Publications by authors named "Vincent T Ho"

168 Publications

Relevance of Plasma Matrix Metalloproteinase-9 for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 Jun 12. Epub 2021 Jun 12.

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

Bronchiolitis obliterans syndrome (BOS) is a highly morbid form of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Several plasma proteins have been identified as biomarkers for BOS after lung transplantation. The relevance of these biomarkers in BOS patients after allogeneic HCT has not been examined. We hypothesized that biomarkers associated with BOS after lung transplantation are also associated with BOS after allogeneic HCT. We tested plasma samples from 33 adult HCT patients who participated in a phase II multicenter study of fluticasone, azithromycin, and montelukast (FAM) treatment for new-onset BOS (NCT01307462), and matched control samples of HCT patients who had non-BOS chronic GVHD (n = 31) and those who never experienced chronic GVHD (n = 29) (NCT00637689 and NCT01902576). Candidate biomarkers included matrix metalloproteinase-9 (MMP-9), MMP-3, and chitinase-3-like-1 glycoprotein (YKL-40). MMP-9 concentrations were higher in the patients with BOS compared with those with non-BOS chronic GVHD (P = .04) or no chronic GVHD (P < .001). MMP-3 concentrations were higher in patients with BOS (P < .001) or non-BOS chronic GVHD (P < .001) compared with those with no chronic GVHD. YKL-40 concentrations did not differ statistically among the 3 groups. MMP-9 concentrations before starting FAM therapy were higher in patients who experienced treatment failure within 6 months compared with those with treatment success (P = .006), whereas MMP-3 or YKL-40 concentrations did not differ statistically between these 2 groups. Patients with an MMP-9 concentration ≥200,000 pg/mL before starting FAM therapy had worse overall survival compared with those with lower MMP-9 concentrations. Our data suggest that plasma MMP-9 concentration could serve as a relevant biomarker at diagnosis of BOS after allogeneic HCT for prognostication of survival and for prediction of treatment response. Further validation is needed to confirm our findings.
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http://dx.doi.org/10.1016/j.jtct.2021.06.006DOI Listing
June 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

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

Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation.

Blood 2021 Jun;137(23):3212-3217

Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and.

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell activation and costimulation such as PD-1, HLA-DR, and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T-cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T-cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GVL outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01822509.
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http://dx.doi.org/10.1182/blood.2021010867DOI Listing
June 2021

Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.

Blood Adv 2021 03;5(6):1648-1659

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.
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http://dx.doi.org/10.1182/bloodadvances.2020003556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993097PMC
March 2021

Safety and reactogenicity of the recombinant zoster vaccine after allogeneic hematopoietic cell transplantation.

Blood Adv 2021 03;5(6):1585-1593

Department of Infectious Disease and.

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. A nonlive adjuvanted recombinant zoster vaccine (RZV) has been developed to prevent herpes zoster (HZ), but there are no recommendations for use in this population. In this single-center prospective observational cohort study, we assessed the safety and reactogenicity of RZV, as well as incidence of graft-versus-host disease (GVHD) and confirmed cases of HZ after vaccination. Between December of 2018 and June of 2020, patients aged ≥18 years received 2 doses of RZV between 9 and 24 months after HCT, with the doses separated by ≥8 weeks. One hundred and fifty-eight patients (mean age, 55 years; 42% women) received ≥1 dose (total vaccinated cohort), and 150 patients (95%) received 2 doses (modified total vaccinated cohort). Solicited reactions occurred in 92.1% of patients (grade 3, 32.5%), owing mostly to injection site pain, which occurred in 86% (grade 3, 16%). The cumulative incidence of GVHD in the peri-vaccination period was no different than in historical controls (adjusted incidence rate ratio, 1.05; 95% confidence interval, 0.8-1.38). There were 4 cases of HZ in the total vaccinated cohort (2.5%) and 3 cases in the modified total vaccinated cohort (28.3/1000 person-years). Among recipients of allogeneic HCT, RZV was safe, tolerable, and did not increase rates of GVHD. Future clinical trials are needed to determine the immunogenicity and efficacy of RZV in this population.
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http://dx.doi.org/10.1182/bloodadvances.2020003749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993108PMC
March 2021

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia 2021 Mar 3. Epub 2021 Mar 3.

Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
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http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
March 2021

Somatic GATA2 mutations define a subgroup of myeloid malignancy patients at high risk for invasive fungal disease.

Blood Adv 2021 01;5(1):54-60

Division of Infectious Diseases and International Medicine, University of Minnesota Medical School, Minneapolis, MN; and.

Invasive fungal disease (IFD) can be a severe treatment complication in patients with myeloid malignancies, but current risk models do not incorporate disease-specific factors, such as somatic gene mutations. Germline GATA2 deficiency is associated with a susceptibility to IFD. To determine whether myeloid gene mutations were associated with IFD risk, we identified 2 complementary cohorts of patients with myeloid malignancy, based on (1) the diagnosis of invasive aspergillosis (IA), or (2) the presence of GATA2 mutations identified during standard clinical sequencing. We found somatic GATA2 mutations in 5 of 27 consecutive patients who had myeloid malignancy and developed IA. Among 51 consecutive patients with GATA2 mutations identified in the evaluation of myeloid malignancy, we found that IFD was diagnosed and treated in 21 (41%), all of whom had received chemotherapy or had undergone an allogeneic stem cell transplant. Pulmonary infections and disseminated candidiasis were most common. The 90-day mortality was 52% among patients with IFD. Our results indicate that patients with somatic GATA2 mutations are a vulnerable subgroup of patients with myeloid malignancy who have high risk for treatment-associated IFD and suggest that a focused approach to antifungal prophylaxis be considered.
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http://dx.doi.org/10.1182/bloodadvances.2020002854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805332PMC
January 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

Acute GVHD Diagnosis and Adjudication in a Multicenter Trial: A Report From the BMT CTN 1202 Biorepository Study.

J Clin Oncol 2021 Jun 28;39(17):1878-1887. Epub 2021 Jan 28.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Purpose: Accurate and reproducible methods to diagnose, grade, and report acute graft-versus-host disease (GVHD) are critical for the evaluation of therapies and biomarkers.

Patients And Methods: The Blood and Marrow Transplant Clinical Trials Network 1202 study is an observational study of 1,709 allogeneic hematopoietic cell transplantation recipients that implemented weekly data reporting and near real-time data adjudication by an end point review committee (ERC), assigning a confidence level (confirmed, probable, possible, or negative) to the diagnosis of acute GVHD at onset.

Results: During the first 100 days, symptoms consistent with GVHD developed in 90% of cases but were often determined by centers to be due to causes other than GVHD. Indeed, GVHD was under consideration in only 23% of cases at symptom onset. Diagnostic biopsies were obtained in 40% of cases, but treatment often was incongruous with biopsy findings and 10.5% of biopsies were equivocal. Importantly, more than 40% of steroid courses were started for reasons other than GVHD. The ERC modified the determination of GVHD diagnosis and/or grade in 12.3% of onset cases. The cumulative incidence of acute GVHD as reported by the centers was 62%. When the ERC adjudicated GVHD onset to be present only if the confidence level was probable or confirmed, the incidence of GVHD declined to 49%.

Conclusion: This study demonstrates that the incidence of GVHD may be overestimated at symptom onset, establishes a contemporary benchmark for acute GVHD, and suggests a structured framework for reporting and adjudication of GVHD that could be used in prospective trials.
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http://dx.doi.org/10.1200/JCO.20.00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260916PMC
June 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

Splenectomy before allogeneic hematopoietic stem-cell transplantation for myelofibrosis: Tumor burden matters!

Am J Hematol 2021 01;96(1):12-13

Department of Oncology-Hematology, University of Milan and Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.

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http://dx.doi.org/10.1002/ajh.26054DOI Listing
January 2021

Fit older adults with advanced myelodysplastic syndromes: who is most likely to benefit from transplant?

Leukemia 2021 04 17;35(4):1166-1175. Epub 2020 Nov 17.

Dana-Farber Cancer Institute, Boston, MA, USA.

