Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma.

Although CD20xCD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in CNS lymphoma is unknown. Here, we report the CD20xCD3 bispecific, glofitamab, penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces responses in CNS lymphoma.

Update on bi-specific monoclonal antibodies for blood cancers.

PURPOSE OF REVIEW: The purpose of this review is to present updates in the field of bispecific antibodies focusing on those agents that have been recently approved for multiple myeloma, follicular lymphoma and diffuse large B cell lymphoma. RECENT FINDINGS: Teclistamab, the ß-cell maturation antigen -targeted bispecific antibody has shown efficacy and tolerability in the fourth line setting for multiple myeloma. Mosunetuzumab, the CD20-targeted bispecific antibody has shown excellent response rates and durability in third line and beyond follicular lymphoma. Epcoritamab and glofitamab have both shown excellent response rates in heavily pretreated patients with diffuse large B cell lymphoma including those with prior chimeric antigen receptor T cell therapy. The toxicity is significant but manageable for both agents. Epcoritamab is approved by the FDA in the United States, while glofitamab is approved for use in Canada for patients with diffuse large B cell lymphoma refractory to 2 or more prior lines of therapy. SUMMARY: Bispecific antibodies represent a novel therapeutic resource that is poised to dramatically change the treatment landscape of many hematologic malignancies, but so far, initial successes include multiple myeloma, follicular lymphoma, and diffuse large B cell lymphoma, where several agents have been recently approved.

Association Between Pretreatment Skeletal Muscle and Outcomes After CAR T-Cell Therapy.

BACKGROUND: The purpose of this study was to examine the association between baseline skeletal muscle measurements, acute toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS], cytokine release syndrome), and treatment efficacy in patients undergoing CAR T-cell therapy for B-lineage lymphoma. PATIENTS AND METHODS: Skeletal muscle measurements were obtained from automated CT measurements in 226 consecutive patients who received CAR T-cell therapy between 2015 and 2021. The Kaplan-Meier method was used to examine progression-free survival (PFS) and overall survival (OS) at 1-year. Multivariable regression was used to calculate the hazard ratio (HR) with 95% confidence intervals, adjusted for covariates. RESULTS: The median age of the cohort was 63.1 years (range, 18.5-82.4 years), and most patients were male (66%) and had primary refractory disease (58%). Patients with abnormally low skeletal muscle at baseline were at greater risk of ICANS (HR, 1.74; 95% CI, 1.05-2.87) and had longer length of hospitalization (mean 27.7 vs 22.9 days; P<.05) compared with those with normal muscle mass. Abnormal skeletal muscle was independently associated with risk of disease progression (HR, 1.70; 95% CI, 1.11-2.57) and worse survival (HR, 2.44; 95% CI, 1.49-4.00) at 1 year compared with normal skeletal muscle. Individuals who had abnormal skeletal muscle and high lactate dehydrogenase (LDH) levels at baseline had poor 1-year PFS (17%) and OS (12%) compared with those with normal skeletal muscle and LDH levels (72% and 82%, respectively; P<.001). Patients who had abnormal skeletal muscle and LDH levels had a 5-fold risk (HR, 5.34; 95% CI, 2.97-9.62) of disease progression and a 10-fold risk (HR, 9.73; 95% CI, 4.81-19.70) of death (reference: normal skeletal muscle, normal LDH), independent of prior lines of therapy, extent of residual disease at time of CAR T-cell therapy, functional status, or product. CONCLUSIONS: This information can be used for risk stratification prior to CAR T-cell therapy or to implement prehabilitation and nutritional optimization before lymphodepletion as well as thereafter. These efforts will be complementary to ongoing efforts toward sustained efficacy after CAR T-cell therapy.

Bendamustine lymphodepletion is a well-tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B-cell lymphoma.

