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1.
EASIX score predicts inferior survival after allogeneic hematopoietic cell transplantation
Sanchez-Escamilla, M., Flynn, J., Devlin, S., Maloy, M., Fatmi, S. A., Tomas, A. A., Escribano-Serrat, S., Ponce, D., Sauter, C. S., Giralt, S. A., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
The Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses common clinical laboratory values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at the onset of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We hypothesized that EASIX calculated at different time points pre- and post- HCT may predict NRM and OS, and that EASIX calculated at onset of GVHD may predict response to steroids. We evaluated the EASIX score pre- and post-HCT in 152 patients with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) alloHCT with uniform GVHD prophylaxis. In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher NRM (HR = 1.64, p = 0.009) and lower OS (HR = 1.33, p = 0.046). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65, p < 0.001; and HR = 1.65, p < 0.001) and decreased OS (HR = 1.27, p = 0.018; and HR = 1.49, p < 0.001), independent of HCT-CI, disease and conditioning regimen. Our study shows that high EASIX scores at various time points pre- and post-HCT are significantly associated with poorer overall outcomes. EASIX provides an independent and easily accessible tool to predict outcomes that can be complementary to other measures of risk stratification for patients undergoing HCT.
PICO Summary
Population
Adults with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) allogeneic HSCT with uniform GVHD prophylaxis, from a single centre in USA (n=152)
Intervention
Evaluation of the EASIX score pre-transplant between day -30 and day -10
Comparison
Evaluation of the EASIX score post-transplant at day 30 and day 100
Outcome
In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher non-relapse mortality (Hazard ratio (HR) = 1.64) and lower overall survival (HR = 1.33). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65; and HR = 1.65) and decreased OS (HR = 1.27; and HR = 1.49), independent of HCT-CI, disease and conditioning regimen.
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2.
A phase 2 study of Interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract
Ponce, D. M., Alousi, A. M., Nakamura, R., Slingerland, J., Calafiore, M., Sandhu, K. S., Barker, J. N., Devlin, S. M., Shia, J., Giralt, S. A., et al
Blood. 2022
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Editor's Choice
Abstract
Graft vs. host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, Interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating safety and efficacy of a novel recombinant human Interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD (NCT02406651; https://clinicaltrials.gov/ct2/show/NCT02406651). The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. 19/27 patients (70%; 80% CI: 56-79) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This work was supported by funding from Evive Biotech., The Society of Memorial Sloan Kettering Cancer Center, and the National Institutes of Health.
PICO Summary
Population
Adults with newly diagnosed lower gastrointestinal acute GvHD (n=27)
Intervention
F-652, a novel recombinant human Interleukin-22 dimer, in combination with systemic corticosteroids
Comparison
None
Outcome
The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. 19/27 patients (70%; 80% CI: 56-79) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis.
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3.
Characteristics of Graft-versus-Host Disease (GvHD) after Post-transplant Cyclophosphamide versus Conventional GvHD Prophylaxis
Saliba, R. M., Majid, A. A., Pidala, J., Arora, M., Spellman, S. R., Hemmer, M. T., Wang, T., Abboud, C., Ahmed, S., Antin, J. H., et al
Transplantation and cellular therapy. 2022
Abstract
Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control GvHD in haploidentical (Haplo) transplants. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated two cohorts: patients with grade 2-4 acute GvHD (aGvHD) including 264 and 1,163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1,018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation +/- antithymocyte globulin (ATG), grade 3-4 aGvHD (28% vs. 39%, P=.001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% vs 21%, P=.01), and chronic GI GvHD (21% vs. 31%, P=.006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGcHD rate after Haplo/PTCY was also lower (HR =.4, P<.001) in comparison with MUD/conventional transplantation without ATG in the non-myeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR=.6, P =.01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rate (HR=.6, P=.04). Mortality rate was higher (HR=1.6, P=.03) within, but not after (HR=.9, P=.6) the first six months subsequent to cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.
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4.
