Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Classical Hodgkin Lymphoma Across the United States.

BACKGROUND: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). PATIENTS/METHODS: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. RESULTS: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). CONCLUSION: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.

Advancements in the Management of Follicular Lymphoma: A Comprehensive Review.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma in Western countries. While FL is generally incurable, standard initial therapies are associated with high response rates and durable remissions for most patients. In addition, novel targeted agents and immunotherapies are changing the treatment algorithm for patients with relapsed or refractory disease. This review discusses initial staging, prognosis, and treatment options for newly diagnosed and relapsed/refractory FL. Initial treatment options for FL include active surveillance, radiotherapy, rituximab monotherapy, and chemoimmunotherapy. Staging with PET/CT and bone marrow biopsy is crucial for identifying early-stage patients. Most patients with FL will receive chemoimmuntherapy as initial treatment with options including rituximab or obinutuzumab plus CVP, CHOP, bendamustine, or lenalidomide. No significant differences in overall survival have been observed in randomized studies comparing these regimens. Maintenance therapy with rituximab or obinutuzumab in responders to initial chemoimmunotherapy improves progression-free survival. For relapsed/refractory FL, treatment options include chemoimmunotherapy, lenalidomide-based regimens, tazemetostat, chimeric antigent receptor (CAR) T cell therapy (axicabtagene ciloleucel and tisagenlecleucel) and CD3/CD20 bispecific antibodies (BsAbs). Given encouraging outcomes with CAR T cell therapy and BsAbs, multiple trials are testing these highly active agents in earlier lines of therapy and among high-risk patients with early relapse after frontline chemoimmunotherapy. Additonal studies and follow-up are needed to understand how these novel agents may further change treatment algorithms for FL.

Frontline Treatment of Mantle Cell Lymphoma.

Despite many recent therapeutic advances, mantle cell lymphoma (MCL) remains a largely incurable disease. Treatments for patients with relapsed/refractory (R/R) disease are limited in number and in response durability. Therefore, improving the efficacy of frontline (1L) treatment, and specifically maximizing the duration of first remission, remains of critical importance to obtain favorable long-term outcomes. As 1L treatments become more effective, improving tolerability is also becoming an increasingly realistic goal. Targeted agents, which are now mainstays of treatment in R/R MCL, are establishing new, paradigm-changing roles in frontline treatment. Here, we review data supporting current standard-of-care (SOC) approaches and explore six main areas of possible focus for advancement of 1L management: optimizing the chemoimmunotherapy (CIT) backbone, adding targeted agents to CIT, redefining the role of autologous stem cell transplantation (ASCT), improving maintenance therapy, using targeted agent combinations with omission of CIT, and employing MRD-guided therapy. We highlight several ongoing phase 3 trials that may soon impact frontline MCL management and outline some areas of necessary investigation as the field continues to strive towards a cure for this disease.

Brentuximab Vedotin and Chemotherapy in Relapsed/Refractory Hodgkin Lymphoma: a Propensity Score Matched Analysis.

Several single-arm studies have explored the inclusion of brentuximab vedotin (BV) in salvage chemotherapy followed by autologous stem-cell transplantation (ASCT) for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). However, no head-to-head comparisons with standard salvage chemotherapy have been performed. This study presents a propensity score-matched analysis encompassing individual patient data from ten clinical trials to evaluate the impact of BV in transplant-eligible R/R cHL patients. We included 768 patients, of whom 386 were treated with BV +/- chemotherapy (BV-cohort), while 382 received chemotherapy alone (chemo-cohort). Propensity score matching resulted in balanced cohorts of 240 patients each. No significant differences were observed in pre-ASCT complete metabolic response (CMR) rates (p=0.69) or progression free survival (PFS) (p=0.14) between the BV- and chemo-cohorts. However, patients with relapsed disease had a significantly better 3-year PFS of 80% versus 70% in the BV- versus chemo-cohort (p=0.02), while there was no difference for primary refractory patients (56% versus 62%, respectively; p=0.67). Patients with stage IV disease achieved a significantly better 3-year PFS in the BV-cohort (p=0.015). Post-ASCT PFS was comparable for patients achieving a CMR after BV monotherapy and those receiving BV followed by sequential chemotherapy (p=0.24). While 3-year overall survival was higher in the BV-cohort (92% versus 80%, p<0.001, respectively), this is likely attributed to the use of other novel therapies in later lines for patients experiencing progression, given that studies in the BV-cohort were conducted more recently. In conclusion, BV +/- salvage chemotherapy appears to enhance PFS in relapsed but not primary refractory cHL patients.

