Evaluating the impact of laboratory-based eligibility criteria by race/ethnicity in first-line clinical trials of DLBCL.

ABSTRACT: Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 laboratory-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression, suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Using data from the prospectively enrolled Lymphoma Epidemiology Outcomes cohort study, with demographics broadly similar to the US patients diagnosed with lymphoma, we evaluated the impact of laboratory eligibility criteria from recent first-line DLBCL trials across various racial and ethnic backgrounds. There were significant differences in the baseline laboratory values by race/ethnicity with Black/African American (AA) patients having the lowest mean hemoglobin and highest creatinine clearance. Based on recent clinical trial eligibility criteria, AA and Hispanic patients had higher rates of laboratory-based ineligibility than non-Hispanic White patients. The largest gap in the clinical outcomes between eligible and noneligible patients was noted within AA patients with an overall survival hazard ratio based on POLARIX clinical trial criteria of 4.09 (95% confidence interval, 1.83-9.14). A thoughtful approach to the utility of each criterion and cutoffs for eligibility needs to be evaluated in the context of its differential impact across various racial/ethnic groups.

Impact of race and social determinants of health on outcomes in patients with aggressive B-cell NHL treated with CAR-T therapy.

ABSTRACT: Chimeric antigen receptor (CAR) T-cell (CAR-T) immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care use and outcomes in patients treated with CAR-T therapy for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-Ts were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic, and clinical data were collected and analyzed. In total, 466 adult patients were included in our analysis. Median follow-up after CAR-T therapy was 12.7 months. Median progression-free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months; hazard ratio [HR], 1.56 [1.03-2.4]; P = .04) or Asians (2.7 months; HR, 1.7 [1.02-2.67]; P = .04). Differences in median overall survival (mOS) were not significant. For Medicare (n = 206) vs Medicaid (n = 33) vs private insurance (n = 219) vs self-pay (n = 7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (P < .001), respectively; and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (P < .001), respectively. Our multicenter retrospective analysis showed that race and insurance status can affect outcomes for patients treated with CAR-T therapy.

Outcomes of patients with secondary central nervous system lymphoma following CAR T-cell therapy: a multicenter cohort study.

Chimeric antigen receptor T-cell therapy (CAR-T) has been successful in treating relapsed/refractory B-cell lymphomas. However, its role in the treatment of diseases involving the central nervous system (CNS) is not well studied. We performed a multicenter retrospective cohort study to evaluate the outcomes of patients with secondary CNS lymphoma (SCNSL) who received CAR-T. Eligibility required active CNSL at the time of apheresis. The objectives included evaluation of overall survival (OS), progression-free survival (PFS), identification of predictors of complete response (CR) post-CAR-T, and assessment of risk factors for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Sixty-one patients were included in the analysis. The overall response rate was 68% with a CR rate of 57%. In the multivariable analysis, patients who experienced any grade CRS had higher odds of achieving CR (OR = 3.9, 95% CI = 1.01-15.39, p = 0.047). The median PFS was 3.3 months (95% CI = 2.6-6.0 months) with 6- and 12-month PFS rates of 35% and 16%, respectively. The median OS was 7.6 months (95% CI = 5.0-13.5 months) with 6- and 12-month OS rates of 59% and 41%, respectively. Any grade CRS and ICANS were 70% (n = 43) and 57% (n = 34), respectively with grade ≥ 3 CRS and ICANS rates of 16% and 44%. Factors associated with increased risk of CRS and ICANS included receiving axi-cel or having leptomeningeal ± parenchymal + CNS involvement, respectively. Despite achieving high response rates, most patients experience early relapse or death following CAR-T in SCNSL. The current study provides a benchmark for future trials exploring novel therapeutic options in SCNSL.

Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study.

ABSTRACT: In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.

Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 US institutions.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes.

A multicenter analysis of the outcomes with venetoclax in patients with relapsed mantle cell lymphoma.

To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.

Peri-CAR-T practice patterns and survival predictors for all CAR-T patients and post-CAR-T failure in aggressive B-NHL.

Most patients receiving chimeric antigen receptor T-cell therapy (CAR-T) for aggressive B-cell non-Hodgkin lymphoma (B-NHL) do not experience a durable remission. Several novel agents are approved to treat relapsed, refractory aggressive B-NHL; however, it remains unclear how to sequence these therapies pre- and post-CAR-T. We conducted a multicenter retrospective analysis to describe peri-CAR-T practice patterns and survival predictors for patients receiving CD19-directed CAR-T. Patients (n = 514) from 13 centers treated with CAR-T for B-NHL between 2015-2021 were included in the study. Survival curves were constructed using Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of the variables on survival outcomes. For all patients receiving CAR-T, a greater number of lines of therapy pre-CAR-T apheresis and bridging therapy were predictive of inferior progression-free survival (PFS) and overall survival (OS). The median PFS and OS from the time of CAR-T cell infusion were 7.6 and 25.6 months, respectively. From the time of progression post-CAR-T, the median OS was 5.5 months. The median PFS of treatments administered in the first-line post-CAR-T failure was 2.8 months. Patients with refractory disease on day 30 had inferior OS and were less likely to receive subsequent treatment(s) than other patients with CAR-T failure. Allogeneic hematopoietic cell transplantation for selected patients at any time following CAR-T failure led to durable responses in over half of patients at 1 year. These data provide a benchmark for future clinical trials in patients with post-CAR-T cell progression, which remains an unmet clinical need.

