Advanced-stage classical Hodgkin lymphoma (cHL) has been traditionally treated with effective chemotherapy regimens, albeit some associated with substantial toxicity. The recently introduced brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone (BrECADD) regimen has proved more effective and less toxic than escalated BEACOPP (escBEACOPP: bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). Our retrospective multicentre study assessed outcomes of this treatment in the real-world setting. It incorporated 100 advanced-stage cHL patients receiving BrECADD at 19 cancer centres between July 2023 and October 2025. The primary end-point was progression-free survival (PFS); secondary end-points included overall response rate (ORR), positron emission tomography (PET)-2 negativity, complete response (CR), overall survival (OS) and toxicity. The median age was 30 (18-65) years; 80% had stage IV disease; 85% had an International Prognostic Score ≥3. ORR and CR were 100% and 95%, respectively; 83% achieved PET-2 negativity, enabling therapy de-escalation from six to four cycles. At a median follow-up of 13.7 months, estimated 1-year PFS and OS were 96% and 100% respectively. Only 4% required radiotherapy. Grade ≥3 neutropenia (83%) and febrile neutropenia (55%) were common; yet, 95% of patients completed all planned cycles. Peripheral neuropathy occurred in 25%, mostly grade 1-2. In this real-world cohort, including high-risk patients, BrECADD demonstrated remarkable efficacy and tolerability, supporting its feasibility and potential to reduce chemotherapy and radiotherapy exposure, while maintaining high treatment efficacy.

BACKGROUND:The GALLIUM trial showed improved progression-free survival (PFS) with obinutuzumab (O)-based chemoimmunotherapy in first-line treatment of follicular lymphoma (FL), although with increased toxicity compared to rituximab (R). Our previous real-world study found similar toxicity between these protocols during induction. AIM:To compare real-world toxicity and outcomes of R versus O maintenance therapy in FL patients following first-line chemoimmunotherapy. METHODS:A multicenter retrospective study included FL patients treated with first-line R- or O-based chemoimmunotherapy. The primary outcome was any infection up to 6 months post-maintenance. Secondary outcomes included other toxicities, PFS, and overall survival (OS). RESULTS:We analyzed 134 patients (R: 71, O: 63). Baseline characteristics were similar except for higher diabetes and hypertension rates in the R group. The median number of maintenance cycles was comparable. Infections occurred in 56% of patients, with no significant difference (50.7% R vs. 61.9% O, p = 0.21). Grade  ≥  3 infections, febrile neutropenia, and treatment discontinuation rates were comparable between groups. Pneumonia and viral infections were less frequent with R versus O (13.8% vs. 28.1%, p = 0.019 and 19% vs. 39%, p = 0.004, respectively), while infusion reactions were higher (8.4% vs. 0%, p = 0.028). After 5.5 years, PFS favored O (19.7% vs. 4.8%, p = 0.028), with similar OS. CONCLUSIONS:In real-world settings, rituximab- and obinutuzumab-based chemoimmunotherapy with maintenance for FL exhibited a similar toxicity profile, with differences in specific infections. Obinutuzumab had superior PFS and similar OS compared with rituximab therapy, supporting obinutuzumab usage in first-line chemoimmunotherapy, especially in selected young and fit patients.

The development of Bruton Tyrosine Kinase inhibitors (BTKis) has revolutionized the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, increased infection rates have been reported in patients receiving BTKis in multiple clinical trials. This study aimed to evaluate the risk of infections associated with BTKis compared to other therapeutic regimens in CLL/SLL patients. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. We included trials comparing BTKi-containing regimens (e.g., BTKi alone or combined with anti-CD20 or venetoclax) to other therapeutic regimens, as well as studies comparing different BTKis or BTKi combinations. Primary outcomes were the risk of any infection and grade 3–4 infections. Secondary outcomes included pneumonia, sepsis, septic shock, COVID-19, fungal infections, fatal infections, bacteremia, and febrile neutropenia. Pooled risk ratios (RR) with 95

Introduction - Glofitamab is a CD20-directed CD3 T-cell engager that has recently been approved by the FDA for relapsed and refractory diffuse large B cell lymphoma (R/R DLBCL). The approval was based on a pivotal phase II study including 154 patients with a median of 3 lines of treatment (a third post chimeric antigen receptor T (CAR-T) cell therapy) demonstrating an overall response rate (ORR) and complete response (CR) rate of 52% and 39%, respectively 1. However real-life data is still lacking. The present study was aimed to determine the efficacy and safety of glofitamab in real-life settings. Methods -A retrospective multicenter study including consecutive patients aged 18 years and older with R/R DLBCL, treated through a national compassionate program with at least 1 dose of glofitamab, after failing at least three lines of therapy. The first patient was recruited in September 2020 till January 2023. Outcomes included ORR and CR, defined by the Lugano criteria; progression free survival (PFS) and overall survival (OS), defined from the day of obinutuzimab infusion until event; cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS) were defined by the ASTCT consensus 2019. Risk factors for PFS and OS were identified by univariate and multivariate analyses, using logistic regression. Results - A total of 35 patients treated in 6 Israeli centers, were included. Median age at the time of initiation of glofitamab was 67 years (59-74) and 66% of the patients were males. The median number of previous therapies was 5 (IQR, 4-6) and 83% received more than 3 previous lines of therapy. 43% were primary refractory, all but 3 received CAR-T cell therapy (91%) and 23% underwent autologous stem cell transplantation (Table 1). Median follow up was 34 months (IQR, 18-57). Outcomes: 34% achieved ORR with 14% achieving CR. Median PFS and OS was 2 (IQR, 1-6) and 4 months (IQR, 2-10), respectively (Figure 1). At the end of follow up - 12 (34%) patients survived, 21 died and 2 patients were lost to follow- up. Causes of death included disease progression in 15 patients and infections in 6. Treatment was discontinued earlier than 12 cycles in 86%, mostly due to progressive disease (76%), and 24% due to infections (3 - COVID-19; 3- bacterial). Adverse events included CRS in 37% - all grade 1-2. 2 patients developed grade 1 ICANS. In a multivariate analysis including age, male, bulky disease, elevated LDH and CRS, only male sex was found to be significant risk factor for PFS and OS (p=0.02, p=0.04 respectively). Conclusions - In this real-life cohort of R/R DLBCL, glofitamab showed less efficacy than in the pivotal study. This might be due to the more heavily pretreated patients in our series with nearly all patients post CAR-T. Nevertheless, toxicity in our real-life analysis was better than reported in the pivotal study, supporting the role of glofitamab in R/R DLBCL patients. References- 1. Dickinson et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. NEJM 2022;387:2220-31

