Publications by authors named "Jonathan W Friedberg"

226 Publications

SWOG 1918: A phase II/III randomized study of R-miniCHOP with or without oral azacitidine (CC-486) in participants age 75 years or older with newly diagnosed aggressive non-Hodgkin lymphomas - Aiming to improve therapy, outcomes, and validate a prospective frailty tool.

J Geriatr Oncol 2021 Oct 19. Epub 2021 Oct 19.

University of Chicago, Chicago, IL, USA.

Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75 years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgo.2021.10.003DOI Listing
October 2021

Association of Treatment Intensity With Survival in Older Patients With Hodgkin Lymphoma.

JAMA Netw Open 2021 Oct 1;4(10):e2128373. Epub 2021 Oct 1.

Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts.

Importance: Hodgkin lymphoma is an aggressive blood cancer that is highly curable in younger patients who receive multiagent chemotherapy. Worse survival in older patients may reflect less-aggressive treatment, competing risks of death, or different disease biological factors.

Objective: To examine the association between treatment intensity and cause-specific mortality among older adults with Hodgkin lymphoma.

Design, Setting, And Participants: This was a population-based cohort study of patients aged 65 years or older with Medicare Part A and B fee-for-service coverage who received a diagnosis of Hodgkin lymphoma from 2000 to 2013. The association between treatment intensity and cause-specific mortality was estimated separately for early-stage and advanced-stage disease with Cox proportional hazards models. Multivariable adjustment and propensity score weighting helped control for confounding. Data are from the 1999 to 2016 Surveillance, Epidemiology, and End Results Medicare database. Data analysis was performed from April 2020 to June 2021.

Exposures: First-line treatment categorized as (1) full chemotherapy regimen, (2) partial chemotherapy regimen, (3) single chemotherapy agent or radiotherapy, or (4) no treatment.

Main Outcomes And Measures: The main outcome was 3-year Hodgkin lymphoma-specific and other-cause mortality.

Results: Among 2686 patients (mean [SD] age, 75.7 [6.9] years; 1333 men [50%]), 1307 had early-stage disease and 1379 had advanced-stage disease. For Hodgkin lymphoma-specific mortality in patients with early-stage disease, hazard ratios (HRs) were higher for partial regimens (HR, 1.77; 95% CI, 1.22-2.57) or no treatment (HR, 1.91; 95% CI, 1.31-2.79) than for full regimens; there was no difference between single-agent chemotherapy or radiotherapy and full regimens. For other-cause mortality in patients with early-stage disease, HRs were higher for partial regimens (HR, 1.69; 95% CI, 1.18-2.44), single-agent chemotherapy or radiotherapy (HR, 1.62; 95% CI, 1.13-2.33), or no treatment (HR, 2.71; 95% CI, 1.95-3.78) than for full regimens. For Hodgkin lymphoma-specific mortality in patients with advanced-stage disease, HRs were higher for partial regimens (HR, 3.26; 95% CI, 2.44-4.35), single-agent chemotherapy or radiotherapy (HR, 2.85; 95% CI, 1.98-4.11), or no treatment (HR, 4.06; 95% CI, 3.06-5.37) than for full regimens. For other-cause mortality in patients with advanced-stage disease, HRs were higher for partial regimens (HR, 1.76; 95% CI, 1.32-2.33), single-agent chemotherapy or radiotherapy (HR, 1.65; 95% CI, 1.15-2.37), or no treatment (HR, 2.24; 95% CI, 1.71-2.94) than for full regimens.

Conclusions And Relevance: This cohort study found variability in the magnitude of the association between treatment intensity and mortality by stage and cause-specific mortality, possibly reflecting competing risks of death. However, full chemotherapy regimens were associated with lower mortality and could be considered for older adults who can tolerate them.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2021.28373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531990PMC
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 Aug 20. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-021-01288-9DOI Listing
August 2021

Development and validation of a prediction model for 1-year mortality among older adults with Hodgkin Lymphoma who receive dose-intense chemotherapy.

J Geriatr Oncol 2021 Nov 28;12(8):1233-1239. Epub 2021 Jul 28.

Institute for Clinical Research & Health Policy Studies, Tufts Medical Center, Boston, MA, United States of America; Division of Hematology/Oncology, Tufts Medical Center, Boston, MA, United States of America; Department of Medicine and Pediatrics, Tufts University School of Medicine, Boston, MA, United States of America.

