Publications by authors named "Yi-Bin Chen"

192 Publications

Immune reconstitution following high-dose chemotherapy and autologous stem cell transplantation with and without pembrolizumab maintenance therapy in patients with lymphoma.

Transplant Cell Ther 2021 Oct 17. Epub 2021 Oct 17.

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

Background: Autologous stem cell transplantation (ASCT) is a standard of care for patients with chemosensitive, relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). While the clinical benefit of ASCT has traditionally been attributed solely to cytoreduction from intensive chemotherapy, ASCT has important immunogenic effects which may contribute to its anti-tumor efficacy and could provide a favorable immune environment for post-ASCT immune-based maintenance treatments. We previously reported clinical results of a phase II trial (NCT02362997) testing 8 doses of pembrolizumab maintenance therapy after ASCT for patients with R/R cHL or DLBCL. To clarify the impact of pembrolizumab on immune reconstitution, we compared the kinetics of peripheral blood immune cell recovery after ASCT for trial patients receiving pembrolizumab maintenance to those of a contemporaneous control cohort of similar patients undergoing ASCT without pembrolizumab maintenance.

Objective: To characterize the impact of post-ASCT pembrolizumab maintenance therapy on immune reconstitution for patients with R/R DLBCL and cHL and to identify candidate biomarkers of efficacy and immune-related adverse events (irAEs).

Study Design: Peripheral blood mononuclear cell (PBMC) samples were prospectively collected 1-18 months after ASCT and analyzed by flow cytometry using a panel of fluorophore-conjugated monoclonal antibodies to identify B cells, natural killer (NK) cells, and various dendritic cell (DC) and T cell subsets.

Results: A median of 5 (range 1-8) post-ASCT PB samples were collected from 144 patients (59 pembrolizumab, 85 control). Clinical characteristics of the two cohorts were similar. Compared to cHL patients, DLBCL patients (who all received anti-CD20 monoclonal antibody therapy before ASCT) had delayed CD19+ cell reconstitution which persisted for at least 18-month after ASCT. No other differences in immune reconstitution were observed based on lymphoma subtype. Post-ASCT pembrolizumab maintenance therapy was associated with 1) an elevation in circulating DCs (driven by higher levels of plasmacytoid and immature DCs) which persisted for the duration of pembrolizumab treatment, and 2) a significant reduction in PD-1+ T cells which persisted for 6-12 months after completion of pembrolizumab therapy. Despite the key role of T cells in mediating the effects of PD-1 blockade, pembrolizumab maintenance did not affect recovery of any T cell subsets. In an exploratory analysis, a higher baseline CD4+ TEMRA cell count (defined as CD3+ CD4+ CD45RA+ CD62L-) was associated with inferior PFS, but only among patients who received pembrolizumab maintenance (p=0.003). As continuous variables, lower absolute levels of NK cells (p=0.009), PD-1+ CD4+ T cells (p=0.005), and PD-1+ CD8+ T cells (p=0.005) before pembrolizumab initiation were each associated with a higher risk of grade 2+ irAEs.

Conclusion: Post-ACST pembrolizumab maintenance therapy is associated with a persistent elevation in circulating DCs, but its impact on the reconstitution of other immune cells in peripheral blood appears limited. Our study suggests that early features of post-ASCT immune reconstitution could be associated with PFS and risk of irAE and warrant additional investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.10.010DOI Listing
October 2021

Emerging approaches to improve allogeneic hematopoietic cell transplantation outcomes for non-malignant diseases.

Blood 2021 Oct 6. Epub 2021 Oct 6.

University of Minnesota, Minneapolis, Minnesota, United States.

Many congenital or acquired non-malignant diseases (NMD) of the hematopoietic system can be potentially cured by allogeneic hematopoietic cell transplantation (HCT) with varying types of donor grafts, degrees of HLA matching, and intensity of conditioning regimens. Unique features that distinguish the use of allogeneic HCT in this population include higher rates of graft failure, immune-mediated cytopenias, and the potential to achieve long-term disease-free survival in a mixed chimerism state. Additionally, in contrast to patients with hematologic malignancies, a priority is to completely avoid graft-versus-host disease in patients with NMD, as there is no theoretical beneficial graft-versus-leukemia effect that can accompany graft-versus-host responses. In this review, we discuss the current approach to each of these clinical issues and how emerging novel therapeutics hold promise to advance transplant care for patients with NMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009014DOI Listing
October 2021

Previously unreported WRAP53 gene variants in a patient with dyskeratosis congenita.

