Publications by authors named "Corey S Cutler"

104 Publications

A positive psychology intervention to promote health outcomes in hematopoietic stem cell transplantation: the PATH proof-of-concept trial.

Bone Marrow Transplant 2021 Apr 20. Epub 2021 Apr 20.

Harvard Medical School, Boston, MA, USA.

Allogeneic hematopoietic stem cell transplantation (HSCT) recipients often experience deficits in positive psychological well-being (PPWB) due to intensive treatment and follow-up care. Positive psychology interventions (PPIs) that promote PPWB via deliberate and systematic exercises (e.g., writing a gratitude letter) have consistently improved PPWB in medical populations, yet have never been studied in early HSCT recovery. In this single-arm, proof-of-concept study, we assessed the feasibility and acceptability of a novel eight-session, telephone-delivered PPI in early HSCT recovery. A priori, we defined feasibility as >50% of eligible patients enrolling in the study and >50% of participants completing 5/8 sessions, and acceptability as mean ease and utility scores of weekly participant ratings of PP exercises as 7/10. Of 45 eligible patients, 25 (55.6%) enrolled, 20 (80%) completed baseline assessments, 15 (75%) started the intervention, and 12 (60%) completed the intervention and follow-up assessments. The intervention was feasible (55.6% of eligible participants enrolled; 60% of baseline assessment completers finished 5/8 sessions) and led to very small-to-medium effect-size improvements in patient-reported outcomes. A novel, eight-week, telephone-delivered PPI was feasible and acceptable in allogeneic HSCT recipients. Larger, randomized studies are needed to examine the efficacy of PPIs for improving outcomes in this population.
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http://dx.doi.org/10.1038/s41409-021-01296-9DOI Listing
April 2021

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

Transplant Cell Ther 2021 Feb 25. 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
February 2021

Alternative donor transplantation for myelodysplastic syndromes: haploidentical relative and matched unrelated donors.

Blood Adv 2021 Feb;5(4):975-983

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

We compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.
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http://dx.doi.org/10.1182/bloodadvances.2020003654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903230PMC
February 2021

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

Survival following allogeneic transplant in patients with myelofibrosis.

Blood Adv 2020 05;4(9):1965-1973

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Carolinas HealthCare System, Charlotte, NC.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.
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http://dx.doi.org/10.1182/bloodadvances.2019001084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218417PMC
May 2020

Oral health in allogeneic hematopoietic stem cells transplantation survivors.

Bone Marrow Transplant 2020 11 7;55(11):2211-2214. Epub 2020 May 7.

Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1038/s41409-020-0927-0DOI Listing
November 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

Inhibition of inositol kinase B controls acute and chronic graft-versus-host disease.

Blood 2020 01;135(1):28-40

Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T cells, and can control T-cell-mediated autoimmunity. In this study, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine-induced, Itpkb-deleted (Itpkb-/-) T cells attenuated acute GVHD in 2 models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against 2 acute myeloid leukemia lines (MLL-AF9-eGFP and C1498-luciferase). Compared with FK506, GNF362 more selectively deleted donor alloreactive vs nominal antigen-responsive T cells. Consistent with these data and as compared with FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a pathophysiology distinct from acute GVHD, Itpkb-/- donor T cells reduced active chronic GVHD in a multiorgan system model of bronchiolitis obliterans (BO), driven by germinal center reactions and resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is essential to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.
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http://dx.doi.org/10.1182/blood.2019000032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940197PMC
January 2020

Disability Related to Chronic Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2020 04 24;26(4):772-777. Epub 2019 Oct 24.

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

Chronic graft-versus-host disease (cGVHD) is a heterogenous syndrome whose symptoms and treatment are often associated with decreases in functional status and quality of life among survivors of transplantation. We explored definitions of cGVHD-related disability and factors associated with disability in cGVHD. We analyzed 371 patients with cGVHD requiring a new systemic therapy with enrollment and 18-month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any 1 of 5 impairments previously defined by Fatobene et al [1] (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability, defined as an ≥8-point decline in a human activity profile (HAP) score or a ≥20% decline in Karnofsky Performance Status (KPS) from enrollment to 18 months. At enrollment, 47% of patients had at least 1 of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 patients (53%) with no Flowers disability at enrollment, 50% progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with a decline in HAP/KPS as well as with increased National Institutes of Health severity scores at 18 months. Enrollment mouth scores and patient-reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent nonrelapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180104PMC
April 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

Endogenous thrombopoietin levels are elevated following double cord blood unit transplantation.

