Indolent non-Hodgkin Lymphoma Research Articles

IBCL-081 MAGNIFY Phase 3b Study of Lenalidomide + Rituximab (R2) Followed by Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma: Complete Induction Phase Analysis

Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide + rituximab (R2) has shown complimentary clinical activity and is tolerable in both untreated and relapsed/refractory (R/R) iNHL. MAGNIFY is a multicenter, phase 3b trial in R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865). In the induction phase, lenalidomide 20mg PO d1-21 of a 28-d cycle + rituximab IV 375mg/m2/week cycle 1 and then q8w starting with cycle 3 (R2) are administered for 12 cycles. Patients with ≥SD were randomized 1:1 to R2 vs rituximab maintenance for 18 months. Data here are the complete induction phase analysis in efficacy-evaluable patients with FL grades 1-3a or MZL. The focus of this interim analysis was ORR by 1999 IWG criteria in the induction ITT population. As of March 5th, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. Median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% with 42% CR/CRu. All patients have completed R2 induction (n=232, 59%) or discontinued study treatment (n=162, 41%); 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to AEs (n=54, 14%) or PD (n=42, 11%). The majority who have completed induction have been randomized and entered maintenance (n=217). Median DOR in the induction period was NR (95% CI, 43.9 mo-NR); median PFS in the induction safety population was 50.5 mo (95% CI, 39.5-NR). Most common all-grade TEAEs were 47% fatigue, 43% neutropenia, 37% diarrhea. Grade 3/4 AEs occurring in ≥5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, 5% fatigue. These data represent a complete analysis of all patients in the induction phase of MAGNIFY that continue to support that R2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients.

Safety and antitumor activity of copanlisib in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma: a phase Ib/II study

The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg (n = 3) or 60 mg (n = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II (n = 15). Although all patients experienced at least one treatment-emergent adverse event (TEAE), with hyperglycemia being the most common AE, no AE-related deaths were reported. The ORR was 68.0% (17/25 patients), median PFS was 302 (95% CI 231–484) days, and the duration of response was 330 (range 65–659) days. The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients. Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL.

CLL-211 Humoral Immune Response Following COVID-19 Vaccination in Patients With Chronic Lymphocytic Leukemia (CLL) and Indolent Non-Hodgkin Lymphoma (NHL): Results From a Large, Single-Center Observational Study

Context: CLL and indolent NHL are hematologic malignancies that typically result in immune dysfunction. Infection represents a major cause of morbidity and mortality in these patients. Patients with CLL and NHL are at higher risk of hospitalization and death from COVID-19.3 Data is lacking regarding the effectiveness of COVID-19 vaccination in this patient population. Objective: Determine antibody (Ab) response rate (RR) to the COVID-19 vaccination in patients with CLL and indolent NHL. Design: A retrospective, observational study of patients seen between January and October 2021. Updated data was collected until May 27, 2022. Setting: Patients followed in a lymphoma clinic at the Robert H. Lurie Comprehensive Cancer Center. Participants: 398 patients were screened for eligibility. Inclusion criteria were confirmed diagnosis of CLL or indolent NHL, completion of a full vaccination series with either Johnson & Johnson, Moderna, or Pfizer, and Ab testing within 6 months of the initial vaccination series. Main Outcome Measures: SARS-CoV-2 Ab titers were obtained after completion of a full vaccination series and, if applicable, after a third vaccine dose. Ab response was considered positive if either total Ab titer or IgG spike protein Ab was positive. Comparisons were performed using chi-square tests. Results: 240 patients were included in the final analysis. Ab response to the initial vaccination series was 50% (91/181) in CLL and 69% (41/59) in other indolent NHLs. For CLL patients, there was a higher Ab RR in patients receiving the Moderna compared to the Pfizer vaccine (61% vs 44%, p=0.028). Current or prior cancer therapy correlated with a lower Ab RR (36% vs 68%, p<0.0001). Use of anti-CD20 agents in the year prior to vaccination resulted in a lower Ab RR (12% vs 53%, p<0.0001). Of the 71 patients with negative Ab response who subsequently received a third vaccine dose, 38% (27/71) developed a measurable Ab response. Conclusions: Ab RR to COVID-19 vaccination is suboptimal in patients with CLL and indolent NHL, and continued infection precautions should be employed. The Moderna vaccine may provide superior humoral immunity to COVID-19 in patients with CLL. A third vaccine dose increases Ab RR in this patient population.