ABSTRACT:Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that complicates hematologic malignancies. The Optimized HLH Inflammatory (OHI) index, based solely on the combined elevation of soluble CD25 (sCD25; >3900 U/mL) and ferritin (1000 ng/mL) levels, predicts mortality more effectively than the conventional HLH criteria. This study aimed to determine whether mortality in OHI-positive (OHI+) patients is primarily caused by lymphoma or inflammation-related causes. In a multicenter, retrospective study of patients with newly diagnosed lymphoma with sCD25 and ferritin measurements available, patients were classified as OHI+ or OHI negative (OHI-). The 1-year and 3-year overall survival (OS), event-free survival, and causes of death were analyzed, along with predicted vs observed mortality based on other lymphoma-relevant prognostic indexes. Among 135 patients with lymphoma (70 OHI- and 65 OHI+), OHI+ patients had significantly lower OS at 1 year (33% vs 81%; P < .0001) with a median survival of 190 days. OHI+ patients had a 13-fold increased mortality risk (odds ratio, 13.3; 95% confidence interval, 6.0-28.5) despite similar predicted OS based on conventional indexes (72% vs 65%; P = .46). Mortality causes differed significantly. A total of 58% of OHI+ patients died from multiorgan failure, whereas only 6% died from progressive lymphoma. In contrast, 43% of the OHI- patients died from lymphoma progression. The incorporation of etoposide into lymphoma-directed treatment was associated with improved OS in OHI+ T-cell lymphomas (P = .007). These findings underscore the clinical significance of the OHI index as a prognostic tool in lymphoma, to elucidate the mechanisms of mortality, and to identify a high-risk subgroup for which tailored treatments may lead to improved outcomes.

BACKGROUND:Cancer is characterized by accelerated glycolysis with enhanced glucose uptake and lactate production, a phenomenon termed Warburg effect (WE). We studied the incidence and clinical impact of Warburg-driven lactic acidosis in lymphoma. METHODS:Patients admitted with newly diagnosed or relapsed/refractory lymphoma and documented lactate levels during the first week of admission were included. Patients with lactatemia were classified as secondary (with a recognizable cause for elevated lactate) or none (WE group). RESULTS:WE and secondary lactatemia were documented in 58 and 44 patients (15% and 12% of evaluable patients, respectively). Both WE and secondary lactatemia were associated with poor short-term survival. WE at presentation correlated with tumor burden, with most patients having aggressive disease, advanced stage, and extranodal involvement. WE was associated with high rates of early death (26% and 43% at 30- and 60-days, respectively). Higher lactate levels correlated with worse survival. Earlier initiation of chemotherapy was associated with a (nonsignificant) trend toward better outcomes, whereas steroid and/or thiamine therapy did not alter patient outcomes. Glucose administration was associated with worse survival. CONCLUSION:WE-driven lactatemia is associated with high tumor burden and increased short-term mortality in lymphoma. Prompt initiation of anti-lymphoma therapy may improve outcomes.