Fludarabine/cyclophosphamide (Flu/Cy) is established for lymphodepletion (LD) prior to standard-of-care CAR T-cell therapy for lymphoma. There is ongoing need to test alternative LD regimens to preserve efficacy, improve safety, and address challenges including the recent national fludarabine shortage. We retrospectively evaluated outcomes among patients with relapsed/refractory aggressive B-cell lymphoma who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axicabtagene ciloleucel (axi-cel) at our institution. The median change in absolute lymphocyte count from pre-LD to time of axi-cel infusion was -0.6×109 /L in bendamustine cohort and -0.7×109 /L in Flu/Cy cohort. The best overall response/complete response rates were 77.8% (95% CI: 57.7%-91.4%)/48.1% (95% CI: 28.7%-68.1%) among bendamustine cohort and 81.0% (95% CI: 65.9%-91.4%)/50.0% (95% CI: 34.2%-65.8%) among Flu/Cy cohort. Six-month progression-free survival were 43.8% (95% CI: 24.7%-61.3%) and 55.6% (95% CI: 39.0%-69.3%) in bendamustine and Flu/Cy cohorts, while 6-month overall survival were 81.5% (95% CI: 61.1%-91.8%) and 90.4% (95% CI: 76.4%-96.3%), respectively. Relative to Flu/Cy-treated patients, bendamustine-treated patients did not show an increase in hazards associated with experiencing progression/relapse/death (aHR:1.4 [95% CI: 0.7-2.8]; p = .32) or death (aHR:1.6 [95% CI: 0.5-5.6]; p = .46), after adjusting for baseline number of prior therapies and refractory disease. Any grade/grade ≥3 CRS were observed in 89%/3.7% and 86%/4.8% among bendamustine and Flu/Cy cohorts, while any grade ICANS/grade ≥3 ICANS were observed in 30%/19% and 55%/31% respectively. While more Flu/Cy-treated patients experienced grade ≥3 neutropenia compared with bendamustine-treated patients (100% vs. 68%), grade ≥3 infectious complications were comparable (24% vs. 19% respectively). More patients received bendamustine LD and axi-cel as outpatient than Flu/Cy cohort, without increased toxicities and with shorter median inpatient stays. In conclusion, we observed comparable efficacy and lower any grade ICANS among patients receiving bendamustine relative to Flu/Cy LD, followed by axi-cel.

Current status of phosphoinotiside-3 kinase inhibitors in blood cancers.

PURPOSE OF REVIEW: Treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) underwent paradigm shifts, with targeted agents rapidly displacing chemotherapy. Phosphoinotiside-3 kinase (PI3K) is essential for survival and proliferation of neoplastic B cells and has proven a tractable target in NHL, with four agents receiving FDA approval in the last decade. This review summarizes key data and challenges associated with use of PI3K inhibitors in routine practice. RECENT FINDINGS: Idelalisib and duvelisib are active in CLL and indolent NHL, including in patients with high-risk features. Despite differential targeting of PI3K isoforms, they exhibit comparable efficacy and adverse event profile including autoimmune events (transaminitis, colitis, pneumonitis), mediated by Treg/Th17 imbalance. Although copanlisib, a pan-PI3K inhibitor, is associated with a distinct safety profile (hyperglycemia, hypertension), preclinical studies indicate that umbralisib, a dual inhibitor of PI3Kδ and casein kinase 1ε, may have less effect on Tregs. However, both drugs may still cause immune-mediated toxicities. SUMMARY: With close monitoring and management of adverse events, PI3K inhibitors continue to have a role in therapy of R/R CLL and NHL. Strategies to mitigate adverse events and increase efficacy of PI3K inhibitors include time-limited combination approaches, intermittent dosing schedules.

CAR T-Cell Therapy in the Older Person: Indications and Risks.

