Publications by authors named "George L Chen"

37 Publications

Serological Response to Vaccination after Autologous Transplantation for Multiple Myeloma Is Associated with Improved Progression-Free and Overall Survival.

Transplant Cell Ther 2021 Mar 13;27(3):245.e1-245.e8. Epub 2020 Dec 13.

Transplant and Cellular Therapy Program, Department of Medicine, RPCCC, Buffalo, New York. Electronic address:

Revaccination after autologous hematopoietic cell transplantation (AHCT) is recommended in post-HCT survivorship guidelines to restore humoral immunity. Data on seroconversion after AHCT and vaccination in multiple myeloma (MM) patients are limited. We investigated the feasibility and effectiveness of vaccination post-AHCT and analyzed the restoration of humoral immunity and patient prognosis. Anti-pathogen titers were measured within a median of 2 days before and 96 days after AHCT and following revaccination in 139 MM patients who had a first AHCT from 2013 to 2016. Most (84%) patients received at least one dose of any planned vaccines. High-dose melphalan with AHCT restored measurable immunity in 18% of patients. In an additional >60% of patients, seroconversion occurred after vaccination; however, despite vaccination, 20% of patients remained seronegative for most pathogens. Attainment of MM complete response post-AHCT was associated with higher rates of seroconversion which yielded significantly longer progression-free and overall survival. Our study demonstrates the feasibility of post-AHCT vaccination, supporting measurement of post-vaccination titers to determine which patients should be considered for antimicrobial prophylaxis, as seroconversion does not occur in all patients. Titer seroconversion is a potential indicator of the immunological effects of AHCT, with restoration of humoral immunity demonstrating improved survival.
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http://dx.doi.org/10.1016/j.jtct.2020.11.009DOI Listing
March 2021

Initial therapy for chronic graft-versus-host disease: analysis of practice variation and failure-free survival.

Blood Adv 2021 11;5(22):4549-4559

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

Prior clinical trials largely considered prednisone 1 mg/kg per day with or without calcineurin inhibitor as standard initial therapy for chronic graft-versus-host disease (cGVHD), but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 patients with cGVHD treated with initial systemic immune suppressive (IS) therapy from 3 prior cGVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥0.4 mg/kg per day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were nonprednisone 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 failure-free survival (FFS; a composite of death, relapse, and new IS therapy), overall survival (OS), or nonrelapse mortality (NRM). Among the prednisone-based approaches, steroid dose was <0.25 (9%), 0.25 to 0.74 (36%), 0.75 to 1.25 (42%), or >1.25 mg/kg per day (13%). Prednisone dose within the patients treated with steroids 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 nonsteroid 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759136PMC
November 2021

Nonrelapse mortality among patients diagnosed with chronic GVHD: an updated analysis from the Chronic GVHD Consortium.

Blood Adv 2021 10;5(20):4278-4284

Blood and Marrow Transplant Program, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH.

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

Replicated Risk Index of Patient Functional Status Prior to Allogeneic Hematopoietic Cell Transplantation Predicts Healthcare Utilization and Survival.

Transplant Cell Ther 2021 10 30;27(10):875.e1-875.e9. Epub 2021 Jun 30.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Poor physical functioning is associated with adverse outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Analytic tools to predict mortality in alloHCT recipients include the HCT Comorbidity Index (HCT-CI) based on comorbidities and the Disease Risk Index (DRI) based on disease and disease status. We developed and replicated a risk model for overall survival (OS), early mortality (ie, death from any cause at or before day +100), initial hospital length of stay (LOS), and percentage of inpatient days within the first year post-alloHCT. In this study, we incorporated a physical therapy (PT) assessment with the HCT-CI and DRI to improve outcome predictions. The well-defined and feasible measure of functional status for assessing risk includes (1) the number of sit-to-stands performed in 30 seconds, (2) performance of 25 step-ups on the right/left side with (3) oxygen saturation recovery and (4) heart rate recovery, (5) weight-bearing ability, (6) assistance with ambulation, (7) motor and grip strength, (8) sensory and coordination impairment (eg, self-reported peripheral neuropathy, imbalance), (9) self-reported pain, and (10) limited endurance (ie, inability to complete step-ups and/or sit-to-stands). Our training cohort (TC) included 349 consecutive alloHCT recipients at Roswell Park treated between 2010 and 2016 and a subsequent replication cohort (RC; n = 163) treated between 2016 and 2019. Four of the 10 metrics-self-reported pain, limited endurance, self-reported neuropathy, and <10 sit-to-stands in 30 seconds-were identified as significant predictors and were included in the multivariable models with the HCT-CI and DRI to create a new risk index (HCT-PCDRI: HCT-physical, comorbidity, and DRI) for outcomes. Models were tested in the RC. Shorter OS was associated with self-reported pain, limited endurance, higher HCT-CI, and higher DRI. At a median follow-up of 34 months, the 3-year OS based on the HCT-PCDRI was 30% for the very-high-risk group, 54% for the high-risk group, 49% for the intermediate-risk group, and 80% for the low-risk group. The number of patients identified as very high risk increased from 55 using HCT-CI alone to 120 with the new HCT-PCDRI, whereas the number in the low-risk group decreased from 91 to 45. Early mortality and a higher percentage of inpatient days within the first year post-alloHCT (a proxy for poor quality of life and high healthcare utilization) were associated with self-reported pain, higher HCT-CI, and higher DRI. A shorter initial LOS (ie, initial low healthcare utilization) was associated with performance of >10 sit-to-stands in 30 seconds, no self-reported neuropathy, and lower HCT-CI. These PT metrics combined with the HCT-CI and DRI created the HCT-PCDRI, which resulted in more patients being categorized accurately as high risk versus low risk. The HCT-PCDRI results were replicated in an independent cohort. Pre-alloHCT PT metrics with self-reported symptoms (pain and neuropathy) were associated with survival post-alloHCT and prolonged hospital LOS. The HCT-PCDRI scoring system for risk stratification of alloHCT recipients more accurately identifies patients at potential risk of poor outcomes. The HCT-PCDRI can be tested in <15 minutes to identify patients for intervention before or during treatment to potentially improve outcomes.
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http://dx.doi.org/10.1016/j.jtct.2021.06.021DOI Listing
October 2021