Background: Despite recent advances, R/R LBCL remains clinically challenging with poor outcomes and a critical need for effective and durable treatment options, particularly for patients with high-risk characteristics. In this open-label, multicenter, Phase Ib/II study (NCT03533283), glofitamab in combination with polatuzumab vedotin (Glofit+Pola) demonstrated high and durable efficacy and manageable safety in patients with R/R LBCL after ≥1 line of therapy, including in those with high-grade B-cell lymphoma (HGBCL; Hutchings, et al. ASH 2024). We report the efficacy of Glofit+Pola in patients with R/R LBCL, with subgroup analyses in the 2L and 3L+ setting. Methods: Patients aged ≥18 years with R/R LBCL after ≥1 prior systemic therapy were included. After obinutuzumab pre-treatment on Cycle (C)1 Day (D)1, glofitamab was administered as step-up dosing in C1 (D8, 2.5mg; D15, 10mg) then the target dose of 30mg on D1 of C2–12 (21-day cycles), and polatuzumab vedotin (1.8mg/kg) was given on C1D2 and D1 of C2–6 (21-day cycles). Patients received fixed treatment of 12 cycles of glofitamab and six cycles of polatuzumab vedotin unless treatment was discontinued. Efficacy was assessed by overall response, durability of response, and survival outcomes. Results: At the clinical cut-off date (September 2, 2024), 129 patients with LBCL were enrolled (HGBCL, n=44) and treated with Glofit+Pola: 53 (41.1%) patients in the 2L and 76 (58.9%) in the 3L+ subgroups. In the 2L and 3L+ subgroups, 66.0% (n=35) and 59.2% (n=45) of patients, respectively, were refractory to their first-line therapy; 88.2% (n=67) of patients in the 3L+ subgroup were refractory to any prior therapy. Prior chimeric antigen receptor T-cell therapy was reported in 1.9% (n=1; refractory) of patients in the 2L subgroup and 35.5% (n=27; 21 refractory) of patients in the 3L+ subgroup. The median survival follow up was 32.7 months (range: 0–55; 2L: 29.7 months [range: 1–55]; 3L+: 33.6 months [range: 0–55]). The overall response rate (ORR) and complete response (CR) rate in the overall population were 80.6% and 62.0%, respectively. Comparable response rates were seen in patients in the 2L (ORR: 79.2%; CR: 66.0%) and 3L+ (ORR: 81.6%; CR: 59.2%) subgroups. The median (m) duration of response (DOR) and duration of CR (DOCR) in the overall population were 24.3 months (95% confidence interval [CI]: 15.0–37.8) and 31.8 (95% CI: 21.9–not estimable [NE]), respectively. Similarly, in the 2L subgroup, the mDOR was 31.8 months (95% CI: 8.8–NE) and the mDOCR was also 31.8 months (95% CI: 17.8–NE). In the 3L+ subgroup, the mDOR and mDOCR were 23.5 months (95% CI: 10.9–37.8) and 37.8 months (95% CI: 21.9–NE), respectively. In the overall population, the 12- and 24-month DOR rates were 62.4% (95% CI: 52.5–72.2) and 50.5% (95% CI: 39.6–61.4), respectively. The 12- and 24-month DOR rates, respectively, were 64.6% (95% CI: 49.5–79.6) and 53.3% (95% CI: 36.3–70.3) for the 2L subgroup, and 60.7% (95% CI: 47.7–73.7) and 48.6% (95% CI: 34.5–62.7) for the 3L+ subgroup. The 12- and 24-month DOCR rates were also comparable across the overall population and 2L and 3L+ subgroups. In the overall population, 12- and 24-month DOCR rates were 75.1% (95% CI: 65.1–85.2) and 59.9% (95% CI: 47.5–72.3), respectively. Similarly, the 2L and 3L+ subgroups, respectively, achieved 12-month DOCR rates of 72.8% (95% CI: 57.5–88.0) and 76.7% (95% CI: 63.2–90.2), and 24-month DOCR rates of 59.3% (95% CI: 40.7–77.9) and 60.4% (95% CI: 43.8–77.0). Median progression-free survival (PFS) in the overall population was 12.3 months (95% CI: 8.8–27.7). In the 2L subgroup, the mPFS was 17.7 months (95% CI: 8.1–NE) and in the 3L+ subgroup mPFS was 12.3 months (95% CI: 5.6–25.7). Safety profiles in the 2L and 3L+ subgroups were comparable and manageable, and no new safety signals were observed. Updated data, with >3 years of follow up, along with response in molecular subgroups, including cell of origin, will be presented. Conclusions: Glofit+Pola in heavily pre-treated patients with R/R LBCL, including HGBCL, demonstrated high and durable efficacy, with comparable response rates and durability observed in the overall population and across both the 2L and 3L+ subgroups. These findings support the potential of this drug combination as an effective treatment option in a population with limited therapeutic alternatives.

Introduction: Traditionally, the management of patients with advanced-stage classical Hodgkin lymphoma (cHL) relied exclusively on chemotherapy. However, the advent of novel therapeutic agents such as brentuximab vedotin (BV) and integration into first-line regimens led to enhanced efficacy outcomes. This study retrospectively evaluates the clinical outcomes of advanced-stage cHL patients treated with the BrECADD protocol in real-world settings. Methods: This retrospective multicenter study analyzed data from 79 patients with cHL treated with the BrECADD protocol across 15 cancer centers in Israel. Patient demographics and disease features at baseline were characterized using descriptive statistics. Therapeutic responses were assessed per Lugano criteria, with response-evaluable patients defined as those who received at least one cycle of BRECADD chemotherapy. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier survival curves, with log-rank testing employed for statistical analysis. Results: Data collection for this multicenter retrospective study spanned July 1 2023 to July 1 2025, enrolling 79 patients across 15 Israeli medical centers. Among the cohort, 56% of patients were male, the median age was 30.0 years (range, 18–60) and 99% (78 patients) underwent pretreatment evaluation with PET-CT. Stage 2 disease was identified only in 7.6% (6 patients) and Stage IV disease was identified in 83% (64 patients). An International Prognostic Score (IPS) >2 was noted in 80% of the cohort (IPS available for 100% of patients). PET-2-guided treatment was employed in 99% of cases (78 patients). Negative PET-2 results were observed in 83% (65 patients), permitting completion of treatment after four cycles. Of the remaining 14 patients (17%), eight achieved complete metabolic response (CMR) after four cycles, and two reached CMR following six cycles. Among 79 response-evaluable patients, the overall response rate (ORR) and complete response (CR) rate following end of chemotherapy were 99% and 95%, respectively. At our cohort, only 3 patients (4%) underwent radiation therapy consolidation. At a median follow-up duration of 11.0 months (range: 2.1-31 months), PFS events recorded at 6.3%, corresponding to 5 documented cases of relapse in this cohort. All of them proceed to salvage treatment and alive, which bring the 1-year OS to 100%. Grade 4 hematological toxicities represented the most frequent adverse events, with grade 4 neutropenia and thrombocytopenia observed in 77% and 14% of patients, respectively. Peripheral neuropathy occurred in 24% of patients, of them only 3.8% with grade 3-4). Serious adverse events included two cases requiring ICU admission due to infectious complications and full recovery. 12 patients (15%) underwent any dose reduction in their treatment. Beside of them, 5 patients, based on physician discretion, underwent treatment de-escalation to the A-AVD protocol. Conclusion: This retrospective, multi-center, real world study of BrECADD protocol, characterized by robust data quality in most of the participants, demonstrated comparable efficacy and safety in treating advanced-stage cHL in real-world settings, aligning with outcomes reported in clinical trials. Notably, there was higher rate of CMR after 2 cycles of therapy (83%) and a markedly lower rate of radiation consolidation in this study compared to the pivotal trial (Borchmann, Peter et al, The Lancet, Volume 404, Issue 10450, 341 – 352).

