Madan Jagasia

Gateway-Vanderbilt Cancer Treatment Center, Clarksville, Tennessee, United States

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Publications (148)

  • [Show abstract] [Hide abstract] ABSTRACT: Hematopoietic cell transplantation (HCT) survivors are at risk for development of late complications and require lifelong monitoring for screening and prevention of late effects. There is an increasing appreciation of the issues related to healthcare delivery and coverage that are faced by HCT survivors. The 2016 National Institutes of Health Blood and Marrow Transplant Late Effects Initiative included an international and broadly representative Healthcare Delivery Working Group that was tasked with identifying research gaps pertaining to healthcare delivery and to identify initiatives that may yield a better understanding of the long-term value and costs of care for HCT survivors. There is a paucity of literature in this area. Critical areas in need of research include pilot studies of novel and information technology supported models of care delivery and coverage for HCT survivors along with development and validation of instruments that capture patient reported outcomes. Investment in infrastructure to support this research such as linkage of databases including electronic health records and routine inclusion of endpoints that will inform analyses focused around care delivery and coverage are required.
    Article · Oct 2016 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    [Show abstract] [Hide abstract] ABSTRACT: Chronic graft-versus-host disease (GVHD) is the leading cause of late, non-relapse, mortality and disability in allogeneic hematopoietic cell transplantation (HCT) patients and a major obstacle to improving outcomes. Chronic GVHD biology remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: • Summarize the current "state-of-the-science" regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps. • Develop working hypotheses/overriding concepts for chronic GVHD development. • Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies. • Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.
    Full-text available · Article · Oct 2016 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: Late acute (LA) graft vs. host disease (GVHD) is persistent, recurrent, or new onset acute GVHD symptoms occurring after 100 days post-allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, mortality, 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, IQR 128-204) days after HCT. While 51/83 (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 two 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 the AREG/EGF ratio ≥ median was associated with inferior OS and increased NRM 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.
    Article · Sep 2016 · Blood
  • [Show abstract] [Hide abstract] ABSTRACT: Rationale: The natural history of lung function in patients with bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation is poorly characterized. Understanding the trajectory of lung function is necessary for prompt clinical recognition, treatment, and the rational design of prospective studies. Objectives: To describe the longitudinal trajectory of lung function parameters including FEV1 in patients with BOS after hematopoietic cell transplantation. Methods: Subjects with BOS defined by National Institutes of Health consensus guidelines criteria from a recent multi-center prospective trial of combination treatment with fluticasone, azithromycin and montelukast and a retrospective cohort from Fred Hutchinson Cancer Research Center (FHCRC) were included. Longitudinal change in FEV1 for each patient was calculated from available pulmonary function tests in three periods: pre-BOS, from BOS diagnosis to 6 months, and 6-18 months after diagnosis. The effect of treatment on FEV1 trajectory was analyzed by univariate and multivariate linear regression. Kaplan-Meier method was used to estimate survival. Measurements and main results: FEV1% predicted at diagnosis was 46% (IQR, 35, 57) for trial participants and 53% (IQR 41, 64) for the retrospective cohort. There was concomitant mild reduction in FVC and marked reduction in FEF25-75% at diagnosis. While there was individual heterogeneity, overall FEV1 trajectory was characterized by marked decline within 6 months prior to BOS diagnosis, followed by stability of FEV1 early after diagnosis and a slow rate of decline beyond 6 months. The effect of the trial medications on FEV1 trajectory after BOS diagnosis was a mean rate of change of 0.92% predicted/month (95% CI -0.53, 2.37) compared to the retrospective cohort, but this was not statistically significant. Two-year overall survival was 76% and 72% for the study participants and the retrospective cohort patients, respectively. Earlier time to diagnosis after hematopoietic cell transplantation and severity of FVC at diagnosis were significantly associated with reduced survival. Conclusions: The FEV1 trajectory in patients with BOS after hematopoietic cell transplantation in a contemporary era of management follows a predominant pattern of rapid FEV1 decline in the 6 months prior to diagnosis followed by FEV1 stabilization after diagnosis.
    Article · Aug 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.Bone Marrow Transplantation advance online publication, 18 July 2016; doi:10.1038/bmt.2016.188.
