Anti-lymphoma Treatment Research Articles

Genome-Wide Methylation Profiling of Peripheral T-Cell Lymphomas Identifies TRIP13 as a Critical Driver of Tumor Proliferation and Survival.

Cytosine methylation contributes to the regulation of gene expression and normal hematopoiesis in mammals. It is catalyzed by the family of DNA methyltransferases that include DNMT1, DNMT3A, and DNMT3B. Peripheral T-cell lymphomas (PTCLs) represent aggressive mature T-cell malignancies exhibiting a broad spectrum of clinical features with poor prognosis and inadequately understood molecular pathobiology. To better understand the molecular landscape and identify candidate genes involved in disease maintenance, we profiled DNA methylation and gene expression of PTCLs. We found that the methylation patterns in PTCLs are deregulated and heterogeneous but share 767 hypo- and 567 hypermethylated differentially methylated regions (DMRs) along with 231 genes up- and 91 genes downregulated in all samples, suggesting a potential association with tumor development. We further identified 39 hypomethylated promoters associated with increased gene expression in the majority of PTCLs. This putative oncogenic signature included the TRIP13 (thyroid hormone receptor interactor 13) gene whose genetic and pharmacologic inactivation inhibited the proliferation of T-cell lines by inducing G2-M arrest and apoptosis. Our data thus show that human PTCLs have a significant number of recurrent methylation alterations that may affect the expression of genes critical for proliferation whose targeting might be beneficial in anti-lymphoma treatments.

Lymphoma-associated hemophagocytic syndrome: a retrospective, single-center study of 86 patients.

To explore the clinical features, treatment, and prognosis of patients with lymphoma-associated hemophagocytic syndrome (LAHS) in a real-world clinical setting. We retrospectively examined LAHS patients diagnosed at our center between January 2016 and August 2023, focusing primarily on their clinical features, therapeutic approaches, overall response rate (ORR), and overall survival (OS). A combination of univariate and multivariate analyses was conducted to identify potential prognostic factors. A total of 86 patients diagnosed with LAHS were included to evaluate clinical characteristics and prognostic factors. Patients with T/NK cell lymphoma had a higher probability of developing hemophagocytic syndrome (HPS) during the clinical process than those with B cell lymphoma. The median survival time was 55 days for all patients, and 47 and 81 days for the T/NK cell LAHS and B cell LAHS cohorts, respectively (P = 0.025). Among the patients evaluated, the ORR was 42.2%. Patients starting with anti-lymphoma treatment had a better, albeit not significant, ORR than those beginning with anti-HPS treatment. In the univariate analysis, T/NK cell LAHS (P = 0.027), HPS onset at relapse (P = 0.036), higher baseline plasma EBV-DNA levels (> 4,000 copies/mL, P = 0.034), and treatments including cytokine adsorption and ruxolitinib (P < 0.001 and P = 0.017, respectively) were potentially associated with worse OS, while corticosteroid therapy benefited OS. In the multivariate analysis, T/NK cell LAHS (adjusted hazard ratio (aHR) = 2.007), cytokine adsorption therapy (aHR = 4.547), and corticosteroid therapy (aHR = 0.118) were independently associated with mortality. T/NK cell lymphoma was the main cause of LAHS and carried a worse prognosis. Whether anti-lymphoma or anti-HPS treatment should start first still requires prospective studies with larger sample sizes. The key point in controlling HPS is to block the cytokine storm promptly. Corticosteroid therapy is both effective and accessible and should be used early and in sufficient quantities.

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 &amp; 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.

Multi-Center Study of COVID-19 Infection in Elderly Patients with Lymphoma: On Behalf of Jiangsu Cooperative Lymphoma Group (JCLG)

Objective: To survey the vaccination status, lymphoma status, characteristics and outcomes of COVID-19 infections in elderly patients with lymphoma in Jiangsu Province of China. Methods: Elderly patients with lymphoma (age≥60 years) in Jiangsu Province was investigated by questionnaire and telephone follow-up during December 2022 to June 2023. Basic information, Lymphoma status, comorbidities, vaccination, severity and outcome of COVID-19 infection were collected. Results: A total of 402 patients were followed up in this study, 364 were confirmed with COVID-19 infection during December 2022 to June 2023. Among these patients, median age was 70 years (range 60-92), Of which 50.25% (202/402) were over 70 years old. Most patients (85.9%,313/364) were symptomatic at COVID-19 diagnosis. 45.6% (166/364) and 54.4% (198/364) was defined as mild COVID-19 and severe COVID-19 infections according to Diagnosis and treatment plan for COVID -19（trial version 10）in China, all patients with severe COVID-19 infection were hospitalized. 56.0% (204 /364) of patients were aggressive lymphoma and 43.4%(158 /364) were indolent lymphoma. Only 43.9% of the patients had received two or more doses of SARS-CoV-2 vaccine at the onset of COVID-19. In univariable analysis, age &amp;gt;70 years(OR 1.88;95% CI 1.24-2.85,p=0.003), the presence of comorbidities (OR 1.41;95% CI 1.41-1.11,p=0.005), active hematological disease(progressive disease or relapsed/refractory disease, OR 2.02;95% CI 1.53-2.67,P&amp;lt;0.001), ≥2 prior treatment(OR 1.88,95% CI 1.42-2.47,p&amp;lt;0.001), and time from anti-lymphoma treatment to COVID-19 (OR 1.90,95% CI 1.53-2.36,p&amp;lt;0.001) were associated with severe COVID-19 infection in the entire cohort. For anti-lymphoma treatment, anti-CD20-based treatments within the last 6 months was associated with severe COVID-19 infection in the aggressive lymphoma patients (OR 2.17,95% CI 1.21-3.88, p=0.009) as well as in the indolent lymphoma patients (OR 5.67,95% CI 1.97-16.29, p=0.001). Of note, among the indolent lymphoma subsets, only anti-CD20-based maintenance therapy might be a risk factor for exacerbating COVID-19 infection (OR 4.42,95% CI 1.15-17.03,p=0.031), while continuous BTK inhibitors might be protective effect on the outcome when compared with other targeted drugs(OR 0.44,95% CI 0.20-0.97,p=0.043). Overall, 7.7% of patients (28/364) ceased，among them 57.4% (16/28) was due to COVID-19 infection,14.9% (4/28) was due to lymphoma deteriation, 17.9%(5/28) due to COVID-19 infection concurrent with lymphoma progression and 10.7%(3/28) with heart failure . Mortality rate increase by lymphoma status [ Controlled disease: 8.67%(15/173) ; Stable disease: 9.80%(5/51);Active disease:16,67%(6/36), p=0.006)], prior lines of anti-lymphoma therapy [1 prior: 7.14%(13/182)；2 prior: 5.26%(3/57);≥3 prior: 25%(9/36), p&amp;lt;0.001] and anti-lymphoma therapy within one month of COVID-19 infection[&amp;gt;1 months: 8.52%(11/129) ;&amp;lt;1 months: 16.67%(17/102); p=0.002]. Conclusions: Elderly patients with lymphoma have a low rate of COVID-19 vaccination and a high rate of severe COVID-19 infection. Patients with active disease, multiple lines of prior therapy, advanced age, multiple comorbidities, and anti-CD20-based treatments within the last 6 months was associated with severe COVID-19 infection..

