Anti-lymphoma Therapy Research Articles

Multi-center study of COVID-19 infection in elderly patients with lymphoma: on behalf of Jiangsu Cooperative Lymphoma Group (JCLG).

Elderly patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we retrospectively described the clinical features and outcomes of the first time infection of Omicron SARS-CoV-2 in 364 elderly patients with lymphoma enrolled in Jiangsu Cooperative Lymphoma Group (JCLG) between November 2022 and April 2023 in China. Median age was 69years (range 60-92). 54.4% (198/364) of patients were confirmed as severe and critical COVID-19 infection. In univariable analysis, Age > 70years (OR 1.88, p = 0.003), with multiple comorbidities (OR 1.41, p = 0.005), aggressive lymphoma (OR 2.33, p < 0.001), active disease (progressive or relapsed/refractory, OR 2.02, p < 0.001), and active anti-lymphoma therapy (OR 1.90, p < 0.001) were associated with severe COVID-19. Multiple (three or more) lines of previous anti-lymphoma therapy (OR 3.84, p = 0.021) remained an adverse factor for severe COVID-19 in multivariable analysis. Moreover, CD20 antibody (Rituximab or Obinutuzumab)-based treatments within the last 6months was associated with severe COVID-19 in the entire cohort (OR 3.42, p < 0.001). Continuous BTK inhibitors might be protective effect on the outcome of COVID-19 infection (OR 0.44, p = 0.043) in the indolent lymphoma cohort. Overall, 7.7% (28/364) of the patients ceased, multiple lines of previous anti-lymphoma therapy (OR 3.46, p = 0.016) remained an adverse factor for mortality.

Abstract 633: Integrin αVβ3 activation by thyroid hormones triggers JAK/STAT oncogenic pathways that promote T cell lymphoma dissemination

Abstract T cell lymphomas (TCL) are a heterogeneous group of lymphoproliferative disorders with poor prognosis. Aberrant activation of JAK/STAT pathway is associated with lymphoma dissemination in TCL patients. Although the FDA approved the use of inhibitors to target this pathway (Ruxolitinib), significant toxic effects have been reported and their use is limited. Thus making an excellent opportunity to study biological factors that regulate the activation of these pathways. In this sense, we recently showed that thyroid hormones (THs) acting through integrin αVβ3 induced TCL proliferation, which is reduced in vitro and in vivo in the presence of integrin αVβ3 pharmacological inhibitor. Our aim is to evaluate the impact of THs on JAK/STAT pathway activation and their implications on anti-lymphoma therapy. For the in vitro assays we used human and murine TCL cell lines. We used EL4 cells and c57bl/6 syngeneic mice for in vivo analysis. Proteomic profiles were evaluated by LC-MS-MS analysis. The GSE58445 database was used for in silico analysis. We found that THs induced STAT1, 3 and 5 phosphorylation in TCL cells and that the integrin αVβ3 inhibitor, Cilengitide (Cile) blunted these effects (p&amp;lt;0.05). Interestingly, we found that high mRNA expression levels of integrin β3 significantly correlate with worse overall survival in a cohort of TCL patients (p&amp;lt;0.05). Additionally, Ruxolitinib (Ruxo) diminished THs-induced STATs phosphorylation (p&amp;lt;0.05). As Ruxo reported toxic effects we aim to study alternative therapies such as Bexarotene (Bex), a synthetic retinoid used for cutaneous LCT treatment. We found that Bex significantly reduced cell viability in vitro of all TCL subtypes analyzed and combination with Cile resulted in improved anti-lymphoma activity (p&amp;lt;0.01). Also, Ruxo significantly decreased TCL cell viability but to a lesser extent than Bex+Cile (p&amp;lt;0.05). We previously found that BexT4+Cile (T4+, thyroxine supplementation) significantly decreases the in vivo growth of TCL tumors. To understand the mechanisms under this effects we analyzed tumor proteomics profiles and metalloprotease activity after 12 days of treatment. We found that BexT4+Cile regulates proteomic profiles related not only to lymphoma progression (JAK/STAT and PI3K-Akt signaling) but also pathways that impact the tumor microenvironment (TNF and angiogenic factors secretion and Th1/Th2 T cell differentiation). Regarding metalloprotease activity, we found that BexT+Cile inhibited MMP2 and MMP9 activity (p&amp;lt;0.05). Finally, we evaluated the dissemination of TCL in an in vivo model (by vain tail) and found that BexT4+Cile reduced EL4 cell implantation into the liver and kidneys (p&amp;lt;0.05). These results described the mechanisms by which THs induce the activation of JAK/STAT oncogenic pathway and showed how the inhibition of integrin αvβ3 in combination with bexarotene has therapeutic potential for TCL. Citation Format: María M. Debernardi, María V. Revuelta, Helena Sterle, Gonzalo Gonzalez, Ingrid L M Souza, Alejandro Correa, Leandro Cerchietti, Graciela Cremaschi, Florencia Cayrol. Integrin αVβ3 activation by thyroid hormones triggers JAK/STAT oncogenic pathways that promote T cell lymphoma dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 633.

Outcomes of subsequent antilymphoma therapies after second-line axicabtagene ciloleucel or standard of care in ZUMA-7

AbstractThe optimal management of patients with relapsed/refractory large B-cell lymphoma (LBCL) after disease progression or lack of response to second-line (2L) therapy remains unclear. Here, we report outcomes among patients who received subsequent antilymphoma therapy per investigator discretion separately by their randomized 2L arm in ZUMA-7, namely axicabtagene ciloleucel (axi-cel) vs standard of care (SOC). Progression-free survival (PFS) and overall survival (OS) were calculated from 3L therapy initiation. In the SOC arm, 127 of 179 randomized patients (71%) received 3L therapy. Median PFS among those who received 3L cellular immunotherapy (n = 68) vs those who did not (n = 59) was 6.3 vs 1.9 months, respectively; median OS was 16.3 vs 9.5 months, respectively. In the axi-cel arm, 84 of 180 randomized patients (47%) received 3L therapy. Median PFS among those who received 3L chemotherapy (n = 60) vs cellular immunotherapy (n = 8) was 1.7 vs 3.5 months, respectively; median OS was 8.1 months vs not reached, respectively. Of the 60 patients who received 3L chemotherapy, 10 underwent stem cell transplantation (SCT) after salvage chemotherapy. Median PFS was 11.5 vs 1.6 months, and median OS was 17.5 vs 7.2 months for those who did vs did not reach SCT, respectively. Eight patients received 3L cellular immunotherapy after 2L axi-cel. Of these, 6 patients received subsequent SCT in any line; all 6 were alive at data cutoff. These findings help inform subsequent treatment choices after 2L therapy failure for relapsed/refractory LBCL. The trial was registered at www.clinicaltrials.gov as #NCT03391466.