Central nervous system (CNS) lymphomas, including primary CNS lymphoma (PCNSL) and secondary CNS lymphoma (sCNSL), are aggressive and challenging diseases with dismal outcomes. Due to its CNS-penetrating properties, ifosfamide, carboplatin, and etoposide (ICE) protocol with or without rituximab has become a frequently used salvage regimen for these lymphomas. However, the short-term efficacy and toxicity of this therapeutic approach as well as its effect on subsequent treatment approaches such as autologous stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CAR-T) therapy, remain limited. This study aimed to evaluate clinical outcomes following R-ICE therapy in patients with CNS lymphoma. A retrospective analysis of consecutive adult patients with primary or secondary CNS lymphoma treated with R-ICE at a large tertiary center. Patient demographics, disease characteristics, treatment response, subsequent therapy with ASCT/CAR-T, toxicity, and overall survival (OS) were analyzed. Twenty-four patients were included with a median age of 71 years (range 33-85), 11 of them females. The majority of patients had newly-diagnosed isolated PCNS lymphoma (62.5%), while the remainder had DLBCL with CNS involvement at the initial diagnosis (12.5%), relapsed/refractory DLBCL (20.8%), and mantle cell lymphoma (MCL, 4.2%). The median number of R-ICE cycles was 2, with 87.5% receiving between one and three cycles. ICE dose reductions were common, with a median dose intensity of 90%. Approximately half of the patients received a reduced ICE dose (<100%). 37.5% of patients proceeded to autologous stem cell transplantation (ASCT), 16.7% received CAR-T cell therapy, and 4.2% underwent allogeneic transplantation. No further treatment was given to 41.7% of patients. Among all patients, 29% achieved a complete metabolic response (CMR), 33% had a partial response (PR), and 37.5% failed to achieve response. At a median follow-up of 11 months (range: 0–58 months), 75.0% (18/24) of patients had died. A trend toward better 2y-OS was observed among patients who achieved a CMR (2y-OS 57%) compared to those without CMR responses (2y-OS of 17%) (χ²(1) = 2.08, p = 0.150). All CMR patients (100%) proceeded to advanced therapies, including ASCT or CAR-T therapy, whereas only 41% of non-CMR patients transitioned to such treatments (χ²(1) = 4.85, p = 0.028). Treatment-related toxicity was tolerable. 6 patients (25.0%) demonstrated grade>3 non-hematologic-toxicity (encephalopathy, nausea, cystitis). Early-death (within 30 and 60 dats of ICE initiation) was documented in 35% and 40% of patients, respectively. Prior methotrexate (MTX) exposure did not appear to influence treatment response. The leading cause of death was disease progression, followed by sepsis and one case of CAR-T associated ICANS. In summary, R-ICE regimen is effective and tolerable in patients with CNS involvement and can serve as a bridge to advanced and potentially curative approaches. These findings support the role of R-ICE in CNS lymphoma and highlight areas for further prospective investigation.