Background: Older adults with Hodgkin Lymphoma (HL) have poorer outcomes than younger patients. There are little data about which baseline patient and disease factors inform prognosis among older patients. We sought to create a prediction model for 1-year mortality among older patients with new HL who received dose-intense chemotherapy.

Methods: We included adults ≥65 years old with a new diagnosis of classical HL between 2000-2013 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset who received full-regimen chemotherapy. Through a non-random 2:1 split, we created development and validation cohorts. Multiple imputation was used for missing data. Using stepwise selection and logistic regression, we identified predictive variables for 1-year mortality. The model was applied to the validation cohort. A final model was then fit in the full cohort.

Results: We included 1315 patients. In the development cohort (n = 813), we identified significant predictors of 1-year mortality including age, Charlson comorbidity index (CCI), B symptoms at diagnosis, and advanced stage at diagnosis. The c-statistic was 0.70. When this model was applied to the validation cohort (n = 502), the c-statistic was 0.65. Predictors of 1-year mortality in the final model were CCI (OR = 1.41), B symptoms (OR = 1.54), advanced stage (OR = 1.44), and older age at diagnosis (OR = 1.33).

Conclusion: We present a prediction model for use among older adults with HL who receive intensive chemotherapy. We identify risk factors for death within 1 year of diagnosis. Future work will build upon prognostication and shared decision-making after diagnosis for this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgo.2021.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557127PMC
November 2021

An Oncology Renaissance.

J Clin Oncol 2021 09 16;39(25):2737-2738. Epub 2021 Jul 16.

Wilmot Cancer Institute, Rochester, NY.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.01649DOI Listing
September 2021

A phase 3, randomized study of ofatumumab combined with bendamustine in rituximab-refractory iNHL (COMPLEMENT A + B study).

Br J Haematol 2021 06 10;193(6):1123-1133. Epub 2021 May 10.

Wilmot Cancer Institute, University of Rochester Medical Centre, Rochester, NY, USA.

The standard of care for indolent non-Hodgkin lymphoma (iNHL) is rituximab, an anti-CD20 antibody, with/without chemotherapy. However, multiple relapses are common in these patients. This phase 3, randomized study compared outcomes of a combination of ofatumumab (a second-generation anti-CD20 antibody) and bendamustine, with bendamustine alone in patients unresponsive to prior rituximab-based treatment. Overall, 346 patients were randomized to receive either the combination or bendamustine alone. Bendamustine was given for ≤8 cycles and ofatumumab for ≤12 cycles. The primary end-point was progression-free survival (PFS) after 215 protocol-defined events assessed by independent review committee (IRC). Median IRC-assessed PFS was 16·7 and 13·8 months in the combination and monotherapy arms respectively [hazard ratio (HR) = 0·82; P = 0·1390]. Median overall survival (OS) was 58·2 and 51·8 months in the combination and monotherapy arms respectively (HR = 0·89, P = 0·4968). The safety profile was consistent with previous reports. Overall, 73% and 80% of patients in the combination and monotherapy arms, respectively, experienced a ≥grade 3 adverse event. The study did not meet its primary end-point. No significant improvement in PFS and OS was seen with the combination of ofatumumab and bendamustine as compared with bendamustine alone in rituximab-refractory iNHL (NCT01077518).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17420DOI Listing
June 2021

Brentuximab Vedotin Combined With Chemotherapy in Patients With Newly Diagnosed Early-Stage, Unfavorable-Risk Hodgkin Lymphoma.

J Clin Oncol 2021 07 28;39(20):2257-2265. Epub 2021 Apr 28.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma.

Methods: In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4-negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4.

Results: Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering-defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible.

Conclusion: BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4-negative patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00108DOI Listing
July 2021

Addition of Lenalidomide to R-CHOP Improves Outcomes in Newly Diagnosed Diffuse Large B-Cell Lymphoma in a Randomized Phase II US Intergroup Study ECOG-ACRIN E1412.

J Clin Oncol 2021 04 8;39(12):1329-1338. Epub 2021 Feb 8.

Division of Hematology, Mayo Clinic, Rochester, MN.

Purpose: Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell-like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL.

Patients And Methods: Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles. Tumors were analyzed using the NanoString Lymph2Cx for cell of origin. The primary end point was progression-free survival (PFS) in all patients with the co-primary end point of PFS in ABC-DLBCL. Secondary end points included overall response rate (ORR), complete response (CR) rate, and overall survival (OS).

