Publications by authors named "Sairah Ahmed"

125 Publications

Follicular lymphoma microenvironment characteristics associated with tumor cell mutations and MHC class II expression.

Blood Cancer Discov 2022 Jun 10. Epub 2022 Jun 10.

The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Follicular lymphoma (FL) is a B-cell malignancy with a complex tumor microenvironment that is rich in non-malignant immune cells. We applied single-cell RNA-sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T-cells including a cytotoxic CD4 T-cell population. Their relative proportions of T-cells defined four major FL subtypes, characterized by differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced MHC expression on FL cells. In turn, expression of MHC class II genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics of T-cells. This provides a classification framework of the FL microenvironment, their association with FL genotypes and MHC expression, and informs different potential immunotherapeutic strategies based upon tumor cell MHC class II expression.
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http://dx.doi.org/10.1158/2643-3230.BCD-21-0075DOI Listing
June 2022

A randomized phase III study of pretransplant conditioning for AML/MDS with fludarabine and once daily IV busulfan ± clofarabine in allogeneic stem cell transplantation.

Bone Marrow Transplant 2022 May 24. Epub 2022 May 24.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Pretransplant conditioning with Fludarabine (Flu)-Busulfan (Bu) is safe, but clofarabine (Clo) has improved antileukemic activity. Hypothesis: Flu+Clo-Bu (FCB) yields superior progression-free survival (PFS) after allogeneic transplantation. We randomized 250 AML/MDS patients aged 3-70, Karnofsky Score ≥80, with matched donors, to FCB (n = 120) or Flu-Bu (n = 130), stratifying complete remission (CR) vs. No CR, (NCR). HCT-CI scores varied, from 0 to 10. All evaluable patients engrafted. Median follow-up was 66 months (interquartile range: 58-80). Three-year relapse incidence (RI), 25% with FCB, vs. 39% with Flu-Bu (p = 0.018), offset by higher non-relapse mortality, 22.6% (95%CI: 16-30.2%) vs. 12.3% (95%CI: 6.5-19%). Three-year PFS was 52% (95%CI: 44-62%) (FCB), vs. 48% (95%CI: 41-58%) (Flu-Bu). FCB benefited CR patients less, NCR patients age ≤ 60 had 3-year 34% RI (95%CI: 19-49%) (FCB) vs. 56% (95%CI: 38-70%) after Flu-Bu (p = 0.037). NCR patients >60 years had 3-year RI 10.0% (FCB), vs. 56.0%, after Flu-Bu (p = 0.003). Bayesian regression analysis including treatment-covariate interactions showed FCB superiority in NCR patients with low HCT-CI (0-2). Serious adverse event profiles were similar for the regimens. Conditioning with FCB did not improve PFS overall, but improved disease control in NCR patients, mandating confirmatory trials. Remission status and HCT-CI should be considered when using FCB.
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http://dx.doi.org/10.1038/s41409-022-01705-7DOI Listing
May 2022

Real-World Evidence of Axicabtagene Ciloleucel for the Treatment of Large B Cell Lymphoma in the United States.

Transplant Cell Ther 2022 May 21. Epub 2022 May 21.

Medical College of Wisconsin/Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin. Electronic address:

Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) would have been ineligible for inclusion in the ZUMA-1 cohort. Efficacy and safety outcomes were described for the entire cohort and by ZUMA-1 eligibility. Their associations with age, Eastern Cooperative Oncology Group Performance Score, and comorbidities were evaluated using multivariable logistic and Cox regressions. At a median follow-up of 12.9 months, the overall response rate (ORR) was 73%, with a 56% complete response (CR) rate. Median overall survival (OS) and progression-free survival (PFS) were 21.8 months (95% confidence interval [CI], 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. Duration of response (DOR) was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients (62% by 1 year [95% CI, 57% to 66%] versus 67% [95% CI, 62% to 72%]). Patients age ≥65 years had favorable ORR (odds ratio [OR], 1.39; 95% CI, 1.05 to 1.83) despite having a higher risk of cytokine release syndrome (CRS) (OR, 1.41; 95% CI, 1.02 to 1.94) and immune effector cell-associated neurotoxicity syndrome (ICANS) (OR, 1.77; 95% CI, 1.39-2.26). Eastern Cooperative Oncology Group Performance Score ≥2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; 95% CI, 0.18-0.56; hazard ratio [HR] for OS, 3.27; 95% CI, 2.37 to 4.52) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93). The patients ineligible for ZUMA-1 still had a durable response with axi-cel. Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility.
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http://dx.doi.org/10.1016/j.jtct.2022.05.026DOI Listing
May 2022

Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma.

Transplant Cell Ther 2022 May 20. Epub 2022 May 20.