Effect of atorvastatin versus placebo on efficacy in patients with diffuse large B-cell lymphoma receiving R-CHOP.

STOP-CA was a multicenter, double-blind, randomized, placebo-controlled trial comparing atorvastatin to placebo in treatment-naïve lymphoma patients receiving anthracycline-based chemotherapy. We performed a preplanned subgroup to analyze the impact of atorvastatin on efficacy in patients with diffuse large B-cell lymphoma (DLBCL). Patients received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at standard doses for six 21-day cycles and were randomly assigned to receive atorvastatin 40 mg daily (n = 55) or placebo (n = 47) for 12 months. The complete response (CR) rate was numerically higher in the atorvastatin arm (95% [52/55] vs. 85% [40/47], p = .18), but this was not statistically significant. Adverse event rates were similar between the atorvastatin and placebo arms. In summary, atorvastatin did not result in a statistically significant improvement in the CR rate or progression-free survival, but both were numerically improved in the atorvastatin arm. These data warrant further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies.

Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL.

ABSTRACT: We previously reported high rates of undetectable minimal residual disease <10-4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548.

A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma.

Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).

Evaluation of mediastinal lymph node segmentation of heterogeneous CT data with full and weak supervision.

Accurate lymph node size estimation is critical for staging cancer patients, initial therapeutic management, and assessing response to therapy. Current standard practice for quantifying lymph node size is based on a variety of criteria that use uni-directional or bi-directional measurements. Segmentation in 3D can provide more accurate evaluations of the lymph node size. Fully convolutional neural networks (FCNs) have achieved state-of-the-art results in segmentation for numerous medical imaging applications, including lymph node segmentation. Adoption of deep learning segmentation models in clinical trials often faces numerous challenges. These include lack of pixel-level ground truth annotations for training, generalizability of the models on unseen test domains due to the heterogeneity of test cases and variation of imaging parameters. In this paper, we studied and evaluated the performance of lymph node segmentation models on a dataset that was completely independent of the one used to create the models. We analyzed the generalizability of the models in the face of a heterogeneous dataset and assessed the potential effects of different disease conditions and imaging parameters. Furthermore, we systematically compared fully-supervised and weakly-supervised methods in this context. We evaluated the proposed methods using an independent dataset comprising 806 mediastinal lymph nodes from 540 unique patients. The results show that performance achieved on the independent test set is comparable to that on the training set. Furthermore, neither the underlying disease nor the heterogeneous imaging parameters impacted the performance of the models. Finally, the results indicate that our weakly-supervised method attains 90%- 91% of the performance achieved by the fully supervised training.

Classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (HL) is rare disease, with an incidence of approximately 85,000 patients globally per year and a predilection for adolescents and young adults (ages 15-39). Since the introduction of combination chemotherapy in the 1960's and radiation dating back to the early 1900's, therapeutic options and by extension, clinical outcomes have improved dramatically with 5-year overall survival (OS) approaching 90% today. [1](#ref-0001) Advances in understanding HL biology have additionally facilitated development of targeted agents and immunotherapy which have further improved short and long-term outcomes. Despite continued improvements in up-front and salvage therapy, long-term survivors of HL experience several treatment-associated late toxicities, thus, along with efforts to improve therapeutic efficacy, efforts to reduce late effects remain a high-priority in the field.