Introduction: Despite excellent outcomes for young patients(pts) with HL, pts age 60 have less favorable outcomes with a 5-year PFS of about 60% (Cheng et al. Blood Advances 2022). This disparity is attributed to disease biology factors such as mixed cellularity, EBV positivity, and advanced-stage disease, as well as comorbidities that make patients more vulnerable to treatment toxicity, dose reductions, and interruptions. Brentuximab vedotin (BV) is increasingly used in the front-line setting for older pts. While BV concurrent with AVD (CON) is approved based on ECHELON-1, its use in older pts is limited by toxicity. A phase 2 study (Evens et al., JCO 2018) showed promising results by administering BV sequentially with AVD (SEQ) to improve safety. This study aimed to assess real-world outcomes with BV-based regimens in newly diagnosed older pts with HL. Methods: This retrospective multicenter study was conducted at five medical centers in the US and Israel. Older pts age ≥60 consecutively diagnosed with HL between 03/2013-04/2023 were identified. Data on demographics, comorbidities (including cumulative illness rating scale-geriatrics [CIRS-G] score), AEs, treatment reductions, interruptions, PFS and OS were manually collected from electronic medical records. Results: 136 pts were treated with BV-based regimens. Pt characteristics included a median age of 71 years (range 60-91), 65% male, a median CIRS-G score of 5 (range 0-16), 34% with a history of other malignancy, 54% stage IV disease, 29% with bone marrow involvement, 67% with B symptoms, 46% EBV positive in tumor, and 32% with non-nodular sclerosis histology. Of these pts, 56 (41%) received CON BV-AVD, 54 (40%) were treated with SEQ BV-AVD; the rest (26, 19%) received BV monotherapy or BV-based palliative regimens. Patients treated with CON BV-AVD were younger compared to those treated with SEQ BV-AVD (median 69 vs. 72 years old, p=0.049); Other baseline characteristics did not differ significantly between the two groups. At a median follow up of 2.3 years (range 0.06-10.4), 2-year PFS and OS were 65% (95% CI 56-74%) and 83% (95% CI 76-90%), respectively. After excluding 26 pts treated with palliative regimens, 2-year PFS and OS were 73% (95% CI 64-83%) and 86% (95% CI 80-94%), respectively. We found no significant difference in PFS between SEQ and CON BV-AVD (76% vs. 70% 2-year PFS; p=0.5). In a multivariable Cox regression analysis including age and treatment regimen (SEQ or CON), the regimen was not statistically significant (p=0.2) with no difference in OS (p=0.7). The most common AEs were neuropathy (all 44%/CON 45%/ SEQ 48%), infections (all 29%/CON 29%/ SEQ 26%), and neutropenic fever (all 16%/CON 28%/SEQ 11%), leading to treatment interruption in 33% of pts and treatment reduction in 52%, primarily involving BV. Of 107 patients treated with curative intent with full treatment data, 78 (73%) completed six cycles of AVD. However, only 58 (54%) completed the treatment as initially planned, mainly due to toxicity. Patients on CON BV-AVD were significantly more likely to complete treatment as planned when compared to those on SEQ (74% vs 34%, p<0.001). Rate of treatment interruption between cycles, or dose reduction did not differ significantly between CON and SEQ regimens. During the study follow-up, 20 patients treated with curative intent died: 5 from infections (2 CON/3 SEQ including 3 from COVID-19), 7 from disease progression (4 CON/3 SEQ), and 8 from other comorbidities (2 CON/ 6 SEQ). Among 36 pts who relapsed or had primary refractory disease, 4 died upon progression, and 2 were missing information after progression. Thirteen underwent treatment with PD-1-based combinations, while 17 received alternative chemotherapies. Conclusions: In a multicenter study, evaluating the real-world outcomes of frontline BV in elderly HL pts, both CON and SEQ BV-AVD regimens demonstrated comparable efficacy and safety to those reported previously and to each other. More SEQ pts discontinued the treatment plan. SEQ BV-AVD had similar outcomes to CON BV-AVD, even after adjusting for age, indicating SEQ may not mitigate the adverse outcomes associated with older age. Recently, SWOG 1826 reported nivolumab-AVD over BV-AVD in advanced stage HL (Herrera et al., ASCO and ICML 2023) with similar findings in geriatric subsets (Torka et al, ICML 2023; Rutherford et al, ASH 2023). These finding support combining anti-PD-1 in frontline treatment for older patients.

Background: TheCD20xCD3 bispecific antibody glofitamab (Glofit) engages and redirects T cells to eliminate B cells. Polatuzumab vedotin (Pola), an antibody-drug conjugate targeting CD79b, has a complementary mechanism of action to Glofit. In this open-label, multicenter, Phase Ib/II study (NCT03533283), Glofit+Pola demonstrated durable responses and manageable safety in patients (pts) with R/R LBCL (Hutchings, et al. ASH 2023). We present updated results with longer follow-up in a greater number of pts with R/R LBCL, including pts with HGBCL and prior chimeric antigen receptor (CAR) T-cell therapy, at the previously confirmed recommended Phase II dose of Glofit (30mg, from Part I of the study) when combined with Pola. Methods: Pts received 1000mg obinutuzumab pre-treatment (Gpt) on Cycle (C)1 Day (D)1, 7 days prior to the first Glofit dose to mitigate risk of cytokine release syndrome (CRS). Pola 1.8mg/kg was given on C1D2 and D1 of C2-6 (21-day cycles), and Glofit as step-up dosing in C1 (D8, 2.5mg; D15, 10mg) followed by the target dose (30mg) on D1 of C2-12 (21-day cycles). Fixed treatment of 6 cycles of Pola and 12 cycles of Glofit were administered, unless pts discontinued treatment due to disease progression, unacceptable toxicities, or withdrawal of consent. Results: At the clinical cutoff date (CCOD; Feb 16, 2024), 129 pts had received ≥1 dose of study treatment (DLBCL, n=57; HGBCL, n=44; transformed follicular lymphoma [trFL], n=26; primary mediastinal LBCL [PMBCL], n=2). Median age was 67 years (range: 23-84), 64% were male (n=82), median prior lines of therapy was 2 (range: 1-7), 71% were refractory to the last line of prior therapy (n=92), and 22% received prior CAR T-cell therapy (n=28; 17% were refractory [n=22]); 43% of pts completed treatment (n=56), 7% had treatment ongoing, and 50% discontinued treatment (n=64; primarily due to progressive disease [33%; n=42/129]). Of 128 efficacy-evaluable pts, best overall response rate (ORR; per Lugano 2014) was 80%, with a complete response (CR) rate of 62%. By histology, best ORR and CR rate, respectively, were: DLBCL 84% (48/57) and 61% (35/57); HGBCL 79% (34/43) and 65% (28/43); trFL 73% (19/26) and 54% (14/26); PMBCL 100% for ORR and CR (2/2). In pts who had prior CAR T-cell therapy (n=28), ORR was 75% and CR rate was 50%. With a median follow-up of 23.5 months (range: 0-46), median progression-free survival (PFS) was 12.3 months (95% confidence interval [CI]: 8.8-23.5). Median PFS by histology was 10.4 months (95% CI: 7.0-22.8) for DLBCL, 9.6 months (95% CI: 5.1-33.0) for trFL, and 15.5 months (95% CI: 9.3-not reached [NR]) for HGBCL. Median PFS follow-up was 26.3, 30.3, and 9.3 months for DLBCL, trFL, and HGBCL, respectively. Median duration of response was 21.9 months (95% CI: 14.3-37.8). Median duration of complete response was 31.8 months (95% CI: 21.1-NR); 64.6% of complete responders were in remission at CCOD. Median overall survival (OS) was 39.2 months (95% CI: 20.6-NR), with a 24-month OS event free rate of 54%. The most common adverse event (AE) was CRS (43%), which was mostly Grade (Gr) 1-2 (Gr 1 27%, Gr 2 15% per ASTCT criteria); one pt had Gr 3 CRS and one had fatal Gr 5 CRS (occurred in the context of unresolved infection; pt declined further CRS management at Gr 3). CRS events were managed with tocilizumab (34%), fluids (23%), low flow oxygen (20%), or corticosteroids (14%) and 3 pts (5.4%) were admitted to intensive care. Neurologic AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 4 pts (Gr 1, n=2; Gr 2, n=1; Gr 3, n=1 [syncope]), all in the context of CRS. Gr 3-4 AEs occurred in 59% of pts, mostly neutropenia (32%); febrile neutropenia was reported in 2 pts (1.6%). Serious AEs occurred in 60% of pts and 8% of pts had Gr 5 AEs (5/10 due to COVID-19). In total, 11% of pts discontinued Glofit due to AEs (3/14 due to COVID-19; 1 pt due to COVID-19 pneumonia); 5% of pts withdrew from Glofit treatment due to Glofit-related AEs and 5% withdrew due to Pola-related AEs. Exploratory biomarker analyses including response in molecular subgroups and circulating tumor DNA kinetics will be presented. Conclusions: Heavily pretreated pts with R/R LBCL treated with Glofit+Pola continued to demonstrate high and durable response rates across all histologies, including pts with HGBCL and those who had received prior CAR T-cell therapy. The safety profile was manageable and consistent with the known profiles of the individual drugs.