Department of Stem Cell Transplantation & Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) have disease that relapses. Allogeneic (allo-) hematopoietic cell transplantation (HCT) is a potentially curative option for a subgroup of patients with high-risk MM. This study assessed the long-term outcome of MM patients who underwent allo-HCT while in first remission as consolidation treatment. Thirty-three patients with newly diagnosed MM who underwent allo-HCT as part of consolidation therapy between 1994 and 2016 were reviewed retrospectively. Of these patients, 70% underwent autologous HCT before allo-HCT. All patients were chemosensitive and achieved at least partial response before proceeding to allo-HCT. Most received nonmyeloablative/reduced-intensity conditioning (88%) and a matched sibling donor graft (85%). Acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 30% and 61% of patients, respectively. The median duration of follow-up was 64.1 months (range, 1.4 to 199.2 months) for all patients and 164.4 months (range, 56.0 to 199.2 months) for survivors. The median progression-free survival (PFS) was 36 months (95% confidence interval (CI), 8.6 to 73.0 months). The median time from treatment to progression was 73.0 months (95% CI, 30.6 months to not reached). The median overall survival (OS) was 131.9 months (95% CI, 38.4 months to not reached). Of all patients, 39% were alive for more than 10 years, with 46% (n = 6) without progression or relapse. The cumulative incidence of relapse was 18% at 1 year, 39% at 5 years, and 46% at 10 years post-allo-HCT. The cumulative incidence of nonrelapse mortality was 3% at 100 days, 18% at 1 year, 21% at 3 years, and 24% at 5 year post-allo-HCT. On multivariable analysis, high-risk cytogenetics were associated with a shorter PFS (hazard ratio [HR], 2.7; 95% CI, 1.01 to 7.21; P = .047) and OS (HR, 4.91; 95% CI, 1.48 to 16.27; P = .009). Achieving complete remission after allo-HCT also was associated with longer PFS (HR, 0.24; 95% CI, 0.09 to 0.64; P = .004) and OS (HR, .23; 95% CI, .07 to .72; P = .012). Allo-HCT may confer a survival advantage in a selected population of MM patients when performed early in the disease course; additional data on identifying the patients who will benefit the most are needed.
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http://dx.doi.org/10.1016/j.jtct.2022.05.023DOI Listing
May 2022

Clonal hematopoiesis is associated with increased risk of severe neurotoxicity in axicabtagene ciloleucel therapy of large B-cell lymphoma.

Blood Cancer Discov 2022 May 9. Epub 2022 May 9.

The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

To explore the role of clonal hematopoiesis (CH) on chimeric antigen receptor (CAR) T therapy outcomes, we performed targeted deep-sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pre-treatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade {greater than or equal to}3 immune-effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, p=0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2 and ASXL1 genes (DTA mutations). Grade {greater than or equal to}3 ICANS (58.9% vs. 25%, p=0.02) and {greater than or equal to}3 cytokine release syndrome (17.7% vs. 4.2%, p=0.08) incidences were higher in DTA-positive than CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T therapy was higher in CH-positive than CH-negative patients (19% [95%CI: 5.5-38.7] vs. 4.2% [95%CI: 0.3-18.4], p=0.028).
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http://dx.doi.org/10.1158/2643-3230.BCD-21-0177DOI Listing
May 2022

Risk assessment with low pass whole genome sequencing of cell free DNA before CD19 CAR T-cells for large B-cell lymphoma.

Blood 2022 May 5. Epub 2022 May 5.

The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States.

Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low pass whole genome sequencing (lpWGS) of cell free DNA (cfDNA) prior to CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNA). In multivariable selection, high focal CNA score (FCS) denoting genomic instability was the most significant pretreatment variable associated with inferior 3-month complete response rates (28% versus 56%, p=0.0029), progression free survival (PFS) (p=0.0007, hazard ratio 2.11) and overall survival (OS) (p=0.0026, hazard ratio 2.10). We identified 34 unique focal CNAs in 108 (89%) patients; of these, deletion 10q23.3 leading to loss of FAS death receptor was the most prognostic for poor outcomes, leading to inferior PFS (p<0.0001, hazard ratio 3.49) and OS (p=0.0027, hazard ratio 2.68). By combining FCS with traditional markers of increased tumor bulk (elevated LDH and >1 extranodal sites), we built a simple risk model that could reliably risk stratify patients. Thus, lpWGS of cfDNA is a minimally invasive assay that could rapidly identify high-risk patients and may guide patient selection for and targeted therapies to evaluate in future clinical trials.
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http://dx.doi.org/10.1182/blood.2022015601DOI Listing
May 2022

A review of pathobiology and therapies for classic Hodgkin lymphoma.

Blood Rev 2022 Mar 25:100949. Epub 2022 Mar 25.

Department of Lymphoma/Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, 77030, TX, USA; Department of Stem Cell Transplant & Cellular Therapy, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, 77030, TX, USA. Electronic address:

Hodgkin lymphoma can be classified as classical Hodgkin lymphoma (cHL) based on the presence of hallmark Hodgkin and Reed-Sternberg cells. Through radiotherapy and modern chemotherapy, cHL has an impressive cure rate. We discuss normal B-cell maturation and the pathobiology of cHL, correlate significant cHL maturation steps with the sites of action of novel drugs, and highlight these drugs' efficacy in prior trials. In relapsed cHL, the approved agents brentuximab vedotin and immune checkpoint inhibitors have shown efficacy both alone and in combination with chemotherapy for salvage therapy, as maintenance after an autologous stem cell transplant, and after failure of this transplant. Chimeric antigen receptor T-cell therapy is being explored as a potential treatment option in relapsed/refractory cHL, and ongoing clinical trials show promising data without significant toxicity. We illustrate available novel therapeutic options and their efficacy in frontline and relapsed settings and discuss therapeutic benefit in relation to regimen toxicity.
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http://dx.doi.org/10.1016/j.blre.2022.100949DOI Listing
March 2022

Reappraising the Role of Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed and Refractory Hodgkin's Lymphoma: Recent Advances and Outcomes.