Long-Term Efficacy of a 6-Month Regimen of Rituximab and Lenalidomide in Follicular Lymphoma Patients in Need of First Therapy: Updated Analysis of the SAKK 35/10 Randomized Trial

Background:The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) conducted the SAKK 35/10 randomized phase-2 trial (NCT0137605) to compare the effectiveness of rituximab (R) alone versus R combined with lenalidomide (L) as the initial treatment for symptomatic follicular lymphoma (FL). The primary endpoint analysis, which demonstrated higher complete remission (CR) rates with the combination therapy, was previously reported (Zucca et al. Blood 2019). This report provides a long-term analysis of time-to-event endpoints with a median follow-up of approximately 10 years. Methods:A total of 154 eligible patients with untreated grade 1 to 3a FL requiring systemic therapy were centrally randomized to receive either R monotherapy (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 for responding patients) or R+L. In the combination arm, R was administered at the same schedule as the monotherapy, while L was taken orally at a daily dose of 15 mg, starting 14 days before the first R administration, and continued until 14 days after the last R administration, for a total of 18 weeks. Random assignment to treatment arms was stratified based on histological grade (1-2 vs 3a), bulky disease (&amp;lt;6 vs ≥6 cm), Follicular Lymphoma International Prognostic Index (FLIPI) score (1-2 vs ≥3), and centre, using the minimization method. The sample size was determined to detect a 20% increase in the CR/CRu rate with 90% power, using a one-sided Z-test with a false positive rate of 10% to compare the two treatment arms. The assessed endpoints, including progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), duration of CR/CRu (DoR), and overall survival (OS), were defined according to NCI international standardized criteria (Cheson et al. J Clin Oncol 1999). Results:Seventy-seven patients (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were assigned to the single-agent rituximab arm, and 77 patients (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) were assigned to the combination arm. The results for the primary endpoint were consistent with the positive initial analysis. At a median follow-up of 9.5 years, the overall survival was similar in both arms (77% vs. 78% at 10 years, p=0.881). However, significant, and sustained improvements were seen in all other time-to-event endpoints. Patients in the R+L arm had a longer PFS (median, 9.3 vs. 2.3 years; HR=0.58, 95% CI: 0.37-0.89; p=0.013) and TTNT (median, not reached vs. 2.1 years; HR=0.43, 95% CI: 0.27-0.67; p&amp;lt;0.001). DoR with R+L was also longer (median not reached vs 3.2 years with R only; HR=0.42, 95% CI: 0.21-0.86; p=0.014) and with over 60% of responders still in first remission at 10 years. The improved outcomes with R+L were not associated with unexpected toxicity. Grade ≥3 adverse events were more common with the combination regimen (56% vs. 22% of patients), with grade 3-4 neutropenia in 23% of patients receiving R+L and in 7% of those receiving R alone. Fatigue, diarrhea, and skin rash were more frequent with R+L, but mostly of grade 1-2 (grade 3 occurred in ≤ 5% in both arms, and no grade 4 was reported). The side effects were manageable, and there were no treatment-related deaths in either arm. Two cases of biopsy-proven into diffuse large B-cell lymphoma were reported in the R+L arm, and two cases of Hodgkin lymphoma were described in the R arm. Although their causal relationship with treatment is not completely clear, the number of second solid cancers was significantly higher in the R+L arm. Two cases of prostate cancer, two lung adenocarcinomas (one in situ), one small cell lung carcinoma, one rectal cancer, and four skin cancers (three squamous cell and one basal cell), were observed in the R+L arm, while only one solid tumor (prostate cancer) occurred in the R arm (p=0.09). Only one patient died of a second solid cancer (small cell lung carcinoma in the R+L arm). The rate of POD24 was 29% in the R+L arm vs. 34% in the R-arm (p=0.483). Conclusions:The long-term results of the SAKK 35/10 trial demonstrated a durable benefit for the R+L combination compared to R alone. Notably, the adopted R+L schedule is considerably shorter than the standard R2 regimen (18 vs. 120 weeks). This provides a promising alternative when treatment is required but durable immunosuppression is undesirable.

