Publications by authors named "Taiga Nishihori"

180 Publications

Cytokine Release Syndrome Following Peripheral Blood Stem Cell Haploidentical HCT with Post-Transplant Cyclophosphamide: CRS post haploidentical HCT with PTCy.

Transplant Cell Ther 2021 Nov 26. Epub 2021 Nov 26.

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

Background: Post-transplant cyclophosphamide (PTCy) is a safe and efficacious graft-versus-host-disease (GvHD) prophylaxis following hematopoietic cell transplantation (HCT) from haploidentical (haplo) donors. Cytokine release syndrome (CRS) is a common complication of this platform. Early fever post-haplo HCT using bone marrow grafts is associated with higher CD3+ cell dose and CRS. However, the impact of CD3+ and CD34+ cell dose on CRS post-haplo HCT using peripheral blood stem cell (PBSCT) grafts is unknown.

Objective: Our goals were to evaluate the incidence of CRS following PBSCT and to identify factors that can be modified to prevent the development of severe CRS in this setting.

Study Design: In 271 patients, we investigated factors associated with development of CRS following haplo PBSCT and examined the impact of CRS on clinical outcomes.

Results: Ninety-three percent of patients developed CRS of any grade post-haplo PBSCT. In multivariate analysis, severe CRS (grade 3-4 vs. grade 0-1) was associated with higher non-relapse mortality (HR=6.42; 95% CI: 2.68-15.39; p<0.001), worse 1-year overall survival (HR=3.40; 95% CI: 1.63-7.08; p=0.005), and disease-free survival (HR=4.02, 95% CI: 1.99-8.08; p<0.001). Moderate to severe CRS (grade 2-4) did not impact 1-year relapse and acute GvHD (grade II-IV and III-IV) at 100 days (p=0.71 and p=0.19, respectively). Importantly, higher CD3+ cell dose but not CD34+ cell dose predicted higher incidence of CRS grades 2-4 (HR=1.20, 95% CI:1.07-1.36; p 0.003) and grades 3-4 (HR=1.40, 95% CI:1.05-1.86; p=0.022). Older age (HR=8.57, 95% CI: 1.73-42.36; p<0.001) and non-radiation-based RIC (fludarabine/melphalan; HR=15.38, 955 CI: 2.06-114.67; p<0.001) were both predictors of CRS grade 3-4.

Conclusions: Overall, we observed that severe CRS (grade 3-4) negatively affected transplant outcome and that higher CD3 cell dose was associated with development of any grade and severe CRS.
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http://dx.doi.org/10.1016/j.jtct.2021.11.012DOI Listing
November 2021

HLA Informs Risk Predictions after Haploidentical Stem Cell Transplantation with Post-transplantation Cyclophosphamide.

Blood 2021 Nov 1. Epub 2021 Nov 1.

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States.

Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence and survival after haploidentical donor transplantation with post-transplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1-mismatching with HLA-DQB1-matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-non-permissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1 and -DPB1 predicted disease-free survival, as did patient and donor CMV serostatus, patient age and co-morbidity index. A web-based tool was developed to facilitate selection of the best haploidentical related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.
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http://dx.doi.org/10.1182/blood.2021013443DOI Listing
November 2021

Phase 2 multicenter trial of ofatumumab and prednisone as initial therapy of chronic graft-vs-host disease.

Blood Adv 2021 Oct 14. Epub 2021 Oct 14.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States.

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal and transient responses in a significant number of patients. Safety and feasibility of anti-CD20 directed B-cell therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n=12). We now report the mature results of the phase II expansion of the trial (n=38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The combined therapy was generally well tolerated, with some anticipated infusion reactions to ofatumumab, and common toxicities of glucocorticoids. Total B-cell depletion following therapy was profound, with marginal recovery within first 12 months from initial therapy. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR=complete + partial response[CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial IS agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial is registered at www.clinicaltrials.gov as NCT01680965.
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http://dx.doi.org/10.1182/bloodadvances.2021005552DOI Listing
October 2021

Maintenance therapy after second autologous hematopoietic cell transplantation for multiple myeloma. A CIBMTR analysis.

