Publications by authors named "Nancy L Bartlett"

196 Publications

Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study.

Lancet Haematol 2021 Oct 8. Epub 2021 Oct 8.

Weill Cornell Medicine, Meyer Cancer Center, New York, NY, USA.

Background: Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma.

Methods: We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m on day 1, intravenous etoposide 50 mg/m on days 1-4, oral prednisone 60 mg/m twice daily on days 1-5, intravenous vincristine 0·4 mg/m on days 1-4, intravenous cyclophosphamide 750 mg/m on day 5, and intravenous doxorubicin 10 mg/m on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed.

Findings: Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response.

Interpretation: Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448).

Funding: Genentech.
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http://dx.doi.org/10.1016/S2352-3026(21)00273-8DOI Listing
October 2021

CD3xCD20 bispecific T-cell redirectors for relapsed or refractory B-cell lymphoma.

Lancet 2021 Sep 8;398(10306):1109-1110. Epub 2021 Sep 8.

Department of Medicine, Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA.

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http://dx.doi.org/10.1016/S0140-6736(21)01070-9DOI Listing
September 2021

Comparison of 2-year outcomes with CAR T cells (ZUMA-1) versus salvage chemotherapy in refractory large B-cell lymphoma.

Blood Adv 2021 Sep 3. Epub 2021 Sep 3.

Hopital Saint-Louis, Paris, France.

The SCHOLAR-1 international retrospective study highlighted poor clinical outcomes and survival among patients with refractory large B-cell lymphoma (LBCL) treated with conventional chemotherapy. Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, demonstrated durable responses in patients with refractory LBCL in the pivotal phase 1/2 ZUMA-1 study (NCT02348216). Here, we compared SCHOLAR-1 with the 2 year outcomes of ZUMA-1. Prior to comparison of clinical outcomes, propensity scoring (based on a broad set of prognostic covariates) was used to create balance between ZUMA-1 and SCHOLAR-1 patients. In the pivotal phase 2 portion of ZUMA-1, 101 patients received axi-cel and were evaluable for response and survival. In SCHOLAR-1, 434 and 424 patients were evaluable for response and survival, respectively. ZUMA-1 patients were more heavily pretreated than SCHOLAR-1 patients. The median follow-up was 27.1 months in ZUMA-1. The objective response rate and complete response rate were 83% and 54% in ZUMA 1 vs 34% and 12% in SCHOLAR-1, respectively. The 2-year survival rate was 54% in ZUMA-1 and 20% in SCHOLAR-1, and a 73% reduction in the risk of death was observed in ZUMA-1 vs SCHOLAR-1. These results were consistent with those of an additional standardization analysis in which strata were limited to 2 prognostic factors (refractory categorization and presence/absence of stem cell transplant after refractoriness to chemotherapy) to conserve sample size. Despite the limitations of a nonrandomized analysis, these results indicate that axi-cel produces durable responses and a substantial survival benefit versus non-CAR T-cell salvage regimens for patients with refractory LBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020003848DOI Listing
September 2021

Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classical Hodgkin lymphoma.

Blood Adv 2021 Sep;5(18):3623-3632

Division of Hematology/Oncology, University of Virginia, Charlottesville, VA.

We performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale-Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.
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http://dx.doi.org/10.1182/bloodadvances.2021004645DOI Listing
September 2021

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL.

Blood 2021 Aug 24. Epub 2021 Aug 24.

Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, New York, United States.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated -year and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.
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http://dx.doi.org/10.1182/blood.2021011679DOI Listing
August 2021

Optimizing Second-Line Therapy for Hodgkin Lymphoma: A Work in Progress.

Authors:
Nancy L Bartlett

J Clin Oncol 2021 Oct 24;39(28):3097-3103. Epub 2021 Aug 24.

Washington University Medical Center, St Louis, MO.

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http://dx.doi.org/10.1200/JCO.21.01552DOI Listing
October 2021

Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma.

Br J Haematol 2021 Aug 22;194(4):690-700. Epub 2021 Jul 22.

University Medical Center Groningen, Groningen, Netherlands, on behalf of HOVON/PPLC.

