Indolent non-Hodgkin Lymphoma Research Articles

EPCORE FL-1: Phase 3 Trial of Subcutaneous Epcoritamab with Rituximab and Lenalidomide (R 2) Vs R 2 Alone in Patients with Relapsed or Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma (NHL). Several treatment options are approved by the US Food and Drug Administration for second- or later-line FL therapy, including rituximab + lenalidomide (R 2). However, advanced-stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab, a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B cells, induces potent and selective T-cell-mediated killing of malignant CD20 + B cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human, phase 1/2 EPCORE NHL-1 trial (NCT03625037) in heavily pretreated patients with B-cell NHL (N=68), epcoritamab showed manageable safety and promising single-agent anti-tumor activity (Hutchings et al, Lancet 2021). Among 10 patients with R/R FL, objective response rate (ORR) was 90% (95% CI: 55-100) and complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab + R 2 for R/R FL (EPCORE NHL-2 arms 2a and 2b; NCT04663347), ORR was 98% among 104 efficacy-evaluable patients, with a complete metabolic response in 87%. Most cytokine release syndrome (CRS) events were low grade (n=111; grade 1-2, 46%; grade 3, 2%) and occurred in cycle 1; all CRS events resolved with routine management. These encouraging data, and the distinct mechanisms of action of epcoritamab and R 2, support ongoing evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 EPCORE FL-1 trial was designed to evaluate epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL with ≥1 prior line of anti-lymphoma therapy. We present an updated protocol, reflecting recent developments and revisions implemented in this study. Study Design and Methods: EPCORE FL-1 (NCT05409066) is a global, randomized, open-label, multicenter phase 3 trial designed to evaluate efficacy and safety of epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL. Adult patients must have histologically confirmed classic FL (previously grades 1 to 3a FL) stage II, III, or IV with a CD20 + tumor on a representative biopsy based on local pathology report and no evidence of histologic transformation. Patients must have R/R disease after ≥1 prior anti-lymphoma regimen that contained an anti-CD20 monoclonal antibody in combination with chemotherapy; patients receiving only prior anti-CD20 monoclonal antibody monotherapy and/or radiation are not eligible. Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography-avid disease, and ≥1 measurable disease site per Lugano 2014 criteria. Lenalidomide-refractory FL (best response to lenalidomide of stable or progressive disease or progressive disease within 6 months of completion of lenalidomide) is excluded. Approximately 520 patients will be enrolled and randomized 1:1 to receive a full dose of epcoritamab in combination with R 2 or R 2 alone ( Figure); the trial is currently enrolling in 2 arms, Arms A & C. Based on emerging safety and efficacy data, Arm B has been closed to enrollment and the recommended dose of epcoritamab in combination with R 2 is 48 mg. Epcoritamab will be subcutaneously administered using a step-up dosing regimen to full dose in cycle 1 (28 days/cycle). Full dose of epcoritamab will be administered weekly in cycles 2-3 and monthly from cycle 4 onward for up to 12 cycles of treatment. Patients will be serially assessed for disease progression at prespecified intervals. The primary endpoint is progression-free survival assessed by independent review committee (IRC) per Lugano criteria. Key secondary efficacy endpoints include CR rate (by IRC per Lugano criteria), overall survival, and minimal residual disease negativity. Other efficacy endpoints include best overall response, duration of response, duration of complete response, time to progression, event-free survival, time to next anti-lymphoma treatment, and patient-reported outcomes. Safety endpoints include incidence and severity of treatment-emergent adverse events and adverse events of special interest. Exploratory endpoints include assessments of pharmacodynamic and pharmacokinetic data. The study opened for enrollment in 2022 in North America, South America, Europe, Africa, Asia, and Australia.

Prognostic Value of Tumor Mutational Burden in Follicular Lymphoma Patients Treated with Immunochemotherapy

INTRODUCTION: Follicular lymphoma (FL) is the most prevalent indolent non-Hodgkin lymphoma subtype. It is characterized by frequent relapses, and patients who progress or relapse within 24 months (POD24) of front-line immunochemotherapy (ICT) have a poor outcome. Several prognostic indices have been proposed to identify high-risk patients, but none of them are currently used in clinical practice to guide treatment. Tumor mutational burden (TMB), defined as the number of somatic mutations/megabase (mut/Mb), has been proposed as a biomarker for predicting response to immune checkpoint inhibitors in several types of cancer. Therefore, this study aimed to explore the role of TMB in FL patients treated with frontline ICT. METHODS: The study included a total of 103 patients with FL grade 1-3a treated with frontline ICT. TMB was determined by Next Generation Sequencing (NGS) in 98 diagnostic lymph node biopsies with enough material available, with the Oncomine Tumor Mutational Load Assay (Thermo Fisher). This assay covers 1.65Mb across 409 genes frequently mutated in cancer, allowing an accurate estimation of TMB. Sequencing was performed on the Ion GeneStudio S5 system with >300X mean read depth. Only exonic non-synonymous variants remaining after manual variant refinement to exclude artefacts were considered. In addition, the mutational profile of 56 of the 98 patients was analyzed using a QIAgen custom DNA panel which covered 64 genes frequently mutated in FL. Sequencing was performed using NextSeq (Illumina) with >3000X mean read depth. Variants were analyzed and interpreted for pathogenicity using several databases, and only pathogenic or presumed pathogenic variants (P/PP) were considered. Statistical analysis was performed using SPSS and R. RESULTS: The final cohort included 94 patients, as in 4/98 patients (4%) TMB could not be accurately estimated due to a high frequency of artefacts caused by cytosine deamination. Median age at diagnosis of 61 years (range 24-86), 51% males and 49% females. Patients with advanced disease stage at diagnosis represented 87% of the cohort. Median TMB was 5.08mut/Mb (range 1.69-13.80 mut/Mb), and all cases genetically profiled presented at least one P/PP variant. The number of P/PP mutations correlated with TMB at diagnosis (p=0.004). TMB did not correlate with clinical parameters, such as age at diagnosis (p=0.891), histologic grade (p=0.243), Ann Arbor stage (p=0.200), ECOG (p=0.190), FLIPI (p=0.363), FLIPI2 (p=0.693), or LDH levels (p=0.483). However, lower TMB at diagnosis was associated with the absence of the t(14;18)(q32;q21) translocation (mean 3.93 vs 5.42 mut/Mb, p=0.006). The analysis of the mutational status of the 64 genes frequently mutated in FL revealed that mutations in genes involved in cellular migration ( GNA13, GNAI2) were associated with higher TMB values (4.50 vs 7.56 mut/Mb, p=0.001). An statistically significant association between low TMB and shorter progression-free survival (PFS) (p=0.011) was found when stratifying patients into two groups: high basal TMB (>2.55mut/Mb) and low basal TMB (≤2.55mut/Mb) (Figure 1). 2-year PFS was 54.5% (95%CI: 33.2-89.5%) in low-TMB patients and 84.9% (95%CI: 77.3-93.7%) in high-TMB patients. 5-year PFS was 39.0% (95%CI: 19.7-77.0%) in low-TMB patients and 70.5% (95%CI: 60.0-82.9%) in high-TMB patients. The proportion of POD24 cases was higher in the low-TMB group (46.1% vs 16.9%, p=0.039), none of them being refractory to treatment (7/70 in the high-TMB group). Genetically, the low-TMB group was enriched in patients with mutations affecting genes involved in the mTOR signaling pathway ( ATP6AP1, ATP6AP2, ATP6V1B2, RRAGC) (50.0% vs 8.7%, p=0.006). CONCLUSIONS: FL patients harboring t(14;18) or mutations in genes involved in migration have higher TMB values at diagnosis. Patient stratification based on TMB values allows the identification of a subgroup of FL patients with ≤2.55 mut/Mb with shorter PFS after treatment with frontline ICT. The prognostic usefulness of TMB should also be explored at relapse, in particular in patients receiving novel immunotherapies such as bispecific antibodies and CAR T-cell therapies, that are being approved for relapsed/refractory FL. ACKNOWLEDGMENTS: Work supported by Institut de Salud Carlos III-Federación Española de Enfermedades Raras (ISCIII-FEDER) grant PI19/00034, GLD18/00117, 2017SGR205, PT20/00023, and Xarxa de Banc de Tumors de Catalunya.

