Refractory B-cell non-Hodgkin Lymphoma Research Articles

Chimeric Antigen Receptor T Cell Targeting to CD19 and CD22 Combined with Anti-PD-1 Antibody Induce High Response in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Objective: Despite the remarkable success of chimeric antigen receptor modified T (CAR-T) cell therapy for refractory or relapsed B cell non-Hodgkin lymphoma (R/R B-NHL), high rates of treatment failure and relapse after CAR-T cell therapy are considerable obstacles to overcome. Preclinical models have demonstrated that anti-PD-1 antibody is an attractive option following CAR-T therapy to reverse T cell exhaustion. Thus, we investigated their combination in R/R B-NHL.Methods: We performed a prospective, single-arm study of CAR-T cell combined with anti-PD-1 antibody treatment in R/R B-NHL (NCT04539444). Anti-PD-1 antibody was administrated on day 1 after patients received sequential infusion of anti-CD19 and anti-CD22 second-generation CAR-T cells, and the efficacy and safety of the combination treatment were evaluated.Results: From August 1, 2020 to June 30, 2021, a total of 11 patients were enrolled and completed at least 3 months follow-up. The median follow-up time is 5.8 months. Overall response was achieved in 9 of 11 patients (81.8%), and the complete response (CR) was achieved in 8 of 11 patients (72.7%). All 8 patients achieving CR still sustained remission at the last follow-up. The progression-free survival (PFS) and overall survival (OS) rates at 6 months were 80.8% and 100.0%, respectively. Cytokine release syndrome (CRS) occurred in only 4 patients (all were grade 1), and no neurotoxicity were observed.Conclusion: This study suggests that CAR-T cells combined with anti-PD-1 antibody elicit a safe and durable response in R/R B-NHL.Keywords: chimeric antigen receptor modified T cell, anti-PD-1 antibody, CD19/CD22, refractory or relapsed B cell non-Hodgkin lymphoma DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:We use the T cells were transduced with a lentivirus encoding the CD19-4-1BB-CD3 z and CD22-4-1BB-CD3 ztransgene to produce CAR-T cells. The main purpose of our study is to improve the response rate in patients with R/R B-NHL.

A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts

A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts

A Phase 1 Safety and Efficacy Study of ADI-001 Anti-CD20 CAR-Engineered Allogeneic Gamma Delta (γδ) T Cells in Adults with B Cell Malignancies, in Monotherapy and Combination with IL-2

A Phase 1 Safety and Efficacy Study of ADI-001 Anti-CD20 CAR-Engineered Allogeneic Gamma Delta (γδ) T Cells in Adults with B Cell Malignancies, in Monotherapy and Combination with IL-2

Overview of Adverse Events Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a novel immunotherapy that has shown remarkable success in the treatment of adult relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma, adult R/R mantle cell lymphoma, and R/R acute paediatric lymphoblastic leukaemia. One barrier to the widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) with a variable grade of severity. The main manifestations of CRS are fever, hypotension, cytopenia, organ dysfunction among others. Neurological toxicities vary widely and range from headaches to encephalopathy. In addition, anti-CD19 CAR T-cell therapy provokes an array of less frequent events, such as coagulopathies, delayed cytopenia, and cardiovascular toxicities. In general, toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care and immunosuppressive therapy. Deaths due to CRS, neurologic toxicity and infectious complications have been reported, which highlights the gravity of these syndromes and the critical nature of appropriate intervention. In this paper, we look at all available FDA- and EMA-approved information about the pathophysiology, clinical manifestations, risk factor reviews of existing toxicity grading systems, current management strategies, and guidelines for anti-CD19 CAR T-cell toxicities. We also present new approaches, which are under investigation, to mitigate these adverse events.

Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells. For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing. Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels. Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies. Genmab and AbbVie.

840P Preliminary phase I/II study results of orelabrutinib combined with MIL62 in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

MIL62 is a glycoengineered anti-CD20 antibody with a nearly completely afucosylated N-glycans in Fc region that demonstrated superior activity in comparison with rituximab and obinutuzumab in vitro and in vivo, respectively. Orelabrutinib (ICP-022) is a novel and highly selective irreversible Bruton’s tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase (ITK) or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combined therapy with anti-CD20 antibodies.

CD3xCD20 bispecific T-cell redirectors for relapsed or refractory B-cell lymphoma

The treatment options for patients with relapsed or refractory B-cell non-Hodgkin lymphoma who do not respond to traditional treatment are rapidly evolving. In addition to chimeric antigen receptor T-cell (CAR-T) therapy, antibody–drug conjugates, and targeted therapies such as Bruton's tyrosine kinase inhibitors and PI3 kinase inhibitors, bispecific T-cell redirectors have shown promising activity in this setting. Although not yet approved for non-Hodgkin lymphoma, bispecific T-cell redirecting technology is under investigation for several haematological and solid malignancies.