J Pers Med 2022 Jan 18;12(2). Epub 2022 Jan 18.

MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.

Hodgkin's lymphoma is a rare yet highly curable disease in the majority of patients treated with modern chemotherapy regimens. For patients who fail to respond to or relapse after initial systemic therapies, treatment with high-dose chemotherapy and autologous hematopoietic stem cell transplantation can provide a cure for many with chemotherapy-responsive lymphoma. Patients who relapse after autologous transplant or those with chemorefractory disease have poor prognosis and represent a high unmet need. Allogeneic hematopoietic stem cell transplantation provides a proven curative therapy for these patients and should be considered, especially in young and medically fit patients. The use of newer agents in this disease such as brentuximab vedotin and immune checkpoint inhibitors can help bring more patients to transplantation and should be considered as well.
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http://dx.doi.org/10.3390/jpm12020125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880200PMC
January 2022

Impact of conditioning regimen intensity on the outcomes of peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma patients undergoing allogeneic transplant.

Br J Haematol 2022 04 2;197(2):212-222. Epub 2022 Feb 2.

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

There have been no large studies comparing reduced-intensity/non-myeloablative conditioning (RIC/NMA) to myeloablative conditioning (MAC) regimens in T-cell non-Hodgkin lymphoma (T-NHL) patients undergoing allogeneic transplant (allo-HCT). A total of 803 adults with peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma (age 18-65 years), undergoing allo-HCT between 2008-2019 and reported to the Center for International Blood and Marrow Transplant Research with either MAC (n = 258) or RIC/NMA regimens (n = 545) were evaluated. There were no significant differences between the two cohorts in terms of patient sex, race and performance scores. Significantly more patients in the RIC/NMA cohort had peripheral blood grafts, haematopoietic cell transplantation-specific comorbidity index (HCT-CI) of ≥3 and chemosensitive disease compared to the MAC cohort. On multivariate analysis, overall survival (OS) was not significantly different in the RIC/NMA cohort compared to the MAC cohort (hazard ratio (HR) = 1.01, 95% confidence interval (CI) = 0.79-1.29; p = 0.95). Similarly, non-relapse mortality (NRM) (HR = 0.85, 95% CI = 0.61-1.19; p = 0.34), risk of progression/relapse (HR = 1.29; 95% CI = 0.98-1.70; p = 0.07) and therapy failure (HR = 1.14; 95% CI = 0.92-1.41, p = 0.23) were not significantly different between the two cohorts. Relative to MAC, RIC/NMA was associated with a significantly lower risk of grade 3-4 acute graft-versus-host disease (HR = 0.67; 95% CI = 0.46-0.99, p = 0.04). Among chemorefractory patients, there was no difference in OS, therapy failure, relapse, or NRM between RIC/NMA and MAC regimens. In conclusion, we found no association between conditioning intensity and outcomes after allo-HCT for T-cell NHL.
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http://dx.doi.org/10.1111/bjh.18052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018546PMC
April 2022

Outcomes Among Classical Hodgkin Lymphoma Patients After an Interim PET Scan: A Real-World Experience.

Clin Lymphoma Myeloma Leuk 2022 Jul 25;22(7):e435-e442. Epub 2021 Dec 25.

University of Tennessee Medical Center, Knoxville TN.

Introduction: The utility of dose escalation after positive positron emission tomography following 2 cycles of ABVD (PET2) for Hodgkin Lymphoma (HL) remains controversial. We describe the United States real-world practice patterns for PET2 positive patients.

Patients And Methods: Data was collected from 15 sites on PET2 positive HL patients after receiving frontline treatment between January, 2015 and June, 2019. Descriptive analyses between those with therapy change and those continuing initial therapy were assessed.

Results: A total of 129 patients were identified; 111 (86%) were treated with ABVD therapy and 18 (14%) with an alternate regimen. At PET2 assessment, 74.4% (96/129) had Deauville score (DS) 4 and 25.6% (33/129) had DS 5. Of the 66 limited stage (LS) patients with PET2 DS score of 4/5, 77.3% (51/66) continued initial therapy and 22.7% (15/66) changed to escalated therapy. The 12-month progression-free survival (PFS) for DS 4/5 LS patients was 67.0% (95% CI; 54.9-81.7) for patients without escalation compared with 51.4% (95% CI; 30.8-85.8) for those who escalated. Of the 63 DS 4/5 patients with advanced stage (AS) disease, 76.2% (48/63) continued initial therapy and 23.8% (15/63) changed to escalated therapy. The 12-month PFS for DS 4/5 AS patients was 38.3% (95% CI: 26.3%-55.7%) for patients without escalation compared with 57.1% (95% CI: 36.3-89.9) for those with escalation.

Conclusion: A minority of PET2 positive HL patients undergo therapy escalation and outcomes remain overall suboptimal. Improved prognostics markers and better therapeutics are required to improve outcomes for high-risk PET2 positive HL patients.
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http://dx.doi.org/10.1016/j.clml.2021.12.012DOI Listing
July 2022

Day 30 SUVmax predicts progression in patients with lymphoma achieving PR/SD after CAR T-cell therapy.

Blood Adv 2022 05;6(9):2867-2871

Department of Lymphoma and Myeloma.