    Article · Jul 2016 · Bone Marrow Transplantation
  • Vanessa E. Kennedy · Bipin N. Savani · John P. Greer · [...] · Madan Jagasia
    [Show abstract] [Hide abstract] ABSTRACT: Reduced intensity conditioning has been used increasingly for allogeneic hematopoietic cell transplantation to minimize transplant-related mortality while maintaining graft-versus-tumor effect. In B-cell lymphoid malignancies, reduced intensity regimens containing rituximab, an antiCD20 antibody, have been associated with favorable survival; however, the long-term outcomes of rituximab-containing versus non-rituximab containing regimens for allogeneic hematopoietic cell transplantation in B-cell lymphoid malignancies remain to be determined. We retrospectively analyzed 94 patients who received an allogeneic transplant for a B cell lymphoid malignancy. Of these, 33/94 received reduced intensity conditioning with fludarabine, cyclophosphamide, and rituximab (FCR) and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate, and 61/94 received reduced intensity conditioning with fludarabine and busulfan (FluBu) and GVHD prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The 2-year overall survival was superior in patients who received FCR vs. FluBu (72.7% vs. 54.1%, p = 0.031), and in multivariable analysis adjusted for Disease Risk Index and donor type, only the conditioning regimen (FluBu vs. FCR: HR 2.06 (95% CI 1.04 - 4.08), p = 0.037) and Disease Risk Index (low vs. intermediate/high: HR 0.38 (95% CI 0.17 - 0.86), p = 0.02) were independent predictors of overall survival. The 2-year cumulative incidence of chronic GVHD was lower in patients who received FCR vs. FluBu (24.2% vs. 51.7%, p = 0.01). There was no difference in rate of relapse/progression or acute graft-versus-host disease. Our results demonstrate use of reduced intensity conditioning with FCR and GVHD prophylaxis with a calcineurin inhibitor and mini-methotrexate is associated with decreased chronic graft-versus-host disease and improved overall survival.
    Article · Jul 2016 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). Methods: Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. Results: In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). Conclusions: The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. Cancer 2016. © 2016 American Cancer Society.
    Article · Jun 2016 · Cancer
  • [Show abstract] [Hide abstract] ABSTRACT: 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.
    Article · May 2016 · Journal of Clinical Oncology
  • Madan H. Jagasia · Tanya Basu · Brian G. Engelhardt · [...] · Shahram Kordasti
    Article · Mar 2016
  • Article · Mar 2016 · Biology of Blood and Marrow Transplantation
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    Full-text available · Article · Mar 2016 · Circulation
  • M. Christa Krupski · Andrew Bodiford · Kathryn Culos · [...] · Madan H. Jagasia
    Article · Mar 2016
  • Article · Mar 2016
  • Article · Mar 2016
  • Article · Mar 2016
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    Full-text available · Article · Jan 2016 · Haematologica
  • Natasha B Halasa · Bipin N Savani · Ishan Asokan · [...] · Madan Jagasia
    [Show abstract] [Hide abstract] ABSTRACT: Background: Hematopoietic stem cell transplantation (HCT) survivors are less likely to mount a strong immune response to trivalent inactivated influenza vaccine (TIV) when compared to matched, healthy controls. Methods: High-dose (HD) or standard-dose (SD) TIV was given to adult HCT subjects 18 years or older at least six months post-transplant. Subjects were randomized 2:1 to receive either the HD (60μg hemagglutinin [HA]/strain/dose) or the SD (15μg HA/strain/dose) TIV. Injection-site and systemic reactions were documented after each vaccination and immune responses were measured before and after each vaccination. Results: A total of 44 subjects were enrolled (25 in year 1 and 19 in year 2), with 15 in the SD group and 29 in the HD group. The median time to vaccination after transplantation was 7.9 months (range 6-106 months); median age was 50 years (range, 19.6-73 years); and 61% were male. No differences in demographic or lab data were noted between groups; however, the HD group had higher median baseline total IgG level (676 vs. 469 mg/dL, p=0.025). No differences in individual injection-site or systemic reactions were noted in the HD compared to the SD group; however, more events of any injection-site symptom combined were reported in the HD group. No serious adverse events were attributed to vaccination. Post-vaccination, the HD group had a higher percentage of individuals with titers >1:40 and a higher geometric mean titer (GMT) against the H3N2 strain compared to the SD group. Conclusion: HD and SD TIV were found to be safe and well tolerated in adult HCT recipients. However, the HD group had higher frequency of injection-site reactions, but the majority of the reactions were mild and resolved.. The HD group had a higher percentage of individuals with post-vaccination titer >1:40 and GMT for H3N2 antigen, indicating better immunogenicity. These data support the need for a phase II immunogenicity trial in HCT recipients.