PURPOSE OF REVIEW: Validated metrics to optimize older adult patient selection for Chimeric Antigen Receptor T-cell therapy (CART) are lacking; however, some preliminary data suggests that geriatric assessments and cumulative illness rating score may be useful tools. In addition, interventions capable of enhancing outcomes in older adults receiving CART have yet to be elucidated. The purpose of this review is to present data extrapolating from other diseases and therapeutic modalities, related to product selection, toxicity mitigation strategies, comprehensive coordinated models of care, and functional optimization of patients. RECENT FINDINGS: The most robust data in older adults are among relapsed and refractory (r/r) diffuse large B-cell lymphoma (DLBCL) patients where three products are available with the longest clinical follow up and the most abundant real-world evidence (RWE). Data for the approved CART products for follicular lymphoma (FL) and mantle cell lymphoma (MCL) are relatively new and RWE is lacking in general. Data for CART products in multiple myeloma (MM) and B-cell acute lymphoblastic leukemia (B-ALL) are even more recent, but preliminary data in older adults seem to follow the trend of excellent efficacy in this age group with age-stratified toxicity data limited. Landmark trials and RWE studies indicate that the high response rates of CART for older adult patients, age 65 years and older, are maintained, while toxicity may be amplified. Clinically important toxicities include grade 3 or higher cytokine release syndrome (CRS), neurotoxicity, and infections.

Chimeric Antigen Receptor (CAR) T Cell Therapy for B-Acute Lymphoblastic Leukemia (B-ALL).

With the exploitation of adoptive immunotherapies, the outcomes of patients with relapsed and refractory B cell hematologic malignancies have seen drastic improvements. To this end, a paradigm shift away from toxic and ineffective chemotherapies has been visible with the FDA approval of genetically modified autologous T cell products designed to express chimeric antigen receptors able to specifically recognize the CD19 cell surface marker. To date, CAR-T cells have two FDA-approved indications including relapsed or refractory acute lymphoblastic leukemia in children and young adults as well as large B cell lymphoma that is relapsed and/or refractory to two prior therapies. This chapter will discuss the utility of this therapy in B-ALL, common toxicities and their management, relationship to other therapies such as stem cell transplantation, and future directions.

Ibalizumab-uiyk as a bridge therapy for a patient with drug-resistant HIV-1 infection receiving chemotherapy: A case report.

WHAT IS KNOWN AND OBJECTIVE: Treatment for diffuse large B-cell lymphoma (DLBCL) in persons with AIDS consists of chemotherapy alongside antiretroviral therapy (ART). To determine optimal HIV treatment, drug-drug interactions, toxic effects and ART resistance must be considered. CASE DESCRIPTION: A 40-year-old man with drug-resistant HIV and DLBCL initiating chemotherapy which had drug interactions with his ART. During chemotherapy, darunavir/cobicistat was held and ibalizumab-uiyk was started to ensure he was on three active HIV medications. WHAT IS NEW AND CONCLUSION: Ibalizumab-uiyk has no known drug-drug interactions and may be used as bridge therapy for patients with drug-resistant HIV undergoing chemotherapy.

Clonal Hematopoiesis is Associated With Severe Cytokine Release Syndrome in Patients Treated With Chimeric Antigen Receptor T-Cell (CART) Therapy.