Results: Three hundred forty-nine patients were enrolled; 280 patients (145 R2CHOP and 135 R-CHOP) were evaluable: 94 were ABC-DLBCL, 122 germinal center B-cell-like-DLBCL, 18 unclassifiable, and 46 unknowns. Baseline characteristics were well-balanced between arms, and the median age was 66 (range, 24-92); 70% of patients had stage IV disease; 34%, 43%, and 24% had IPI 2, 3, and 4 or 5, respectively. Myelosuppression was more common in the R2CHOP arm. The ORR and CR rate were 92% and 68% in R-CHOP and 97% ( = .06) and 73% ( = .43) in the R2CHOP arm, respectively. The median follow-up was 3.0 years; R2CHOP was associated with a 34% reduction in risk of progression or death versus R-CHOP (hazard ratio [HR], 0.66 95% CI, 0.43 to 1.01) and 3-year PFS of 73% versus 61%, one-sided = .03, and an improvement in OS (83% and 75% at 3 years; HR, 0.67; one-sided = .05). The PFS HR for R2CHOP was 0.67 for ABC-DLBCL, one-sided = .1.

Conclusion: In this signal-seeking study, the addition of lenalidomide to R-CHOP (R2CHOP) improved outcomes in newly diagnosed DLBCL including patients with ABC-DLBCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.01375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078264PMC
April 2021

Classical Hodgkin lymphoma.

Lancet 2021 Oct 22;398(10310):1518-1527. Epub 2021 Jan 22.

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

Classical Hodgkin lymphoma is one of the more frequent lymphomas and is generally considered a highly curable disease with standard first-line chemotherapy and radiotherapy in some cases. Despite these outstanding results, major problems remain unresolved. First, there are still patients who will not be cured with front-line regimens and, second, many patients who are cured of classical Hodgkin lymphoma continue to die prematurely due to the late toxic effects of their therapy. Because the median age of patients with classical Hodgkin lymphoma is in the mid-30s, the disease's impact on the number of years lost from productive life is remarkable. In recent years, the gold standard of chemotherapy (often combined with radiotherapy) has changed, with the approval of immunotherapy mostly in relapse settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(20)32207-8DOI Listing
October 2021

Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.

Hematol Oncol 2021 Apr 16;39(2):185-195. Epub 2021 Feb 16.

Research and Innovation Department, Centre Antoine Lacassagne, Nice, France.

Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247884PMC
April 2021

Axicabtagene ciloleucel and brexucabtagene autoleucel in relapsed and refractory diffuse large B-cell and mantle cell lymphomas.

Future Oncol 2021 Apr 15;17(11):1269-1283. Epub 2021 Jan 15.

Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.

Axicabtagene ciloleucel and brexucabtagene autoleucel are anti-CD19 T-cell therapies that utilize the same second-generation chimeric antigen receptor with a CD28 costimulatory subunit. They have demonstrated high rates of response in high-risk patients with relapsed and refractory B-cell malignancies in multicenter clinical trials, including diffuse large B-cell and mantle cell lymphomas. The high clinical activity has led to the US FDA approval of axicabtagene ciloleucel for diffuse large B-cell lymphoma, and brexucabtagene autoleucel for mantle cell lymphoma. While they are highly effective, they have significant toxicities, including cytokine release syndrome and neurologic toxicities, which can be severe and require specialized management. This review will discuss the development, efficacy and safety of axicabtagene ciloleucel and brexucabtagene autoleucel in B-cell lymphomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-0291DOI Listing
April 2021

Immunotherapy for Hematologic Malignancies.

J Clin Oncol 2021 02 12;39(5):343-345. Epub 2021 Jan 12.

University of Rochester, Rochester, NY.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.03106DOI Listing
February 2021

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lymphoma.

J Immunother Cancer 2020 12;8(2)

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

The recent development and clinical implementation of novel immunotherapies for the treatment of Hodgkin and non-Hodgkin lymphoma have improved patient outcomes across subgroups. The rapid introduction of immunotherapeutic agents into the clinic, however, has presented significant questions regarding optimal treatment scheduling around existing chemotherapy/radiation options, as well as a need for improved understanding of how to properly manage patients and recognize toxicities. To address these challenges, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in lymphoma to develop a clinical practice guideline for the education of healthcare professionals on various aspects of immunotherapeutic treatment. The panel discussed subjects including treatment scheduling, immune-related adverse events (irAEs), and the integration of immunotherapy and stem cell transplant to form recommendations to guide healthcare professionals treating patients with lymphoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-001235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768967PMC
December 2020

Safety and efficacy of navitoclax, a BCL-2 and BCL-X inhibitor, in patients with relapsed or refractory lymphoid malignancies: results from a phase 2a study.

