Publications by authors named "Asmita Mishra"

34 Publications

Increased infections and delayed CD4+ T-cell but faster B-cell Immune Reconstitution after Posttransplant Cyclophosphamide Compared to Conventional GVHD prophylaxis in Allogeneic Transplantation.

Transplant Cell Ther 2021 Jul 27. Epub 2021 Jul 27.

Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Background: Post-transplant cyclophosphamide (PTCY) is increasingly used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT) across various donor types. However, immune reconstitution and infection incidence after PTCY-based vs. conventional GVHD prophylaxis has not been well studied.

Methods: We evaluated the infection density and immune reconstitution (absolute CD4+ T-cell, CD8+ T-cell, NK-cell and B-cell counts) at 3 months, 6 months and 1 year post-HCT in 583 consecutive adult patients receiving myeloablative (n=223) or reduced intensity conditioning (n=360) allo-HCT (2012-2018). Haploidentical (Haplo; n=75) and 8/8 HLA-matched unrelated (MUD, n=508) donor types were included. GVHD prophylaxis was PTCY-based in all Haplo (n=75) and 38 MUD (MUD-PTCY) allo-HCT, while tacrolimus/methotrexate (TAC/MTX) was used in 89 and TAC/Sirolimus (TAC/SIR) in 381 MUD allo-HCT patients. Clinical outcomes including infections, non-relapse mortality (NRM), relapse, and overall survival (OS) were compared across all four treatment groups.

Results: The recovery of absolute total CD4+ T-cell count after Haplo-PTCY and MUD-PTCY was significantly lower compared to TAC/MTX or TAC/SIR throughout 1 year of allo-HCT (p=0.025). In contrast, CD19+ B-cell counts at 6 months and thereafter was higher after Haplo-PTCY and MUD-PTCY in comparison to TAC/MTX and TAC/SIR (p <0.001)). Compared to TAC/MTX, total CD8+ T-cell or NK-cell recovery was not significantly different among the groups. Infection density analysis showed a significantly higher frequency of total infections in Haplo-PTCY and MUD-PTCY vs TAC/MTX and TAC/SIR groups (5.0 and 5.0 vs. 1.8 and 2.6 per 1000-person days, p<0.01) within 1 year of allo-HCT. Cumulative incidence of CMV reactivation/infection at 1-year of allo-HCT was higher in patients receiving Haplo-PTCY (51%) compared to those receiving MUD-PTCY (26 %) or MUD- TAC/MTX (26%) or MUD-TAC/SIR (13%; p<0.001). The incidence of BK, HHV6 and other viruses were also higher in PTCY based groups. Overall, the treatment groups had similar 2 year NRM (p=0.27) and OS outcomes (p=0.78).

Conclusion: Our data shows that PTCY-based GVHD prophylaxis is associated with delayed CD4+ T cell but faster B-cell immune reconstitution and a higher frequency of infections in comparison to conventional GVHD prophylaxis but has no impact on non-relapse mortality or overall survival.
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http://dx.doi.org/10.1016/j.jtct.2021.07.023DOI Listing
July 2021

A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.

Blood Adv 2021 07;5(13):2740-2750

Blood & Marrow Transplant & Cellular Immunotherapy.

Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8-matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor-stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.
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http://dx.doi.org/10.1182/bloodadvances.2021004225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288668PMC
July 2021

Biologic Assignment Trial of Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients 50-75 Years of Age With Advanced Myelodysplastic Syndrome.

J Clin Oncol 2021 Jun 9:JCO2003380. Epub 2021 Jun 9.

Dana Farber Cancer Institute, Boston, MA.

Purpose: Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined.

Methods: We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration.

Results: The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; = .003). The survival benefit was seen across all subgroups examined.

Conclusion: We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.
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http://dx.doi.org/10.1200/JCO.20.03380DOI Listing
June 2021

Breaking the Age Barrier: Physicians' Perceptions of Candidacy for Allogeneic Hematopoietic Cell Transplantation in Older Adults.

Transplant Cell Ther 2021 07 6;27(7):617.e1-617.e7. Epub 2021 Apr 6.

City of Hope, Duarte, California.