PI3Kδ Inhibitor Linperlisib As a ≥ 3-Line Treatment for Relapsed or Refractory Follicular Lymphoma: A Subgroup Analysis of a Phase II, Single-Arm, Open-Label Trial

Introduction Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma (NHL), originating in follicular central B cells, and accounts for approximately 22% of all newly diagnosed cases of NHL. Chemo-immunotherapy is the standard treatment option for FL. Unfortunately, the progression of the disease to relapsed or refractory FL (r/r FL) is still inevitable, which raised concern about subsequent effective treatments. Several δ isoform of phosphatidylinositol 3-kinase (PI3K-δ) inhibitors have ever been approved for r/r FL after ≥2 lines of prior therapies. However, most of their indications for r/r FL were withdrawal for increased risk of death and serious side effects. The latest data from the Chinese phase II clinical trial of linperlisib (Trial registration ID: NCT04370405), a novel oral PI3Kδ-selective inhibitor, in patients with r/r FL who had received at least two systemic therapies were presented. In this trial, linperlisib demonstrated compelling efficacy and was generally well-tolerated in the treatment of r/r FL patients after ≥2 prior systemic therapies. Linperlisib was approved by China National Medical Products Administration (NMPA) for adult r/r FL previously treated with at least two system therapies in November 2022. The ≥3 lines of treatment options are still unmet for the r/r FL. In this setting, this subgroup analysis of the linperlisib phase II trial aimed to evaluate outcomes of linperlisib in later-line treatment of r/r FL. Methods This study included all the patients with r/r FL who had received at least two systemic therapies previously enrolled in the open-label, single-arm, phase II trial (linperlisib, 80mg, po, q.d., in a 28-day cycle), with overall response rate (ORR) as the primary endpoint. In this subgroup analysis, the patients were divided into two groups according to the treatment lines they received: >3 prior lines of treatment and ≤3 prior lines of treatment. All of the statistical analyses were descriptive. Results A total of 84 r/r FL patients from 25 sites in China from April 2019 to September 2020 were enrolled in this trial, with a cutoff date of September 30, 2021. The ORR was 79.8%, with statistical significance in a heavily pretreated FL patient population with a median of 4 prior therapies, with a well-tolerated safety profile. A total of 43 patients received >3 prior lines of treatment, while 41 patients received ≤3 prior lines of treatment. The median age between the two groups was similar (range: 29.0 - 78.0, 52.0 years for >3 prior lines vs. 48.0 years for ≤3 prior lines). The majority of patients had Ann Arbor staging III-IV (40 for >3 prior lines vs. 34 for ≤3 prior lines). The median number of prior regimens was 4 for >3 prior lines and 3 for ≤3 prior lines. Overall, there were 67 patients achieved responses, with ORR of 83.7% (36, 95%CI:69.3, 93.2) for >3 prior lines vs. 75.6% (31, 95% CI: 59.7, 87.6) for ≤3 prior lines based on independent review committee assessment. Compared with patients who received ≤3 prior lines, patients received ≤3 prior lines achieved higher disease control rate (41[95.3] vs. 37 [90.2%]). The median DOR was 12 months (95% CI: 7.3, 15.9) for >3 prior lines vs. 13 months (95% CI: 9.2, NE). The median PFS was 11.9 months (95% CI: 9.1,19.4) for >3 prior lines vs. 13.3 months (95% CI: 8.2, NE) for ≤3 prior lines. The OS of both groups was not reached. The most common treatment-related adverse events (≥20%, TRAEs) were neutropenia (21 [48.8%] for >3 prior lines vs. 18 [43.9%] for ≤3 prior lines), leukocyte count decreased (15 [34.9%] vs. 15 [36.6%]), alanine aminotransferase increased (10 [23.3%] vs. 9 [22.0%]), lymphocyte count decreased (9 [20.9%] vs. 5 [12.2%]), hypertriglyceridemia (9 [20.9%] vs. 11 [26.8%]), and hypercholesteremia (6 [24.0%] vs. 7 [11.9%]). The most common grade ≥3 TRAEs (≥10%) were neutropenia (9 [20.9%] vs. 4 [9.8%]), pulmonary inflammation (3 [7.0%] vs. 6 [14.6%]), infectious pneumonia (2 [4.7%] vs. 5 [12.2%]). Conclusions This subgroup analysis revealed that linperlisib could achieve benefit in r/r FL patients who received at least 2 prior system therapies regardless of treatment lines. The AEs were well-tolerated. Further trials with large-scale samples were warranted.

Patterns of Care and Resource Use Among Elderly Relapsed/Refractory Follicular Lymphoma Patients: US Medicare Claims Analysis

Background: Follicular lymphoma (FL)is the second most common type of non-Hodgkin lymphoma (NHL) and most common indolent NHL. Rituximab-based chemotherapy is highly effective and considered the mainstay first-line (1L) treatment for FL, though many patients relapse and continue through successive lines of therapy. These relapsed/refractory (R/R) patients experience worse outcomes and represent an unmet need for more effective treatment approaches. This study examined treatment patterns, health care resource utilization (HCRU), and costs among R/R FL patients initiating third line (3L) therapy between 2011 and 2020. Methods: This retrospective, observational study used Center for Medicare and Medicaid fee-for-service Medicare data. The sample included treated patients with FL (identified via 1 inpatient or 2 outpatient claims) aged ≥66 years who initiated 1, 2, and 3L therapy between January 1, 2011, and December 31, 2020. Patients were required to have continuous coverage in the 12 months pre-FL diagnosis and 3 months post-diagnosis and were followed until discontinuation of enrollment or death. Line of therapy (LoT) was calculated until the end of treatment, death, or transformation to diffuse large B-cell lymphoma. Outcomes included patient characteristics, treatment patterns, health care costs and HCRU. R esults: This analysis identified 8737 1L, 1847 2L, and 410 3L treated FL patients. Median age at the start of each LoT was 75 years at 1L, 77 at 2L, and 79 at 3L. Of R/R FL patients initiating 3L, the most common baseline Charlson comorbidities included diabetes without chronic complications (23%), chronic pulmonary disease (22%) and renal disease (20%), 32% were defined as having progression of disease within 2 years of 1L (POD24), and 30% were defined as double refractory to both an anti-CD20 agent and an alkylating agent. Treatment utilization rates were similar across LoTs; the most used regimens were rituximab/obinutuzumab (R/O) (used 35% of the time in 1L, 33% in 2L, and 31% in 3L) and bendamustine + R/O (39% in 1L, 33% in 2L, and 21% in 3L). Mean duration of 1L treatment was longer for patients who only initiated 1L (10.1 months) vs. those with R/R FL who went on to initiate 2L and 3L (7.5 and 7.4 months, respectively). As R/R FL patients who initiated 3L moved through LoTs, increases were observed in the number of patients with at least 1 inpatient admission (17% in 1L and 31% in 3L) and with at least 1 emergency room visit (27% in 1L and 41% in 3L). Mean total all-cause costs per-member per-month (PMPM) also increased with each subsequent LoT ($15,917 in 1L, $17,767 in 2L, and $18,266 in 3L). In addition, mean total all-cause costs of R/R FL patients defined as POD24 and double refractory were higher in 3L; $20,172 PMPM and $21,724 PMPM, respectively). Conclusions: In this elderly R/R FL population, similar therapies were used across multiple LoTs. With each subsequent LoT, treatment duration shortened and notably, costs and HCRU increased. Additionally, patients defined as POD24 and double-refractory experienced higher costs. This research highlights a substantial unmet need in R/R FL for novel therapeutic options that can provide better outcomes and reduce HCRU.

Outcomes of COVID-19 in patients with lymphomas participating in registered clinical trials: A real-world study from China in the Omicron outbreak era.