Leuk Lymphoma 2021 04 25;62(4):810-818. Epub 2020 Nov 25.

George Washington University, Washington, DC, USA.

Navitoclax, a novel BCL-2 and BCL-X inhibitor, demonstrated promising antitumor activity in the dose-escalation part of a phase 1/2a study (NCT00406809) in lymphoid tumors. Herein, we report the continued safety and efficacy results of the phase 2a portion. Twenty-six adult patients with relapsed/refractory follicular lymphoma ( = 11, Arm A) and other relapsed/refractory lymphoid malignancies ( = 15, Arm B) were enrolled. Navitoclax administration schedule consisted of a 150-mg 7-day lead-in dose followed by 250-mg daily dosing with the option to further increase to 325 mg after 14 days if the 250-mg dose was tolerated. All patients experienced at least 1 treatment-related adverse event (TRAE). Seventeen (65.4%) patients reported grade 3/4 TRAEs; thrombocytopenia (38.5%) and neutropenia (30.8%) were the most common. Two patients reported serious AEs; none were fatal (no deaths occurred within 30 days of last dose of study drug). The objective response rate (complete and partial) was 23.1% (6/26; Arm A: 9.1%, Arm B: 33.3%). Median progression-free survival and time to progression were identical: 4.9 months (95% CI: 3.0, 8.2); median overall survival: 24.8 months (95% CI could not be computed). Navitoclax monotherapy has an acceptable safety profile and meaningful clinical activity in a minority of patients with relapsed/refractory lymphoid malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1845332DOI Listing
April 2021

Reply to E. Hawkes et al.

J Clin Oncol 2020 12 26;38(35):4222-4223. Epub 2020 Oct 26.

Daniel O. Persky, MD, University of Arizona Cancer Center, Tucson, AZ; Sonali M. Smith, MD, University of Chicago, Chicago, IL; Michael L. LeBlanc, PhD, Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA; and Jonathan W. Friedberg, MD, Wilmot Cancer Institute, University of Rochester, Rochester, NY.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02856DOI Listing
December 2020

Toxicity patterns of novel PI3K combinations in patients with non-Hodgkin lymphoma.

Leuk Lymphoma 2021 03 25;62(3):598-605. Epub 2020 Oct 25.

James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Phosphoinositide-3-kinase (PI3K) inhibitors have efficacy in lymphoid malignancies; however, inflammatory and infectious toxicities can compromise the treatment course. An improved understanding of these toxicities will guide clinical use and further development. We evaluated the occurrence of treatment-related adverse events (AEs) in a retrospective review of 79 patients treated in standard fashion with PI3K inhibitor monotherapy or with anti-CD20 monoclonal antibodies or as part of a novel combination regimen. Patients treated with a novel combination were at a higher risk of developing a severe AE compared to those treated with standard therapy (HR 1.89, 95% CI 1.02, 3.49;  = .04). Additionally, previously untreated patients were at higher risk of developing a severe AE compared to previously treated patients (HR 3.19, 95% CI 1.48, 6.84;  = .003). These results caution against the use of untested PI3K inhibitor combinations in routine practice and suggest that early phase clinical trials should utilize conservative treatment schemas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1837796DOI Listing
March 2021

Optimizing the Use of Oral Therapy in Lymphoma.

Clin Adv Hematol Oncol 2020 Aug;18(8):454-456

Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
August 2020

Key Clinical and Translational Research Questions to Address Unmet Needs in Mantle Cell Lymphoma.

Hematol Oncol Clin North Am 2020 10 5;34(5):983-996. Epub 2020 Aug 5.

James P. Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA.

Survival for patients with mantle cell lymphoma has improved dramatically over the last 2 decades owing to a better understanding of disease biology and the development of more effective treatment regimens for patients with untreated and relapsed disease. With these advancements, we are now poised to ask questions that challenge old treatment strategies, use new technologies, and improve our understanding of disease heterogeneity. This article focuses on questions that we believe will drive the future of mantle cell lymphoma treatment. Although not an exhaustive list, we review current literature, ongoing studies, and provide expert opinion on future trial design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hoc.2020.06.012DOI Listing
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.00999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479758PMC
September 2020

Toward a Cure for Follicular Lymphoma.