ZUMA-1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi-cel), an autologous CD19-directed chimaeric antigen receptor (CAR)-T cell therapy, in refractory large B-cell lymphoma. To reduce treatment-related toxicity, several exploratory safety management cohorts were added to ZUMA-1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end-points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days -5 through -3), 2 × 10  CAR-T cells/kg (day 0) and once-daily oral dexamethasone [10 mg, day 0 (before axi-cel) through day 2]. Forty patients received axi-cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty-eight per cent of patients did not experience CRS or NEs within 72 h of axi-cel. With a median follow-up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.
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http://dx.doi.org/10.1111/bjh.17527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457222PMC
August 2021

Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202.

Leukemia 2021 Oct 17;35(10):2854-2861. Epub 2021 Jul 17.

Division of Hematology, The Ohio State University, Columbus, OH, USA.

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AE) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AE was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AE decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AE and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.
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http://dx.doi.org/10.1038/s41375-021-01342-xDOI Listing
October 2021

Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial.

Lancet Haematol 2021 Jun;8(6):e410-e421

University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

Background: Despite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population.

Methods: ECHELON-1 was an international, open-label, randomised, phase 3 trial done at 218 clinical sites, including hospitals, cancer centres, and community clinics, in 21 countries. Previously untreated patients (≥18 years with an Eastern Cooperative Oncology Group performance status of ≤2) with stage III or IV classical Hodgkin lymphoma were randomly assigned (1:1) to receive A+AVD (brentuximab vedotin, 1·2 mg/kg of bodyweight, doxorubicin 25 mg/m of body surface area, vinblastine 6 mg/m, and dacarbazine 375 mg/m) or ABVD (doxorubicin 25 mg/m, bleomycin 10 U/m, vinblastine 6 mg/m, and dacarbazine 375 mg/m) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Stratification factors included region (Americas vs Europe vs Asia) and International Prognostic Score risk group (low, intermediate, or high risk). The primary endpoint was modified progression-free survival; this 5-year update includes analysis of progression-free survival as per investigator assessment in the intention-to-treat population, which was an exploratory endpoint, although the 5-year analysis was not prespecified in the protocol. This trial is registered with ClinicalTrials.gov (NCT01712490) and EudraCT (2011-005450-60), and is ongoing.

Findings: Between Nov 19, 2012, and Jan 13, 2016, 1334 patients were randomly assigned to receive A+AVD (n=664) or ABVD (n=670). At a median follow-up of 60·9 months (IQR 52·2-67·3), 5-year progression-free survival was 82·2% (95% CI 79·0-85·0) with A+AVD and 75·3% (71·7-78·5) with ABVD (hazard ratio [HR] 0·68 [95% CI 0·53-0·87]; p=0·0017). Among PET-2-negative patients, 5-year progression-free survival was higher with A+AVD than with ABVD (84·9% [95% CI 81·7-87·6] vs 78·9% [75·2-82·1]; HR 0·66 [95% CI 0·50-0·88]; p=0·0035). 5-year progression-free survival for PET-2-positive patients was 60·6% (95% CI 45·0-73·1) with A+AVD versus 45·9% (32·7-58·2) with ABVD (HR 0·70 [95% CI 0·39-1·26]; p=0·23). Peripheral neuropathy continued to improve or resolve over time with both A+AVD (375 [85%] of 443 patients) and ABVD (245 [86%] of 286 patients); more patients had ongoing peripheral neuropathy in the A+AVD group (127 [19%] of 662) than in the ABVD group (59 [9%] of 659). Fewer secondary malignancies were reported with A+AVD (19 [3%] of 662) than with ABVD (29 [4%] of 659). More livebirths were reported in the A+AVD group (n=75) than in the ABVD group (n=50).

Interpretation: With 5 years of follow-up, A+AVD showed robust and durable improvement in progression-free survival versus ABVD, regardless of PET-2 status, and a consistent safety profile. On the basis of these findings, A+AVD should be preferred over ABVD for patients with previously untreated stage III or IV classical Hodgkin lymphoma.

Funding: Millennium Pharmaceuticals (a wholly owned subsidiary of Takeda Pharmaceutical Company), and Seagen.
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http://dx.doi.org/10.1016/S2352-3026(21)00102-2DOI Listing
June 2021

Survival after autologous versus allogeneic transplantation in patients with relapsed and refractory Hodgkin lymphoma.