Clinical Features of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndrome: a Retrospective Study.

This study aims to improve the understanding of lymphoma-associated hemophagocytic syndrome, and find effective methods to identify and manage this fatal disease. Patients diagnosed with non-Hodgkin lymphoma-associated hemophagocytic syndrome from January 2008 to December 2022 in our center were included. Univariate and multivariate analyses were also conducted using the Cox proportional hazards model. Among 26 patients, 22 patients were diagnosed with T/NK cell lymphoma, while 4 patients were diagnosed with diffuse large B cell lymphoma. A total of 16 patients died with a median follow-up of 71 (26, 236) days. Compared with B cell lymphoma-associated hemophagocytic syndrome patients, T/NK cell lymphoma patients are younger, have lower platelet count, fibrinogen concentration, and serum albumin, have higher blood β2-mi-croglobulin levels and ferritin, are more likely to be infected with Epstein-Barr virus, are more inclined have a simultaneously occurrence of lymphoma and hemophagocytic syndrome. In multivariate analysis, fibrinogen, albumin, cholinesterase, uric acid, triglyceride, and ferritin are significantly associated with overall mortality. LAHS is a rare disease with poor prognosis. Early anti-inflammatory treatment combined with anti-lymphoma therapy can improve the overall survival time of patients. Prospective multi-center studies with larger sample sizes and longer follow-up periods are needed to further investigate optimal treatment and prognosis.

Renomegaly and acute kidney injury as primary manifestations of non-Hodgkin’s lymphoma: a report of three cases

BackgroundIn adults with non-Hodgkin's lymphoma, renal enlargement and acute kidney injury occur infrequently at first presentation, especially in T lymphocytic lymphomas.Case presentationWe report three cases of non-Hodgkin’s lymphoma with acute renal injury and bilateral renal enlargement. At diagnosis, one patient presented with an adrenal mass, one patient's lymph node biopsy was consistent with a renal biopsy, and one patient had primary renal lymphoma with no extrarenal disease. Assessment of renal pathology in Case 2 and Case 3 showed interstitial lymphocyte infiltration; the pathological types were non-Hodgkin's diffuse large B lymphoma originating from activated B cells outside germinal centers and non-Hodgkin's T-lymphoblastic lymphoma/leukemia, respectively. Case 1 did not receive anti-lymphoma therapy and died from infection and multiple organ failure within 1 month of hospitalization. Case 2 received eight courses of R-CHOP; her lymphoma recurred 2 years after diagnosis and she died from severe pulmonary infection 3 years after diagnosis. Case 3 received hyper-CVAD regularly and achieved stable renal function; this patient remains under follow-up.ConclusionsRenal lymphoma may have diverse manifestations, especially primary renal lymphoma without extrarenal involvement. Nephrologists should pay careful attention to these manifestations to ensure accurate diagnosis.

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..

Warburg-Effect Driven Lactic Acidosis Is Associated with Early Death in Patients with Lymphoma

Introduction: Lactic acidosis is a medical emergency and in most cases results from an imbalance between tissue oxygenation and oxygen demand (Type A). However, Type B lactic acidosis occurs in the absence of a recognizable impairment in systemic oxygen delivery, and is most commonly associated with drug or toxin ingestion, sepsis, severe nutritional deficits such as thiamine, and less commonly, malignancy. The capacity of shifting glucose metabolism to anaerobic pathway despite the presence of adequate oxygen, enhancing the rate of glucose uptake, accelerated glycolysis and hence producing more lactate, is a well-defined phenomenon in malignant cell metabolism, and is called the Warburg Effect (WE) or aerobic glycolysis. A systemic rise in lactate and lactic acidosis has been reported in hematologic malignancies and less commonly in solid tumors, and is thought to occur as a consequence of both increased production of lactate- reflecting high malignancy burden, and impaired lactate turnover or elimination by liver or kidney. Few case reports or series have demonstrated a possible correlation between early death and elevated lactate in patients with hematologic malignancy (Table 1). We aimed to characterize the incidence and clinical impact of Warburg-driven lactic acidosis on outcome including early death. Methods: A retrospective study of patients admitted to the haemato-oncology department in a large tertiary medical center between the years 2013- 2022, that presented with elevated lactate levels during the first week of admission. Patients with hematologic diseases other than lymphoma were excluded. Of 40 patients reviewed, 21 patients were excluded because of underlying hematological malignancy other than lymphoma. Medical records were retrieved and reviewed for a recognizable cause for elevated lactate, or non (assigned as the WE group). Early-death was defined as death of any cause within 4 weeks of admission. Results: Nineteen patients had lymphoma and elevated lactate levels within the first week of admission. Of these, 12 patients fulfilled the criteria for WE and 7 patients had their high lactate attributed to other causes such as hemorrhagic shock (n=1), sepsis (n=5) and concomitant metformin use (n=1). Median age among patients with WE was 72.5 years (range 66-86) with 41.6% (n=5) males. All but one had aggressive lymphoma. Diffuse Large B cell Lymphoma was the most frequent type (n=9) followed by T cell Lymphoma (n=2) and follicular lymphoma (n=1). Most patients had advanced disease (Stage III-IV in 75%) and the median International Prognostic Index (IPI) of the patients was 4 (range 3-5). The median lactate level was 31.5 mg/dL (range 25-64; with upper limit of normal value-20 mg/dL). Two patients received thiamin therapy once WE was recognized. Early-death rate was 75% (9 patients) among patients with WE. The established cause of death in this population was: sepsis (n=3), DIC (n=1), uremia and multi organ failure (n=2) and respiratory failure due to lung infiltration by lymphoma (n=3). Both steroid and chemotherapy were initiated earlier in surviving patients as compared to those who died early (within 4 weeks of admission); in surviving patients, chemotherapy was initiated at a median of 3 days before first elevated lactate was detected (range (-)7-1), and steroids at median of 3 days before first elevated lactate was detected, while in those who died early, chemotherapy was initiated at median of 5 days after first elevated lactate was detected (range (-)2-18) and steroids at median 1 day after first elevated lactate (p=0.29 and 0.05 for steroids and chemo, respectively). (Table 2). Conclusion: Warburg driven lactic acidosis is a marker of ‘acute cancer’ in lymphoma patients and is associated with a very high mortality rate. Early recognition of this very high-risk clinical scenario is of utmost importance and should prompt immediate anti-lymphoma therapy that may improve outcome.

