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.

Management of aggressive lymphoma after CAR T-cell therapy failure.

Several recent advances have affected the treatment landscape of diffuse large B-cell lymphoma. Chimeric antigen receptor (CAR) T-cell therapy has transformed the management of chemorefractory disease. Two randomized studies in early relapse disease have expanded the label to provide access to CAR T-cell therapy as early as second line for some patients. Despite the durable remissions that have been achieved, many patients will experience relapse. There is a growing population of patients previously treated with CAR T-cell therapy facing dismal outcomes. We review the prospective studies that inform treatment options in later lines and highlight the limited data examining outcomes with novel therapies after CAR T-cell failure. The treatment landscape is anticipated to continue to evolve with the emergence of bispecific antibodies that appear to be a promising approach, particularly after CAR T-cell therapy, although little is known about overlapping mechanisms of resistance. Enrichment for patients who have received prior CAR T-cell therapy on prospective trials is a critical unmet need to inform the preferred management for these high-risk patients.

Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Importance: Immune checkpoint inhibitors (ICIs) are increasingly used in patients with advanced hepatocellular carcinoma (HCC). However, data on ICI therapy in patients with advanced HCC and impaired liver function are scarce. Objective: To conduct a systematic review and meta-analysis to determine the efficacy and safety of ICI treatment for advanced HCC with Child-Pugh B liver function. Data Sources: PubMed, Embase, Web of Science, and Cochrane Library were searched for relevant studies from inception through June 15, 2022. Study Selection: Randomized clinical trials, cohort studies, or single-group studies that investigated the efficacy or safety of ICI therapy for Child-Pugh B advanced HCC were included. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline was followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 > 50%); otherwise, a fixed-effect model was used. Main Outcomes and Measures: The objective response rate (ORR) and overall survival (OS) were considered to be the primary efficacy outcomes of ICI treatment for Child-Pugh B advanced HCC, and the incidence of treatment-related adverse events (trAEs) was set as the primary measure for the safety outcome. Results: A total of 22 studies including 699 patients with Child-Pugh B and 2114 with Child-Pugh A advanced HCC comprised the analytic sample (median age range, 53-73 years). Upon pooled analysis, patients treated with ICIs in the Child-Pugh B group had an ORR of 14% (95% CI, 11%-17%) and disease control rate (DCR) of 46% (95% CI, 36%-56%), with a median OS of 5.49 (95% CI, 3.57-7.42) months and median progression-free survival of 2.68 (95% CI, 1.85-3.52) months. The rate of any grade trAEs in the Child-Pugh B group was 40% (95% CI, 34%-47%) and of grade 3 or higher trAEs was 12% (95% CI, 6%-23%). Compared with the Child-Pugh A group, the ORR (odds ratio, 0.59; 95% CI, 0.43-0.81; P < .001) and DCR (odds ratio, 0.64; 95% CI, 0.50-0.81; P < .001) were lower in the Child-Pugh B group. Child-Pugh B was independently associated with worse OS in patients with advanced HCC treated with ICIs (hazard ratio, 2.72 [95% CI, 2.34-3.16]; adjusted hazard ratio, 2.33 [95% CI, 1.81-2.99]). However, ICIs were not associated with increased trAEs in the Child-Pugh B group. Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that although the safety of ICI treatment was comparable between patients with HCC with vs without advanced liver disease and the treatment resulted in a significant number of radiologic responses, survival outcomes are still inferior in patients with worse liver function. More study is needed to determine the effectiveness of ICI treatment in this population.

How to Treat Diffuse Large B-Cell Lymphoma: Oncologic and Cardiovascular Considerations.

Anthracycline-containing therapy is the cornerstone of frontline treatment for diffuse large B-cell lymphoma (DLBCL), and autologous stem cell transplantation, and more recently, chimeric antigen receptor T-cell therapy are the primary treatment options for relapsed refractory DLBCL. Given these therapies are all associated with cardiovascular toxicities, patients with underlying cardiac comorbidities are severely limited in treatment options. The focus of this review is to outline the cardiotoxicities associated with these standard treatments, explore strategies developed to mitigate these toxicities, and review novel treatment strategies for patients with underlying cardiovascular comorbidities. DLBCL patients with underlying cardiac complications are a high-risk patient population who require complicated management strategies that utilize a multidisciplinary approach with collaboration between cardiologists and oncologists.

