Publications by authors named "Mahasweta Gooptu"

30 Publications

  • Page 1 of 1

GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized double blinded phase 2 trial.

Blood Adv 2021 Nov 22. Epub 2021 Nov 22.

Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

Vaccination using irradiated, adenovirus transduced autologous myeloblasts to secrete GM-CSF (GVAX) early after allogeneic hematopoietic stem cell transplantation (HSCT) can induce potent immune responses. We conducted a randomized phase II trial of GVAX after HSCT for MDS-EB or relapsed/refractory AML. Myeloblasts were harvested before HSCT to generate the vaccine. Randomization to GVAX vs. placebo (1:1) was stratified by disease, transplant center, and conditioning. GVHD prophylaxis included tacrolimus and methotrexate. GVAX or placebo started between day +30-45 if there was engraftment and no GVHD. Vaccines were administered SC/ID weekly x 3, then q2 wks x 3. Tacrolimus taper began after vaccine completion. 123 patients enrolled, 92 proceeded to HSCT, and 57 (GVAX 30, Placebo 27) received at least 1 vaccination. No CTC grade ≥ 3 vaccine related adverse events were reported, but injection site reactions were more common after GVAX (10 vs. 1, p=0.006). With a median follow up of 39 months (range, 9-89), 18-month PFS, OS and relapse incidence were 53% vs 55% (p=0.79), 63% vs. 59% (p= 0.86), and 30% vs. 37% (p=0.51) for GVAX and placebo, respectively. NRM at 18 months was 17% vs. 7.7% (p=0.18), Grade II-IV aGVHD at 12 months 34% vs. 12% (p=0.13), and cGVHD at 3 years 49% vs. 57% for GVAX and placebo, respectively, p=0.26. Reconstitution of T, B, and NK cells were not decreased or enhanced by GVAX. There were no differences in serum MICA/B or other immune biomarkers between GVAX and placebo. GVAX does not improve survival after HSCT for MDS/AML. (Clinicaltrials.gov identifier: NCT01773395).
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http://dx.doi.org/10.1182/bloodadvances.2021006255DOI Listing
November 2021

Defibrotide: real-world management of veno-occlusive disease/sinusoidal obstructive syndrome after stem cell transplant.

Blood Adv 2022 Jan;6(1):181-188

Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Hepatic veno-occlusive disease or sinusoidal obstructive syndrome (VOD/SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Defibrotide is the only medication approved by the US Food and Drug Administration for the management of severe VOD/SOS after HSCT. We report our center's experience with commercially available defibrotide as treatment of patients with VOD/SOS. We retrospectively identified 28 cases of VOD/SOS, based on the European Society for Blood and Marrow Transplantation criteria, from March 2016 through June 2019. The median day of VOD/SOS onset was 25 days (range, 8-69 days), and defibrotide was initiated on day of diagnosis in 71% of patients. Complete resolution of VOD/SOS occurred in 75% of patients. Day 100 survival was 64% for all HSCT patients and 53% for those with very severe VOD/SOS. Response rates and survival were similar in patients with VOD/SOS after myeloablative or reduced-intensity chemotherapy HSCT. Therapy-related adverse events were mild and included hematuria (43%), epistaxis (18%), and hypotension (11%). Severe hemorrhagic adverse events occurred in 2 patients (pulmonary hemorrhage and upper gastrointestinal hemorrhage; 7%) and both in the setting of progressive VOD/SOS. Early diagnosis, prompt initiation of defibrotide, and minimization of dosing interruptions may be key to successful treatment of VOD/SOS.
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http://dx.doi.org/10.1182/bloodadvances.2021005410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753224PMC
January 2022

Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active.

Blood Adv 2021 12;5(24):5536-5545

Department of Medical Oncology, and.

Adding the selective BCL-2 inhibitor venetoclax to reduced-intensity conditioning chemotherapy (fludarabine and busulfan [FluBu2]) may enhance antileukemic cytotoxicity and thereby reduce the risk of posttransplant relapse. This phase 1 study investigated the recommended phase 2 dose (RP2D) of venetoclax, a BCL-2 selective inhibitor, when added to FluBu2 in adult patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and MDS/myeloproliferative neoplasms (MPN) undergoing transplant. Patients received dose-escalated venetoclax (200-400 mg daily starting day -8 for 6-7 doses) in combination with fludarabine 30 mg/m2 per day for 4 doses and busulfan 0.8 mg/kg twice daily for 8 doses on day -5 to day -2 (FluBu2). Transplant related-toxicity was evaluated from the first venetoclax dose on day -8 to day 28. Twenty-two patients were treated. At study entry, 5 patients with MDS and MDS/MPN had 5% to 10% marrow blasts, and 18 (82%) of 22 had a persistent detectable mutation. Grade 3 adverse events included mucositis, diarrhea, and liver transaminitis (n = 3 each). Neutrophil/platelet recovery and acute/chronic graft-versus-host-disease rates were similar to those of standard FluBu2. No dose-limiting toxicities were observed. The RP2D of venetoclax was 400 mg daily for 7 doses. With a median follow-up of 14.7 months (range, 8.6-24.8 months), median overall survival was not reached, and progression-free survival was 12.2 months (95% confidence interval, 6.0-not estimable). In patients with high-risk AML, MDS, and MDS/MPN, adding venetoclax to FluBu2 was feasible and safe. To further address relapse risk, assessment of maintenance therapy after venetoclax plus FluBu2 transplant is ongoing. This study was registered at clinicaltrials.gov as #NCT03613532.
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http://dx.doi.org/10.1182/bloodadvances.2021005566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714724PMC
December 2021

Impact of cryopreservation and transit times of allogeneic grafts on hematopoietic and immune reconstitution.