CAR T-cell Therapy in Indolent Lymphoma

Introduction CD19 directed chimeric antigen receptor (CAR) T-cell therapy has had a transformative impact on the natural history of chemotherapy refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL) and B-cell acute lymphoblastic leukemia (B-ALL), inducing long-term remissions in 40–50% of patients.1–5 It does this, however, at the expense of both financial and clinical toxicity. But the cost and risk of care in the absence of CAR T-cells in these instances outweighs the risk of the therapy itself, and so it has broadly been accepted as a standard of care for these patients. Moving CD19 directed CAR T-cell therapy into the slower growing, but historically incurable, indolent B-NHLs has the potential to challenge this balance between risks and benefits. Will CAR T-cells offer definitive therapy for these otherwise incurable diseases? If not, will CAR T-cells positively affect long-term survival over alternative therapies? The answer to these questions will determine how oncologists weigh the financial and clinical costs against the therapeutic benefits.

A phase I trial of inotuzumab ozogamicin in combination with temsirolimus in patients with relapsed or refractory CD22-positive B-cell non-Hodgkin lymphomas

This phase I trial evaluated the safety, tolerability, and preliminary activity of inotuzumab ozogamicin in combination with temsirolimus in patients with relapsed/refractory CD22 positive B-cell non-Hodgkin lymphomas. Nineteen patients received at least one dose of both study drugs. Dose-limiting toxicities consisted of thrombocytopenia, hypertriglyceridemia, oral mucositis, clinical deterioration, and the inability to receive at least three doses of temsirolimus during cycle 1. The most common grade ≥3 treatment-related adverse events were thrombocytopenia (n = 8), neutropenia (n = 5), and two patients each hyperphosphatemia, lymphopenia, and hypertriglyceridemia. The recommended phase II dose was inotuzumab ozogamicin 0.8 mg/m2 on day 1 in combination with temsirolimus 10 mg on days 8, 15, and 22 every 28 days. Among 18 patients evaluable, seven (39%) with follicular lymphoma had a partial remission. This drug combination is not possible within a therapeutically useful range of doses due to toxicities. Antitumor activity was observed in heavily pretreated patients (ClinicalTrials.gov, Identifier NCT01535989).

Anti-CD19 CART (C-CAR011) Therapy for Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

To evaluate the safety and efficacy of C-CAR011 in the treatment of relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) patients. B-NHL patients treated with C-CAR011 infusion following lympho-depletion were enrolled. All the patients were followed up for 1 year after C-CAR011 treatment(5.0×106 /kg). The primary endpoint of this research was safety; and the secondary endpoints included objective response rate (ORR), progression-free survival (PFS), duration of overall response (DOR), overall survival (OS) at Week 4, 12 and Month 6 and 12. The ratio of the male and female of 6 patients was 1∶1, and the patients were treated with C-CAR011 at a dose of 5.0×106 /kg. The median age was 46.5 years old (37-62 years); 5 patients were diagnosed as diffuse large b-cell lymphoma (DLBCL) and 1 patient was diagnosed as follicular lymphoma (FL). The most common adverse events (AEs) were hematological toxicities (100%, Grade 3-4), cytokine release syndrome (CRS) (66.7%, Grade 1-3), neurotoxicity (16.7%, Grade 3). All these AEs were reversible and could be conversed. The ORR at Week 4, 12 and Month 6, 12 were 50%(3/6), 50%(3/6), 16.7%(1/6) and 16.7%(1/6), respectively. Three patients (50%) achieved complete response (CR) and one of them stayed evaluated as CR until Month 12. The median PFS was 178 days (91->365 days). For 3 patients with response, the DOR were 150 days, 154 days and >12 months, respectively. The OS rates of the patients at Week 12, Month 6, 12 were 100%, 100%, 83.3%, respectively, while the median OS was not reached. C-CAR011 is a safe treatment option for R/R B-NHL; some patients could achieve long-term sustained responses after C-CAR011 infusion（ClinicalTiral.gov number, NCT03483688）.