Antithymocyte globulin exposure in CD34+ T-cell depleted allogeneic hematopoietic cell transplantation
Lakkaraja, M., Scordo, M., Mauguen, A., Cho, C., Devlin, S. M., Ruiz, J. D., Klein, E., Avecilla, S., Boulad, F., Cancio, M. I., et al
Blood advances. 2021
Abstract
Traditional weight-based dosing results in variable rabbit anti-thymocyte-globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+IR) leading to higher mortality. In a retrospective, pharmacokinetic (PK)/pharmacodynamic analysis of patients undergoing their first CD34+ T-cell depleted (TCD) Allogeneic Hematopoietic Cell Transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area-under-the-curve (AUC;AU*d/L) using a validated population-PK model. We related rATG exposure to non-relapse mortality (NRM), CD4+IR (CD4+ =50/µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute-graft versus host disease (GVHD) to de?ne an optimal rATG-exposure. Cox-proportional hazard models, and multi-state competing risk models were used. 554 patients were included (age 0.1-73 years). Median post-HCT rATG exposure was 47AU*d/L (range 0-101). Low post-HCT AUC (<30AU*d/L) was associated with lower risk of NRM (p<0.01) and higher probability of achieving CD4+IR (p<0.001). Patients who attained CD4+IR had a 7-fold lower 5-year NRM (p<0.0001). Probability of achieving CD4+IR was 2.5-fold and 3-fold higher in the <30AU*d/L-group, compared to 30-55AU*d/L and =55AU*d/L-groups, respectively. In multivariable analyses, post-HCT rATG-exposure =55AU*d/L was associated with an increased risk of NRM (HR 3.42,95%CI 1.26-9.30). In the malignancy subgroup (n=515) a 10-fold and 7-fold increased NRM, was observed in the >55AU*d/L and 30-55AU*d/L groups, respectively, compared to <30AU*d/L group. Post-HCT rATG exposure =55AU*d/L was associated with higher risk of acute GVHD (HR 2.28,95%CI 1.01-5.16). High post-HCT rATG-exposure is associated with higher NRM secondary to poor CD4+IR after TCD-HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.
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5.
Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label, phase 2 trial
Jagasia, M., Perales, M. A., Schroeder, M. A., Ali, H., Shah, N. N., Chen, Y. B., Fazal, S., Dawkins, F. W., Arbushites, M. C., Tian, C., et al
Blood. 2020
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Editor's Choice
Abstract
Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label, phase 2 study (ClinicalTrials.gov identifier, NCT02953678), patients aged ≥12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally starting at 5 mg twice daily plus corticosteroids until treatment failure, unacceptable toxicity, or death. The primary endpoint was overall response rate (ORR) at Day 28; the key secondary endpoint was duration of response (DOR) at 6 months. As of July 2, 2018, 71 patients received ≥1 dose of ruxolitinib. Forty-eight patients (67.6%) had grade III/IV aGVHD at enrollment. At Day 28, 39 patients (54.9% [95% CI, 42.7%-66.8%]) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At Day 28, 24/43 patients (55.8%) receiving ruxolitinib and corticosteroids had a ≥50% corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.
PICO Summary
Population
Patients aged >/=12 years with grades II to IV steroid-refractory aGVHD (n=71)
Intervention
Oral ruxolitinib starting at 5 mg twice daily plus corticosteroids until treatment failure, unacceptable toxicity, or death
Comparison
None
Outcome
At Day 28, 39 patients (54.9%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At Day 28, 24/43 patients (55.8%) receiving ruxolitinib and corticosteroids had a >/=50% corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%).
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6.
Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide
Im, A., Rashidi, A., Wang, T., Hemmer, M., MacMillan, M. L., Pidala, J., Jagasia, M., Pavletic, S., Majhail, N. S., Weisdorf, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with relatively low incidence of GVHD. Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haploHCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced intensity (RIC) conditioning and bone marrow (BM) or peripheral blood (PB) graft source. 646 patients were identified (MA-BM=79, MA-PB=183, RIC-BM=192, RIC-PB=192). The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (p=0.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD (HR 1.53, 95% CI 1.11-2.12, p=0.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR 1.70, 95% CI 1.11-2.62, p=0.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haploHCT. Our results indicate that in RIC haploHCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
PICO Summary
Population
Adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (n=646)
Intervention
Myeloablative conditioning with a bone marrow graft source (MA-BM, n=79), Myeloablative conditioning with a peripheral blood graft source (MA-PB, n=183)
Comparison
Reduced intensity conditioning with a bone marrow graft source, (RIC-BM, n=192) Reduced intensity conditioning with a peripheral blood graft source, (RIC-PB, n=192).