Optical Coherence Tomography for Quantifying Human Cutaneous Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 03 16;27(3):271.e1-271.e8. Epub 2020 Dec 16.

Department of Creative IT Engineering and Electrical Engineering, Pohang University of Science and Technology, Pohang, Republic of Korea. Electronic address:

Chronic graft-versus-host disease (cGVHD) is the most common cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation (alloHCT). Cutaneous cGVHD is characterized by thickening of the skin and connective tissues, causing discomfort and limited mobility. Current assessment of these skin lesions is based on physical examination of their thickening, pinchability, and movability. Optical coherence tomography (OCT) is a noninvasive, high-resolution technique using near-infrared light to interrogate tissues and image the microstructure without the use of contrast agents. We determined the applicability of OCT to human cutaneous cGVHD. Seven patients with varying degrees of cutaneous cGVHD, including 3 controls who underwent autologous HCT were prospectively examined using the cGVHD Skin (Vienna) Scale and imaged with OCT. Analysis of OCT images and clinical exams revealed that stratum corneum thickness, epidermal thickness, and depth of light transmission were correlated with cutaneous cGVHD severity in the hands, forearms, upper arms, legs, thighs, and upper back (P ≤ .03). Longitudinal OCT changes during cGVHD treatment paralleled clinical changes in the arm and upper back. OCT changes were observed in the absence of clinical changes. OCT imaging reflects the severity of cutaneous cGVHD and can be used to follow these lesions. OCT may facilitate the design of therapeutic trials in cGVHD by providing a quantitative measurement of cGVHD severity. Additional studies are needed.
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http://dx.doi.org/10.1016/j.jtct.2020.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010224PMC
March 2021

Identification of Neurotoxicity after Chimeric Antigen Receptor (CAR) T Cell Infusion without Deterioration in the Immune Effector Cell Encephalopathy (ICE) Score.

Biol Blood Marrow Transplant 2020 11 29;26(11):e271-e274. Epub 2020 Jul 29.

Transplant and Cellular Therapy Program, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

A consensus grading schema for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) resulting from chimeric antigen receptor (CAR) T cell therapy was published in 2019. Although this consensus grading schema has been imperative in identifying and monitoring CRS and ICANS in our CAR T cell population, we observed patients exhibiting subtle neurotoxicity symptoms prior to a decrease in their immune effector cell (ICE) score, which is one component of ICANS. Because we treat grade 1 ICANS at our institution, identification of early neurotoxicity symptoms is important. Additionally, we found changes in personality, occupational confusion, or inability to answer dichotomous questions were early signs of neurotoxicity. Therefore, we developed a 3-step command tool to supplement the ICE evaluation. We present 2 examples of patients who exhibited early neurotoxicity symptoms and led us to develop this tool and 1 in whom it was effective. We propose that CAR T cell patients are consistently followed by a clinical care provider who is familiar with the patient to recognize early changes in personality, behavior, and cognition. Additionally, we propose that the multistep command tool be used in conjunction with the ICE score to detect early symptoms of ICANS. Early intervention has the potential to prevent irreversible neurotoxicity.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.031DOI Listing
November 2020

Low-Level Cytomegalovirus Antigenemia Promotes Protective Cytomegalovirus Antigen-Specific T Cells after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 11 25;26(11):2147-2154. Epub 2020 Jul 25.

Department of Medicine, Transplant and Cellular Therapy Program, Roswell Park, Buffalo, New York.

Previous studies have reported a beneficial effect from cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (alloHCT) on immune reconstitution. We determined the CMV antigenemia level associated with increased CMV antigen-specific T cells (CASTs) at day +100 and decreased CMV reactivation after day +100. CMV reactivation and CASTs were measured with CMV antigenemia and CMV-specific major histocompatibility complex multimers. The analysis consisted of 775 CAST measurements obtained before and 30, 100, and 365 days post-alloHCT from 327 consecutive patients treated between 2008 and 2016. Detectable CASTs correlated with recipient (P < .0001) and donor (P < .0001) CMV seropositivity pre-alloHCT. CMV reactivation before day +100 was associated with a higher proportion of patients who achieved ≥3 CASTs/µL by day +100 (61% with versus 39% without reactivation, P < .001). In alloHCT recipients at high risk for CMV reactivation (RD) with a maximum of grade II acute graft-versus-host-disease, reactivating CMV before day +100 and achieving ≥3 versus <3 CASTs/µL at day +100 was associated with reduced CMV reactivation from day +100 to +365 (27% versus 62%, P = .04). This protective effect was observed with low-level but not high-level CMV reactivation (<5 versus ≥5/50,000 polymorphonuclear leukocytes + pp65, respectively). These findings suggest low-level CMV reactivation may be beneficial and that treatment may be delayed until progression. These findings will need validation in prospective clinical trials using CMV PCR and antigenemia assays.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609607PMC
November 2020

β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Medicine, Transplant and Cellular Therapy Program, and.