This real-world study investigated the outcome of COVID-19 in lymphoma patients participating in registered clinical trials and explored potential risk factors with the outcome of COVID-19 during the first wave of the Omicron outbreak in China. One hundred and ten patients participating in registered clinical trials and diagnosed with COVID-19 in our center between December 1, 2022, and January 31, 2023, were included. Four (3.6%) patients were identified as severe COVID-19 and 2 (1.8%) as critical COVID-19, respectively. The mortality rate observed was 2.73% for the entire cohort, 33.3% for the severe/critical COVID-19 group, and 18.8% for the hospitalized group. The 90-day OS was 98.2% for the entire cohort, 66.7% for the severe/critical COVID-19 group, and 87.5% for the hospitalized group. Advanced age (≥70 years), comorbidities, and PI3K inhibitor-containing regimen were significantly associated with the severity of COVID-19. Patients with indolent B-cell non-Hodgkin lymphomas were less likely to be hospitalized for COVID-19. This study reported similar clinical features of COVID-19 in our cohort with that of non-hematological malignancy (HM) patients, while the proportion of severe/critical COVID-19 and the mortality rate were relatively higher than non-HM patients. Our findings provided valuable experience to aid clinical researchers with managing lymphoma patients participating in registered clinical trials during the ongoing pandemic of the Omicron variant.

Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience

AbstractBendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicenter observational study evaluating bendamustine toxicity in real-world practice. Patients receiving at least 1 dose of bendamustine with/without rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details, and grade 3 to 5 adverse events (AEs) were analyzed and correlated. In total, 323 patients were enrolled from 9 National Health Service hospitals. Most patients (96%) received bendamustine-R, and 46%, R maintenance. Overall, 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%) and the relative risk highest during maintenance (54%), induction (34%), and follow-up (28%). Toxicity led to permanent treatment discontinuation for 13% of patients, and 2.8% died of bendamustine-related infections (n = 5), myelodysplastic syndrome (n = 3), and cardiac disease (n = 1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor preinduction performance status (PS), poor premaintenance PS, and abnormal preinduction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3 of 10 opportunistic infections occurred despite prophylaxis. In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to those of trial populations of younger, fitter patients. Poor PS, mantle cell histology, and maintenance R were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death, warranting extended antimicrobial prophylaxis and infectious surveillance, especially for maintenance-treated patients.

Abstract 16092: Oncology Meets Cardiology: Sustained Ventricular Tachycardia With a Pulse

Introduction: Palpitations are one of the most common presenting symptoms. While usually benign, they can be life-threatening. We present a case of a sustained VT in the setting of a rare transformation of Follicular Lymphoma (FL). Case Description: An 86-year-old female with a history of FL with cardiac involvement, hypothyroidism, and hypertension presented with three episodes of palpitations. The first lasted about 20 minutes and spontaneously resolved. The second occurred a few hours later and was resolved within 15 minutes. Her third did not resolve. On presentation, she was complaining of palpitations and lightheadedness. BP 136/97, HR 193. Physical exam revealed no respiratory distress, rapid rate, clear lung fields, and unremarkable neurological exam with clear mentation. ECG (below) demonstrated sustained VT with rates of ~260 bpm. Amiodarone bolus was started. Cardioversion was attempted, but her VT degenerated into Ventricular Fibrillation. She achieved ROSC and was admitted with sinus rhythm. It was suspected that her FL had transformed into a more aggressive lymphoma, i.e. Diffuse Large B cell Lymphoma (DLBCL). On Cardiac MRI, she had metastasis to the right AV groove consistent with cardiac lymphoma, which was the etiology of her arrhythmia. She elected to enroll in hospice and was discharged in sinus rhythm. Impact/Discussion: Histological transformation (HT) of indolent non-Hodgkin lymphoma subtypes (FL) to clinically aggressive subtypes (DLBCL) is estimated to occur 1-2 %/year. Although there have been studies examining risk factors suggestive of HT, much still needs to be studied to effectively manage patients with cardiac metastasis. In this case, metastasis involved the right AV groove, which was the cause of her arrhythmia. Patients with sustained VT usually present with severe symptoms including cardiac arrest, but can present with mild symptoms, as was the case of this patient. Prompt evaluation and management of palpitations is paramount.

Bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy for indolent lymphoma

Classic follicular (FL) and marginal zone (MZL) lymphomas are the primary indolent non-Hodgkin lymphomas (iNHL). Once first-line therapy is initiated, the majority of patients eventually experience treatment failure and face progressively shorter disease-free periods following subsequent lines of conventional chemotherapy. Patients with progressive disease within 24 months of first-line therapy (POD24) represent a significant unmet need. The five-year overall survival (OS) for patients with FL and POD24 is only 50% vs 90% for those without POD24. The three-year OS for patients with MZL is 53% and 95% respectively.

Coping and Perception of Prognosis in Patients With Indolent Non-Hodgkin's Lymphoma.

Indolent non-Hodgkin's lymphomas (iNHL) are a heterogenous group of mostly incurable diseases with prolonged illness courses and prognostic uncertainty. Yet, studies evaluating coping and perception of prognosis are limited. We conducted a cross-sectional study of adults newly diagnosed with iNHL in the past 3 months at a single academic center. We assessed quality of life (QOL: Functional Assessment of Cancer Therapy-General), psychological symptoms (Hospital Anxiety and Depression Scale), coping (Brief-COPE), and perception of prognosis (Prognosis Awareness Impact Scale). We enrolled 70.6% (48/68) of eligible patients. Patients had older age (mean = 66.9,sd = 10.5), were female (60.4%), predominantly identified as White (85.4%), and had at least received a college degree (75%). Chronic lymphocytic leukemia (39.6%) and follicular lymphoma (33.3%) were the most common diagnoses. Overall, 27.1% and 14.6% of patients reported clinically significant anxiety and PTSD symptoms, respectively. Patients highly utilized acceptance (56.2%), seeking emotional support (47.9%), and denial (47.9%) as coping strategies at diagnosis. While 66.7% of patients recalled their oncologist assessment of illness as incurable, only 35.4% reported that the illness is unlikely to be cured. Overall, 45.8% indicated that they were worried about prognosis and 31.2% reported perseverating on their prognosis. Higher emotional coping with prognosis was associated with fewer anxiety (B = -0.6, SE = 0.2, P < .001), depression (B = -0.3, SE = .1, P = .005), and PTSD (B = -1.3, SE = 0.4, P < .001) symptoms and better QOL (B = 1.7, SE = 0.4, P < .001). Patients with iNHL report substantial psychological distress, a diversity of coping strategies, and complex cognitive understanding of their prognosis. Interventions, which address prognostic uncertainty and promote positive emotional coping with prognosis, may ameliorate psychological distress in this population.

Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: 4-Year Follow-up from the Phase 2 ZUMA-5 Trial