Among patients receiving CD19 or B-cell maturation antigen (BCMA) CAR T therapy, inflammation pre- and post-CAR T infusion is implicated in the development of toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and likely contributes to prolonged cytopenias. Clonal hematopoiesis (CH), the clonal expansion of hematopoietic stem cells harboring somatic mutations, has been associated with inflammasome upregulation. Herein, we examined the prevalence of pre-CAR T CH in a predominantly transplant-naïve cohort of recipients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), and assessed the relationship between the presence of CH mutations and CAR T-related outcomes including CRS, ICANS, prolonged cytopenia, progression-free survival (PFS), and overall survival (OS). This study included 62 patients with NHL or MM who underwent CD19 or BCMA CAR T therapy from 2017 to 2022 at City of Hope and had available pre-CAR T cryopreserved peripheral blood mononuclear cells (PBMCs). DNA was isolated with QIAamp DNA Mini Kit (Qiagen) from PBMC samples (94% collected <30d of CART infusion), on which we performed targeted exome sequencing (108 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CH (variant allele frequency [VAF] ≥2%). Multivariable logistic regression was used to examine the association between CH and absolute neutrophil count (ANC) recovery at day +30 and +60, maximum grade CRS and ICANS, grade <2 versus 2+, and OS and PFS at 1y. Covariates considered were age at CART, baseline ANC, sex, race, CAR-HEMATOTOX, LDH, bridging therapy (Y/N), and number of prior lines of therapy. Fifteen (24%) patients had at least one pathogenic CH mutation; 2 (13%) had ≥2 CH mutations concurrently. DMT3A mutations were the most common; 29% of mutations had VAFs >10%. Patients with CH were significantly more likely to develop grade ≥2 CRS (60% versus 28%, p = .03) compared to those without CH (odds ratio [OR] 3.9, 95% CI 1.2-13.2; p = .027). Accounting for baseline ANC (which was higher among the CH cohort and associated with delayed ANC recovery, p = .02) patients with CH did not have a significantly different rate of delayed ANC recovery compared to those without CH (adjusted OR 0.37, 95% CI 0.09-1.5; p = .17). There was no association between CH and ICANS, nor with 1y PFS or OS. CH was frequent (24%) in this cohort of CAR T recipients and was associated with a higher risk of development of grade ≥2 CRS after CAR T. Additional validation studies are currently underway, which may set the stage for consideration of pre-CAR T CH as a biomarker for risk stratification towards more proactive CRS prophylaxis. Translational studies could aim to prove a direct relationship between CH-mutated myeloid cells and CRS.

Sirolimus Is an Acceptable Alternative to Tacrolimus for Graft-versus-Host Disease Prophylaxis after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide.

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor HCT. A phase II study from the Moffitt Cancer Center substituting sirolimus (Siro) for Tac in this prophylactic regimen reported comparable rates of grade II-IV acute GVHD (aGVHD). Many centers have substituted Siro for Tac in this setting based on a preferable side effect profile, although comparative data are limited. In this study, we retrospectively compared outcomes in haplo-HCT with PTCy/Siro/MMF versus haplo-HCT with PTCy/Tac/MMF. The study cohort included all consecutive patients receiving haploidentical donor T cell-replete peripheral blood stem cell (PBSC) HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. A total of 423 patients were included, of whom 84 (20%) received PTCy/Siro/MMF and 339 (80%) received PTCy/Tac/MMF. The median age for the entire cohort was 54 years (range, 18 to 78 years), and the median follow-up was 30 months. The Siro group had a higher proportion of patients age ≥60 years (58% versus 34%; P < .01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV aGVHD (45% versus 47%; P = .6) at day +100 or chronic GVHD (cGVHD) (47% versus 54%; P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better in the Tac group (odds ratio, .30; 95% confidence interval, .1 to .83; P = .02), with a median time to engraftment of 17 days versus 18 days in the Siro group, but platelet engraftment was similar in the 2 groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on aGVHD or cGVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease-free survival, or overall survival after PBSC haplo-HCT. These findings suggest that Siro is a comparable alternative to Tac in combination with PTCy/MMF for GVHD prophylaxis, with overall similar clinical outcomes despite delayed engraftment after peripheral blood stem cell haplo-HCT. Although Tac remains the standard of care, Siro may be substituted based on the side effect profile of these medications, with consideration of patient medical comorbidities at HCT.

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.

HEAT repeat 1 motif is required for B56γ-containing protein phosphatase 2A (B56γ-PP2A) holoenzyme assembly and tumor-suppressive function.