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.

A Respective Analysis of EBV DNA Status in T/NK Cell Lymphoma Associated-Hemophagocytic Lymphohistiocytosis

Background: To explore the clinical characteristics and prognostic implication of Epstein-Barr virus (EBV) DNA status in patients with T-cell or natural-killer cell lymphoma-associated hemophagocytic lymphohistiocytosis (T/NK-LAHLH). Method: Patients who diagnosed with T/NK-LAHLH in the First Affiliated Hospital of Zhejiang University from January 2017 to August 2022 were included. Baseline characteristics were summarized and compared. Complete response (CR), partial response (PR) and no response (NR) were used to evaluate the 2-week efficacy of HLH treatment. Overall survival (OS) was estimated by Kaplan-Meier method and log-rank test. Cox proportional hazard model for potential factors were conducted. Result: Eight-five T/NK-LAHLH patients were finally enrolled, with a median age of 52 (18-81) years. According to EBV DNA status, sixty-seven were classified as EBV DNA positive group and 18 were EBV DNA negative group. Patients in EBV DNA positive T/NK-LAHLH group displayed significantly lower PLT (P=0.003), and globulin level (P=0.033), higher IL-10 level (P=0.011) and longer activated partial thromboplastin time (APTT, P=0.034) than those of EBV DNA negative T/NK-LAHLH group at HLH diagnosed. For patients received the anti-HLH therapy only, the ORR was 33.9%, patients in the liposomal doxorubicin-etoposide-prednisolone (DEP) group and ruxolitinib combined with corticosteroid (Ru-D) group achieved relatively better efficacy, with ORR 56.3% and 64.3%, respectively. Whereas the ORR in the HLH-94 group was 23.1% and corticosteroid with or without intravenous immunoglobulins (GC±IVIG) regimen had no effect on T/NK-LAHLH, all patients showed no response to GC±IVIG regimen. The difference of ORR was significance among the four anti-HLH regimens (P&amp;lt;0.001). The median period of anti-HLH therapy was 5 days for patients who received anti-HLH therapy and then switched to anti-lymphoma chemotherapy, with ORR 78.3%. There was a significant difference in the efficacy and OS for whether converted to anti-lymphoma therapy within 2 weeks after receiving anti-HLH (P&amp;lt;0.001 and P=0.018, respectively). Patients who obtained HLH control within 2 weeks have a better OS (P&amp;lt;0.0001) than no response to therapy. EBV DNA-positive patients displayed significantly worse OS than EBV DNA-negative patients (P&amp;lt;0.0001). Furthermore, all 5 patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) were still alive during the follow-up period and achieved significantly prolonged survival (P=0.013) than those who did not. By multivariate analysis, EBV DNA positive, advanced age, prolonged APTT, elevated fibrinogen level and no response to HLH treatment were independent risk factors of OS. Conclusion: EBV infection, along with coagulation abnormalities, advanced age and no response to HLH therapy were independent prognostic factors for patients with T/NK-LAHLH. Early diagnosis and appropriate chemotherapy plus HSCT are essential to achieve improved outcomes in T/NK-LAHLH patients. Keywords ：hemophagocytic lymphohistiocytosis, T/NK cell lymphoma, EBV, HSCT, treatment, prognosis

Efficacy and Safety of Axicabtagene Ciloleucel (Axi-cel) for the Treatment of Relapse/Refractory Non-Hodgkin Lymphoma: Real-World Data in Chinese Population

Background: Autologous CD-19 directed chimeric antigen receptor (CAR) T-cell therapy has become the standard of care of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who have received two or more prior lines of therapy. In June 2021, Axi-cel was approved by the China National Medical Products Administration (NMPA) for the treatment of these patients as the first commercial CAR-T product in China. To better understand the efficacy and safety of commercial Axi-cel in Chinese R/R NHL patients in a real-world setting, we conducted this multi-center, non-interventional study (ChiCTR2100047990). The accrual goal is 200 patients, and the primary endpoint is mOS. Here we made the pre-specific interim analysis and the reported the clinical outcomes. Methods: We included R/R NHL patients treated with commercial Axi-cel at 17 authorized treatment centers from November 2021 to February 2023. All the patients signed written informed consent. We reported best objective response rate (bORR), best complete response (bCR) rate and adverse events of special interest (AESI), including cytokine release syndrome (CRS) and neurological events (NE). Results: To the cut-off date of June 8, 2023, a total of 101 R/R NHL patients had undergone efficacy evaluation at month 3. The median age of patients was 56.5 (22, 80) years, with 23 patients (22.8%) aged 65 years or older. Fifty-nine patients were male. The baseline characteristics of these patients included 81 (80.2%) with diffuse large B-cell lymphoma, 4 (4.0%) with primary mediastinal B-cell lymphoma, and 7 (6.9%) with high-grade B-cell lymphoma. More than 50% of patients had an International Prognostic Index (IPI) score ≥3. The median number of prior treatment was 2. Thirty-eight patients (37.6%) had received 3 or more previous therapies and 10 patients (9.9%) had undergone autologous stem cell transplantation (ASCT). The primary refractory subgroup reached 46 (45.5%), and 41(40.6%) patients were refractory to second-line or subsequent therapy. Notably, compared to the baseline characteristics of Axi-cel real-world studies for R/R LBCL in other countries, a greater proportion of Chinese patients had an ECOG PS score ≥2 (32.7%), HBsAg (+) with normal HBV-DNA (23.1%), HBsAg (-) accompany with HBcAb (+) (37.1%). Bridging therapy was given in 73 patients (72.3%), while combination anti-lymphoma therapy was used after Axi-cel infusion and before disease progression in 52 patients (51.5%). The median follow-up was 12.7 months. The bORR and bCR rate was 83.2% (95%CI, 74.4 - 89.9) and 63.4% (95%CI, 53.2 - 72.7), respectively (Fig 1). The bORR was consistent across covariates including disease type, cell of origin and refractory subgroup, ECOG PS score ≥2, HBsAg (+) and normal HBV-DNA, and HBsAg (-) accompany with HBcAb (+), etc.. The median duration of response (DOR) was 13.7 months (95% CI, 11.1 - NA). mDOR was not reached in bCR patients (95% CI, 11.2 - NA), while patients with best response as PR have a median DOR as 4.7 months (95% CI, 1.8- 6.7). Median progression-free survival (PFS) was 14.6 months (95% CI, 7.6 - NA). Patients with ECOG PS score ≥2 had a shorter median PFS [7.6 months (95%CI 3.0 - NA)] compared to patients with PS 0-1 [14.6 months (95%CI 12.1 - NA)]. Median PFS also differed among patients based on their response at month 3. Patients with CR/PR/non-response at month3 had a median PFS of NR (95% CI, 12.1 - NA), NR (95%CI, 6.1 - NA) and 3.0 months (95%CI, 2.4 - 3.3), respectively (Fig 2). The median OS was not reached, and the estimated OS at 12 months was 80.4% (95%CI, 70.5 - 87.2). No new safety signals were observed in the Chinese population. The most common adverse events of grade ≥3 were decreased white blood cell count (82.2% of patients), neutropenia (81.3%) and lymphocytopenia (68.2%). CRS of any grade occurred in 90 patients (84.1%), with 15 patients (14.0%) experiencing grade ≥3. NE of any grade occurred in 27 patients (25.2%), with only 1 patient (0.9%) experiencing grade 4. No grade 5 CRS or NE appeared. Conclusions: This pre-specific interim analysis demonstrated the consistent efficacy of Axi-cel in Chinese R/R NHL patients, while NE of any grade and ≥grade 3 were lower. Similar to the result of the ZUMA-1 study, response at month 3 may predict PFS in Chinese R/R NHL patients treated with Axi-cel in real-world practice.