R-GemOx Plus Nivolumab Vs R-GemOx As Second-Line Therapy for Large B-Cell Lymphoma in Transplant-Ineligible Patients: Interim Analysis of the Niveau Trial, an International, Randomized Phase 3 Study of the AGMT, GLA, HOVON, Lysa and PLRG

Introduction: Patients (pts) with relapsed or refractory ( R/ R) large B-cell lymphoma (LBCL) after first-line treatment who are unable to undergo consolidative high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) have poor outcomes and limited treatment options. Rituximab, gemcitabine and oxaliplatin (R-GemOx) is a common immuno-chemotherapy regimen used in this setting. The objective of the open-label, phase 3, NIVEAU study (NCT03366272) was to evaluate the efficacy and safety of Nivolumab added to R-GemOx in pts with R/ R LBCL after 1 prior line of therapy not eligible for HDCT/HSCT owing to age and/or comorbidities. Patients and Methods: Eligible pts were adults with R/R LBCL that were refractory to or had relapsed after first-line immuno-chemotherapy and who were not deemed candidates for HDCT/HSCT based on physician's assessment and at least one of the following criteria: age ≥65 years; age ≥18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score ≥3; or age ≥18 years and prior ASCT (as 1st line consolidation). Therapy consisted of 8 cycles R-GemOx (arm A) or 8 cycles of nivolumab plus R-GemOx followed by nivolumab as maintenance for up to 1 year in total or until progression or unacceptable toxicity (arm B). The primary endpoint was progression-free survival (PFS) after 1 year. Major secondary endpoints were response rates, event-free- (EFS) (time to progression, relapse, death or unplanned anti-lymphoma treatment), overall survival (OS) and toxicity. The protocol specified a pre-planned interim analysis after the first 180 pts completed up to at least 1 follow-up investigation. Results: Between Jan 2018 and May 2021, 180 pts were randomized. Two pts did not receive any treatment (one withdrawn informed consent, one death) resulting in a full analysis set of n=90 (arm A) and n=88 (arm B). Median age was 76 years (range 44-87), 52% of pts were &amp;gt;75 years of age, 37% were primary progressive after first-line therapy, 62% had IPI 3-5. Overall response (OR) and complete response (CR) rates were similar with 34% and 20% (arm A) vs. 34% and 22% (arm B), respectively. Rates of progressive disease (PD) were 53% (arm A) vs. 50% (arm B). After a median follow-up of 21 months, 1-year PFS was 28% (95%-CI: 18%-37%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.827) in arm B (Figure A). 1-year EFS was 22% (95%-CI: 13%-31%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.654) in arm B. One-year OS was 48% (95%-CI: 38%-59%) in arm A vs. 58% (95%-CI: 47%-68%), (p=0.126) in arm B. At 2 years, PFS, EFS and OS were 15% (95%-CI: 6%-24%), 13% (95%.CI: 5%-21%) and 34% (95%-CI: 22%-46%) in arm A vs. 15% (95%-CI: 7%-23%), 15% (95%-CI: 7%-23%) an 43% (95%-CI: 32%-55%) in arm B. Because of an identical PFS but a trend toward better OS for arm B, we performed an event-driven OS analysis of pts after second progression or relapse (n=70 in arm A, n= 73 in arm B). OS survival was superior in arm B vs. arm A after second progression or relapse (Log Rank p= 0.010) (Figure B). There was a small increase in number of pts with grade 3-5 AEs in arm B (arm A/arm B: thrombocytopenia 37%/39%; anemia 19%/26%; leukopenia 19%/24%; infection 15%/22%). No increase in number of pts with immune-related grade 3-5 AEs was observed except asymptomatic increase of lipase (arm A/arm B: 23%/27%), (p=0.625) and amylase (arm A/arm B: 5%/11%), (p=0.192). Most common grade 3-5 AEs during nivolumab consolidation in arm B were leukopenia 13%, peripheral neuropathy 10%, increase of lipase 8%, anemia 5% and infection 5% of pts). In total, 7 treatment-related deaths occurred (arm A/arm B: 3 (3%)/4 (5%). After this interim analysis revealed futility to demonstrate superiority for the primary endpoint, recruitment was stopped in March 2023. At that point, 270 of 310 initially intended pts had been recruited. Conclusions: In pts with R/R LBCL, the addition of nivolumab to R-GemOx followed by nivolumab maintenance is feasible without relevant additive toxicity. The addition of Nivolumab did not improve PFS of the R-GemOx regimen alone. These results demonstrate the poor prognosis of R/R transplant-ineligible pts treated with immuno-chemotherapy. However, a trend towards a better OS was observed, which allows for the hypothesis that nivolumab might enhance the efficacy of subsequent therapies. The final analysis of the study is scheduled after completion of follow-up of the last patient included as defined by the study protocol.

Phase I Study of Response-Adapted Treatment with Venetoclax, Obinutuzumab, and Magrolimab (VENOM) in Relapsed and Refractory Indolent B-Cell Malignancies