    Article · Dec 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • Mukta Arora · Corey S Cutler · Madan H Jagasia · [...] · Stephanie J Lee
    [Show abstract] [Hide abstract] ABSTRACT: Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the NIH 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 four GVHD syndromes: late acute GVHD, chronic GVHD, bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. Most patients received peripheral blood stem cell transplant (81%) using a non myeloablative or reduced intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood were underrepresented in our cohort (<=11%). The cumulative incidence of late acute GVHD (late onset and recurrent) was 10% at a median of 5.5 months, chronic GVHD was 47% at a median of 7.4 months, bronchiolitis obliterans was 3% at a median of 12.2 months, and cutaneous sclerosis was 8% at a median onset of 14.0 months after HCT. Late acute GVHD and bronchiolitis obliterans had particularly high non-relapse mortality of 23% and 32% by 2 years after diagnosis. The probability of late acute- and chronic- GVHD-free, relapse-free survival at one and two years after HCT was 38% and 26%. This multi-center, prospective study confirms the high rate of late acute and chronic GVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success.
    Article · Nov 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: Purpose: We hypothesized that FAM (inhaled Fluticasone, Azithromycin, and Montelukast) with a brief steroid pulse could avert progression of new-onset BOS. Experimental design: We tested this in a phase II, single-arm, open label, multicenter study (NCT01307462). Results: Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater FEV1% decline at 3 months. At 3 months, 6% (2/36, 95% CI 1%-19%) had treatment failure (vs. 40% in historical controls, p<0.001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n=27). Patient-reported outcomes at 3 months were statistically significantly improved for SF-36 social functioning score and mental component score, FACT emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n=24). At 6 months, 36% had treatment failure (95% CI 21%-54%, n=13/36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% CI 84%-100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.
    Article · Oct 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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    [Show abstract] [Hide abstract] ABSTRACT: Background Although advances in sequencing technologies have popularized the use of microRNA (miRNA) sequencing (miRNA-seq) for the quantification of miRNA expression, questions remain concerning the optimal methodologies for analysis and utilization of the data. The construction of a miRNA sequencing library selects RNA by length rather than type. However, as we have previously described, miRNAs represent only a subset of the species obtained by size selection. Consequently, the libraries obtained for miRNA sequencing also contain a variety of additional species of small RNAs. This study looks at the prevalence of these other species obtained from bone marrow aspirate specimens and explores the predictive value of these small RNAs in the determination of response to therapy in myelodysplastic syndromes (MDS). Methods Paired pre and post treatment bone marrow aspirate specimens were obtained from patients with MDS who were treated with either azacytidine or decitabine (24 pre-treatment specimens, 23 post-treatment specimens) with 22 additional non-MDS control specimens. Total RNA was extracted from these specimens and submitted for next generation sequencing after an additional size exclusion step to enrich for small RNAs. The species of small RNAs were enumerated, single nucleotide variants (SNVs) identified, and finally the differential expression of tRNA-derived species (tDRs) in the specimens correlated with diseasestatus and response to therapy. Results Using miRNA sequencing data generated from bone marrow aspirate samples of patients with known MDS (N = 47) and controls (N = 23), we demonstrated that transfer RNA (tRNA) fragments (specifically tRNA halves, tRHs) are one of the most common species of small RNA isolated from size selection. Using tRNA expression values extracted from miRNA sequencing data, we identified six tRNA fragments that are differentially expressed between MDS and normal samples. Using the elastic net method, we identified four tRNAs-derived small RNAs (tDRs) that together can explain 67 % of the variation in treatment response for MDS patients. Similar analysis of specifically mitochondrial tDRs (mt-tDRs) identified 13 mt-tDRs which distinguished disease status in the samples and a single mt-tDR which predited response. Finally, 14 SNVs within the tDRs were found in at least 20 % of the MDS samples and were not observed in any of the control specimens. Discussion This study highlights the prevalence of tDRs in RNA-seq studies focused on small RNAs. The potential etiologies of these species, both technical and biologic, are discussed as well as important challenges in the interpretation of tDR data. Conclusions Our analysis results suggest that tRNA fragments can be accurately detected through miRNA sequencing data and that the expression of these species may be useful in the diagnosis of MDS and the prediction of response to therapy.
    Full-text available · Article · Sep 2015 · BMC Genomics