Mosunetuzumab Monotherapy Continues to Demonstrate Durable Responses in Patients with Relapsed and/or Refractory Follicular Lymphoma after ≥2 Prior Therapies: 3-Year Follow-up from a Pivotal Phase II Study

Background: Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. In a pivotal Phase II study (NCT02500407), mosunetuzumab demonstrated a high complete response (CR) rate with a manageable safety profile in patients with relapsed/refractory (R/R) follicular lymphoma (FL) and ≥2 prior lines of therapy (Budde et al. Lancet Oncol 2022). Mosunetuzumab is a fixed-duration treatment that can be administered in an outpatient setting. Here, we present updated data for patients with R/R FL and ≥2 prior lines of therapy, after 3 years of follow-up. Methods: Eligible patients with R/R FL Grade (Gr) 1-3a and ≥2 prior therapies received intravenous mosunetuzumab in 21-day cycles with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1mg; C1D8, 2mg; C1D15/C2D1, 60mg; C3D1 and onwards, 30mg). Hospitalization for treatment was not required. Patients achieving a CR by C8 completed treatment without additional cycles; patients with a partial response or stable disease received a total of 17 cycles. The primary endpoint was CR rate as determined by an Independent Review Committee (as best response; Cheson 2007 criteria). Duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), event-free survival (EFS), and safety were secondary endpoints. Time to next treatment (TTNT), response to retreatment, biomarkers of minimal residual disease (MRD), and circulating B-cell counts were exploratory endpoints. Results: Ninety patients with R/R FL were enrolled. As of May 2, 2023, median time on study was 37.4 (range: 2.0-48.0) months. Investigator-assessed best overall response and CR rates were 77.8% (95% CI: 67.8-85.9) and 60.0% (95% CI: 49.1-70.2), respectively. The median DOR was 35.9 months (95% CI: 20.7-not reached [NR]). Median DOCR was NR (95% CI: 33.0-NR); the estimated 30-month DOCR rate was 72.4% (95% CI: 59.2-85.6) ( Table). Three years after the end of treatment, 57.1% of 70 responding patients were alive and disease progression-free. Median PFS was 24.0 months (95% CI: 12.0-NR) ( Figure). The median TTNT was 37.3 months (95% CI: 18.0-NR); estimated EFS at 36 months was 51.8% (95% CI: 40.8-62.8). After initial mosunetuzumab treatment, 34/90 (37.8%) patients had received a new anti-lymphoma therapy, including 33/90 (36.7%) patients who received a new systemic treatment (8/33 [24.2%] of these patients received chimeric antigen receptor T-cell therapy); 8/90 (8.9%) had radiotherapy; 2/90 (2.2%) had excision of tumor; 2/90 (2.2%) had an allogeneic stem cell transplant; and 1/90 (1.1%) had an autologous stem cell transplant. Five patients received retreatment with mosunetuzumab, 3/5 of these patients had a CR. No new cytokine release syndrome (CRS) events, serious, or Gr ≥3 adverse events (AEs) were reported since the previous analysis (median follow-up of 28.3 months; Bartlett et al. ASH 2022). CRS events occurred in 44.4% of patients and 2.2% were Gr 3/4 in severity; all CRS events resolved. Overall AEs and serious AEs were comparable to the previous analysis (Bartlett et al. ASH 2022); febrile neutropenia was not reported. Forty-six (51.1%) patients experienced Gr 3/4 AEs related to mosunetuzumab; the rate of AEs leading to discontinuation was low (4.4%). Peripheral blood B-cell depletion following treatment with mosunetuzumab occurred in all patients, and recovery was observed after a median of 18 months following the end of treatment in patients with a sustained response using follow-up samples. MRD kinetics following mosunetuzumab therapy will be presented. Conclusions: In this updated analysis, with a median follow-up of 37.4 months, durable responses continued to be observed with fixed-duration mosunetuzumab in patients with R/R FL. The manageable safety profile was consistent with previous reports. Evidence of B-cell recovery was observed after a median of 18 months following the end of treatment.