Acute graft versus host disease (aGvHD) remains a major impediment to successful allogeneic hematopoietic cell transplantation (allo-HCT). To solve this problem, a greater knowledge of factors that regulate the differentiation of donor T cells toward cytotoxic cells or Tregs is necessary. We report that the β2-adrenergic receptor (β2-AR) is critical for regulating this differentiation and that its manipulation can control aGvHD without impairing the graft-versus-tumor (GvT) effect. Donor T cell β2-AR expression and signaling is associated with decreased aGvHD when compared with recipients of β2-AR-/- donor T cells. We determined that β2-AR activation skewed CD4+ T cell differentiation in vitro and in vivo toward Tregs rather than the T helper 1 (Th1) phenotype. Treatment of allo-HCT recipients with a selective β2-agonist (bambuterol) ameliorated aGvHD severity. This was associated with increased Tregs, decreased cytotoxic T cells, and increased donor BM-derived myeloid-derived suppressor cells (MDSCs) in allogeneic and humanized xenogeneic aGvHD models. β2-AR signaling resulted in increased Treg generation through glycogen synthase kinase-3 activation. Bambuterol preserved the GvT effect by inducing NKG2D+ effector cells and central memory T cells. These data reveal how β-AR signaling can be targeted to ameliorate GvHD severity while preserving GvT effect.
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http://dx.doi.org/10.1172/jci.insight.137788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406296PMC
June 2020

Correction: Immune profiling in diffuse large B-cell lymphoma and mantle cell lymphoma patients treated with autologous hematopoietic cell transplant.

Bone Marrow Transplant 2020 Jan;55(1):272

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41409-019-0647-5DOI Listing
January 2020

The Chronic Graft-versus-Host Disease Failure-Free Survival (cGVHD-FFS) Index.

Biol Blood Marrow Transplant 2019 12 5;25(12):2468-2473. Epub 2019 Aug 5.

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

In clinical trials of chronic graft-versus-host disease (cGVHD), the need to start a new systemic treatment is considered a treatment failure. A composite endpoint called "failure-free survival" (FFS), where events are initiation of a new systemic cGVHD treatment, recurrent malignancy, and death, has been suggested as a possible long-term indicator of success. The goal of the current study was to identify changes in cGVHD manifestations from baseline to 6 months that could accurately predict subsequent longer-term FFS, thereby making it possible to assess outcomes earlier than would otherwise be possible. We used data from 2 prospective, multicenter, observational studies to develop the cGVHD-FFS index. The cGVHD-FFS index was calculated at 6 months, a typical timepoint for assessment of the primary endpoint of phase II cGVHD trials. Subsequent FFS was only 45% within the next 2 years. We found that changes in the scores for the eyes, joint/fascia, and mouth ulcers from baseline to 6 months were associated with subsequent FFS, but the prognostic accuracy of these changes was not adequate for use in trials. Biomarker studies might help to identify criteria that improve prediction of long-term clinical outcomes in patients with cGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900444PMC
December 2019

Immune profiling in diffuse large B-cell lymphoma and mantle cell lymphoma patients treated with autologous hematopoietic cell transplant.

Bone Marrow Transplant 2020 01 21;55(1):77-85. Epub 2019 Jun 21.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

This is the first longitudinal study of immune profiles and autologous hematopoietic cell transplant (AHCT) survival in B-cell non-Hodgkin lymphoma (B-NHL) patients and the effect of plerixafor mobilization on immune reconstitution in this population. A comprehensive immunophenotyping panel was performed in 104 consecutive adult B-NHL patients (58% diffuse large B cell and 42% mantle cell) who received AHCT (1/2008-11/2014), at a median of 28 days pre-AHCT (N = 104) and Day +100 (N = 83) post-AHCT. Median follow-up post-AHCT was 61 months (range: 8-120 months). Compared to patients mobilized with filgrastim and plerixafor, patients mobilized with filgrastim alone had a higher proportion of CD4+ naïve (p = 0.006) and CD8+ central memory T-cells (p = 0.006) pre-AHCT. For patients transplanted in complete remission (CR), a higher proportion of CD8+ effector memory T-cells pre-AHCT was associated with worse progression-free survival (PFS; p < 0.01) and overall survival (OS; p < 0.01). A higher ratio of CD8:CD4+ central memory T-cells pre-AHCT was associated with worse PFS (p < 0.0001) and OS (p = 0.0034). This same ratio measured post-AHCT among patients in CR on Day +100 was associated with worse and OS (p = 0.008) but not PFS (p = not significant). These immune subsets are complementary biomarkers which identify patients transplanted in CR who have poor survival prognoses and may warrant further clinical interventions.
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http://dx.doi.org/10.1038/s41409-019-0591-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925359PMC
January 2020

Organ Changes Associated with Provider-Assessed Responses in Patients with Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2019 09 11;25(9):1869-1874. Epub 2019 May 11.