Abstract CT176: Phase 2 study of tazemetostat in Japanese patients with relapsed or refractory EZH2 mutation-positive B-cell Non-Hodgkin's Lymphoma

Abstract Background: Tazemetostat is a selective, reversible, small-molecule inhibitor of enhancer of zest homolog 2 (EZH2), a histone methyltransferase. EZH2 is the catalytic subunit of polycomb repressive complex 2, which methylates lysine 27 on histone 3 (H3K27). Recurrent gain-of-function alterations in EZH2 occur in approximately 30% of germinal center B-cell like diffuse large B-cell lymphoma (GCB-DLBCL) and 27% of follicular lymphoma (FL). The aim of this multicenter, open-label, Phase 2 study was to assess the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory B-cell Non-Hodgkin's Lymphoma (NHL) harboring the EZH2 mutation. Methods: Patients with histologically diagnosed FL (cohort 1) or DLBCL (cohort 2) were screened centrally for EZH2 mutation using the cobas EZH2 Mutation Test. Tazemetostat (800 mg BID) was administered orally for 28 days/cycle until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. The primary endpoint was the objective response rate (ORR) based on IWG-2007 by independent imaging review and safety was evaluated as the secondary endpoint. Results: Among the 20 eligible patients, 17 were enrolled in cohort 1, and 3 were enrolled in cohort 2. In cohort 1, the median number of prior chemotherapy was 2 (range 1-4) and the ORR was 76.5% , including 6 patients (35.3%) achieving a complete response and 7 patients (41.2%) achieving a partial response (PR) as of the data cutoff. The ORR in subjects who received prior treatment with bendamustine, rituximab, and CHOP was 87.5%, 76.9%, and 76.9%, respectively. All 3 patients in cohort 2 (100%) achieved PR. In cohort 1, 3 of the 17 subjects (17.6%) had progression-free survival (PFS) events. The median PFS was not reached. Estimated PFS rates at 12 and 15 months based on the Kaplan-Meier analysis were 94.1% and 73.2%, respectively. The median duration of response (DOR) was not reached, and the DOR rate at 9 and 12 months was 100% and 80.0%, respectively. The median time to response was 3.6 months. The most common grade-3 treatment emergent adverse event (TEAE) was lymphopenia (2 patients, 10.0%). Grade-4 TEAEs included hypertriglyceridemia and pneumonia aspiration (1 patient each, 5.0%). TEAEs leading to study drug discontinuation were reported by 4 of 20 (20.0%) patients, including fatigue (2 patients, 10.0%), atypical pneumonia, traumatic intracranial haemorrhage, non-small cell lung cancer, muscle spasticity, and dysgeusia (1 patient each, 5.0%), indicating that the safety profile was acceptable and manageable. Conclusion: Tazemetostat at a dose of 800 mg BID showed encouraging efficacy in patients with relapsed or refractory EZH2 mutation-positive FL with an acceptable safety profile in the overall population. Thus, tazemetostat may be a potential option for the treatment of relapsed or refractory EZH2 mutation-positive FL. Citation Format: Shinya Rai, Kiyoshi Ando, Akifumi Takaori-Kondo, Hirohiko Shibayama, Takanori Teshima, Junya Kuroda, Koji Kato, Yoshitaka Imaizumi, Kisato Nosaka, Rika Sakai, Tadashi Nakanishi, Seiichiro Hojo, Koji Izutsu. Phase 2 study of tazemetostat in Japanese patients with relapsed or refractory EZH2 mutation-positive B-cell Non-Hodgkin's Lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT176.

Abstract 1366: Integrated population modeling of loncastuximab tesirine (Lonca) exposure in B-cell non-Hodgkin lymphoma (B-NHL)