Leuk Lymphoma 2021 May 14:1-8. Epub 2021 May 14.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

For relapsed Hodgkin lymphoma, salvage chemotherapy followed by auto-HCT is the standard of care. It is important to identify subpopulations who could benefit from allo-HCT. This retrospective analysis included 277 patients with rrHL who underwent first transplant with auto-HCT or allo-HCT between 2007-2017. Patients in the auto-HCT cohort ( = 218) were older, more likely to be in CR at the time of transplant and receive maintenance therapy post-transplant. Patients who underwent allo-HCT ( = 59) had a higher MSKCC relapse score. Factors associated with an inferior PFS and OS included early relapse, advanced stage, extranodal involvement and not achieving CR following salvage chemotherapy. After controlling for these 4 risk factors and MSKCC score, PFS ( = 0.112) or OS ( = 0.256) was not affected by the choice of transplant. In patients with ≥ 3 high risk features, the 4-year PFS was 51% in the allo-HCT vs. 39% ( = 0.107) in the auto-HCT cohort.
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http://dx.doi.org/10.1080/10428194.2021.1927016DOI Listing
May 2021

Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma.

Clin Cancer Res 2021 Jun 8;27(12):3339-3350. Epub 2021 Apr 8.

Washington University School of Medicine, St. Louis, Missouri.

Purpose: N-803 is an IL15 receptor superagonist complex, designed to optimize persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8 T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously.

Patients And Methods: Relapsed/refractory patients with indolent non-Hodgkin lymphoma were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase I study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression.

Results: This immunotherapy combination was safe and well tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Furthermore, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes.

Conclusions: N-803 combines with mAbs to enhance tumor targeting in patients, and warrants further investigation in combination with immunotherapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197753PMC
June 2021

Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results.

Blood 2021 Aug;138(6):427-438

City of Hope National Medical Center, Duarte, CA.

This phase 1-2 study evaluated brentuximab vedotin (BV) combined with nivolumab (Nivo) as first salvage therapy in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In parts 1 and 2, patients received staggered dosing of BV and Nivo in cycle 1, followed by same-day dosing in cycles 2 to 4. In part 3, both study drugs were dosed, same day, for all 4 cycles. At end of study treatment, patients could undergo autologous stem cell transplantation (ASCT) per investigator discretion. The objective response rate (ORR; N = 91) was 85%, with 67% achieving a complete response (CR). At a median follow-up of 34.3 months, the estimated progression-free survival (PFS) rate at 3 years was 77% (95% confidence interval [CI], 65% to 86%) and 91% (95% CI, 79% to 96%) for patients undergoing ASCT directly after study treatment. Overall survival at 3 years was 93% (95% CI, 85% to 97%). The most common adverse events (AEs) prior to ASCT were nausea (52%) and infusion-related reactions (43%), all grade 1 or 2. A total of 16 patients (18%) had immune-related AEs that required systemic corticosteroid treatment. Peripheral blood immune signatures were consistent with an activated T-cell response. Median gene expression of CD30 in tumors was higher in patients who responded compared with those who did not. Longer-term follow-up of BV and Nivo as a first salvage regimen shows durable efficacy and impressive PFS, especially in patients who proceeded directly to transplant, without additional toxicity concerns. This trial was registered at www.clinicaltrials.gov as #NCT02572167.
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http://dx.doi.org/10.1182/blood.2020009178DOI Listing
August 2021

Protect our children: Hodgkin lymphoma survivors.

Authors:
Nancy L Bartlett

Blood 2021 03;137(11):1433-1434

Washington University School of Medicine.

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http://dx.doi.org/10.1182/blood.2020010320DOI Listing
March 2021

Approaches to aggressive B-cell lymphomas in less fit patients.

Authors:
Nancy L Bartlett

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):140-147

Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO.