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

Assessments of overall improvement and worsening of chronic graft-versus-host disease (GVHD) manifestations by the algorithm recommended by National Institutes of Health (NIH) response criteria do not align closely with those reported by providers, particularly when patients have mixed responses with improvement in some manifestations but worsening in others. To elucidate the changes that influence provider assessment of response, we used logistic regression to generate an overall change index based on specific manifestations of chronic GVHD measured at baseline and 6 months later. We hypothesized that this overall change index would correlate strongly with overall improvement as determined by providers. The analysis included 488 patients from 2 prospective observational studies who were randomly assigned in a 3:2 ratio to discovery and replication cohorts. Changes in bilirubin and scores of the lower gastrointestinal tract, mouth, joint/fascia, lung, and skin were correlated with provider-assessed improvement, suggesting that the main NIH response measures capture relevant information. Conversely, changes in the eye, esophagus, and upper gastrointestinal tract did not correlate with provider-assessed response, suggesting that these scales could be modified or dropped from the NIH response assessment. The area under the receiver operator characteristic curve in the replication cohort was 0.72, indicating that the scoring algorithm for overall change based on NIH response measures is not well calibrated with provider-assessed response.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755054PMC
September 2019

Impact of conditioning regimen on peripheral blood hematopoietic cell transplant.

World J Clin Oncol 2019 Feb;10(2):86-97

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, United States.

Aim: To investigate infused hematopoietic cell doses and their interaction with conditioning regimen intensity +/- total body irradiation (TBI) on outcomes after peripheral blood hematopoietic cell transplant (PBHCT).

Methods: Our retrospective cohort included 247 patients receiving a first, T-replete, human leukocyte antigen-matched allogeneic PBHCT and treated between 2001 and 2012. Correlations were calculated using the Pearson product-moment correlation coefficient. Overall survival and progression free survival curves were generated using the Kaplan-Meier method and compared using the log-rank test.

Results: Neutrophil engraftment was significantly faster after reduced intensity TBI based conditioning [reduced intensity conditioning (RIC) + TBI] and > 4 × 10 CD34+ cells/kg infused. A higher total nucleated cell dose led to a higher incidence of grade II-IV acute graft-versus-host disease in the myeloablative + TBI regimen group ( = 0.03), but no significant difference in grade III-IV graft-versus-host disease. A higher total nucleated cell dose was also associated with increased incidence of moderate/severe chronic graft-versus-host disease, regardless of conditioning regimen. Overall and progression-free survival were significantly better in patients with a RIC + TBI regimen and total nucleated cell dose > 8 × 10/kg (3 years, overall survival: 70% 38%, = 0.02, 3 years, progression free survival: 64% 38%, = 0.02).

Conclusion: TBI and conditioning intensity may alter the relationship between infused cell doses and outcomes after PBHCT. Immune cell subsets may predict improved survival after unmanipulated PBHCT.
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http://dx.doi.org/10.5306/wjco.v10.i2.86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390118PMC
February 2019

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity.

Biol Blood Marrow Transplant 2019 04 6;25(4):689-698. Epub 2018 Oct 6.

BMT Program, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Disease relapse and toxicity are the shortcomings of reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that adding total body irradiation (TBI) to and decreasing melphalan (Mel) from a base RIC regimen of fludarabine (Flu) and Mel would increase cytoreduction and improve disease control while decreasing toxicity. We performed a phase II trial of Flu 160 mg/m, Mel 50 mg/m, and TBI 400 cGy (FluMelTBI-50, n = 61), followed by a second phase II trial of Flu 160 mg/m, Mel 75 mg/m, and TBI 400cGy (FluMelTBI-75, n = 94) as RIC for alloHCT. Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m and Mel 140 mg/m. Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning. The median (range) follow-up for all patients was 51 (15 to 103) months. Day 100 donor lymphoid chimerism and transplant-related mortality, neutrophil and platelet engraftment, acute and chronic graft versus host disease incidence, overall survival (OS), and progression-free survival (PFS) were equivalent between FluMel, FluMelTBI-50, and FluMelTBI-75. Stomatitis wasdecreased for FluMelTBI versus FluMel (P < .01). PFS for patients not in complete remission on alloHCT was improved for FluMelTBI-75 versus FluMel (P = .03). On multivariate analysis, OS (P = .05) and PFS (P = .05) were significantly improved for FluMelTBI-75 versus FluMel. FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451676PMC
April 2019

Employment, Insurance, and Financial Experiences of Patients with Chronic Graft-versus-Host Disease in North America.

Biol Blood Marrow Transplant 2019 03 5;25(3):599-605. Epub 2018 Oct 5.

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

Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445749PMC
March 2019

Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802.

Blood Adv 2018 08;2(15):1882-1888

National Marrow Donor Program, Minneapolis, MN.

