to find evidence of an improvement in hypoxemia based on an ordinal scale at hospital day 14 in the tocilizumab group (OR 2.2; 95% CI, 0.7-6.5; p = 0.157) or day 28 (OR 1.1; 95% CI, 0.4-3.6; p = 0.82). There also was no evidence of an improvement in ventilator-free survival at day 14 (OR 0.8; 95% CI, 0.18-3.5; p = 0.75) or day 28 (OR 1.1; 95% CI, 0.1-1.8; p = 0.23). There was no increase in secondary bacterial infection rates in the tocilizumab group compared to controls (OR 0.37; 95% CI, 0.09-1.53; p = 0.168).

Conclusions: There was no evidence to support an improvement in hypoxemia or ventilator-free survival with use of tocilizumab 400 mg in the absence of corticosteroids. No increase in secondary bacterial infections was observed in the group receiving tocilizumab.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249349PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031323PMC
April 2021

Peripheral blood stem cell grafts in allogeneic hematopoietic cell transplantation: It is not all about the CD34+ cell dose.

Authors:
Ran Reshef

Transfus Apher Sci 2021 Feb 10;60(1):103081. Epub 2021 Feb 10.

Blood and Marrow Transplantation and Cell Therapy Program, Columbia University Irving Medical Center, New York, NY, 630 W. 168th St. Mailbox 127, New York, NY, United States. Electronic address:

Allogeneic Hematopoietic Cell Transplantation is a curative approach in various malignant and non-malignant disorders. The majority of adult transplants in the current era are performed using mobilized stem cells, harvested from the peripheral blood by leukapheresis. Peripheral blood stem cell (PBSC) collections are designed to target a dose of stem cells that will result in safe engraftment and hematopoietic recovery; however, 99 % of the cells contained in a PBSC graft are not stem cells and a growing number of studies attempt to characterize the associations between graft composition and transplant outcomes. A better understanding of the impact of the quantity and quality of various cell types in PBSC grafts may lead to development of novel collection strategies or improved donor selection algorithms. Here we review relevant findings from recent studies in this area.
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http://dx.doi.org/10.1016/j.transci.2021.103081DOI Listing
February 2021

Variable selection methods for predicting clinical outcomes following allogeneic hematopoietic cell transplantation.

Sci Rep 2021 02 5;11(1):3230. Epub 2021 Feb 5.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative procedure for a large number of diseases. However, the greatest barriers to the success of allo-HCT are relapse and graft-versus-host-disease (GVHD). Many studies have examined the reconstitution of the immune system after allo-HCT and searched for factors associated with clinical outcome. Serum biomarkers have also been studied to predict the incidence and prognosis of GVHD. However, the use of multiparametric immunophenotyping has been less extensively explored: studies usually focus on preselected and predefined cell phenotypes and so do not fully exploit the richness of flow cytometry data. Here we aimed to identify cell phenotypes present 30 days after allo-HCT that are associated with clinical outcomes in 37 patients participating in a trial relating to the prevention of GVHD, derived from 82 flow cytometry markers and 13 clinical variables. To do this we applied variable selection methods in a competing risks modeling framework, and identified specific subsets of T, B, and NK cells associated with relapse. Our study demonstrates the value of variable selection methods for mining rich, high dimensional clinical data and identifying potentially unexplored cell subpopulations of interest.
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http://dx.doi.org/10.1038/s41598-021-82562-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865009PMC
February 2021

Acute GVHD Diagnosis and Adjudication in a Multicenter Trial: A Report From the BMT CTN 1202 Biorepository Study.

J Clin Oncol 2021 06 28;39(17):1878-1887. Epub 2021 Jan 28.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Purpose: Accurate and reproducible methods to diagnose, grade, and report acute graft-versus-host disease (GVHD) are critical for the evaluation of therapies and biomarkers.

Patients And Methods: The Blood and Marrow Transplant Clinical Trials Network 1202 study is an observational study of 1,709 allogeneic hematopoietic cell transplantation recipients that implemented weekly data reporting and near real-time data adjudication by an end point review committee (ERC), assigning a confidence level (confirmed, probable, possible, or negative) to the diagnosis of acute GVHD at onset.