Background and Significance Targeted agents and immunotherapy have changed the treatment landscape for follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL), but indefinite therapy leads to cumulative toxicity and excessive cost. CD47 is a checkpoint for the innate immune system providing an inhibitory signal to phagocytic macrophages and a rational therapeutic target in B-cell lymphoma. Magrolimab is a fully humanized IgG4 anti-human CD47 antibody, with high activity in FL when combined with rituximab (Advani NEJM 2018). Our objective is to test the safety of adding escalating doses of venetoclax to magrolimab and obinutuzumab in a response-adapted study design with planned dose expansion cohorts (www.clinicaltrials.govidentifier NCT04599634). Study Design and Methods Patients with grade 1-3A FL, MCL, MZL, or CLL relapsed after and/or refractory to ≥2 prior lines of therapy are eligible. Pts with FL are eligible after 1 prior therapy if FLIPI ≥2 or disease progression within 24 months of the end of the last therapy. Pts with MCL are eligible after 1 prior therapy if blastoid histology, 17p deletion, TP53 mutation, Ki67 ≥30%, or received Bruton's tyrosine kinase inhibitor (BTKi) as first-line therapy. Pts with CLL are eligible after 1 prior therapy if 17p deletion, TP53 mutation, or received both a BTKi and a BCL2 inhibitor. Eligibility includes age ≥18 and adequate organ function unless dysfunction secondary to lymphoma. A positive direct antiglobulin test without hemolytic anemia is allowed. Patients with a history of hemolytic anemia or autoimmune thrombocytopenia within 3 months of enrollment are excluded. No washout period is required for prior anti-lymphoma treatment. Active HIV, CMV, and hepatitis B or C are excluded. The safety of venetoclax, obinutuzumab, and magrolimab will first be determined in 2 dose-finding cohorts of up to 24 pts (Cohort 1: 6-12 pts with FL and Cohort 2: 6-12 pts with MZL, MCL, or CLL). During dose-finding, all pts start triplet therapy with venetoclax, obinutuzumab, and magrolimab (Figure 1). Magrolimab IV is administered at a 1mg/kg priming dose on D1 of the first cycle, followed by 30mg/kg x 3 weekly loading doses, then 30 mg/kg on D1 of each 4-wk cycle. Obinutuzumab IV is administered at 100mg on D1, 900mg on D2, and 1000mg on D8 and D15 of the first cycle, followed by 1000mg on D1 of each 4-wk cycle. Pts with FL receive venetoclax 800mg (DL1) daily throughout therapy duration, whereas pts with MZL, MCL, and CLL start venetoclax at 20mg with weekly escalation to 400mg (DL1) over 5 weeks. Dose-limiting toxicity is assessed during the first 4 wks for FL, and the first 5 wks for MZL, MCL, and CLL. If ≥2 of 6 pts in either arm experience DLT, 6 additional pts will be enrolled to the respective arm at DL(-1) of venetoclax (600mg for FL and 200mg for MZL, MCL, and CLL). After dose-finding is completed, expansion cohorts of each histology will first receive magrolimab and obinutuzumab for two 4-wk cycles in a window for translational research. On-treatment tumor biopsies are optional during the window. After the window, venetoclax will be added at the dose determined during dose-finding. FDG-PET and CT scans are performed at baseline, after window, and after cycles 3 and 6 of triplet therapy. During both dose-finding and dose-escalation, pts with complete response (CR) after 6 cycles of triplet therapy will stop therapy. If these pts relapse, they can be retreated with an additional 6 cycles of triplet therapy. Pts with partial response (PR) after 6 cycles of triplet therapy receive an additional 6 cycles of triplet therapy. All pts stop treatment after 12 cycles. The primary objective is safety, with secondary endpoints of overall response rate, duration of response, and PFS. Exploratory objectives include the identification of a molecular signature that predicts response to magrolimab and obinutuzumab, and correlation of response with circulating tumor DNA levels.

Bridging therapy with axicabtagene ciloleucel for large B-cell lymphoma: results from the US Lymphoma CAR-T Consortium

AbstractDuring the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received BT had a higher baseline risk profile than patients who did not receive BT, and these patients, as a group, had inferior outcomes compared with those who did not receive BT. However, after propensity score matching between the 2 groups, there were no statistically significant differences in overall response rate (77% vs 87%; P = .13), complete response rate (58% vs 70%; P = .1), progression-free survival (hazard ratio [HR], 1.25; P = .23), and overall survival (HR, 1.39; P=.09) between the BT group and the no-BT group, respectively. Analyzing the effects of BT in the whole cohort that underwent leukapheresis regardless of receiving axi-cel (intention-to-treat analysis) showed similar results. Radiation BT resulted in outcomes similar to those observed with nonradiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival for patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage to using radiation-based BT over nonradiation-based BT.

A targeted drug delivery system based on E. coli ghost for inhibiting non-Hodgkin’s lymphoma

Doxorubicin (DOX) is extensively utilized in the treatment of aggressive lymphomas, while its significant toxic side effects hamper its clinical application. Hence, there is an urgent need for a safe and effective antilymphoma drug delivery system at this stage. This study successfully developed an optimal drug delivery system (R-PEG@BGs-DOX) to safe and efficient delivery of DOX to non-Hodgkin's lymphoma site. The R-PEG@BGs-DOX was prepared by modifying polyethylene glycol (PEG) and Rituximab (R) onto the surface of bacterial ghosts (BGs), which were obtained through NaOH treatment of E. coli BL21 with modulation to achieve target structures. The prepared R-PEG@BGs exhibited efficient loading of DOX, demonstrating excellent targeting properties. The R-PEG@BGs-DOX can significantly inhibit the growth of non-Hodgkin's lymphoma cells while showing minimal toxic side effects on normal tissues. These results strongly suggest that R-PEG@BGs-DOX holds great promise as an intelligent, safe, and effective drug delivery system for anti-lymphoma treatment.

Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL: Final Results From the GALLIUM Study

The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab-based versus rituximab-based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator-assessed progression-free survival (PFS) with obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab- or rituximab-based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0–9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% (P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P &lt; 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long-term benefit of obinutuzumab-based immunochemotherapy and confirm its role as a standard-of-care for the first-line treatment of advanced-stage FL, taking into account patient characteristics and safety considerations.

The impact of CHOP versus bendamustine on bone mineral density in patients with follicular lymphoma enrolled in the GALLIUM study

Introduction: A standard treatment with CHOP or CVP includes a cumulative dose of 3,000–4,000 mg prednisone. Observational studies have shown increased risk of fractures in patients treated with R-CHOP/R-CVP. However, it is not clear whether reductions in bone mineral density (BMD) are mainly caused by glucocorticoids or the combined impact of chemotherapy and glucocorticoids. The objective of this study was to investigate the impact of G/R-bendamustine versus G/R-CHOP on BMD in patients with follicular lymphoma (FL) enrolled in the GALLIUM study. Methods: Patients enrolled in the GALLIUM study, an international randomized phase 3 trial of first-line treatment for FL, were included if they were ≥60 years at inclusion and in complete remission following treatment with G/R-bendamustine or G/R-CHOP. Exclusion criteria were treatment with anabolic or antiresorptive therapies prior to baseline, co-existing medical conditions associated with low BMD, and new anti-lymphoma treatment during the initial 5 years of follow-up. CT scans were performed at baseline, induction treatment completion (ITC), and annually in five years after inclusion. Hounsfield units (HU) measured in an ovoid region in the anterior of L1 were used as surrogate for BMD, which has been shown to correlate with BMD measurements from conventional dual-energy X-ray absorptiometry (DXA). Low HU values represent lower bone density while high values represent more dense bone. Vertebral compression fractures were defined as vertebral height loss of ≥20%. Results: At ITC, 244 patients ≥60 years old were in CR. Of those, 155 fulfilled the inclusion criteria, 55 (35%) received G/R-CHOP and 100 (65%) received G/R-bendamustine. CT scans with contrast were performed at baseline and ITC in 143 patients. Baseline characteristics, including age and gender, were balanced between groups. The mean baseline HU was 143.8 in the CHOP group and 141.5 in the bendamustine group (P = 0.74). The mean HU decrease from baseline to ITC was 27.8 after CHOP versus 17.1 after bendamustine, corresponding to a difference of 12.5 (95% CI: 5.5–19.5) after adjusting for age, sex, B-symptoms, and baseline HU. BMD remained at the ITC level, and thus below baseline, during the first 3 years of follow-up. During treatment and 5 years follow up, a total of nine new compression fractures were recorded in five patients. One patient in the bendamustine group and four patients in the CHOP group developed new vertebral fractures. Keywords: Indolent non-Hodgkin lymphoma, Late Effects in Lymphoma Survivors No conflicts of interests pertinent to the abstract.