Longitudinal assessment of quality of life in indolent non-Hodgkin lymphomas managed with active surveillance

There are limited data describing the impact of active surveillance on longitudinal health-related quality of life (HRQoL) in patients with indolent non-Hodgkin lymphomas (NHL). A cohort of untreated indolent NHL patients completed FACT-LYM questionnaires at 6, 12, 18, 24, and 36 months after diagnosis. Longitudinal FACT-LYM scores were analyzed by ANOVA and generalized linear mixed models. Indolent NHL scores were compared to norm general population scores. A total of 52 patients were identified, of which 46 (88%) remained on active surveillance at 36 months. There was no significant change in any of the FACT-LYM scores over 36 months. As compared to the general population, indolent NHL patients had higher, clinically meaningful scores in physical, functional, and social well-being, but not emotional well-being. Patients with indolent NHL on active surveillance have globally preserved HRQoL for up to 3 years after diagnosis. Emotional well-being continues to be an unmet need during active surveillance.

Abstract A32: Copanlisib plus rituximab vs placebo plus rituximab in patients with follicular lymphoma: 1-year follow-up of the Phase III, randomized CHRONOS-3 trial

Abstract Introduction: In the Phase III CHRONOS-3 trial investigating the efficacy and safety of the PI3K inhibitor copanlisib in combination with rituximab (C+R), superior efficacy in progression-free survival (PFS) was demonstrated vs placebo plus rituximab (P+R) in patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL; hazard ratio [HR] 0.52), including in the subset with follicular lymphoma (FL; HR 0.58) (data cut-off Aug 31, 2020) (Matasar et al. Lancet Oncol 2021). Here we report an updated 1-year follow-up analysis for the subset of pts with FL (data cut-off Aug 6, 2021).Methods: Eligible pts with relapsed iNHL who were progression- and treatment-free for ≥12 months (mo) after the last R-containing regimen, or for &amp;gt;6 mo if unwilling/unfit to receive chemotherapy, were randomized 2:1 to C+R or P+R. Treatment continued until progression or unacceptable toxicity. C 60 mg flat dose was administered i.v. on days 1, 8, and 15 (28-day cycle) and R 375 mg/m2 i.v. on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed PFS. Secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), complete response rate (CRR), and treatment-emergent adverse events (TEAEs). As part of biomarker analysis, PTEN expression level was evaluated using immunohistochemistry.Results: The FL subset comprised 275 pts (184 C+R and 91 P+R). C+R reduced the risk of progression or death by 43% vs P+R; median PFS was 23.2 mo (95% confidence interval [CI] 19.2, 33.1) for C+R and 16.6 mo (11.0, 19.6) for P+R (HR 0.57 [95% CI 0.41, 0.80]. ORRs were 85% vs 56% for C+R vs P+R; CRRs were 38% vs 21%. Median DoR was 25.7 mo (17.2, 31.5) for C+R vs 18.2 mo (12.3, 26.3) for P+R (HR 0.75 [95% CI 0.49, 1.14]); for pts achieving a complete response, median DoR was not reached for C+R vs 24.7 mo (10.8, 29.7) for P+R (HR 0.41 [0.19, 0.87]), with DoR rates at 36 months 63% vs 23%. Median OS was not estimable, and no significant benefit was seen for C+R over P+R (HR 0.95 [95% CI 0.52, 1.74]). Hyperglycemia (76%), hypertension (54%), and decreased neutrophil count (38%) were the most common TEAEs in the C+R arm, consistent with the study population. Grade 5 events occurred in 5 pts (3%) in the C+R arm; 1 (1%) was deemed treatment-related. Of 119 pts with FL who were evaluable for PTEN analysis, 41 (34%) were positive. Percent PTEN positivity was not correlated to best overall response (p=0.44) or responsiveness (p=0.08). Median PFS was improved in PTEN-negative pts regardless of treatment. PTEN-positive pts had improved PFS with C+R vs P+R (p=0.005).Conclusion: Pts with FL from the CHRONOS-3 trial continued to show superior efficacy with C+R vs P+R and an acceptable safety profile 1 year after the primary disclosure, supporting the long-term use of C+R in pts with relapsed FL. Exploratory analysis suggests pts with PTEN-positive disease may experience significant benefit with C+R. Citation Format: Marcelo Capra, Fangfang Lv, Wei Li, Tongyu Lin, Eduardo Yañez, Jifeng Feng, Aryan Hamed, Xiaoling Li, Toshiki Uchida, Ming-Chung Wang, Koji Izutsu, Antonio Salar, Katya Sapunarova, Guray Saydam, Jan Zaucha, Lidia Mongay Soler, Shalini Chaturvedi, Anjun Cao, Barrett H Childs, Pier Luigi Zinzani, Matthew J Matasar. Copanlisib plus rituximab vs placebo plus rituximab in patients with follicular lymphoma: 1-year follow-up of the Phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A32.