Bone Marrow Transplant 2021 Oct 4. Epub 2021 Oct 4.

Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.

The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.
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http://dx.doi.org/10.1038/s41409-021-01455-yDOI Listing
October 2021

An adapted European LeukemiaNet genetic risk stratification for acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplant. A CIBMTR analysis.

Bone Marrow Transplant 2021 Dec 28;56(12):3068-3077. Epub 2021 Sep 28.

Division of Hematology/BMT, Mayo Clinic, Rochester, MN, USA.

Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes in acute myeloid leukemia (AML) but data assessing the prognostic value of combined genetic models in the HCT setting are limited. We developed an adapted European LeukemiaNet (aELN) risk classification based on available genetic data reported to the Center for International Blood and Marrow Transplant Research, to predict post-transplant outcomes in 2289 adult AML patients transplanted in first remission, between 2013 and 2017. Patients were stratified according to aELN into three groups: favorable (Fav, N = 181), intermediate (IM, N = 1185), and adverse (Adv, N = 923). Univariate analysis demonstrated significant differences in 2-year overall survival (OS) (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p < 0.001); disease-free survival (DFS) (Fav: 57.8%, IM: 55.5% and Adv: 45.3; p < 0.001) and relapse (Fav: 28%, IM: 27.5% and Adv: 37.5%; p < 0.001). Multivariate analysis (MVA) revealed no differences in outcomes between the Fav and IM groups, thus they were combined. On MVA, patients in the Adv risk group had the highest risk of relapse (HR 1.47 p ≤ 0.001) and inferior DFS (HR 1.35 p < 0.001) and OS (HR 1.39 p < 0.001), even using myeloablative conditioning or in those without the pre-HCT measurable-residual disease. Novel approaches to mitigate relapse in this high-risk group are urgently needed.
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http://dx.doi.org/10.1038/s41409-021-01450-3DOI Listing
December 2021

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Blood Adv 2021 Sep 22. Epub 2021 Sep 22.

University of Texas Southwestern Medical Center, Dallas, Texas, United States.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease.
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http://dx.doi.org/10.1182/bloodadvances.2021004881DOI Listing
September 2021

Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia.

Blood Adv 2021 Sep 21. Epub 2021 Sep 21.

University of Virginia, Charlottesville, Virginia, United States.

The role of haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariate analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) between haploidentical HCT using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD) , 7/8 HLA-matched UD, or umbilical cord blood (UCB) HCT. Comparing haploidentical to MSD HCT, OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher with MSD HCT. Compared to MUD HCT, OS, LFS, and relapse were not different but MUD HCT had increased NRM (HR 1.42, P=0.02), grade 3-4 aGVHD (HR 1.59, P=0.005), and cGVHD. Compared to 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR 1.38, P=0.01) and increased NRM (HR 2.13, P=<0.001), grade 3-4 aGVHD (HR 1.86, P=0.003), and cGVHD (HR 1.72, P=<0.001). Compared to UCB HCT, late OS , late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months, HR 1.93, P<0.001), worse early LFS (HR 1.40, P=0.007) and increased incidences of NRM (HR 2.08, P<0.001) and grade 3-4 aGVHD (HR 1.97, P<0.001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared to traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in CR.
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http://dx.doi.org/10.1182/bloodadvances.2021004916DOI Listing
September 2021

Outcomes and Utilization Trends of Front-Line Autologous Hematopoietic Cell Transplantation for Mantle Cell Lymphoma.

Transplant Cell Ther 2021 Nov 24;27(11):911.e1-911.e7. Epub 2021 Aug 24.

Division of Hematology and Oncology, University of Chicago Medicine, Chicago, Illinois.