Different situations of identifying second primary malignant tumors in lymphoma patients with synchronous solid tumors.

To our knowledge, the different situations of identifying second primary malignant tumors (SPMTs) in lymphoma patients with synchronous solid tumors remain to be comprehensively investigated. We retrospectively collected information pertaining to lymphoma patients with synchronous solid tumors (diagnosed within 6months) at Peking University Cancer Hospital & Institute between 2009 and 2019. The non-parametric Aalen-Johansen estimator was applied to calculate cumulative incidence function in the competing risk model. Furthermore, propensity score-matched analysis was performed to compare survival differences in lymphoma patients with or without synchronous solid tumors. Thirty-eight patients were enrolled. There were three situations of identifying SPMTs. First, in 15 patients (39.5%), SPMTs were identified before the initiation of any treatment. Among them, priority was given to anti-lymphoma treatment in case of only three patients. Second, in 17 patients (44.7%), SPMTs were unexpectedly detected on surgical specimen assessment; of them, 13 received anti-lymphoma treatment after surgery. Third, in six patients (15.8%), SPMTs were identified after the outset of treatment for the primary tumor; in this population, three of four patients with lymphoma switched toward the treatment plan for SPMTs. The 5-year overall survival was 58.7%. The cumulative incidence function within 5 years was 26.6% for lymphoma and 14.7% for other solid tumors. The early identification of SPMTs was associated with better outcomes (p= 0.048). After balancing the baseline characteristics, no differences in survival were observed between lymphoma patients with and without synchronous solid tumors (p= 0.664). This is the first study to present the different situations of identifying SPMTs in lymphoma patients with synchronous solid tumors. In only <50% patients, SPMTs were identifiable at baseline. SPMT identification at different situations may make it difficult to choose the optimal therapeutic option, which may consequently impact patient survival.

Phase 3 Trial of Subcutaneous Epcoritamab in Combination with Rituximab and Lenalidomide (R2) Vs R2 Among Patients with Relapsed or Refractory Follicular Lymphoma (EPCORE FL-1)

Background: Follicular lymphoma (FL) is the most common 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 R2. However, advanced stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B-cells, inducing 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 the complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab and R2 among 28 evaluable patients with R/R FL (EPCORE NHL-2 arm 2; NCT04663347), ORR was 100%, with a complete metabolic response observed in 96%. Most cytokine release syndrome (CRS) events were of low grade (grade 1, 30%; grade 2, 13%; grade 3, 7%) and occurred in cycle 1; all CRS events resolved with standard management. These encouraging data, as well as the distinct mechanisms of action of epcoritamab and R2, support evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 trial described herein was designed to evaluate epcoritamab in combination with R2 vs R2 alone in patients with R/R FL with at least 1 prior line of therapy. 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 R2 vs R2 alone in adults with histologically confirmed grades 1 to 3a R/R FL after at least 1 prior line of systemic anti-lymphoma therapy, including an anti-CD20 monoclonal antibody (not including prior radiotherapy). Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography-avid disease, and at least 1 measurable disease site. Lenalidomide-refractory FL is excluded. Approximately 642 patients will be randomized in a 1:1:1 ratio to receive alternative full doses of epcoritamab in combination with R2 or R2 alone (Figure). Epcoritamab will be subcutaneously administered using a step-up dosing regimen followed by a full dose of epcoritamab in cycle 1 (28 days/cycle). Full doses of epcoritamab will be administered weekly in cycle 2 and monthly in cycles 3 and beyond. Patients will receive up to 12 cycles of treatment and will be assessed for disease progression per the 2014 Lugano criteria. Primary endpoint is progression-free survival (PFS) as assessed by blinded independent review committee (IRC). Secondary efficacy endpoints include response rates (per Lugano criteria by IRC), overall survival and minimal residual disease negativity. Other efficacy endpoints include duration of response, duration of complete response, 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. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase Ib/II Study of Polatuzumab Vedotin Plus Obinutuzumab and Lenalidomide in Patients with Relapsed/Refractory Follicular Lymphoma: Final Analysis and Progression-Free Survival Update