Blood Adv 2021 12;5(23):5140-5149

Department of Medical Oncology and.

We sought to evaluate the impact of cryopreservation of unrelated donor (URD) peripheral blood stem cell (PBSC) grafts on engraftment, chimerism, and immune reconstitution in the context of the COVID-19 pandemic. We reviewed stem cell product characteristics and clinical outcomes in 101 patients receiving cryopreserved PBSCs from URDs between January 1, 2019 and 31 December, 2020, compared with 203 patients receiving fresh URD PBSCs. We observed no differences in 6-month overall survival, progression-free survival, or nonrelapse mortality. Patients receiving cryopreserved PBSCs had delayed platelet engraftment and impaired reconstitution of white blood cells and T-cell subsets at day 30. Thirty-four percent of patients receiving cryopreserved grafts had CD3 chimerism <50% at day 30 after transplantation, compared with 14% of patients receiving fresh PBSCs (P = .0002). At day 100, this difference persisted (CD3+ chimerism <50%: 17% of cryopreserved cohort vs 6% of fresh cohort; P = .016). Greater product age at infusion was associated with increased graft failure, independent of cryopreservation. Receipt of grafts >48 hours old at time of cryopreservation or infusion significantly increased the risk of graft failure (subdistribution hazard ratio = 4.57; 95% confidence interval, 1.71-12.3; P = .0025). Our data indicate that cryopreservation is associated with similar overall short-term clinical outcomes compared with fresh PBSC. However, patients must be monitored closely for increased risk of other potentially adverse outcomes, including graft failure and poor immune recovery, particularly for grafts with older overall age at infusion. Longer-term follow-up is needed to determine impact on relapse and survival.
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http://dx.doi.org/10.1182/bloodadvances.2021005139DOI Listing
December 2021

Ibrutinib in Steroid-Refractory Chronic Graft-versus-Host Disease, a Single-Center Experience.

Transplant Cell Ther 2021 Dec 2;27(12):990.e1-990.e7. Epub 2021 Sep 2.

Division of Stem Cell Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Massachusetts. Electronic address:

Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality after allogenic hematopoietic stem cell transplantation. Corticosteroid-based therapies are a mainstay of its initial treatment but there is no consensus in how to treat steroid-refractory cGVHD. Ibrutinib is a Bruton tyrosine kinase and IL-2-inducible kinase inhibitor thought to affect pathways driving cGVHD, and it was approved for the treatment of refractory cGVHD by the Food and Drug Administration (FDA) in August 2017 after a landmark phase 1b/2 study. It was the first medication approved for this indication, but how to best treat refractory cGVHD remains an open question, and there has been limited literature on ibrutinib after the FDA approval. This study sought to characterize the utilization and outcomes associated with ibrutinib use in cGVHD via a retrospective single-center study. Fifty-three patients were identified as having been treated with ibrutinib for cGVHD following FDA approval between September 1, 2017, and December 31, 2020, using an institutional data repository. Their records were reviewed for demographics, cGVHD characteristics, and outcomes. For the entire cohort, two-year overall survival was 76% (95% confidence interval [CI], 60% to 86%), with a median follow-up among survivors of 26 months (range, 1.3 to 39.5 months). However, the 2-year failure-free survival (FFS) after initiation of ibrutinib was 9% (95% CI, 2.6% to 20%), and the median FFS was 4.5 months (95% CI, 2.8 to 7.1 months). Events of FFS included treatment change due to lack of response or toxicity, malignant relapse, or non-treatment related mortality. At the time of this report, 11 patients (21%) remained on ibrutinib. At the time of the FFS event or last follow-up, 6 patients (12%) had a complete or partial response, 34 (64%) had stable disease, and 13 (25%) had progressive disease. Ibrutinib use was associated with no reduction in corticosteroid dose between ibrutinib initiation and FFS event or last follow-up (mean difference, 0.00; P = .98). The most frequently used noncorticosteroid cGVHD therapy after ibrutinib was ruxolitinib (n = 14; 33%). The most common adverse events associated with treatment discontinuation were infection (lung, skin, enterocolitis; n = 6), bleeding and bruising (hematoma, epistaxis, gastrointestinal bleed; n = 5), and muscle aches (n = 2). In a real-world setting, ibrutinib is associated with a modest response rate and FFS and its use in a narrower, more targeted patient population may be indicated.
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http://dx.doi.org/10.1016/j.jtct.2021.08.017DOI Listing
December 2021

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

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

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

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

Efficacy and Safety of 1% Progesterone Gel to the Forehead for Ocular Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 05 14;27(5):433.e1-433.e8. Epub 2021 Feb 14.

Dana-Farber Cancer Institute, Boston, Massachusetts.