About 70% of patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel) and who achieve a partial response (PR) or stable disease (SD) on the day 30 (D30) positron emission tomography (PET)-computed tomography (CT) scan progress; however, the factors that are predictive of progression are unknown. This a retrospective study of patients with LBCL who were treated with axi-cel at MD Anderson Cancer Center between January of 2018 and February of 2021. Among 50 patients with D30 PR/SD, 13 (26%) converted to a complete response (CR). Among 95 patients with a D30 CR, 72 (76%) remained in CR. On univariate analysis, the only day -5 characteristic associated with conversion from D30 PR/SD to subsequent CR was a higher platelet count (P = .05). The only D30 factor associated with conversion from D30 PR/SD to subsequent CR was a lower maximum standardized uptake volume (SUVmax; P < .001); all patients with D30 SUVmax ≥ 10 progressed. After a median follow-up of 12 months, no significant difference in median progression-free survival was observed between patients who converted from D30 PR/SD to subsequent CR and those who had been in CR since D30 (P = .19). Novel predictive and prognostic markers based on tissue biopsy and noninvasive diagnostic assays are needed to more effectively identify these patients and characterize the biology of their residual disease.
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http://dx.doi.org/10.1182/bloodadvances.2021006715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092420PMC
May 2022

Autologous stem cell transplantation for large B-cell lymphoma with secondary central nervous system involvement.

Blood Adv 2022 04;6(7):2267-2274

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX.

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare, with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression-free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 and 88 months, respectively. The 4-year PFS and OS were 48% and 57%, respectively. In univariate analysis, complete remission (CR) at transplant, prior lines of therapy (≤2), normal lactate dehydrogenase, and parenchymal involvement were significantly associated with improved PFS. For OS, only CR at transplant and ≤2 prior lines of therapy were associated with improved survival. On multivariable analysis for PFS, CR at transplant (hazard ratio [HR], 0.278; 95% CI, 0.153-0.506; P ≤ .0001) and ≤2 prior lines of therapy (HR, 0.485; 95% CI, 0.274-0.859; P = .0131) were significantly associated with superior PFS. Similarly, CR at transplant (HR, 0.352; 95% CI, 0.186-0.663; P = .0013) and ≤2 prior lines of therapy (HR, 0.476; 95% CI, 0.257-0.882; P = .0183) were associated with improved survival. In the largest single-center study, our findings indicate that ASCT is associated with durable responses and prolonged survival in patients with SCNSL. Patients in CR at transplant and those who received ≤2 lines of therapy have particularly excellent outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2021005602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006305PMC
April 2022

CAR-T in B-Cell Lymphomas: The Past, Present, and Future.

Clin Lymphoma Myeloma Leuk 2022 04 15;22(4):e261-e268. Epub 2021 Oct 15.

University of Texas MD Anderson Cancer Center, Houston, TX.

Aggressive B-cell lymphomas including diffuse large B-cell lymphoma make up the majority of non-Hodgkin's lymphoma globally. While more than half of these patients can be cured with modern chemoimmunotherapy regimens, the outcomes of relapsed or refractory disease continue to be very poor. Despite significant developments in targeted cancer therapies and immuno-oncology, the attainability of a cure remained an elusive goal outside of incorporating high doses of chemotherapy followed by hematopoietic stem cell transplantation, for patients who have chemosensitive disease. The development of chimeric antigen receptor T-cell therapy changed that paradigm and introduced a new field of therapeutic possibilities for these patients. In this review, we will discuss the current state of this therapeutic modality in B-cell lymphomas and provide opinions on where future efforts need to focus in order to further improve their clinical utility.
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http://dx.doi.org/10.1016/j.clml.2021.10.003DOI Listing
April 2022

Post-relapse survival in Waldenstrom macroglobulinemia patients experiencing therapy failure following autologous transplantation.

Hematol Oncol 2022 Feb 20;40(1):48-56. Epub 2021 Nov 20.

Division of Hematology, The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA.

Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative malignancy. Autologous hematopoietic cell transplantation (auto-HCT) is considered in a subset of WM patients with relapsed disease. While registry data has shown a benefit for auto-HCT in relapsed WM, there is a paucity of data on outcomes of patients relapsing after auto-HCT. Eligibility criteria included adult patients with relapsed/refractory WM who underwent auto-HCT between 2007 and 2017. The primary endpoint was post-relapse overall survival (PR-OS). Secondary endpoints were to identify factors prognostic of PR-OS. Of the 48 patients with WM who underwent auto-HCT, 22 (46%) experienced relapse following auto-HCT. Median PR-OS of relapsed WM patients after auto-HCT (n = 22) was not reached (NR) (95% confidence interval [CI]: 17.5 months-NR). Among patients who relapsed <1 year versus ≥1 year from auto-HCT, the median PR-OS was 18.4 months (95%CI: 0.8-NR) months and NR (95%CI: 17.5-NR), respectively (p = 0.06). Of note, disease status at the time of transplant, CR/VGPR versus partial remission did not appear to impact PR-OS. The median PR-OS was significantly longer in patients who received ibrutinib in the post-transplant setting compared to those who did not (NR vs. 18.4 months, 95%CI: 9.1-NR, p = 0.02). On univariable analysis, the presence of complex karyotype (RR = 4.87, 95% CI = 1.22-19.53) and a higher number of prior lines of therapy (RR = 1.81, 95% CI = 1.23-2.67) were associated with a significantly higher risk of relapse. This is the only study to date that evaluated outcomes of WM patients who relapsed following auto-HCT and provides a benchmark for future trials evaluating survival following auto-HCT relapse.
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http://dx.doi.org/10.1002/hon.2946DOI Listing
February 2022

Cardiovascular events in patients treated with chimeric antigen receptor T-cell therapy for aggressive B-cell lymphoma.