Abstract A25: Copanlisib population pharmacokinetics (popPK) and exposure-response (ER) in relapsed indolent non-Hodgkin lymphoma (iNHL): Analysis from the 1-year follow-up of the phase III, randomized CHRONOS-3 trial

Abstract Introduction: CHRONOS-3 randomized patients (pts) with relapsed iNHL to the PI3K inhibitor copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle in combination with standard rituximab (C+R) or placebo plus rituximab (P+R) and demonstrated superior progression-free survival (PFS) of C+R vs. P+R (hazard ratio[HR]: 0.52; Matasar et al. Lancet Oncol 2021). In an updated 1-year follow-up analysis, the benefit of C+R was confirmed in the overall relapsed iNHL population (Zinzani et al., EHA 2022) and in the subset of pts with FL (see Capra et al. AACR Lymphoma 2022 abstract). We investigated popPK and ER relationships for copanlisib efficacy and safety from a pooled analysis, with a particular focus on the 1-year follow-up of CHRONOS-3 to confirm copanlisib dose selection. Methods: A comprehensive popPK model for copanlisib was developed using plasma concentrations from 712 pts across 9 copanlisib clinical Phase 1-3 studies. Demographic, laboratory, and comedication covariates were investigated for their influence on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates for pts enrolled in CHRONOS-3 were derived to investigate relationships to efficacy (PFS, overall response rate [ORR], complete response [CR]) and key treatment-emergent safety events using multivariate cox proportional hazards (CPH) and logistic regression analyses, after accounting for predefined potentially prognostic demographic, laboratory, and/or disease related baseline covariates. Results: Copanlisib PK was best described by a 3-compartment PK model with first-order elimination from the central compartment following intravenous infusion. Copanlisib PK was dose proportional and time independent with no accumulation. Covariates statistically selected as influencing copanlisib PK included rifampin (strong CYP3A inducer) and itraconazole (strong CYP3A inhibitor) co-administration, female sex, Japanese pts, mild or worse hepatic impairment, and a CHRONOS-3 study effect, however all identified covariates, aside from rifampin/itraconazole, had no clinically relevant effect (≤ 35%) on copanlisib AUC. In CHRONOS-3, CPH analyses demonstrated a statistically significant positive ER relationship for PFS where greater copanlisib exposure was associated with prolonged PFS. Relative to P+R, the HR for C+R at the 5th and 95th percentile of copanlisib time-varying exposure was 0.875 and 0.217, respectively. Thus, lower copanlisib doses may result in reduced efficacy in relapsed iNHL. CPH and/or logistic regression analyses demonstrated no significant ER relationship for ORR and investigated adverse events. Based on the modelling, lower starting doses of copanlisib are not anticipated to improve safety and tolerability. The ER analyses support the overall positive benefit/risk assessment of copanlisib reported from the clinical efficacy and results of CHRONOS-3 in iNHL. Conclusions: PopPK and ER analyses support copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle dose selection in the relapsed iNHL population. Citation Format: Jonathan Moss, Dirk Garmann, Rupert Austin, Florian Hiemeyer, Patricia DeLora, Matthew J Matasar, Pier Luigi Zinzani, Vita Beckert, Lidia Mongay Soler, Barrett H Childs, Peter N Morcos. Copanlisib population pharmacokinetics (popPK) and exposure-response (ER) in relapsed indolent non-Hodgkin lymphoma (iNHL): Analysis from the 1-year follow-up of the phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A25.

Immuno-PET Imaging and Radioimmunotherapy of Lymphomas.