Despite continuing increases in the use of allogeneic hematopoietic cell transplantation (alloHCT) in older adults, no standardized geriatric assessment (GA) has been established to risk stratify for transplantation-related morbidity. We conducted a survey of transplant physicians to determine perceptions of the impact of older age (≥60 years) on alloHCT candidacy, and utilization of tools to gauge candidacy. This 23-item online cross-sectional survey was distributed to HCT physicians caring for adults in the United States between May and July 2019. Of the 770 invited HCT physicians, 175 (22.7%) completed the survey. The majority of respondents were age 41 to 60 years and male and practiced in a higher-volume teaching hospital. When considering regimen intensity, 29 physicians (17%) stated they would consider a myeloablative regimen for patients age ≥70 years, and 141 (82%) would consider reduced-intensity/nonmyeloablative conditioning for patients age ≥70 years. Almost all (90%) endorsed the need for a specialized assessment of pre-HCT vulnerabilities to guide candidacy decisions for older adults. Most physicians reported that their centers rarely (33%) or never (46%) use a dedicated geriatrician/geriatric-oncologist to assess alloHCT candidates age ≥60 years. Common barriers to performing a GA included uncertainty about which tools to use, lack of knowledge and training, and lack of appropriate clinical support staff. Many alloHCT physicians will consider alloHCT in patients up to age 75 years and not uncommonly in patients older than that. However, the application of tools and domains to assess candidacy in older adults varies widely. Incorporation of a standardized pretransplantation health assessment tool for risk stratification is a significant unmet need.
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http://dx.doi.org/10.1016/j.jtct.2021.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254775PMC
July 2021

Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis.

Transplant Cell Ther 2021 07 30;27(7):620.e1-620.e9. Epub 2021 Mar 30.

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.
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http://dx.doi.org/10.1016/j.jtct.2021.03.026DOI Listing
July 2021

ELN 2017 Genetic Risk Stratification Predicts Survival of Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 03 2;27(3):256.e1-256.e7. Epub 2021 Feb 2.

Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address:

European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. We included 500 adult (≥18 years) AML patients in first (n = 370) or second (n = 130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and nonrelapse mortality were analyzed by the Fine-Gray regression model. OS at 2 years was 72% in the favorable versus 60% in the intermediate versus 45% in the adverse risk groups (P < .001). In multivariable analyses, the 2017 ELN classifier was an independent predictor of OS after alloHCT with significantly higher overall mortality in the intermediate (hazard ratio [HR] = 1.68, 95% confidence interval [CI], 1.06-2.68; P = .03) and adverse (HR = 2.50, 95% CI, 1.54-4.06; P < .001) risk groups compared to the favorable risk group. Similarly, LFS was worse in the intermediate (HR = 1.63, 95%, CI 1.06-2.53; P = .03) and adverse (HR 2.23, 95% CI, 1.41-3.54; P < .001) risk groups while relapse was higher in the adverse risk group (HR = 2.36, 95% CI, 1.28-4.35; P = .006) as compared to the favorable risk group. These data highlight the prognostic impact of the 2017 ELN genetic risk stratification on the survival of AML patients after alloHCT. Patients in the adverse risk group had the highest risk of relapse and worst survival. Thus the 2017 ELN prognostic system can help identify AML patients who may benefit from clinical trials offering relapse mitigation strategies to improve transplant outcomes.
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http://dx.doi.org/10.1016/j.jtct.2020.12.021DOI Listing
March 2021

Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD Prevention after Allogeneic Hematopoietic Cell Transplantation: Preclinical and Phase I Trial Results.

Clin Cancer Res 2021 May 22;27(10):2712-2722. Epub 2021 Mar 22.

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

Purpose: In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation.

Patients And Methods: The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC ( = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells.

Results: In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4 T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias.

Conclusions: We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127396PMC
May 2021

Impact of infused CD34+ stem cell dosing for allogeneic peripheral blood stem cell transplantation with post-transplant cyclophosphamide.

Bone Marrow Transplant 2021 07 3;56(7):1683-1690. Epub 2021 Mar 3.

Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

Higher infused total nucleated cell dose (TNC) in allogeneic bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy) is associated with improved overall survival. As many centers prefer peripheral blood stem cell grafts (PBSCT) with PTCy, the effect of cell dose on outcomes with this platform also requires elucidation. We retrospectively evaluated 144 consecutive adult patients who received allogeneic T-cell replete PBSCT with PTCy-based graft-versus-host disease (GVHD) prophylaxis for a hematologic malignancy from 2012-2018. The infused CD34+ cell dose was stratified into low (<5 × 10/kg), intermediate (5-10 × 10/kg) and high (>10 × 10/kg) dose level groups. In multivariate analysis, the low CD34+ cell dose group had worse non-relapse mortality (HR = 4.51, 95% CI: 1.92-10.58, p < 0.001), progression- free survival (HR = 4.11, 95% CI: 2.07-8.15, p < 0.001), and overall survival (HR = 4.06, 95% CI: 2.00-8.25, p ≤ 0.001) compared to the intermediate group. Clinical outcomes between the intermediate and high CD34+ cell dose groups were similar. TNC and CD3+ cell dose had no significant impacts on outcomes. These findings suggest that, in patients receiving allogeneic PBSCT with PTCy, infused CD34+ cell doses >5 × 10 cells/kg may result in improved survival. Thus, this study supports targeting a CD34+ cell dose of >5 × 10 cells/kg for allogeneic PBSCT with PTCy.
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http://dx.doi.org/10.1038/s41409-021-01219-8DOI Listing
July 2021

A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation.

Blood Adv 2021 03;5(5):1154-1163

Blood and Marrow Transplant and Cellular Immunotherapy, and.

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.
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http://dx.doi.org/10.1182/bloodadvances.2020003779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948297PMC
March 2021

Present cum future of SARS-CoV-2 virus and its associated control of virus-laden air pollutants leading to potential environmental threat - A global review.

J Environ Chem Eng 2021 Apr 13;9(2):104973. Epub 2021 Jan 13.

Department of Chemical Engineering, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.

The world is presently infected by the biological fever of COVID-19 caused by SARS-CoV-2 virus. The present study is mainly related to the airborne transmission of novel coronavirus through airway. Similarly, our mother planet is suffering from drastic effects of air pollution. There are sufficient probabilities or evidences proven for contagious virus transmission through polluted airborne-pathway in formed aerosol molecules. The pathways and sources of spread are detailed along with the best possible green control technologies or ideas to hinder further transmission. The combined effects of such root causes and unwanted outcomes are similar in nature leading to acute cardiac arrest of our planet. To maintain environmental sustainability, the prior future of such emerging unknown biological hazardous air emissions is to be thoroughly researched. So it is high time to deal with the future of hazardous air pollution and work on its preventive measures. The lifetime of such an airborne virus continues for several hours, thus imposing severe threat even during post-lockdown phase. The world waits eagerly for the development of successful vaccination or medication but the possible outcome is quite uncertain in terms of equivalent economy distribution and biomedical availability. Thus, risk assessments are to be carried out even during the post-vaccination period with proper environmental surveillance and monitoring. The skilled techniques of disinfection, sanitization, and other viable wayouts are to be modified with time, place, and prevailing climatic conditions, handling the pandemic efficiently. A healthy atmosphere makes the earth a better place to dwell, ensuring its future lifecycle.
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http://dx.doi.org/10.1016/j.jece.2020.104973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805399PMC
April 2021

Contribution of Sleep Disruption and Sedentary Behavior to Fatigue in Survivors of Allogeneic Hematopoietic Cell Transplant.

Ann Behav Med 2021 Jan 7. Epub 2021 Jan 7.

Healthcare Delivery Research Program, National Cancer Institute, Bethesda, MD, USA.

Background: Fatigue is a prominent quality of life concern among recipients of hematopoietic cell transplantation (HCT).

Purpose: The present study investigated whether objectively measured sleep efficiency and sedentary behavior are related to greater reports of fatigue.

Methods: Eighty-two allogeneic HCT recipients who were 1-5 years post-transplant and returning for a follow-up visit participated (age M = 56, 52% female, 56% leukemia). They wore an actigraph assessing sleep efficiency and sedentary behavior for one week and completed an electronic log assessing fatigue each evening during the same period.

Results: Twenty-six percent of patients reported clinically meaningful fatigue. On average, fatigue was mild (M = 2.5 on 0-10 scale, SD = 2.0), sleep was disturbed (sleep efficiency M = 78.9%, SD = 8.9), and patients spent the majority of time in sedentary (M = 55.4%, SD = 10.2) or light (M = 35.9%, SD = 8.6) activity. Multilevel model analysis of between-person differences indicated that patients who experienced less efficient sleep the previous evening provided greater evening reports of average fatigue, b = -0.06, 95% CI (-0.11, -0.01). Similarly, within-person analyses indicated that when patients experienced less efficient sleep the previous evening or were more sedentary as compared to their average, they provided greater evening reports of average fatigue, b = -0.02, 95% CI (-0.05, -0.004); b = 4.46, 95% CI (1.95, 6.97), respectively.