Thinking "outside the germinal center": Re-educating T cells to combat follicular lymphoma.

There have been significant advancements in the management of follicular lymphoma (FL), the most common indolent lymphoma. These include immunomodulatory agents such as lenalidomide, epigenetic modifiers (tazemetostat), and phosphoinotiside-3 kinase inhibitors (copanlisib). The focus of this review is T cell-engager therapies, namely chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies, have recently transformed the treatment landscape of FL. Two CAR T cell products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), and one bispecific antibody, mosunetuzumab, recently received FDA approvals in FL. Several other new immune effector drugs are being evaluated and will expand the treatment armamentarium. This review focuses on CAR T-cell and bispecific antibody therapies, details their safety and efficacy and considers their evolving role in the current treatment landscape of FL.

Cost-effectiveness of polatuzumab vedotin in combination with chemoimmunotherapy (pola-R-CHP) in previously untreated diffuse large B-cell lymphoma in Germany.

We evaluated the cost-effectiveness of frontline polatuzumab vedotin-R-CHP (pola-R-CHP) treatment for patients with diffuse large B-cell lymphoma (DLBCL) in Germany by using a Markov model (lifetime horizon). Progression rates and survival outcomes were extrapolated from the POLARIX trial. Outcomes were measured in incremental cost-effectiveness ratios (ICERS) with a willingness-to-pay (WTP) threshold of €80 000/quality-adjusted life-years (QALY). Assuming, 69.6% 5-year PFS with pola-R-CHP and 62.6% 5-year PFS with R-CHOP, the addition of polatuzumab vedotin resulted in an additional 0.52 life-years and an incremental 0.65 QALYs but €31 988 additional cost. Based on this, pola-R-CHP was cost-effective (€49 238/QALY) at a WTP of €80 000/QALY. The cost-effectiveness of pola-R-CHP is highly dependent on its long-term outcomes and cost. Our analysis is limited by the fact that the long-term outcomes of pola-R-CHP are unknown at this time.

Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.

Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.

Long-Term Follow-Up of Bridging Therapies Prior to CAR T-Cell Therapy for Relapsed/Refractory Large B Cell Lymphoma.

BACKGROUND: Bridging therapy (BT) with systemic therapy (ST), radiation therapy (RT), or combined-modality therapy (CMT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). We report the long-term outcomes of the patients who received commercial CAR T-cell therapy with or without BT. METHODS: The patients with LBCL who underwent infusion of a commercial CD19 CAR T product were eligible. The radiation was stratified as comprehensive or focal. The efficacy outcomes and toxicity were analyzed. RESULTS: In total, 156 patients were included and, of them, 52.5% of the patients received BT. The median progression-free survival (PFS) was 0.65 years in the BT cohort compared to 1.45 years in the non-BT cohort. The median overall survival (OS) was 3.16 years in the BT cohort and was not reached in the non-BT cohort. The patients who received comprehensive radiation (versus focal) had significantly improved PFS and OS, achieving a 1-year PFS of 100% vs. 9.1% and 1-year OS of 100% vs. 45.5%. There was no difference in the severe toxicity between any of the nonbridging or BT cohorts. CONCLUSIONS: BT did not appear to compromise outcomes with respect to response rates, disease control, survival, and toxicity. The patients with limited disease treated with RT had favorable outcomes.

Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Pevonedistat (TAK924) is a Nedd8-activating enzyme inhibitor with preclinical activity in non-Hodgkin lymphoma (NHL). This open-label, Phase I, multicenter, investigator-sponsored study enrolled patients with relapsed/refractory (R/R) NHL and chronic lymphocytic leukemia (CLL). The primary objective was safety. Pevonedistat was given intravenously on days 1, 3, 5 of a 21-day cycle for 8 cycles at five dose levels (15 to 50 mg/m2); ibrutinib was administered at 420 or 560 mg orally daily continuously. Eighteen patients with NHL were enrolled, including 8 patients with mantle cell lymphoma (MCL) and 4 patients with CLL. One dose-limiting toxicity (mediastinal hemorrhage) occurred at 50 mg/m2 of pevonedistat which is the estimated maximum tolerated dose. Bruising and diarrhea were the most common adverse events (56% and 44%). Atrial fibrillation occurred in 3 patients (17%). Grade ≥3 toxicities included arthralgia, atrial fibrillation, bone pain, diarrhea, hypertension, and mediastinal hemorrhage (one patient each). The overall response rate (ORR) was 65% (100% ORR in MCL). Pevonedistat disposition was not modified by ibrutinib. scRNA-Seq analysis showed that pevonedistat downregulated NFκB signaling in malignant B-cells in vivo. Thus, pevonedistat combined with ibrutinib demonstrated safety and promising early efficacy in NHL and CLL. NAE inhibition downregulated NFκB signaling in vivo.

Incorporating novel agents into frontline treatment of Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is associated with excellent outcomes with standard frontline chemotherapy or combined modality therapy. However, up to 25% of patients will have relapsed or primary refractory (RR) cHL. Improving the cure rate with frontline treatment, treatment-related complications and late effects, and poor therapy tolerance with high relapse rates in older patients are unmet needs in the initial management of cHL. The introduction of novel therapies, including the CD30-directed antibody drug conjugate brentuximab vedotin and PD-1 blockade (ie, pembrolizumab or nivolumab), has transformed the treatment of RR cHL and has the potential to address these unmet needs in the frontline setting. Incorporation of these potent, targeted immunotherapies into frontline therapy may improve outcomes, may allow for de-escalation of therapy without sacrificing efficacy to reduce treatment complications, and may allow for well-tolerated and targeted escalation of therapy for patients demonstrating an insufficient response. In this article, we provide a case-based approach to the use of novel agents in the frontline treatment of cHL.

Circulating Tumor DNA in Lymphoma.

PURPOSE OF REVIEW: Recent advances have been made in circulating tumor DNA (ctDNA), the method to minimally invasive detect lymphoma sensitively with tumor-derived DNA in the blood of patients with lymphomas. This article discusses these various methods of ctDNA detection and the clinical context in which they have been applied to for a variety of lymphoma subtypes. RECENT FINDINGS: ctDNA has been applied to a variety of subtypes of lymphoma and has been used in the context of genotyping somatic mutations and classification of disease, monitoring of response during treatment, detecting minimal residual disease even with radiographic remission, and predicting relapse and long-term survival outcomes. There are a variety of techniques used to measure ctDNA including digital polymerase chain reaction and next-generation sequencing techniques including high-throughput variable-diversity-joining rearrangement sequencing, high-throughput sequencing of somatic mutations, and Cancer Personalized Profiling by deep sequencing. While the greatest data has been generated in diffuse large B cell lymphoma, there have been studies utilizing application of ctDNA in follicular lymphoma, mantle cell lymphoma, Hodgkin's lymphoma, peripheral T cell lymphoma, and primary CNS lymphoma among others. ctDNA is an emerging biomarker in lymphoma that can minimally invasively provide further genotypic information, diagnostic clarification, and treatment prognostication by detection of minimal residual disease even without radiographic evidence of disease. Future studies are needed to standardize the use of ctDNA and translate its use clinically for the management of lymphoma patients.

Cost-effectiveness of second-line axicabtagene ciloleucel in relapsed refractory diffuse large B-cell lymphoma.

The ZUMA-7 (Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma) study showed that axicabtagene ciloleucel (axi-cel) improved event-free survival (EFS) compared with standard of care (SOC) salvage chemoimmunotherapy followed by autologous stem cell transplant in primary refractory/early relapsed diffuse large B-cell lymphoma (DLBCL); this led to its recent US Food and Drug Administration approval in this setting. We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapsed DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of second-line axi-cel compared with SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year EFS of 35% with second-line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of $150 000 per QALY ($93 547 per QALY). axi-cel was no longer cost-effective if its 5-year EFS was ≤26.4% or if it cost more than $972 061 at a WTP of $150 000. Second-line axi-cel was the cost-effective strategy in 73% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in EFS is maintained over time, second-line axi-cel for aggressive relapsed/refractory DLBCL is cost-effective compared with SOC at a WTP of $150 000 per QALY. However, its cost-effectiveness is highly dependent on long-term outcomes. Routine use of second-line chimeric antigen receptor T-cell therapy would add significantly to health care expenditures in the United States (more than $1 billion each year), even when used in a high-risk subpopulation. Further reductions in the cost of chimeric antigen receptor T-cell therapy are needed to be affordable in many regions of the world.