Monoclonal antibodies (Ab) have revolutionized the management of lymphomas, the most common hematologic malignancy in adults. Indeed, incorporation of rituximab into the regimen for indolent non-Hodgkin's lymphomas (NHLs) has dramatically improved treatment response and disease outcome. Yet, newer Ab therapeutics against promising antigen targets need to be developed to treat refractory or relapsed patients. Treatment efficacy can be further enhanced by conjugating toxic molecules to the Abs. Radioimmunotherapy (RIT) harnesses Abs as vehicles for targeted delivery of therapeutic radionuclide payloads for direct killing of targeted tumor cells. Positron emission tomography (PET) with radiolabeled Abs (called immuno-PET) can facilitate the development of new Ab therapeutics and RIT by providing pharmacokinetic and pharmacodynamic information and by quantifying tumor antigen level relevant for treatment decision. Immuno-PET has recently gravitated toward labeling Abs with 89Zr, a radiometal with a 3.3 day half-life that is trapped following Ab internalization and thus provides high-resolution PET images with excellent contrast. Immuno-PET methods against major lymphoma antigens including CD20 and other promising targets are currently under development. With continued improvements, immuno-PET has the potential to be used in lymphoma management as an imaging biomarker for patient selection and assessment of treatment response.

Axicabtagene ciloleucel for the treatment of relapsed or refractory follicular lymphoma

ABSTRACT Introduction Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that was recently approved for relapsed or refractory follicular lymphoma following progression on two or more lines of therapy including an anti-CD20 monoclonal antibody with an alkylating agent, providing a therapeutic breakthrough in a subset of indolent non-Hodgkin lymphoma associated with poor clinical outcomes. Areas covered In this article, we outline the drug profile of axicabtagene ciloleucel in comparison to currently approved agents and other CAR T-cell and T-cell redirecting therapies under investigation for the treatment of relapsed or refractory follicular lymphoma. We also review the efficacy, safety, and pharmacokinetic data from the ZUMA-5 phase II trial, which forms the basis of the recent approval of axicabtagene ciloleucel. Expert opinion Axicabtagene ciloleucel is the first cellular therapy approved for relapsed or refractory follicular lymphoma, demonstrating high rates of durable responses and a manageable toxicity profile in heavily pre-treated patients.

Obinutuzumab in the treatment of B-cell malignancies: a comprehensive review.

The type II anti-CD20 antibody obinutuzumab has structural and mechanistic features that distinguish it from the first anti-CD20 antibody, rituximab, which have translated into improved efficacy in phase III trials in indolent non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL). These gains have been shown through improvements in, and/or increased durability of, tumor response, and increases in progression-free survival in patients with CLL or follicular lymphoma (FL). Ongoing research is focusing on the use of biomarkers and the development of chemotherapy-free regimens involving obinutuzumab. phase II trials of such treatment regimens have shown promise for CLL, FL and mantle cell lymphoma, while phase III trials have highlighted obinutuzumab as the antibody partner of choice for novel agents in first-line CLL treatment.

Rituximab plus cladribine versus R-CHOP in frontline management of marginal zone lymphoma in China: a propensity-score matched multicenter study.

Marginal zone lymphoma (MZL) is an uncommon subtype of non-Hodgkin lymphoma (NHL). Combination of rituximab and cladribine (R-2CdA) is a potential option for indolent NHL (iNHL) and mantle cell lymphoma (MCL) patients. The goal of this multicenter retrospective study was to assess the efficacy and safety of R-2CdA in MZL to support consensus-reaching in first-line therapy in advanced-stage patients. We searched electronic medical records databases of eight centers in China. Between November 2014 and December 2019, 183 symptomatic advanced MZL patients (42 treated with R-2CdA and 141 with rituximab plus cyclophosphamide, adriamycin, vincristine, and prednisone [R-CHOP]) were identified. After propensity score matching (PSM) (1:1) to adjust for clinical characteristics, 39 patients from each treatment arm were selected. The overall response rate (ORR) (84.6% vs. 94.9%, P = 0.263) and complete response rate (59.0% vs. 66.7%, P = 0.487) were comparable between two protocols. Neither progression-free survival (PFS), including the 5-year PFS (67.7% vs. 56.1%, P = 0.352), nor overall survival was improved by R-2CdA versus R-CHOP. However, R-2CdA was more tolerable than R-CHOP in MZL patients regarding grade 3/4 hematological adverse events (odds ratio [OR] 0.565, 95% confidence interval [CI] neutropenic fever (OR 0.795, 95% CI 0.678-0.932), and infections (OR 0.800, 95% CI 0.640-1.000). Overall, our study demonstrated that R-2CdA is potentially as effective as but safer than R-CHOP in advanced MZL.