Conclusions: Findings demonstrate that poor sleep and daily sedentary behavior are related to evening reports of fatigue and should be considered modifiable targets for intervention.
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http://dx.doi.org/10.1093/abm/kaaa110DOI Listing
January 2021

Sarcopenia and low muscle radiodensity associate with impaired FEV in allogeneic haematopoietic stem cell transplant recipients.

J Cachexia Sarcopenia Muscle 2020 12 29;11(6):1570-1579. Epub 2020 Jul 29.

Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.

Background: Quantification of skeletal muscle using computed tomography (CT) is accessible using cancer patients' standard oncologic images. Reduced muscle mass may be related to reduced respiratory muscle strength; however, the impact of this on lung functional parameters is not characterized in adult allogeneic haematopoietic stem cell transplant (alloHCT) recipients.

Methods: A consecutive retrospective series (n = 296) of patients who had alloHCT at a comprehensive cancer centre between March 2005 and April 2015 were included. Pre-transplant CT scans were used to quantify skeletal muscle and adipose tissue at the fourth thoracic (T4) and/or third lumbar (L3) level. Tumour and patient characteristics were recorded, including forced expiratory volume in 1 second (FEV ) by spirometry. Regression models were created to characterize predictive relationships.

Results: A total of 296 patients (♂n = 161; ♀n = 135) were included, all of whom had chest CT as part of standard care; a subset of these (n = 215, 72.6%) also had abdominal CT. Diagnoses were non-Hodgkins lymphoma (n = 165), acute myeloid leukaemia (n = 66), Hodgkin's disease (n = 14), acute lymphocytic leukaemia (n = 14), myelodysplastic syndromes (n = 18), and other (n = 19). In multivariable linear regression adjusted for sex (P < 0.0001), age (P < 0.0001), haematopoietic cell transplantation-specific co-morbidity index (P = 0.010), and parameters of pulmonary function testing (defined by spirometry, P < 0.0001), both T4 muscle index [β 0.127 (95% confidence interval 0.019; 0.252), P < 0.0001] and T4 muscle radiodensity [β 0.132 (95% confidence interval 0.087; 0.505), P = 0.006] were independently associated with FEV ; disease risk index (P = 0.877) and Karnofsky performance status (P = 0.548) were not associated with FEV . Similar conclusions were obtained when L3 muscle index and radiodensity were considered. Unlike T4, L3 muscle index values can be compared with published cut-off values for sarcopenia. Overall rates of sarcopenia were uniformly higher in the HCT population than in age-matched and sex-matched patients with solid tumours [alloHCT ♂64.7% vs. solid tumour ♂56.6% (P < 0.001); alloHCT ♀57.6% vs. solid tumour ♀36.0% (P < 0.001)]. Significant but moderate correlations (P < 0.001) were found for muscle area and radiodensity between L3 and T4, for both men and women; adipose tissue quantity also correlated significantly (P < 0.001) between L3 and T4 for both men and women.

Conclusions: Lumbar or thoracic CT images are useful for body composition assessment in this population and reveal high rates of sarcopenia, similar to those reported in very elderly patients. Reduced muscle mass and radiodensity associate with impaired FEV even after adjustment for clinical covariables including co-morbidities, performance status, disease risk, and mild intrinsic pulmonary disease (chronic obstructive pulmonary disease) defined by spirometry.
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http://dx.doi.org/10.1002/jcsm.12604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749567PMC
December 2020

Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel.

Clin Cancer Res 2020 09 15;26(18):4823-4831. Epub 2020 Jul 15.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Purpose: One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).

Experimental Design: Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.

Results: We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.

Conclusions: These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501265PMC
September 2020

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report.

Blood Adv 2020 07;4(13):3180-3190

Texas Transplant Institute, San Antonio, TX.

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
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http://dx.doi.org/10.1182/bloodadvances.2019001266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362362PMC
July 2020

Sole Upfront Therapy with Beclomethasone and Budesonide for Upper Gastrointestinal Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2020 07 30;26(7):1303-1311. Epub 2020 Apr 30.

Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida; Department of Oncological Sciences, University of South Florida, Tampa Florida. Electronic address:

Systemic glucocorticoids remain the standard treatment for gastrointestinal (GI) acute graft-versus-host disease (aGVHD) despite their toxicity and incomplete efficacy. Controlled trials have tested poorly absorbable steroids as adjuncts with systemic glucocorticoids, but only small case series have reported treatment with poorly absorbed beclomethasone dipropionate (BDP) and budesonide (BUD) alone. Our team has adopted the practice of administering BDP or BDP+BUD without systemic glucocorticoids as first-line therapy for isolated upper GI (UGI) aGVHD. We report results in 76 patients treated with BDP alone and in 81 patients treated with BDP+BUD, with allocation by physician choice. Almost all patients received peripheral blood stem cells (92%) from a fully HLA-matched related or unrelated donor (80%) after myeloablative conditioning (76%) for acute leukemia (49%), myelodysplastic syndrome (17%), non-Hodgkin lymphoma (14%), or another hematopoietic disorders (20%). After 28 days of treatment with BDP, 46% of the patients had a complete response (CR) and 10% had a partial response (PR); after 200 days, 61 (80%) patients were alive, 34% maintained a CR, and 3% maintained a PR, whereas 53% required additional immunosuppression (IS). After 28 days of treatment with BDP+BUD, 67% had a CR and 10% a PR; after 200 days, 74 (91%) patients were alive, 46% maintained a CR, and 2% maintained a PR, whereas 43% required additional IS. Among the entire cohort of 157 patients, 66 (42%) were treated successfully without systemic glucocorticoids. This study reports the efficacy of poorly absorbable steroids alone for patients with isolated UGI aGVHD. Prospective trials should test for the potential advantages of BDP and BUD use over systemic glucocorticoids.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771266PMC
July 2020

Safety at the Time of the COVID-19 Pandemic: How to Keep our Oncology Patients and Healthcare Workers Safe.

J Natl Compr Canc Netw 2020 04 15:1-6. Epub 2020 Apr 15.

Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center; and.

The novel coronavirus, SARS-CoV-2, was first detected as a respiratory illness in December 2019 in Wuhan City, China. Since then, coronavirus disease 2019 (COVID-19) has impacted every aspect of our lives worldwide. In a time when terms such as social distancing and flattening the curve have become a part of our vernacular, it is essential that we understand what measures can be implemented to protect our patients and healthcare workers. Undoubtedly, healthcare providers have had to rapidly alter care delivery models while simultaneously acknowledging the crucial unknowns of how these changes may affect clinical outcomes. This special feature reviews strategies on how to mitigate transmission of COVID-19 in an effort to reduce morbidity and mortality associated with the disease for patients with cancer without infection, for patients with cancer with COVID-19 infection, and for the healthcare workers caring for them, while continuing to provide the best possible cancer care. [Editor's Note: This article includes the most current information available at time of publication; however, recommendations regarding public safety and practice may change rapidly in this situation. Individuals should get the most up to date information from the CDC website.].
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http://dx.doi.org/10.6004/jnccn.2020.7572DOI Listing
April 2020

Reduced-intensity fludarabine/melphalan confers similar survival to busulfan/fludarabine myeloablative regimens for patients with acute myeloid leukemia and myelodysplasia.

Leuk Lymphoma 2020 07 5;61(7):1678-1687. Epub 2020 Mar 5.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA.

Optimal conditioning chemotherapy for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains uncertain. Myeloablative regimens such as fludarabine/busulfan are favored over reduced-intensity fludarabine/melphalan (Flu/Mel); however, it is not known if Flu/Mel is inferior. We analyzed hematopoietic cell transplantation recipients with AML and MDS who received fludarabine with once-daily intravenous busulfan targeted to either area under the curve (AUC) 5300 µM*L/min (Flu/Bu 5300) ( = 246) or AUC 3500 µM*L/min (Flu/Bu 3500) ( = 81), or Flu/Mel ( = 69). Flu/Bu regimens were compared separately to Flu/Mel. After 2-year follow-up, no differences in overall or relapse-free survival were found between Flu/Bu 5300 or 3500 versus Flu/Mel though relapse rates were significantly higher; 33.1% ( = 0.024), 44.6% ( = 0.002), versus 19.4%, respectively. Flu/Bu 5300 ( = 0.008) and Flu/Bu 3500 ( < 0.001) groups were prognostic for relapse compared to Flu/Mel. Flu/Mel yields lower relapse rates and similar survival benefit when compared to Flu/Bu 3500 or 5300 µM*L/min.
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http://dx.doi.org/10.1080/10428194.2020.1731498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771324PMC
July 2020

Generation of Antitumor T Cells For Adoptive Cell Therapy With Artificial Antigen Presenting Cells.

J Immunother 2020 04;43(3):79-88

Departments of Clinical Science.