Ixazomib With or Without Rituximab Following Maintenance Autologous Stem Cell Transplant in Mantle Cell Lymphoma: A Single-Center Phase I Trial.

BACKGROUND: Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard first-line treatment for fit patients with mantle cell lymphoma (MCL). We conducted a single-center phase I trial investigating post-transplant maintenance with ixazomib, an oral proteasome inhibitor. METHODS: Patients enrolled between days +70 and +180 post ASCT. Patients received ixazomib per dose cohort on days 1, 8, and 15 of each 28-day cycle for up to 10 cycles. During recruitment, published phase III data reported a survival benefit with rituximab maintenance, so all subsequent patients received ixazomib 4 mg at the same schedule along with rituximab 375 mg/m2 on day 1 of cycles 1, 3, 5, 7, and 9. All patients were in complete remission at enrollment. RESULTS: Seven patients received ixazomib monotherapy; 1 dose limiting toxicity (grade 3 neutropenia) occurred at dose level 2 (4 mg). Five patients received combination Ixazomib plus rituximab, with 2 experiencing DLTs (both Grade 4 neutropenia). Grade 3-4 neutropenia, lymphopenia, and thrombocytopenia occurred in 57%, 8%, and 8% of patients, respectively. Non-hematologic adverse events (AE) included nausea (42%), peripheral neuropathy (42%), and abdominal discomfort (33%), all of which were grade 1 or 2 in severity. There were no infectious AEs. With a median follow up of 46 months, all patients are alive and in complete remission. CONCLUSION: The trial was closed to further accrual due to high rates of treatment-related myelosuppression. The current dose and schedule of ixazomib, especially when combined with rituximab, results in unacceptable hematologic toxicity when administered as post-transplant maintenance in MCL. Ixazomib maintenance micro abstract: The authors conducted a phase I study investigating the use of ixazomib, an oral proteasome inhibitor, with or without rituximab in patients with mantle cell lymphoma in first remission following chemoimmunotherapy and autologous stem cell transplantation. All patients treated on study remain in complete remission with a median follow-up of 46 months, but the study was closed early due to a high rate of hematologic adverse events.

SOHO State of the Art Updates and Next Questions: Managing Relapsed Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma i.e., incurable with current therapies. While some patients experience prolonged remissions following initial therapy, most will have a relapsing-remitting course requiring several lines of treatment over the course of their disease. Several targeted therapies are now available to treat patients with relapsed MCL. The Bruton's tyrosine kinase (BTK) inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, are highly active in MCL and currently approved for treating patients with relapsed disease. Bortezomib and lenalidomide are available as monotherapy or in combination with other agents. Venetoclax is active and can be considered for use in relapsed MCL, although it is not currently approved by regulatory agencies. Chimeric antigen receptor T-cell (CAR-T) therapy with brexucabtagene autoleucel yields high response rates and is now approved for patients with relapsed MCL. Allogeneic stem cell transplant remains an option for a small subset of medically fit and motivated patients who have progressed through multiple lines of therapy, although its use is limited by substantial toxicity. There is currently no standard approach to sequencing therapies for patients with relapsed MCL, and the ability to utilize disease biologic and clinical characteristics to guide treatment decisions in this setting remains limited. In this review, we summarize the current evidence to guide the management of patients with relapsed MCL, review emerging agents and combination therapies that are under investigation, and outline our current treatment approach for these patients.

Antibody binding and neutralization of live SARS-CoV-2 variants including BA.4/5 following booster vaccination of patients with B-cell malignancies.

Non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) patients elicit inadequate antibody responses after initial SARS-CoV-2 vaccination and remain at high risk of severe COVID-19 disease. We investigated IgG, IgA, and IgM responses after booster vaccination against recent SARS-CoV-2 variants including Omicron BA.5 in 67 patients. Patients had lower fold increase and total anti-spike binding titers after booster than healthy individuals. Antibody responses negatively correlated with recent anti-CD20 therapy and low B cell numbers. Antibodies generated after booster demonstrated similar binding properties against SARS-CoV-2 variants compared to those generated by healthy controls with lower binding against Omicron variants. Importantly, 43% of patients showed anti-Omicron BA.1 neutralizing antibodies after booster and all these patients also had anti-Omicron BA.5 neutralizing antibodies. NHL/CLL patients demonstrated inferior antibody responses after booster vaccination, particularly against Omicron variants. Prioritization of prophylactic and treatment agents and vaccination of patients and close contacts with updated vaccine formulations are essential.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Sequencing of Novel Therapies for Mantle Cell Lymphoma.