Bone Marrow Transplant 2020 06 28;55(6):1178-1180. Epub 2019 Aug 28.

Division of Hematology, Massachusetts General Hospital, Boston, MA, United States.

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http://dx.doi.org/10.1038/s41409-019-0652-8DOI Listing
June 2020

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

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

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

Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease.

Blood Adv 2019 04;3(7):969-979

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

Chronic graft-versus-host disease (cGVHD) affects >50% of hematopoietic stem cell transplant patients. Extracorporeal photopheresis (ECP), an immunomodulatory therapy, provides clinical benefit in steroid-refractory (SR) cGVHD, possibly via regulatory T (T) and natural killer (NK) cell expansion. We demonstrated that low-dose interleukin-2 (IL2) led to clinical improvement in SR-cGVHD and stimulated preferential T and NK-cell expansion with minimal effect on conventional T (T) cells. We evaluated the effect of ECP (weeks 1-16) plus IL2 (1 × 10 IU/m, weeks 9-16) in 25 adult patients with SR-cGVHD in a prospective phase 2 trial. Objective responses occurred in 29% and 62% of evaluable patients at weeks 8 (ECP alone) and 16 (ECP plus IL2), respectively. Eight weeks of ECP alone was associated with a marked decline in CD4 T ( = .03) and CD8 T cells ( = .0002), with minimal change in T cells, T:T cell ratio, or NK cells. Adding IL2 induced an increase in T cells ( < .05 at weeks 9-16 vs week 8), T:T cell ratio ( < .0001 at weeks 9-16 vs week 8), and NK cells ( < .05 at weeks 9-16 vs week 8). Patients responding to ECP alone had significantly fewer CD4 T and CD8 T cells at baseline compared with patients who responded after IL2 addition and patients who did not respond; neither T nor NK cells were associated with response to ECP alone. Altogether, ECP plus IL2 is safe and effective in patients with SR-cGVHD. ECP and IL2 have distinct immunologic effects, suggesting different therapeutic mechanisms of action. This trial was registered at www.clinicaltrials.gov as #NCT02340676.
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http://dx.doi.org/10.1182/bloodadvances.2018029124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457231PMC
April 2019

Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease.

Am J Transplant 2019 06 19;19(6):1820-1830. Epub 2019 Mar 19.

Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T cells can differentiate into pathogenic T helper (Th)-17 cells and germinal center (GC)-promoting T follicular helper (Tfh) cells, resulting in cGVHD. Phosphoinositide-3-kinase-δ (PI3Kδ), a lipid kinase, is critical for activated T cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T cells that become Tfh cells is required for cGVHD in a nonsclerodermatous multiorgan system disease model that includes bronchiolitis obliterans (BO), dependent upon GC B cells, Tfhs, and counterbalanced by T follicular regulatory cells, each requiring PI3Kδ signaling for function and survival. Although B cells rely on PI3Kδ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3Kδ kinase-dead mutant donor bone marrow-derived GC B cells still supported BO cGVHD generation. A PI3Kδ-specific inhibitor, compound GS-649443, that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1-dependent and Th17-associated scleroderma model, GS-649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of US Food and Drug Administration (FDA)-approved PI3Kδ inhibitors for cGVHD therapy in patients.
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http://dx.doi.org/10.1111/ajt.15305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538456PMC
June 2019

Small-molecule BCL6 inhibitor effectively treats mice with nonsclerodermatous chronic graft-versus-host disease.

Blood 2019 01 2;133(1):94-99. Epub 2018 Oct 2.

Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN.

Patient outcomes for steroid-dependent or -refractory chronic graft-versus-host diesease (cGVHD) are poor, and only ibrutinib has been US Food and Drug Administration (FDA) approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B cells to produce antibodies that are associated with disease pathogenesis. The transcriptional corepressor B-cell lymphoma 6 (BCL6) is a member of the Broad-complex, Tramtrack, and Bric-abrac/poxvirus and zinc finger (BTB/POZ) transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T cells and B cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target. A small-molecule BCL6 inhibitor reversed active cGVHD in a mouse model of multiorgan system injury with bronchiolitis obliterans associated with a robust GC reaction, but not in cGVHD mice with scleroderma as the prominent manifestation. For cGVHD patients with antibody-driven cGVHD, targeting of BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents.
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http://dx.doi.org/10.1182/blood-2018-03-839993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318432PMC
January 2019

Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802.

Blood Adv 2018 08;2(15):1882-1888

National Marrow Donor Program, Minneapolis, MN.