Although autologous hematopoietic cell transplantation (auto-HCT) has become a common practice for eligible patients in the front-line setting with mantle cell lymphoma (MCL), there are limited data regarding trends in auto-HCT utilization and associated outcomes. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to evaluate survival outcomes and auto-HCT utilization in adults age ≥18 years who underwent auto-HCT within 12 months of diagnosis of MCL between January 2000 and December 2018. The 19-year period from 2000 to 2018 was divided into 4 separate intervals-2000 to 2004, 2005 to 2009, 2010 to 2014, and 2015 to 2018-and encompassed 5082 patients. To evaluate transplantation utilization patterns, we combined MCL incidence derived from the SEER 21 database with CIBMTR- reported auto-HCT activity within 12 months of diagnosis of MCL. Primary outcomes included overall survival (OS) along with the auto-HCT utilization rate. The cumulative incidence of nonrelapse mortality at 1 year decreased from 7% in the earliest cohort (2000 to 2004) to 2% in the latest cohort (2015 to 2018). Mirroring this trend, OS outcomes improved continually with time, with a 3-year OS of 72% in the earliest cohort improving to 86% in the latest cohort. In addition, we noted an increase in auto-HCT utilization from 2001 to 2018, particularly in patients age ≤65 years. This large retrospective analysis highlights trends in auto-HCT utilization and outcomes in patients with MCL and emphasizes the need to optimize pretransplantation and post-transplantation treatment strategies to enhance survival outcomes.
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http://dx.doi.org/10.1016/j.jtct.2021.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556305PMC
November 2021

Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults.

Transplant Cell Ther 2021 Nov 21;27(11):923.e1-923.e12. Epub 2021 Aug 21.

Section of Bone Marrow Transplant and Cell Therapy, Rush University Medical Center, Chicago, Illinois.

Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT.
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http://dx.doi.org/10.1016/j.jtct.2021.08.010DOI Listing
November 2021

Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improve Transplantation Outcomes in Older Patients with Myelodysplastic Syndromes.

Transplant Cell Ther 2021 Nov 14;27(11):921.e1-921.e10. Epub 2021 Aug 14.

Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤ .0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤ .0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.007DOI Listing
November 2021

Objective and subjective physical function in allogeneic hematopoietic stem cell transplant recipients.

Bone Marrow Transplant 2021 Dec 11;56(12):2897-2903. Epub 2021 Aug 11.

Health Outcomes and Behavior, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

We conducted a prospective study of adult allogeneic hematopoietic cell transplantation (HCT) recipients to assess pre- and post-HCT physical function. Baseline measurements included a wrist actigraphy, a 6 min walk test (6MWT), an international physical activity questionnaire (IPAQ), and a Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) as well as serial post-HCT assessments of 6MWT, IPAQ, and FACT-BMT. Forty-seven patients were evaluable for functionality assessments, with a median follow-up of 54.5 months for surviving recipients. No patients demonstrated vigorous or very vigorous activity at any time during monitoring by wrist actigraphy; patients spent a median of 6 h daily sedentary. Self-reported activity via the IPAQ showed 36%, 43%, and 21% of subjects reporting light, moderate, and vigorous activity prior to HCT, respectively. Post-HCT 6MWTs on day +30 demonstrated the greatest association with subsequent survival and non-relapse mortality. A decline in 6MWT distance over time also demonstrated worsened overall survival. This study shows the feasibility of fitness assessments and the ability to risk stratify for subsequent mortality, particularly using the 6MWT on the day +30 single time point assessment and change scores from baseline to day +30 post HCT. These pilot findings suggest important targets for future study.
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http://dx.doi.org/10.1038/s41409-021-01428-1DOI Listing
December 2021

Therapeutic roles of antibody drug conjugates (ADCs) in relapsed/refractory lymphomas.

Hematol Oncol Stem Cell Ther 2021 Jul 28. Epub 2021 Jul 28.