Amphiregulin (AREG) is an epidermal growth factor receptor ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously reported that circulating AREG is elevated in late-onset aGVHD (occurring after 100 days posttransplant), but its clinical relevance in the context of aGVHD risk is unknown. We measured AREG in 251 aGVHD onset blood samples from Blood and Marrow Clinical Trials Network (BMT CTN) primary treatment trials and determined their association with GVHD severity, day 28 complete or partial response (CR/PR) to first-line therapy, overall survival (OS), and nonrelapse mortality (NRM). Every doubling of plasma AREG was associated with a 33% decrease in the odds of day 28 CR/PR (odds ratio [OR], 0.67; < .01). An AREG threshold of 33 pg/mL or greater divided patients with Minnesota standard-risk (SR) aGVHD into a distinct group with a significantly lower likelihood of: day 28 CR/PR (72% vs 85%; = .02); greater 2-year NRM (42% vs 15%; < .01); and inferior OS (40% vs 66%; < .01). High AREG ≥ 33 pg/mL also stratified patients with Minnesota high-risk (HR) aGVHD: day 28 CR/PR (54% vs 83%; = .03) and 2-year NRM (53% vs 11%; < .01), with a trend toward inferior 2-year OS (37% vs 60%; = .09). High-circulating AREG (≥33 pg/mL) reclassifies patients into HR subgroups and thereby further refines the Minnesota aGVHD clinical risk score.
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http://dx.doi.org/10.1182/bloodadvances.2018017343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093743PMC
August 2018

BPX-501 T cells interfere with minimal residual disease evaluation of B-cell acute lymphoblastic leukemia.

Bone Marrow Transplant 2018 05 17;53(5):651-653. Epub 2018 Jan 17.

Department of Medicine, Blood and Marrow Transplant Program, Roswell Park Cancer Institute, Buffalo, NY, USA.

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http://dx.doi.org/10.1038/s41409-017-0036-xDOI Listing
May 2018

Immune signatures associated with improved progression-free and overall survival for myeloma patients treated with AHSCT.

Blood Adv 2017 Jun 20;1(15):1056-1066. Epub 2017 Jun 20.

Department of Medicine and.

Multiple therapeutic options exist for multiple myeloma (MM), including autologous hematopoietic stem cell transplantation (AHSCT). Measurement of minimal residual disease (MRD) and immune reconstitution is rapidly becoming an integral part of the care of MM patients. We investigated comprehensive immune profiling (IP) associated with progression-free survival (PFS) and overall survival (OS). From August 2007 to January 2014, 101 consecutive MM patients underwent peripheral blood IP and marrow MRD testing before and approximately 100 days after AHSCT. Higher pre-AHSCT CD19 B-cell counts correlated with improved 2-year PFS (83% [highest quartile] vs 53% [lowest quartile]; = .01) and OS (93% [highest quartile] vs 63% [lowest quartile]; = .0003). This effect was seen primarily in patients with MRD-positive marrow tests. Higher γδ T-cell counts post-AHSCT correlated with improved 2-year PFS (65% [highest quartile] vs 45% [lowest quartile]; = .02) and OS (89% [highest quartile] vs 65% [lowest quartile]; = .01). Higher CD4 central memory (CM) cell counts post-AHSCT were associated with improved 2-year OS (95% [upper quartile] vs 47% [lowest quartile]; = .0003) but not PFS. The higher γδ T-cell and CD4 CM-cell count associations were primarily observed in MRD-negative patients post-AHSCT and in patients not receiving maintenance therapy. This proof-of-concept study demonstrates that IP before and after AHSCT can be of complementary prognostic value for depth of response. Maintenance therapy seems to overcome negative IP. IP and MRD should be measured in clinical trials of maintenance therapy with novel agents post-AHSCT for MM to confirm their utility for prognosis and management.
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http://dx.doi.org/10.1182/bloodadvances.2017005447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728317PMC
June 2017

Anti-Platelet-Derived Growth Factor Receptor Alpha Chain Antibodies Predict for Response to Nilotinib in Steroid-Refractory or -Dependent Chronic Graft-Versus-Host Disease.

Biol Blood Marrow Transplant 2018 02 16;24(2):373-380. Epub 2017 Oct 16.

Department of Medicine, Medicine/BMT Division, Stanford University School of Medicine, Stanford, California. Electronic address:

Imatinib has clinical activity in chronic graft-versus-host disease (cGVHD), a significant complication of allogeneic hematopoietic cell transplant. Nilotinib is a tyrosine kinase inhibitor that targets the same receptors as imatinib but with different affinities. We tested the hypothesis that nilotinib is safe and has clinical activity in cGVHD. Thirty-three participants were enrolled in a phase I/II dose escalation and dose extension clinical trial of nilotinib for the treatment of steroid-refractory or- dependent cGVHD (ClinicalTrials.gov, NCT01155817). We assessed safety, clinical response, and pretreatment anti-platelet-derived growth factor receptor alpha chain (anti-PDGFRA) antibody levels. The 200-mg dose was identified as the maximum tolerated dose and used for the phase II dose extension study. At 6 months the incidence of failure-free survival (FFS), cGVHD progression, and nilotinib intolerance resulting in its discontinuation was 50%, 23%, and 23%, respectively. cGVHD responses in skin, joints, and mouth were observed at 3 and 6 months based on improvement in respective National Institutes of Health organ severity scores. Pretreatment anti-PDGFRA antibody levels ≥ .150 optical density as measured by ELISA correlated with longer FFS time (P < .0005) and trended with time until cGVHD progression (P < .06) but not drug intolerance. Nilotinib may be effective for corticosteroid-resistant or -refractory cGVHD in some patients, but its use is limited by intolerable side effects. Selection of patients with high pretreatment anti-PDGFRA antibody levels might improve the risk-to-benefit ratio of nilotinib and better justify its side effects.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.021DOI Listing
February 2018

Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function.