Introduction: Despite recent advances in the treatment of follicular lymphoma (FL), patients frequently require multiple lines of therapy, and an unmet need remains for patients who experience relapsed or refractory (R/R) disease. After a median follow-up of 27.0 months (safety-evaluable population), the novel triplet combination of polatuzumab vedotin (Pola) plus obinutuzumab (G) and lenalidomide (Len) was shown to be efficacious in a heavily pre-treated and refractory FL population and had a safety profile consistent with known profiles of the individual drugs (Diefenbach C, et al. Lancet Haematol 2021). Here, we report the final analysis with updated safety and efficacy data for this combination. Methods: GO29834 (NCT02600897) was an open-label, multicenter study of patients with R/R FL (excluding Grade 3b) who had received ≥1 prior anti-CD20-containing chemoimmunotherapy regimen. The recommended Phase II dose for Pola and Len in combination with G was established in an initial 3+3 dose-escalation phase and expanded into a Phase II study. Patients in the expansion cohort received induction treatment with six 28-day cycles of: intravenous (IV) G 1000mg (Cycle [C]1: Day [D]1, 8, 15; C2-6: D1); IV Pola 1.4mg/kg (D1), and oral Len 20mg (D1-21). Responders and those with stable disease received maintenance treatment for 24 months (G 1000mg on D1 every 2 months and Len 10mg on D1-21 of Months 1-12). The primary endpoint was complete response (CR) at end of induction (EOI), determined by the Independent Review Committee (IRC) based on positron emission tomography-computed tomography scans by modified Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 56 patients were enrolled across Phase Ib and Phase II; median duration of follow-up was 43.5 months in the safety-evaluable population at the time of final analysis (March 03, 2022). Baseline characteristics were: median age, 62 years; male, 59%; Ann Arbor Stage III-IV, 88%; Follicular Lymphoma International Prognostic Index 1 high-risk (≥3), 55%; bulky disease (≥7cm), 16%; median prior lines of treatment, 3 (range: 1-7); ≥2 prior lines of therapy, 77%; refractory to last line of prior regimen, 59%; refractory to last line of anti-CD20 treatment, 55%; and POD24 (defined as disease progression within 24 months of initiation of first anti-lymphoma treatment with chemoimmunotherapy), 27%. All patients (N=56) had at least one adverse event (AE), 36 (64%) had a serious AE, and 48 (86%) had a Grade 3-4 AE. The most common Grade 3-4 AEs were neutropenia (n=31, 55%), thrombocytopenia (n=14, 25%), infections (n=14, 25%), and anemia (n=8, 14%). AEs leading to dose reduction or interruption of any drug occurred in 18 (32%) and 43 (77%) patients, respectively; the majority were modifications of Len. In addition, 19 (34%) patients had an AE that led to discontinuation of any study drug. Three Grade 5 (fatal) AEs were reported (one case of septic shock and two cases of COVID-19). In the primary efficacy population (N=46), the IRC-assessed objective response rate at EOI was 76%, with a CR rate of 61%. The best overall response rate by investigator assessment (INV) was 91%, with a best CR rate of 72%. After a median follow-up of 43.3 months in the efficacy-evaluable population (N=46), median PFS was not reached (Figure). Landmark PFS by INV was 83% (95% confidence interval [CI]: 72-95) at 12 months, 67% (95% CI: 53-82) at 24 months, and 53% (95% CI: 36-70) at 48 months. Median OS was not reached. Conclusions: In the GO29834 study, we evaluated the safety and efficacy of novel triplet combination Pola-G-Len in patients with R/R FL, a population for whom there is a continued unmet medical need. This final analysis demonstrates a safety profile consistent with the known profiles of the individual drugs. High CR rates at EOI in a heavily pre-treated and refractory population compare favorably with currently available R/R FL therapies. After a median follow-up of 43.3 months in the efficacy-evaluable population, the median PFS and OS were not reached, and more than half of the patients treated with Pola-G-Len had not experienced disease progression after 4 years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Five-Year Results and Overall Survival Update from the Phase 3 Randomized Study Augment: Lenalidomide Plus Rituximab (R2) Vs Rituximab Plus Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Background: The combination of lenalidomide + rituximab (R2) showed superior efficacy vs rituximab + placebo (R-placebo) in patients (pts) with relapsed refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT study results, R2 was approved for the treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL) in the US, Japan, and Brazil, and for FL in Europe. Reported here are updated long-term follow-up results from AUGMENT. Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase 3 study of R2 vs R-placebo (control) in pts with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 mo after last rituximab dose). Pts were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 y), and histology (FL vs MZL), and then randomized 1:1 to R2 or control for up to 1 y. R2 pts received oral lenalidomide 20 mg/d, d1-21/28 for 12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2-5. Control pts received rituximab and placebo on the same schedule. Dose modifications were prespecified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). During the follow-up period, pts were followed every 6 mo to assess endpoints, including overall survival (OS), time-to-next antilymphoma treatment (TTNLT), progression, second primary malignancies (SPMs), and histological transformation. Results: A total of 358 pts were randomized (n = 178 R2; n = 180 control); baseline characteristics were similar in both groups. As of January 26, 2022 at a median follow-up of 65.9 mo, median PFS per 2007 IWG criteria as assessed by Investigator was 27.6 mo for R2 vs 14.3 mo for control, with HR = 0.50 (95% CI, 0.38-0.66; P < 0.0001). Although median OS was not reached for either group, there was an improvement in OS for R2 (HR = 0.59, 95% CI, 0.37-0.95, P = 0.0285; Figure). 5-y OS rates for the R2 vs control groups were 83.2% (95% CI, 76.3-88.3) vs 77.3% (95% CI, 70.1-83.1). Median TTNLT (after 12 cycles of time-limited therapy) was 73.1 mo for R2 vs 31.8 mo for control with HR = 0.53 (95% CI, 0.39-0.71; P < 0.0001). In the R2 group, 73 pts (41%) received ≥ 1 subsequent antilymphoma treatment compared with 109 (61%) in the control group, most commonly rituximab in both groups (25% and 34%). 3 (2%) and 5 (3%) pts received lenalidomide as part of any subsequent anti-lymphoma treatment in the R2 and control groups, respectively. The updated overall safety profile of both groups was consistent with the 1st analysis. SPMs occurred in 13 (7%) R2-treated and 21 (12%) control pts, an increase from 6 (3%) and 10 (6%), respectively, in the previous analysis. 9 pts died of SPM (n = 3 R2, n = 6 R-placebo), an increase from 2 pts (both R-placebo) in the previous analysis. The incidence rate of SPMs per 100 y was 1.62 (95% CI, 0.94-2.78) in the R2 group vs 2.66 (95% CI, 1.73-4.07) in the control group. Fewer histological transformations occurred in the R2 arm than in the control group (n = 10 vs n = 15, respectively). The updated incidence rate of histological transformation in the overall population was 1.24% (95% CI, 0.66-2.3) in the R2 arm and 1.85% (95% CI, 1.12-3.07) in the control arm. Conclusions: R2 continues to demonstrate superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of PFS (as assessed by Investigator in long-term follow up). The updated results for OS are consistent with the improvement observed in PFS. The OS KM curve separation after 5 y continues to favor R2, providing evidence for a survival benefit. The updated TTNLT KM curves continue to demonstrate that fewer R2-treated patients needed subsequent antilymphoma treatment to date, well beyond the 1-y treatment period. The safety profile of R2 and R-placebo remain consistent with the primary analysis, with continued lower rates of SPM and rates of histologic transformation comparable to historical experience. These updated results, including OS data, provide further support for the use of the R2 regimen as a standard of care for pts with R/R iNHL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