INTRODUCTION:High-dose therapy with melphalan followed by autologous stem cell transplant in the upfront setting (upfront ASCT) has significantly improved clinical outcomes of myeloma patients and become the standard of care for the past 30 years. However, with the advent of modern induction therapy, the role of upfront ASCT approach has been called into question. Several prospective studies have examined whether continuing with triplet therapy as consolidation with optional ASCT at relapse (triplet-alone) could result in comparable outcomes. METHODS:This was a systematic review and meta-analysis of randomized controlled trials comparing upfront ASCT versus triplet-alone approach among myeloma patients treated with triplet therapy, which included two novel agents and a corticosteroid, as induction. Cochrane Library, PubMed and conference proceedings were searched. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), safety, and second primary malignancies (SPM). Subgroup analysis was conducted for high-risk cytogenetics. RESULTS:Our search yielded three trials, conducted between 2010-2018, including 1,737 patients. Two trials evaluated bortezomib plus lenalidomide (VRd) induction and the third study tested carfilzomib plus lenalidomide (KRd) induction. Maintenance was given in all trials to both arms. There was no difference in OS between the arms; the pooled OS in all patients and those with high-risk cytogenetics was hazard ratio (HR) 1.03 (95% CI, 0.85-1.26; I2 = 0%; 1,737 patients, 3 trials) and 0.85 (95% CI, 0.59-1.23; I2 = 0%; 222 patients, 2 trials), respectively. The pooled PFS for upfront ASCT versus triplet-alone was significantly improved in all the patients and in the high-risk cytogenetics subgroup, HR 0.67 (95% CI 0.59-0.76; I2 = 0%; 1,737 patients, 3 trials) and HR 0.59 (95% CI: 0.44-0.7; I2 = 0%; 306 patients, 3 trials), respectively. The risk of any grade 3-4 adverse events was higher in the upfront ASCT arm versus triplet-alone approach (relative risk = 1.17 [95% CI, 1.12-1.23; 1,737 patients]). The risk of secondary malignancies was reported in all three trials and was comparable between both arms. Two trials reported on secondary myeloid neoplasms, which were significantly higher among upfront ASCT arm versus triplet-alone approach, OR 9.7 (1.8-52.25, I2 = 0%, 1,422 patients). CONCLUSION:Although upfront ASCT approach, in the era of triplet therapy, resulted in a significantly longer PFS among all patients, this did not translate into a survival benefit, regardless of cytogenetic risk. Upfront ASCT was associated with an increased rate of secondary myeloid neoplasms. In the current plethora of innovative therapies, the role of upfront ASCT is debatable.