Treating unfit patients with aggressive B-cell lymphoma poses the dilemma of balancing potential cure while minimizing toxicity because of frailty and comorbidities. Age greater than 80 years and common comorbidities such as cardiovascular disease and poorly controlled diabetes mellitus often preclude the use of full-dose anthracyclines and steroids, the backbones of standard regimens for aggressive B-cell lymphomas. Assessing patient fitness remains subjective, with no consensus on best practice or how to integrate assessment tools into decision making. Incorporation of prephase steroids for all unfit patients may markedly improve performance status with consideration of standard dose therapy, especially in patients less than age 80. Although randomized studies are lacking, current data suggest patients age ≥ 80 years are considered unfit a priori and should receive dose-reduced anthracycline regimens or anthracycline-free regimens. Severe toxicity is highest after the first cycle of chemotherapy. Dose reductions for cycle 1 in unfit patients with plans to escalate as tolerated is often an effective strategy. Unfit patients often benefit from comanagement with gerontologists, cardio-oncologists, and endocrinologists depending on age and the nature of comorbidities. Palliative therapy for patients with newly diagnosed aggressive B-cell lymphoma results in median survivals of less than 3 months, and in general, should only be considered in patients with untreatable comorbidities such as advanced dementia or refractory metastatic solid tumors. Incorporating new, potentially less toxic agents such as novel antibodies, antibody-drug conjugates, and bispecific antibodies into first-line therapy is an exciting future direction with potential for substantial benefit in less fit patients.
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http://dx.doi.org/10.1182/hematology.2020000099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727524PMC
December 2020

Biomarkers for Risk Stratification in Patients With Previously Untreated Follicular Lymphoma Receiving Anti-CD20-based Biological Therapy.

Am J Surg Pathol 2021 03;45(3):384-393

Cleveland Clinic, Cleveland, OH.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti-CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.
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http://dx.doi.org/10.1097/PAS.0000000000001609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878306PMC
March 2021

CAR-T therapy in solid organ transplant recipients with treatment refractory posttransplant lymphoproliferative disorder.

Am J Transplant 2021 02 5;21(2):809-814. Epub 2020 Dec 5.

Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Chimeric antigen receptor T cells (CAR-T) are genetically modified T cells with a chimeric antigen receptor directed against a specific tumor-associated antigen like CD19 in lymphoma. CAR-T cells have shown encouraging activity against recurrent and refractory diffuse large B cell lymphomas (DLBCL). However concurrent use of immunosuppressive agents was prohibited in most CAR-T trials effectively excluding patients with prior solid organ transplantation (SOT) and posttransplant lymphoproliferative disorders (PTLD). We report the outcomes for three patients with PTLD refractory to immunochemotherapy 10-20 years after SOT who received CAR-T therapy between January 2018 and December 2019. One patient had an orthotopic heart transplant, the second had a deceased donor kidney transplant, and the third had a pancreas after kidney transplant (PAK). All patients developed complications of CAR-T therapy such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and acute kidney injury requiring renal replacement therapy in the two out of three patients. All patients expired after withdrawal of care due to lack of response to CAR-T therapy. In addition, the PAK patient developed acute pancreatitis after CAR-T therapy. This case series identifies the challenges of using CAR-T therapy to manage refractory PTLD in SOT recipients and its possible complications.
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http://dx.doi.org/10.1111/ajt.16367DOI Listing
February 2021

A forgotten friend: CCNU as palliative monotherapy in relapsed Hodgkin lymphoma.

Leuk Lymphoma 2021 02 8;62(2):486-488. Epub 2020 Oct 8.

Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO.

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http://dx.doi.org/10.1080/10428194.2020.1830391DOI Listing
February 2021

Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial.

Lancet Haematol 2020 Nov 1;7(11):e808-e815. Epub 2020 Oct 1.

Division of Medical Oncology, Department of Medicine, Mayo Clinic Rochester, Rochester, MN, USA.

Background: Hodgkin lymphoma is potentially curable. However, 15-35% of older patients (ie, >60 years) have a lower response rate, worse survival outcomes, and greater toxicity than younger patients. Brentuximab vedotin and nivolumab exhibit activity in patients with relapsed or refractory Hodgkin lymphoma. We therefore aimed to evaluate the safety and efficacy of brentuximab vedotin and nivolumab in untreated older patients with Hodgkin lymphoma or in younger patients considered unsuitable for standard ABVD (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy.