OPINION STATEMENT: There is no standard approach to sequencing novel therapies in mantle cell lymphoma (MCL). For initial treatment, intensive induction chemotherapy followed by autologous stem cell transplant and rituximab maintenance remains our preferred approach in young, fit patients. We consider bendamustine plus rituximab or lenalidomide plus rituximab in patients who are ineligible for intensive chemotherapy-based approaches. Bruton's tyrosine kinase inhibitors are our preferred class of agents to use in the second-line setting. When patients inevitably relapse on one of these agents, we proceed with chimeric antigen receptor T-cell (CAR T) therapy in eligible patients, often with the use of bridging therapy with corticosteroids, lenalidomide, or venetoclax. We treat patients who are ineligible for CAR T or clinic trial with venetoclax, lenalidomide, or proteosome inhibitor-based regimens, although efficacy is expected to be limited in this setting with a shortened duration of response to each subsequent line of therapy. Allogeneic stem cell transplant remains an option for carefully selected patients who progress after autologous stem cell transplant and CAR T. Clinical trials involving combinations of novel agents in early lines of therapy are ongoing, and new compounds with unique mechanisms of action are in development. The results of ongoing clinical trials with novel agents will further change the treatment landscape for patients with MCL in the coming years.

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.

Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

Is Limited-Stage Mantle Cell Lymphoma Curable and How Is It Best Managed?

Limited-stage (stage I-II) mantle cell lymphoma (MCL) is rarely encountered. There is no standard approach to treatment and available data to guide management decisions mainly are retrospective studies. A thorough staging evaluation, including positron emission tomography/computed tomography, bone marrow biopsy, and gastrointestinal evaluation, should be completed because disseminated disease is common. Radiation therapy is effective for local control, and, although prolonged remission can be achieved, distant relapses are common and there are insufficient data to say that patients can be cured using this treatment. This article reviews literature pertaining to management of patients with limited-stage MCL and discusses approach to treatment.

Management of Older Adults with Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma that is largely a disease of older adults with a median age at diagnosis of 67 years. MCL is considered incurable with current therapies and has historically been associated with a poor prognosis. A subset of patients will present with features of more indolent disease and can be safely observed for a period of time after diagnosis, but the majority will require treatment at some point in the disease course. Younger patients who are eligible to undergo intensive induction chemotherapy followed by consolidation with an autologous stem cell transplant can experience prolonged survival times with a median overall survival of 13 years; however, there are limited data to support this treatment approach in older adults and these patients often have medical comorbidities that preclude such intensive therapy. Fortunately, an increased understanding of the disease biology has led to the development of novel therapies in recent years that are well-tolerated and have led to improved outcomes in this patient population. In this article, we will review the current treatment landscape for older adults with MCL, with a focus on the safety and efficacy of chemotherapy regimens and novel agents such as lenalidomide, bortezomib, and the Bruton's tyrosine kinase inhibitors that have been formally studied in this population.

The Clinical Significance of Initial Pulmonary Micronodules in Young Sarcoma Patients.

BACKGROUND: The clinical significance of subcentimeter nodules identified on staging chest computed tomography (CT) for sarcoma remains unknown. Our goal was to evaluate the effect of initial pulmonary nodule size and number on survival rates in young, newly diagnosed sarcoma patients. METHODS: Medical records were reviewed for all patients ≤50 years of age with primary, high-grade bone or soft tissue sarcoma at our institution over a 10-year period. This population was divided into patients with no nodules (group 1); 1 nodule <5 mm (group 2);>1 nodule <5 mm (group 3); and ≥1 nodule ≥5 mm (group 4). Kaplan-Meier analyses with log rank tests were performed to compare overall and disease-free survival between these 4 groups, as well as between patients with unilateral and bilateral nodules. RESULTS: There were 74 patients in group 1 (59.2%), 26 in group 2 (21%), 11 in group 3 (9%), and 13 in group 4 (10%). Mean follow-up was 74 (range, 6 to 191 mo) months. Survival was only slightly worse with larger nodules but significantly worse with multiple nodules. In addition, patients with bilateral nodules had a significantly worse prognosis than those with multiple unilateral nodules. CONCLUSIONS: These data suggest that in young patients with high-grade sarcoma, the number and distribution of subcentimeter pulmonary nodules are an important prognostic factor, whereas nodule size may be less relevant.