PD-1 Blockade After Avelumab in Relapsed/Refractory Classical Hodgkin Lymphoma.

BACKGROUND: Anti-PD-1 directed therapy is safe and effective in patients with relapsed/refractory (r/r) cHL and is currently being studied in the frontline setting. There are currently little data regarding the safety and efficacy of PD-1 blockade after prior PD-L1 blockade with agents such as avelumab. METHODS: This is a retrospective case series evaluating r/r cHL patients treated with avelumab who subsequently received at least 1 dose of PD-1 blockade. Primary objective is efficacy as measured by overall response rate. Secondary objectives include duration of response and time to progression on PD-1 blockade as well as safety as evaluated by incidence and severity of immune-related adverse events (irAE) with PD-1 blockade. RESULTS: There were 7 patients treated with PD-1 blockade after avelumab, of whom 4 were re-treated. The median follow-up was 46.8 months. At the time of PD-1 blockade initiation median age was 36.6 years, all patients had advanced stage, 1 patient had B symptoms, and 4 patients had extranodal disease. Patients received median 7 prior lines of therapy including avelumab. Median duration on anti-PD-1 treatment was 15.9 months. A response was observed in 86% of patients with median duration of response of 26.4 months and median time to progression of 22.2 months. Only 1 patient experienced an irAE (grade 2 pneumonitis). CONCLUSION: Our study suggests that PD-1 blockade after PD-L1 blockade in r/r cHL appears safe and may be effective with durable responses observed in a subset of patients.

Cost-effectiveness of polatuzumab vedotin combined with chemoimmunotherapy in untreated diffuse large B-cell lymphoma.

In patients with treatment-naive diffuse large B-cell lymphoma (DLBCL), the POLARIX study (A Study Comparing the Efficacy and Safety of Polatuzumab Vedotin With Rituximab-Cyclophosphamide, Doxorubicin, and Prednisone [R-CHP] Versus Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [R-CHOP] in Participants With Diffuse Large B-Cell Lymphoma) reported a 6.5% improvement in the 2-year progression-free survival (PFS), with no difference in overall survival (OS) or safety using polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) compared with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We evaluated the cost-effectiveness of pola-R-CHP for DLBCL. We modeled a hypothetical cohort of US adults (mean age, 65 years) with treatment-naive DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of pola-R-CHP and R-CHOP using a range of plausible long-term outcomes. Progression rates and OS were estimated from POLARIX. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year PFS of 69.6% with pola-R-CHP and 62.7% with R-CHOP, pola-R-CHP was cost-effective at a WTP of $150 000 (incremental cost-effectiveness ratio, $84 308/QALY). pola-R-CHP was no longer cost-effective if its 5-year PFS was 66.1% or lower. One-way sensitivity analysis revealed that pola-R-CHP is cost-effective up to a cost of $276 312 at a WTP of $150 000. pola-R-CHP was the cost-effective strategy in 56.6% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in PFS is maintained over time, pola-R-CHP is cost-effective compared with R-CHOP at a WTP of $150 000/QALY. However, its cost-effectiveness is highly dependent on its long-term outcomes and costs of chimeric antigen receptor T-cell therapy. Routine usage of pola-R-CHP would add significantly to health care expenditures. Price reductions or identification of subgroups that have maximal benefit would improve cost-effectiveness.

Role of Salvage Radiation Treatment of Relapses in Relapsed/Refractory Diffuse Large B Cell Lymphoma Post-Autologous Stem Cell Transplant.