Methods: We did a multicentre, single-arm, phase 2 trial at eight cancer centres in the USA. Previously untreated patients with classic Hodgkin lymphoma were eligible for study enrolment if they were 60 years or older, or younger than 60 years but considered unsuitable for standard chemotherapy because of a cardiac ejection fraction of less than 50%, pulmonary diffusion capacity of less than 80%, or a creatinine clearance of 30 mL/min or more but less than 60 mL/min, or those who refused chemotherapy. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received brentuximab vedotin at 1·8 mg/kg (dose cap at 180 mg) and nivolumab at 3 mg/kg both intravenously every 21 days for 8 cycles. The primary endpoint was the overall response, defined as a partial metabolic response or complete metabolic response at the end of 8 cycles of treatment. A per protocol analysis was done including all patients who received treatment in the activity and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02758717.

Findings: Between May 13, 2016, and Jan 30, 2019, the study accrued 46 patients. The median age was 71·5 years (IQR 64-77), with two (4%) of 46 patients younger than 60 years. Median follow-up was 21·2 months (IQR 15·6-29·9), and 35 (76%) of 46 patients completed all 8 cycles of therapy. At the interim analysis on Oct 11, 2019, the first 25 evaluable patients had an overall response rate of 64% ([95% CI 43-82] 16 of 25 patients; 13 [52%] had a complete metabolic response and three [12%] had a partial metabolic response). The trial was closed to accrual on Oct 14, 2019, after the interim analysis failed to meet the predefined criteria. In all 46 evaluable patients, 22 (48%) patients achieved a complete metabolic response and six (13%) achieved a partial metabolic response (overall response rate 61% [95% CI 45-75]). 14 (30%) of 46 patients had 16 dose adjustments, primarily due to neurotoxicity. 22 (48%) of 46 patients had peripheral neuropathy (five [11%] patients had grade 3 peripheral neuropathy). Grade 4 adverse events included increased aminotranferases (one [2%] of 46), increased lipase or amylase (two [4%]), and pancreatitis (one [2%]). One (2%) patient died from cardiac arrest, possibly treatment related.

Interpretation: Although the trial did not meet the prespecified activity criteria, brentuximab vedotin plus nivolumab is active in older patients with previously untreated Hodgkin lymphoma with comorbidities. The regimen was also well tolerated in the majority of patients in this older population. Future trials should be based on optimising the dose and schedule, perhaps combined with other targeted agents that might permit chemotherapy-free strategies in older patients with Hodgkin lymphoma.

Funding: Seattle Genetics and Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S2352-3026(20)30275-1DOI Listing
November 2020

A Pilot Study of Lenalidomide Maintenance Therapy after Autologous Transplantation in Relapsed or Refractory Classical Hodgkin Lymphoma.

Biol Blood Marrow Transplant 2020 12 20;26(12):2223-2228. Epub 2020 Aug 20.

Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212249PMC
December 2020

Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma.

Leuk Lymphoma 2020 12 6;61(13):3188-3197. Epub 2020 Aug 6.

Department I of Internal Medicine and German CLL Study Group, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.

We report final analysis outcomes from the phase 3 HELIOS study (NCT01611090). Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma without deletion 17p ( = 578) were randomized 1:1 to 420 mg daily ibrutinib or placebo plus ≤6 cycles of bendamustine plus rituximab (BR), followed by ibrutinib or placebo alone. Median follow-up was 63.7 months. Median investigator-assessed progression-free survival was longer with ibrutinib plus BR (65.1 months) than placebo plus BR (14.3 months; hazard ratio [HR] 0.229 [95% confidence interval (CI) 0.183-0.286];  < .0001). Despite crossover of 63.3% of patients from the placebo plus BR arm to ibrutinib treatment upon disease progression, ibrutinib plus BR versus placebo plus BR demonstrated an overall survival benefit (HR 0.611 [95% CI 0.455-0.822];  = .0010; median not reached in either arm). Long-term follow-up data confirm the survival benefit of ibrutinib plus BR over BR alone. Safety profiles were consistent with those known for ibrutinib and BR.
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http://dx.doi.org/10.1080/10428194.2020.1795159DOI Listing
December 2020

A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma.

Blood 2020 11;136(21):2401-2409

Division of Hematology, Mayo Clinic, Rochester, MN.

In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/R HL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation. This phase 1b study was registered at www.clinicaltrials.gov as NCT02665650.
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http://dx.doi.org/10.1182/blood.2019004701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685206PMC
November 2020

Hodgkin lymphoma.