Abstract Lonca is an antibody (Ab) drug conjugate comprising a humanized monoclonal Ab directed against B-cell antigen CD19, conjugated with a potent pyrrolobenzodiazepine (PBD) dimer toxin. In a Phase 1 (NCT02669017) study in relapsed or refractory (R/R) B-NHL, a recommended Phase 2 dosing regimen for Lonca of 150 µg/kg once every 3 weeks (Q3W) for two doses, followed by 75 µg/kg Q3W was identified then evaluated in a Phase 2 (NCT03589469) study in R/R diffuse large B-cell lymphoma (DLBCL). A population pharmacokinetic (PPK) model was developed to characterize the pharmacokinetics (PK) of the Lonca dosing regimen and evaluate exposure covariates. The integrated PPK model was used to describe drug concentrations for Lonca PBD-conjugated Ab (5,301 samples), total Ab (5,241 samples), and unconjugated warhead SG3199 (239 samples) in serum from 328 patients. Samples were taken pre-dose, at end of infusion and at pre-determined timepoints post-infusion throughout the trials. Analysis was performed using non-linear mixed-effects modeling (NONMEM, v7.4 [ICON Solutions]). Subgroup analyses were conducted on model-predicted exposure metrics derived from simulation of Lonca PK profiles based on empirical Bayesian estimates of individual PK parameters. Concentration-time data of Lonca PBD-conjugated Ab and total Ab were best characterized by a two-compartment model with parallel linear clearance (0.218 L/day), and a time-dependent clearance component which approached zero by ~15 weeks. The estimated volume of distribution of central compartment was 3.86 L and the estimated typical half-life at steady state of Lonca is ~3 weeks. The effect of body weight, age, sex, race, renal impairment, drug formulation, anti-drug Ab, ECOG, and concomitant P-gp inhibitors did not show clinically important influence on exposure (< ±30% change relative to reference). Based on model-predicted Cycle 1 average concentration (Cavg) patients with low albumin (<35 g/L, n=49) had 52% lower Cavg than patients with normal albumin levels (≥35 g/L, n=279). Patients with non-DLBCL (n=44) had 61% lower Cavg than patients with DLBCL (n=284). Trends of lower exposures with baseline mild/moderate hepatic impairment and ECOG status >1 were noted but did not appear to be of clinical relevance. In conclusion, Lonca exposure was well described by a two-compartment model with linear and time-dependent clearance; the latter is thought to reflect reduction of tumor cells. Lonca exposure was lower in non-DLBCL patients, and lower in patients with hypoalbuminemia secondary to enhanced protein clearance in patients with critical illness. Overall, modeling demonstrates rapid attainment of steady-state exposure for Lonca given 150 µg/kg Q3W for two doses, and a sustaining profile for Lonca given 75 µg/kg Q3W thereafter for patients with DLBCL. Citation Format: Melhem Solh, Juan Pablo Alderuccio, Anastasios Stathis, David Ungar, Sam Liao, Lisa Khouri, Xiaoyan Zhang, Joseph Boni. Integrated population modeling of loncastuximab tesirine (Lonca) exposure in B-cell non-Hodgkin lymphoma (B-NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1366.

Short-Interval Sequential CAR-T Cell Infusion May Enhance Prior CAR-T Cell Expansion to Augment Anti-Lymphoma Response in B-NHL.

Chimeric antigen receptor (CAR)-T cell therapy emerges as a new treatment for refractory or relapsed (r/r) B-cell non-Hodgkin lymphoma (B-NHL); however, the overall response rate (ORR) of which in the B-NHL patients is much lower compared to the patients with r/r B acute lymphoblastic leukemia (B-ALL). We previously confirmed that sequential infusions of CD20 and CD22 CAR-T cells significantly improved the prognosis of the B-NHL patients, while some advanced patients still progressed to death during these CAR-T cell treatments. In this study, we showed that timely sequential administration of the second CAR-T cells could enhance expansion of prior CAR-T cells with stronger tumor-killing capacity in vitro and in vivo. We further conducted compassionate treatments on two advanced B-NHL patients with short-interval sequential infusions of CD19/22/20 CAR-T cells. Disease progression was observed in both patients after primary CAR-T cell infusion but robust re-expansion of prior CAR-T cells and anti-tumor effects was induced by infusion of a secondary CAR-T cells. These results indicate sequential infusions of CAR-T cells with a short interval may improve therapeutic efficacy in the B-NHL patients by promoting expansion of prior CAR-T cells.

Dose-Adjusted Rituximab Mini-CYVE (CYtarabine bolus, VEpeside and dexamethasone) for Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma Not Eligible for High Dose Therapy