Adoptive cell therapy with ex vivo expanded tumor infiltrating lymphocytes or gene engineering T cells expressing chimeric antigen receptors (CAR) is a promising treatment for cancer patients. This production utilizes T-cell activation and transduction with activation beads and RetroNectin, respectively. However, the high cost of production is an obstacle for the broad clinical application of novel immunotherapeutic cell products. To facilitate production we refined our approach by using artificial antigen presenting cells (aAPCs) with receptors that ligate CD3, CD28, and the CD137 ligand (CD137L or 41BBL), as well as express the heparin binding domain (HBD), which binds virus for gene-transfer. We have used these aAPC for ex vivo gene engineering and expansion of tumor infiltrating lymphocytes and CAR T cells. We found that aAPCs can support efficacious T-cell expansion and transduction. Moreover, aAPCs expanded T cells exhibit higher production of IFN-γ and lower traits of T-cell exhaustion compared with bead expanded T cells. Our results suggest that aAPC provide a more physiological stimulus for T-cell activation than beads that persistently ligate T cells. The use of a renewable cell line to replace 2 critical reagents (beads and retronectin) for CAR T-cell production can significantly reduce the cost of production and make these therapies more accessible to patients.
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http://dx.doi.org/10.1097/CJI.0000000000000306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077957PMC
April 2020

Circadian Rhythmicity as a Predictor of Quality of Life in Allogeneic Hematopoietic Cell Transplant Patients.

J Pain Symptom Manage 2019 05 31;57(5):952-960.e1. Epub 2019 Jan 31.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida, USA. Electronic address:

Context: Quality of life (QoL) is increasingly recognized as an important outcome of cancer treatment. Previous studies have examined clinical predictors of QoL, but with the increasing prevalence of wearable sensors that monitor sleep and activity patterns, further investigation into whether these behaviors are predictive of post-treatment QoL is now feasible. Among patients receiving aggressive cancer treatment such as hematopoietic cell transplantation (HCT), analysis of circadian rhythms (24-hour patterns of sleep and activity) via wearable sensors is limited.

Objective: To evaluate the relationship between overall QoL and circadian rhythms in patients receiving allogeneic HCT.

Methods: Patients wore an ActiGraph GT3X (Pensacola, FL) activity monitor for at least 72 hours before the initiation of conditioning chemotherapy and transplantation and completed a QoL (Functional Assessment of Cancer Therapy-General [FACT-G]) assessment. QoL assessments were also completed 1, 3, and 6 months after HCT.

Results: Patients (n = 45, M age = 55) were mostly male (66%) with a total FACT-G score of 80.96 (SD = 16.05) before HCT. Mixed models revealed robust cross-sectional associations between overall QoL and multiple circadian rhythmicity parameters, including durations of high physical activity, overall circadian rhythmicity, and earlier starts of daily activity (P's < .01). Recovery of QoL after transplant was predicted by longer pre-transplant durations of high physical activity (P = .04) and earlier evening retirement (P = .04).

Conclusion: Our findings suggest that wearable sensor information is a promising method of predicting recovery of QoL after HCT. Additional studies are needed to confirm these findings in a larger sample.
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http://dx.doi.org/10.1016/j.jpainsymman.2019.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486418PMC
May 2019

Phase I trial of histone deacetylase inhibitor panobinostat in addition to glucocorticoids for primary therapy of acute graft-versus-host disease.

Bone Marrow Transplant 2018 11 18;53(11):1434-1444. Epub 2018 Apr 18.

Blood & Marrow Transplant & Cellular Immunotherapy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Glucocorticoids for primary therapy of acute GVHD have limited responses. A phase I/II trial tested 4 weeks of deacetylase inhibitor panobinostat started within 48 h of glucocorticoids (1 mg/kg/day prednisone or equivalent) as primary treatment for patients with either classic acute GVHD (n = 16) or acute GVHD overlapping with chronic (n = 6). Four patients received 2.5 mg/m IV three times a week (TIW). Subsequent to discontinuation of IV panobinostat, patients received oral doses (PO). Two patients treated with 10 mg TIW (PO level 1) had progressive GVHD, after which patients were treated with 5 mg TIW (PO level -1; n = 16); 31/41 adverse events were possibly related, including thrombocytopenia (n = 13), leukopenia (n = 7), hypercholesterolemia (n = 3), hypertriglyceridemia (n = 5), anemia (n = 1), fatigue (n = 1), and hepatobiliary disorder (n = 1). GVHD responses were complete (n = 12) or partial (n = 3), with 1 progression at PO level -1. T-regulatory cells increased at day 8, CD4/CD8 and monocytes exhibited enhanced H3 acetylation, and CD4 or CD8 numbers remained unchanged with a decreased interleukin 12p40 plasma level. Panobinostat in combination with prednisone is safe and warrants further testing in GVHD.
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http://dx.doi.org/10.1038/s41409-018-0163-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771280PMC
November 2018

IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation.