Amphiregulin (AREG) is an epidermal growth factor receptor ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously reported that circulating AREG is elevated in late-onset aGVHD (occurring after 100 days posttransplant), but its clinical relevance in the context of aGVHD risk is unknown. We measured AREG in 251 aGVHD onset blood samples from Blood and Marrow Clinical Trials Network (BMT CTN) primary treatment trials and determined their association with GVHD severity, day 28 complete or partial response (CR/PR) to first-line therapy, overall survival (OS), and nonrelapse mortality (NRM). Every doubling of plasma AREG was associated with a 33% decrease in the odds of day 28 CR/PR (odds ratio [OR], 0.67; < .01). An AREG threshold of 33 pg/mL or greater divided patients with Minnesota standard-risk (SR) aGVHD into a distinct group with a significantly lower likelihood of: day 28 CR/PR (72% vs 85%; = .02); greater 2-year NRM (42% vs 15%; < .01); and inferior OS (40% vs 66%; < .01). High AREG ≥ 33 pg/mL also stratified patients with Minnesota high-risk (HR) aGVHD: day 28 CR/PR (54% vs 83%; = .03) and 2-year NRM (53% vs 11%; < .01), with a trend toward inferior 2-year OS (37% vs 60%; = .09). High-circulating AREG (≥33 pg/mL) reclassifies patients into HR subgroups and thereby further refines the Minnesota aGVHD clinical risk score.
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http://dx.doi.org/10.1182/bloodadvances.2018017343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093743PMC
August 2018

A phase II/III randomized, multicenter trial of prednisone/sirolimus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft--host disease: BMT CTN 0801.

Haematologica 2018 11 28;103(11):1915-1924. Epub 2018 Jun 28.

University of Minnesota, Minneapolis, MN.

Initial therapy of chronic graft--host disease is prednisone ± a calcineurin-inhibitor, but most patients respond inadequately. In a randomized, adaptive, phase II/III, multicenter trial we studied whether prednisone/sirolimus or prednisone/sirolimus/photopheresis was more effective than prednisone/sirolimus/calcineurin-inhibitor for treating chronic graft--host disease in treatment-naïve or early inadequate responders. Primary endpoints of this study were proportions of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III. The prednisone/sirolimus/photopheresis arm closed prematurely because of slow accrual and the remaining two-drug three-drug study ended in phase II due to statistical futility with 138 evaluable subjects. The two-drug and three-drug arms did not differ in rates of 6-month complete or partial response (48.6% 50.0%, =0.87), or 2-year complete response (14.7% 15.5%, =0.90). Serum creatinine values >1.5 times baseline were less frequent in the calcineurin-inhibitor-free arm at 2 months (1.5% 11.7%, =0.025) and 6 months (7.8% 24.0%, =0.016). Higher adjusted Short Form-36 Physical Component Summary and Physical Functioning scores were seen in the two-drug arm at both 2 months (=0.02 and =0.04, respectively) and 6 months (=0.007 and =0.001, respectively). Failure-free survival and overall survival rates at 2 years were similar for patients in the the two-drug and three-drug arms (48.6% 46.2%, =0.78; 81.5% 74%, =0.28). Based on similar long-term outcomes, prednisone/sirolimus is a therapeutic alternative to prednisone/sirolimus/calcineurin-inhibitor for chronic graft--host disease, being easier to administer and better tolerated.
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http://dx.doi.org/10.3324/haematol.2018.195123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278959PMC
November 2018

Integrated genomic characterization of oral carcinomas in post-hematopoietic stem cell transplantation survivors.

Oral Oncol 2018 06 10;81:1-9. Epub 2018 Apr 10.

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

Objectives: Secondary oral squamous cell carcinoma (OSCC) is a late complication in allogeneic hematopoietic stem cell transplantation (HSCT) patients, but little is known about long-term outcomes and prognostication. Additionally, molecular alterations and immunologic insights unique to this disease remain largely unexplored.

Methods: We present a cohort of 31 patients with post-HSCT OSCC and reported on clinicopathologic predictors of survival. Whole-exome sequencing was performed on 6 (19%) matched pairs of peripheral blood (post-conditioning, pre-HSCT) and tumor samples. The entire cohort had archival tumor available for immunoprofiling with PD-1/L1 immunohistochemistry.