PURPOSE: Approximately 50% of patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) will relapse post-autologous stem cell transplant (ASCT), and the role of salvage therapy is not well defined. We examined radiation therapy (RT) as salvage treatment in this patient population. MATERIALS AND METHODS: A retrospective review of patients with DLBCL who had an ASCT during 2004 to 2016 and subsequently relapsed was performed. Clinical and pathologic characteristics were collected, including detailed information regarding post-ASCT treatment. Response rates were tabulated and survival analysis was performed, stratified by salvage modality. RESULTS: A total of 165 patients with R/R DLBCL who relapsed after ASCT were identified; 91 of these patients received salvage chemotherapy as their first line of relapse therapy, and 14 received salvage radiation. Median salvage RT dose was 36 Gy (range, 24-50). The objective response rate with salvage chemotherapy and RT was 53.0% and 78.5%, respectively (P = 0.07), and the complete response rate was 31.3% and 57.1%, respectively (P = 0.06). Median follow-up among living patients was 48.9 months (range, 4.8-136.17). Among patients with one site of relapse post-ASCT, median overall survival in patients who received salvage RT was significantly improved (P = 0.008) relative to chemotherapy (not reached [95% confidence interval {CI}, 8.4-not reached] versus 10.0 months [95% CI, 5.3-17.8]). Median progression-free survival in patients who received salvage RT was not significantly different (P = 0.16) relative to chemotherapy (8.4 months [95% CI, 2.5-47.7] versus 3.9 months [95% CI, 2.4-8.5]). CONCLUSIONS: Patients who received RT as first salvage therapy post-ASCT, particularly with localized disease, had favorable oncologic outcomes. Future studies are needed to understand which patients with R/R DLBCL who relapse after ASCT may benefit from early salvage RT versus chemotherapy.

Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T-cell therapy.

B-cell maturation antigen-targeted chimeric antigen receptor T-cell therapy (BCMA CAR-T) is an effective treatment of relapsed refractory multiple myeloma (MM). However, the pattern of infectious complications is not well elucidated. We performed a single-center retrospective analysis of infection outcomes up to 1 year after BCMA CAR-T for MM from 2018 to 2020. Fifty-five patients with MM were treated with BCMA CAR-T. Before lymphodepletion (LD), 35% of patients had severe hypogammaglobulinemia and 18% had severe lymphopenia. Most patients (68%) received bridging chemotherapy (BC) before LD. In the first month after CAR-T, 98% patients had grade 3 to 4 neutropenia. At 1 year after infusion, 76% patients had hypogammaglobulinemia. With a median follow-up of 6.0 months (95% confidence interval, 4.7-7.4), there were a total of 47 infection events in 29 (53%) patients: 40% bacterial, 53% viral, and 6% fungal. Most (92%) were mild-moderate and of the lower/upper respiratory tract system (68%). Half of the infections (53%) occurred in the first 100 days after CAR-T infusion. Although no statistically significant risk factors for infection were identified, prior lines of therapy, use of BC, recent infections, and post-CAR-T lymphopenia were identified as possible risk factors that need to be further explored. This is the largest study to date to assess infectious complications after BCMA CAR-T. Despite multiple risk factors for severe immunosuppression in this cohort, relatively few life-threatening or severe infections occurred. Further larger studies are needed to better characterize the risk factors for and occurrence of infections after BCMA CAR-T.

Early Time-to-Tocilizumab after B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy in Myeloma.