Haematologica 2018 03 14;103(3):531-539. Epub 2017 Dec 14.

Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.

T-helper 1 and T-helper 17 lymphocytes mediate acute graft--host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at ).
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http://dx.doi.org/10.3324/haematol.2017.171199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830373PMC
March 2018

TP53 and IDH2 Somatic Mutations Are Associated With Inferior Overall Survival After Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome.

Clin Lymphoma Myeloma Leuk 2017 11 16;17(11):753-758. Epub 2017 Jun 16.

Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Background: Next-generation sequencing has identified somatic mutations that are prognostic of cancer.

Patients And Methods: We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen.

Results: The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P = .03) and IDH2 mutations (HR, 4.74; 95% CI, 1.33-16.91; P = .02) as predictors of inferior 3-year overall survival.

Conclusion: This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy.
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http://dx.doi.org/10.1016/j.clml.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675815PMC
November 2017

Obstructed labour due to locked twins and role of destructive procedure in its management - A case report.

J Obstet Gynaecol 2017 Aug 1;37(6):813-814. Epub 2017 Apr 1.

a Department of Obstetrics & Gynaecology , Silchar Medical College , Silchar , India.

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http://dx.doi.org/10.1080/01443615.2017.1291591DOI Listing
August 2017

IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.

Haematologica 2017 05 19;102(5):948-957. Epub 2017 Jan 19.

Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.

Graft--host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16 April 2014 and 19 December 2015, 20 patients received IL-2 (200,000 IU/m thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% 16.0%, =0.0016; 0.052 k/uL 0.037 k/uL, =0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% 50%, =0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3 CD4 T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. ().
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http://dx.doi.org/10.3324/haematol.2016.153072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477614PMC
May 2017

Nonfluorodeoxyglucose-Avid Persistent Splenomegaly at Time of Transplantation Delays Neutrophil and Platelets Engraftment without Affecting Survival in Patients with Lymphomas Undergoing Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2016 12 19;22(12):2201-2207. Epub 2016 Sep 19.

Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

It is unclear if persistent splenomegaly in the presence of a negative positron emission tomography (PET) scan before allogeneic hematopoietic cell transplantation (HCT) influences post-transplantation outcomes in patients with lymphoma. We retrospectively reviewed records of 152 patients who underwent allogeneic HCT for various lymphomas. Centralized review of pretransplantation computed tomography (CT) and PET images was performed. Spleen volume (SV) was measured using the freehand volume segmentation tool in AW Workstation software (General Electric, Waukesha, WI). Splenic index (SI) was calculated as a product of width, thickness, and length of the spleen. Normal SV was defined as SV < 314.5 cm and normal SI was defined as SI ≤ 480 cm, as described in the literature. Among the study population, 42.8% received an allogeneic HCT from an HLA-matched related donor, 36.2% from a matched unrelated donor, 12.5% from a mismatched unrelated donor, and 8.6% received a double umbilical cord blood transplantation. Most (61.8%) received myeloablative conditioning. Median age at transplantation was 52 (range, 21 to 68) years. Pre-allogeneic HCT spleen CT and PET images were available on 88% and 70.3% patients, respectively. SV ranged from 90 cm to 4684 cm with a median of 290.5 cm and a mean of 400.3 cm. SI calculation showed a range from 50.3 cm to 8276.4 cm with a median of 582.1 cm and a mean of 771.2 cm. The majority of patients (83.1%) had PET-negative spleen before allogeneic transplantation. Engraftment was delayed in PET-negative patients with persistent splenomegaly, with median days to neutrophil engraftment of 17 versus 16 (P = .03) and median days to platelet engraftment of 16 versus 14 (P = .04) when using SV. However, persistent splenomegaly did not appear to impact progression-free survival (P = .11) or overall survival (P = .37). Splenomegaly in the setting of a PET-negative study before allogeneic HCT delays neutrophil and platelet engraftment but does not appear to affect survival. Future studies using registry data or larger multicenter studies would be required to evaluate the impact of splenomegaly and its fluorodeoxyglucose avidity on allogeneic HCT outcomes in specific subtypes of lymphomas.
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http://dx.doi.org/10.1016/j.bbmt.2016.09.014DOI Listing
December 2016

Bladder rupture with incomplete rupture of the uterus.