Nivolumab-AVD Is Better Tolerated and Improves Progression-Free Survival Compared to Bv-AVD in Older Patients (Aged ≥60 Years) with Advanced Stage Hodgkin Lymphoma Enrolled on SWOG S1826

Background: Survival rates in patients (pts) with classic Hodgkin lymphoma (HL) aged ≥60 years (y) are lower than younger pts. The difference is due to comorbidities, impaired performance status, decreased chemotherapy tolerance, and increased treatment-related toxicity and mortality. The frontline regimen Bv-AVD can be challenging to administer in older patients due to toxicities, particularly infection and neuropathy. The PD-1 pathway is central to pathogenesis of HL; PD-1 blockade is effective in HL. The randomized, phase 3 trial, S1826, was conducted by the National Clinical Trials Network to evaluate N-AVD vs Bv-AVD in pts with newly diagnosed advanced stage (AS) HL and enrolled 994 pts; 97 were eligible and aged ≥60y. Methods: In this subset analysis, eligible pts were ≥60y with stage 3-4 HL. Pts were randomized 1:1 to 6 cycles of N-AVD or Bv-AVD. G-CSF neutropenia prophylaxis was optional with N-AVD and required with Bv-AVD. Pre-specified pts could receive radiation therapy (RT) to residual lesions on end of treatment PET. Pts were stratified by age, international prognostic score (IPS), and intent to use RT. Response and progression were assessed by investigators using 2014 Lugano Classification. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), event-free survival (EFS), and detailed toxicity and safety events. EFS events were death without progression, progression/relapse, receipt of non-protocol systemic anti-lymphoma therapy without progression, or receipt of RT in a pt not declared eligible for RT at registration or who did not meet protocol-specified criteria for RT. Results: 97 pts aged ≥60y were enrolled from 7/9/19-10/5/22 and were randomized to N-AVD (n=48) or Bv-AVD (n=49). Median age was 66y (range, 60-83y), 62% were male, 86% were white, 3% were black, and 10% were Hispanic. 61% had stage IV disease and 47% had IPS 4-7. 69% of pts on N-AVD and 92% of pts on Bv-AVD received any G-CSF. No pts received RT per protocol. 95 pts were evaluable for safety analysis. While grade (gr) ≥3 hematologic toxicity occurred in 52% of pts on N-AVD and 38% on Bv-AVD (gr 3 neutropenia 48% vs 30%), febrile neutropenia, sepsis, and infections were lower for pts who received N-AVD vs Bv-AVD. (Table) Peripheral neuropathy was much less frequent with N-AVD than Bv-AVD in overall incidence (sensory: 31% vs 66% and motor: 8% vs 15%, respectively) and severity (grades ≥2, sensory: 10% vs 49% and motor: 0% vs 8%, respectively). (Table) The following adverse events, AEs (mainly &amp;lt;gr 3) were less frequent on N-AVD vs Bv-AVD: nausea (38% vs 62%), diarrhea (25% vs 45%), anorexia (15% vs 38%) and weight loss (4% vs 36%). Hypothyroidism (15% vs 0%), and rash (16% vs 2%, no gr ≥3) were more frequent on N-AVD than Bv-AVD; rates of other immune-related toxicities were similar between arms. In this subset analysis, median follow-up 12.1 months, PFS was superior in the N-AVD arm [HR 0.35 (95% CI 0.12-1.02) stratified one-sided logrank p=0.022]; 1-yr PFS was 93% (95% CI 79-98%) for N-AVD and 64% (95% CI 45-77%) for Bv-AVD. (Figure) 1-yr EFS was 93% (95% CI 79-98%) for N-AVD and 57% for Bv-AVD (95% CI 38-72%) [HR 0.19 (95% CI 0.06-0.61) stratified one-sided logrank p=0.0011]. 1-yr OS was 95% (95% CI 83-99%) for N-AVD and 83% (95% CI 67-92%) for Bv-AVD [HR 0.35 (95% CI 0.07-1.75) stratified one-sided logrank p=0.091]. On N-AVD, there were 2 deaths (due to infection/sepsis) and 3 progressions/relapses; on Bv-AVD, there were 7 deaths (5 due to infection/sepsis, 1 to pneumonitis, 1 unknown) and 8 progressions/relapses. Non-relapse mortality was 4% for N-AVD vs 14% for Bv-AVD. Treatment was discontinued early in 5 pts (10%) on N-AVD and 16 pts (33%) on Bv-AVD. N was discontinued early in 7 pts (15%) and Bv in 19 pts (39%). Reasons for discontinuation included (N vs Bv): AE (5 vs 14 pts), death (1 vs 3 pts), and disease progression (0 vs 1 pt). Conclusions: N-AVD improved PFS and EFS, and was better tolerated than Bv-AVD in pts aged ≥60 with AS HL. Substantially more pts discontinued Bv-AVD than N-AVD, primarily due to toxicity. Fewer deaths occurred on N-AVD than Bv-AVD. N-AVD is poised to become a standard of care for older AS HL pts fit for anthracycline-based combination therapy. Funding provided by the National Cancer Institute of the National Institutes of Health CA180888, CA180819, CA180821, CA180820, CA180863, CA189955 and funding/drug provided by BMS, drug provided by SeaGen for pts enrolled in Canada.