Department of Blood & Marrow Transplant and Cellular Immunotherapy (BMT CI), Moffitt Cancer Center, United States. Electronic address:

Relapsed or refractory lymphoma is commonly treated with combination chemoimmunotherapy and cellular immunotherapy. Modest response rates and associated toxicities are obstacles to achieving durable remission using traditional cytotoxic chemotherapy, especially in frail patients with advanced disease. Antibody drug conjugates represent a new class of novel targeted agents with significant improvement in therapeutic efficacy in the treatment of lymphomas. Several of these agents, which offer improved targeting, greater potency, and better therapeutic index over traditional chemotherapy, are changing the treatment landscape for lymphomas and other hematological malignancies. Despite the therapeutic potential of these agents, the delivery and release of cytotoxic agents to malignant cells through the combination of a monoclonal antibody, payload, and linker represents a complex design challenge. This article reviews the clinical data on currently available antibody drug conjugates and the ongoing development of novel antibody drug conjugates. Antibody drug conjugates constitute an important armamentarium for treatment of lymphomas and their evolving roles in the treatment spectrum are discussed.
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http://dx.doi.org/10.1016/j.hemonc.2021.07.002DOI Listing
July 2021

Assessment of Clonotypic Rearrangements and Minimal Residual Disease in Lymphoid Malignancies: A Large Cancer Center Experience Using clonoSEQ.

Arch Pathol Lab Med 2021 Aug 3. Epub 2021 Aug 3.

Malignant Hematology (Shah, Pinilla-Ibarz, Shain), Moffitt Cancer Center, Tampa, Florida.

Context.—: Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been incorporated into consensus criteria regarding treatment response, strategy, and clinical trial endpoints. clonoSEQ (a next-generation sequencing [NGS]-MRD assay) uses multiplex polymerase chain reaction and NGS to identify clonotypic rearrangements at the immunoglobulin (Ig) H, IgK, IgL, T-cell receptor (TCR)-β, and TCR-γ loci, and translocated B-cell lymphoma 1/IgH and 2/IgH sequences for MRD assessment. Additionally, it can be used to confirm diagnoses of cutaneous T-cell lymphoma (CTCL).

Objective.—: To review the technical aspects of our experience using the clonoSEQ Assay in routine clinical practice.

Design.—: In this single-center experience, 390 patients with lymphoid and plasma cell malignancies were assessed with the NGS-MRD Assay at a central laboratory.

Results.—: Median time from arrival of the shipment to initiation of the assay (defined as captured in Adaptive's secure tracking system) was 2.1 hours. Overall, 317 patients had 1 or more samples submitted for sequence identification. Of these, 290 (91.5%) had trackable sequences identified. The median calibration rate of samples by malignancy (where n ≥ 10 samples, excluding CTCL samples) was 88.1%, across a variety of fresh and archived sample sources (177 of 201 samples). TCR-β and/or TCR-γ clonotypes were identified in 40 of 95 samples (42.1%) from 66 patients with suspected CTCL.

Conclusions.—: This NGS-MRD Assay is a valuable and sensitive tool for monitoring MRD in patients with plasma cell and lymphoid malignancies and assisting in the diagnosis of CTCL.
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http://dx.doi.org/10.5858/arpa.2020-0457-OADOI Listing
August 2021

Increased Infections and Delayed CD4 T Cell but Faster B Cell Immune Reconstitution after Post-Transplantation Cyclophosphamide Compared to Conventional GVHD Prophylaxis in Allogeneic Transplantation.

Transplant Cell Ther 2021 Nov 28;27(11):940-948. Epub 2021 Jul 28.