Results: During the first 100 days, symptoms consistent with GVHD developed in 90% of cases but were often determined by centers to be due to causes other than GVHD. Indeed, GVHD was under consideration in only 23% of cases at symptom onset. Diagnostic biopsies were obtained in 40% of cases, but treatment often was incongruous with biopsy findings and 10.5% of biopsies were equivocal. Importantly, more than 40% of steroid courses were started for reasons other than GVHD. The ERC modified the determination of GVHD diagnosis and/or grade in 12.3% of onset cases. The cumulative incidence of acute GVHD as reported by the centers was 62%. When the ERC adjudicated GVHD onset to be present only if the confidence level was probable or confirmed, the incidence of GVHD declined to 49%.

Conclusion: This study demonstrates that the incidence of GVHD may be overestimated at symptom onset, establishes a contemporary benchmark for acute GVHD, and suggests a structured framework for reporting and adjudication of GVHD that could be used in prospective trials.
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http://dx.doi.org/10.1200/JCO.20.00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260916PMC
June 2021

Gastrointestinal toxicity of high-dose melphalan in autologous hematopoietic stem cell transplantation: identification of risk factors and a benchmark for experimental therapies.

Ann Hematol 2021 Jul 3;100(7):1863-1870. Epub 2021 Jan 3.

Department of Medicine, Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.

Gastrointestinal side effects are the dose-limiting toxicity of high-dose melphalan (HDM) in autologous hematopoietic stem-cell transplantation, but there are limited contemporary data on the incidence and severity of gastrointestinal toxicity associated with this regimen. We retrospectively studied 100 consecutive patients who received HDM alone or in combination with other conditioning agents. Patients had a median age of 56 (range 20-73); underlying diseases were myeloma (42%), lymphoma (42%), or amyloidosis (16%) and melphalan dosages were 200 (40%), 140 (59%), or 100 mg/m (1%). Ninety-seven percent of patients experienced diarrhea with a range of 1-18 bowel movements per day, 88% developed nausea, and 60% experienced vomiting. Abdominal CT scans rarely altered patient management, but stool studies were useful in identifying a treatable infectious source. Grade ≥ 2 diarrhea was associated with longer duration of diarrhea, longer length of stay, worse hypoalbuminemia, higher use of antibiotics, abdominal imaging, electrolyte repletions, and anti-diarrheal agents. Risk factors for severe diarrhea were female sex, melphalan dose, age > 50, creatinine clearance < 60 ml/min, and having a plasma cell neoplasm as opposed to lymphoma. Female sex was also associated with more severe nausea and vomiting. In summary, diarrhea remains an important toxicity of HDM and novel therapies for chemotherapy-induced diarrhea for patients undergoing stem-cell transplantation are needed. Grade 2 or higher diarrhea is associated with significant clinical consequences and should be used as the primary endpoint in prospective clinical trials.
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http://dx.doi.org/10.1007/s00277-020-04378-8DOI Listing
July 2021

Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin.

Blood Adv 2020 12;4(24):6098-6105

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept "preemptive" treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.
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http://dx.doi.org/10.1182/bloodadvances.2020003336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756981PMC
December 2020

Baloxavir treatment of oseltamivir-resistant influenza A/H1pdm09 in two immunocompromised patients.

Transpl Infect Dis 2021 Jun 22;23(3):e13542. Epub 2020 Dec 22.

Laboratory of Viral Diseases, Wadsworth Center, New York State Department of Health, Albany, NY, USA.

Few treatment options are available for oseltamivir-resistant influenza. It has been proposed that baloxavir can be effective in this setting due to its distinct mechanism of action but clinical experience is lacking for immunocompromised patients. We report two such cases treated with baloxavir after failure of oseltamivir and detection of oseltamivir resistance mutations. Baloxavir/zanamivir combination therapy was effective in one patient, but persistent viral shedding was noted with baloxavir monotherapy in the other patient.
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http://dx.doi.org/10.1111/tid.13542DOI Listing
June 2021

Extended letermovir administration, beyond day 100, is effective for CMV prophylaxis in patients with graft versus host disease.

Transpl Infect Dis 2021 Apr 27;23(2):e13487. Epub 2020 Oct 27.

Division of Hematology/Oncology, Department of Internal Medicine, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA.