There is no Food and Drug Administration-approved treatments for ocular chronic graft-versus-host disease (oGVHD) to date, and current therapeutic options are limited. Forehead application of 1% progesterone gel provides corneal antinociception in preclinical models, suggesting it may be useful in alleviating ocular irritations. This study was conducted to evaluate the efficacy and safety of 1% progesterone gel in treating moderate to severe symptomatic oGVHD. Thirty-three patients with oGVHD following allogeneic stem cell transplantation were enrolled in this single-center, sponsor-initiated, prospective exploratory randomized double-masked placebo-controlled phase II clinical trial. The inclusion criteria included a National Institutes of Health consensus score of ≥2, moderate to severe ocular discomfort level, and receipt of a stable immunosuppression regimen. Twenty-one of the 22 patients in the progesterone arm and all 11 patients in the placebo arm completed the course of twice-daily forehead drug application for 10 weeks. The changes from baseline of self-reported ocular symptom scores and physician-recorded cornea fluorescein staining scores were analyzed using mixed-model repeated-measures regression model in an intention-to-treat population. The 33 patients included 12 women and 21 men, with a median age of 66 years (range, 24 to 75 years). At 10 weeks, there was a significant reduction in ocular symptoms from baseline in the progesterone group compared with the placebo group in symptom frequency (-30.7 versus -2.2; P < .001) and severity (-19.8 versus +1.6; P = .005). At 10 weeks, there was also greater reduction of cornea fluorescein staining centrally (-1.2 versus +.1; P = .001) and inferiorly (-1.4 versus -0.2; P = .005). No difference was noted in superior cornea staining. There were no severe adverse events in the progesterone group. Forehead application of 1% progesterone gel significantly improved ocular signs and symptoms within 10 weeks. It appears to be a safe and effective new therapy for oGVHD, and a novel mechanism for neuroaxis drug delivery. A multicenter phase III clinical trial is planned for further validation.
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http://dx.doi.org/10.1016/j.jtct.2021.02.008DOI Listing
May 2021

GVHD Prophylaxis 2020.

Front Immunol 2021 7;12:605726. Epub 2021 Apr 7.

Dana-Farber Cancer Institute, Boston, MA, United States.

Graft-vs. host disease (GVHD), both acute and chronic are among the chief non-relapse complications of allogeneic transplantation which still cause substantial morbidity and mortality despite significant advances in supportive care over the last few decades. The prevention of GVHD therefore remains critical to the success of allogeneic transplantation. In this review we briefly discuss the pathophysiology and immunobiology of GVHD and the current standards in the field which remain centered around calcineurin inhibitors. We then discuss important translational advances in GVHD prophylaxis, approaching these various platforms from a mechanistic standpoint based on the pathophysiology of GVHD including and T-cell depletion alongwith methods of selective T-cell depletion, modulation of T-cell co-stimulatory pathways (checkpoints), enhancing regulatory T-cells (Tregs), targeting T-cell trafficking as well as cytokine pathways. Finally we highlight exciting novel pre-clinical research that has the potential to translate to the clinic successfully. We approach these methods from a pathophysiology based perspective as well and touch upon strategies targeting the interaction between tissue damage induced antigens and T-cells, regimen related endothelial toxicity, T-cell co-stimulatory pathways and other T-cell modulatory approaches, T-cell trafficking, and cytokine pathways. We end this review with a critical discussion of existing data and novel therapies that may be transformative in the field in the near future as a comprehensive picture of GVHD prophylaxis in 2020. While calcineurin inhibitors remain the standard, post-transplant eparinsphamide originally developed to facilitate haploidentical transplantation is becoming an attractive alternative to traditional calcinuerin inhibitor based prophylaxis due to its ability to reduce severe forms of acute and chronic GVHD without compromising other outcomes, even in the HLA-matched setting. In addition T-cell modulation, particularly targeting some important T-cell co-stimulatory pathways have resulted in promising outcomes and may be a part of GVHD prophylaxis in the future. Novel approaches including targeting early events in GVHD pathogenesis such as interactions bvetween tissue damage associated antigens and T-cells, endothelial toxicity, and T-cell trafficking are also promising and discussed in this review. GVHD prophylaxis in 2020 continues to evolve with novel exicitng therapies on the horizon based on a more sophisticated understanding of the immunobiology of GVHD.
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http://dx.doi.org/10.3389/fimmu.2021.605726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059368PMC
June 2021

Cytomegalovirus events in high-risk allogeneic hematopoietic-cell transplantation patients who received letermovir prophylaxis.

Transpl Infect Dis 2021 Aug 5;23(4):e13619. Epub 2021 May 5.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Letermovir is approved for the prevention of cytomegalovirus (CMV) reactivation and clinical disease in patients undergoing allogeneic hematopoietic-cell transplantation (HCT). However, there is uncertainty about letermovir's ability to prevent clinical events during the period of prophylaxis as well as after the discontinuation of prophylaxis in the post-transplant setting. We performed a retrospective cohort study in CMV-seropositive allogeneic HCT recipients at high risk of CMV events, who received letermovir for primary prophylaxis from November 2017 through December 2019. We analyzed CMV outcomes for these patients during and after prophylaxis was discontinued. Patient outcomes were followed through June 2020. Sixty patients received letermovir for a median of 13 weeks (range, 1-72 weeks). Thirteen (22%) patients had quantifiable CMV DNAemia (reactivation) during letermovir prophylaxis a median of 9 days (range, 1-59 days) after starting letermovir. Five (8%) of these patients discontinued prophylaxis and received preemptive therapy (PET) with valganciclovir; eight (13%) continued letermovir as prophylaxis and CMV DNAemia resolved without PET. Thirteen patients (22%) had post-prophylaxis CMV reactivation a median of 33 days (range, 14-109 days) after letermovir discontinuation. In four (7%) of these patients, CMV DNAemia resolved without PET, and nine (15%) received PET. No patient developed CMV disease. Patients who developed CMV reactivation during prophylaxis did so shortly after initiation of letermovir, and most patients who developed CMV reactivation post-prophylaxis did so within 60 days after discontinuation of letermovir. Letermovir prophylaxis has changed the presentation of CMV infection in high-risk HCT patients.
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http://dx.doi.org/10.1111/tid.13619DOI Listing
August 2021

Outcomes for Patients With IDH-Mutated Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 06 25;27(6):479.e1-479.e7. Epub 2021 Feb 25.