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

Post-transplantation cyclophosphamide (PTCy) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT) across various donor types. However, immune reconstitution and infection incidence after PTCy-based versus conventional GVHD prophylaxis has not been well studied. We evaluated the infection density and immune reconstitution (ie, absolute CD4 T cell, CD8 T cell, natural killer cell, and B cell counts) at 3 months, 6 months, and 1 year post-HCT in 583 consecutive adult patients undergoing allo-HCT with myeloablative (n = 223) or reduced-intensity (n = 360) conditioning between 2012 and 2018. Haploidentical (haplo; n = 75) and 8/8 HLA-matched unrelated (MUD; n = 08) donor types were included. GVHD prophylaxis was PTCy-based in all haplo (n = 75) and in 38 MUD allo-HCT recipients, whereas tacrolimus/methotrexate (Tac/MTX) was used in 89 and Tac/Sirolimus (Tac/Sir) was used in 381 MUD allo-HCT recipients. Clinical outcomes, including infections, nonrelapse mortality (NRM), relapse, and overall survival (OS), were compared across the 4 treatment groups. The recovery of absolute total CD4 T-cell count was significantly lower in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups throughout 1 year post-allo-HCT (P = .025). In contrast, CD19 B-cell counts at 6 months and thereafter were higher in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (P < .001). Total CD8 T cell and NK cell recovery was not significantly different among the groups. Infection density analysis showed a significantly higher frequency of total infections in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (5.0 and 5.0 vs 1.8 and 2.6 per 1000-person days; P < .01) within 1 year of allo-HCT. The cumulative incidence of cytomegalovirus reactivation/infection at 1 year post-allo-HCT was higher in the haplo-PTCy group (51%) compared with the MUD-PTCy (26%), Tac/MTX (26%), or Tac/Sir (13%) groups (P < .001). The incidence of BK, human herpesvirus 6, and other viruses were also higher in the PTCy-based groups. Overall, the treatment groups had similar 2 year NRM (P = .27) and OS (P = .78) outcomes. Our data show that PTCy-based GVHD prophylaxis is associated with delayed CD4 T cell but faster B cell immune reconstitution and a higher frequency of infections compared with conventional GVHD prophylaxis but has no impact on nonrelapse mortality or overall survival.
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http://dx.doi.org/10.1016/j.jtct.2021.07.023DOI Listing
November 2021

Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy.

Transplant Cell Ther 2021 08;27(8):642-649

West Virginia University, Morgantown, West Virginia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized.
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http://dx.doi.org/10.1016/j.jtct.2021.04.007DOI Listing
August 2021

Patterns and Predictors of Failure in Recurrent or Refractory Large B-Cell Lymphomas After Chimeric Antigen Receptor T-Cell Therapy.

Int J Radiat Oncol Biol Phys 2021 12 6;111(5):1145-1154. Epub 2021 Jul 6.

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

Purpose: Chimeric antigen receptor T-cell (CAR T) therapy is capable of eliciting durable responses in patients with relapsed/refractory (R/R) lymphomas. However, most treated patients relapse. Patterns of failure after CAR T have not been previously characterized, and may provide insights into the mechanisms of resistance guiding future treatment strategies.

Methods And Materials: This is a retrospective analysis of patients with R/R large B-cell lymphoma who were treated with anti-CD19 CAR T at a National Cancer Institute-designated Comprehensive Cancer Center between 2015 and 2019. Pre- and posttreatment positron emission/computed tomography scans were analyzed to assess the progression of existing (local failures) versus new, nonoverlapping lesions (de novo failures) and identify lesions at a high risk for progression.

Results: A total of 469 pretreatment lesions in 63 patients were identified. At a median follow-up of 12.6 months, 36 patients (57%) recurred. Most (n = 31; 86%) had a component of local failure, and 13 patients (36%) exhibited strictly local failures. Even when progressing, 84% of recurrent patients continued to have a subset of pretreatment lesions maintain positron emission/computed tomography resolution. Lesions at a high risk for local failure included those with a diameter ≥5 cm (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.55-3.55; P < .001), maximum standardized uptake value ≥10 (OR, 2.08; 95% CI, 1.38-3.12; P < .001), or those that were extranodal (OR, 1.49; 95% CI, 1.10-2.04; P = .01). In the 69 patients eligible for survival analysis, those with any lesion ≥5 cm (n = 46; 67%) experienced inferior progression-free survival (hazard ratio, 2.41; 95% CI, 1.15-5.04; P = .02) and overall survival (hazard ratio, 3.36; 95% CI, 1.17-9.96; P = .02).