Introduction: ZUMA-5 is a multicenter Phase 2 study of axi-cel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL; follicular lymphoma [FL] and marginal zone lymphoma [MZL]). After a median of ≥3 years of follow-up, medians of progression-free survival (PFS) in patients with FL and MZL were 40.2 months and not reached, respectively, and no new safety signals were observed (Neelapu et al. ASH 2022. Abstract 4660). Here, we report updated outcomes from ZUMA-5 after a median follow-up of ≥4 years. Methods: Eligible patients had R/R FL or MZL after ≥2 lines of therapy including an anti-CD20 monoclonal antibody plus an alkylating agent. Patients underwent leukapheresis at enrollment, then received lymphodepletion and axi-cel infusion (2×10 6 CAR T cells/kg). The primary endpoint was overall response rate (ORR; complete response [CR] + partial response [PR]). Time-to-event endpoints were assessed by investigators in all enrolled patients. Exploratory analyses included lymphoma-specific survival, using competing risk assessment, in which deaths unrelated to progression, axi-cel, or lymphodepletion were competing risks. Results: In 159 enrolled patients (FL: 127, MZL: 31) at data cutoff (March 31, 2023), median follow-up was 52.5 months (range, 20.3-69.4; FL: 53.7, MZL: 43.8). The ORR in enrolled patients remained consistent with prior analyses (90% ORR, 75% CR rate). Median duration of response (DOR) was 55.5 months (95% CI, 38.6-not estimable; FL: 55.5, MZL: not reached). Medians for DOR were 60.4 months in those with a best response of CR and 4.9 months in those with a PR. At data cutoff, responses were ongoing in 48% of patients, consistent by disease type. Median PFS was 57.3 months (95% CI, 34.9-not estimable; FL: 57.3, MZL: 46.9); estimated 48-month PFS rate was 52% (FL: 53%, MZL: 47%; Figure 1). After data cutoff of the prior analysis, 1 patient with FL had disease progression. PFS rates at 48 months in patients with FL were consistent regardless of high-risk characteristics, including progression &amp;lt;2 years from initiating first anti-CD20-containing chemoimmunotherapy (POD24). Median time to next therapy was 62.2 months (95% CI, 37.8-not estimable; FL: 62.2, MZL: 46.9). Median overall survival (OS) was not reached (95% CI, 62.2-not estimable); 48-month OS rate was 72% (FL: 72%, MZL: 68%). Among enrolled patients with FL, the 48-month cumulative incidence of lymphoma-specific progression or death was 34%, while the cumulative incidence of competing risks was 13% (Figure 2). Additionally, the cumulative incidence of lymphoma-specific death at 48 months was 14%; the cumulative incidence of other or unknown death was 14%. After the 3-year analysis, among 152 treated patients (124 FL; 28 MZL), 6 experienced serious adverse events, 1 of which was related to axi-cel (FL, Grade 3 myelodysplastic syndrome). No new neurologic events, hypogammaglobulinemia cases, Grade ≥3 cytopenias, or Grade ≥3 infections occurred. Seven additional patients died due to progression (n=2; both patients received subsequent therapy after progression), new malignancy (n=1; not axi-cel related), and other causes (n=4; 2 cardiac arrest, 1 infection, and 1 unknown). Among treated patients with FL, those with ongoing response at 48 months continued to have higher median postinfusion CAR T-cell expansion by peak (52.2 cells/µL) and area under the curve (583.6 cells/µL×days) than those who relapsed (29.6 cells/µL and 337.6 cells/µL×days) or had no response (25.4 cells/µL and 269.9 cells/µL×days). Additionally, those with ongoing response had a higher proportion of naive (CCR7+CD45RA+) T cells in axi-cel product (25%) than relapsed (13%) or nonresponding patients (9%). Similar trends were observed in MZL. Conclusions: With a median ≥4 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable response and long-term survival in patients with R/R FL and R/R MZL. Late progression or lymphoma-specific death was uncommon in FL, suggesting curative potential for those patients. The long-term safety profile of axi-cel was manageable.

Phase II, Single Arm, Open Label, Single Center Study of Obinutuzumab and Ibrutinib in the Front Line Treatment of Indolent B-Cell Non-Hodgkin Lymphomas

Background: Anti-CD-20 immunochemotherapy with cytotoxic agents has been the traditional front-line therapy for patients with the advanced stage indolent non-Hodgkin lymphomas (iNHL) such as follicular (FL) and marginal zone lymphoma (MZL) requiring treatment. For patients with medical comorbidities and advanced age at iNHL diagnosis, treatment regimens without cytotoxic chemotherapy may offer an effective but less toxic option. Combination therapies with non-cytotoxic treatments and anti-CD20 antibodies have been developed in FL and MZL, such as lenalidomide and the anti-CD20 antibody obinutuzumab. The combination of Obinutuzumab and ibrutinib was previously reported in first line treatment of follicular lymphoma (Schmidt et al ASH 2018), but not MZL. In a phase II study, we investigated the front line combination of Ibrutinib plus Obinutuzumab in FL and MZL. Methods: Adult patients with untreated, histologically confirmed Ann Arbor Stage II-IV FL (WHO classification grade 1, 2 or 3a) or MZL (nodal, splenic and extranodal) who had an indication for systemic therapy on the basis of symptoms, high tumor burden, cytopenias and/or other evidence of end-organ damage as per standard modified GELF criteria were eligible. In this single-arm study, patients received ibrutinib 560 mg daily and obinutuzumab in 28-day cycles. Obinutuzumab induction was given on days 1, 8 and 15 of cycle 1, and on day 1 of cycles 2-6. Maintenance therapy was administered if there was at least a partial response based on PET-CT after cycle 7 with obinutuzumab every 8 weeks for a total of 12 doses and ibrutinib 560 mg daily until progression. Treatment response was assessed with PET/CT scans after cycle 4 and 7, followed by every 6 months for 2 years and then annually. Overall response rate (ORR) included complete response (CR) and partial response (PR). The primary study endpoint was ORR after 7 cycles of therapy. Results: Twenty-eight patients were enrolled (15 FL, 13 MZL) and 26 patients were evaluable for ORR after 7 cycles of therapy. The median age was 65 years (range 36-84 years), 11 (39%) presented with B symptoms, 23 (82%) had Ann Arbor Stage III-IV disease, and 18 (64%) had bone marrow involvement. For patients with FL, 11 (73%) had a morphologic grade of 1-2, and 4 (27%) had a morphologic grade of 3a. For patients with MZL, 3 (23%) had nodal, 2 (15%) had splenic, and 8 (62%) had extranodal involvement. The median follow-up time was 2.2 years (3.7 years for FL, 2.1 years for MZL). The overall response rate (ORR) following 7 cycles of therapy was 22/26 (85%) with 11/15 (73%) for FL with 10 having a CR and 1 having a PR for patients with FL and 11/11 (100%) for MZL with 8 having a CR and 3 having a PR for patients with MZL. Progression-free survival (PFS) at 24 months was 81% [67% - 97%, 95%CI] with 66% [45% - 95%, 95%CI] for FL and 100% for MZL patients. Six (5 FL, 1 MZL) patients withdrew due to progression. The most common adverse event was grade 1-2 arthralgia (N=21). The most common grade 3-4 adverse event was infection (N=10), including COVID-19 (N=5), pneumonia (N=2), neutropenic fever not otherwise specified (N=1), influenza (N=1), and diverticulitis (N=1). Conclusions: The chemotherapy free combination of Ibrutinib and Obinutuzumab is effective and well tolerated. The regimen was particularly effective in patients in MZL patients with an ORR and PFS of 100 % after median follow up of 2.1 years, and represents an attractive approach for these patients.

Machine Learning-Based Time-Series Clustering Identifies Archetypal Trajectories of Hematotoxicity after CAR T-Cell Therapy