Current status of phosphoinotiside-3 kinase inhibitors in blood cancers.

Treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) underwent paradigm shifts, with targeted agents rapidly displacing chemotherapy. Phosphoinotiside-3 kinase (PI3K) is essential for survival and proliferation of neoplastic B cells and has proven a tractable target in NHL, with four agents receiving FDA approval in the last decade. This review summarizes key data and challenges associated with use of PI3K inhibitors in routine practice. Idelalisib and duvelisib are active in CLL and indolent NHL, including in patients with high-risk features. Despite differential targeting of PI3K isoforms, they exhibit comparable efficacy and adverse event profile including autoimmune events (transaminitis, colitis, pneumonitis), mediated by Treg/Th17 imbalance. Although copanlisib, a pan-PI3K inhibitor, is associated with a distinct safety profile (hyperglycemia, hypertension), preclinical studies indicate that umbralisib, a dual inhibitor of PI3Kδ and casein kinase 1ε, may have less effect on Tregs. However, both drugs may still cause immune-mediated toxicities. With close monitoring and management of adverse events, PI3K inhibitors continue to have a role in therapy of R/R CLL and NHL. Strategies to mitigate adverse events and increase efficacy of PI3K inhibitors include time-limited combination approaches, intermittent dosing schedules.

A phase I/II study of 10-min dosing of bendamustine hydrochloride (rapid infusion formulation) in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, mantle cell lymphoma, or relapsed/refractory diffuse large B-cell lymphoma in Japan

PurposeThis phase I/II clinical study was conducted to examine the safety, tolerability, pharmacokinetics, and efficacy of 10-min dosing of bendamustine in patients with previously untreated indolent B-cell non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL) (Group 1) and patients with relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) (Group 2).MethodsRituximab 375 mg/m2 was administered intravenously every 28 days to Group 1 patients on day 1 and every 21 days to Group 2 patients on day 1. Bendamustine 90 mg/m2/day was administered to the former on days 1 and 2; bendamustine 120 mg/m2/day was administered to the latter on days 2 and 3. Each regimen was delivered up to six cycles for both groups. The primary endpoints were safety and tolerability in Groups 1 and 2, respectively.ResultsAmong 37 enrolled patients, safety was assessed in 36. In Group 1 (n = 30), 27 patients (90%) had follicular lymphoma. Adverse events (AEs) were observed in all 30 patients in Group 1. Dose-limiting toxicities were observed in two of six patients in Group 2. Common AEs included lymphocyte count decreased (86.7%, 100%). In Group 1, overall response and complete response rates were 93.1% (95% confidence interval [CI] 77.2–99.2%) and 75.9% (95% CI 56.5–89.7%), respectively. The Cmax and AUC of bendamustine tended to be higher in Group 2 than in Group 1.ConclusionsThis study showed that bendamustine is safe, well-tolerated and effective for patients with previously untreated iNHL, MCL or rrDLBCL. Pharmacokinetic data were equivalent to those obtained outside of Japan.Registration numbersRegistration NCT03900377; registered April 3, 2019.

PB2080: EFFICACY AND SAFETY OF BENDAMUSTINE-BASED REGIMENS AS FIRST-LINE TREATMENT FOR INDOLENT B-CELL NON-HODGKIN LYMPHOMA: A PROSPECTIVE, MULTICENTER, REAL-WORLD STUDY IN CHINA

