Myeloablative Vs. Non-Myeloablative Consolidation for Primary Central Nervous System Lymphoma: Results of Alliance 51101.

While it is evident that standard dose whole brain radiotherapy as consolidation is associated with significant neurotoxicity, the optimal consolidative strategy for primary central nervous system lymphoma (PCNSL) is not defined. We performed a randomized phase 2 clinical trial via the U.S. Alliance cancer cooperative group to compare myeloablative consolidation supported by autologous stem cell transplantation with non-myeloablative consolidation after induction therapy for PCNSL. This is the first randomized trial to be initiated that eliminates whole brain radiotherapy as a consolidative approach in newly-diagnosed PCNSL. Patients, age 18-75 years, were randomly assigned in a 1:1 manner to induction therapy (methotrexate, temozolomide, rituximab and cytarabine) followed by consolidation with either thiotepa plus carmustine and autologous stem cell rescue versus induction followed by non-myeloablative, infusional etoposide plus cytarabine (EA) The primary endpoint was progression-free survival (PFS). 113 patients were randomized and 108 (54 in each arm) were evaluable. More patients in the non-myeloablative arm experienced progressive disease or death during induction (28% versus 11%, p = 0.05). Thirty-six patients received autologous stem cell transplant and 34 received non-myeloablative consolidation. The estimated 2-year PFS was higher in the myeloablative versus non-myeloablative arm (73% versus 51%; p= 0.02). However, a planned secondary analysis, landmarked at start of consolidation, revealed that the estimated 2-year PFS in those who completed consolidation therapy was not significantly different between the arms (86% versus 71%; p = 0.21). Both consolidative strategies yielded encouraging efficacy and similar toxicity profiles. Clinicaltrials.gov (NCT01511562).

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 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.

Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children.

Importance: Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain. Objective: To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials. Design, Setting, and Participants: For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023. Exposures: All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane. Main Outcomes and Measures: Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease. Results: The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines. Conclusions and Relevance: In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

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.

Classic Hodgkin Lymphoma in Adolescents and Young Adults.

Hodgkin lymphoma (HL) represents one of the more common cancers occurring in adolescent and young adults (AYAs) age 15-39 years. Despite a generally high cure rate, age-related differences in HL biology and the optimal therapeutic approaches including supportive care and risks for long-term adverse effects in the AYA population remain understudied. After an overview of HL epidemiology and biology in the AYA population, this review will cover frontline pediatric and adult treatment approaches. Recently completed and ongoing studies will foster harmonization of risk group definition and trial eligibility criteria across the AYA spectrum, enabling more rapid progress. In addition to treatment approaches, an evolving holistic care approach to AYA HL will result in enhanced understanding of unique challenges, and continued improved short- and long-term outcome for these patients.

Response-adapted, time-limited venetoclax, umbralisib, and ublituximab for relapsed/refractory chronic lymphocytic leukemia.

ABSTRACT: Many patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Owing to the synergistic antitumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment. We conducted a phase 1/2 clinical trial to determine the safety and efficacy of venetoclax in combination with umbralisib and the anti-CD20 monoclonal antibody, ublituximab, (U2-VeN) in patients with relapsed/refractory CLL (N = 46) and Richter transformation (N = 5). After 12 cycles, treatment was stopped for patients with CLL who achieved undetectable minimal residual disease (uMRD). Adverse events of special interest included diarrhea in 50% of patients (11% grade 3/4), and aspartate aminotransferase and/or alanine aminotransferase elevation in 15 patients (33%), with 3 (7%) grade 3/4. There were no cases of tumor lysis syndrome related to venetoclax, with outpatient initiation in 96% of patients. The intent-to-treat overall response rate for CLL was 98% with best response of 100% in evaluable patients (42% complete responses). The end-of-treatment rate of uMRD at 10-4 in bone marrow was 77% (30/39), including a 71% uMRD rate among 14 patients refractory to prior BTK inhibitor. Time-limited venetoclax and U2 is safe and highly effective combination therapy for patients with relapsed/refractory CLL including those who have been previously treated with covalent BTK inhibitors. This trial was registered on www.clinicaltrials.gov as #NCT03379051.

T-Cell-Rich Hodgkin Lymphoma With Features of Classic Hodgkin Lymphoma and Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Borderline Category With Overlapping Morphologic and Immunophenotypic Features.

CONTEXT.­: It is known that a subset of cases of classic Hodgkin lymphoma (CHL) with B-cell-rich nodules (lymphocyte-rich CHL) exhibits morphologic and immunophenotypic features that overlap with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), raising diagnostic difficulties that can be resolved in most cases by performing an adequate battery of immunohistochemical studies. OBJECTIVE.­: To fully characterize cases of T-cell-rich Hodgkin lymphoma where a specific diagnosis of NLPHL (ie, pattern D) or CHL could not be made even after complete immunophenotypic investigation. DESIGN.­: The clinical, immunomorphologic, and molecular (when applicable) presentation of 3 cases of T-cell-rich Hodgkin lymphoma was thoroughly investigated. RESULTS.­: These 3 cases harbored lymphocyte-predominant-like and Hodgkin and Reed-Sternberg-like cells that partially expressed B-cell and CHL markers and were negative for Epstein-Barr virus-encoded small RNA, in a T-cell-rich background with residual follicular dendritic cell meshworks; 1 case had frequent and the other 2 cases scant/absent eosinophils and plasma cells. Two patients with advanced-stage (III or IV) disease presented with axillary and supraclavicular lymphadenopathy, respectively, and without B symptoms. These patients underwent NLPHL-like therapeutic management with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], vincristine sulfate [Oncovin], and prednisone) chemotherapy; both are in complete remission 7 years posttherapy. One patient presented with stage I disease involving an internal mammary lymph node without B-symptoms and was treated with surgical excision alone; this patient is also in complete remission 1 year later. CONCLUSIONS.­: These cases illustrate overlapping features of T-cell-rich NLPHL and CHL with neoplastic cells expressing both B-cell program and CHL markers. This underrecognized overlap has not been fully illustrated in the literature, although it portrays a therapeutic challenge. These neoplasms may deserve in-depth investigation in the future that may bring up diagnostic or theragnostic implications.