BACKGROUND Severe hematotoxicity has been reported in a subset of patients (pts) after chimeric antigen receptor (CAR) T-cell therapy, leading to severe infections, transfusion dependency, and worse outcomes. Early identification of pts at risk for severe hematotoxicity could inform the consideration of an autologous stem cell boost, allogeneic HCT, and/or additional infectious prophylaxis. While distinct archetypal trajectories of blood count recovery have been proposed (e.g., quick vs. intermittent vs. aplastic), manual trajectory classification is subjective and labor-intensive. To address these limitations, we automated the identification of distinct trajectories of hematotoxicity by applying time-series clustering to longitudinal absolute neutrophil count (ANC) data from &amp;gt;400 pts treated with CAR T-cell therapy. Next, we sought to identify factors associated with the identified trajectories and to assess the predictive ability of the CAR-HEMATOTOX score (Rejeski, Blood 2021). STUDY DESIGN AND METHODS Adults ≥18 years of age who received their first infusion of CAR T cells for hematologic malignancies with commercial or investigational products at the Fred Hutchinson Cancer Center (2013-2023) were included. ANC trajectories were clustered using non-supervised longitudinal k-means based on Euclidean distances using the latrend and kml packages in R 4.1.3. We applied logistic regression to pre-lymphodepletion (pre-LD) variables to predict poor/very poor ANC recovery. Sensitivity and specificity were computed using a probability threshold based on the Youden criteria. RESULTS A total of 509 pts were identified; 106 were excluded due to insufficient data, with 403 pts included for the analysis. The most common disease types were aggressive NHL (n = 161; 40%), indolent NHL (n = 82; 20%), and ALL (n = 74; 18%). CAR T-cell products were axi-cel, n= 101 (25%); brexu-cel, n = 24 (6%); cilta-cel, n = 21 (5%); liso-cel, n = 46 (11%); ide-cel, n = 25 (6%); tisa-cel, 12 (3%); and investigational CD19 or CD20 CAR T-cell products, n = 174 (43%). As shown in Figure 1A, the ANC longitudinal data clustered into four distinct trajectories as follows: 1) high nadir followed by rapid recovery (“very good recovery”), n = 294 (73%); 2) low nadir followed by rapid recovery (“good recovery”), n = 87 (22%); 3) low nadir followed by intermittent recovery (“poor recovery”), n = 13 (3%); 4) aplastic phenotype (“very poor recovery”), n = 9 (2%). In univariate logistic regression, ALL (reference: aggressive NHL; OR = 5.43, 95% CI, 1.71-20.6, p = 0.006), pre-LD lower ANC (OR = 3.33 per log 10 , 95% CI, 1.82-6.25, p &amp;lt; 0.001), lower pre-LD platelet count (OR = 10 per log 10, 95% CI, 3.70-33.3), p &amp;lt; 0.001), and higher pre-LD disease burden as measured by lactate dehydrogenase (LDH) were associated with poor/very poor ANC recovery (OR = 16.6 per log 10, 95% CI, 4.79-59.3, p &amp;lt; 0.001). Next, we assessed the predictive ability of CAR-HEMATOTOX to identify poor/very poor ANC recovery in n = 356 pts with a calculable score. The CAR-HEMATOTOX score high/low showed modest discrimination (C-index: 0.65), which improved when used as a continuous variable (C-index: 0.85). As previously reported, these models had high sensitivity (&amp;gt;90%) but low specificity (high/low: 31%, continuous: 58%). To improve risk prediction of poor/very poor ANC recovery, we built a logistic regression model using restricted cubic splines - allowing for non-linear effects - including pre-LD ANC, platelet, Hb, LDH, CRP, and ferritin, which showed higher discrimination (C-index: 0.91), high sensitivity (88%), and higher specificity (79%) ( Figure 1B). CONCLUSION We introduce an automated, scalable, and disease-agnostic framework to analyze hematologic toxicity after CAR T-cell therapy. K-means clustering of longitudinal ANC data categorized pts into archetypal trajectories of hematologic recovery. A logistic regression model using pre-LD ANC, platelet, Hb, LDH, CRP, and ferritin showed improved discrimination and sensitivity compared to CAR-HEMATOTOX in our training set, but both models had low specificity (poor ability to “rule in” pts at risk of severe hematotoxicity) and thus low clinical utility at this time. We plan to further improve our predictive models by incorporating post-infusion biomarkers of systemic inflammation that we have previously shown to be associated with delayed count recovery after CAR T-cell therapy (Juluri, Blood Advances 2022).

TRANSCEND FL: Phase 2 Study Primary Analysis of Lisocabtagene Maraleucel as Second-Line Therapy in Patients with High-Risk Relapsed or Refractory Follicular Lymphoma

Background: Results with CD19-directed CAR T cell therapy in patients (pts) with second-line (2L) R/R follicular lymphoma (FL) and high-risk features, such as progression of disease within 24 months (POD24) from diagnosis or double refractory to anti-CD20 antibody plus alkylator, have not been previously reported. TRANSCEND FL (NCT04245839), a global, phase 2, open-label, single-arm, multicohort, pivotal study, assessed efficacy and safety of the anti-CD19 CAR T cell therapy lisocabtagene maraleucel (liso-cel) in pts with second line or later (2L+) R/R indolent NHL. Some data from the primary analysis were previously reported, including safety in 2L+ R/R FL, and focused on efficacy in third line or later R/R FL (Morschhauser F, et al. Hematol Oncol 2023;41[S2]:877‒880). Here, we report primary analysis results in the cohort of pts with 2L high-risk R/R FL. Methods: Eligible pts in the 2L R/R FL cohort had biopsy-confirmed FL before enrollment and must have had POD24 with treatment ≤ 6 months from original FL diagnosis and/or must have had high tumor burden as defined by modified Groupe d'Etude des Lymphomes Folliculaires (mGELF) criteria. All pts received 1 prior combination systemic therapy with an anti-CD20 antibody and alkylator. Eligible pts received liso-cel (100 × 10 6 CAR + T cells) after lymphodepleting chemotherapy (LDC). Bridging therapy was allowed with reconfirmation of PET-positive disease before LDC. The primary endpoint was ORR per independent review committee (IRC) by PET/CT using Lugano 2014 criteria. Secondary endpoints included CR rate, duration of response (DOR), PFS, OS, safety, and cellular kinetics. Pharmacodynamic endpoints were exploratory. Results: At data cutoff (January 27, 2023), 23 of 25 leukapheresed pts received liso-cel and were evaluable for safety and efficacy per IRC; 1 received nonconforming product and 1 reached CR after bridging therapy and no longer met eligibility criteria. Median (range) age was 53 y (34-69), 74% had stage III/IV disease, and 35% were high-risk per FL International Prognostic Index (FLIPI). Sixty-five percent of pts had POD24 from initiation of first-line combination chemoimmunotherapy (52% had POD24 from diagnosis), 70% met mGELF criteria (mGELF only, 48%; mGELF and POD24 from diagnosis, 22%), and 48% were double refractory to anti-CD20 antibody plus alkylator. Median (range) on-study follow-up was 18.1 months (1.0-26.8). In efficacy-evaluable pts, the ORR and CR rate were both 95.7% (95% CI, 78.1-99.9; 1-sided P &amp;lt; 0.0001; Table). With a median follow-up of 16.8 months and 17.8 months, respectively, median DOR and PFS were not reached; 12-month DOR and PFS were 89.8% and 91.3%, respectively. The most common grade (gr) ≥ 3 treatment-emergent AEs (TEAE) were cytopenias; neutropenia was most frequent (52%). Cytokine release syndrome (CRS) occurred in 12 (52%) pts (no gr ≥ 3). Median (range) time to onset and resolution of CRS was 6 days (2-9) and 3 days (2-7), respectively. Neurological events (NE) occurred in 4 (17%) pts, with 1 (4%) gr 3 and no gr 4-5 (Table). Median (range) time to onset and resolution of NEs was 8.5 days (6-11) and 2.5 days (1-4), respectively. Three (13%) pts received tocilizumab/steroids for CRS/NEs. Prolonged cytopenia (gr ≥ 3 laboratory values at Day 29) occurred in 3 (13%) pts; all recovered to gr ≤ 2 by Day 90. No gr ≥ 3 infections were reported. One TEAE death occurred in the context of IRC-assessed disease progression due to gr 5 macrophage activation syndrome (MAS). Liso-cel showed rapid expansion with median (range) time to maximum transgene levels of 10 days (7-11). Persistence of liso-cel transgene was detected up to Month 12 in 5 of 18 (28%) pts. B-cell aplasia (&amp;lt; 3% CD19 + B cells in peripheral blood lymphocytes) after liso-cel infusion was rapid and maintained in ≥ 95% of pts through Month 2. Conclusions: This is the first report of outcomes in 2L high-risk R/R FL with CD19-directed CAR T cell therapy. In this population, liso-cel achieved very high CR rates (22 of 23 pts); deep and durable remissions, with follow-up ongoing; and a favorable safety profile with low rates of severe (gr ≥ 3) CRS, NEs, and prolonged cytopenia, and no severe infections. These data support liso-cel as a potential new treatment option in pts with 2L R/R FL at high-risk for treatment failure.