Background: Cytomegalovirus (CMV) reactivation is associated with significant morbidity and mortality after an allogeneic hematopoietic cell transplant (AHCT), and graft versus host disease (GVHD) increases the risk of CMV reactivation. Letermovir is approved for CMV prophylaxis in CMV-seropositive patients, but has only been studied through day 100 post-transplantation in the registration trial. Its efficacy in preventing CMV in patients with GVHD requiring treatment beyond the day 100 milestone has not been studied.

Methods: We retrospectively analyzed all patients who underwent an AHCT at a single center over a period of 24 months, and identified a cohort of 20 patients who received extended duration of letermovir (beyond 100 days) after the diagnosis of GVHD. The primary end point was the incidence of clinically significant CMV infection, defined as onset of CMV disease or initiation of preemptive therapy with alternative antiviral agents.

Results: In this high-risk cohort, only one patient (5%) developed a clinically significant CMV infection, requiring preemptive therapy. No patients developed CMV organ disease. Three additional patients developed CMV viremia of ≥150 IU/mL while on letermovir and after the onset of GVHD, and none required additional treatment. Receipt of post-transplant cyclophosphamide (PTCy) and low CD4 count after the development of GVHD were associated with breakthrough CMV viremia while on extended duration letermovir.

Conclusions: Extended duration letermovir was efficacious in preventing clinically significant CMV infections in patients with GVHD.
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http://dx.doi.org/10.1111/tid.13487DOI Listing
April 2021

COVID-19 Infections and Clinical Outcomes in Patients with Multiple Myeloma in New York City: A Cohort Study from Five Academic Centers.

Blood Cancer Discov 2020 Nov 30;1(3):234-243. Epub 2020 Jul 30.

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos ( = 21), OR = 4.7 (95% confidence interval, 1.3-16.7), and African American Blacks ( = 33), OR = 3.5 (1.1-11.5), as compared with White patients ( = 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated ( > 0.05) with adverse outcome: hypertension ( = 56), OR = 2.2 (0.9-5.4); diabetes ( = 18), OR = 0.9 (0.3-2.9); age >65 years ( = 63), OR = 1.8 (0.7-4.6); high-dose melphalan with autologous stem cell transplant <12 months ( = 7), OR = 0.9 (0.2-5.4); and immunoglobulin G <650 mg/dL ( = 42), OR = 0.9 (0.3-2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome.

Significance: Patients with multiple myeloma are immunocompromised, raising the question whether they are at higher risk of severe COVID-19 disease. In this large case series on COVID-19 in patients with multiple myeloma, we report 29% mortality rates among hospitalized patients and identify race/ethnicity as the most significant risk factor for severe outcome.. .
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http://dx.doi.org/10.1158/2643-3230.BCD-20-0102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668224PMC
November 2020

Revving the CAR - Combination strategies to enhance CAR T cell effectiveness.

Blood Rev 2021 01 5;45:100695. Epub 2020 May 5.

Division of Hematology/Oncology, Columbia University Irving Medical Center, 630 W. 168(th) Street Mailbox 127, New York, NY 10032, USA. Electronic address:

Chimeric antigen receptor (CAR) T cell therapy is currently approved for treatment of refractory B-cell malignancies. Response rates in these diseases are impressive by historical standards, but most patients do not have a durable response and there remains room for improvement. To date, CAR T cell activity has been even more limited in solid malignancies. These limitations are thought to be due to several pathways of resistance to CAR T cells, including cell-intrinsic mechanisms and the immunosuppressive tumor microenvironment. In this review, we discuss current experimental strategies that combine small molecules and monoclonal antibodies with CAR T cells to overcome these resistance mechanisms. We describe the biological rationale, pre-clinical data and clinical trials in progress that test the efficacy and safety of these combinations.
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http://dx.doi.org/10.1016/j.blre.2020.100695DOI Listing
January 2021

Fertility Concerns and Access to Care for Stem Cell Transplantation Candidates with Sickle Cell Disease.

Biol Blood Marrow Transplant 2020 08 18;26(8):e192-e197. Epub 2020 Apr 18.