Introduction: Patients with relapsed or refractory (R/R) DLBCL have a poor prognosis, even if treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). CAR T therapy provides long-term remission in only 40% of patients, and some cannot receive CAR T therapy due to fitness, geographic, or financial limitations. Epcoritamab is a subcutaneous CD3×CD20 bispecific antibody approved for adults with R/R large B-cell lymphomas and follicular lymphoma after ≥2 lines of systemic therapy. Combining epcoritamab with lenalidomide provides a chemotherapy-free regimen that may enhance T-cell proliferation and augment natural killer cell activity, thereby increasing antitumor cytotoxicity. EPCORE NHL-5 (NCT05283720) is an ongoing, phase 1b/2, open-label, multi-arm, dose-escalation/expansion trial of epcoritamab in combination with antineoplastic agents for the treatment of non-Hodgkin lymphoma. Preliminary results from arm 1 of EPCORE NHL-5 demonstrated antitumor activity and tolerable safety in patients with R/R DLBCL treated with epcoritamab plus lenalidomide (Avivi Mazza, et al. Blood. 2023;142[Suppl1]:438). Here, we report updated results. Methods: Eligible patients were ≥18 years old with CD20+ R/R DLBCL, had an Eastern Cooperative Oncology Group performance status of 0-2, were previously treated with at least 1 systemic therapy containing an anti-CD20 antibody, and were ineligible for or failed ASCT. Patients received epcoritamab (cycles 1-3, once weekly; cycles 4-12, once every 4 weeks) and oral lenalidomide (25 mg/day on days 1-21) for a total of twelve 28-day cycles. Epcoritamab was administered with two step-up doses in cycle 1: day 1, 0.16 mg; day 8, 0.8 mg; followed by 48 mg full dose from day 15 onward. Corticosteroid prophylaxis for cytokine release syndrome (CRS) was required during cycle 1. Key endpoints included dose-limiting toxicities (DLTs), investigator-assessed response (overall response rate [ORR] and complete response [CR] rate), duration of response (DOR), time to response, and safety. Results: At the cutoff date of January 18, 2024, 40 patients received epcoritamab plus lenalidomide (60% male; median age 71.5 years, range, 26-85). Median (range) follow-up time was 11.5 (0.3-16.8) months. Among response-evaluable patients (n=37), ORR was 67.6%, with 51.4% of patients achieving a CR. Median DOR and CR have not been reached. Consistently high CR rates were observed across subgroups, including second-line patients (56.3%; n=16), patients who received prior CAR T (50%; n=10), and by molecular origin classification (GCB, 46.7%, n=15; ABC/non-GCB/unclassified, 46.7%, n=15). The safety profile was similar to that previously presented (Avivi Mazza, et al. Blood. 2023;142[Suppl1]:438). The most common grade 3-4 treatment-emergent adverse events (TEAEs) were neutropenia (60%), anemia (20%), thrombocytopenia (17.5%), and CRS (10%). Febrile neutropenia occurred in 2 patients (5%). Two patients (5%) experienced DLTs: CRS (Gr 3; n=1) and increased aspartate aminotransferase (Gr 4; n=1) during dose expansion. Overall, 65% of patients experienced CRS, mostly low grade: Gr 1: 14 (35%), Gr 2: 8 (20%), Gr 3: 4 (10%). Median onset of CRS was 16 days from the first dose (1 day after first full dose of epcoritamab) and all events resolved with a median time to resolution of 2 days. Immune effector cell-associated neurotoxicity syndrome occurred in 1 patient (2.5%; Gr 3), which resolved in 3 days. CRS rates and peak IL-6 levels were lower in patients receiving dexamethasone vs prednisone for CRS prophylaxis. There was 1 grade 5 TEAE considered related to epcoritamab of COVID-19 pneumonia. TEAEs leading to discontinuation of epcoritamab occurred in 4 (10%) patients (thrombocytopenia, n=2; COVID-19 pneumonia, n=1; pneumonia pneumococcal, n=1). Conclusion: With longer follow-up, the combination of fixed-duration epcoritamab with lenalidomide continues to demonstrate deep and durable responses with a manageable safety profile for R/R DLBCL. CRS was predictable and mostly low grade; of note, most patients received prednisone vs the recommended dexamethasone for CRS prophylaxis. This chemotherapy-free combination may provide an alternative option to platinum-based or other standard of care therapies and thus supports the ongoing phase 3 trial of this combination for the treatment of R/R DLBCL (NCT06508658).

Mantle cell lymphoma (MCL) is a difficult to treat B-cell malignancy characterized by cyclin D1 (CD1) overexpression and deregulated AKT, NFκB, MAPK, B-cell receptor and BCL2 pathways. Breakthrough treatments such as BTK inhibitors present clinical benefits in MCL, but resistance inevitably develops and most patients relapse. Prognosis for these relapse/refractory (R/R) patients is very poor, justifying an urgent demand for novel therapies. MCL therapy resistance is associated with evasion of apoptosis frequently involving upregulation of the pro-survival BCL2 protein. The BCL2 inhibitor venetoclax overcomes apoptosis evasion due to BCL2 overexpression however, resistances to venetoclax has also been described. This resistance relies on a switch in apoptosis dependency via overexpression of other anti-apoptotic BCL2 family members, mainly MCL1, compensating for BCL2 inhibition by venetoclax. Several MCL1 inhibitors have entered developmental stages. However, due to cardiotoxicities the FDA placed some of them on clinical hold. Deferasirox (DFX), a clinically approved iron chelator, exerts anti-tumoral effects in several cancers. We have shown that clinically relevant concentrations of DFX induce apoptosis in MCL cells via CD1 degradation, AKT/GSK3β signaling deregulation and NFκB inhibition. Deregulation of these specific targets is known to interfere with the efficiency of current MCL therapies. Interestingly, MCL1 levels are known to be regulated via NFκB and via the AKT/GSK3β pathway. Taken together, these data alongside DFX's safe profile, suggest that DFX can potentially overcome venetoclax resistance via targeting overexpressed anti-apoptotic BCL2 family members such as MCL1. These data also raise the possibility of a potential synergy when combining venetoclax and DFX. In this study, our objective was to assess the potential of DFX to overcome resistance in MCL, to assess possible synergism with venetoclax and to investigate the mechanism by which DFX exerts these effects. We generated venetoclax resistant Jeko-1(Jeko-1VR) and Z138 (Z138VR) lines. Initially, we determined which anti-apoptotic BCL2 family member our Jeko-1VR cells utilize to acquire resistance. We revealed a 3.5-fold increase in MCL1 expression in Jeko-1VR cells compared to its expression in Jeko-1 cells. This upregulation may, at least partially, explain Jeko-1VR's resistance to venetoclax. Interestingly, we observed that DFX treatment reduces MCL1 level in these cells to the level seen in the parental venetoclax sensitive Jeko-1 cells. In addition, as we previously observed regarding sensitive Jeko-1 cells, DFX was able to reduce CD1 levels in the resistant Jeko-1VR cells as well. In parallel, we found that clinically relevant concentrations of DFX induce apoptosis in both Jeko-1 and Jeko-1VR cells (48h exposure to 10µM DFX induced >75% annexinV+ cells). Numerous reports describe a synergistic effect when treating B-cell malignancies with a combination of venetoclax and MCL1 inhibitors. We found DFX to have a synergistic anti-tumoral effect with venetoclax in both Jako-1 and Z138 cells (Bliss, ZIP p<0.001) thus supporting our hypothesis that DFX can act as a surrogate MCL1 inhibitor. Indeed, we found, DFX to significantly reduce MCL1 expression in the Jeko-1 venetoclax-sensitive cells in a dose- and time-dependent manner. This reduction in MCL1 levels was partially rescued by the GSK3β inhibitor LiCl suggesting that DFX reduces MCL1 via the PI3K/AKT/GSK3β pathway. Interestingly, we found that this co-treatment also synergistically enhances CD1 degradation, suggesting an additional mechanism of synergy between DFX and venetoclax. In conclusion, in this study, we investigated the potential of repurposing the clinically approved drug DFX to combat the issue of MCL resistance. Notably, our results indicate that DFX reduces MCL1 levels in MCL cells. MCL1 overexpression is one of the main causes of venetoclax resistance. Thus, it is an attractive target for overcoming resistance. Several MCL1 inhibitors that have entered developmental stages have been put on hold due to cardiotoxicities. The clinically approved and safe agent, DFX can potentially fill this unmet need and serve as a surrogate for MCL1 inhibitors. To the best of our knowledge, this is the first study to assess the potential of DFX to serve as a therapeutic approach to overcome drug-resistance in MCL.