Int Urogynecol J 2017 Feb 27;28(2):329-330. Epub 2016 Sep 27.

Department of Obstetrics and Gynaecology, Silchar Medical College and Hospital, Silchar, India.

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http://dx.doi.org/10.1007/s00192-016-3141-2DOI Listing
February 2017

Selection of Patients With Myelodysplastic Syndrome for Allogeneic Hematopoietic Stem Cell Transplantation.

Clin Lymphoma Myeloma Leuk 2016 08;16 Suppl:S49-52

Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with myelodysplastic syndrome (MDS). Because MDS predominantly affects an older population, age-associated comorbidities can preclude patients from cure. HSCT is associated with the risk of morbidity and mortality; however, with safer conditioning regimens and improved supportive care, eligible patients with an appropriately matched donor can receive this therapy without exclusion by older age alone. We discuss the role of improved MDS prognostic scoring systems and molecular testing for selection for HSCT, and review the pre-HSCT tolerability assessment required for this advanced aged population.
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http://dx.doi.org/10.1016/j.clml.2016.02.023DOI Listing
August 2016

Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury.

Hematol Oncol Stem Cell Ther 2016 Dec 27;9(4):157-161. Epub 2015 Nov 27.

Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Oncologic Sciences, H. Lee Moffitt Cancer Center/University of South Florida, Morsani College of Medicine, Tampa, FL, USA. Electronic address:

Allogeneic hematopoietic cell transplantation is a potential curative treatment option for various malignant and nonmalignant hematologic disorders. Patients undergoing an allogeneic hematopoietic cell transplant are prescribed immune-suppressant therapies to facilitate hematopoietic donor-cell engraftment and prevent graft-versus-host disease. Drug-drug interactions may occur, owing to exposure to complex multidrug regimens with narrow therapeutic windows and high toxicity profiles. Here, we describe a unique case of a 65-year-old man with poor-risk acute myeloid leukemia who underwent a matched-sibling hematopoietic cell allograft. Sirolimus and tacrolimus were used for graft-versus-host disease prophylaxis. He developed oral thrush requiring treatment with clotrimazole troches, which subsequently resulted in serious renal toxicity attributed to supratherapeutic levels of sirolimus and tacrolimus. Patient renal function improved after temporarily holding both immune suppressants, and administering phenytoin to help induce sirolimus and tacrolimus metabolism. This case highlights sudden and serious toxicities that resulted from clotrimazole-sirolimus and clotrimazole-tacrolimus drug-drug interactions, even when administered topically.
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http://dx.doi.org/10.1016/j.hemonc.2015.11.001DOI Listing
December 2016

Impact of tobacco usage on disease outcome in myelodysplastic syndromes.

Leuk Res 2015 Jul 7;39(7):673-8. Epub 2015 Apr 7.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

We hypothesized that tobacco usage is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). To evaluate the impact of tobacco usage in this population, we identified patients diagnosed with MDS in our Center's MDS database and reviewed individual charts retrospectively. Of the 767 MDS patients identified, 743 patients (97%) had a known tobacco usage history. Given that the majority of tobacco users were smokers, we stratified patients as having never smoked (never-smoker group) versus current or former smokers (ever-smoker group). Greater than 60% of ever-smokers were risk stratified as having low or intermediate-1 (int-1) risk at diagnosis based on the International Prognostic Scoring System for MDS. In patients with lower-risk MDS, we found that ever-smokers had an increased proportion of poor-risk karyotypes (8.8%) compared with never-smokers (2.4%) (P=0.003). The adverse effect of smoking was greatest in the low-risk and int-1-risk groups, where median overall survival was 69 months (95% CI 42-96) in never-smokers versus 48 months (95% CI 41-55) in ever-smokers (P=0.006). The median overall survival for never-smokers, former smokers, and current smokers was 69 months (95% CI 42-96), 50 months (95% CI 43-57), and 38 months (95% CI 23-53), respectively, in patients risk stratified as lower-risk MDS (P=0.01). Our findings suggest that tobacco usage negatively impacts overall survival in patients with lower-risk MDS.
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http://dx.doi.org/10.1016/j.leukres.2015.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992898PMC
July 2015

Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease.

Haematologica 2015 Jul 3;100(7):970-7. Epub 2015 Apr 3.

Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.

Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.
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http://dx.doi.org/10.3324/haematol.2015.123588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486232PMC
July 2015
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