Pixantrone-rituximab versus gemcitabine-rituximab in relapsed/refractory aggressive non-Hodgkin lymphoma.

UNLABELLED: We describe the rationale and design of the ongoing randomized, active-controlled, multicenter, Phase III study evaluating the efficacy of pixantrone and rituximab versus gemcitabine and rituximab in patients with diffuse large B-cell lymphoma or follicular grade 3 lymphoma, who are ineligible for high-dose chemotherapy and stem cell transplantation, and who failed front-line regimens containing rituximab. The administration schedule is pixantrone 50 mg/m(2) intravenously (iv.) or gemcitabine 1000 mg/m(2) iv. on days 1, 8 and 15, combined with rituximab 375 mg/m(2) iv. on day 1, up to six cycles. Pixantrone has a conditional European marketing approval for monotherapy in adults with multiple relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Our trial explores the efficacy of combining pixantrone with rituximab and completes postauthorization measures. TRIAL REGISTRATION NUMBER: NCT01321541

Perspective: The Role of Cryopreservation Techniques in Manufacturing, Transport, and Storage of Car-T Therapy Products

Several clinical trials have proved the efficacy and safety of T-cells chimeric antigen receptor (CAR-T cells) in treatment of malignant lymphoma and the first products were registered in the European Union in 2018. The shelf-life of CAR-T cell products in the liquid state is short, so cryopreservation offers a significant benefit for logistics in manufacturing and patient management. Direct shipment of the cryopreserved CAR-T cell therapy products to the clinical department is feasible, nevertheless, intermediate storage in the hospital cryostorage facility gives significant advantage in planning of their administration to patients. Moreover, some manufacturers prefer transport of the starting material cryopreserved at the collection site. The cryopreservation protocol used for starting material by the authors is based on combining dimethyl sulphoxide (DMSO) with hydroxyethyl starch (HES) and slow controlled cooling in cryobags housed in metal cassettes. This achieves the mononuclear cell post-thaw viability of 98.8 ± 0.5 % and recovery of 72.8, ± 10.2 %. Transport of the starting material to the manufactures and return transport of the CAR-T therapy product is performed by authorized courier companies. Intermediate cryostorage of the final CAR-T cell therapy product is performed in a separate dry-storage liquid nitrogen container. On the day of infusion, the cryopreserved products are transported to the clinical department in a dry shipper. On the wards the product is removed from the cassette, inserted into a sterile plastic bag, thawed in a 37 °C water bath followed by immediate intravenous administration. The authors discuss the adherence of the used technology to good manufacturing practice (GMP) principles and genetic safety assurance rules

Efficacy and safety of rituximab biosimilar (DRL_RI) versus MabThera®in low-tumor-burden follicular lymphoma: the FLINTER study

Background and objectives: This phase III study (RI-01-006; FLINTER) was conducted to demonstrate equivalent efficacy of DRL_RI to EU-approved rituximab (MabThera (R)) in patients with previously untreated Stage II-IV, CD20-positive, low-tumor-burden follicular lymphoma (LTB-FL). This study also evaluated safety, immunogenicity, rituximab concentrations, and pharmacodynamics (PD) of DRL_RI compared with MabThera.Design and methods: Previously untreated, stage II-IV, CD20-positive LTB-FL patients (N = 317) were randomized (1:1) to receive DRL_RI (n = 162) or MabThera (n = 155) as intravenous infusions of 375 mg/m(2) weekly for 4 weeks (induction period), and thereafter every 8 weeks from Week 12 to Week 36 (maintenance treatment), and followed up till Week 52. The primary end point was best overall response rate (BORR) up to Week 28 based on blinded independent central review. Efficacy equivalence was demonstrated if the two-sided 90% confidence interval (CI) for BORR difference was within the prespecified equivalence margin (+/- 17%). Secondary end points included objective and complete responses, duration of response, progression-free survival, overall survival, safety, immunogenicity, mean serum concentrations, and PD.Results: The BORR up to Week 28 was 80.2% versus 79.4% for DRL_RI versus MabThera group; with a difference of 0.89% (90% CI: -6.67 to 8.48; 95% CI: -8.05 to 9.93 within the prespecified margin). Both treatment groups were comparable for all secondary efficacy end points. Treatment-emergent adverse events were reported in 68.6% of patients; safety, immunogenicity, and mean serum concentrations were similar between groups. Peripheral B-cell counts declined below quantifiable limits in most patients, with a median time to B-cell depletion of 6.9 versus 7.0 days for DRL_RI versus MabThera.Conclusion: The study demonstrated efficacy equivalence of DRL_RI to MabThera; with comparable safety, immunogenicity, serum concentrations, and PD between groups.Trial registration: This trial was registered at ClinicalTrials.gov identifier: NCT03976102 and EudraCT (2018-004223-36)

Fixed-Duration Epcoritamab + R-CHOP Induces High Complete Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma With high-Risk Features: Long-Term Results from the Epcore NHL-2 Trial

Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, has been approved as a single agent for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma after ≥2 lines of systemic therapy based on results from the phase 1/2 EPCORE® NHL-1 trial (NCT03625037). Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is an accepted standard treatment for patients with previously untreated (1L) DLBCL; however, relapse rates can reach 40%. High-risk patients with International Prognostic Index (IPI) 3-5 and patients with double-hit/triple-hit lymphoma have suboptimal complete response (CR) rates and long-term outcomes. Following R-CHOP, 5-y estimates of progression-free/overall survival (OS) decreased from 81%/88% in patients with IPI 0-1 to 67%/76% for IPI 2, 58%/67% for IPI 3, and 46%/54% for IPI 4-5 (Ruppert et al, Blood 2020), suggesting a need for novel regimens to increase cure rates for newly diagnosed patients with DLBCL with high-risk features. Previously, in arm 1 of the EPCORE NHL-2 trial (phase 1b/2; NCT04663347), the combination of epcoritamab + R-CHOP showed encouraging response rates and a manageable safety profile in 1L DLBCL, including in high-risk patients (Clausen et al, EHA 2023). Here, we present long-term follow-up beyond 2 y, including in subgroups, and minimal residual disease (MRD) analyses for the first time.Methods: Adults with 1L CD20+ DLBCL and IPI ≥3 received subcutaneous epcoritamab (QW in cycles 1-4; Q3W in cycles 5-6) + R-CHOP for 6 cycles (21 d each) followed by epcoritamab monotherapy Q4W in 28-d cycles for up to 1 y. The primary endpoint was overall response rate (ORR) based on best overall response per Lugano criteria. MRD negativity was assessed as a secondary endpoint using the exploratory AVENIO ctDNA method. Double-hit/triple-hit status was assessed by central lab.Results: As of May 15, 2024, 47 patients had received epcoritamab 48 mg + R-CHOP, with a median follow-up of 27.4 mo (range, 0.8-33.9). All patients had IPI 3-5 at screening, 6 (21%) of 28 patients with evaluable tissue available had double-hit/triple-hit DLBCL, and 16 patients (34%) had bulky disease (>10 cm). The median time from diagnosis to first dose was 4 wk (range, 1.3-60.4). Median relative dose intensity for all R-CHOP components was ≥95%.Among 46 evaluable patients, the ORR was 100%, with a CR rate of 87%. Most patients (96%; 44/46) completed 6 cycles of R-CHOP; 91% (40/44) had a CR, and the 2 patients who did not complete 6 cycles of R-CHOP had a partial response. Notably, patients with double-hit/triple-hit DLBCL had a CR rate (83%; 5/6) similar to the overall population. An estimated 74%/87% of patients remained progression free/alive at 24 mo. Durable responses were observed, with an estimated 83% of patients with CR remaining in CR at 24 mo. MRD negativity (cutoff, <1 mutant molecule per mL) was observed in 91% of evaluable patients (30/33).The most common treatment-emergent AEs (TEAEs) of any grade (G) were neutropenia (70%), anemia (68%), CRS (60%), fatigue (49%), nausea (47%), pyrexia (43%), and injection-site reaction (40%). Four patients (9%) discontinued epcoritamab due to TEAEs; G5 TEAEs occurred in 2 patients (COVID-19 and septic shock). CRS events were mostly low grade (45% G1, 11% G2, 4% G3) and mainly occurred after the first full dose; all resolved, and none led to discontinuation. ICANS occurred in 2 patients (G1, n=1; G2, n=1) and resolved in a median of 2.5 d without leading to discontinuation.Conclusions: Fixed-duration epcoritamab + R-CHOP induced deep, durable CRs (24-mo estimated duration of CR, 83%) and high rates of MRD negativity (91% of evaluable patients), leading to long-term remissions (24-mo estimated OS, 87%) beyond 2 y in patients with 1L DLBCL, including those with high-risk features, such as double-hit/triple-hit disease. These results suggest a high curative potential for this potent first-line combination. The safety profile was manageable, with no new safety signals detected, underscoring the combinability of epcoritamab with standards of care in 1L DLBCL. These data compare favorably with R-CHOP alone in this setting and further support the ongoing phase 3 trial of epcoritamab + R-CHOP in 1L DLBCL(NCT05578976)

Epcoritamab plus GemOx in transplant-ineligible relapsed/refractory DLBCL:results from the EPCORE NHL-2 trial

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes (complete response [CR] rates with standard salvage therapy gemcitabine plus oxaliplatin [GemOx], ∼30%; median overall survival [OS], 10 to 13 months). Patients with refractory disease fare worse (CR rate with salvage therapy, 7%; median OS, 6 months). Epcoritamab, a CD3×CD20 bispecific antibody approved for R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE NHL-2 trial evaluating epcoritamab plus GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL. Patients received 48 mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given once every 2 weeks for 8 doses. The primary end point was overall response rate (ORR). As of 15 December 2023, 103 patients were enrolled (median follow-up, 13.2 months; median age, 72 years). Patients had challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior chimeric antigen receptor T-cell therapy, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR and CR rate were 85% and 61%, respectively. Median duration of CR and OS were 23.6 and 21.6 months, respectively. Common treatment-emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab plus GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT-ineligible R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT04663347.</p

Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval [CI]: 1.352.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15-1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy

Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial

Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, p<0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7-90·2) and in non-complete metabolic responders was 54·9% (40·5-67·3; HR 0·2, 95% CI 0·1-0·3, p<0·0001).Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.F Hoffmann-La Roche

Acalabrutinib Plus Bendamustine-Rituximab in Untreated Mantle Cell Lymphoma

The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL.Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m2 once daily; days 1 and 2) and rituximab (375 mg/m2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points.In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively.The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity

End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)-based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n 5 706) or rituximab (n 5 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-D-glucose-PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee-assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P , .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P , .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point