J Immunol 2017 07 26;199(1):336-347. Epub 2017 May 26.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage genetically distinct normal host tissues. In addition to TCR signaling, costimulatory pathways are involved in T cell activation. CD27 is a TNFR family member expressed on T cells, and its ligand, CD70, is expressed on APCs. The CD27/CD70 costimulatory pathway was shown to be critical for T cell function and survival in viral infection models. However, the role of this pathway in allo-HCT is previously unknown. In this study, we have examined its contribution in GVHD pathogenesis. Surprisingly, Ab blockade of CD70 after allo-HCT significantly increases GVHD. Interestingly, whereas donor T cell- or bone marrow-derived CD70 plays no role in GVHD, host-derived CD70 inhibits GVHD as CD70 hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased histopathologic damage compared with wild-type hosts. In addition, CD70 hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4 and CD8 effector T cells is increased in CD70 versus wild-type hosts. Mechanistic analyses suggest that CD70 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Together, our findings demonstrate that host CD70 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.
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http://dx.doi.org/10.4049/jimmunol.1502181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503479PMC
July 2017

Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors.

Blood 2016 11 13;128(19):2350-2358. Epub 2016 Sep 13.

Blood and Marrow Transplantation Program, The Icahn School of Medicine at Mount Sinai, New York, NY.

Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.
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http://dx.doi.org/10.1182/blood-2015-09-669846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106113PMC
November 2016

Quantifying MHC dextramer-induced NFAT activation in antigen-specific T cells as a functional response parameter.

Methods 2017 01 17;112:75-83. Epub 2016 Jun 17.

Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

MHC-multimers are reagents used for the detection and enumeration of antigen-specific T cells (ASTs). These reagents exploit the mechanism by which T cell receptors (TCR) on cytotoxic CD8 T cells recognize specific antigens in the context of a major histocompatibility complex (MHC) molecule during antigen presentation. MHC-multimers are fluorescently-labeled dextran polymers that carry MHC Class I molecules and peptide sequences that can be modified to represent specific cognate sequences of the antigen of interest with dextramers having a 10-fold multiplicity of the MHC/peptide combination within a single multimer. Since the binding of antigen-specific dextramers mimics antigen presentation to the TCR, the present study sought to determine whether this TCR engagement on the AST was sufficient to elicit a functional T cell response. The effect of binding of CMV specific dextramers on the activation of the NFAT signal transduction cascade was assessed in peripheral blood from bone marrow transplant recipients previously determined to be positive for CMV-ASTs (CASTs). NFAT activation was quantified by measuring nuclear translocation of NFAT1 in CD8+ CASTs and CD8+ non-CASTs by imaging flow cytometry. Our results demonstrate that an increase in the nuclear localization of NFAT1 was detectable in the CASTs following the CMV-dextramer binding and could be observed as early as 10min post-exposure. The NFAT1 activation correlated with a downstream functional response in the form of interferon gamma production. Sample preparation, temperature, and duration of dextramer exposure were important parameters affecting the dextramer-induced NFAT activation with 2h exposure in whole blood at room temperature being the optimal of the conditions tested. Intra- and inter-individual heterogeneity was observed with regards to the NFAT activation in the CASTs. Importantly, no effect of the dextramers was observed in the CD8+ non-CASTs, and therefore dextramer negative cell populations. Exposure to PMA/ionomycin following dextramer exposure resulted in a homogeneous NFAT activation in both the dextramer-positive but NFAT1 nonresponsive CAST and non-CAST cells. Thus, the data demonstrate that binding of antigen-specific dextramers to ASTs specifically results in activation of NFAT, that the NFAT activation correlates with a downstream functional response and that the response can be heterogeneous. This functional parameter may provide insight to the issue whether enumeration alone of ASTs is a sufficient parameter to assess an individual's immune status against a specific antigen.
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http://dx.doi.org/10.1016/j.ymeth.2016.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821144PMC
January 2017

Biomarker Panel for Chronic Graft-Versus-Host Disease.

J Clin Oncol 2016 08 23;34(22):2583-90. Epub 2016 May 23.

Jeffrey Yu, Kushi Kushekhar, Mohammad Abu Zaid, and Sophie Paczesny, Indiana University School of Medicine, Indianapolis, IN; Barry E. Storer, Paul J. Martin, Mary E. Flowers, John A. Hansen, Stephanie J. Lee, Qing Zhang, Philip R. Gafken, and Yuko Ogata, Fred Hutchinson Cancer Research Center; Barry E. Storer, University of Washington School of Medicine, Seattle, WA; Mukta Arora, University of Minnesota, Minneapolis, MN; Corey Cutler, Dana-Farber Cancer Institute, Boston, MA; Madan Jagasia, Vanderbilt University, Nashville, TN; Joseph Pidala, H. Lee Moffitt Cancer Center, Tampa, FL; Betty K. Hamilton, Cleveland Clinic Foundation, Cleveland, OH; George L. Chen, Roswell Park Cancer Institute, Buffalo, NY; and Iskra Pusic, Washington University School of Medicine, St Louis, MO.