Preemptive administration of tocilizumab (toci) to manage cytokine release syndrome (CRS) after chimeric antigen receptor T cell (CAR-T) therapy may reduce rates of serious CRS but conversely may worsen neurotoxicity or risk of infections. Optimal toci administration strategies for patients with relapsed/refractory multiple myeloma (RRMM) receiving B cell maturation antigen (BCMA)-directed CAR-T therapies have not been evaluated. The objective of this study was to identify whether shorter time-to-toci intervals (hours between first fever attributed to CRS and first dose of toci) have any impact on therapy-related toxicities or clinical outcomes among patients with RRMM receiving BCMA-directed CAR-T therapies. We retrospectively analyzed our institution's experience with 4 BCMA-directed CAR-T therapies (idecabtagene vicleucel, bb21217, ciltacabtagene autoleucel, and orvacabtagene autoceucel) for RRMM over a 3-year period ending in June 2020. We divided patients based on the administration of toci and median time-to-toci interval into early-toci (time-to-toci ≤50th percentile), late-toci (time-to-toci >50th percentile), and no-toci (no toci received) groups. We compared the early-toci and late-toci groups with regard to patient characteristics, weight-based CAR-T toxicities, selected toxicities (CRS, neurotoxicity, macrophage activation syndrome, or infections), and clinical outcomes. Of 50 analyzed patients with a median follow-up of 15.3 months, 76% (n = 38) received ≥1 dose of toci (range, 1 to 3) and were classified into early-toci (time-to-toci ≤12 hours) or late-toci (time-to-toci >12 hours) groups. The 2 groups (n = 19 each) had similar CRS grade distributions, hours to CRS onset, CRS-related biomarkers, and incidences of neurotoxicity or severe infections; however, weight-adjusted CAR-T cell doses were higher in the early-toci group (median 5.99 versus 3.80 × 106 cells/kg, P < 0.01). Peak CRS grades (range, 0 to 2) using American Society for Transplantation and Cellular Therapy consensus criteria, neurotoxicity rates, and rates of severe infections were similar between groups; however, the median CRS duration was 18.6 hours for the early-toci group versus 84.7 hours for the late-toci group. The median progression-free survival was 35.7 months in the early-toci group and 13.2 months in the late-toci group. While limited by small sample size and known confounders such as CAR-T cell dose, our analysis suggests that preemptive toci strategies for CRS management with BCMA-directed CAR-T therapy-specifically, toci administration within 12 hours of the first fever attributed to CRS-do not appear to increase rates of therapy-related toxicities or compromise efficacy. However, total CRS duration may be shorter with early-toci workflows. Prospective validation of our findings may lead to improved safety and cost-effectiveness profiles for CAR-T therapy in RRMM.

Carfilzomib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma: A Phase I Trial.

INTRODUCTION: We designed a multicenter, phase Ib dose-escalation trial of carfilzomib with bendamustine and rituximab in patients with relapsed/refractory non-Hodgkin lymphoma (NCT02187133) in order to improve the response rates of this difficult-to-treat population. Chemoimmunotherapy with bendamustine and rituximab has shown activity in a variety of lymphomas, and proteasome inhibitors have demonstrated pre-clinical synergy and early clinical activity in this population. The objectives were to determine the maximum tolerated dose of carfilzomib and the preliminary efficacy of this combination. PATIENTS AND METHODS: The protocol followed a 3+3 design of carfilzomib dose escalation combined with standard doses of bendamustine and rituximab. Patients were treated for up to 6 cycles with an interim positron emission tomography/computed tomography after cycle 3. RESULTS: Ten patients were treated on the dose-escalation phase. The study was terminated at a carfilzomib dose of 56 mg/m2, and the maximum tolerated dose was not reached. The most common grade 3/4 adverse event was thrombocytopenia. There was 1 dose-limiting toxicity observed, grade 3 febrile neutropenia, and there were no treatment-related deaths. The overall response rate was 40% (complete response rate, 30%), with a median duration of response of 12 months and a median progression-free survival of 2.1 months. CONCLUSION: Carfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for patients with relapsed/refractory non-Hodgkin lymphoma. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options.

Barriers to achieving a cure in lymphoma.

Lymphoma is a diverse disease with a variety of different subtypes, each characterized by unique pathophysiology, tumor microenvironment, and underlying signaling pathways leading to oncogenesis. With our increasing understanding of the molecular biology of lymphoma, there have been a number of novel targeted therapies and immunotherapy approaches that have been developed for the treatment of this complex disease. Despite rapid progress in the field, however, many patients still relapse largely due to the development of drug resistance to these therapies. A better understanding of the mechanisms underlying resistance is needed to develop more novel treatment strategies that circumvent these mechanisms and design better treatment algorithms that personalize therapies to patients and sequence these therapies in the most optimal manner. This review focuses on the recent advances in therapies in lymphoma, including targeted therapies, monoclonal antibodies, antibody-drug conjugates, cellular therapy, bispecific antibodies, and checkpoint inhibitors. We discuss the genetic and cellular principles of drug resistance that span across all the therapies, as well as some of the unique mechanisms of resistance that are specific to these individual classes of therapies and the strategies that have been developed to address these modes of resistance.