Blood and Marrow Transplantation Program, Division of Hematology & Oncology, Columbia University Irving Medical Center, New York, New York. Electronic address:

Sickle cell disease (SCD) affects 100,000 Americans and causes significant psychiatric illness and poor quality of life in many domains, including infertility. Hematopoietic cell transplantation (HCT) is the only available cure for SCD, but it can entail chronic toxicities, including psychiatric conditions, such as depression and anxiety, and sterility in both men and women. There is scant literature on fertility or psychiatric outcomes for patients with SCD receiving HCT, and none considering the additive ramifications of the stresses of SCD, transplantation, and infertility. Financial toxicity is a significant concern for all patients undergoing HCT. Treatment for infertility is also very expensive, and access to fertility services is variable in the United States, adding to the medical and quality of life burden for this patient population. Here we review the relevant areas of SCD and infertility, SCD and psychiatric wellness, access to care, and infertility and quality of life. Collectively, these data suggest that the group of patients with SCD who undergo HCT and experience infertility are at particularly high risk for poor quality of life, worsening psychiatric health, and poor access to adequate fertility treatment.
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http://dx.doi.org/10.1016/j.bbmt.2020.03.025DOI Listing
August 2020

Disease risk and GVHD biomarkers can stratify patients for risk of relapse and nonrelapse mortality post hematopoietic cell transplant.

Leukemia 2020 07 4;34(7):1898-1906. Epub 2020 Feb 4.

Pediatric Blood and Marrow Transplantation Program, Children's Hospital, University of Würzburg, Würzburg, Germany.

The graft-versus-leukemia (GVL) effect after allogeneic hematopoietic cell transplant (HCT) can prevent relapse but the risk of severe graft-versus-host disease (GVHD) leads to prolonged intensive immunosuppression and possible blunting of the GVL effect. Strategies to reduce immunosuppression in order to prevent relapse have been offset by increases in severe GVHD and nonrelapse mortality (NRM). We recently validated the MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers. In this study we tested whether the MAP could identify patients whose risk for relapse is higher than their risk for severe GVHD and NRM. The multicenter study population (n = 1604) was divided into two cohorts: historical (2006-2015, n = 702) and current (2015-2017, n = 902) with similar NRM, relapse, and survival. On day 28 post-HCT, patients who had not developed GVHD (75% of the population) and who possessed a low MAP were at much higher risk for relapse (24%) than severe GVHD and NRM (16 and 9%); this difference was even more pronounced in patients with a high disease risk index (relapse 33%, NRM 9%). Such patients are good candidates to test relapse prevention strategies that might enhance GVL.
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http://dx.doi.org/10.1038/s41375-020-0726-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332389PMC
July 2020

The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease.

Blood Adv 2019 12;3(23):4034-4042

Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP), derived from 2 serum biomarkers, measures damage to crypts in the gastrointestinal tract during graft-versus-host disease (GVHD). We hypothesized that changes in MAP after treatment could validate it as a response biomarker. We prospectively collected serum samples and clinical stages of acute GVHD from 615 patients receiving hematopoietic cell transplantation in 20 centers at initiation of first-line systemic treatment and 4 weeks later. We computed MAPs and clinical responses and compared their abilities to predict 6-month nonrelapse mortality (NRM) in the validation cohort (n = 367). After 4 weeks of treatment, MAPs predicted NRM better than the change in clinical symptoms in all patients and identified 2 groups with significantly different NRM in both clinical responders (40% vs 12%, P < .0001) and nonresponders (65% vs 25%, P < .0001). MAPs successfully reclassified patients for NRM risk within every clinical grade of acute GVHD after 4 weeks of treatment. At the beginning of treatment, patients with a low MAP that rose above the threshold of 0.290 after 4 weeks of treatment had a significant increase in NRM, whereas patients with a high MAP at onset that fell below that threshold after treatment had a striking decrease in NRM that translated into clear differences in overall survival. We conclude that a MAP measured before and after treatment of acute GVHD is a response biomarker that predicts long-term outcomes more accurately than change in clinical symptoms. MAPs have the potential to guide therapy for acute GVHD and may function as a useful end point in clinical trials.
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http://dx.doi.org/10.1182/bloodadvances.2019000791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963240PMC
December 2019

Maintenance Tyrosine Kinase Inhibitors Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia: A Center for International Blood and Marrow Transplant Research Study.

Biol Blood Marrow Transplant 2020 03 25;26(3):472-479. Epub 2019 Oct 25.

The Blood and Marrow Transplant Group of Georgia, Northside Hospital, Atlanta, Georgia.