Nat Rev Dis Primers 2020 07 23;6(1):61. Epub 2020 Jul 23.

Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.

Hodgkin lymphoma (HL) is a B cell lymphoma characterized by few malignant cells and numerous immune effector cells in the tumour microenvironment. The incidence of HL is highest in adolescents and young adults, although HL can affect elderly individuals. Diagnosis is based on histological and immunohistochemical analyses of tissue from a lymph node biopsy; the tissue morphology and antigen expression profile enable classification into one of the four types of classic HL (nodular sclerosis, mixed cellularity, lymphocyte-depleted or lymphocyte-rich HL), which account for the majority of cases, or nodular lymphocyte-predominant HL. Although uncommon, HL remains a crucial test case for progress in cancer treatment. HL was among the first systemic neoplasms shown to be curable with radiation therapy and multiagent chemotherapy. The goal of multimodality therapy is to minimize lifelong residual treatment-associated toxicity while maintaining high levels of effectiveness. Recurrent or refractory disease can be effectively treated or cured with high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation, and prospective trials have demonstrated the potency of immunotherapeutic approaches with antibody-drug conjugates and immune checkpoint inhibitors. This Primer explores the wealth of information that has been assembled to understand HL; these updated observations verify that HL investigation and treatment remain at the leading edge of oncological research.
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http://dx.doi.org/10.1038/s41572-020-0189-6DOI Listing
July 2020

Positron Emission Tomography-Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001.

J Clin Oncol 2020 09 13;38(26):3003-3011. Epub 2020 Jul 13.

Division of Hematology/Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY.

Purpose: Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)-directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity.

Methods: Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy.

Results: Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes.

Conclusion: To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
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http://dx.doi.org/10.1200/JCO.20.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479758PMC
September 2020

CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas.

Blood 2020 11;136(20):2308-2318

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.

Natural killer (NK) cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with interleukin-12 (IL-12), IL-15, and IL-18, exhibit potent antitumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CARs) have been used to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that ML differentiation and CAR engineering would result in complementary improvements in NK cell responses against NK-resistant cancers. To test this idea, peripheral blood ML NK cells were modified to express an anti-CD19 CAR (19-CAR-ML), which displayed significantly increased interferon γ production, degranulation, and specific killing against NK-resistant lymphoma lines and primary targets compared with nonspecific control CAR-ML NK cells or conventional CAR NK cells. The 19-CAR and ML responses were synergistic and CAR specific and required immunoreceptor tyrosine-based activation motif signaling. Furthermore, 19-CAR-ML NK cells generated from lymphoma patients exhibited improved responses against their autologous lymphomas. 19-CAR-ML NK cells controlled lymphoma burden in vivo and improved survival in human xenograft models. Thus, CAR engineering of ML NK cells enhanced responses against resistant cancers and warrants further investigation, with the potential to broaden ML NK cell recognition against a variety of NK cell-resistant tumors.
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http://dx.doi.org/10.1182/blood.2020006619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702478PMC
November 2020

Polatuzumab vedotin for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma.

Expert Opin Biol Ther 2021 Jul 15;21(7):831-839. Epub 2020 Jun 15.

Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.

Introduction: Polatuzumab vedotin is an antibody-drug conjugate comprised of an anti-CD79b monoclonal antibody conjugated to monomethyl auristatin (MMAE), a microtubule-disrupting cytotoxin. CD79b is almost exclusively expressed on normal and malignant B-cells, making it an appealing target for novel therapeutics.

Areas Covered: This article reviews the current literature on polatuzumab vedotin, including its pharmacology, as well as summarizing the results of clinical trials in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) as a single agent and in combination with other chemotherapies and chemoimmunotherapies. The current landscape of approved therapies for relapsed and refractory DLBCL, as well as other promising novel approaches, is discussed.