Results: Five-year overall survival (OS) was 57% (95% CI: 46.1-69.8) with a median disease-free survival (DFS) of 13.3 months. Advanced initial staging, a buccal or oral tongue subsite, chronic oral graft-versus-host disease (GVHD) and smoking all negatively impacted survival. High tumor mutational burden (TMB) (median 11.3 vs. 5.0) and unique mutational signatures were noted between unrelated and related donor groups - with a strong correlation between infiltrating PD-1+ lymphocytes and TMB (R = 0.98, p < 0.01). Some differences were observed when comparing commonly mutated genes among our cohort and TCGA, with a predominance of TP53 events.

Conclusion: Survival outcomes appear similar in HSCT survivors with OSCC compared with non-HSCT OSCC populations. We identified somatic alterations in genes with therapeutic potential unique to this subpopulation of oral cancers.
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http://dx.doi.org/10.1016/j.oraloncology.2018.04.007DOI Listing
June 2018

Graft-versus-host disease in recipients of male unrelated donor compared with parous female sibling donor transplants.

Blood Adv 2018 05;2(9):1022-1031

Department of Hematology, Hospital Clinic, University of Barcelona, Institut d'investigacions Biomediques August Pi i Sunyer, and Institute of Research Josep Carreras, Barcelona, Spain.

Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD ( < .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk [RR] = 1.43, < .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs.
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http://dx.doi.org/10.1182/bloodadvances.2017013052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941995PMC
May 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

α-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease.

Blood 2018 03 2;131(12):1372-1379. Epub 2018 Feb 2.

Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.

Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. α-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (T) to effector T cells (Ts). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated Ts to Ts after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01700036.
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http://dx.doi.org/10.1182/blood-2017-11-815746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865235PMC
March 2018

Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results.

Haematologica 2018 03 11;103(3):522-530. Epub 2018 Jan 11.

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

Aprior phase I/II trial of bortezomib/tacrolimus/methotrexate prophylaxis after human leukocyte antigen (HLA)-mismatched reduced intensity conditioning allogeneic hematopoietic stem cell transplantation documented low acute graft--host disease incidence, with promising overall and progression-free survival. We performed an open-label three-arm 1:1:1 phase II randomized controlled trial comparing grade II-IV acute graft--host disease between conventional tacrolimus/methotrexate (A) bortezomib/tacrolimus/methotrexate (B), and bortezomib/sirolimus/tacrolimus (C), in reduced intensity conditioning allogeneic transplantation recipients lacking HLA-matched related donors. The primary endpoint was grade II-IV acute graft--host disease incidence rate by day +180. One hundred and thirty-eight patients (A 46, B 45, C 47) with a median age of 64 years (range: 24-75), varying malignant diagnoses and disease risk (low 14, intermediate 96, high/very high 28) received 7-8/8 HLA-mismatched (40) or matched unrelated donor (98) grafts. Median follow up in survivors was 30 months (range: 14-46). Despite early immune reconstitution differences, day +180 grade II-IV acute graft--host disease rates were similar (A 32.6%, B 31.1%, C 21%; =0.53 for A B, =0.16 for A C). The 2-year non-relapse mortality incidence was similar (A 14%, B 16%, C 6.4%; =0.62), as were relapse (A 32%, B 32%, C 38%; =0.74), chronic graft--host disease (A 59%, B 60% C 55%; =0.66), progression-free survival (A 54%, B 52%, C 55%; =0.95), and overall survival (A 61%, B 62%, C 62%; =0.98). Overall, the bortezomib-based regimens evaluated did not improve outcomes compared with tacrolimus/methotrexate therapy. .
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http://dx.doi.org/10.3324/haematol.2017.176859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830392PMC
March 2018

Phase 1 study of the Hedgehog pathway inhibitor sonidegib for steroid-refractory chronic graft-versus-host disease.

Blood Adv 2017 Oct 5;1(22):1919-1922. Epub 2017 Oct 5.

Blood and Marrow Transplant Program.