Haematologica 2022 Jul 1;107(7):1555-1566. Epub 2022 Jul 1.

Cardiology, MD Anderson Cancer Center, Houston.

Standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapies such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are associated with multisystem toxicities. There is limited information available about cardiovascular (CV) events associated with SOC axi-cel or tisa-cel. Patients with CV comorbidities, organ dysfunction, or lower performance status were often excluded in the clinical trials leading to their Food and Drug Adminsitration approval. An improved understanding of CV toxicities in the real-world setting will better inform therapy selection and management of patients receiving these cellular therapies. Here, we retrospectively reviewed the characteristics and outcomes of adult patients with relapsed/refractory large B-cell lymphoma treated with SOC axi-cel or tisa-cel. Among the 165 patients evaluated, 27 (16%) developed at least one 30-day (30-d) major adverse CV event (MACE). Cumulatively, these patients experienced 21 arrhythmias, four exacerbations of heart failure/cardiomyopathy, four cerebrovascular accidents, three myocardial infarctions, and one patient died due to myocardial infaction. Factors significantly associated with an increased risk of 30-d MACE included age ≥60 years, an earlier start of cytokine release syndrome (CRS), CRS ≥ grade 3, long duration of CRS, and use of tocilizumab. After a median follow-up time of 16.2 months (range, 14.3-19.1), the occurrence of 30-d MACE was not significantly associated with progression-free survival or with overall survival. Our results suggest that the occurrence of 30-d MACE is more frequent among patients who are elderly, with early, severe, and prolonged CRS. However, with limited follow-up, larger prospective studies are needed, and multidisciplinary management of these patients is recommended.
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http://dx.doi.org/10.3324/haematol.2021.280009DOI Listing
July 2022

Allogeneic transplant and CAR-T therapy after autologous transplant failure in DLBCL: a noncomparative cohort analysis.

Blood Adv 2022 01;6(2):486-494

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

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic model to CAR-T recipients. A total of 584 patients were included. The 1-year relapse, nonrelapse mortality, overall survival (OS), and progression-free survival for CAR-T treatment after autoHCT failure were 39.5%, 4.8%, 73.4%, and 55.7%, respectively. The corresponding rates in the alloHCT cohort were 26.2%, 20.0%, 65.6%, and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3%, respectively (P = .002). The corresponding rates for low-, intermediate-, and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (P < .001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in a subset of patients with DLBCL relapsing after a prior autoHCT. The simple CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high-risk patients.
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http://dx.doi.org/10.1182/bloodadvances.2021005788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791562PMC
January 2022

Allogeneic hematopoietic cell transplantation for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Bone Marrow Transplant 2022 01 11;57(1):51-56. Epub 2021 Oct 11.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, USA.

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematological malignancy; however, some patients achieve durable remission with allogeneic hematopoietic cell transplantation (allo-HCT). We report on all 17 patients with BPDCN who underwent allo-HCT at our center between 2000 and 2020. The median age was 39 (18-67) years. All (n = 16, 94%), except one patient, had systemic disease involving bone marrow and/or other organs. Ten patients (59%) were in first complete remission (CR1) at allo-HCT. The donor source was matched related or unrelated in ten (59%) and alternate donor in seven (41%) patients. Five (31%) patients developed acute graft-versus-host disease (GVHD), all grade I-II. The cumulative incidence (CI) of chronic GVHD at five-year was 34%. The CI of non-relapse mortality at one-year was 29%. Progression-free survival (PFS) rates at two-year and five-year were 49% (95% CI = 22-71%) and 39% (95% CI = 14-64%), respectively. The two-year and five-year overall survival (OS) rates were 65% (95% CI = 38-82%) and 40% (95% CI = 12-68%), respectively. The five-year rate for both PFS and OS was 80% in CR1 patients versus 0% in patients not in CR1. In conclusion, allo-HCT provides long-lasting remissions in BPDCN patients, particularly when performed in CR1.
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http://dx.doi.org/10.1038/s41409-021-01478-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9126091PMC
January 2022

The Unique Symptom Burden of Patients Receiving CAR T-Cell Therapy.

Semin Oncol Nurs 2021 12 7;37(6):151216. Epub 2021 Oct 7.

Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston.

Objectives: There is little research on the patient experience of symptom burden from CAR T-cell therapy, and no validated measure specific to the symptoms of CAR T-cell therapy currently exists. The purpose of this study was to identify symptoms experienced and to determine the content domain for a patient-reported outcome (PRO) measuring symptom burden for patients who had received standard of care CAR T-cell therapy for advanced B-cell lymphoid malignancies.

Data Sources: Semi-structured qualitative interviews were conducted with a sample of 21 patients who had received CAR T-cell therapy. Content analysis was used to define the symptom burden content domain.