Background. There is no current standard of care for the management of patients with relapsed or refractory B-cell non-Hodgkin Lymphoma (R/R B-NHL) ineligible for high-dose therapy. While cytarabine and etoposide are commonly used drugs in salvage regiments for patients eligible for high dose therapy (HDT) and auto-stem cell transplant, data are sparse in the context of ineligibility for high-dose therapy. We designed a dose-adjusted combination of rituximab plus mini-CYVE (CYtarabine bolus, VEpeside and dexamethasone) regimen (R-mini-CYVE), for R/R B-NHL patient's ineligible for HDT.Patients and methods. We retrospectively included patients over 60 years old and ineligible for HDT that received R-mini-CYVE regimen for R/R B-cell NHL between January 2009 and November 2015 at Gustave Roussy, Villejuif, France. Patients must be previously treated with anthracycline-containing chemotherapy regimen. Patients could be included regardless of performance status statement and comorbidity. Treatment consisted of combination of intravenously rituximab mini-CYVE given for six to eight cycles every three weeks. All patients received the same doses of rituximab intravenously 375 mg/m2 at day 1, and oral dexamethasone 40 mg/d at days 1-4. Patients received intravenously cytarabine bolus at days 1 and 2 and vepeside at days 1 to 3. Patients were allocated in four dose levels of chemotherapy (cytarabine bolus and vepeside), according to physician discretion among age and comorbidity. Dose levels of cytarabine/vepeside in mg/m2/d were 500/75 for level 1, 1000/75 for level 2, 1000/100 for level 3 and 1500/100 for level 4. Patients were assessed for response after two cycles and at the end of treatment, by computerized tomography scan according to the international harmonized project Cheson 1999 criteria. Primary endpoints were overall survival, and overall response rate (ORR) at the end of treatment. Toxicity was registered according to the CTCAEv4.03.Results. Thirty-seven patients (21 men and 16 woman) received at least one cycle of rituximab mini-CYVE treatment. Among them, the reasons for no eligibility to HDT were a poor performance status over 2 (n=28), renal impairment with glomerular filtration rate below 60 ml/min (n=7), hearing impairment (n=2). Histological types were diffuse large B-cell lymphoma in 31/37 (84 %) patients and indolent B-cell NHL in 6/37 (16 %) patients. At inclusion, median age was 75 [61-88] years old, median number of prior therapies lines was 1 [1-5], Ann-Arbor stage was 3 or 4 in 28/37 (76%) and serum lactate dehydrogenase was increase in 19/37 (51%) patients. Thirteen, 9, 8 and 7 patients received the dose levels 1, 2, 3 and 4, respectively. Median number of cycles was 4 [1-8]. Hematological adverse events grade 3-5 were experienced in 26/37 (70%) patients, and non-hematological grade 3-4 adverse event in 7/37 (19%) patients. One patient died from febrile neutropenia grade 5 during treatment. Non-hematological grade 3-4 adverse events were sepsis in 6/37 (16%) patients and acute cerebellar syndrome related to aracytine at dose level 2 in 1/37 (3%) of patients. Adverse events led to treatment discontinuation in 4/37 (11 %) of pts. ORR was 43% (16/37 pts) including 35% (13/37 pts) of CR or CRu and 8% (3/37) of PR. Median OS and PFS were 13.2 (95% C.I, 9.8-16.6 months), and 6.4 (95% C.I, 1.2 - 11.5) months. With a median follow-up of 12 [range 1 to 60] months, 25/37 patients (67%) had died from progressive disease (n=21), sepsis (n=3) or pulmonary embolism (n=1).Conclusion. The dose-adjusted rituximab mini-CYVE regimen demonstrated a favorable safety and efficacy profile in R/R B-cell NHL patients not eligible for high-dose chemotherapy. Further studies are warranted to investigate this regimen in this population of patients. DisclosuresRibrag:BMS: Honoraria; Roche: Honoraria; Infinity: Honoraria; MSD: Honoraria; Nanostring: Honoraria; Gilead: Honoraria; Servier: Consultancy, Honoraria; ArgenX: Research Funding; Epizyme: Honoraria.

Improved Outcome of Newly Diagnosed Childhood Mature B-Cell Lymphoma/Leukemia with High Tumor Burden Treated with BFM95-Based Protocol Combining Rituximab: A Report from Shanghai, China