Safety and Efficacy of Parsaclisib in Combination with Rituximab in Patients with Previously Untreated Indolent B-Cell Lymphoma: Primary Analysis from a Phase 2 Study (REPLY)

Background: Advanced-stage follicular lymphoma (FL) and marginal zone lymphoma (MZL) represent incurable indolent B-cell lymphomas and perplex elders mainly. Chemoimmunotherapy can induce durable remissions; however, the side effects of chemotherapy remain a major source of concern for patients. Parsaclisib, a next-generation PI3K inhibitor, has demonstrated significant clinical activity in refractory or relapsed indolent B-cell lymphomas, including FL and MZL. This study investigated the efficacy and safety of a chemo-free regimen in patients with FL and MZL tumors. Here, we present preliminary results from a response-adapted study utilizing parsaclisib and rituximab as frontline therapy for FL and MZL (NCT05073250). Methods: Eligible patients aged ≥18 years with previously untreated indolent B-cell non-Hodgkin lymphoma (NHL) of either FL grade 1-3a or MZL and stage III-IV disease (Patients with stage I-II FL and MZL who have received radiation therapy and subsequently relapsed were also eligible) were included in the study. Patients with active HIV, CMV, Hepatitis B or C infections, and autoimmune conditions requiring therapy were excluded. Patients received 6 28-day cycles of parsaclisib at a daily dose of 20mg during the first two cycles, followed by a reduced dose of 2.5mg daily for the subsequent four cycles; rituximab was administered at 375mg/m 2 weekly for 4 weeks, and then on day 1 of each cycle. All patients received PCP prophylaxis. Baseline FDG-PET and CT scans were performed, and additional scans were conducted after cycles 3 and 6 to assess treatment response. Patients achieving complete response (CR) after the 6 cycles discontinued therapy, while patients with partial response (PR) received another 6 cycles of the combination therapy. Non-responding patients were offered standard chemotherapy. The primary endpoint of the study is the overall rate of complete response (CR), with secondary endpoints including safety, objective response rate (ORR), duration of CR, and progression-free survival (PFS). Results: As of the data cut-off on July 20, 10 patients were enrolled, with a median follow-up time of 10.2 months, and 7 patients were eligible for response evaluation. The median age of patients was 47 years (range 35-52), and three were older than 60. Fifty percent (5/10) of the patients were Follicular Lymphoma (FL), while the remaining 50% were the extra-nodal MZL of mucosa-associated lymphoid tissue. Three patients had bone marrow involvement, and one had C-MYC/BCL-2 double expression. The Complete Response (CR) rate was 71.4%, with the FL cohort showing a CR rate of 75% (3/4) and the MZL cohort showing a CR rate of 66.7% (2/3). The Overall Response Rate (ORR) was 85.7% (6/7, with 3 cases in FL and 3 cases in MZL). The median duration of CR was 3.9 months (range 0.6-7.7), and the median Progression-Free Survival (PFS) was not reached. Five patients are still receiving treatment, two patients who completed treatment were followed up and remained in sustained complete remission. Among the 10 treated patients, treatment-emergent adverse events (TEAEs) occurred in 60% (n=6), and no serious adverse events (SAEs) were observed. The most common TEAEs were infusion reaction (40%, rituximab-related), neutropenia (30%), anemia (30%), and total cholesterol elevation (30%). Only one patient experienced grade 3 neutropenia, no grade 4-5 TEAEs occurred. Two patients experienced delayed medication due to COVID-19 infection. Conclusion: The combination of parsaclisib with rituximab showed a deep and durable response, with a favorable safety profile and generally good tolerability in patients with previously untreated indolent B-Cell Lymphoma.

Subcutaneous Mosunetuzumab Is Active and Has a Manageable Safety Profile in Patients with Previously Untreated, Low-Tumor Burden Follicular Lymphoma: Initial Results from the Phase II Morningsun Study

Background: Mosunetuzumab is a CD20xCD3 bispecific antibody that is approved for the intravenous (IV) treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) who have received at least two prior lines of systemic therapy, and is suitable for administration in the outpatient setting. In an ongoing Phase I/II study (NCT02500407), IV mosunetuzumab induced durable responses and had a manageable safety profile in patients with heavily pre-treated R/R indolent and aggressive B-cell non-Hodgkin lymphomas (NHL) when administered as a fixed-duration treatment (Budde et al. J Clin Oncol 2022). Subcutaneous (SC) dosing was also evaluated and showed similar efficacy to IV dosing and a manageable safety profile (Budde et al. ASH 2022). MorningSun (NCT05207670) is an ongoing, open-label, multicenter, Phase II study evaluating the efficacy, safety and pharmacokinetics of SC mosunetuzumab in patients with selected B-cell NHLs, including those without prior treatment (Flinn et al. ASCO 2022). For the first time, we present initial efficacy and safety data for patients with previously untreated, low-tumor burden FL who were enrolled into MorningSun at community and academic centers in the United States. Methods: Inclusion criteria include previously untreated Grade (Gr) 1 or 2 FL, low tumor burden by GELF criteria, Ann Arbor stage III or IV disease, and ECOG performance status 0-2. Mosunetuzumab is administered without mandatory hospitalization by SC injection in 21-day cycles. In Cycle (C) 1, mosunetuzumab is given on Day (D) 1 (5mg), D8 (45mg) and D15 (45mg). In C2+, mosunetuzumab is given on D1 only (45mg). Treatment is continued for up to 17 cycles (~1 year). Patients who are in complete metabolic response (CMR) at C8 can discontinue active treatment and enter long-term follow-up. Premedication with dexamethasone (20mg) is mandatory in C1 and C2 and optional thereafter. Acetaminophen and diphenhydramine may also be given. The primary endpoint is the rate of progression-free survival at 24 months. Results: At data cut-off (March 6, 2023), 30 patients had been enrolled (19 at community centers and 11 at academic centers). Median age was 56 years. All patients had ECOG performance status 0-1, and a minority had B symptoms ( Table 1). The median duration of follow-up was 4.2 months (range: 0.2-11.1) and the median number of cycles received was 7 (range: 1-13). Among 24 patients who had at least one post-baseline tumor assessment, 23 achieved an objective response (95.8%; 95% CI: 78.9-99.9), including 20 who achieved a CMR (83.3%; 95% CI: 62.6-95.3). All responses were observed at the first post-baseline tumor assessment in C4 (median time to response: 2.6 months; 95% CI: 2.6-2.8). At cut-off, responses were ongoing in all patients who achieved CMR and 2 of 3 patients who achieved partial metabolic response. The most common adverse event (AE) was injection site reaction (53.3% of patients), all of which were Gr 1 (43.3%) or Gr 2 (10.0%). Cytokine release syndrome (CRS) occurred in 43.3%. Most patients had Gr 1 CRS ( Table 2). No Gr ≥3 CRS events or discontinuations due to CRS were reported. CRS occurred in C1 only. All CRS events resolved. Other common (&amp;gt;20%) AEs were headache (50.0%), nausea (30.0%), fatigue (26.7%), pyrexia (23.3%), chills (23.3%) and alanine aminotransferase increased (23.3%). Gr ≥3 AEs in ≥5% of patients were neutrophil count decreased (2 patients; 6.7%). Serious AEs (SAEs) in ≥5% were CRS (2 patients; 6.7%). No SAEs of infection were reported. AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients (Gr 1 confusional state and Gr 1 memory impairment in one patient each); both events resolved. No mosunetuzumab-related AEs leading to discontinuation occurred and no Gr 5 (fatal) AEs were reported. Conclusions: Initial MorningSun data support that SC mosunetuzumab is active in patients with previously untreated, low-tumor burden FL. Safety data demonstrate a manageable safety profile that is consistent with that seen in patients with R/R B-cell NHLs and is supportive of outpatient administration.

Single-Cell RNA Sequencing Reveals Hypo-Responsiveness of T and NK Cells to Interferon Stimulation As an Immune Hallmark in Asymptomatic Waldenstrom's Macroglobulinemia