We conducted a prospective observational study of fit adults aged 60-75 with advanced MDS, enrolled hierarchically for adverse MDS risk (intermediate-2 or high-risk international prognostic score [IPSS], low or intermediate-1 IPSS with poor-risk cytogenetics, or therapy-related MDS) or standard risk with severe cytopenia. A total of 290 patients enrolled at two centers: 175 for adverse risk and 115 for standard risk with severe cytopenia. 113 underwent HCT after a median of 5 months; median follow-up for all was 39.5 months. In univariable analyses, the hazard ratio (HR) for death comparing HCT with no HCT was 0.84 (p = 0.30). The HR for death was 0.64 (p = 0.04) for HCT ≤ 5 months after enrollment and 1.20 (p = 0.39) for HCT > 5 months. In multivariable analyses controlling for age, gender, ECOG performance status, cytogenetic risk, and IPSS risk group, HR for death was 0.75 (p = 0.13) for HCT compared to no HCT, 0.57 (p = 0.01) for adverse MDS risk and 1.33 (p = 0.36) for standard risk with severe cytopenia. In this large, prospective cohort of fit older adults with advanced MDS, we found that survival was significantly improved if HCT was performed early or for adverse risk disease but not for standard risk disease with severe cytopenia.
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http://dx.doi.org/10.1038/s41375-020-01092-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035144PMC
April 2021

Parroting Lymphoma.

N Engl J Med 2020 10;383(14):1376-1381

From the Departments of Medicine (J.D.A., V.T.H., B.D.L., J.L.) and Pathology (K.T.W.), Brigham and Women's Hospital, Boston.

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http://dx.doi.org/10.1056/NEJMcps1915728DOI Listing
October 2020

Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to the graft-versus-leukemia effect.

Sci Transl Med 2020 09;12(561)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic, and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post-HSCT relapse are shaped by distinct molecular dynamics. Early relapses after allo-HSCT exhibited notable genetic stability; single CLL cell transcriptional analysis demonstrated a cellular heterogeneity that was static over time. In contrast, CLL cells relapsing late after allo-HSCT displayed notable genetic evolution and evidence of neoantigen depletion, consistent with marked single-cell transcriptional shifts that were unique to each patient. We observed a greater rate of epigenetic change for late relapses not seen in early relapses or relapses after chemotherapy alone, suggesting that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for human leukocyte antigen (HLA) loss was observed, even when present in pretransplant subpopulations. Gain of stem cell modules was a common signature associated with leukemia relapse regardless of posttransplant relapse kinetics. These data elucidate the biological pathways that underlie GvL resistance and posttransplant relapse.
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http://dx.doi.org/10.1126/scitranslmed.abb7661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829680PMC
September 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

Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease.

J Clin Invest 2020 09;130(9):4624-4636

Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.
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http://dx.doi.org/10.1172/JCI129965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456221PMC
September 2020

A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation.

Blood 2020 06;135(24):2182-2191

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

Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti-PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti-PD-1 antibody for post-alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti-PD-1 therapy post-alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT01822509.
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http://dx.doi.org/10.1182/blood.2019004710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290092PMC
June 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

Prior Gemtuzumab Ozogamicin Exposure in Adults with Acute Myeloid Leukemia Does Not Increase Hepatic Veno-Occlusive Disease Risk after Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis.

Biol Blood Marrow Transplant 2020 05 28;26(5):884-892. Epub 2019 Dec 28.

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

Gemtuzumab ozogamicin (GO) therapy before allogeneic hematopoietic cell transplantation (alloHCT) has been historically associated with an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with acute myeloid leukemia (AML). The current analysis examined VOD/SOS risk and outcomes in a cohort of patients who in recent years were reported to the Center for International Blood and Marrow Transplant Research. Adults with AML who had GO exposure before myeloablative alloHCT were matched 1:4 by age and disease status at transplant to recipients without GO exposure (control subjects). One hundred thirty-seven patients with GO exposure and 548 matched control subjects who underwent alloHCT between 2008 and 2011 were included in this analysis. With a median ∼8-year follow-up of survivors, the 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control groups (P = .97). Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% (95% confidence interval [CI], 1% to 7%) and 3% (95% CI, 1% to 6%) in GO-exposed patients and 3% (95% CI, 2% to 5%) and 1% (95% CI, 0% to 2%) in control subjects. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% (95% CI, 5% to 72%) and 27% (95% CI, 11% to 47%; P = .78). In multivariate analyses, GO exposure before alloHCT was not associated with an increased risk of VOD/SOS (odds ratio, 1.10; P = .85) or death (hazard ratio, 1.08; P = .57). Three deaths (3%) in the GO group and 3 deaths (<1%) in the control group were attributed to VOD/SOS. Our results suggest that GO treatment before myeloablative alloHCT in the recent era is not associated with an increased risk of post-transplant VOD/SOS or death.
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http://dx.doi.org/10.1016/j.bbmt.2019.12.763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439134PMC
May 2020

Incidence, Predictors, and Outcomes of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 03 31;26(3):529-539. Epub 2019 Oct 31.

Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer, Institute, Harvard Medical School, Boston, Massachusetts. Electronic address:

fludarabine with intravenous busulfan at doses of 3.2 mg/kg (Flu/Bu1) or 6.4 mg/kg (Flu/Bu2). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced-intensity conditioning (RIC) HCT is low compared with myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007 and 2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range, 5 to 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval [CI], 1.1% to 2.4%). Day 100 nonrelapse mortality rate was 23% in the VOD/SOS cohort compared with 6.4% in patients without VOD/SOS (P = .006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2 ± ATG (fludarabine with two doses of busulfan, total dose 6.4 mg/kg, with or without anti-thymocyte globulin), compared with 0.15% after Flu/Bu1 ± ATG (fludarabine with single busulfan dose 3.2 mg/kg, with or without anti-thymocyte globulin) (P = .0002); the incidence rate was 2.1% after RIC HCT with sirolimus-containing graft-versus-host disease prophylaxis, compared with 0.8% for RIC without sirolimus (P = .06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio [HR], 5.1; 95% CI, 1.8 to 14.2; P = .002) and RIC regimen with Flu/Bu2 ± ATG (HR, 34; 95% CI, 4.5 to 252; P < .001) or other (HR, 32; 95% CI, 3.9 to 257; P = .001) compared with Flu/Bu1 ± ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared with a previously published cohort of 76 patients with VOD/SOS who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.024DOI Listing
March 2020

A phase II study of reduced intensity double umbilical cord blood transplantation using fludarabine, melphalan, and low dose total body irradiation.

Bone Marrow Transplant 2020 04 15;55(4):804-810. Epub 2019 Oct 15.

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

In this multicenter Phase 2 single arm study, we substituted low dose total body irradiation (TBI) for antithymocyte globulin (ATG) in a reduced intensity conditioning regimen with the intent to lower the risk for viral infections after double umbilical cord blood (UCB) transplantation. The conditioning regimen consisted of fludarabine (30 mg/m/day, Day -7 to -2), melphalan (100 mg/m/day, Day -1), and TBI (200cGy, Day 0). Graft-versus-host disease prophylaxis was sirolimus and tacrolimus. Thirty-one patients were treated on the protocol. The median time of follow-up for survivors was 24 months (range, 3.3-55.1). Nineteen patients experienced a total of 24 clinically significant viral reactivations or infections, with 1-year cumulative incidence rate of first significant viral event as 64% (95% CI, 43-79%), compared with our historical control of 53%. Within the context of these 24 clinically significant viral reactivations, there were a total of 10 infections with organ involvement. Nonrelapse mortality was 28% (95% CI 13-45%) at 2 years. The 2-year overall and progression-free survivals were 53% (95% CI 33-69%) and 47% (95% CI 28-64%), respectively. In conclusion, the substitution of low dose TBI for ATG did not decrease the incidence of significant viral events after UCB transplantation.
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http://dx.doi.org/10.1038/s41409-019-0715-xDOI Listing
April 2020

Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children.

Blood Adv 2019 09;3(17):2550-2561

Harvard Medical School, Boston, MA.