Background In the GALLIUM trial, patients with follicular lymphoma treated with obinutuzumab (O)-based chemoimmunotherapy had higher progression-free survival but experienced more toxicity compared with rituximab (R)-based chemoimmunotherapy as first-line therapy. Conversely, in our previous real-world study, toxicity was similar during the induction and the 6 months postinduction period. Aim To compare real-life toxicity profile between O and R maintenance therapy in follicular lymphoma after first-line induction chemoimmunotherapy. Methods A multicenter retrospective study of patients with follicular lymphoma treated with O- or R-based chemoimmunotherapy. The primary outcome was any infection recorded during maintenance and 6 months post maintenance period. Results A total of 156 patients (78 in each group in the induction phase) from 5 medical centers in Israel from 2016-2019 were included. We excluded 22 patients due to missing data or lack of maintenance therapy. Accordingly, 134 patients were included in the maintenance phase analysis; 63 and 71 patients received O and R maintenance, respectively. The most common adjacent induction chemotherapy was bendamustine (n=79, 59%) followed by CHOP (n=43, 32%). Baseline characteristics of patients were comparable between groups, except for higher incidence of diabetes mellitus and hypertension in the R group. The median number of maintenance cycles in the O vs the R group were 11 (IQR 7-12) and 12 (IQR 8-12), respectively. Overall, any infection occurred in 75 patients (56%), with comparable rates between the O and R groups (61.9% and 50.7%; P=0.21). Severe infections (19% vs 19.7%; P=0.64), febrile neutropenia (6.35% vs 4.2%; P=0.71), and treatment discontinuation rates (P=0.278) were also comparable. Other hematological and nonhematological adverse events were also comparable between the 2 groups, apart from more infusion-related reactions in the R group (8.4% vs 0%; P=0.028). There was no difference in all-cause mortality between the groups (9% and 17% in O vs R group, respectively; P=0.301). In a univariate analysis, none of the baseline characteristics were significantly associated with any infection. Conclusions In our real-world study of first-line anti-CD20 maintenance therapy post chemoimmunotherapy in patients with follicular lymphoma, we observed similar toxicity between O therapy compared with R therapy in the maintenance and 6 months post maintenance period.

Parsaclisib, a potent and highly selective PI3K5 inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell lymphomas. The phase 2 CITADEL-204 study (NCT03144674, EudraCT 2017-000970-12) assessed efficacy and safety of parsaclisib in Bruton tyrosine kinase (BTK) inhibitor-experienced (cohort 1) or BTK inhibitor-naive (cohort 2) patients with R/R marginal zone lymphoma (MZL). Patients aged >= 18 years with histologically confirmed R/R MZL, treated with >= 1 prior systemic therapy (including >= 1 anti-CD20 antibody) received parsaclisib 20 mg once daily for 8 weeks then 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg once daily for 8 weeks then 2.5 mg once daily (daily dosing group [DG]); DG was selected for further assessment. Primary end point of the study was objective response rate (ORR). Owing to slower than expected recruitment, cohort 1 was closed with 10 patients (WG, n = 4; DG, n = 6) enrolled. Based on a planned interim analysis in cohort 2, the futility boundary was not crossed, and enrollment continued to study completion. At data cutoff (15 January 2021), 100 patients were enrolled and treated in cohort 2 (WG, n = 28; DG, n = 72). In the DG, the ORR was 58.3% (95% confidence interval [CI], 46.1-69.8), with a complete response rate of 4.2% (95% CI, 0.9-11.7); the lower bound of the ORR 95% CI exceeded the protocol-defined threshold of 40%. The median duration of response was 12.2 months (95% CI, 8.1-17.5) and progression-free survival was 16.5 months (95% CI, 11.5-20.6); median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) among all patients were