Background: Indolent non-Hodgkin lymphoma is typically responsive to initial immune-chemotherapy, but it is also prone to persistent recurrence. Bendamustine, an alkylating agent with properties of a purine analog, has been approved for first-line treatment of indolent non-Hodgkin lymphoma in Japan. Although China has approved the second-line treatment of bendamustine for indolent B-cell non-Hodgkin lymphoma in 2019, evidence of bendamustine as first-line treatment for this patient population in China is still scanty currently. Aims: To evaluate the efficacy and safety of bendamustine-based regimens as first-line treatment for Chinese patients with indolent B-cell non-Hodgkin lymphoma in real-world setting. Methods: Treatment-naïve patients with indolent B-cell non-Hodgkin lymphoma were enrolled in this prospective, multicenter, single-arm, real-world study (ChiCTR2000039605). Eligible patients will be given 4-6 cycles (4 weeks/cycle) of bendamustine-based regimens including bendamustine monotherapy (90 mg/m2 on Day 1-2), bendamustine (90 mg/m2 on Day 1-2) plus rituximab (375 mg/m2 on Day 1), bendamustine (70 mg/m2 on Day 1-2) plus rituximab and cytarabine (500 mg/m2 on Day 2-4), or bendamustine (90 mg/m2 on Day 1-2) plus rituximab and bortezomib (1.6 mg/m2 on Day 1, 8 and 15). Tumor response was assessed by independent central review according to Lugano 2014 response criteria. Primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR) and safety. Results: Between December 2019 and February 2022, 29 patients were enrolled in this study. The median age of the 29 patients was 63.0 years (range, 35.0-83.0 years). Majority of patients were female (17/29, 58.6%), had stage II-IV disease (23/29, 79.3%), had an International Prognostic Index (IPI) score of 0-2 (20/29, 69.0%), and had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (21/29, 72.4%). Sixteen patients (55.2%) completed 6 cycles of treatment, and 22 patients (75.9%) completed 4-6 cycles of treatment. Of the 29 patients, 19 (65.5%) achieved a complete response, 5 (17.2%) achieved a partial response, 1 (3.5%) had a stable disease, and 4 unknown (13.8%). The ORR and DCR were 82.8% (95% CI, 64.2-94.2%) and 86.2% (95% CI, 68.3-96.1%), respectively. Hematological and non-hematological adverse events were reported in 75.9% and 17.2% of patients, respectively. Summary/Conclusion: Bendamustine-based regimens as first-line treatment were effective and well-tolerated in patients with indolent B-cell non-Hodgkin lymphoma, suggesting that this first-line regimen might offer a potential therapeutic option for this patient population in China.

P1103: INMIND: A PHASE 3 STUDY OF TAFASITAMAB PLUS LENALIDOMIDE AND RITUXIMAB VERSUS PLACEBO PLUS LENALIDOMIDE AND RITUXIMAB FOR RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA (FL) OR MARGINAL ZONE LYMPHOMA (MZL)