Center for Leukemia, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Disease relapse after hematopoietic cell transplantation (HCT) is a major cause of treatment failure for patients with acute myeloid leukemia (AML). Maintenance therapy after HCT for patients with targetable mutations such as mutated IDH1 or IDH2 may improve outcomes, and clinical trials evaluating this strategy are ongoing. However, clinical outcomes of IDH1- and IDH2-mutated AML patients after HCT have not been well described. The primary objective of this study was to describe the clinical characteristics and post-HCT outcomes of IDH-mutated AML patients. Survival outcomes included progression-free survival (PFS), overall survival, and cumulative incidences of relapse and nonrelapse mortality. In this multicenter retrospective analysis, 112 adult patients with IDH1- or IDH2-mutated AML who underwent HCT and did not receive an IDH inhibitor as maintenance therapy after HCT were identified at Massachusetts General Hospital, Dana Farber Cancer Institute, and Ohio State University. Mutation testing was performed using next-generation sequencing panels. Patient characteristics were collected retrospectively, and their survival outcomes were analyzed. Univariate and multivariate analyses were performed. The median patient age was 64.1 years. The median follow-up was 27.5 months. Among patients, 78.5% had intermediate- or adverse-risk disease by European LeukemiaNET criteria. Fifty-eight percent of patients received intensive induction chemotherapy, 82% of patients underwent HCT during first complete remission (CR) or CR with incomplete hematologic recovery (CRi), and 34% of patients received myeloablative conditioning. Frequently detected co-mutations were DNMT3A (35.7%), NPM1 (33.1%), and FLT3-ITD (13.4%); TP53 mutations were detected in 3.6% of patients. For IDH1-mutated patients transplanted during first CR/CRi, the 1- and 2-year PFS was 75% and 58%, respectively. For IDH2-mutated patients transplanted in first CR/CRi, the 1- and 2-year PFS was 64% and 58%, respectively. The 2-year cumulative incidence of relapse was 31% and 25% for IDH1- and IDH2-mutated cohorts, respectively. Multivariable analysis suggested first CR/CRi and age ≤60 was associated with improved outcomes for IDH2-mutated patients. To date, this is the largest multicenter study of outcomes of IDH-mutated AML patients after HCT. Our analysis provides important benchmarks for analysis and interpretation of results emerging from clinical trials evaluating maintenance IDH1 and IDH2 inhibitor therapy for AML patients after HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.02.028DOI Listing
June 2021

COVID-19 and hematopoietic stem cell transplantation and immune effector cell therapy: a US cancer center experience.

Blood Adv 2021 02;5(3):861-871

Division of Hematologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified in late 2019 as the causative agent of COVID-19, was declared a pandemic by the World Health Organization on 11 March 2020. Widespread community transmission in the United States triggered a nationwide shutdown, raising major challenges for administration of hematopoietic stem cell transplant (HSCT) and chimeric antigen receptor (CAR)-T cell therapies, leading many centers to delay or cancel operations. We sought to assess the impact of the COVID-19 pandemic on operations and clinical outcomes for HSCT and CAR-T cellular therapies at the Dana-Farber Cancer Institute by reviewing administration and outcomes in 127 cell therapy patients treated during the initial COVID-19 surge: 62 adult allogeneic HSCT (allo-HSCT), 38 autologous HSCT (auto-HSCT), and 27 CAR-T patients. Outcomes were compared with 66 allo-HSCT, 43 auto-HSCT, and 33 CAR-T patients treated prior to the pandemic. A second control cohort was evaluated for HSCT groups to reflect seasonal variation in infections. Although there were changes in donor selection and screening as well as cryopreservation patterns of donor products, no differences were observed across groups in 100-day overall survival, progression-free survival, rates of non-COVID-19 infections, including hospital length of stay, neutrophil engraftment, graft failure, acute graft-versus-host disease in allo-HSCT patients, or cytokine release syndrome and neurotoxicity in CAR-T patients. No HSCT patients contracted COVID-19 between days 0 and 100. One CAR-T patient contracted COVID-19 at day +51 and died of the disease. Altogether, our data indicate that cellular therapies can be safely administered throughout the ongoing COVID-19 pandemic with appropriate safeguards.
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http://dx.doi.org/10.1182/bloodadvances.2020003883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869610PMC
February 2021

Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide.

Blood Adv 2021 01;5(2):352-364

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.

Administration of posttransplant cyclophosphamide (PTCy) has significantly expanded the number of patients undergoing HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). To examine immune reconstitution in these patients, we monitored T- and natural killer (NK)-cell recovery in 60 patients receiving bone marrow or peripheral blood stem cell (PBSC) grafts after haplo-HCT with PTCy and 35 patients receiving HLA-matched donor PBSC grafts with standard graft-versus-host disease (GVHD) prophylaxis. Compared with HLA-matched recipients, early T-cell recovery was delayed in haplo-HCT patients and skewed toward effector memory T cells with markedly reduced naive T cells. We found higher regulatory T (Treg)-cell/conventional T (Tcon)-cell ratios early after HCT and increased PD-1 expression on memory T cells. Within the haplo-HCT, patients who did not develop chronic GVHD (cGVHD) had higher PD-1 expression on central and effector memory CD4+ Treg cells at 1 month after transplant. These findings suggest an immunologic milieu that promotes immune tolerance in haplo-HCT patients. NK cells were decreased early after haplo-HCT with preferential expansion of immature CD56brightCD16- NK cells compared with matched donor transplants. One month after transplant, mass cytometry revealed enrichment of immature NK-cell metaclusters with high NKG2A, low CD57, and low killer-cell immunoglobulin-like receptor expression after haplo-HCT, which partially recovered 3 months post-HCT. At 2 months, immature NK cells from both groups were functionally impaired, but interleukin-15 priming corrected these defects in vitro. Increased immature/mature NK-cell ratios were associated with cytomegalovirus reactivation and increased incidence of cGVHD after haplo-HCT. These homeostatic imbalances in T- and NK-cell reconstitution after haplo-HCT reveal opportunities for early immune-based interventions to optimize clinical outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020003005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839379PMC
January 2021

Translational and clinical advances in acute graft-versus-host disease.