211P Chemotherapy delivery time affects anti-lymphoma treatment outcome in a sex-dependent manner

Chronotherapy is a drug intervention at specific times of the day to optimize efficacy and minimize adverse effects. Although chronochemotherapy has been proven to be effective in solid tumors, its value in hematologic malignancy remains unknown. In this study, we tried to identify a chronotherapeutic effect and underlying mechanism of immunochemotherapy in diffuse large B cell lymphoma (DLBCL) patients.

P006: Clinical outcome of classical Hodgkin Lymphoma patients receiving systemic anti-lymphoma treatment during SARS-COV-2 positivity: Results from the chemo-covid study on behalf of fondazione italiana linfomi

Patients (pts) affected by classical Hodgkin Lymphoma (cHL) infected by SARS-CoV-2 are at risk of protracted positivity due to immunodeficiency, and consequent delay of anti-lymphoma treatment may worsen cHL prognosis. Feasibility of chemo-therapy (CT) administration during SARS-CoV-2 infection in cHL pts has not been investigated so far. We collected data of cHL pts enrolled in Haematocovid observational trial and treated with CT while positive for SARS-CoV-2, with the aim to describe CT feasibility and to assess the risk of infection worsening. Thirteen cHL pts treated since May 2020 to May 2022 were included: median age was 39 years (17–68), 6 pts (46%) presented with advanced stage, 8 pts (62%) with B symptoms and 5 pts (38%) with bulky. Seven pts (54%) were treatment-naïve and waiting for ABVD start at time of COVID diagnosis, while in 6 pre-treated pts (46%) SARS-CoV-2 infection occurred after a median time of 18 days (1–42) from administration of the last CT cycle and the median number of prior therapeutic lines was 1 (1–4). Eight pts (62%) previously received m-RNA vaccines, while 5 pts (38%) were infected in the pre-vaccine era. At COVID onset, 6 (46%) pts were asymptomatic and 7 (54%) pauci-symptomatic, being fever (n=5) the most reported symptom; pneumonia was documented in 2 pts, but no case of respiratory failure was described. Viral variant was identified in 7 pts: 1 alpha, 1 delta and 5 omicron, while in 6 pts the presumed variant was derived from pandemic wave (3 pts alpha, 1 pt delta and 3 pts omicron). Four pts (31%) received antiviral treatment, consisting in monoclonal antibodies (n=3) and remdesivir (n=1). A median of 1 cycle of CT (1–2) after a median time of 25 days (1–45) from the first SARS-CoV-2 positivity was delivered. Ten pts (77%) received ABVD, in two cases with bleomycine omission, 1 pt (8%) received escBEACOPP and 2 pts (15%) brentuximab-vedotin. None of the pts experienced COVID worsening following CT administration. Median duration of SARS-CoV-2 positivity was 21 days (9–60). After a median follow-up of 11 months (1–61), one pt died due to cHL progressive disease while positive but asymptomatic for SARS-CoV-2. All the remaining pts were alive and negative for SARS-CoV-2 infection, and 8 pts (62%) achieved cHL complete response. In conclusion, in this preliminary analysis CT administration to high-risk cHL pts positive but asymptomatic for SARS-CoV-2 seems feasible and did not induce clinical worsening of viral infection.

Clinical characteristics and prognosis of lymphoma-associated hemophagocytic syndrome

Subjective To investigate clinical characteristics, treatment, and prognosis of lymphoma-associated hemophagocytic syndrome (LAHS) patients. Methods: The clinical data of patients diagnosed with LAHS from January 2010 to October 2021 in West China Hospital were retrospectively analyzed. Clinical characteristics, treatment, overall response rate (ORR), and overall survival (OS) were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of all 94 patients included, 59 were male and 35 were female. The age at hemophagocytic lymphohistiocytosis (HLH) diagnosis was (40.5±17.3) years. Seventy-four cases were T/NK cell lymphoma; 15 were B cell lymphoma; 5 were Hodgkin lymphoma. The age at HLH diagnosis of T/NK cell LAHS patients was (37.9±16.2) years, while that of B cell LAHS patients was (55.9±14.0) years. T/NK cell LAHS patients were significantly younger than B cell LAHS patients (P<0.001). Baseline fibrinogen of T/NK cell LAHS patients was 1.34 (0.86, 2.44) g/L, while that of B cell LAHS patients was 2.20 (1.75, 4.25) g/L. T/NK cell LAHS patients showed significantly lower fibrinogen levels than B cell LAHS patients (P=0.008). Combined treatment of anti-HLH and anti-lymphoma treatment was conducted in 35 patients; anti-HLH treatment was conducted in 31 patients; anti-lymphoma treatment was conducted in 8 patients; glucocorticoid treatment was conducted in 7 patients. ORR was 49.4%, and the median OS was 61 days for overall patients. Patients who received anti-HLH treatment and turned to anti-lymphoma treatment early displayed the best ORR and OS, significantly higher than those of anti-HLH patients (69.0 vs 38.7%, P=0.019, and 192.0 vs 24.5 days, P=0.028, respectively), which were also insignificantly higher than those of anti-lymphoma patients. Extranodal NK/T-cell lymphoma or aggressive natural killer cell leukemia was the risk factor of LAHS prognosis (HR=0.113, 95%CI: 0.018-0.728, P=0.022). Conclusions: Prognosis of LAHS patients is poor. Anti-lymphoma treatment should be initiated as soon as HLH is rapidly controlled.

