Citations

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

We present a subset analysis on the adolescent cohort of the S1826 randomized phase three trial, comparing nivolumab, doxorubicin, vinblastine, dacarbazine (N-AVD) to brentuximab vedotin-AVD (BV-AVD) in newly diagnosed advanced-stage (AS, stages III and IV) classic Hodgkin lymphoma (cHL). Among 994 patients enrolled, 24% (n = 240) were age 12-17 years. The 3-year progression-free survival (PFS) was significantly higher in the N-AVD group (93% [95% CI, 87 to 96]) compared with the BV-AVD group (82% [95% CI, 73 to 88]; hazard ratio, 0.37 [95% CI, 0.17 to 0.80]). One N-AVD and two BV-AVD patients received protocol-specified residual site radiotherapy (RT). Rates of febrile neutropenia and sepsis were low in both groups. Severe immune-related adverse events were infrequent, although thyroid dysfunction was seen in 7% with N-AVD. Sensory neuropathy (grade ≥2) was more frequent with BV-AVD (14% v 7%) by clinician report. Although premature discontinuation of therapy was reported in 12 N-AVD patients and four BV-AVD patients, no PFS events were noted in the N-AVD group. Patient-reported outcomes indicated less toxicity with N-AVD. N-AVD demonstrated high 3-year PFS in adolescents with AS cHL, with minimal RT use. S1826 exemplifies the benefits of harmonized clinical trial protocols, resulting in timely access to novel agents for adolescents.

Abstract Introduction CAR T cell treatment is the standard of care for patients (pts) with primary refractory and relapsed large B-cell lymphoma (LBCL) within the first 12 months of chemoimmunotherapy, or for those unfit for autologous stem cell transplant (ASCT) regardless of timing of relapse. Consequently, the role of ASCT is limited to pts with late relapse (>12 months) who achieve a complete or partial response (CR or PR) to salvage therapy and are deemed eligible for ASCT based on comorbidities and performance status. In this report, we evaluated post-ASCT outcomes in this population of pts. Methods We conducted a retrospective cohort study using publicly available data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult pts (age ≥18 years) with DLBCL, NOS, and high-grade large B-cell lymphomas (HGBL) who relapsed after having responded to initial treatment and who remained on response for at least 12 months since diagnosis were selected. We considered for this analysis only pts who achieved a CR or PR after salvage treatment at the time of relapse, documented on pre-ASCT CT or PET scan (per the 2014 Lugano definition). CIBMTR databases used for this study included pts who received ASCT from 2013 to 2021. We compared baseline characteristics between ASCT in CR vs PR using the Wilcoxon rank sum test for continuous variables and the Pearson's χ2 test for categorical variables after ignoring missing data. Primary endpoints included Progression-free survival (PFS) and overall survival (OS). Non-relapse mortality (NRM) and relapse rate were among the secondary endpoints. Results 182 were included in the analysis: 100 were in CR and 82 in PR before ASCT. The median age at ASCT was 60 years (range, 26-79). Race distribution was similar across CR and PR pts. Advanced-stage disease at diagnosis (stage III–IV) was seen in 61% of CR pts and 55% of PR pts. High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements was similar in the CR and PR groups (7% vs 4%). The median number of lines of treatment before ASCT were identical in CR and PR pts (N=2). BEAM was the most frequently used transplant conditioning regimen in both groups (80%). Median follow-up after ASCT was 34 months (range, 1–95): it was 37 months (range 1-95) in the CR group and 26 months (range 1-79) in the PR group For the entire cohort, OS at 3 years was 67.6% and PFS was 50.6%. NRM was 1.7% at 100 days and 3.4% at 1 year. Cumulative incidence of relapse at 3 years was 43.9%. The NRM analysis showed no statistically significant difference between pts in CR and PR. The 3-year OS for CR pts was 73.9%% compared to 59.4% for PR pts (95% CI, 0.334-0.99; p=.044). The 3-year PFS for CR pts was 59.8%, compared to 38.6% for PR pts (95% CI, 0.321-0.784; p=.001). The median PFS for CR pts was 52.01 months, compared to 14.05 months for PR pts. The cumulative incidence of relapse at 3 years in CR and PR pts was 35.2% vs 55.7%, respectively (95% CI, 0.311-0.811; p=.003.). Higher age (HR 1.03; p=.026) and number of previous lines of treatment (HR 1.43; p=.002) were associated with inferior OS. For PFS, no variables showed any significant impact in univariable analysis. The stepwise multivariable analysis showed that only the number of previous treatments had a significant impact on the OS (p=.009), while undergoing ASCT on a PR was the only factor significantly associated with shorter PFS (HR 1.41; 95% CI, 1.09-1.82; p=.029). Conclusion This dataset supports that ASCT provides high efficacy in pts experiencing late relapses (after 12 months) achieving CR following pre-transplant savage and validates the value of achieving CR. Outcomes for PR are inferior, and this analysis provides a benchmark for future investigations. At this time, until convincing on other non-transplant treatment show superior outcomes in this setting, ASCT remains a standard of care for fit pts with chemo-sensitive late relapsed DLBCL. In this group of patients, who have a better prognosis compared to patients who relapse within a year the major hurdle is achieving a remission pre-ASCT.