Haematologica 2020 11 1;105(11):2550-2560. Epub 2020 Nov 1.

Dana-Farber Cancer Institute, Boston, MA.

Acute graft-versus-host disease (aGvHD) is induced by immunocompetent alloreactive T lymphocytes in the donor graft responding to polymorphic and non-polymorphic host antigens and causing inflammation in primarily the skin, gastrointestinal tract and liver. aGvHD remains an important toxicity of allogeneic transplantation, and the search for better prophylactic and therapeutic strategies is critical to improve transplant outcomes. In this review, we discuss the significant translational and clinical advances in the field which have evolved based on a better understanding of transplant immunology. Prophylactic advances have been primarily focused on the depletion of T lymphocytes and modulation of T-cell activation, proliferation, effector and regulatory functions. Therapeutic strategies beyond corticosteroids have focused on inhibiting key cytokine pathways, lymphocyte trafficking, and immunologic tolerance. We also briefly discuss important future trends in the field, the role of the intestinal microbiome and dysbiosis, as well as prognostic biomarkers for aGvHD which may improve stratification-based application of preventive and therapeutic strategies.
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http://dx.doi.org/10.3324/haematol.2019.240309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604566PMC
November 2020

Phase II trial of natalizumab with corticosteroids as initial treatment of gastrointestinal acute graft-versus-host disease.

Bone Marrow Transplant 2021 05 8;56(5):1006-1012. Epub 2020 Sep 8.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

The α4ß7 integrin is upregulated on naive and memory T cell subsets in patients who subsequently develop gastrointestinal (GI) acute GVHD. Natalizumab (Tysabri, Biogen Inc.) acts against the α4 subunit that mediates homing of lymphocytes to the GI tract. We initiated a phase II study of natalizumab with corticosteroids for initial treatment of acute GI GVHD. In total, 300 mg IV of natalizumab was given, with steroids initiated up to 3 days prior. Twenty-one subjects were treated, median age was 63 years (range 38-74), and 15 (71%) were male. Eighteen (86%) underwent RIC, 15 (71%) received MUD, and all received PBSCs. Overall GVHD at enrollment was grade II in 4 and grade III in 17. The primary endpoint, day 56 GVHD-free survival rate, was attained in 33.3%. The overall response rate at day 28 and 56 was 57% and 52%, respectively. Six of eight CRs were durable for 1 year. Five experienced toxicity possibly related to natalizumab and ten had infections before day 100. 2-year OS was 43% (95% CI 22-62%) and 2-year NRM was 52% (95% CI 29-71%). Natalizumab with corticosteroids as initial treatment of acute GI GVHD is safe, effective, and durable.
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http://dx.doi.org/10.1038/s41409-020-01049-0DOI Listing
May 2021

Allogeneic hematopoietic cell transplantation after prior targeted therapy for high-risk chronic lymphocytic leukemia.

Blood Adv 2020 09;4(17):4113-4123

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Allogeneic hematopoietic cell transplantation (alloHCT) can cure previously treated high-risk chronic lymphocytic leukemia (CLL) patients if they are suitable for transplant through the graft-versus-leukemia effect. However, since the emergence of targeted therapies, the role of alloHCT for high-risk CLL is less clear. To address this question, we evaluated 108 high-risk CLL patients who underwent alloHCT from 2010 to 2018. Thirty patients from the period of 2013 to 2018 received targeted therapy prior to alloHCT. The median age for the targeted therapy cohort was 60 years (range, 30-71 years), and 20% and 73% had complete and partial remission, respectively: 76% had del(17p), 46.2% had 5 or more cytogenetic abnormalities, and 78.9% were IGHV unmutated. The median number of prior therapies was 4 (range, 1-9). With a median follow-up time of 36 months (range, 10-72 months), the 3-year overall (OS) and progression-free survival (PFS) were 87% and 69%, respectively. The 3-year cumulative incidence of nonrelapse mortality and relapse was 7% and 24%, respectively. For the control cohort of 78 patients who underwent alloHCT from 2010 to 2014 and received only chemoimmunotherapy prior to transplant, the 3-year OS and PFS were 69% and 58%, respectively. Patients treated with targeted therapy prior to alloHCT had a significantly higher number of circulating T and B cells and a lower ratio of CD4 regulatory T cells to CD4 conventional T cells early after transplant. In summary, despite multiple high-risk features, the clinical outcome of CLL patients who receive targeted therapy prior to transplant is excellent and alloHCT should be offered while the disease is under control.
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http://dx.doi.org/10.1182/bloodadvances.2020002184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479951PMC
September 2020

BK virus-specific T-cell immune reconstitution after allogeneic hematopoietic cell transplantation.