Conclusion: Sixty-two percent of patients were interviewed within 3 months of therapy; 81.0% experienced cytokine release syndrome and 28.6% experienced neurotoxicity. Content analysis found 31 symptoms related to disease and treatment. The most common disease-related symptom identified by patients was pain (43%). The most common symptoms identified by patients as related to CAR T-cell therapy included fatigue (tiredness) (62%), lack of appetite (29%), headache (29%), chills or feeling cold (24%), and feeling confused (24%). The qualitative analysis also confirmed that symptoms interfere with daily activities, work, walking, relationships with others, mood, and enjoyment of life.

Implications For Nursing Practice: Patients who receive standard CAR T-cell therapy experience numerous symptoms related to disease and CAR T-cell therapy, including symptoms related to the T-cell infusion. Symptoms may result in interference with daily activities, relationships, treatment adherence, and mood. Oncology nurses should be aware of and assess symptom related to CAR T-cell therapy.
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http://dx.doi.org/10.1016/j.soncn.2021.151216DOI Listing
December 2021

Disparities in the long-term survival of adolescent and young adult diffuse large B cell lymphoma survivors.

Cancer Epidemiol 2021 12 28;75:102044. Epub 2021 Sep 28.

Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Purpose: The population of adolescent and young adult (AYA, ages 15-39 years) diffuse large B-cell lymphoma (DLBCL) survivors is growing, however long-term overall survival patterns and disparities are largely unknown.

Methods: The current study utilized the Surveillance, Epidemiology, and End Results (SEER) registry to assess the impact of race/ethnicity, sex, socioeconomic status, and rurality on long-term survival in 5-year DLBCL survivors using an accelerated failure time model.

Results: Included were 4767 5-year survivors of AYA DLBCL diagnosed between the years 1980 and 2009 with a median follow-up time of 13.4 years. Non-Hispanic Black survivors had significantly worse long-term survival than non-Hispanic White survivors (Survival Time Ratio (STR): 0.53, p < 0.0001). Male sex (STR: 0.57, p < 0.0001) and older age at diagnosis were also associated with reduced long-term survival. There was no evidence that survival disparities improved over time.

Conclusions: Racial disparities persist well into survivorship among AYA DLBCL survivors. Studies investigating specific factors associated with survival disparities are urgently needed to better address these disparities.
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http://dx.doi.org/10.1016/j.canep.2021.102044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627460PMC
December 2021

Increased Incidence of Human Papillomavirus-Related Precancer or Second Malignancy Among Allogeneic Stem Cell Transplantation Patients: A SEER-Medicare Population Study.

Transplant Cell Ther 2021 12 30;27(12):1016.e1-1016.e9. Epub 2021 Aug 30.

Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Each year, more than 8000 allogeneic stem cell transplantations (allo-SCT) are performed in the United States, with approximately 30% of these patients age ≥60 years. Allo-SCT recipients are at increased risk for developing human papillomavirus (HPV)-related precancer or second malignancy. It is important to evaluate HPV-related precancer or second malignancy among allo-SCT recipients to develop or enhance screening and preventive practice guidelines to improve patients' survival and quality of life. In this retrospective matched case-control study, we estimated the cumulative incidence of HPV-related precancer or second malignancy in both male and female Medicare beneficiaries who underwent allo-SCT and compared it with the cumulative incidence in non-SCT controls and noncancer controls. Hematologic cancer patients age ≥18 years who underwent allo-SCT between 2002 and 2011 were matched 1:5 to non-SCT controls and to noncancer controls by age, sex, race/ethnicity, and duration of follow-up. Proportions of HPV-related precancer or second malignancy were estimated and compared between cases and controls using the chi-square test and logistic regression. Kaplan-Meier cumulative incidences were estimated and compared using log-rank tests. We identified 700 allo-SCT cases (median age, 64 years; median follow-up post-transplantation, 4.3 years) matched with 3159 non-SCT controls and 3302 noncancer controls. Approximately 3.7% of allo-SCT cases developed HPV-related precancer or second malignancy post-transplantation, compared with 1.9% of the non-SCT controls and 1.1% of the noncancer controls. The odds ratio of developing HPV-related precancer or second malignancy of allo-SCT cases compared with non-SCT controls and noncancer controls was 2.0 (95% confidence interval [CI], 1.25 to 3.18) and 3.5 (95% CI, 2.1 to 5.8), respectively. Both allo-SCT cases and non-SCT controls had significantly higher proportions and odds of developing HPV-related precancer or second malignancy compared with noncancer controls. The 5-year cumulative incidence in allo-SCT cases was 5%, compared with 2.1% in non-SCT controls and 1.2% in noncancer controls. The cumulative incidence of HPV-related precancer or second malignancy was statistically significantly higher in the allo-SCT than in either of the 2 matched control groups, and the non-SCT controls had a higher cumulative incidence of HPV-related precancer or second malignancy than the noncancer controls. The allo-SCT cases were at increased risk of developing HPV-related precancer or second malignancy compared with the non-SCT controls and noncancer controls. Routine screening of HPV-related precancer or second malignancy in allo-SCT recipients is needed to help prevent HPV-related precancer or second malignancy. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8671185PMC
December 2021

American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma.

Transplant Cell Ther 2021 09;27(9):720-728

Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
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http://dx.doi.org/10.1016/j.jtct.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447221PMC
September 2021

ASTCT, CIBMTR, and EBMT clinical practice recommendations for transplant and cellular therapies in mantle cell lymphoma.