Low-dose interleukin-2 (IL-2) therapy for chronic graft-versus-host disease (cGVHD) generates a rapid rise in plasma IL-2 levels and CD4CD25CD127Foxp3 regulatory T-cell (CD4Treg) proliferation, but both decrease over time despite continued daily administration. To test whether IL-2 dose escalation at the time of anticipated falls in plasma levels could circumvent tachyphylaxis and enhance CD4Treg expansion, we conducted a phase 1 trial in 10 adult and 11 pediatric patients with steroid-refractory cGVHD (www.clinicaltrials.gov: NCT02318082). Daily IL-2 was initiated in children and adults (0.33 × 10 and 0.67 × 10 IU/m per day, respectively). Dose escalations were scheduled at weeks 2 and 4 to a maximum dose of 1 × 10 IU/m per day in children and 2 × 10 IU/m per day in adults. Patients continued at their maximum tolerated dose (MTD) until week 8. Children tolerated IL-2 dose escalation with partial responses (PRs) in 9 of 11 patients (82%) at multiple cGVHD sites, including lung. Patient-reported outcome scores for skin and lung improved significantly in pediatric patients. In contrast, 5 of 10 adults required dose reduction, and only 2 of 7 evaluable patients (29%) had PRs at week 8. CD4Tregs and natural killer cells expanded in both cohorts without significant changes in conventional CD4 T cells (Tcons) or CD8 T cells. Children achieved a higher median CD4Treg/Tcon ratio at week 8 (0.4 vs 0.18, = .02) despite lower IL-2 doses. We show for the first time that low-dose IL-2 is safe and effective in children with advanced cGVHD. In adults, escalation above the previously defined MTD did not improve CD4Treg expansion or clinical response.
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http://dx.doi.org/10.1182/bloodadvances.2019000631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737411PMC
September 2019

Allogeneic Stem Cell Transplantation Provides Durable Remission in Patients with Primary Mediastinal Large B Cell Lymphoma.

Biol Blood Marrow Transplant 2019 12 5;25(12):2383-2387. Epub 2019 Aug 5.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Medical Oncology Division, University of Washington, Seattle, Washington.

Standard therapy for relapsed or refractory (rel/ref) primary mediastinal large B cell lymphoma (PMBCL) is salvage therapy followed by autologous (auto) hematopoietic stem cell transplantation (HSCT). However, many patients have refractory disease and are unable to undergo autoHSCT, and a sizeable proportion of patients will relapse after autoHSCT. By analogy to diffuse large B cell lymphoma, these patients may be treated with allogeneic (allo) HSCT with curative intent, but at the risk of significant morbidity and mortality. Given the advent of effective immunotherapy approaches for rel/ref PMBCL, it is important to better understand the toxicity and efficacy of alloHSCT in these patients, to which these new approaches could be an alternative. Therefore, we retrospectively studied the outcomes of alloHSCT in a multicenter cohort of 28 patients with rel/ref PMBCL who underwent transplantation at 4 centers. Most patients (79%) were sensitive to pretransplantation therapy and 86% received reduced-intensity conditioning. The overall progression-free survival (PFS), overall survival (OS), and cumulative incidences of nonrelapse mortality and relapse in the cohort at 5 years were 34%, 45%, 32%, and 33%, respectively. Outcomes were significantly better in patients with pretransplantation responsive disease (2-year PFS and OS of 50% and 58%, respectively) compared with refractory patients (2-year PFS and OS of 0%). In our multicenter retrospective study, alloHSCT produced durable remissions in a proportion of patients with treatment-sensitive disease before transplantation (5-year PFS of 44%) and should be considered in the treatment of patients with rel/ref PMBCL.
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http://dx.doi.org/10.1016/j.bbmt.2019.07.041DOI Listing
December 2019

Recurrent genetic HLA loss in AML relapsed after matched unrelated allogeneic hematopoietic cell transplantation.

Blood Adv 2019 07;3(14):2199-2204

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

Immune evasion is a hallmark of cancer and a central mechanism underlying acquired resistance to immune therapy. In allogeneic hematopoietic cell transplantation (alloHCT), late relapses can arise after prolonged alloreactive T-cell control, but the molecular mechanisms of immune escape remain unclear. To identify mechanisms of immune evasion, we performed a genetic analysis of serial samples from 25 patients with myeloid malignancies who relapsed ≥1 year after alloHCT. Using targeted sequencing and microarray analysis to determine HLA allele-specific copy number, we identified copy-neutral loss of heterozygosity events and focal deletions spanning class 1 HLA genes in 2 of 12 recipients of matched unrelated-donor HCT and in 1 of 4 recipients of mismatched unrelated-donor HCT. Relapsed clones, although highly related to their antecedent pretransplantation malignancies, frequently acquired additional mutations in transcription factors and mitogenic signaling genes. Previously, the study of relapse after haploidentical HCT established the paradigm of immune evasion via loss of mismatched HLA. Here, in the context of matched unrelated-donor HCT, HLA loss provides genetic evidence that allogeneic immune recognition may be mediated by minor histocompatibility antigens and suggests opportunities for novel immunologic approaches for relapse prevention.
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http://dx.doi.org/10.1182/bloodadvances.2019000445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650729PMC
July 2019