Blood Adv 2020 05;4(9):1881-1893

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Clinical disease caused by BK virus reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Because of the lack of effective antiviral agents, BK virus-specific T cells are emerging as a potential therapy for BK virus disease, but the immune response to BK virus after allogeneic HCT has not been well characterized. Our study describes reconstitution of BK virus-specific T-cell immunity in 77 adult patients after HCT. All patients had urinary symptoms, and urine was tested for BK virus replication; 33 patients were positive for BK virus (cases), and 44 were negative (controls). In BK virus cases, the median time to first positive test was 75 days (range, 2-511). BK virus cases had lower CD4 T-cell counts 3 to 9 months after transplant, but CD8 T-cell counts were similar in cases and controls. BK virus-specific T cells were identified by cytokine flow cytometry in cryopreserved samples collected prospectively. BK virus-specific CD4 T cells producing T helper 1 (Th1) cytokines recovered quickly after HCT. BK virus-specific T cells were detected more frequently in patients with BK virus reactivation at most time points, and CD4 T cells producing Th1 cytokines were more frequent than BK virus-specific cytolytic CD8 T cells. Early detection of interferon-γ+ and cytolytic BK virus-specific CD4 T cells was associated with lower rates of hematuria among cases. Overall, our study describes recovery of BK virus-specific T cells after HCT and the distinct roles for BK virus-specific T cells in the development and resolution of clinical symptoms.
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http://dx.doi.org/10.1182/bloodadvances.2019001120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218418PMC
May 2020

Reply to "The Reversed Halo Sign: Criteria for Differentiation of Infectious and Noninfectious Diseases".

AJR Am J Roentgenol 2019 12;213(6):W296

Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.2214/AJR.19.21975DOI Listing
December 2019

Effect of Sirolimus on Immune Reconstitution Following Myeloablative Allogeneic Stem Cell Transplantation: An Ancillary Analysis of a Randomized Controlled Trial Comparing Tacrolimus/Sirolimus and Tacrolimus/Methotrexate (Blood and Marrow Transplant Clinical Trials Network/BMT CTN 0402).

Biol Blood Marrow Transplant 2019 11 2;25(11):2143-2151. Epub 2019 Jul 2.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.

Although allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for hematologic neoplasms, one of its limiting toxicities continues to be graft-versus-host disease, both acute (aGVHD) and chronic (cGVHD). Sirolimus is a mammalian target of rapamycin inhibitor that has proven effective in GVHD prophylaxis in combination with a calcineurin inhibitor, such as tacrolimus. The impact of sirolimus on immune reconstitution has not been comprehensively investigated in vivo thus far, however. Here we present an ancillary analysis of the randomized study BMT-CTN 0402 that examined the effect of sirolimus on immune subsets post-transplantation. We further examine the association between different lymphocyte subsets and outcomes post-transplantation in each arm. BMT-CTN 0402 was a randomized trial (n = 304) comparing 2 GVHD prophylaxis regimens, tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/MTX), in patients with acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome undergoing myeloablative HLA-matched HCT. There were no differences in 114-day GVHD-free survival (primary endpoint), aGVHD, cGVHD, relapse, or overall survival (OS) between the 2 arms. Of the 304 patients, 264 had available samples for the current immune reconstitution analysis. Blood samples were collected at 1, 3, 6, 12, and 24 months post-HCT. Multiparameter flow cytometry was performed at the project laboratory (Esoterix Clinical Trials Services) in a blinded fashion, and results for the 2 arms were compared. Multivariable Cox regression models, treating each phenotypic parameter as a time-dependent variable, were constructed to study the impact of reconstitution on clinical outcomes. There were no significant differences in patient and transplantation characteristics between the Tac/Sir and Tac/MTX arms in this analysis. Absolute lymphocyte count and CD3 cell, CD4 cell, and conventional T cell (Tcon) counts were significantly decreased in the Tac/Sir arm for up to 3 months post-HCT, whereas CD8 cells recovered even more slowly (up to 6 months) in this arm. Interestingly, there was no clear difference in the absolute number of regulatory T cells (Tregs, defined as CD4CD25 cells) between the 2 arms at any point post-HCT; however, the Treg:Tcon ratio was significantly greater in the Tac/Sir arm in the first 3 months after HCT. B lymphocyte recovery was significantly compromised in the Tac/Sir arm from 1 month to 6 months after HCT, whereas natural killer cell reconstitution was not affected in the Tac/Sir arm. In the outcomes analysis, higher numbers of CD3 cells, CD4 cells, CD8 cells, and Tregs were associated with better OS. Neither Treg numbers nor the Treg:Tcon ratio was correlated with GVHD. Our findings indicate that Tac/Sir has a more profound T cell suppressive effect than the combination of Tac/MTX in the early post-transplantation period, and particularly compromises the recovery of CD8 T cells, which have been implicated in aGVHD. Sirolimus used in vivo with tacrolimus does not appear to result in increased absolute numbers of Tregs, but might have a beneficial effect on the Treg:Tcon balance in the first 3 months after transplantation. Nonetheless, no differences in aGVHD or cGVHD between the 2 arms were observed in the parent randomized trial. Calcineurin-inhibitor free, sirolimus-containing GVHD prophylaxis strategies, incorporating other novel agents, should be investigated further to maximize the potential favorable effect of sirolimus on Treg:Tcon balance in the post-transplantation immune repertoire. Sirolimus significantly compromises B cell recovery in the first 6 months post-HCT, with potential complex effects on cGVHD that merit further study.
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http://dx.doi.org/10.1016/j.bbmt.2019.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304072PMC
November 2019

A post-transplant optimized transplant-specific risk score in myelodysplastic syndromes.

Haematologica 2019 05;104(5):859-861

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA, USA.