Abstract Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Although patients with FL have high response rates to therapy, most develop increasingly resistant disease. In addition, transformation into an aggressive lymphoma is associated with unfavorable outcomes. Many novel agents are under investigation, and early clinical data are encouraging. Aligning treatment with the underlying tumor biology and sequencing of therapies remain key clinical challenges. At the Lymphoma Research Foundation’s biannual 2024 Follicular Lymphoma Scientific Workshop, experts convened to discuss the role of chemotherapy in the context of new therapies, the impact of early progression on treatment sequencing, novel end points in clinical trials, disease biology and the tumor microenvironment, and new treatments on the horizon. This report focuses on updates in FL biology, first-line treatment, the role of progression of disease in 24 months, clinical trial design, and redefining cure in FL.

Abstract Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events, such as transformation or progression, have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, whether a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from 2 immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase 3 clinical trial, in which it assigned 169 patients to the low-risk group with 29 events before 24 months (17.2%) and 63 patients to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high-risk group relative to patients who were classified into the low-risk group was 2.2 (95% confidence interval, 1.41 to 3.51). An up-front GEP biomarker, such as the FL24Cx, rigorously validated in a clinical laboratory and with a clinically relevant turnaround time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

PURPOSE Lymphomas are a heterogeneous group of diseases that develop in individuals of all ages and have variable prognoses. Improved survival resulting from therapy advances has led to the emergence of diverse late effects. Although several (US)–based organizations have developed survivorship guidelines, the distinct features of lymphoma subtypes and diverse therapies used raise concerns regarding their applicability to lymphoma survivors. We compared survivorship recommendations (outside primary disease monitoring) between US clinical guidelines. METHODS We extracted information from 17 guidelines from five US-based organizations: ASCO (n = 11), American Cancer Society (n = 1), Children's Oncology Group (n = 1), Center for International Blood and Marrow Transplant Research (n = 1), and the National Comprehensive Cancer Network (n = 3). Guidelines were evaluated to determine whether they offer recommendations on physical effects , psychosocial and quality of life ( QOL ), and health promotion and prevention . Comparisons were focused on second primary malignancy, cardiovascular complications, and vaccination. RESULTS Survivorship recommendations on physical effects and psychosocial and QOL mainly differ in the timing and approaches for screening. Vaccination recommendations were primarily derived from other cancer populations. Identified research gaps were a lack of understanding of the risk of late effects across lymphoma subtypes, the role of social determinants of health in survivorship, and the lack of a survivorship care model that integrates lymphoma subtypes and treatment exposures. CONCLUSION This study raises awareness about the complexity and challenges of managing survivors under the umbrella diagnosis of lymphoma. The inconsistency and incompleteness of existing guidelines may lead to suboptimal survivorship care. We propose expert-based research priorities to address gaps and unmet needs to help develop risk-based follow-up recommendations to optimize survivorship care for lymphoma survivors.