The Berlin-Frankfurt-Münster (BFM) based protocols have been wildly used in children with non-Hodgkin lymphoma (NHL) and leukemia for more than ten years in China. At the same time, rituximab has become a standard medicine in the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) and relapsed or refractory B-cell NHL. In this study, we explored the efficacy of rituximab in childhood CD20 positive B-NHL and B-cell acute leukemia (B-AL).To explore the effect of rituximab in mature B-cell lymphoma (B-NHL)/mature B-cell leukemia ((B-AL) in children, this study included children and adolescents aged younger than 18 years with newly diagnosed CD20 positive, stage III/IV B-NHL/B-AL for treatment combining NHL-BFM95-based protocol with rituximab. A total of 4 injections with 375 mg/m2 rituximab each were administered intravenously after prephase V course at one day before the following 4 course of chemotherapy. Retrospective cases diagnosed with stage III/IV B-NHL/B-AL in our center were used as historical control. All of these patients were treated under NHL-BFM90 based protocol. Patient characteristics, event free survival (EFS), recurrence and mortality were analyzed.From April 2009 to December 2015, 46 patients were recruited and treated with rituximab combining BFM95-based protocol (R+BFM95 protocol). 23 cases diagnosed with stage III/IV B-NHL/B-AL from January 2005 to March 2009 treated with BFM90-based protocol. All patients followed till December 31, 2016. This study recruited 35 males and 11 females with an average age of 6.9 years who were treated with R+BFM95 protocol. Among the historical control of 23 patients treated with BFM90-based chemotherapy, 18 were males and 5 were females and the average age of our historical control was 7.2 years. Among patients treated with R+BMF95 protocol, the average duration of continuous complete remission (CR) was 3.6 years. Compared with patients treated with BFM90-based protocol, the 5-year event free survival (EFS) of patients under R+BMF95 was higher (83.7±5.7% vs 69.6%±9.6% in R+BMF95 and BFM90 respectively), however the difference was not statistically significant (P=0.1062). Among subgroups of our patients between patients treated with R+BMF95 and BFM90, the 5-year EFS of patients with stage III disease was 87.3±6.1% vs 77.8±9.8% (P=0.2998), stage IV subgroup was 72.7%±13.4% vs 40.0±21.9% (P=0.0878), respectively. Among patients whose LDH level were below 500 U/L at diagnosis, R+BFM95 protocol achieved 100% EFS during our follow-up, nevertheless the 5-year EFS of patients in this group was not statistically different from that of patients treated with BFM90 (92.3±7.4%, P=0.2994). Among patients had LDH >500 U/L at diagnosis, the 5-year EFS in R+BFM95 group was 77.2±7.7% and significantly higher than that of BFM90 group (40.0±15.5%, P=0.0048). In the patient group treated with R+BFM95, there were 2 (2/46, 4.3%) did not achieve CR. During the follow-up, recurrence occurred in 5 patients (5/46, 10.9%) including 2 partial remission (PR). Early death occurred in 1 patient (1/46, 2.2%) in the first course due to tumor lysis syndrome. Two cases with recurrence were treated with R-ICE regimen however remission did not occur. All patients with recurrent disease died. In the control patients treated with BFM90-based protocol, there were 3 (3/23, 13.0%) did not achieve CR. One patient did not respond to chemotherapy therefore received second-look operation however the pathology was positive and he died of disease progression. The other 2 patients give up treatment after 2 courses of chemotherapy. One patient (1/23, 4.3%) died in the first course because of sepsis. One patient with relapsed disease received R-ICE treatment however not achieved remission again. All patients with recurrent disease also died in BFM90 group.To summarize, our study demonstrated the feasibility of rituximab for Chinese children with B-NHL/B-AL. Rituximab improved the prognosis of Chinese B-NHL/B-AL children, especially among patients with LDH >500U/L. However, the limited number of patients and retrospective study design suggested further randomized trial with larger number of patients to confirm the efficacy, as well as cost-effectiveness of rituximab in childhood B-NHL/B-AL in China. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase I Study of the Anti-CD79b THIOMABTM-Drug Conjugate DCDS0780A in Patients (pts) with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (B-NHL)

A Phase I Study of the Anti-CD79b THIOMABTM-Drug Conjugate DCDS0780A in Patients (pts) with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (B-NHL)

CC-122, a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed and Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL)