Protein phosphatase 2A (PP2A) enzyme consists of a heterodimeric core (AC core) comprising a scaffolding subunit (A), a catalytic subunit (C), and a variable regulatory subunit (B). Earlier studies suggest that upon DNA damage, a specific B subunit, B56γ, bridges the PP2A AC core to p53, leading to dephosphorylation of p53 at Thr-55, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation and transformation. In addition to dephosphorylation of p53, B56γ-PP2A also inhibits cell proliferation and transformation by an unknown mechanism. B56γ contains 18 α-helices that are organized into eight HEAT (Huntington-elongation-A subunit-TOR) repeat motifs. Although previous crystal structure study has revealed the residues of B56γ that directly contact the A and C subunits, the contribution of HEAT repeats to holoenzyme assembly and to B56γ-PP2A tumor-suppressive function remains to be elucidated. Here, we show that HEAT repeat 1 is required for the interaction of B56γ with the PP2A AC core and, more importantly, for B56γ-PP2A tumor-suppressive function. Within this region, we identified a tumor-associated mutation, C39R, which disrupts the interaction of B56γ with the AC core and thus was unable to mediate dephosphorylation of p53 by PP2A. Furthermore, due to its lack of AC interaction, C39R was also unable to promote the p53-independent tumor-suppressive function of B56γ-PP2A. This study provides structural insight into the PP2A holoenzyme assembly and emphasizes the importance of HEAT repeat 1 in B56γ-PP2A tumor-suppressive function.

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.

T Cell-intrinsic Immunomodulatory Effects of TAK-981 (Subasumstat), a SUMO-activating Enzyme Inhibitor, in Chronic Lymphocytic Leukemia.

Novel targeted agents used in therapy of lymphoid malignancies are recognized to have complex immune-mediated effects. Sumoylation, a posttranslational modification of target proteins by small ubiquitin-like modifiers (SUMO), regulates a variety of cellular processes indispensable in immune cell activation. Despite this, the role of sumoylation in T-cell biology in context of cancer is not known. TAK-981 (subasumstat) is a small-molecule inhibitor of the SUMO-activating enzyme (SAE) that forms a covalent adduct with an activated SUMO protein. Using T cells derived from patients with chronic lymphocytic leukemia (CLL), we demonstrate that targeting SAE activates type I IFN response. This is accompanied by largely intact T-cell activation in response to T-cell receptor engagement, with increased expression of CD69 and CD38. Furthermore, TAK-981 decreases regulatory T cell (Treg) differentiation and enhances secretion of IFNγ by CD4+ and CD8+ T cells. These findings were recapitulated in mouse models, suggesting an evolutionarily conserved mechanism of T-cell activation regulated by SUMO modification. Relevant to the consideration of TAK-981 as an effective agent for immunotherapy in hematologic malignancies, we demonstrate that the downstream impact of TAK-981 administration is enhancement of the cytotoxic function of CD8+ T cells, thus uncovering immune implications of targeting sumoylation in lymphoid neoplasia.

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.

A validated composite comorbidity index predicts outcomes of CAR T-cell therapy in patients with diffuse large B-cell lymphoma.

Chimeric antigen receptor T-cell therapy (CART) has extended survival of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, limited durability of response and prevalent toxicities remain problematic. Identifying patients who are at high risk of disease progression, toxicity, and death would inform treatment decisions. Although the cumulative illness rating scale (CIRS) has been shown to correlate with survival in B-cell malignancies, no prognostic score has been independently validated in CART recipients. We retrospectively identified 577 patients with relapsed/refractory DLBCL indicated for CART at 9 academic centers to form a learning cohort (LC). Random survival forest modeling of overall survival (OS) and progression-free survival (PFS) was performed to determine the most influential CIRS organ systems and severity grades. The presence of a severe comorbidity (CIRS score ≥ 3) in the respiratory, upper gastrointestinal, hepatic, or renal system, herein termed "Severe4," had the greatest impact on post-CART survival. Controlling for other prognostic factors (number of prior therapies, Eastern Cooperative Oncology Group performance status, BCL6 translocation, and molecular subtype), Severe4 was strongly associated with shorter PFS and OS in the LC and in an independent single-center validation cohort (VC). Severe4 was also a significant predictor of grade ≥3 cytokine release syndrome in the LC, while maintaining this trend in the VC. Thus, our results indicate that adverse outcomes for patients with DLBCL meant to receive CART can be predicted using a simplified CIRS-derived comorbidity index.