Severe Herpes Zoster Requiring Intravenous Antiviral Treatment in Allogeneic Hematopoietic Cell Transplantation Recipients on Standard Acyclovir Prophylaxis.

Biol Blood Marrow Transplant 2019 08 17;25(8):1642-1647. Epub 2019 Apr 17.

Department of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk for varicella zoster virus (VZV) reactivation and associated complications. The incidence, timing, and risk factors for severe herpes zoster (HZ) are not well described in the era of acyclovir (ACV) prophylaxis. We performed a retrospective cohort study of all patients who underwent first allogeneic HCT between October 2006 and December 2015 at our institution. Patients were followed until December 2017 for the development of severe HZ, defined as necessitating administration of i.v. antiviral medication. Out of 2163 patients who underwent allogeneic HCT, 22 (1.0%) developed severe HZ at a rate of 1 per 228 person-years, including dermatomal/multidermatomal disease (n = 5), disseminated skin disease (n = 5), HZ ophthalmicus (n = 4), meningitis/encephalitis (n = 4), pneumonia (n = 2), viremia (n = 1), and erythema multiforme (n = 1). Severe HZ infection occurred in a bimodal distribution during the early peri-HCT period and at 12 to 24 months post-HCT (median, 12.7 months). Twelve patients (54.5%) were compliant with ACV prophylaxis at the time of HZ diagnosis. Eleven patients (50%) died during the study period, only 2 of whom (9.1%) with active VZV infection. Mortality was higher in patients on immunosuppressive therapy (62.5% versus 16.7%; P = .045) and with concurrent graft-versus-host disease (75.0% versus 35.7%; P= .044). These data suggest that severe HZ remains an important consideration despite ACV prophylaxis.
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http://dx.doi.org/10.1016/j.bbmt.2019.04.015DOI Listing
August 2019

Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease.

Blood Adv 2019 04;3(7):984-994

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

Patients with chronic graft-versus-host disease (cGVHD) have a paucity of regulatory CD4 T cells (CD4Tregs) that mediate peripheral tolerance. In clinical trials, daily low-dose interleukin-2 (IL-2) has been administered safely for prolonged periods in patients with steroid-refractory cGVHD. Peripheral CD4Tregs expand dramatically in all patients during IL-2 therapy but clinical improvement was observed in ∼50% of patients. Here, we examined the impact of low-dose IL-2 therapy on functional T-cell markers and the T-cell repertoire within CD4Tregs, conventional CD4 T cells (CD4Tcons), and CD8 T cells. IL-2 had profound effects on CD4Tregs homeostasis in both response groups including selective expansion of the naive subset, improved thymic output, and increased expression of Ki67, FOXP3, and B-cell lymphoma 2 within CD4Tregs. Similar changes were not seen in CD4Tcons or CD8 T cells. Functionally, low-dose IL-2 enhanced, in vitro, CD4Treg-suppressive activity in both response groups, and all patient CD4Tcons were similarly suppressed by healthy donor CD4Tregs. High-throughput sequencing of the T-cell receptor β (TCRβ) locus demonstrated that low-dose IL-2 therapy increased TCR repertoire diversity and decreased evenness within CD4Tregs without affecting CD4Tcons or CD8 T cells. Using clone-tracking analysis, we observed rapid turnover of highly prevalent clones in CD4Tregs as well as the conversion of CD4Tcons to CD4Tregs. After 12 weeks of daily IL-2, clinical responders had a greater influx of novel clones within the CD4Treg compartment compared with nonresponders. Further studies to define the function and specificity of these novel CD4Treg clones may help establish the mechanisms whereby low-dose IL-2 therapy promotes immune tolerance.
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http://dx.doi.org/10.1182/bloodadvances.2018027474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457229PMC
April 2019
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