Purpose: To identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT).

Patients And Methods: Using a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172).

Results: Of 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively.

Conclusion: We conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD.
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http://dx.doi.org/10.1200/JCO.2015.65.9615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012688PMC
August 2016

Late Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2016 Mar 2;22(3):449-55. Epub 2015 Nov 2.

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

Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the National Institutes of Health Consensus Conference. We enrolled a prospective cohort of 911 hematopoietic cell transplantation (HCT) recipients at 13 centers between March 2011 and May 2014 to evaluate 4 GVHD syndromes: late acute GVHD (aGVHD), chronic GVHD (cGVHD), bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. The majority of patients received a peripheral blood stem cell transplant (81%) following nonmyeloablative or reduced-intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood grafts were underrepresented in our cohort (≤11%). The cumulative incidence of late aGVHD (late onset and recurrent) was 10% at a median of 5.5 months post-HCT, that of cGVHD was 47% at a median of 7.4 months, that of bronchiolitis obliterans was 3% at a median of 12.2 months, and that of cutaneous sclerosis was 8% at a median onset of 14.0 months. Late aGVHD and bronchiolitis obliterans had particularly high nonrelapse mortality of 23% and 32%, respectively, by 2 years after diagnosis. The probability of late aGVHD- and cGVHD-free, relapse-free survival was 38% at 1 year post-HCT and 26% at 2 years post-HCT. This multicenter prospective study confirms the high rate of late aGVHD and cGVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success.
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http://dx.doi.org/10.1016/j.bbmt.2015.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4787270PMC
March 2016

Housing Temperature-Induced Stress Is Suppressing Murine Graft-versus-Host Disease through β2-Adrenergic Receptor Signaling.

J Immunol 2015 Nov 12;195(10):5045-54. Epub 2015 Oct 12.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation, a potentially curative therapy for hematologic diseases. It has long been thought that murine bone marrow-derived T cells do not mediate severe GVHD because of their quantity and/or phenotype. During the course of experiments testing the impact of housing temperatures on GVHD, we discovered that this apparent resistance is a function of the relatively cool ambient housing temperature. Murine bone marrow-derived T cells have the ability to mediate severe GVHD in mice housed at a thermoneutral temperature. Specifically, mice housed at Institutional Animal Care and Use Committee-mandated, cool standard temperatures (∼ 22°C) are more resistant to developing GVHD than are mice housed at thermoneutral temperatures (∼ 30°C). We learned that the mechanism underlying this housing-dependent immunosuppression is associated with increased norepinephrine production and excessive signaling through β-adrenergic receptor signaling, which is increased when mice are cold stressed. Treatment of mice housed at 22°C with a β2-adrenergic antagonist reverses the norepinephrine-driven suppression of GVHD and yields similar disease to mice housed at 30°C. Conversely, administering a β2-adrenergic agonist decreases GVHD in mice housed at 30°C. In further mechanistic studies using β2-adrenergic receptor-deficient (β2-AR(-/-)) mice, we found that it is host cell β2-AR signaling that is essential for decreasing GVHD. These data reveal how baseline levels of β-adrenergic receptor signaling can influence murine GVHD and point to the feasibility of manipulation of β2-AR signaling to ameliorate GVHD in the clinical setting.
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http://dx.doi.org/10.4049/jimmunol.1500700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637222PMC
November 2015

Granzyme B-Mediated Activation-Induced Death of CD4+ T Cells Inhibits Murine Acute Graft-versus-Host Disease.

J Immunol 2015 Nov 21;195(9):4514-23. Epub 2015 Sep 21.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;

Granzyme B (GzmB) has previously been shown to be critical for CD8(+) T cell-mediated graft-versus-host disease (GVHD) but dispensable for GVHD mediated by CD4(+) T cells. However, previous studies used high doses of CD4(+) T cells in MHC-mismatched models that caused rapid and lethal GVHD. Because of the hyperacute lethality, it is possible that the role of GzmB was concealed by the system. Therefore, in this study, we have titrated down the T cell dose to precisely determine the contribution of GzmB in GVHD mediated by CD4(+)CD25(-) T cells. Surprisingly, we have found that GzmB(-/-)CD4(+)CD25(-) T cells cause more severe GVHD compared with wild-type CD4(+)CD25(-) T cells in both MHC-matched and mismatched models. Mechanistic analyses reveal that although GzmB does not affect donor T cell engraftment, proliferation or tissue-specific migration, GzmB(-/-) CD4(+)CD25(-) T cells exhibit significantly enhanced expansion because of GzmB-mediated activation-induced cell death of wild-type CD4(+)CD25(-) T cells. As a result of enhanced expansion, GzmB(-/-) T cells produced higher amounts of proinflammatory cytokines (e.g., TNF-α and IFN-γ) that may contribute to the exacerbated GVHD. These results reveal that GzmB diminishes the ability of CD4(+) T cells to cause acute GVHD, which contradicts its established role in CD8(+) T cells. The differential roles suggest that targeting GzmB in selected T cell subsets may provide a strategy to control GVHD.
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http://dx.doi.org/10.4049/jimmunol.1500668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610854PMC
November 2015

A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.