Ann Hematol 2021 Oct 2. Epub 2021 Oct 2.

Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04678-7DOI Listing
October 2021

Distress in a Pandemic: Association of the Coronavirus Disease-2019 Pandemic with Distress and Quality of Life in Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 Sep 15. Epub 2021 Sep 15.

Harvard Medical School, Boston, Massachusetts; Massachusetts General Hospital, Boston, Massachusetts.

The global coronavirus disease 2019 (COVID-19) pandemic has drastically disrupted cancer care, potentially exacerbating patients' distress levels. Patients undergoing hematopoietic stem cell transplantation (HSCT) may be especially vulnerable to this pandemic stress. However, the associations of the COVID-19 pandemic with distress, fatigue, and quality of life (QoL) are not well understood in this population. In a cross-sectional analysis of data from 205 patients undergoing HSCT enrolled in a supportive care trial, we compared baseline pre-HSCT distress symptoms (depression, anxiety, and posttraumatic stress disorder [PTSD]), fatigue, and QoL between enrollees before (ie, March 2019-January 2020) and during (ie, March 2020-January 2021) the COVID-19 pandemic. We used linear regression models adjusting for sociodemographics and cancer diagnosis to examine the associations between enrollment period and patient-reported outcomes. We used semistructured qualitative interviews in 20 allogeneic HSCT recipients who were ≥3-months post-HSCT to understand the impact of the COVID-19 pandemic on their recovery post-HSCT. One hundred twenty-four participants enrolled before COVID-19, and 81 participants enrolled during the pandemic. The 2 cohorts had similar baseline demographics and disease risk factors. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT symptoms of depression, anxiety, PTSD, fatigue, or QoL impairment. COVID-19-era participants reported themes of negative (eg, increased isolation) and positive (eg, engagement with meaningful activities) implications of the pandemic on HSCT recovery. We found no differences in pre-HSCT distress, fatigue, or QoL in patients undergoing HSCT before or during the COVID-19 pandemic; however, patients in early recovery post-HSCT report both negative and positive implications of the COVID-19 pandemic in their lives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442257PMC
September 2021

Evaluation of Elafin as a Prognostic Biomarker in Acute Graft-versus-Host Disease.

Transplant Cell Ther 2021 Aug 30. Epub 2021 Aug 30.

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

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3α in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3α were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3α or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P = .19). OS at 6 months (68% versus 68%; P > .99) and 4-week response (78% versus 78%; P = .98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3α. The addition of elafin to the other 2 biomarkers did not improve the AUC. Our data indicate that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD did not predict 6-month NRM, OS, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM, and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.08.021DOI Listing
August 2021

Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2021: Looking Forward as the Network Celebrates its 20th Year.

Transplant Cell Ther 2021 Aug 27. Epub 2021 Aug 27.

Center for International Blood & Marrow Transplant Research, Minneapolis, Minnesota.

In 2021 the BMT CTN held the 4th State of the Science Symposium where the deliberations of 11 committees concerning major topics pertinent to a particular disease, modality, or complication of transplant, as well as two committees to consider clinical trial design and inclusion, diversity, and access as cross-cutting themes were reviewed. This article summarizes the individual committee reports and their recommendations on the highest priority questions in hematopoietic stem cell transplant and cell therapy to address in multicenter trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.08.016DOI Listing
August 2021

Case 26-2021: A 49-Year-Old Man with Relapsed Acute Myeloid Leukemia.

N Engl J Med 2021 Aug;385(9):834-843

From the Departments of Medicine (A.M.B., R.A.N., Y.-B.C.) and Pathology (A.M.C.), Massachusetts General Hospital, and the Departments of Medicine (A.M.B., R.A.N., Y.-B.C.) and Pathology (A.M.C.), Harvard Medical School - both in Boston.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMcpc2103458DOI Listing
August 2021

Hypoxemic Respiratory Failure Following Ruxolitinib Discontinuation in Allogeneic Hematopoietic Cell Transplantation Recipients.