Background: Patients (pts) with indolent non-Hodgkin lymphoma (NHL) subtypes FL or MZL respond to first-line treatment but relapse is common; there is no standard treatment for pts with relapsed/refractory (R/R) FL or MZL. Tafasitamab (TAFA) is an Fc-engineered humanized monoclonal antibody (mAb) against CD19, which is broadly expressed in FL and MZL and regulates proliferation via B-cell receptor signaling. In preclinical studies, TAFA has shown activity against NHL cell lines in combination with rituximab (anti-CD20 mAb) and lenalidomide (LEN). TAFA monotherapy demonstrated promising clinical activity in a phase 2a study in pts with R/R NHL (NCT01685008), with an ORR of 29% (n/N=10/34) in pts with FL and 33% (n/N=3/9) in pts with MZL. In an ongoing phase 2, single-arm study (L-MIND, NCT02399085), TAFA + LEN followed by TAFA alone demonstrated an ORR of 57.5% (n/N=46/80) with CR of 40% (n/N=32/80) and median DOR of 34.6 mo (95% CI: 26.1–NR), in pts with R/R diffuse large B-cell lymphoma (FDA approved indication). These observations suggest a potential clinical benefit of TAFA + LEN and rituximab for pts with R/R FL or MZL. Aims: Phase 3 double-blind, placebo-controlled, randomized study designed to investigate whether TAFA + LEN and rituximab provides improved clinical benefit compared with LEN and rituximab in pts with R/R FL or MZL. Methods: Pts will be randomized 1:1 to receive TAFA (12 mg/kg IV on days 1, 8, 15, and 22 of 28-day cycle [cycles 1–3], then days 1 and 15 [cycles 4–12]) + LEN (20 mg PO QD [or starting dose 10 mg PO QD if creatinine clearance ≥30 to <60 mL/min], days 1–21/cycle for 12 cycles) and rituximab (375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, then day 1 of cycles 2–5), or placebo (0.9% saline solution IV) + LEN and rituximab. Stratification will include progression of disease within 24 mo (FL; yes vs no), refractoriness to prior anti-CD20 mAb therapy (FL; yes vs no), and number of prior lines of therapy (FL or MZL; <2 vs ≥2). Radiological (PET) assessment will be performed at baseline, every 12 (± 2) weeks in year 1, 16 (± 2) weeks in years 2–3, and 24 (± 3) weeks in years 4–6; additional assessment performed within 4 (± 2) weeks if progressive disease confirmed before end-of-treatment (EOT) visit. The primary study endpoint is PFS (investigator assessed [INV] by Lugano 2014 criteria) for pts with FL. Key secondary endpoints are PFS (INV) in the overall population (FL and MZL), PET-CR rate (INV) at EOT (90 days after last treatment) and OS in pts with FL. Other secondary endpoints include PET-CR rate (INV) at EOT and OS in the overall population, and ORR (INV), DOR (INV), health related quality of life, safety, and minimum residual disease-negativity rate at EOT in FL and the overall population. Inclusion criteria include age ≥18 y, histologically confirmed FL (grade 1, 2, or 3a) or MZL (nodal, splenic, or extranodal), documented R/R disease, ≥1 prior systemic anti-CD20 therapy (including anti-CD20 refractory disease), ECOG PS ≤2, adequate systemic organ function, and high tumor burden (per GELF criteria). Exclusion criteria include prior rituximab + LEN treatment, history of radiotherapy for other diseases (≥25% of bone marrow), nonhematologic malignancy, congestive heart failure (LVEF <50%), active systemic infection, known CNS lymphoma, or severe immunocompromised state. inMIND (NCT04680052, EudraCT2020-004407-13) is currently enrolling pts; planned enrollment is 528 pts with R/R FL and 60–90 pts with R/R MZL across North America, Europe, and Asia Pacific. Results: Not applicable. Summary/Conclusion: Not applicable.

P1138: COPANLISIB + RITUXIMAB VS RITUXIMAB + PLACEBO IN PATIENTS WITH RELAPSED INDOLENT NON-HODGKIN LYMPHOMA (NHL): UPDATED SAFETY AND EFFICACY FROM THE PHASE III CHRONOS-3 TRIAL

Background: The Phase III CHRONOS-3 trial of copanlisib plus rituximab (C+R) vs placebo plus rituximab (P+R) in patients (pts) with indolent NHL (iNHL) showed a significant improvement in progression-free survival (PFS; hazard ratio [HR] 0.52; Matasar et al. Lancet Oncol 2021). At the time of data cut-off (August 31, 2020), 23% of pts were ongoing on treatment in the C+R arm and 43% of pts had discontinued treatment and entered active follow-up; corresponding numbers in the P+R arm were 19% and 17%. Aims: Here we report an updated 1-year follow-up analysis of efficacy and safety for all pts from CHRONOS-3 based on a data cut-off of August 6, 2021. Methods: Eligible pts with iNHL who relapsed after the last R-containing regimen and were progression-free and treatment-free for ≥12 months (mo) after the last R-containing regimen, or for >6 mo if unwilling/unfit to receive chemotherapy, were randomized 2:1 to receive C+R or P+R. All pts provided informed consent. Treatment continued until progression or unacceptable toxicity and was administered i.v. on a 28-day cycle, with C 60 mg/P given on days 1, 8, and 15 and R 375 mg/m2 given on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed PFS and secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), complete response rate (CRR), and treatment-emergent adverse events (TEAEs). Results: 307 pts were randomized to C+R and 151 to P+R. As of the August 2021 cut-off, 46 pts (15.0%) receiving C+R and 16 (10.6%) receiving P+R were ongoing on treatment. The most common reason for discontinuation was adverse events (AEs) unrelated to clinical progression (35.8%) for C+R and radiologic progression (49.7%) for P+R. Similar to the initial disclosure, C+R reduced the risk of progression or death vs P+R by 47%, with median PFS of 22.3 mo (95% confidence interval [CI] 19.4, 30.7) for C+R and 13.8 mo (10.8, 17.5) for P+R (HR 0.53 [95% CI 0.41, 0.70]; p=0.000001). PFS benefit was preserved across all cancer subtypes (HR [95% CI]): follicular lymphoma (n=275; 0.57 [0.41, 0.80]); marginal zone lymphoma (n=95; 0.53 [0.28, 0.99]); small lymphocytic lymphoma (n=50; 0.22 [0.10, 0.49]); lymphoplasmacytic/Waldenström macroglobulinemia (n=38; 0.42 [0.15, 1.16]). Updated ORRs were 80.8% vs 49.7% and CRRs were 34.9% vs 14.6% for C+R vs P+R, respectively. Median OS was not estimable and no significant benefit was seen for C+R over P+R, although the risk of death was reduced (HR 0.86 [95% CI 0.55, 1.32]) vs the August 2020 disclosure (HR 1.07 [0.63, 1.82]). Median DoR was 25.7 mo (17.6, 31.5) for C+R vs 17.3 mo (12.6, 25.3) for P+R; for pts with complete responses, median DoR was 42.3 mo (29.2, not estimable) vs 24.7 mo (10.2, 29.7) (HR 0.46 [0.24, 0.87]). Safety profiles for C+R and P+R were mostly unchanged from the initial disclosure, and the most common treatment-related AEs for pts receiving C+R were hyperglycemia (69.4%), hypertension (49.5%), and diarrhea (33.9%). For C+R, 6 additional pts (2.0%) discontinued C due to an AE, bringing the total to 33.2%. The incidence of grade 3/4 treatment-related TEAEs was generally unchanged with the longer follow-up (2 new grade 4 for C+R; 1 new grade 4 for P+R), with no new grade 5 events. Summary/Conclusion: 1 year after the primary disclosure of CHRONOS-3, C+R continued to demonstrate acceptable safety and superior efficacy with durable complete responses vs P+R in pts with relapsed iNHL. These data support the long-term use of C+R in pts with relapsed iNHL.