Outcome
The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively. In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD. In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD in the RIC setting. There were no differences in relapse or overall survival between groups.
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A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease
Schroeder, M. A., Khoury, H. J., Jagasia, M., Ali, H., Schiller, G. J., Staser, K., Choi, J., Gehrs, L., Arbushites, M. C., Yan, Y., et al
Blood advances. 2020;4(8):1656-1669
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Abstract
Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation (HCT) is a primary cause of nonrelapse mortality and a major barrier to successful transplant outcomes. Itacitinib is a Janus kinase (JAK)1-selective inhibitor that has demonstrated efficacy in preclinical models of aGVHD. We report results from the first registered study of a JAK inhibitor in patients with aGVHD. This was an open-label phase 1 study enrolling patients aged ≥18 years with first HCT from any source who developed grade IIB to IVD aGVHD. Patients with steroid-naive or steroid-refractory aGVHD were randomized 1:1 to itacitinib 200 mg or 300 mg once daily plus corticosteroids. The primary endpoint was safety and tolerability; day 28 overall response rate (ORR) was the main secondary endpoint. Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting toxicity was reported (grade 3 thrombocytopenia attributed to GVHD progression in a patient receiving 300 mg itacitinib with preexisting thrombocytopenia). The most common nonhematologic treatment-emergent adverse event was diarrhea (48.3%, n = 14); anemia occurred in 11 patients (38%). ORR on day 28 for all patients in the 200-mg and 300-mg groups was 78.6% and 66.7%, respectively. Day 28 ORR was 75.0% for patients with treatment-naive aGVHD and 70.6% in those with steroid-refractory aGVHD. All patients receiving itacitinib decreased corticosteroid use over time. In summary, itacitinib was well tolerated and demonstrated encouraging efficacy in patients with steroid-naive or steroid-refractory aGVHD, warranting continued clinical investigations. This trial was registered at www.clinicaltrials.gov as #NCT02614612.
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8.
Microbe-derived short chain fatty acids butyrate and propionate are associated with protection from chronic GVHD
Markey, K. A., Schluter, J., Gomes, A. L., Littmann, E., Pickard, A., Taylor, B. P., Giardina, P. A., Weber, D., Dai, A., Docampo, M., et al
Blood. 2020
Abstract
Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have, thus far, largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFA) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication in the initial case-control cohort of transplant patients, and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed, however serum was available - rather than plasma - and the differences in SCFA observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort, and one of two cross-sectional cohorts explored, suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived short chain fatty acids.
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9.
Establishing a standardized system for review and adjudication of chronic graft-vs-host disease data in accordance with the National Institutes Consensus criteria
Dierov, D., Webb, N., Fatmi, S., Nwanne, C., Ciolino, C., Mosesso, K., Nieves, J., Perales, M. A., Prockop, S. E., Ponce, D. M.
Advances in cell and gene therapy. 2019;2(4)
Abstract
GVHD is a frequent complication following allo-HCT. The NIH consensus group established new guidelines for the evaluation of chronic GVHD. However, GVHD assessment remains challenging due its complexity and requirement for laborious evaluation. We, therefore, established a standardized approach for the assessment of chronic GVHD in accordance with the NCC guidelines. At a single institution, all allograft recipients were evaluated for GVHD within the first-year post allo-HCT following a 3-step workflow (real-time assessment, consensus review, and documentation). A GVHD adjudication committee was created and a dynamic electronic GVHD data capture form was developed guiding the clinician through a comprehensive review of systems following the NCC guidelines. We found that the assessment and reporting of GVHD reached 100% compliance. The establishment of an institutional GVHD adjudication committee enabled standardized assessment of GVHD. Our workflow can be adopted by other centers to create a similar framework for dedicated GVHD evaluation.
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10.
Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials
Pasquini, M. C., Logan, B., Jones, R. J., Alousi, A. M., Appelbaum, F. R., Bolaños-Meade, J., Flowers, M. E. D., Giralt, S., Horowitz, M. M., Jacobsohn, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018;24(6):1274-1280
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Abstract
Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials.
Clinical Commentary
What is known?
NIHMS933037
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