Oncologist 2021 Jul 17. Epub 2021 Jul 17.

Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, Massachusetts, USA.

Ruxolitinib, a selective inhibitor of Janus kinases 1 and 2, is increasingly being used in allogeneic hematopoietic cell transplantation (HCT) recipients following its approval by the U.S. Food and Drug Administration for the treatment of steroid-refractory acute graft-versus-host disease. Although there is extensive experience using ruxolitinib for patients with myeloproliferative neoplasms, the biologic effects and clinical implications of its dosing, tapering, and discontinuation for allogeneic HCT recipients are incompletely characterized. We describe three allogeneic HCT recipients who developed acute hypoxemic respiratory failure within 3 months of ruxolitinib discontinuation. Radiographic findings included marked bilateral ground-glass opacities. Systemic corticosteroids and reinitiation of ruxolitinib resulted in rapid clinical improvement in all three patients. All three patients achieved a significant clinical response, with decrease in oxygen requirement and improvement in radiographic changes. Given the increasing use of ruxolitinib in allogeneic HCT recipients, there is significant impetus to characterize the biologic and clinical effects resulting from discontinuation of ruxolitinib, to better tailor treatment plans and prevent potential adverse effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13903DOI Listing
July 2021

A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease.

Bone Marrow Transplant 2021 10 9;56(10):2477-2488. Epub 2021 Jun 9.

Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA, USA.

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn's disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-021-01356-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486663PMC
October 2021

Erythroid nuclear dysplasia is associated with inferior outcomes for patients with myelodysplastic syndrome undergoing allogeneic hematopoietic cell transplantation.

Leuk Res 2021 Oct 18;109:106625. Epub 2021 May 18.

Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA, USA.

Disease burden prior to hematopoietic cell transplantation (HCT) is difficult to assess in myelodysplastic syndrome (MDS), particularly in patients without excess blasts. We assessed whether morphologic dysplasia at the time of transplant can be a metric of disease burden that is associated with post-transplant outcomes in MDS patients. We identified 84 MDS patients undergoing allogeneic HCT at our institution between 2010 and 2017 who received a bone marrow evaluation immediately prior to HCT. Dysplasia was independently determined by two hematopathologists blinded to existing pathology reports. Erythroid nuclear dysplasia, but not megakaryocytic or myeloid, was associated with post-HCT outcomes. Presence compared to absence of erythroid nuclear dysplasia was associated with lower 2-year progression-free survival (PFS; 34 % vs 62 %, p = 0.0495) and 2-year overall survival (OS; 34 % vs 62 %, p = 0.042). In a multivariate analysis including age, IPSS-R at the time of transplant, pre-HCT therapy, and donor type as covariates, erythroid nuclear dysplasia remained associated with lower PFS (HR 2.6, p = 0.036) and OS (HR 2.7, p = 0.028). Dysplasia assessment prior to transplant may serve as an estimate of disease burden in MDS and identify high-risk patients who merit additional therapies pre- or post-transplant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2021.106625DOI Listing
October 2021

Acute Myeloid Leukemia Presenting Less Than 3 Weeks After Living Donor Kidney Transplant: A Case Report.

Transplant Proc 2021 May 20;53(4):1360-1364. Epub 2021 Apr 20.

Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut; Hartford Hospital Transplant and Comprehensive Liver Center, Hartford, Connecticut. Electronic address:

Acute myeloid leukemia (AML) is a rare malignancy with increased incidence in the kidney transplantation (KT) population for which immunosuppression has been implicated as a putative cause. The average time interval from KT to AML development is 5 years. We present the case of a 61-year-old man who was found to have peripheral blood blasts on a postoperative day 20 routine blood draw after an uneventful unrelated living donor kidney transplant. He subsequently had a bone marrow biopsy and next-generation sequencing (NGS)-based molecular testing, which demonstrated AML characterized by SMC1A and TET2 mutations. He received induction chemotherapy followed by hematopoietic cell transplantation (HCT) from the kidney donor, who happened to be matched at one haplotype. At 12 months after his HCT and 15 months after his KT, his AML remained in remission, normal renal function was preserved, no active graft-versus-host disease was present, and immunosuppression was tapering. With full donor-derived hematopoietic chimerism, we expect to be able to discontinue immunosuppression shortly, thereby achieving tolerance. The short time interval between KT and development of AML suggests the malignancy was likely present before KT. Modern NGS-based analysis offers a promising method of identifying transplant candidates with unexplained hematologic abnormalities on pre-KT testing who may benefit from formal hematologic evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.transproceed.2021.03.003DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.02.028DOI Listing
June 2021

Association Between Baseline Patient-Reported Outcomes and Complications of Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 06 25;27(6):496.e1-496.e5. Epub 2021 Feb 25.

Department of Medicine, Division of Hematology & Oncology, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston Massachusetts.

Hematopoietic cell transplantation (HCT) is a potentially curative therapy for hematologic malignancies, but it often results in significant toxicities and impaired quality of life (QOL). Although the value of patient-reported outcomes (PROs) is increasingly recognized in HCT, data are limited regarding the relationship between PROs and HCT complications. We conducted a secondary data analysis of 250 patients who were hospitalized for autologous or allogeneic HCT at Massachusetts General Hospital from 2011 through 2016. We assessed QOL (Functional Assessment of Cancer Therapy-General), mood (Hospital Anxiety and Depression Scale), and fatigue (FACT-Fatigue) at baseline. We abstracted from the Electronic Health Record (1) hospitalization during the first 100 days after HCT, (2) days alive and out of the hospital in the first 100 days after HCT, and (3) cumulative incidence of acute graft-versus-host disease (GVHD) among allogeneic HCT recipients. We assessed the association of baseline PROs with HCT complications using multivariable models adjusting for patient and transplant characteristics. Overall, 44.4% (111/250) of patients underwent an autologous HCT, 25.2% (63/250) received a myeloablative allogeneic HCT, and 30.4% (76/250) underwent a reduced-intensity allogeneic HCT. In multivariable logistic regression, higher anxiety (odds ratio [OR] = 1.14, P = .004) was associated with higher likelihood of rehospitalization within 100 days after HCT. In multivariable Poisson regression, lower fatigue (β = 0.003, P = .015) was associated with increased days alive and out of the hospital in the first 100 days post-HCT. In multivariable logistic regression, lower baseline QOL (OR = 0.97, P = .034), higher fatigue (OR = 0.95, P = .004), and higher depression (OR = 1.15, P = .020) were associated with increased likelihood of acute GVHD. Baseline PROs are associated with health care utilization after HCT and risk of acute GVHD in allogeneic HCT recipients. These findings underscore the potential utility of pretransplantation PROs as important prognostic factors for HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.02.029DOI Listing
June 2021

Acute GVHD: do we trust our gut?

Authors:
Yi-Bin Chen

Blood 2021 03;137(11):1447-1448

Massachusetts General Hospital.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009596DOI Listing
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993097PMC
March 2021

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

Leukemia 2021 09 3;35(9):2672-2683. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01193-6DOI Listing
September 2021

Sharing and caring: The impact of social support on quality of life and health outcomes in hematopoietic stem cell transplantation.

Cancer 2021 Apr 17;127(8):1260-1265. Epub 2021 Feb 17.

Harvard Medical School, Boston, Massachusetts.

Background: Social support is crucial for successful recovery after hematopoietic stem cell transplantation (HSCT) and has the potential to affect patient quality of life (QOL) and health outcomes. However, there are limited data on the relationship between a patient's perception of his or her social support and these outcomes.