Introduction: Patients (pts) with R/R NHL, including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) have a poor prognosis with limited 2L and 3L treatment options (MacDonald et al. Curr Oncol 2016). Early relapse (ER) pts with FL experiencing progression within 2 years of initial diagnosis and those double refractory (DR) to both rituximab and chemotherapy have particularly poor outcomes (Casulo et al. J Clin Oncol 2015; Gopal et al. N Eng J Med 2014). CC-122 is a novel oral agent that binds the cereblon ubiquitin ligase complex, resulting in degradation of the hematopoietic transcription factors Aiolos and Ikaros. Preliminary results from CC-122-NHL-001, a phase Ib study of CC-122 in combination with obinutuzumab, have shown promising response rates in pts with R/R B-cell NHL (Michot et al. ASH 2016). Herein, we report updated results for safety and efficacy from CC-122-NHL-001 (NCT02417285) with further 12 months follow up. Methods: Eligible pts age ≥18 years had histologically or cytologically confirmed CD20+ B-cell R/R NHL after ≥1 prior regimen for FL/marginal zone lymphoma (MZL) or after ≥2 regimens and/or autologous stem cell transplant (ASCT) for DLBCL. CC-122 was given orally (5 of 7 d) for 28-d cycles in escalating doses plus a fixed dose of intravenous obinutuzumab 1000 mg on d2, 8, 15 of cycle 1 (c1), and d1 of c2-8, upon informed consent. CC-122 active ingredient in capsule formulation (AIC) 1, 2, 3, and 4 mg and CC-122 formulated capsules (F6) 3 and 4 mg were evaluated in separate cohorts. Primary endpoints included safety and tolerability, non-tolerated dose (NTD), and maximum-tolerated dose (MTD). Response was assessed using the Cheson 2007 criteria every 2 cycles to c6, every 3 cycles to c12, and every 6 cycles thereafter. Results: As of May 1, 2017, 38 pts with R/R B-cell NHL were enrolled in the dose-escalation phase of the study. Tumor types included 19 pts with DLBCL, 18 with FL, and 1 with MZL. Of the 18 pts with FL, 10 (5 DR+ER and 5 ER) were difficult to treat, high-risk pts. Median age was 60 years (range, 26-81), 26 (68%) were male, and 29 (76%) had stage III/IV disease. Of the 19 pts with DLBCL, 8 (42%) had transformed DLBCL, and of the 19 pts with FL/MZL, 8 (42%) relapsed in 1 pt. Three deaths occurred during the study (2 PD; 1 AE-related, tumor flare). Median duration of CC-122 treatment was 23.6 weeks (range, 3.4-87.0), equivalent to 7 cycles (range, 1-22). CC-122 dose reduction or temporary interruption occurred in 12 (32%, all due to AEs) or 32 (84%, 26 due to AEs) pts, respectively. Fifty-five percent of pts had Conclusions: The novel, chemotherapy-free combination of CC-122 and obinutuzumab was well tolerated with promising response rates, and durable remissions in R/R B-cell NHL. The safety profile was consistent with other studies of CC-122, with AEs being mainly hematological and manageable. Notably, subgroup analysis showed that the combination has similar efficacy in the high-risk ER and DR subgroups of RR FL compared with the overall FL population. A CC-122 dose of ≥3 mg with obinutuzumab shows the best response rates to date, with deep response upon prolonged treatment. Expansion part B is currently on-going in both lenalidomide naive and lenalidomide refractory FL pts. Disclosures Doorduijn: Celgene: Honoraria; Roche: Honoraria. Vitolo: Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria; Takeda: Honoraria; Mundipharma: Honoraria. Kersten: Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Milennium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; Kite Pharma: Honoraria; Amgen: Honoraria; MSD: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chiappella: Teva: Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Nanostring: Speakers Bureau; Pfizer: Speakers Bureau. Zinzani: Celgene, Janssen, Gilead, Roche, Takeda, BMS, MSD, Sandoz, Servier, Mundipharma: Speakers Bureau; Merck: Consultancy, Other: Advisory board; ​Celgene, Roche, Janssen, Gilead, Takeda, BMS, MSD, Servier, Sandoz, Mundipharma: Honoraria. Sarmiento: Celgene Research S.L.: Employment, Equity Ownership. Mosulen: Celgene Institute for Translational Research Europe: Employment. Mendez: Celgene Institute for Translational Research Europe: Employment. Petrarca: Celgene Corporation: Employment, Equity Ownership. Pourdehnad: Celgene Corporation: Employment, Equity Ownership. Hege: Celgene Corporation: Employment, Equity Ownership. Li: Celgene Corp.: Employment. Nikolova: Celgene International Sarl: Employment, Equity Ownership. Ribrag: Epizyme: Honoraria; BMS: Honoraria; MSD: Honoraria; Infinity: Honoraria; Gilead: Honoraria; Nanostring: Honoraria; Roche: Honoraria; ArgenX: Research Funding; Servier: Consultancy, Honoraria.

Anti-CD19 chimeric antigen receptor T-cell therapy in B-cell lymphomas: current status and future directions.

Aims:To review recent data and relevant of the role of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell non-Hodgkin lymphoma (NHL).Methods:Review and compilation of the most recent and relevant data published in full text and abstract forms of anti-CD19 CAR T-cell therapy for B-cell NHL.Results:Different anti-CD19 CAR T-cell therapy products have been tested and shown significant clinical activity across B-cell NHL patients. The objective responses in relapsed DLBCL, FL and MCL were 50–83%, 83–93% and 93%, respectively.Conclusions:Anti-CD19 CAR T-cell therapy is a viable option for poor risk refractory B-cell NHLs.

Subcutaneous epcoritamab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: Safety profile and antitumor activity.