Introduction Waldenstrom macroglobulinemia (WM) is a rare, indolent non-Hodgkin lymphoplasmacytic lymphoma of the bone marrow (BM), characterized by monoclonal IgM protein production. WM is preceded by IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and smoldering WM (SWM), which are clinically detectable but asymptomatic precursor phases (collectively referred to as asymptomatic WM; AWM). Recent work has revealed significant changes in the immune microenvironment of patients with overt WM, however, less is known about immune dysregulation in patients with early-stage disease. Methods We performed 5' single-cell RNA sequencing (scRNAseq) on BM immune cells from patients with AWM (n=28), healthy donors (HD, n=23), and patients with smoldering multiple myeloma (SMM) (n=27). We also performed an in vitro stimulation experiment using universal Type I interferon (IFN) and subsequent scRNAseq on bone marrow mononuclear cells (BMMCs) and peripheral blood mononuclear cells (PBMCs) from AWM (n=3) and HD (n=3). Results Overall, we annotated 210,019 immune cells, excluding normal B cells. Despite their early stage, AWM patients showed significantly altered BM immune cell composition, including increased proportions of CD56dim NK cells, CD8+ effector memory cells, and CD16 + Monocytes and decreased proportions of pro-inflammatory CD14 + monocytes and activated and interferon (IFN)-stimulated T and NK cells (q&amp;lt;0.2). Low-risk AWM presented similar changes in immune cell composition as intermediate- and high-risk AWM, implying that compositional alterations may be established early in the disease course. Notably, however, the proportion of Tregs was significantly increased in patients with SWM compared to IgM MGUS (p=0.04), suggesting that Tregs may play a role in disease progression. Next, we compared BM immune cell composition between patients with AWM and SMM. In both tumor types, patients showed significantly higher proportions of CD56dim NK cells and CD16 + monocytes compared to healthy donors. However, strikingly, a significant decrease in activated and IFN-stimulated T and NK cells was only observed in AWM, suggesting it may be a hallmark of disease. Comparison of BMMCs and PBMCs from patients with AWM following in vitro culture revealed that the lack of IFN-stimulated cells was systemic-in both BMMCs and PBMCs-although the effect was significantly more pronounced in BMMCs than PBMCs. Interestingly, while in vitro stimulation with Type I IFN resulted in the generation of IFN-stimulated T and NK cells in both HD and AWM, the levels of IFN stimulation did not entirely normalize, reproducing the gradient observed in the control samples without in vitro stimulation: AWM BM &amp;lt; AWM PB &amp;lt; HD BM. To test whether the observed defect was due to a lack of IFN in AWM, we next compared the gene expression profile of monocytes from AWM and HD, which revealed significantly higher activity of the IFN signature in monocytes from AWM compared to HD (p &amp;lt; 10 -5). This suggests that IFN levels in patients are at least not reduced. Collectively, these results indicate that T and NK cells from AWM are hypo-responsive to IFN stimulation, despite the presence of normal or possibly increased IFN in the BM microenvironment. Conclusion Our results indicate that despite the absence of symptoms, patients with AWM already have immune dysregulation in the BM, including the absence of IFN-stimulated T and NK cells, which may provide a rationale for therapeutic intervention. Previous studies have demonstrated clinical responses to therapeutic IFN administration, suggesting that novel formulations with improved therapeutic windows may have a role in treating patients with WM in the future.

Retrospective Analysis of the Impact of Bendamustine Dose Reduction and Chemotherapy on the Outcomes of Follicular Lymphoma

Introduction Follicular lymphoma (FL) is the most common indolent non-Hodgkin's lymphoma and primarily affects the elderly population. While bendamustine serves as a pivotal drug in standard therapy, it is often not administered as planned due to side effects, especially among the elderly. Clinical studies have shown that dose reduction and chemotherapy delays in the treatment of diffuse large B-cell lymphoma are associated with lower survival rates. However, few studies have analyzed the impact of bendamustine delays and dose reduction on the outcome of FL. Thus, the aim of our study was to clarify the effect of bendamustine dose reduction and chemotherapy course delay on treatment outcomes and to evaluate the effects of chemotherapy modification on FL. Patients and Methods This is a retrospective pooled analysis of previously untreated patients with FL who underwent consecutive bendamustine-based regimens at our institute. Patients receiving less than four courses of bendamustine-based regimens were excluded. Bendamustine dose reduction was defined as a cumulative dose reduction of at least 20% of the total prescribed dose. The total dose was defined as the sum of six cycles administered at 100% of the prescribed dose. Chemotherapy delays were defined as the total number of days of delay exceeding 21 days. The main goal of the study was to assess the impact of the chemotherapy scheme modification (dose reduction or delay) on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method was used for single-variable survival data analysis. Differences in survival rate were determined using the log-rank test. Comparison among subgroups was performed using ANOVA for continuous covariates and Fisher's exact test for categorical variables. Results From January 2016 to June 2023, 43 untreated FL patients (23 females and 20 males) were started on rituximab-bendamustine (R-B) or obinutuzumab-bendamustine (G-B) at our institution. Median patient age was 69 years (range, 41-90 years) and the median follow-up time was 44 months (range, 5-74 months). Thirteen patients were treated with R-B, and 30 with G-B. Only one patient received obinutuzumab maintenance therapy due to the COVID-19 pandemic. Patients were divided into for three bendamustine delay/reduction groups. No bendamustine dose reduction or chemotherapy delays was observed in 27 patients (62.7%). The chemotherapy scheme was modified in 16 patients (37.2%): 10 patients (23.2%) experienced a bendamustine-only dose reduction and 6 patients (13.9%) experienced chemotherapy-only delays. None of the patients experienced both bendamustine dose reduction and delays. The main reasons for bendamustine dose reductions were the following: elderly/ frailty (60.0%), neutropenia (10.0%), thrombocytopenia (10.0%), and patient request (10.0%). The main reasons for chemotherapy delays were the following: patient request (33.3%), thrombocytopenia (33.3%), infection (16.6%), and skin rash (16.6%). Baseline characteristics were summarized in Table 1. The PFS of the three groups was comparable (Figure. 1a). The OS of the group with chemotherapy delays was comparable to the group with no dose reduction or delay, while that of the group with dose reduction was inferior (Figure. 1b). There were no differences in objective response rate (Table1). Conclusion Our study showed that chemotherapy delays or bendamustine dose reduction did not adversely affect PFS, and only chemotherapy delays adversely affected OS. No clinically significant differences in PFS were observed among patients with chemotherapy delays, which could be attributed to insufficient statistical power. Our cohorts comprised a heterogeneous population, including patients treated with R-B and G-B. However, considering the lack of evidence regarding the optimal dose intensity or chemotherapy interval for different populations, reducing the bendamustine dose may be a valid option for vulnerable patients.

Copanlisib in Combination with Nivolumab in Subjects with Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Primary Mediastinal Large B-Cell Lymphoma: A Phase II Study

Introduction: Diffuse Large B-cell Lymphoma (DLBCL) are aggressive B-cell non-Hodgkin lymphomas (NHL). One particular subtype, Primary Mediastinal B-cell Lymphoma (PMBCL), is often grouped with DLBCL, but it possesses distinct biological and clinical characteristics. While initial therapy successfully cures approximately two-thirds of patients (pts), those who do not respond or experience progression within the first two years have a poor prognosis despite novel cellular therapies and bispecifics and ultimately succumb to their disease. There is a pressing need for more effective therapeutic approaches in this patient population. Recent advances in the understanding of DLBCL pathogenesis have led to the targeting of various signaling pathways, including the PI3K-AKT-mTOR pathway. One such drug, copanlisib (C), a pan-PI3K inhibitor with potent PI3K-α/PI3K-δ inhibition, exhibited activity in both indolent and aggressive NHL. In preclinical studies using a DLBCL mouse model, treatment with C effectively reduced the immunosuppressive tumor-infiltrating T-regulatory cells (Tregs). Moreover, when combined with a surrogate anti-mouse programmed death -1 (PD-1) blocker, C demonstrated significant in vivo responses (75%) compared to the monotherapy groups (0%). These findings support the rationale for exploring the combination of nivolumab, a PD-1 blocker, and copanlisib (C-N) in DLBCL. Thus, a phase 2 prospective study has been developed, focusing on two relapsed/refractory (RR) cohorts (DLBCL and PMBCL), treated with the combination of C-N. A prespecified interim analysis was planned upon enrollment of 14 pts. Herein, we report outcomes of the 12 enrolled pts, as the study was halted prematurely due to a safety signal deemed possibly related to the combination. Study design: C 60 mg was given intravenously on days 1, 8, and 15 during cycles 1-8, and on days 1 and 15 in subsequent cycles. N 240 mg IV was given on days 1 and 15 during cycles 1-8, and 480 mg on day 1 on subsequent cycles. Each treatment cycle is 28 days. Therapy was given for up to 2 years, as long as there is no disease progression or unacceptable side effects. The primary objective of the study is to determine the ORR, which includes complete and partial responses (CR+PR). Secondary objectives include evaluating the safety of the combination, as well as assessing progression-free survival (PFS), duration of response (DOR), CR, and overall survival (OS). The study plan was to enroll a maximum of 106 pts, including a safety cohort of 6 pts. The study received funding from Bayer and conducted through NCI-CTEP (NCI Protocol #10193; NCT03484819). Results: Twelve pts who received at least one cycle of C-N were included in this analysis. Pt characteristics are illustrated in table 1. All enrolled pts had DLBCL histology. Only one patient received a prior autologous stem cell transplant. Interestingly 4/12 received prior chimeric antigen receptor T-cell therapy (CART). Of the 12 enrolled pts, seven were evaluated for response. The ORR was 25% (3/12) (95% CI: 5 - 57%), all CR. The median number of cycles received was 2.5 (range 1-24) with two pts receiving 23 and 24 cycles. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 10/12 (83.3%), while hematologic AEs were seen in 5/12 (41.7%) pts. A relatively higher incidence of cardiac events (4/12) were noted including one cardiac arrest after one cycle of therapy, and four atrial fibrillation events, all grade 3, but only two were deemed possibly attributed to therapy. The cardiac arrest was deemed unrelated to therapy. Conclusions: C-N combination had modest clinical activity in pts with R/R DLBCL with some prolonged responses. However, due to the relatively high number of cardiac events and the changing therapeutic landscape with recent approvals, a decision was made to halt the study. These findings likely reflect possibly older and sicker patient population. Biomarker studies for predictors of response are under consideration.