Methods: The authors conducted a secondary analysis of 250 autologous and allogeneic HSCT recipients enrolled in 2 supportive care trials at Massachusetts General Hospital from April 2011 through February 2016. They assessed social support as a patient's perception of his or her social well-being via the social well-being subscale of the Functional Assessment of Cancer Therapy. The authors used multivariate regression analyses to examine the relationship between pretransplant social well-being and QOL (Functional Assessment of Cancer Therapy-Treatment Outcome Index), psychological distress (Hospital Anxiety and Depression Scale), posttraumatic stress disorder [PTSD] symptoms (PTSD Checklist), fatigue (Functional Assessment of Cancer Therapy-Fatigue), and health care utilization (hospitalizations and days alive and out of the hospital) 6 months after HSCT.

Results: Participants were on average 56.4 years old (SD, 13.3 years); 44% (n = 110) and 56% (n = 140) received autologous and allogeneic HSCT, respectively. Greater pre-HSCT social well-being was associated with higher QOL (B = 0.10; 95% CI, 0.06-0.13; P < .001), lower psychological distress (B = -0.21; 95% CI, -0.29 to -0.12; P < .001), and lower PTSD symptoms (B = -0.12; 95% CI, -0.19 to -0.06; P < .001). Pre-HSCT social well-being was not significantly associated with fatigue or health care utilization 6 months after HSCT.

Conclusions: Patients with higher pre-HSCT perceptions of their social support reported better QOL and lower psychological distress 6 months after HSCT. These findings underscore the potential for social support as a modifiable target for future supportive care interventions to improve the QOL and care of HSCT recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33455DOI Listing
April 2021

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

J Clin Oncol 2021 06 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260916PMC
June 2021

Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin.

Blood Adv 2020 12;4(24):6098-6105

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

Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept "preemptive" treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756981PMC
December 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01049-0DOI Listing
May 2021

Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity.

J Clin Oncol 2020 09 15;38(27):3095-3106. Epub 2020 Jul 15.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Axicabtagene ciloleucel (axi-cel) was approved by the Food and Drug Administration for relapsed aggressive B-cell non-Hodgkin lymphoma in part on the basis of durable remission rates of approximately 40% in a clinical trial population. Whether this efficacy, and the rates of toxicity, would be consistent in a postcommercial setting, with relaxed eligibility criteria and bridging therapy, is unknown. This study describes the efficacy and safety correlates and outcomes in this setting.

Patients And Methods: One hundred twenty-two patients from 7 medical centers in the United States were treated with axi-cel and were included in a modified intent-to-treat (mITT) analysis. Seventy-six patients (62%) were ineligible for the ZUMA-1 trial. Response and toxicity rates, duration of response (DOR), survival, and covariates are described on the basis of the mITT population. Correlative studies on blood and tumor samples were performed to investigate potential biomarkers of response and resistance.

Results: Median follow-up was 10.4 months. In the mITT population, the best overall and complete response (CR) rates were 70% and 50%, respectively. Median DOR and progression-free survival (PFS) were 11.0 and 4.5 months in all patients and were not reached (NR) in CR patients. Median overall survival (OS) was NR; 1-year OS was 67% (95% CI, 59% to 77%). Although response rates were similar in the ZUMA-1-eligible and ZUMA-1-ineligible groups (70% 68%), there was a statistically significant improvement in CR rate (63% 42%, = .016), DOR (median, NR 5.0 months; = .014), PFS (median, NR 3.3 months; = .020), and OS (1-year OS, 89% 54%; < .001) in patients who were ZUMA-1 eligible. Rates of grade ≥ 3 cytokine release syndrome and neurotoxicty were 16% and 35%, respectively.

Conclusion: Axi-cel yields similar rates of overall response and toxicity in commercial and trial settings, although CR rates and DOR were more favorable in patients eligible for ZUMA-1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499617PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019004710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290092PMC
June 2020

T Cell Clonal Dynamics Determined by High-Resolution TCR-β Sequencing in Recipients after Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2020 09 15;26(9):1567-1574. Epub 2020 May 15.

Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Delayed reconstitution of the immune system is a long-recognized complication after allogeneic hematopoietic cell transplantation (HCT). Specifically, loss of T cell diversity has been thought to contribute to infectious complications, graft-versus-host disease (GVHD), and disease relapse. We performed serial high-resolution next-generation sequencing of T cell receptor (TCR)-β in 99 related or unrelated donor (57 unrelated, 42 related) allogeneic HCT recipients (55 with reduced-intensity conditioning, 44 with myeloablative conditioning) during the first 3 months after HCT using the immunoSEQ Assay. We measured T cell fraction, clonality (1- Peilou's evenness) and Daley-Smith richness from recipient samples at multiple time points. In agreement with previous studies, we found that although absolute T cell numbers recover relatively quickly after HCT, T cell repertoire diversity remains diminished. Restricted diversity was associated with conditioning intensity, use of antithymocyte globulin, and donor type. Increased number of expanded clones compared to donor T cell clones at day +30 was associated with the incidence of acute GVHD (hazard ratio [HR], 1.11; P = .00005). Even after exclusion of the 12 patients who developed acute GVHD before day +30, the association between acute GVHD and increased clonal expansion at day +30 remained (HR, 1.098; P = .041), indicating that increased clonal T cell expansion preceded the development of acute GVHD. Our results highlight T cell clonal expansion as a potential novel biomarker for acute GVHD that warrants further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279830PMC
September 2020

A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease.

Blood Adv 2020 04;4(8):1656-1669

Division of Oncology, Section of Bone Marrow Transplantation and Leukemia, Washington University School of Medicine in St. Louis, St. Louis, MO.

Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation (HCT) is a primary cause of nonrelapse mortality and a major barrier to successful transplant outcomes. Itacitinib is a Janus kinase (JAK)1-selective inhibitor that has demonstrated efficacy in preclinical models of aGVHD. We report results from the first registered study of a JAK inhibitor in patients with aGVHD. This was an open-label phase 1 study enrolling patients aged ≥18 years with first HCT from any source who developed grade IIB to IVD aGVHD. Patients with steroid-naive or steroid-refractory aGVHD were randomized 1:1 to itacitinib 200 mg or 300 mg once daily plus corticosteroids. The primary endpoint was safety and tolerability; day 28 overall response rate (ORR) was the main secondary endpoint. Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting toxicity was reported (grade 3 thrombocytopenia attributed to GVHD progression in a patient receiving 300 mg itacitinib with preexisting thrombocytopenia). The most common nonhematologic treatment-emergent adverse event was diarrhea (48.3%, n = 14); anemia occurred in 11 patients (38%). ORR on day 28 for all patients in the 200-mg and 300-mg groups was 78.6% and 66.7%, respectively. Day 28 ORR was 75.0% for patients with treatment-naive aGVHD and 70.6% in those with steroid-refractory aGVHD. All patients receiving itacitinib decreased corticosteroid use over time. In summary, itacitinib was well tolerated and demonstrated encouraging efficacy in patients with steroid-naive or steroid-refractory aGVHD, warranting continued clinical investigations. This trial was registered at www.clinicaltrials.gov as #NCT02614612.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019001043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189299PMC
April 2020

Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial.

Blood 2020 05;135(20):1739-1749

Winship Cancer Institute of Emory School of Medicine, Atlanta, GA.

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020004823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229262PMC
May 2020

Current Approaches to Transplantation for FLT3-ITD AML.

Curr Hematol Malig Rep 2020 02;15(1):1-8

Massachusetts General Hospital, 0 Emerson Place, Suite 118, Boston, MA, 02114, USA.

Purpose Of Review: This review discusses the current standard of care for incorporation of FLT3 TKIs and HCT into the treatment of FLT3-ITD AML. Additionally, this review provides an approach to the patient with relapsed/refractory disease.

Recent Findings: Over the last decade, the routine use of HCT as consolidative therapy and the development of FLT3 TKIs have significantly improved remission rates and overall survival. The value and challenges of MRD assessment in FLT3 disease are discussed and current mechanisms of relapse are explored, as are the ongoing questions in the field that current clinical trials are seeking to answer. FLT3-ITD mutations are common in acute myeloid leukemia and historically have been associated with a poor prognosis, but with the incorporation of FLT3 TKIs and routine use of allogeneic stem cell transplant as consolidative therapy, outcomes have improved dramatically. Ongoing research seeks to answer how and when to best use current therapies, and how to overcome resistance to FLT3 inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11899-020-00558-5DOI Listing
February 2020
-->