Conclusions: Most patients who recur after CAR T experience a component of local progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T treatment failure. Locally directed therapies to high-risk lesions, such as radiation therapy, may be a viable strategy to prevent CAR T failures in select patients.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.038DOI Listing
December 2021

Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation.

Br J Haematol 2021 07 14;194(1):145-157. Epub 2021 Jun 14.

Department of Medicine, City of Hope, Duarte, CA, USA.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.
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http://dx.doi.org/10.1111/bjh.17563DOI Listing
July 2021

Outcomes of CD19 Chimeric Antigen Receptor T Cell Therapy in Patients with Gastrointestinal Tract Involvement of Large B Cell Lymphoma.

Transplant Cell Ther 2021 09 30;27(9):768.e1-768.e6. Epub 2021 May 30.

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

CD19-directed chimeric antigen receptor (CAR) T cell therapy with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) is approved for the standard of care treatment of relapsed or refractory large B cell lymphoma (LBCL). Patients with LBCL involving the gastrointestinal (GI) tract are at risk of perforation after lymphoma-directed therapy. The outcomes of CAR T cell therapy in patients with GI involvement have not been reported previously. This study aimed to determine the safety and efficacy of CD19 CAR T cell therapy in patients with LBCL involvement of the GI tract. This was a single-center retrospective study of 130 consecutive patients treated with standard of care or expanded-access axi-cel or tisa-cel for LBCL. Twenty-four of these patients had radiologic involvement of the GI tract before CAR T infusion. Incidence rates of severe immune effector cell-mediated toxicities and clinical outcomes were compared between the GI involvement and non-GI involvement groups. Three of the 24 patients with GI tract involvement experienced perforation. One patient had a contained gastric perforation after leukapheresis while receiving bridging radiation therapy to the stomach. This patient was eventually able to proceed with lymphodepletion and product infusion. In the other 2 patients, GI tract perforation occurred at day +13 and day +35 after CAR T infusion. All 3 patients subsequently died while experiencing lymphoma progression. Upper GI bleeding occurred in 1 other patient in the context of progressive disease at 6 months after product infusion. The incidence rates of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, length of hospital stay, and use of anti-IL-6 and steroids were similar in the 24 patients with GI tract involvement and the 106 patients without GI tract involvement. No significant between-group differences were seen in the best overall response rate, progression-free survival, or overall survival. Our data show that outcomes of patients with GI tract involvement before CAR T cell therapy are similar to those without GI involvement, and that durable remissions can be observed. However, patients with preexisting GI tract involvement are at risk of perforation from disease progression before and after CAR T cell infusion.
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http://dx.doi.org/10.1016/j.jtct.2021.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403629PMC
September 2021

Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma.

J Proteome Res 2021 06 20;20(6):3134-3149. Epub 2021 May 20.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States.

Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge. Here, we describe a proteometabolomic approach to examine mechanisms of acquired melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP, data available at PRIDE: PXD019725), acute-treatment metabolomics, and western blot analyses have allowed us to further elucidate metabolic processes associated with melphalan resistance. Proteometabolomic data indicate that drug-resistant cells have higher levels of pentose phosphate pathway metabolites. Purine, pyrimidine, and glutathione metabolisms were commonly altered, and cell-line-specific changes in metabolite levels were observed, which could be linked to the differences in steady-state metabolism of naïve cells. Inhibition of selected enzymes in purine synthesis and pentose phosphate pathways was evaluated to determine their potential to improve melphalan's efficacy. The clinical relevance of these proteometabolomic leads was confirmed by comparison of tumor cell transcriptomes from newly diagnosed MM patients and patients with relapsed disease after treatment with high-dose melphalan and autologous stem-cell transplantation. The observation of common and cell-line-specific changes in metabolite levels suggests that omic approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the use of high-dose melphalan.
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http://dx.doi.org/10.1021/acs.jproteome.1c00022DOI Listing
June 2021

Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States.