Bone Marrow Transplant 2021 12 20;56(12):2911-2921. Epub 2021 Aug 20.

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

Autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities for mantle cell lymphoma (MCL). Recently, chimeric antigen receptor (CAR) T-cell therapy received approval for MCL; however, its exact place and sequence in relation to HCT is unclear. The ASTCT, CIBMTR, and the EBMT, jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-, allo-HCT, and CAR T-cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated; in the first-line setting auto-HCT consolidation represents standard-of-care in eligible patients, whereas there is no clear role of allo-HCT or CAR T-cell therapy, outside of a clinical trial. In the R/R setting, the preferential option is CAR T-cell therapy especially in MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T-cell therapy has failed or is not feasible. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.
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http://dx.doi.org/10.1038/s41409-021-01288-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639670PMC
December 2021

Patient-Reported Symptom and Functioning Status during the First 12 Months after Chimeric Antigen Receptor T Cell Therapy for Hematologic Malignancies.

Transplant Cell Ther 2021 11 12;27(11):930.e1-930.e10. Epub 2021 Jul 12.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Chimeric antigen receptor (CAR) T cell therapy is being increasingly used to treat patients with advanced hematologic malignancies; however, the symptoms related to standard of care CAR T cell therapy during the first year after treatment have not been assessed using patient-reported outcome (PRO) measurements. This study aimed to quantify patients' perspectives of symptom burden and functional status using PROs during the first year after CAR T cell therapy for hematologic malignancies, especially in patients who experienced grade 2-4 toxicities. Sixty patients were enrolled in this observational cross-sectional study at any time during their first 12 months post-treatment. All 60 had received CAR T cell therapy as standard of care at MD Anderson Cancer Center in 2019. PROs were measured using the MD Anderson Symptom Inventory (MDASI), the PROs Measurement Information System 29 (PROMIS-29), the global health tool EQ5D-5L, and the single-item health-related quality of life scale (HRQoL). Twenty-two additional symptoms related to CAR T cell therapy, as identified by an expert panel, were also evaluated. CAR T cell therapy-related toxicities were rated according to the ASTCT consensus grading criteria. The majority of patients (52 of 60; 87%) received axicabtagene ciloleucel (Yescarta). One-third of the patients developed grade 2-4 cytokine release syndrome or neurotoxicity. The first 90 days after infusion represented the most symptomatic period, in which >10% of patients rated 18 symptoms as severe (ie, MDASI symptom score of 7 to 10 on scale of 0 to 10), strongly indicating the need for effective symptom management. Physical functioning, measured by interference on the "general activity" item on the MDASI and this domain on the PROMIS-29, were significantly worse in patients who underwent therapy during the first 30 days compared with those who underwent therapy over 90 days (all P < .05 with the Hochberg step-up procedure), whereas the EQ5D-5L and single-item HRQoL did not detect such differences. Compared with patients who had mild cytokine release syndrome or neurotoxicity (grade 0-1), patients who developed grade 2-4 toxicities persistently reported multiple severe symptoms after 30 days following therapy (all P < .05). Furthermore, although using a different recall period, patient-reported scores on several PROMIS-29 domains were significantly correlated with the scores of corresponding MDASI symptom items. This real-world quantitative PRO symptoms study provides evidence of unique profiles of the physical, psychological, and cognitive symptom burden in patients undergoing CAR T cell therapy that varies within the first year after infusion and demonstrates differences among PRO measurement scales. These results support the need for validation of fit-for-purpose PRO measurements for routinely monitoring symptom and toxicity burdens in CAR T cell therapy care settings.
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http://dx.doi.org/10.1016/j.jtct.2021.07.007DOI Listing
November 2021

CRP and ferritin in addition to the EASIX score predict CAR-T-related toxicity.

Blood Adv 2021 07;5(14):2799-2806

Department of Stem Cell Transplantation and Cellular Therapy.

The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study's objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T-related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.
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http://dx.doi.org/10.1182/bloodadvances.2021004575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341350PMC
July 2021

Impact of Race, Ethnicity, and Socioeconomic Status over Time on the Long-term Survival of Adolescent and Young Adult Hodgkin Lymphoma Survivors.

Cancer Epidemiol Biomarkers Prev 2021 09 8;30(9):1717-1725. Epub 2021 Jul 8.

Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Although there are growing numbers of adolescent and young adult (AYA) Hodgkin lymphoma (HL) survivors, long-term overall survival (OS) patterns and disparities in this population are underreported. The aim of the current study was to assess the impact of race/ethnicity, socioeconomic status (SES), rurality, diagnosis age, sex, and HL stage over time on long-term survival in AYA HL survivors.

Methods: The authors used the Surveillance, Epidemiology, and End Results (SEER) registry to identify survivors of HL diagnosed as AYAs (ages 15-39 years) between the years 1980 and 2009 and who were alive 5 years after diagnosis. An accelerated failure time model was used to estimate survival over time and compare survival between groups.

Results: There were 15,899 5-year survivors of AYA HL identified, with a median follow-up of 14.4 years and range up to 33.9 years from diagnosis. Non-Hispanic black survivors had inferior survival compared with non-Hispanic white survivors [survival time ratio (STR): 0.71, = 0.002]. Male survivors, older age at diagnosis, those diagnosed at higher stages, and those living in areas of higher SES deprivation had unfavorable long-term survival. There was no evidence of racial or sex-based survival disparities changing over time.