Introduction: Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) Prognosis is highly variable due to underlying biological and molecular heterogeneity. The first-line (1L) treatment paradigm for MCL continues to evolve with increasing use of bruton tyrosine kinase inhibitors (BTKi) and decreasing use of autologous stem cell transplant (ASCT). TP53 alterations are associated with inferior outcomes in MCL. The aim of this retrospective study is to determine treatment strategies and clinical outcomes in MCL patients based on TP53 gene mutation status. Methods: Retrospective data were collected from 19 institutions in the United States from 1/1993 to 1/2024. We examined treatment patterns and outcomes among MCL patients >18 years of age with known TP53 mutation status by sequencing. Patients who did not receive treatment were excluded. The analysis was stratified based on presence of TP53 mutations. Systemic therapies were categorized as chemo-immunotherapy (CIT), non-chemotherapy (including monoclonal antibodies, lenalidomide, venetoclax, and novel agents on clinical trial), and regimens containing BTKi. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS) and time to next treatment (TTNT). OS and PFS were estimated with the Kaplan-Meier method and log-rank tests were used to compare groups. Results: 645 patients were included in the study, with 468 men (72.6%) and median age was 64 years (range 30-89). 230/645 patients (35.7%) had a TP53 mutation, of which 182 (79%) were identified prior to 1L. While the male/female distribution was the same between the mutated and unmutated groups, median age at diagnosis and MIPI risk score was higher in the TP53 mutated group (age 65.9 vs 63.1 yrs, p= 0.015; MIPI 6.4 vs 6.1, p<0.001). TP53 unmutated patients had a median of 1 line of therapy vs. 2 for the mutated group (p<0.001, range 1-8). Blastoid histology and higher ki67 were also associated with the TP53 mutated group (p=0.045, 0.01 respectively) The median OS was 14.2 years for TP53 unmutated and 8.3 years for TP53 mutated patients (p<0.0001). PFS in 1L was 0.95 years in TP53 mutated compared to 2.02 years in TP53 unmutated group (p<0.0001). Selection of 1L therapeutic strategy was not associated with presence of TP53 mutation (Χ2 p= 0.21) although more patients in the TP53 unmutated group underwent ASCT (119/415 vs 38/230; Χ2 p=0.0006) TP53 mutation was associated with inferior survival compared to TP53 unmutated patients for CIT in 1L but the difference did not reach statistical significance when non-chemotherapy regimens and regimens containing BTKi were used. For CIT in 1L, 5 year OS was 78% [71-84%] for unmutated compared to 58% [48-67%] for the mutated group (p=0.0001 ). For non-chemotherapy regimens, 5 year OS for unmutated patients was 73% [52- 86%] compared to 52% [25-73%] for the mutated group (p=0.09). For regimens containing BTKi, 5 year OS for unmutated was 93% [81-97%] compared to 57% [28-78%] for mutated (p=0.07). Within the TP53 mutated group, there were no differences in any clinical outcomes between those receiving CIT, non-chemotherapy, or BTKi in 1L. While median OS appeared numerically longer in the BTKi group (14.4 yrs vs 8.8 yrs for CIT and 6.8 yrs for non-chemotherapy), the difference did not reach statistical significance (p=0.58). In contrast,TP53 unmutated patients who received CIT in 1L had better TTNT (p=0.0039) compared to those in non-chemotherapy and BTKi groups. There was no improvement in PFS (p=0.79) or OS (p=0.47). Conclusions To our knowledge this is the largest retrospective real world dataset of MCL treatment outcomes stratified by TP53 mutation. As in prior studies, TP53 mutation portends a worse prognosis in MCL compared to TP53 unmutated patients, but outcomes are better than historically reported. CIT in 1L was not associated with improved OS in either group. Irrespective of TP53 mutation status, incorporation of BTKi in first line was not associated with improved clinical outcomes. The gap in OS between TP53 mutated and unmutated MCL may be narrowing as treatment paradigms shift away from intensive induction chemotherapy and ASCT, and due to an increasing number of effective therapies for relapsed patients. Clinical trials of novel agents are needed to further improve the OS of TP53 mutated MCL patients.

SummaryDespite the clinical and molecular heterogeneity of follicular lymphoma (FL), there remains a lack of biomarker‐directed therapeutic approaches in routine clinical practice, with the notable exception of the EZH2 inhibitor tazemetostat in EZH2‐mutant FL. Here we examined whether gene mutation status predicts response to clinical mTOR inhibitors (mTORi) in FL, by performing targeted mutational profiling of biopsies from 21 relapsed/refractory FL patients treated with mTORi everolimus or temsirolimus within clinical trials. We observed an enrichment of mutations within the catalytic histone acetyltransferase (HAT) domain of CREBBP in mTORi‐responders, and describe distinct transcriptional characteristics and co‐occurring mutations of FL harbouring these mutations; reinforcing the growing appreciation of CREBBPHAT mutation as a key biological determinant and its promise as a therapeutic biomarker in FL.