Transplant Cell Ther 2021 08 22;27(8):679.e1-679.e8. Epub 2021 Apr 22.

Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, Minnesota.

Young adult (YA) survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk for late psychosocial challenges, including the inability to return to work post-HCT. Work-related outcomes in this population remain understudied, however. We conducted this study to assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YAs and to analyze the patient-, disease-, and HCT-related factors associated with their work status at 1 year post-HCT. Using Center for International Blood and Marrow Transplant Research data, we evaluated the post-HCT work status (full-time, part-time work, unemployed, or medical disability) of 1365 YA HCT survivors who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at 4 time points: 6 months, 1 year, 2 years, and 3 years post-HCT. Percentages of post-HCT work status categories at the 1-year time point were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. From 6 months to 3 years post-HCT, the percentage of survivors working full-time increased from 18.3% to 50.7% and the percentage working part-time increased from 6.9% to 10.5%. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1 year post-HCT. Female sex (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.40 to 0.77), HCT Comorbidity Index score ≥3 (OR, 0.57; 95% CI, 0.39 to 0.82), pre-HCT unemployment (OR, 0.37; 95% CI, 0.24 to 0.56), medical disability (OR, 0.44; 95% CI, 0.28 to 0.70), development of grade III-IV acute graft-versus-host disease (OR, 0.52; 95% CI, 0.34 to 0.80), and relapse within 1 year post-HCT (OR, 0.34; 95% CI, 0.21 to 0.56) were associated with a lower likelihood of employment at 1 year post-HCT. Compared with myeloablative conditioning (MAC) with total body irradiation (TBI), MAC without TBI (OR, 1.71; 95% CI, 1.16 to 2.53) was associated with a greater likelihood of employment at 1 year post-HCT. Graduate school-level education (OR, 2.47; 95% CI, 1.49 to 4.10) was also associated with a greater likelihood of employment at 1 year post-HCT. Although the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective interventions to support return to work in this population.
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http://dx.doi.org/10.1016/j.jtct.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425287PMC
August 2021

Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 09 16;56(9):2108-2117. Epub 2021 Apr 16.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.
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http://dx.doi.org/10.1038/s41409-021-01261-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425595PMC
September 2021

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

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

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

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

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

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

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

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

Incidence and Management of Effusions Before and After CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Large B Cell Lymphoma.

Transplant Cell Ther 2021 03 27;27(3):242.e1-242.e6. Epub 2020 Dec 27.

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

In patients with lymphoma, third-space fluid accumulations may develop or worsen during cytokine release syndrome (CRS) associated with chimeric antigen receptor (CAR) T cell therapy. Pre-existing symptomatic pleural effusions were excluded by the ZUMA-1 trial of axicabtagene ciloleucel for large B cell lymphoma (LBCL) and variants. The incidence and management of effusions during CAR T cell therapy for LBCL are unknown. We performed a single-center retrospective study evaluating 148 patients receiving CD19-directed CAR T cell therapy for LBCL between May 2015 and September 2019. We retrospectively identified patients who had radiographic pleural, pericardial, or peritoneal effusions that were present prior to the time of CAR T infusion (pre-CAR T) or that newly developed during the first 30 days after CAR T-cell infusion (post-CAR T). Of 148 patients, 19 patients had a pre-CAR T effusion, 17 patients without pre-existing effusion developed a new infusion after CAR T, and 112 patients had no effusions. Comparing pre-CAR T effusions to new effusions post-CAR T, pre-CAR T effusions were more often malignant (84% versus 12%), persistent beyond 30 days (95% versus 18%), and required interventional drainage after CAR T infusion (79% versus 0%). Compared to patients with no effusion, patients with pre-CAR T therapy effusions had a higher frequency of high-risk baseline characteristics, such as bulky disease and high International Prognostic Index. Similarly, patients with pre-CAR T therapy effusions had a higher rate of toxicity with grade 3 or higher CRS occurring in 32% of patients. On multivariate analysis adjusting for age, Eastern Cooperative Oncology Group status, bulky disease, albumin, and lactate dehydrogenase, a pre-CAR T therapy effusion was associated with reduced overall survival (hazard ratio, 2.34; 95% confidence interval, 1.09 to 5.03; P = .03). Moreover, there was higher non-relapse mortality (11% versus 1%; P = .005). Post-CAR T effusions were not associated with significant difference in survival. Effusions commonly complicate CAR T cell therapy for lymphoma. Malignant effusions that occur prior to CAR T therapy are frequently persistent and require therapeutic intervention, and patients have a higher rate of toxicity and death. Effusions that newly occur after CAR T therapy can generally be managed medically and tend not to persist.
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http://dx.doi.org/10.1016/j.jtct.2020.12.025DOI Listing
March 2021