Conclusions: Racial, SES, and sex-based disparities persist well into survivorship among AYA HL survivors.

Impact: Disparities in long-term survival among AYA HL survivors show no evidence of improving over time. Studies investigating specific factors associated with survival disparities are needed to identify opportunities for intervention.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419153PMC
September 2021

Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma.

Nat Commun 2021 05 17;12(1):2877. Epub 2021 May 17.

Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and targeting BIRC5 results in marked tumor inhibition in preclinical models. In addition, we discover notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveals diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.
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http://dx.doi.org/10.1038/s41467-021-22872-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128874PMC
May 2021

Eltrombopag for Post-Transplantation Thrombocytopenia: Results of Phase II Randomized, Double-Blind, Placebo-Controlled Trial.

Transplant Cell Ther 2021 05 6;27(5):430.e1-430.e7. Epub 2021 Feb 6.

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Prolonged thrombocytopenia occurs in up to 37% of patients after hematopoietic stem cell transplantation (HSCT) and is associated with adverse prognosis and increased risk of bleeding. Eltrombopag, a thrombopoietin receptor agonist, can increase platelet counts in thrombocytopenic patients. We conducted a phase II study, adaptively randomizing patients at ≥35 days post-HSCT to receive placebo or eltrombopag at a platelet count ≤20,000/µL for 7 days or platelet transfusion-dependent and a neutrophil count ≥1500/µL. Sixty patients were randomized to eltrombopag (n = 42) or placebo (n = 18) and received at least 1 dose. Fifteen patients (36%) in the eltrombopag arm achieved a platelet count of ≥30,000/µL, compared with 5 patients (28%) in the placebo arm, with a posterior probability of 0.75. (The protocol required this probability to be >0.975 to declare a winner; thus, the results are inconclusive.) However, 9 patients (21%) in the eltrombopag arm achieved a platelet count of ≥50,000/µL, compared with no patients in the placebo arm (P = .046). The overall survival, progression-free survival, relapse rate, and nonrelapse mortality were similar in the 2 arms. In conclusion, compared with placebo, treatment with eltrombopag led to a higher percentage of patients achieving a platelet count of ≥50,000/µL in patients with persistent thrombocytopenia after HSCT.
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http://dx.doi.org/10.1016/j.jtct.2021.02.004DOI Listing
May 2021

Impact of Cell of Origin Classification on Survival Outcomes after Autologous Transplantation in Relapsed/Refractory Diffuse Large B Cell Lymphoma.

Transplant Cell Ther 2021 05 12;27(5):404.e1-404.e5. Epub 2021 Feb 12.

Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

The cell of origin (COO) classification into germinal center B cell (GCB) and non-GCB types has been shown to predict survival outcomes in newly diagnosed diffuse large B cell lymphoma (DLBCL). In the relapsed/refractory (R/R) setting, there is building evidence that COO does not predict prognosis after high-dose chemotherapy and autologous stem cell transplantation (auto-SCT). The present analysis aimed to compare survival outcomes based on COO classification in R/R DLBCL patients who underwent auto-SCT. This retrospective study included adult patients with R/R DLBCL who underwent auto-SCT at MD Anderson Cancer Center between January 2007 and December 2016. The Hans algorithm using CD10, BCL6, and MUM1 markers was used to classify patients by COO. A total of 122 patients with DLBCL (71 GCB, 51 non-GCB) were included in the analysis. There were no significant differences in patient characteristics between the 2 groups, except for older median age in the GCB cohort (64 years versus 58 years; P < .004). The median overall survival (OS) time was 68.5 (95% confidence interval [CI], 51.3 to not reached) months for the total population, 68.5 (95% CI, 44.8 to not reached) for GCB, and not reached for non-GCB. The 3-year OS rate was 0.659 (95% CI, 0.575 to 0.755) for the total population, 0.653 (95% CI, 0.547 to 0.779) for GCB, and 0.666 (95% CI, 0.537 to 0.824) for non-GCB. When adjusted for age and other factors of interest, no statistically significant associations for OS or progression-free survival were observed between the 2 cohorts. Our results confirm that COO loses its prognostic potential in patients with R/R DLBCL who receive high-dose chemotherapy followed by auto-SCT and both GCB and non-GCB types of DLBCL derive similar benefit from auto-SCT. Younger age, female sex, and pretransplantation disease status were associated with better OS.
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http://dx.doi.org/10.1016/j.jtct.2021.02.009DOI Listing
May 2021

Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant.

JAMA Oncol 2021 Jul;7(7):993-1003

Division of Blood & Marrow Transplantation, Stanford University, Stanford, California.

Importance: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens.

Objective: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM).

Design, Setting, And Participants: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021.

Interventions: Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65).

Main Outcomes And Measures: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival.

Results: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC.

Conclusions And Relevance: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.
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http://dx.doi.org/10.1001/jamaoncol.2021.1074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283558PMC
July 2021

Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis.

Haematologica 2022 04 1;107(4):899-908. Epub 2022 Apr 1.

Nuclear Medicine at the University of Texas MD Anderson Cancer Center.

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.
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http://dx.doi.org/10.3324/haematol.2021.278311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968895PMC
April 2022
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