NCCN Guidelines® Insights: B-Cell Lymphomas, Version 6.2023.

Novel targeted therapies (small molecule inhibitors, antibody-drug conjugates, and CD19-directed therapies) have changed the treatment landscape of relapsed/refractory B-cell lymphomas. Bruton's tyrosine kinase (BTK) inhibitors continue to evolve in the management of mantle cell lymphoma (MCL), in both the relapsed/refractory and the frontline setting. Anti-CD19 CAR T-cell therapies are now effective and approved treatment options for relapsed/refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and MCL. Bispecific T-cell engagers represent a novel immunotherapeutic approach for relapsed FL and DLBCL after multiple lines of therapies, including prior CAR T-cell therapy. These NCCN Guideline Insights highlight the significant updates to the NCCN Guidelines for B-Cell Lymphomas for the treatment of FL, DLBCL, and MCL.

Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.

Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.

Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: a population-based study.

BACKGROUND: Mental health disorders can potentially decrease quality of life and survival in patients with cancer. Little is known about the survival implications of mental health disorders in patients with diffuse large B-cell lymphoma (DLBCL). We aimed to evaluate the effect of pre-existing depression, anxiety, or both on survival in a US cohort of older patients with DLBCL. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we identified patients aged 67 years or older, diagnosed with DLBCL in the USA between Jan 1, 2001, and Dec 31, 2013. We used billing claims to identify patients with pre-existing depression, anxiety, or both before their DLBCL diagnosis. We compared 5-year overall survival and lymphoma-specific survival between these patients and those without pre-existing depression, anxiety, or both using Cox proportional analyses, adjusting for sociodemographic and clinical characteristics, including DLBCL stage, extranodal disease, and B symptoms. FINDINGS: Among 13 244 patients with DLBCL, 2094 (15·8%) had depression, anxiety, or both disorders; 6988 (52·8%) were female, and 12 468 (94·1%) were White. The median follow-up for the cohort was 2·0 years (IQR 0·4-6·9 years). 5-year overall survival was 27·0% (95% CI 25·1-28·9) for patients with these mental health disorders versus 37·4% (36·5-38·3) for those with no mental health disorder (hazard ratio [HR] 1·37, 95% CI 1·29-1·44). Although survival differences between mental health disorders were modest, those with depression alone had the worst survival compared with no mental health disorder (HR 1·37, 95% CI 1·28-1·47), followed by those with depression and anxiety (1·23, 1·08-1·41), and then anxiety alone (1·17, 1·06-1·29). Individuals with these pre-existing mental health disorders also had lower 5-year lymphoma-specific survival, with depression conferring the greatest effect (1·37, 1·26-1·49) followed by those with depression and anxiety (1·25, 1·07-1·47) and then anxiety alone (1·16, 1·03-1·31). INTERPRETATION: Pre-existing depression, anxiety, or both disorders present within 24 months before DLBCL diagnosis, worsens prognosis for patients with DLBCL. Our data underscore the need for universal and systematic mental health screening for this population, as mental health disorders are manageable, and improvements in this prevalent comorbidity might affect lymphoma-specific survival and overall survival. FUNDING: American Society of Hematology, National Cancer Institute, Alan J Hirschfield Award.

A phase 2 study of pembrolizumab after autologous stem cell transplantation in patients with T-cell non-Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) is often used as consolidation for several subtypes of peripheral T-cell lymphoma (PTCL) in first remission. However, many patients relapse after ASCT and have a very poor prognosis. There are no approved treatment options for posttransplantation maintenance or consolidation in PTCL. PD-1 blockade has demonstrated some efficacy for patients with PTCL. We, therefore, conducted a phase 2 multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab after ASCT in patients with PTCL in first remission. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles within 21 days from post-ASCT discharge (and within 60 days of stem cell infusion). The primary end point was progression-free survival (PFS) at 18 months after ASCT. Twenty-one patients were treated in this study and 67% (n = 14) completed 8 cycles of treatment. Among all patients who were evaluable, 13 of 21 were alive and achieved PFS at 18 months after ASCT, meeting the study's primary end point. The estimated 18-month PFS was 83.6% (95% confidence interval [CI], 68-100), and overall survival 94.4% (95% CI, 84-100). The toxicity profile was consistent with the known toxicity profile of pembrolizumab, with no grade 5 toxicities. In conclusion, PD-1 blockade after ASCT with pembrolizumab is feasible with a favorable safety profile and promising activity, supporting further confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Exploring Influencing Factors of Anxiety Improvement Following Mindfulness-Based Music Therapy in Young Adults with Cancer.