A Phase 1, Open-Label, Dose Escalation and Dose Expansion Study of CLN-978 (CD19XCD3XHSA) in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Background: Patients with B-cell non-Hodgkin lymphoma (B-NHL) who are refractory to/or have relapsed (R/R) after treatment with anti-CD20 monoclonal antibodies, either alone or in combination with standard-of-care chemotherapy, have a poor prognosis. Response rates tend to decrease and duration of response shortens with each successive line. CD19 represents a significant target for the development of novel immunotherapies for the treatment of patients with R/R B-NHL, many of whom develop disease that is refractory to CD20-containing regimens. CD19-directed therapies approved for B-NHL include an Fc-enhanced anti-CD19 monoclonal antibody, a CD19-directed antibody-drug conjugate, and several CD19-directed CAR-T cell products. While CAR-T approaches are an important alternative for some B-NHL subtypes, many patients still relapse, and challenges remain with toxicity and accessibility in the community setting. Consequently, substantial unmet needs remain for effective treatments with broad applicability across B-NHL subtypes and practice settings. CLN-978 is a fully human, half-life extended, single-chain T cell engaging construct targeting CD19 and CD3, with a human serum albumin (HSA) binding moiety for half-life extension. Preclinically, CLN-978 effectively redirects T cells to kill CD19-expressing malignant cells and has demonstrated potent in vitro and in vivo efficacy against cancer cells expressing very low levels of human CD19. Study Design and Methods: This is a phase 1, open-label, multi-center, first-in-human, dose escalation, and dose expansion study of CLN-978 in patients with R/R B-NHL. Adult patients (≥ 18 years of age) with one of the following CD19+ B-cell histologies: diffuse large B-cell lymphoma - de novo or transformed, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, or marginal zone lymphoma (nodal, extranodal, or mucosa-associated) for whom there is no available approved standard therapy will be recruited. Other key eligibility criteria include: ≥ 2 lines of prior chemotherapy, Eastern Cooperative Oncology Group Performance Status 0-2. Key exclusion criteria include prior treatment with allogeneic hematopoietic stem cell transplantation or any other investigational CD19 x CD3 T cell engager. Prior CAR-T therapy, unconjugated or radio-conjugated CD19 mAb, and CD19 antibody-drug conjugate are allowed. The study consists of 2 parts: 1) a dose escalation phase commencing with accelerated titration in single-patient cohorts followed by a conventional 3+3 dose escalation design to identify the recommended phase 2 dose (RP2D) and 2) a dose expansion phase to further characterize the safety and preliminary efficacy of CLN-978 in disease-specific cohorts at the RP2D. CLN-978 will be subcutaneously (SC)-administered once weekly (QW) in 28-day cycles until progressive disease, intolerable toxicity, or a maximum of 24 cycles of treatment. Initial administration of CLN-978, inclusive of potential priming doses and the first target dose, will be administered on an inpatient basis. Subsequent doses may be given in the outpatient setting. Based on emerging data, less frequent administration schedules may be implemented in Cycle 4 and beyond as approved by the Safety Review Committee. Safety, pharmacokinetic (PK), pharmacodynamic, and preliminary efficacy assessments will guide the selection of the dose and schedule for further evaluation. The primary endpoint is safety. Key secondary endpoints include PK, anti-drug antibodies, overall response rate, duration of response, time to response, time to subsequent anti-lymphoma therapy, progression-free survival, and overall survival. Approximately 90 patients (30 in dose escalation and 60 in dose expansion) will be enrolled at approximately 6 sites in the U.S., reflecting both community and academic centers. The study is currently enrolling (NCT05879744).

Rituximab and Lenalidomide (R 2) Vs Rituximab Alone As Maintenance Treatment after Chemoimmunotherapy for Elderly Patients with Relapsed/Refractory Follicular Lymphoma (FL): Final Analysis of Renoir Phase III Study of the Fondazione Italiana Linfomi (FIL)

Background: Elderly patients with relapsed/refractory (R/R) FL have limited treatment options. Lenalidomide has direct tumoricidal and antiangiogenetic actions on tumor cells and is able to modulate tumor-cell microenvironment. Lenalidomide combined with Rituximab (R 2) in induction has shown a good clinical activity with low toxicity in both untreated and R/R FL patients. R 2 as maintenance treatment is less studied. Methods: RENOIR (NCT02390869) is an Italian FIL multicenter phase III open-label study for elderly subjects with grades 1-3a R/R FL in advanced stage who received 1 or 2 prior anti-lymphoma therapy and required treatment. Induction treatment consisted in 4 cycles of standard Rituximab-chemotherapy (Bendamustine or CHOP or CVP) according to physician choice or to previous lines. Two additional courses of R-chemotherapy were given for patients with partial remission (PR) or stable disease (SD). Those with stable disease (SD) or better after induction were randomized 1:1 to standard arm (ARM A) with Rituximab maintenance (Rituximab IV 375 mg/m 2 every 12 weeks for 8 doses) or to experimental arm (ARM B) with R 2 maintenance (Rituximab IV 375 mg/m 2 every 12 weeks for 8 doses and Lenalidomide 10 mg/day, days 1-21 per 28-day cycle for 24 cycles). The primary endpoint was 2-yr progression-free survival (PFS) comparing R 2 vs standard Rituximab maintenance using a two-sided test with alpha=0.05. An improvement of PFS from 60% to 78% in favor of R 2 arm was considered relevant. Secondary endpoints included safety, overall survival (OS), response rates (ORR), complete remission (CR), minimal residual disease (MRD) and quality of life (QOL). Results: From May 2014 to October 2022, 152 subjects were enrolled. Median age was 71 years (range, 67-77), 55% male, 82% had stage III/IV disease, 41% and 39% were at FLIPI intermediate-high or high risk, 25% had LDH above normal value, 78% relapsed and 22% were refractory to last treatment. One or 2 prior lines were given to 71% and 29%, R-Bendamustine was the preferred induction treatment (83%). All patients received prior Rituximab. At the end of induction ORR was 84% (n = 128) with CR 57% (n = 87). One hundred and twenty-eight (84%) completed the induction phase and 24 (16%) discontinued treatment because of: 9 progressive disease, 6 withdrawals of consent, 6 adverse events (AEs), 1 death, 2 other. One hundred and twenty-eight patients were randomized (ARM A 64 and ARM B 64) with well-balanced clinical characteristics. During maintenance 34 patients in ARM A and 38 in ARM B discontinued the treatment or are ongoing. At a median follow up of 58 months, 2-yr PFS rate was higher in R 2 arm, though not statistically significant: ARM B vs ARM A 2-yr PFS 72% vs 60% (HR 0.69, 95%CI 0.42-1.14, p=0.149 Fig 1). Subgroup analysis suggests a greater benefit in terms of PFS of R 2 in patients &amp;lt;70y (R 2 vs. R HR=0.34 vs HR=1.00 p-interaction=0.066 for patients &amp;lt; 70 and &amp;gt;=70 respectively). Two-yr OS rates for ARM B vs ARM A were: 80% vs 89% (HR 0.91, 95%CI 0.48-1.73, p=0.777). At three years from the randomization, patients who required further treatment were: 14% in ARM B vs 28% in ARM A (HR 0.64, 95%CI 0.31-1.32, p=0.225). The overall 2-yr PFS and OS rates from enrollment were: 66% (95%CI 57-73) and 83% (95%CI 75-89). The most common grade 3/4 AEs during maintenance in ARM A vs ARM B were: neutropenia (15% vs 41%, p=0.002), gastrointestinal disorders (2% vs 9%, p=0.116), infections (3% vs 11%, p=0.166). Deaths were 49: 10 patients not randomized (5 progressive disease, 1 COVID, 2 infections, 1 secondary neoplasia, 1 cachexia); 20 in ARM A (4 secondary neoplasia, 4 COVID, 4 other infections, 4 unknown, 2 progressive disease, 1 car accident, 1 cachexia) and 19 in arm B (3 secondary neoplasia, 5 COVID, 2 infections, 2 heart attack, 2 unknown, 3 progressive disease, 2 cachexia). Conclusions: the addition of Lenalidomide to Rituximab as maintenance treatment had a clinical benefit but with a limited impact on the overall outcome in this cohort of elderly R/R FL. R 2 maintenance reduced the risk of progression mostly in patients &amp;lt; 70 years, but without a statistically significant difference and with a higher number of adverse events that led to R 2 interruption more frequently. Indeed, the overall outcome of this elderly R/R cohort of FL patients was excellent with a short chemoimmunotherapy followed by two years of Rituximab ± Lenalidomide. Different treatment strategies or a different R 2 schedule might improve the outcome.