It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358778PMC
March 2020

Chimeric antigen receptor T cells for treatment of transformed Waldenström macroglobulinemia.

Leuk Lymphoma 2020 02 22;61(2):465-468. Epub 2019 Sep 22.

Division of Hematology & Oncology, Columbia University Irving Medical Center, New York, NY, USA.

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http://dx.doi.org/10.1080/10428194.2019.1665668DOI Listing
February 2020

Prognostic Score and Cytogenetic Risk Classification for Chronic Lymphocytic Leukemia Patients: Center for International Blood and Marrow Transplant Research Report.

Clin Cancer Res 2019 08 28;25(16):5143-5155. Epub 2019 Jun 28.

Seidman Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio.

Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).

Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.

Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high ( < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years).

Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697588PMC
August 2019

Standardized Semi-structured Psychosocial Evaluation before Hematopoietic Stem Cell Transplantation Predicts Patient Adherence to Post-Transplant Regimen.

Biol Blood Marrow Transplant 2019 11 24;25(11):2222-2227. Epub 2019 Jun 24.

Blood and Marrow Transplantation Program, Division of Hematology & Oncology, Columbia University Medical Center, New York, New York.

In patients undergoing stem cell transplantation (SCT), nonadherence has potential for significant medical impact and potentially life-threatening complications. No study thus far has demonstrated an effective way to predict adherence in SCT recipients. A structured rating scale, the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), has been shown to predict psychosocial outcomes and medical morbidity in solid organ transplant recipients. We assessed the SIPAT in SCT recipients. We hypothesized that the SIPAT rating would be associated with nonadherence to the post-SCT regimen. We retrospectively studied SCT recipients who had psychiatric evaluations with the SIPAT before SCT. The primary outcome was nonadherence, defined a priori as at least 1 life-threatening nonadherence event in the first 6 months post-transplant. Association of the SIPAT with outcomes was evaluated by logistic regression, and an optimal cutoff score was determined using a receiver operating characteristic curve. Of 85 patients (mean age 47 years; range, 18 to 74 years), 56 (66%) were male, and 43 (50.5%) received autologous SCT. Eighteen (21%) patients were nonadherent. The SIPAT rating, treated as a continuous variable and controlling for autologous versus allogeneic SCT, was significantly associated with nonadherence (per 1 point; odds ratio [OR], 1.162; P< .0001). Allogeneic SCT also conferred a significantly increased risk of nonadherence (OR, 14.184; P= .005). Multivariate analysis stratifying for allogeneic versus autologous transplantation and controlling for age, sex, and disease confirmed an independent association between the SIPAT score and nonadherence. A cutoff score of 18 provided optimal specificity (89.6%) and sensitivity (55.6%) for nonadherence. Nonadherence rates were 58.8% and 11.8% for subjects with SIPAT ratings of 18 and above or 17 and below, respectively (relative risk = 4.98, P < .0001). Psychosocial risk as quantified by the SIPAT correlated with SCT recipients' adherence to the post-transplant regimen, suggesting that this instrument can contribute to medical risk stratification models. Further study should evaluate long-term mortality data and the effects of intervention on psychosocial risks.
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http://dx.doi.org/10.1016/j.bbmt.2019.06.019DOI Listing
November 2019

Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 09 11;25(9):1875-1883. Epub 2019 May 11.

Division of Hematology/Oncology/Bone Marrow Transplantation, Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3 T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3 T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3 T cell dose cutoff of 14 × 10 cells/kg identified MSD/low CD3 (n = 223) and MSD/high CD3 (n = 1214), and a dose of 15 × 10 cells/kg identified MUD/low CD3 (n = 197) and MUD/high CD3 (n = 1102). On univariate analysis, the MSD/high CD3 group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3 group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3 group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3 group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3 T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4 T cells, CD8 T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3 T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4 and CD8 T cell doses were not possible given our small sample size.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071947PMC
September 2019

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203).

Lancet Haematol 2019 Mar;6(3):e132-e143

Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.

Background: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial.

Methods: In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m intravenous bolus on day 1 and 10 mg/m intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037.

Findings: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively).

Interpretation: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial.

Funding: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.
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http://dx.doi.org/10.1016/S2352-3026(18)30221-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503965PMC
March 2019
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