The purpose of this secondary analysis was to explore physiological, psychological, and situational influencing factors that may affect the impact of a mindfulness-music therapy intervention on anxiety severity in young adults receiving cancer treatment. Young adults receiving cancer treatment for ≥ eight weeks were recruited from adult and pediatric oncology outpatient centers at Dana-Farber Cancer Institute. Participants were asked to attend up to four, in-person (offered virtually via Zoom video conference after the onset of the COVID-19 pandemic) 45-min mindfulness-based music therapy sessions over twelve weeks with a board-certified music therapist. Participants completed questionnaires about anxiety, stress, and other cancer treatment-related outcomes before and after participating in the intervention. Changes in anxiety (i.e., PROMIS Anxiety 4a) over time were compared among baseline physiological (e.g., age or sex), psychological (e.g., stress), and situational influencing (i.e., intervention delivery format) factors using Wilcoxon-rank sum tests. Thirty-one of the 37 enrolled participants completed the baseline and post-intervention measures and were eligible for inclusion in the secondary analysis. Results revealed that higher baseline physical functioning (median change = -6.65), anxiety (median change=-5.65), fatigue (median change = -5.6), sleep disturbance (median change = -5.6),female sex (median change = -5.15), or virtual intervention delivery(median change = -4.65) were potential physiological, psychological, or situational influencing factors associated with anxiety improvement following mindfulness-based music therapy. Additional investigation into physiological, psychological, or situational influencing factors associated with anxiety response will help to tailor the design of future mindfulness-music therapy interventions to decrease psychological distress and address the unique psychosocial concerns among young adults receiving cancer treatment. Trial Registration ClinicalTrials.gov Identifier: NCT03709225.

Exploring Young Adults' Perspectives of Participation in a Mindfulness-Based Music Therapy Intervention Before and During the COVID-19 Pandemic.

Purpose: To explore adolescent and young adults' (AYAs) experiences with participation in a mindfulness-based music therapy intervention during cancer treatment before and during the COVID-19 pandemic. Methods: Sixteen young adults (20-39 years old) who received cancer treatment and participated in a mindfulness-based music therapy intervention for anxiety and stress were interviewed using a semistructured interview guide. Interviews were audio recorded and transcribed verbatim. The interview guide contained prompts about reasons for joining the study, usual coping strategies, experience with the in-person and virtual delivery formats of the intervention, and suggestions for improvement. Themes were derived from the data using inductive content analysis methods. Results: Findings from the interviews included the following: (1) virtual group participants reported difficulty finding a private place to attend the intervention sessions, (2) participants experienced a sense of relaxation in response to intervention participation, (3) in-person group participants felt a sense of connection to the music and their family members who were present during the intervention, while virtual group participants felt a sense of connection to mindfulness, (4) virtual group participants reported that practicing music and mindfulness together was synergistic, and (5) in-person intervention delivery was preferred to virtual intervention delivery. Conclusion: This study provides insight into the contextual factors that impact satisfaction with the intervention and the effect of the intervention on anxiety and stress. Overall, while virtual mindfulness-based music therapy delivery may be more feasible, there are still important advantages to in-person delivery that should be considered in the design of future mindfulness-based music therapy interventions. ClinicalTrials.gov Identifier: NCT03709225.