Stratified management based on surface antibody for the prevention of hepatitis B virus reactivation in lymphoma patients.

This study aimed to investigate a stratified approach based on hepatitis B virus (HBV) surface antibody (anti-HBs) for managing HBV reactivation (HBVr) in lymphoma patients with serological protection against HBV. A retrospective analysis was conducted on 209 lymphoma patients with a baseline anti-HBs titre of ≥10 iu/L, who were either positive or negative for HBV core antibody (anti-HBc). The results revealed that 15.7% of patients lost serological protection following 6-month anti-lymphoma therapy. With a median follow-up of 28.1 months, the cumulative rates of HBVr at 6 months, 2 years and 4 years were 2.9%, 4.7% and 6.3% respectively. Without intervention, the overall rate of reactivation was 2.0% for patients with isolated anti-HBs and 10.5% for those with positive anti-HBs and anti-HBc. To identify patients at high risk of losing seroprotection and susceptible to HBVr, a predictive model was developed. The high-risk group had significantly higher rates of serological protection loss (27.8% vs. 2.2%) and cumulative incidence of HBVr (22.0% vs. 0%) compared to the low-risk group. Overall, this study highlights the risk of HBVr in lymphoma patients with positive anti-HBs, with or without positive anti-HBc, and recommends periodic monitoring for low-risk patients and early intervention for high-risk patients.

Trial-in-Progress: AMC 112: Axicabtagene Ciloleucel in Relapsed or Refractory HIV-Associated Aggressive B-Cell Non-Hodgkin Lymphoma (NCT05077527)

Background: Persons living with HIV (PLWH) have an increased risk of B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), even with well-controlled HIV. The lifetime cancer risk in PLWH is 25% to 40%1-3, and cancer is the leading cause of death in PLWH in economically advanced countries. Non-Hodgkin lymphoma (NHL) is the most common cancer in PLWH in the United States. Despite aggressive frontline treatments, about 20-30% of patients with HIV-associated B-NHL will not be cured with current therapies4, comparable to the non-PLWH B-NHL population. Axicabtagene ciloleucel (axi-cel) is an FDA-approved CD19-directed CAR-T cell product for the treatment of patients with relapsed or refractory (R/R) DLBCL based on the ZUMA-1 (>2 prior lines of therapy5) and ZUMA-7 (primary refractory or relapse within 12 months of initial therapy6) trials. As patients with HIV were excluded from registrational studies, only sparse case reports or small case series7 exist to guide treatment in this context. With regards to safety concerns, a study of CD4 cell count trends in a subset of HIV-negative patients receiving axi-cel demonstrated low CD4 cell counts (median baseline 220/μL) that decreased over time and remained persistently low after lymphodepletion and axi-cel therapy (median CD4 cell count 155/μL at 1 year post treatment).8 This critical gap in evidence can potentially lead to lives lost in patients with HIV, typically aged 25 to 65 years. We hypothesize that axi-cel will be safe and feasible in treating R/R HIV-associated DLBCL. Study Design and Methods: This is a multicenter phase I study to define the safety and feasibility of axi-cel in R/R HIV-associated DLBCL (NCT05077527). Concurrent correlative studies will investigate immune reconstitution and HIV virologic response. All participants will receive the standard dose of axi-cel at AMC sites following conditioning chemotherapy; bridging therapy may be given at the discretion of the treating physician (Figure 1). Key eligibility criteria include HIV positivity with viral load <50 copies/mL; diagnosis of R/R DLBCL, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, or follicular lymphoma grade 3B; either post 2 prior lines of therapy or refractory/relapsed within 12 months of frontline treatment; evaluable disease; adequate organ/marrow function; and CD19 positivity confirmed if previously received CD19-directed therapy. The study will enroll 20 participants, including at least 6 participants with a CD4 cell count <100/μL. A safety assessment of participants with CD4 cell count <100/μL will be done after 6 participants in that cohort have been enrolled in this study (Figure 2). If >2/6 participants experience dose-limiting toxicity, the study will halt recruitment of participants with CD4 cell count <100/μL and continue to recruit participants with CD4 cell count of ≥100/μL. The primary endpoint of the study is safety and feasibility. Safety is defined by blood count recovery of neutrophils to grade ≤2, and platelets to grade ≤2 within 6 weeks of axi-cel infusion, incidence/severity of infection, and incidence/severity CRS/ICANS9 among patients who receive axi-cel. The incidence of toxicity will be summarized using frequency and percentage and presented overall and for each CD4 cell count cohort (<100 versus ≥100/μL). The feasibility assessment will be evaluated as the proportion of participants who receive axi-cel among all enrolled participants who undergo leukapheresis. Based on published data10 from patients without HIV (success rate ~85%) and anticipating potential difficulties in clinical progression, leukapheresis, and manufacture, we assigned >50% as the acceptable feasibility cutoff for our study population. Key secondary endpoints include 1) complete response (CR) rate per Lugano criteria,11 2) event-free survival (time from enrollment to earliest of disease progression; commencement of new anti-lymphoma therapy; or death), and 3) response duration (time from date when response criteria are met to relapse or progression). Key exploratory endpoints include 1) differences in cytokine profiles between patients who achieve CR and those achieving <CR per Lugano criteria (tested for statistical significance using Wilcoxon rank sum test) and 2) associations between cytokine profile and CRS and ICANS severity (≥ grade 3 vs < grade 3, tested for statistical significance using Wilcoxon rank sum test). 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