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http://dx.doi.org/10.3324/haematol.2018.214452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518899PMC
May 2019

Significance of the Reverse Halo Sign in Immunocompromised Patients.

AJR Am J Roentgenol 2019 09 30;213(3):549-554. Epub 2019 Apr 30.

Department of Radiology, Division of Thoracic Imaging, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

The purpose of this study is to assess the most common causes of the reverse halo sign (RHS) in immunocompromised patients and to identify clinicoradiologic features that help in achieving a specific diagnosis. This retrospective study included 70 patients with hematologic malignancy, neutropenia, or history of solid organ transplant or stem cell transplant who had the RHS at chest CT. Absolute neutrophil count, imaging features of the RHS, and presence of pleural effusions were noted and correlated with the specific diagnosis. A decision tree was constructed from predictive imaging features and compared with radiologist assessment for infectious versus noninfectious cause. Infection, including fungal and bacterial pneumonia, was the most common cause of the RHS (66%), followed by organizing pneumonia (26%). Noninfectious causes such as organizing pneumonia were more likely in the solid organ transplant group, whereas infections were more likely in patients with hematologic malignancy and stem cell transplant. Among fungal pneumonias, aspergillosis (20%) was as common as mucormycosis (19%). In univariate analysis, neutropenia, rim thickness, central ground-glass attenuation, and lesion diameter correlated with infectious cause. A decision tree using neutropenia, rim thickness, central ground-glass attenuation, and pleural effusion could differentiate infectious from noninfectious cause with accuracy of 78%, compared with radiologist accuracy of 81%. Infections are more likely to cause RHS than noninfectious processes in immunocompromised patients, and aspergillosis may be as likely overall as mucormycosis because of its higher frequency in these patients. A decision tree using clinical and imaging features can help differentiate infectious from noninfectious causes of RHS.
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http://dx.doi.org/10.2214/AJR.19.21273DOI Listing
September 2019

PTCy-based haploidentical vs matched related or unrelated donor reduced-intensity conditioning transplant for DLBCL.

Blood Adv 2019 02;3(3):360-369

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

This study retrospectively compared long-term outcomes of nonmyeloablative/reduced intensity conditioning (NMC/RIC) allogeneic hematopoietic cell transplantation (allo-HCT) from a haploidentical family donor (haplo-HCT) using posttransplant cyclophosphamide (PTCy) with those of matched sibling donor (MSD) and matched unrelated donor (MUD) with or without T-cell depletion (TCD+/TCD-) in patients with relapsed diffuse large B-cell lymphoma (DLBCL). Adult patients with DLBCL who had undergone their first NMC/RIC allo-HCT between 2008 and 2015 were included. Recipients of haplo-HCT were limited to those receiving graft-versus-host disease (GVHD) prophylaxis with PTCy. GVHD prophylaxis in MSD was limited to calcineurin inhibitor (CNI)-based approaches without in vivo TCD, while MUD recipients received CNI-based prophylaxis with or without TCD. Outcome analyses for overall survival (OS) and progression-free survival (PFS), nonrelapse mortality (NRM), and disease relapse/progression were calculated. A total of 1438 patients (haplo, 132; MSD, 525; MUD TCD+, 403; and MUD TCD-, 378) were included. Patients with haplo donors were significantly older, had a better performance status and had more frequently received total body irradiation-based conditioning regimens and bone marrow grafts than MSD and MUD TCD+ or TCD-. 3-year OS, PFS, NRM and relapse/progression incidence after haplo-HCT was 46%, 38%, 22%, and 41%, respectively, and not significantly different from outcomes of matched donor transplants on multivariate analyses. Haplo-HCT was associated with a lower cumulative incidence of chronic GVHD compared with MSD, MUD TCD+/TCD-. NMC/RIC haplo-HCT with PTCy seems to be a valuable alternative for patients with DLBCL considered for allo-HCT but lacking a matched donor.
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http://dx.doi.org/10.1182/bloodadvances.2018027748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373757PMC
February 2019

Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors: Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial.

Biol Blood Marrow Transplant 2018 11 10;24(11):2216-2223. Epub 2018 Jul 10.

Dana-Farber Cancer Institute, Department of Biostatistics and Computation Biology, Boston, Massachusetts USA.

We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3 and CD4 T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD425127-) numbers were lower only in the first 100 days. Analysis of the CD4 Treg and conventional T cells (Tconv) (CD425127) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post-HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3, CD4, CD8 T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3 and CD4 T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4 cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.002DOI Listing
November 2018

A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation, for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis.

Biol Blood Marrow Transplant 2018 08 16;24(8):1733-1740. Epub 2018 Mar 16.

Division of Hematological Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.