Impact of Pretransplantation Renal Dysfunction on Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 05 26;27(5):410-422. Epub 2021 Feb 26.

Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania.

Renal dysfunction is a recognized risk factor for mortality after allogeneic hematopoietic cell transplantation (alloHCT), yet our understanding of the effect of different levels of renal dysfunction at time of transplantation on outcomes remains limited. This study explores the impact of different degrees of renal dysfunction on HCT outcomes and examines whether the utilization of incremental degrees of renal dysfunction based on estimated glomerular filtration rate (eGFR) improve the predictability of the hematopoietic cell transplantation comorbidity index (HCT-CI). The study population included 2 cohorts: cohort 1, comprising patients age ≥40 years who underwent alloHCT for treatment of hematologic malignancies between 2008 and 2016 (n = 13,505; cohort selected given a very low incidence of renal dysfunction in individuals age <40 years), and cohort 2, comprising patients on dialysis at the time of HCT (n = 46). eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. The patients in cohort 1 were assigned into 4 categories-eGFR ≥90 mL/min (n = 7062), eGFR 60 to 89 mL/min (n = 5264), eGFR 45 to 59 mL/min (n = 897), and eGFR <45 mL/min (n=282)-to assess the impact of degree of renal dysfunction on transplantation outcomes. Transplantation outcomes in patients on dialysis at the time of alloHCT were analyzed separately. eGFR <60 mL/min was associated with an increased risk for nonrelapse mortality (NRM) and requirement for dialysis post-HCT. Compared with the eGFR ≥90 group, the hazard ratio (HR) for NRM was 1.46 (P = .0001) for the eGFR 45 to 59 mL/min group and 1.74 (P = .004) for the eGFR <45 mL/min group. Compared with the eGFR ≥90 mL/min group, the eGFR 45 to 59 mL/min group (HR, 2.45; P < .0001) and the eGFR <45 mL/min group (HR, 3.09; P < .0001) had a higher risk of renal failure necessitating dialysis after alloHCT. In addition, eGFR <45 mL/min was associated with an increased overall mortality (HR, 1.63; P < .0001). An eGFR-based revised HCT-CI was also developed and shown to be predictive of overall survival (OS) and NRM, with predictive performance similar to the original HCT-CI. Among 46 patients on dialysis at alloHCT, the 1-year probability of OS was 20%, and that of NRM was 67%. The degree of pretransplantation renal dysfunction is an independent predictor of OS, NRM, and probability of needing dialysis after alloHCT. An eGFR-based HCT-CI is a validated index for predicting outcomes in adults with hematologic malignancies undergoing alloHCT. The outcomes of alloHCT recipients on dialysis are dismal; therefore, one should strongly weigh the significant risks of being on hemodialysis as a factor in determining alloHCT candidacy.
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http://dx.doi.org/10.1016/j.jtct.2021.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168834PMC
May 2021
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