Overcoming barriers to drug development and enrollment in clinical trials for adolescents and young adults with lymphoma.

Lymphoma is one of the most common cancers in adolescents and young adults, but historically, this population has had lower clinical trial enrollment and improvements in overall survival as compared to other age populations. There are multiple challenges that are unique to this population that have affected drug development and clinical trial enrollment. Our panel of experts have identified barriers, and in this review, we discuss current methods to address these barriers as well as potential solutions moving forward.

Current directions in the treatment of classical Hodgkin lymphoma.

Optimal management of patients who present with Hodgkin lymphoma continues to evolve. Most patients are cured with current treatment strategies, some but both short and long-term morbidity and mortality from treatment have particular relevance given the youth of the patient population. Combininations of targeted agents together with conventional chemotherapy have recently been investigated in phase 3 cliniial trials for advanced-stage Hodkgkin lymphoma, and have demonstrated improved efficacy compared with chemotherapy alone. These include both antibody-drug conjugates and PD-1 blockade. Treatment approaches have historically differed between pediatric and adult groups, but recent collaborations between adullt and pediatric groups via the NCTN mechanism have resulted in the successful completion of enrollment in an advanced-stage Hodgkin lymphoma and the opening of an early-stage trial that will enroll patients accross a broad age spectrum. Novel approachs incorporating targeted and immunomodulatory agents in the relapse setting are being actively investagated in the relapse setting as well.

Understanding treatment decisions for Hodgkin lymphoma: a qualitative study.

Hodgkin lymphoma (HL) affects older and younger patients and includes multiple options for initial treatment. We sought to examine the decision processes of practicing oncologists caring for patients with newly diagnosed HL. Through semi-structured interviews, we explored their perspectives about treatment decisions. We completed thematic analysis using the Anderson Behavioral Model of Health Services framework to identify factors associated with initial decisions. We completed 22 interviews, grouping findings into contextual factors, individual characteristics, and physician preferences. Paternalism was widely cited, along with collaboration between community and academic colleagues. Participants used sequential therapy but not geriatric assessment in care for older patients. Physicians had varied responses about use of frontline brentuximab vedotin (Bv)-based therapy based on perceptions about benefit versus toxicity. Our work suggests a need to further understand the heterogeneity of clinical practices, especially in the post-approval setting of new therapies.

Subclonal TP53 mutations are frequent and predict resistance to radioimmunotherapy in follicular lymphoma.

Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in <5% of pretreatment follicular lymphoma (FL) specimens. We assayed archival follicular B-cell non-Hodgkin lymphoma specimens from a completed clinical trial, Southwest Oncology Group S0016, a phase 3 randomized intergroup trial of CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone) chemotherapy plus R-CHOP (rituximab-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radioimmunotherapy [RIT]-CHOP). Subclonal TP53 mutations (median allele frequency 0.02) were found in 25% of diagnostic FL specimens and in 27% of a separate validation cohort. In the R-CHOP arm, pathogenic TP53 mutations were not associated with progression-free survival (PFS) (10-year PFS 43% vs 44%). In contrast, among patients with no detectable pathogenic TP53 mutation, RIT-CHOP was associated with a longer PFS than with R-CHOP (10-year PFS 67% vs 44%; hazard ratio = 0.49; P = .008). No relationship was detected between PFS and the extent of activation-induced cytidine deaminase (AICDA)-mediated heterogeneity. In summary, subclonal TP53 mutations are common in FL and are a distinct phenomenon from AICDA-mediated genetic heterogeneity. The absence of a detectable subclonal mutation in TP53 defined a population that particularly benefited from RIT.

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.

Healthcare Utilization Disparities of Adolescent and Young Adults Compared to the Older Lymphoma Population.

BACKGROUND: Adolescent and Young Adults (AYAs) are an underserved, high-risk population. Identifying health care utilization patterns, and particularly acute care visits, is important as these are high-intensity, expensive services. We investigated whether differences exist in health care utilization between the AYA lymphoma population compared to their older adult counterparts. MATERIALS AND METHODS: Two correlated outcomes were used to measure health care utilization: 4 or more acute visits (emergency department or urgent care) and number of nonacute visits (office or telephone visits). We studied 442 patients with aggressive lymphoma patients 15 years or older at time of diagnosis managed at our cancer center within 2 years of their diagnosis. A multivariate generalized linear mixed model simultaneously estimated the effect of baseline predictors on 4 or more acute care visit with robust Poisson regression and nonacute visit counts with negative binomial regression allowing for a within-subject random effect. RESULTS: AYAs had increased risk of having ≥4 acute visits (RR = 1.96; P = .047) compared to their older counterparts. Obesity (RR = 2.04, P = .015) and living less than 50 miles from the cancer center (RR = 3.48, P = .015) were independently associated with higher risk of acute care usage. Acute care visits for psychiatric or substance use related reasons were significantly higher (P = .0001) among AYA (10/114, 8.8%) vs. non-AYA (3/328, 0.9%). CONCLUSION: Disease-targeted interventions to address high acute health care utilization is needed amongst AYAs. Additionally, early multidisciplinary involvement after cancer diagnosis particularly with psychiatric expertise amongst AYAs and palliative care involvement in both groups is needed.