Hedgehog signaling plays a key role in tissue fibrosis, the pathological hallmark of chronic graft-versus-host disease (cGVHD). We conducted a phase 1 trial of sonidegib, a selective antagonist of the hedgehog coreceptor Smoothened, for the treatment of steroid-refractory cGVHD. After a 3+3 study design, sonidegib was administered for up to 12 cycles of 28 days each, using 3 doses: 200 mg/day (dose level 1), 400 mg/day (dose level 2), and 600 mg/day (dose level 3). Seventeen patients were enrolled. The median number of cycles completed was 6 (range, 0-12). There was only 1 dose-limiting toxicity (cohort 2, grade 3 creatine phosphokinase increase) observed. Immunohistochemical evaluation of skin biopsies revealed decreased protein expression of hedgehog signaling pathway molecules with sonidegib therapy. Clinically, 8 patients (47%) had a partial response in skin or sclerodermatous disease, 6 patients had no response, and 3 were not evaluable. Clinical responses were assessed by treating physicians and not by National Institutes of Health criteria. Overall, patients reported worsening of quality of life, which was more severe in clinical nonresponders. Accrual was terminated early as a result of the cumulative toxicity burden not attributed to sonidegib and patient decisions to stop taking sonidegib. We believe hedgehog signaling inhibition warrants further investigation in patients with cGVHD because of the association with clinical responses and immunohistochemical changes. This trial was registered at www.clinicaltrials.gov as #NCT02086513.
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http://dx.doi.org/10.1182/bloodadvances.2017011239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728150PMC
October 2017

Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma.

Biol Blood Marrow Transplant 2018 03 28;24(3):514-520. Epub 2017 Nov 28.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.

Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P = .24; OS 31% versus 49%, P = .17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P = .62; OS 50% versus 38%, P = .46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826860PMC
March 2018

Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease.

Blood 2017 12 14;130(26):2889-2899. Epub 2017 Nov 14.

Division of Hematologic Malignancies, Department of Medical Oncology, and.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplant reflects a complex immune response resulting in chronic damage to multiple tissues. Previous studies indicated that donor B cells and the antibodies they produce play an important role in the development of cGVHD. To understand the pathogenic role of antibodies in cGVHD, we focused our studies on posttransplant production of immunoglobulin G antibodies targeting cell surface antigens expressed in multiple cGVHD affected tissues, due to their potential functional impact on living cells in vivo. Using plate-bound cell membrane proteins as targets, we detected a significantly higher level of antibodies reactive with these membrane antigens in patients who developed cGVHD, compared with those who did not and healthy donors. Plasma-reactive antibody levels increased significantly prior to the clinical diagnosis of cGVHD and were reduced following cGVHD therapies including prednisone, interleukin-2, or extracorporeal photophoresis. Using cell-based immunoprecipitation with plasma from cGVHD patients and mass spectrometry, we identified 43 membrane proteins targeted by these antibodies. The presence of antibodies in cGVHD patients' plasma that specifically target 6 of these proteins was validated. Antibodies reactive with these 6 antigens were more frequently detected in patients with cGVHD compared with patients without cGVHD and healthy donors. These results indicate that antibodies that target membrane antigens of living cells frequently develop in cGVHD patients and further support a role for B cells and antibodies in the development of cGVHD.
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http://dx.doi.org/10.1182/blood-2017-08-801001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746671PMC
December 2017

Association of Socioeconomic Status with Chronic Graft-versus-Host Disease Outcomes.

Biol Blood Marrow Transplant 2018 02 12;24(2):393-399. Epub 2017 Oct 12.

Division of Hematology/Oncology, Vanderbilt University, Nashville, Tennessee. Electronic address:

Chronic graft-versus host disease (GVHD) is a chronic and disabling complication after hematopoietic cell transplantation (HCT). It is important to understand the association of socioeconomic status (SES) with health outcomes in patients with chronic GVHD because of the impaired physical health and dependence on intensive and prolonged health care utilization needs in these patients. We evaluated the association of SES with survival and quality of life (QOL) in a cohort of 421 patients with chronic GVHD enrolled on the Chronic GVHD Consortium Improving Outcomes Assessment study. Income, education, marital status, and work status were analyzed to determine the associations with patient-reported outcomes at the time of enrollment, nonrelapse mortality (NRM), and overall mortality. Higher income (P = .004), ability to work (P < .001), and having a partner (P = .021) were associated with better mean Lee chronic GVHD symptom scores. Higher income (P = .048), educational level (P = .044), and ability to work (P < .001) also were significantly associated with better QOL and improved activity. In multivariable models, higher income and ability to return to work were both significantly associated with better chronic GVHD Lee symptom scores, but income was not associated with activity level, QOL, or physical/mental functioning. The inability to return to work (hazard ratio, 1.82; P = .019) was associated with worse overall mortality, whereas none of the SES indicators were associated with NRM. Income, race, and education did not have statistically significant associations with survival. In summary, we did not observe an association between SES variables and survival or NRM in patients with chronic GVHD, although we found some association with patient-reported outcomes, such as symptom burden. Higher income status was associated with less severe chronic GVHD symptoms. More research is needed to understand the psychosocial, biological, and environmental factors that mediate this association of SES with major HCT outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767523PMC
February 2018