Clin Cancer Res 2016 Jan 16;22(2):319-27. Epub 2015 Sep 16.

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

Purpose: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life.

Experimental Design: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy.

Results: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients.

Conclusions: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715914PMC
January 2016

Dextramer reagents are effective tools for quantifying CMV antigen-specific T cells from peripheral blood samples.

Cytometry B Clin Cytom 2015 Jan 23;88(1):6-20. Epub 2014 Oct 23.

Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, 14263.

The enumeration of antigen-specific T cells is increasingly relevant in clinical and research settings. This information is useful for evaluating immune responses to treatment, monitoring the efficacy of anticancer vaccines, and for detecting self-reactive T cells in autoimmune disorders. Quantifying antigen-specific T cells can be accomplished via IFNγ ELISpot assay, the measurement of intracellular cytokine production by flow cytometry, or by lymphocyte proliferation assays in response to antigen. While robust, these technologies are labor-intensive and can take several days to obtain results. New technology has led to more powerful tools for quickly and accurately measuring antigen-specific T cells by flow cytometry via fluorescently-labeled TCR-specific multimers. In this study, we evaluated the use of an assay based on Dextramer reagents for enumerating cytomegalovirus (CMV) antigen-specific T cells (CASTs). Assay performance characteristics were assessed by establishing Dextramers' sensitivity (median=0.4; range=0.1-1.4 CASTs μl(-1) ), determining their specificity (100%), evaluating assay robustness with different leukocyte sources and assay reproducibility via interlaboratory and interinstrument investigations. Furthermore, the levels of CASTs in 95 peripheral blood samples from 62 unique blood and marrow transplants recipients correlated well between Dextramers and Tetramers (R(2)  =0.9042).
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http://dx.doi.org/10.1002/cyto.b.21196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376327PMC
January 2015

Early versus late preemptive allogeneic hematopoietic cell transplantation for relapsed or refractory acute myeloid leukemia.

Biol Blood Marrow Transplant 2014 Sep 24;20(9):1369-74. Epub 2014 May 24.

Department of Medicine, BMT Program, Roswell Park Cancer Institute, Buffalo, New York. Electronic address:

Many patients with relapsed or refractory acute myeloid leukemia (AML) do not receive allogeneic hematopoietic cell transplantation (alloHCT) because they are unable to achieve a complete remission (CR) after reinduction chemotherapy. Starting in January 2003, we prospectively assigned patients with AML with high-risk clinical features to preemptive alloHCT (p-alloHCT) as soon as possible after reinduction chemotherapy. High-risk clinical features were associated with poor response to chemotherapy: primary induction failure, second or greater relapse, and first CR interval <6 months. We hypothesized that any residual disease would be maximally reduced at the time of transplant, resulting in the best milieu and most lead time for developing a graft-versus-leukemia effect and in improved long-term overall survival (OS) without excess toxicity. This analysis studied the effect of transplant timing on p-alloHCT in 30 patients with high-risk clinical features of 156 consecutive AML patients referred for alloHCT. We compared early p-alloHCT within 4 weeks of reinduction chemotherapy before count recovery with late p-alloHCT 4 weeks after reinduction chemotherapy with count recovery. OS and progression-free survival (PFS) at 2 years were not significantly different for early versus late p-alloHCT (OS 23% versus 33%, respectively, P > .1; PFS 18% versus 22%, respectively, P > .1). Day 100 and 1-year transplant-related mortality were similar (33.3% versus 22.2%, P > .1; 44.4% versus 42.9%, P > .1, respectively). Preemptive alloHCT allowed 30 patients to be transplanted who would normally not receive alloHCT. Clinical outcomes for early p-alloHCT are similar to those for late p-alloHCT without excess toxicity. Early p-alloHCT is a feasible alternative to late p-alloHCT for maximizing therapy of AML that is poorly responsive to induction chemotherapy.
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http://dx.doi.org/10.1016/j.bbmt.2014.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292802PMC
September 2014

Remestemcel-L for acute graft-versus-host disease therapy.

Expert Opin Biol Ther 2014 Feb 19;14(2):261-9. Epub 2013 Dec 19.

Roswell Park Cancer Institute, Department of Medicine, BMT Program , Elm and Carlton Streets, Buffalo, NY 14263 , USA +1 716 845 8412 ;

Introduction: Remestemcel-L (Prochymal®, Osiris) is an off-the-shelf adult mesenchymal stromal cell product that has been applied to acute graft-versus-host disease (aGvHD) for its immunomodulatory properties.

Areas Covered: This article discusses preclinical and clinical studies supporting the use of remestemcel-L in aGvHD as well as the current regulatory status. This information was based upon a PubMed and Internet search.

Expert Opinion: Phase II studies suggest remestemcel-L may have clinical activity in aGvHD and confirm tolerability. However, these results must be interpreted cautiously with any use of remestemcel-L optimally occurring in the context of a clinical trial. Further clarity will be obtained when the results of a completed Phase III study are published. There is a small market for remestemcel-L in aGvHD. A possible future scenario is that a more prevalent indication is found and remestemcel-L is approved for that indication, but use continues for aGvHD.
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http://dx.doi.org/10.1517/14712598.2014.873027DOI Listing
February 2014
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