Hematol Oncol Clin North Am 2020 08 20;34(4):xiii-xiv. Epub 2020 May 20.

Wilmot Cancer Institute, University of Rochester School of Medicine, 601 Elmwood Avenue, Box 704, Rochester, NY 14610, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hoc.2020.05.001DOI Listing
August 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).
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1768388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704391PMC
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019003277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316220PMC
June 2020

First-line treatment in older patients with Hodgkin lymphoma: a Surveillance, Epidemiology, and End Results (SEER)-Medicare population-based study.

Br J Haematol 2020 07 23;190(2):222-235. Epub 2020 Feb 23.

Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA.

While Hodgkin lymphoma (HL) is highly curable in younger patients, older patients have higher relapse and death rates, which may reflect age-related factors, distinct disease biology and/or treatment decisions. We described the association between patient, disease and geographic factors and first-line treatment in older patients (≥65 years) with incident HL using Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 1999 to 2014 (n = 2825). First-line treatment initiated at ≤4 months after diagnosis was categorised as: full chemotherapy regimen (n = 699, 24·7%); partial chemotherapy regimen (n = 1016, 36·0%); single chemotherapy agent or radiotherapy (n = 382, 13·5%); and no treatment (n = 728, 25·8%). Among the fully treated, ABVD [doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine]/AVD was most common (n = 635, 90·8%). Adjusted multinomial logistic regression identified factors associated with treatment. Older age, Medicaid dual eligibility, not married, frailty, cardiac comorbidity, prior cancer, earlier diagnosis date, histology, advanced disease Stage, B symptoms and South region were independently associated with increased odds of not receiving full chemotherapy regimens. In conclusion, we found variability in first-line HL treatment for older patients. Treatment differences by Medicaid and region may indicate disparities. Even after adjusting for frailty and cardiac comorbidity, age was associated with treatment, suggesting factors such as end-of-life care or shared decision-making may influence treatment in older patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368808PMC
July 2020

Efficacy of lenalidomide in high-risk diffuse large B-cell lymphoma.

Br J Haematol 2020 02 17;188(4):e33-e36. Epub 2019 Dec 17.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16302DOI Listing
February 2020

Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma.

Blood 2019 10;134(15):1238-1246

Division of Hematology/Oncology, University of Rochester, Rochester NY.

Patients with advanced-stage Hodgkin lymphoma (HL) demonstrated excellent 2-year progression-free survival (PFS) after receiving positron emission tomography (PET)-adapted therapy on SWOG S0816. Patients received 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients achieving complete response (CR) on PET scan following cycle 2 of ABVD (PET2) continued 4 additional cycles of ABVD. Patients not achieving CR on PET2 were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for 6 cycles. After a median follow-up of 5.9 years, a subset of 331 eligible patients with central review of PET2 was analyzed. PET2 was negative in 82% and positive in 18%. For all patients, the estimated 5-year PFS and OS was 74% (95% confidence interval [CI], 69%-79%) and 94% (95% CI, 91%-96%), respectively. For PET2- and PET2+ patients, the 5-year PFS was 76% (95% CI, 70%-81%) and 66% (95% CI, 52%-76%), respectively. Seven (14%) and 6 (2%) patients reported second cancers after treatment with eBEACOPP and ABVD, respectively (P = .001). Long-term OS of HL patients treated on S0816 remains high. Nearly 25% of PET2- patients experienced relapse events, demonstrating limitations ABVD therapy and of the negative predictive value of PET2. In PET2+ patients who received eBEACOPP, PFS was favorable, but was associated with a high rate of second malignancies compared with historical controls. Our results emphasize the importance of long-term follow-up, and the need for more efficacious and less toxic therapeutic approaches for advanced-stage HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00822120.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019000719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788007PMC
October 2019

Patients with diffuse large B-cell lymphoma requiring urgent treatment: its implication on trial design and interpretation.

Leuk Lymphoma 2019 12 8;60(14):3569-3572. Epub 2019 Jul 8.

James P. Wilmot Cancer Center, Division of Hematology and Oncology, University of Rochester Medical Center, Rochester, NY, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2019.1639172DOI Listing
December 2019
-->