With improvement in transplantation practices in the modern era, nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has improved, while disease relapse rates have remained unchanged. Survival outcomes are therefore driven by NRM in the modern era. Myeloablative conditioning (MAC) regimens are used to maximize disease control and facilitate engraftment; however, their use is often limited by toxicity. The commonly used MAC regimens incorporate either chemotherapy plus total body irradiation (TBI) or combination chemotherapy. Furthermore, reduced-toxicity myeloablative (RTM) regimens, such as fludarabine/busulfan (FluBu), have emerged as alternatives to traditional MAC and their impact on outcomes in the current era have not been fully investigated. In this study, we compare outcomes following HSCT, using the chemotherapy only RTM MAC regimens FluBu with the chemoradiotherapy regimen cyclophosphamide/TBI (CyTBI), for patients with hematologic malignancies who underwent MAC HSCT at the Dana-Farber Cancer Institute. We hypothesized that the chemotherapy-only regimen would fare better, primarily due to improved NRM. A retrospective cohort analysis was performed on 387 patients with myeloid or lymphoid hematologic malignancies who underwent HLA-matched related (8/8), matched unrelated (8/8), or single-antigen mismatched unrelated (7/8) HSCT following myeloablative conditioning. Patients received FluBu (n = 158) or CyTBI (n = 229). The primary outcome was overall survival (OS) and all other outcomes were regarded as secondary. A subset analysis was performed for patients <55 years of age and for acute myelogenous leukemia/myelodysplastic syndrome patients of age <55 years. For the whole cohort, 3-year OS was similar for FluBu compared with CyTBI in unadjusted analysis. However, in multivariable analysis, FluBu resulted in superior OS compared with CyTBI (3-year adjusted estimate: 65% versus 55%, respectively; HR for death, .62; 95% CI, .40 to .97; P = .036). While relapse rates were similar between the 2 regimens, NRM and acute graft-versus-host disease (GVHD) (grade II to IV) were significantly worse with CyTBI compared with FluBu. Rates of chronic GVHD were similar between 2 regimens. These results were consistent in a subset of patients <55 years of age and in acute myelogenous leukemia/myelodysplastic syndrome patients below 55 years of age. The RTM chemotherapy-only regimen FluBu appears to be as effective and more tolerable than the chemoradiotherapy regimen CyTBI, leading to better OS driven by better NRM. The improvement in NRM was attributable chiefly to lower rates of grade II to IV acute GVHD. Relapse rates were not increased with FluBu. In the absence of randomized data, FluBu appears to be the optimal regimen for myeloablative HSCT in patients of all age groups.
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http://dx.doi.org/10.1016/j.bbmt.2018.03.011DOI Listing
August 2018

Mitochondrial and glycolytic metabolic compartmentalization in diffuse large B-cell lymphoma.

Semin Oncol 2017 06 10;44(3):204-217. Epub 2017 Oct 10.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA. Electronic address:

Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non-neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor-associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should be studied to determine if it could represent a novel treatment target in DLBCL.
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http://dx.doi.org/10.1053/j.seminoncol.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737785PMC
June 2017

Better acute graft--host disease outcomes for allogeneic transplant recipients in the modern era: a tacrolimus effect?

Haematologica 2017 05;102(5):806-808

Division of Hematologic Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

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http://dx.doi.org/10.3324/haematol.2017.165266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477598PMC
May 2017

Orbital Compartment Syndrome as the Presenting Sign of Disseminated Intravascular Coagulation From Metastatic Prostatic Cancer to the Orbit.

Urology 2015 Aug 10;86(2):e7-8. Epub 2015 Jul 10.

Department of Urology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA.

A 70-year-old man with castrate-resistant metastatic prostate cancer to the lumbar spine presented with sudden onset of left orbital compartment syndrome. Hematologic workup revealed disseminated intravascular coagulation with isolated left orbital hemorrhage. A canthotomy and blood product transfusions failed to control the bleeding and restore vision. Operative intervention found a new left orbital roof metastasis from primary prostatic carcinoma. Acute onset of headache or ocular pain in patients with metastatic prostate cancer warrants further workup to rule out orbital and intracranial metastases, rare but significant clinical entities that can lead to severe complications.
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http://dx.doi.org/10.1016/j.urology.2015.05.017DOI Listing
August 2015

Association between common allergic symptoms and cancer in the NHANES III female cohort.

PLoS One 2012 18;7(9):e42896. Epub 2012 Sep 18.

Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Background: Previous epidemiological studies have investigated the association between allergic symptoms and cancer occurrence. However, the role of allergy in cancer has been elusive, especially for the female population.

Methods: We examined the relationship between cancer prevalence and common allergic symptoms of rhinoconjunctivitis (RC) and wheezing (WZ) among NHANES III female participants.

Results: Among 4600 people, 36.3% (n = 1669) did not have any allergic symptoms (NO), while 47.6% (n = 2188) reported RC, and 16.2% (n = 743), WZ. The proportion of cancer among NO groups was 5.43% (91/1669), among RC group, 7.63% (167/2188), and among WZ group, 11.23% (83/743) (RC group- OR 1.44 with 95% CI 1.00-2.08; p = 0.05 while for WZ group- OR 2.20 with 95%CI 1.27-3.80; p = 0.01). After adjusting for all the possible confounding variables including age, smoking, or COPD, having symptoms of RC (AOR 1.49 with 95%CI 1.12-2.36; p = 0.01) or WC (AOR 2.08 with 95%CI 1.11-3.89; p = 0.02) demonstrated consistent strong association with cancer. Among nonsmokers (n = 2505, 54.5%) only symptoms of RC showed association with cancer (AOR 1.51 with 95%CI 1.00-2.28; p = 0.05). Among former or current smokers (n = 2094, 45.5%), only symptoms of WZ demonstrated association with cancer (AOR 2.38 with 95%CI 1.16-4.87; p = 0.02). Among different types of cancers, odds of having breast cancer among participants with symptoms of RC or WZ were approximately twice the odds of having breast cancer among participants without any of these symptoms. AOR for RC group was 1.89 with 95%CI 1.04-3.42 and p = 0.04 while AOR for WC group was 2.08 with 95%CI 0.90-4.78 and p = 0.08.

Conclusions: In summary, we found associations between common allergic symptoms like rhinitis/conjunctivitis and wheezing and prevalence of cancer, specifically between rhinitis/conjunctivitis and breast cancer that were not found in previous studies. Larger prospective studies are required to validate our findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042896PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445609PMC
March 2013
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