Expert Opinion: The recent approval of polatuzumab vedotin in combination with bendamustine and rituximab (BR) offers another option to patients with DLBCL who are not eligible for autologous hematopoietic cell transplant or chimeric antigen receptors (CAR)-T cell therapy. In younger patients and those without serious comorbidities, polatuzumab vedotin-BR may serve as bridging therapy to more intensive therapies with reasonable efficacy and tolerability. Polatuzumab vedotin is currently being studied in a randomized trial in the front line setting in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).
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http://dx.doi.org/10.1080/14712598.2020.1777979DOI Listing
July 2021

Longitudinal Toxicity over Time (ToxT) analysis to evaluate tolerability: a case study of lenalidomide in the CALGB 50401 (Alliance) trial.

Lancet Haematol 2020 Jun;7(6):e490-e497

Alliance Statistics and Data Center, Mayo Clinic, Scottsdale, AZ, USA.

Evaluation of tolerability is increasingly relevant for patients with haematological malignancies treated with chronically administered therapies. Adverse events from these agents might affect the ability of patients to tolerate treatment over time. Conventional toxicity tables that include the incidence of high-grade adverse events, defined by the Common Terminology Criteria for Adverse Events, do not provide information on the time profile of these adverse events or reflect the continuous, lower grade symptomatic toxicities that are particularly relevant to treatment tolerability for patients living with indolent disease. Modern approaches to the evaluation and reporting of toxicity that capture the tolerability of treatment to the patient are imperative. In this Viewpoint, we present a focused, pilot, and longitudinal Toxicity over Time analysis of adverse events from lenalidomide and lenalidomide with rituximab in patients with follicular lymphoma treated in the CALGB 50401 (Alliance; NCT00238238) trial to define the trajectory of adverse events and quantify the burden of continuous, low-grade events. Toxicity over Time analyses provided clinically relevant descriptions of neutropenia and fatigue trajectories caused by lenalidomide that were not identified by standard analysis of the maximum grade events defined by the Common Terminology Criteria for Adverse Events. Systematic, rigorous incorporation of patient-reported outcomes in clinical trials will be crucial to our understanding of the tolerability of chronically administered therapies in patients with haematological malignancies.
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http://dx.doi.org/10.1016/S2352-3026(20)30067-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457391PMC
June 2020

Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.

J Clin Oncol 2020 08 26;38(22):2519-2529. Epub 2020 May 26.

Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD.

Purpose: Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma.

Methods: We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS).

Results: Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare.

Conclusion: Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).
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http://dx.doi.org/10.1200/JCO.20.00303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392744PMC
August 2020

Potential impact of consolidation radiation therapy for advanced Hodgkin lymphoma: a secondary analysis of SWOG S0816.

Leuk Lymphoma 2020 10 26;61(10):2442-2447. Epub 2020 May 26.

Department of Medicine, Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA.

The role of radiotherapy (RT) in the management of advanced Hodgkin Lymphoma (HL) is inadequately defined in this era of functional imaging with PET scan. SWOG-S0816 treated advanced stage Hodgkin lymphoma patients with ABVD+/- escBEACOPP and no RT. We queried whether RT might have benefited patients in S0816 who would have met the GHSG-HD15 criteria for RT by simulating RT use as per HD15 criteria of PET + residual disease ≥2.5 cm. Receiver-operating-characteristics analyses were performed by varying disease-control rates within radiation fields and size cutoffs for residual disease. Among the 49 PET3+ S0816 patients, RT would have raised the 2-year PFS from 30.6% to 50.2-58.1% using three residual disease cutoffs (1.5, 2.0 and 2.5 cm) and assuming 80 and 90% in-field control rates . Although there may be improvement in PFS as size cutoff point is lowered, consequential toxicities from RT require further definition to assess relative benefits.
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http://dx.doi.org/10.1080/10428194.2020.1768388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704391PMC
October 2020

Diffuse Telangiectatic Rash Associated With Novel Antibody Drug Conjugate Therapies.

JAMA Dermatol 2020 05;156(5):601-603

Division of Dermatology, Washington University in St Louis, St Louis, Missouri.

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http://dx.doi.org/10.1001/jamadermatol.2020.0208DOI Listing
May 2020

Prognostic value of interim FDG-PET in diffuse large cell lymphoma: results from the CALGB 50303 Clinical Trial.

Blood 2020 06;135(25):2224-2234

Department Medicine, Washington University School of Medicine, St. Louis, MO.

As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.
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http://dx.doi.org/10.1182/blood.2019003277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316220PMC
June 2020
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