Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma.

BACKGROUND: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause. RESULTS: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation. CONCLUSIONS: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.).

Brentuximab vedotin with dacarbazine or nivolumab as frontline cHL therapy for older patients ineligible for chemotherapy.

ABSTRACT: Older patients with advanced-stage classical Hodgkin lymphoma (cHL) have inferior outcomes compared with younger patients, potentially due to comorbidities and frailty. This noncomparative phase 2 study enrolled patients aged ≥60 years with cHL unfit for conventional chemotherapy to receive frontline brentuximab vedotin (BV; 1.8 mg/kg) with dacarbazine (DTIC; 375 mg/m2) (part B) or nivolumab (part D; 3 mg/kg). In parts B and D, 50% and 38% of patients, respectively, had ≥3 general comorbidities or ≥1 significant comorbidity. Of the 22 patients treated with BV-DTIC, 95% achieved objective response, and 64% achieved complete response (CR). With a median follow-up of 63.6 months, median duration of response (mDOR) was 46.0 months. Median progression-free survival (mPFS) was 47.2 months; median overall survival (mOS) was not reached. Of 21 patients treated with BV-nivolumab, 86% achieved objective response, and 67% achieved CR. With 51.6 months of median follow-up, mDOR, mPFS, and mOS were not reached. Ten patients (45%) with BV-DTIC and 16 patients (76%) with BV-nivolumab experienced grade ≥3 treatment-emergent adverse events; sensory peripheral neuropathy (PN; 27%) and neutropenia (9%) were most common with BV-DTIC, and increased lipase (24%), motor PN (19%), and sensory PN (19%) were most common with BV-nivolumab. Despite high median age, inclusion of patients aged ≤88 years, and frailty, these results demonstrate safety and promising durable efficacy of BV-DTIC and BV-nivolumab combinations as frontline treatment, suggesting potential alternatives for older patients with cHL unfit for initial conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Real-world impact of differences in the WHO and ICC classifications of non-Hodgkin lymphoma: a LEO Cohort Study analysis.

Recent introduction of two different lymphoma classifications has raised concerns about consistency in diagnosis, management, and clinical trial enrollment. Data from a large cohort reflecting real-world clinical practice suggest that differences between the classifications will impact <1% of non-Hodgkin lymphomas.

Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.

ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.

Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma.

BACKGROUND: Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody-drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available. METHODS: We randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed. RESULTS: A total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P = 0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up. CONCLUSIONS: Patients who received A+AVD for the treatment of stage III or IV Hodgkin's lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.).

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

High-dose vitamin D to attenuate bone loss in patients with prostate cancer on androgen deprivation therapy: A phase 2 RCT.

BACKGROUND: Androgen deprivation therapy (ADT) inhibits prostate cancer growth. However, ADT causes loss of bone mineral density (BMD) and an increase in fracture risk; effective interventions for ADT-induced bone loss are limited. METHODS: A phase 2 randomized controlled trial investigated the feasibility, safety, and preliminary efficacy of high-dose weekly vitamin D (HDVD, 50,000 IU/week) versus placebo for 24 weeks in patients with prostate cancer receiving ADT, with all subjects receiving 600 IU/day vitamin D and 1000 mg/day calcium. Participants were ≥60 years (mean years, 67.7), had a serum 25-hydroxyvitamin D level <32 ng/mL, and initiated ADT within the previous 6 months. At baseline and after intervention, dual-energy x-ray absorptiometry was used to assess BMD, and levels of bone cell, bone formation, and resorption were measured. RESULTS: The HDVD group (N = 29) lost 1.5% BMD at the total hip vs. 4.1% for the low-dose group (N = 30; p = .03) and 1.7% BMD at the femoral neck vs. 4.4% in the low-dose group (p = .06). Stratified analyses showed that, for those with baseline 25-hydroxyvitamin D level <27 ng/mL, the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the low-dose group (p < .01). Those in the HDVD arm showed significant changes in parathyroid hormone (p < .01), osteoprotegerin (p < 0.01), N-terminal telopeptide of type 1 collagen (p < 0.01) and C-terminal telopeptide of type 1 collagen (p < 0.01). No difference in adverse events or toxicity was noted between the groups. CONCLUSIONS: HDVD supplementation significantly reduced hip and femoral neck BMD loss, especially for patients with low baseline serum 25-hydroxyvitamin D levels, although demonstrating safety and feasibility in prostate cancer patients on ADT.

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.

Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

Update on follicular lymphoma.

The past two decades have seen remarkable progress in both biological understanding and optimizing treatment of follicular lymphoma. Historically considered an incurable disease, long-term follow-up of several induction approaches demonstrates that up to 40% of patients enjoy remission durations of 10 or more years, and risk of dying of lymphoma continues to fall. This update will focus on progress in follicular lymphoma over the past 3 years, which has included refinements in staging and prognosis, novel immunotherapy treatment approaches for relapsed and refractory disease, and long-term follow-up of pivotal trials. Ongoing trials will define the optimal sequence for these novel treatments, including whether earlier incorporation of these approaches may result in definitive cure of this disease. Through ongoing and planned correlative studies, we are poised to ultimately achieve the goal of a precision management approach to follicular lymphoma.

Classical Hodgkin lymphoma.

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.

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

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.

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

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).

Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study.

Serum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)-positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.

Genomic alterations important for the prognosis in patients with follicular lymphoma treated in SWOG study S0016.

Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy-number aberrations (CNAs) and copy-neutral loss of heterozygosity (cnLOH) identified by chromosome genomic-array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in the SWOG study S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression-free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (ie, the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: whereas early progression was correlated with 2p gain (P = .007; odds ratio [OR] = 2.55 [1.29, 5.03]) and 2p cnLOH (P = .005; OR = 10.9 [2.08, 57.2]), 2p gain specifically encompassing VRK2 and FANCL predicted PFS (P = .01; hazard ratio = 1.80 [1.14, 2.68]) as well as OS (P = .005; 2.40 [1.30, 4.40]); CDKN2A/B (9p) deletion correlated with worse PFS (P = .004, 3.50 [1.51, 8.28]); whereas CREBBP (16p) (P < .001; 6.70 [2.52, 17.58]) and TP53 (17p) (P < .001; 3.90 [1.85, 8.31]) deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies.

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

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.

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.

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.

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

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.

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

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.

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

BACKGROUND: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. METHODS: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. RESULTS: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. CONCLUSIONS: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).