Survival of Patients with Transformed Marginal Zone Lymphoma in the United States: A Population-Based Cohort Study

Background: Marginal zone lymphomas (MZLs) are a heterogenous group of indolent non-Hodgkin lymphomas that include extranodal MZL of mucosa-associated lymphoid tissue (EMZL or MALT lymphoma), nodal MZL (NMZL), and splenic (SMZL). All three subtypes can transform to diffuse large B-cell lymphoma (DLBCL). However, the cumulative incidence of histologic transformation (HT) and survival of patients with transformed MZL (t-MZL) in the US population have not been reported to date. Hence, we sought to estimate the risk of HT and relative survival (RS) in patients diagnosed with MZL in USA using a population-based study. Method: We conducted a population-based cohort study of t-MZL using the Surveillance, Epidemiology, and End Results-17 database. We included adults diagnosed with MZL in the US between 2011-2015. This time period was selected to provide a contemporary estimate of survival and allow for adequate follow-up. We identified patients with t-MZL by following patients with MZL and identifying those patients with subsequent diagnoses of DLBCL. All patients with t-MZL had biopsy-proven HT. We estimated the post-transformation RS of patients with t-MZL using flexible parametric survival models with 5 degrees of freedom for the baseline cumulative hazard. We compared the survival of the different MZL subtypes using multivariable modeling after adjusting for age, year, race, Ann Arbor stage, B symptoms, and geographic location. P values less than 0.05 were considered statistically significant. Results: A total of 5372 patients with MZL were included in the study. There were 3446 (64.2%) patients with EMZL, 1485 (27.6%) with NMZL, and 441 with SMZL (8.2%). Among the 5372 patients, 121 (2.3%) had biopsy-proven HT after a median follow-up of 6.2 years (95% confidence interval (CI), 6.1-6.3). HT was associated with decreased survival for patients with MZL ( Figure 1A). Among the MZL subtypes, SMZL was the most likely to develop HT (24/441, 5.4%), followed by NMZL (49/1436, 3.3%) and EMZL (48/3398, 1.4%) ( P &amp;lt; 0.001) despite similar follow-up between groups. The 5-year post-transformation RS was highest for t-EMZL (61%) followed by t-NMZL (51%) and t-SMZL (46%) (Figure 1B). On multivariable analysis, however, the subtype of MZL was not a significant predictor of RS. In addition, there were no significant predictors of RS identified among the study covariates. Conclusion: This is the first population-based study to date reporting outcomes associated with t-MZL in the USA. The risk of HT in MZL may vary depending on the subtype of MZL with cumulative incidence of 1.4-5.4% observed after 6 years of follow-up in the contemporary era. HT was associated with increased mortality irrespective of MZL subtype. Among the MZL subtypes, SMZL was most likely to develop HT and had the lowest estimated 5-year RS. Additional studies are needed to better understand factors associated with prognosis in t-MZL.

Ilyad: A Phase III Double Blind, Randomized Trial Evaluating Vitamin D (Cholecalciferol) in Patients with Low Tumor-Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab Therapy

Background: We and others have reported a significant association between low vitamin D levels at diagnosis of indolent B-cell lymphomas and inferior overall survival; the magnitude of this association is stronger than conventional clinical prognostic features. Vitamin D insufficiency impairs rituximab-mediated cytotoxicity and impairs macrophage function, which impacts rituximab responses in vivo. We therefore conducted a phase III, double-bind study of oral cholecalciferol vs. placebo for three years in patients with indolent lymphoma treated with rituximab monotherapy. Methods: Patients had biopsy-confirmed low tumor burden (GELF criteria) follicular lymphoma (grade 1-3A), marginal zone lymphoma or small lymphocytic lymphoma. Patients with osteoporosis requiring treatment, known symptomatic hyperparathyroidism, hypercalcemia (&amp;gt; normal), history of calcium-related nephrolithiasis, or creatinine &amp;gt; 2X normal were excluded to minimize risk of cholecalciferol therapy. Supplemental vitamin D was discouraged but allowed at doses up to 1000 IU daily. Treatment included rituximab or approved biosimilar 375 mg/m 2 weekly x 4 (or subcutaneous equivalent dosing per investigator discretion). Patients were randomized in a double-blind, 2:1 fashion to receive 2000 IU vitamin D 3 or placebo daily (BioTech Pharmacal Inc) beginning on day 1 of rituximab. Randomization was stratified by histology (follicular vs all other) and FLIPI score (high vs low and intermediate). Restaging PET/CTs were performed at week 13; responding patients continued on study with daily dosing for 36 months or until disease progression. Patients with stable disease or disease progression at week 13 were counted as events. Blinded serum 25(OH) vitamin D2 and D3, was measured by tandem mass spectrometry; saliva was collected for the isolation of germline DNA and SNP analysis using Oragene collection kits, OGR-500 (DNA Genotek Inc). The primary endpoint for this study is the time from randomization to progression or death, right-censored by the time of last follow-up, the cohort included all eligible, treated patients. The study provided 81% power to detect HR = 0.55 at a two-sided α = 0.05 level of significance. Results: 206 patients (follicular, n=137; MZL, n=33; SLL, n=22 and MALT, n=14) constituted the final analysis cohort. Median age was 62 (range 30-80 years); 57% female; 89% White; and 76% were overweight or obese. The median vitamin D level at baseline was 33ng/mL (range 6-80); at week 13, mean vitamin D level was 41.6 ng/mL in Vit D arm vs. 31.3 ng/mL in the placebo arm; these differences persisted throughout the study confirming compliance. Toxicity was as expected with rituximab; specific events of interest were rare and included hypercalcemia (n=2; all placebo arm); renal calculi (n=4; all vit D arm) and bone fractures (n=3; all vit D arm). At week 13, 172 pts (84%) responded, including CR (n=110) and PR (n=62). There was no difference in response between the arms. Responses by subtype: FL: 93%; SLL: 50%; MZL: 67%; MALT: 83%. With median follow-up of 19.5 months, the median EFS was 34.5 months (95% CI: 24 - 42+ months) for all patients; there was no statistically significant difference in EFS between placebo and vitamin D (p=0.7; Figure 1). Subgroup analysis of histology, FL-IPI score, sex and vitamin D level at enrollment also showed no significant difference in EFS between placebo and vitamin D, including those patients with the lowest tertile of baseline vitamin D level (28 or lower; p=0.27). Polymorphisms of vitamin D receptor binding protein and vitamin D receptor were available in 94% of patients and were balanced between treatment arms; there was no statistically significant association between any specific polymorphism and EFS. Conclusion: We observed no statistically significant benefit of vitamin D supplementation in patients with indolent lymphoma treated with rituximab in this phase III, placebo-controlled clinical trial. These results suggest that the association of low vitamin D with outcome in this disease likely represents a surrogate for illness and comorbidity rather than a modifiable risk factor, and may have implications for ongoing and planned studies of vitamin D supplementation in other malignancies.