7518 Background: Epcoritamab is a CD20xCD3 bispecific antibody that induces T-cell–mediated killing of CD20–positive malignant B-cells. We present updated data, including progression-free survival (PFS) from the dose escalation part of the first-in-human phase 1/2 study of epcoritamab in pts with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT03625037). Methods: Adults with R/R CD20+ B-NHL received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1–2; q2w: cycles 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Step-up dosing and standard prophylaxis were used to mitigate severity of cytokine release syndrome (CRS). Results: At data cut off (1/31/2021), 68 pts with B-NHL were enrolled across histologies including diffuse large B-cell lymphoma (DLBCL; n = 46 [67.6%]; de novo and transformed), follicular lymphoma (FL; 12 [17.6%]), mantle cell lymphoma (MCL; 4 [5.9%]), and others (6 [8.8%]). Majority were heavily pretreated (median [range] prior lines: DLBCL, 3 [1–6]; FL, 4.5 [1–18]); including prior CAR-T (n = 6) and prior ASCT (n = 10). At median follow-up of 14.1 mo (DLBCL, 10.2 mo; FL, 15.2 mo), treatment was ongoing in 15 (22%) pts. Most common treatment-emergent adverse events (AEs) were pyrexia (69%), CRS (59%), and injection site reaction (47%). CRS events were all grade 1 or 2 and most occurred in cycle 1; neurotoxicity was limited (6%; grade 1: 3%; grade 3: 3%; all transient). One case of tumor lysis syndrome was observed (1.5%; grade 3); there were no cases of febrile neutropenia or treatment-related death. Overall response is shown for DLBCL ≥12 mg and ≥48 mg and FL ≥12 mg, corresponding to the minimal efficacy threshold (Table). Responses deepened over time (PR converted to CR: DLBCL, 6 pts; FL, 3 pts). Median time to response was 1.4 mo (DLBCL) and 1.9 mo (FL). Among DLBCL pts achieving CR with ≥6 mg (n = 11), none relapsed while on treatment. The median PFS for pts with DLBCL ≥12 mg (n = 22) was 9.1 mo (95% CI: 1.6, NE; median follow-up 9.3 mo) and for pts with DLBCL ≥48 mg (n = 11) median PFS was not reached (median follow-up 8.8 mo). Updated analyses will be presented. Conclusions: With longer follow-up, SC epcoritamab demonstrated substantial single-agent activity, inducing deep and durable clinically meaningful responses, with a consistent safety profile. Notably no severe (grade ≥3) CRS events, no febrile neutropenia, and limited neurotoxicity was observed. Clinical trial information: NCT03625037. [Table: see text]

CD19 CAR T-cell product type independently impacts CRS and ICANS severity in patients with aggressive NHL.

7532 Background: CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells achieve high response rates in patients (pts) with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL), but are limited by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Pivotal trial data suggested distinct toxicity risks across CD19 CAR T-cell products, but differences in pt and disease characteristics may have confounded these observations. Thus, we assessed the independent impact of 3 CD19 CAR T-cell products (axicabtagene ciloleucel[axicel], tisagenlecleucel [tisacel], and JCAR014) on CRS and ICANS severity in 136 pts with R/R aggressive NHL. Methods: We retrospectively analyzed aggressive NHL pts treated at our institutions with cyclophosphamide and fludarabine lymphodepletion (LD) followed by CD19 CAR T-cell therapy. Axicel and tisacel pts were treated off trial using commercial products. JCAR014 (defined-composition 4-1BB-costimulated CD19 CAR T cells) was administered in all pts at the dose of 2x106/kg on a phase I/II clinical trial (NCT01865617). CRS and ICANS were graded according to the ASTCT criteria and CTCAE 4.03, respectively. We used multivariable proportional odds logistic regression to model CRS and ICANS grade. Results: The CAR T-cell product was axicel, tisacel, or JCAR014 in 50%, 28%, and 22% of pts, respectively. Compared to axicel pts, we observed higher preLD LDH levels in tisacel and JCAR014 pts, and lower preLD albumin with tisacel (p < 0.001) with comparable age and hematopoietic cell transplantation comorbidity (HCT-CI) indexes across CAR T-cell products. Higher day-28 overall response rate by Lugano criteria was observed after axicel (71%) compared to tisacel (56%) and JCAR014 (53%). Adjusting for age, HCT-CI, preLD LDH, preLD albumin, CAR T-cell product type was associated with CRS severity (tisacel versus [vs] axicel, OR = 0.45, p = 0.05; JCAR014 vs axicel, OR = 0.29, p = 0.005;). Age had limited or no impact on CRS severity (OR 95%CI, 0.97-1.02), while the effect of HCT-CI was undetermined (OR 95%CI, 0.85-1.27). In a multivariable model including the same covariates as above, CAR T-cell product type (tisacel vs axicel, OR =.14, p <.001; JCAR014 vs axicel, OR = 0.31, p = 0.009), preLD LDH (OR, 3.96 per log10 increase; p = 0.04) and age (OR per 10-year increase, 1.32; p =.06) were associated with ICANS severity. Interaction effect testing suggested effect modification of age by the CAR T-cell product type (tisacel/JCAR014 versus axicel, p = 0.06); using a multivariable model including this interaction term, the predicted probabilities of grade ≥3 ICANS in a 70 year-old after axicel, tisacel, and JCAR014 were 40%, 6%, and 8%, respectively. Conclusions: CAR T-cell product type independently impacts CRS and ICANS severity in NHL pts. Our findings provide key insights to guide patient and CAR T-cell product selection.