Antibody Response to SARS-CoV-2 Vaccination in Patients With Lymphoproliferative Disorders and Plasma Cell Dyscrasias: Anti-Lymphoma Therapy as a Predictive Biomarker of Response to Vaccination.

We retrospectively analyzed SARS-CoV-2 vaccination antibody responses in a cohort of 273 patients with lymphoproliferative disorders or plasma cell dyscrasias who were seen at a single tertiary cancer center. Semi-quantitative anti-spike protein serologic testing was performed with enzyme immunoassay method. We found that the antibody response rate to SARS-CoV-2 vaccination was 74.7% in our patient cohort with no difference based on gender, age or race. The highest response rate was found in patients with Multiple Myeloma (MM) (95.5%). The response rates found in Diffuse Large B-Cell Lymphoma (DLBCL), Chronic Lymphocytic Leukemia (CLL), and Low-Grade Non-Hodgkin Lymphoma (LG-NHL) were 73.2%, 61.5% and 53% respectively. We also evaluated the effects of receiving active chemo-immunotherapy on SARS-CoV-2 vaccination antibody response. We found that the patients on treatment had lower response than the patients off treatment (62.1% versus 84.4% p<0.001). Thirty-four of 58 LG-NHL patients were receiving anti-lymphoma treatment with a lower SARS-CoV-2 vaccination response as compared to the patients who were not on treatment (29.4% v 87.5% p<0.001). We observed a similar pattern in CLL patients receiving treatment (48.1 v 76.0 p:0.049). We found that only disease type and treatment status (on-treatment vs. off- treatment), but not gender, age or race were significant predictors of non-response in the multivariable logistic regression model. The interaction between disease type and treatment status was not statistically significant by multivariate analysis. In conclusion, receiving anti-cancer treatment was found to play a significant role in decreasing the response to COVID-19 vaccination.

S206: OBINUTUZUMAB PLUS CHEMOTHERAPY DEMONSTRATES LONG-TERM BENEFIT OVER RITUXIMAB PLUS CHEMOTHERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA: FINAL ANALYSIS OF THE GALLIUM STUDY

Background: Immunochemotherapy with rituximab plus chemotherapy (R-chemo) has significantly improved outcomes for patients (pts) with previously untreated follicular lymphoma (FL). However, most pts still experience disease relapse, progression, or death. Obinutuzumab (G) is a type II anti-CD20 monoclonal antibody with enhanced direct cell killing, antibody-dependent cellular cytotoxicity and antibody-dependent phagocytosis versus R. The safety and efficacy of G-chemo versus R-chemo was assessed in pts with previously untreated, advanced stage FL in the randomized, Phase III GALLIUM (NCT01332968) study. In the primary analysis, G-chemo demonstrated a significant improvement in progression-free survival (PFS) versus R-chemo, with a manageable safety profile (Marcus, et al. 2017); this efficacy benefit was maintained after 5 years of observation (Townsend, et al. 2020). Aims: To report the final analysis of the GALLIUM study after a median observation time of 8 years. Methods: Pts aged ≥18 years with previously untreated histologic Grade 1–3a FL requiring treatment were enrolled. Pts were randomized 1:1 to receive G 1000mg intravenously (IV; Days [D]1, 8 and 15 of Cycle 1 and D1 of subsequent cycles) or R 375mg/m2 IV (D1 of each cycle) plus chemo for 6 or 8 cycles depending on the chemo backbone selected at each institution (cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP]; cyclophosphamide, vincristine, and prednisolone [CVP]; or bendamustine). Pts attaining a complete or partial response received maintenance with the same antibody every 2 months for 2 years or until disease progression (PD). The primary endpoint was investigator-assessed PFS; secondary endpoints included time-to-next anti-lymphoma treatment (TTNLT), overall survival (OS) and incidence of adverse events (AEs). All pts provided written informed consent. Results: 1202 pts with FL were enrolled (G-chemo, n=601; R-chemo, n=601). As of July 30, 2021, median observation time was 8 years. Seven-year PFS was improved with G-chemo (63.4%) versus R-chemo (55.7%; hazard ratio [HR], 0.77; 95% confidence interval [CI]: 0.64–0.93; p=0.006; Figure). TTNLT was also improved with G-chemo versus R-chemo (HR, 0.71; 95% CI: 0.58–0.87; p=0.001); the proportion of pts who had not started their next treatment at 7 years was 74.1% and 65.4%, respectively. Disease transformation was observed in 4.2% of pts with G-chemo and 5.0% of pts with R-chemo. Seven-year OS was similar in both arms, 88.5% with G-chemo versus 87.2% with R-chemo (HR, 0.86; 95% CI: 0.63–1.18; p=0.36). Seventy-five pts in the G-chemo arm and 86 pts in the R-chemo arm had died, most commonly due to PD (4.2% and 6.0%, respectively). The incidence of serious AEs (SAEs) was 48.9% with G-chemo (28.2% and 24.4% during induction and maintenance, respectively) and 43.4% with R-chemo (24.6% and 21.7%, respectively). Rates of fatal AEs were similar with G-chemo (4.4%) and R-chemo (4.5%); pneumonia was the most common fatal AE (0.8% [n=5] and 0.2% [n=1], respectively) and SAE (5.9% [n=35] and 6.2% [n=37], respectively). Second malignancies occurred in 13.1% of pts in the G-chemo arm and 9.9% of pts in the R-chemo arm. After adjusting for observation time, rates were similar between arms. These safety findings are consistent with previous analyses. Image:Summary/Conclusion: After a median observation time of 8 years, a meaningful improvement in PFS was maintained with G-chemo versus R-chemo in pts with previously untreated FL, confirming the role of G-chemo as a standard of care for the first-line treatment of pts with FL.