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

Inferior Outcomes of EU Vs. US Patients with Relapsed/Refractory Large B-Cell Lymphoma after CD19 CAR T-Cell Therapy Are Associated with Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization and CAR-T Product Selection

CD19 CAR T-cell therapy (CAR-T) has significantly improved the prognosis of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Real-world evidence has largely mirrored the clinical outcomes observed in registrational trials for these patients. However, a trend towards inferior survival in European (EU) patients and with tisagenlecleucel has been noted (Bethge WA et al., Blood 2022; Bachy E et al, EHA Annual Meeting 2022). The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. Here, we sought to characterize potential differences between EU and US R/R LBCL patients treated with standard-of-care tisagenlecleucel (Tisa-cel) or axicabtagene ciloleucel (Axi-cel) and their influence on survival outcomes. To this end, we retrospectively evaluated CAR-T time intervals from indication (usually time of tumor board decision) to infusion, baseline demographic, disease and laboratory features together with survival in 374 patients treated at five EU and one US CAR-T centers. A significant proportion of patients received intermediary anti-lymphoma therapy not only between apheresis and CAR-T infusion ("bridging"), but also between indication to CAR-T therapy and apheresis (coined "holding therapy"). While 22% of EU patients and 27% of US patients received holding therapy (p=0.33), a significantly higher proportion of EU patients were treated with bridging therapy (90% vs. 70% in US, p<0.0001). EU patients displayed prolonged apheresis-to-infusion intervals (49 vs. 30 days, p<0.0001). Tisa-cel was significantly more frequently applied in Europe (74% of EU patients) than in the US (15%, p<0.0001). Baseline characteristics are summarized in table 1. Interestingly, LDH levels (321 vs. 271 U/l in US, p=0.02) and the inflammatory marker ferritin (675 vs. 425 ng/ml in US, p=0.004) were significantly elevated in the EU vs. the US cohort. Overall, we observed inferior survival outcomes in the patients treated in the EU cohort (median progression-free survival [PFS] 3.1 vs. 9.2 months in the US, p<0.0001; 1-year PFS estimate 26% in EU vs. 48% in US) and with Tisa-cel (median PFS 3.2 vs. 9.2 months with Axi-cel, p<0.0001, 1-year PFS estimate 23% with Tisa-cel vs. 49% with Axi-cel). In univariate Cox regression analysis, more prior therapy lines, refractoriness to the latest therapy prior to CAR-T indication, ECOG ≥ 2, Ann-Arbor stage ≥ III, presence of extranodal disease (END), longer apheresis-to-infusion intervals, higher ferritin, CRP and LDH levels, non-response to bridging, and Tisa-cel use were significantly associated (p<0.05) with impaired progression-free survival (PFS). On multivariate Lasso modelling of these variables (from n=277 patients, excluding CAR-T product to delineate product-independent risk factors), non-response to bridging, elevated ferritin, and increased CRP remained independent risk factors for inferior PFS. These factors were weighted into a patient-individual "HRscore" using factor-specific Lasso coefficients (non-response to bridging: 0.35, ferritin: 0.10, CRP: 0.01). The HRscore was significantly elevated in EU patients (p=0.03 for EU vs. US), and notably also in the Tisa-cel cohort (p=0.0009 for Tisa-cel vs. Axi-cel). Risk stratification by the HRscore was confirmed by a second Lasso model only incorporating variables that were available at CAR-T indication (ferritin: 0.13, LDH: 0.09, END: 0.04, CRP: 0.03). Notably, PFS of Axi-cel was superior to Tisa-cel in patients with lower HRscores (median PFS not reached for Axi-cel vs. 7.4 months for Tisa-cel, p=0.002). In patients with high HRscores, PFS was similar for Axi-cel and Tisa-cel (2.9 months for both products, p=0.49). Taken together, these data provide insight on potential explanations for the inferior survival outcomes in EU patients receiving CD19 CAR-T cells for r/r LBCL. Differences in tumor burden and chemo-sensitivity (evidenced by LDH, END and non-response to bridging), systemic inflammation (ferritin, CRP), and CAR-T product were associated with observed PFS disparities between EU and US. Of note, superior outcomes with Axi-cel were mainly observed in patients with lower-risk disease. Our results highlight the importance of careful patient selection and, importantly, identify a high-risk patient cohort with significant medical need for further CAR-T treatment optimization. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ibrutinib in mantle cell lymphoma: a real-world retrospective multi-center analysis of 77 patients treated in the Czech Republic

Ibrutinib revolutionized therapy for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Real-world data on the outcome of unselected patients are still limited. We analyzed 77 R/R MCL patients receiving ibrutinib with at least one prior systemic anti-lymphoma therapy. After a median follow-up of 14.0 months, 56 patients relapsed/progressed, and 45 died. The overall response rate was 66%, with 31% of complete metabolic remissions on PET/CT. The median progression-free and overall survival (OS) rates were 10.3 and 23.1 months, respectively. The median OS from ibrutinib failure was 3.7 months. High proliferation rate by Ki67 (≥ 30%) and two or more previous therapy lines both negatively correlated with outcome (HR = 2.2, p = 0.04, and HR = 2.06, p = 0.08, respectively). Female gender borderline correlated with better outcome (HR = 0.53, p = 0.08). In multivariate analysis, Ki67 and response to ibrutinib both correlated with OS (p < 0.05). Importantly, ibrutinib appeared to better control nodal and extranodal lymphoma than bone marrow (BM) involvement. From 20 patients with detectable BM infiltration (before ibrutinib initiation) achieving complete (n = 13) or partial (n = 7) metabolic remission, none achieved remission in BM. We confirmed good efficacy of ibrutinib in unselected heavily pre-treated MCL patients. Our findings support the use of a combination of ibrutinib and rituximab in patients with BM involvement.