P1095: TREATMENT ATTRIBUTES FOR 3RD LINE FOLLICULAR LYMPHOMA TREATMENT DECISION-MAKING: PHYSICIAN PERSPECTIVES FROM A SURVEY ACROSS WESTERN EUROPE AND THE UNITED STATES

Background: Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL), and is the most common of the clinically indolent NHLs. Treatment (tx) selection must integrate a myriad of clinical and patient factors, including disease resistance, cumulative toxicities and treatment efficacy, as well as patient quality of life (QoL) and the costs of therapies. However, real-world data regarding physician perspectives on tx selection is lacking, especially at later lines of therapy. Aims: This study aims to assess physician perspectives regarding key tx selection attributes including those beyond efficacy and safety, as well as physician perception of patient’s tx preference, when selecting a 3rd line (3L) FL tx. Methods: Descriptive data were drawn from the Adelphi FL Disease-Specific Programme™, a point-in-time study that was fielded June 2021-Jan 2022. Haematologists, haem-oncologists and medical oncologists (med-onc) in EUR [France, Germany, Italy, Spain, United Kingdom (UK)] and the US completed online surveys regarding self-reported demographics and the top 7 tx attributes contributing to their rationale for 3L FL tx selection from a comprehensive prespecified list of 28 attributes derived from expert opinions. Physicians also provided their perception on patient’s preference regarding tx attributes for choosing 3L tx. Results: Of 251 physicians surveyed in EUR (France: n=46; Germany: n=40; Italy: n=43; Spain: n=41; UK: n=31) and the US (n=50), 49% were haem-oncologists, 41% haematologists and 10% med-oncs. 52% primarily worked at academic hospitals. Progression free survival (74.1%), overall survival (70.1%), duration of response (59.8%), evidence-based efficacy overall / overall response rate (57.4%) and ability to achieve complete response (46.2%) were most frequently physician reported top 7 attributes for 3L tx selection. Notably, long-term safety and impact on patients’ QoL were reported by 38.6% and 34.3% of physicians, respectively. Fewer physicians reported cost (4.8%), patient acceptability of lag time between leukapheresis and CAR-T infusion (7.2%), patient acceptability of frequency of administration (8.0%), less monitoring needed (8.8%) and fewer outpatient / inpatient consultations needed (5.6% and 7.6% respectively) as their top 7 3L tx attributes considered. Frequency of some 3L tx selection attributes reported differed substantially between EUR and the US including long-term safety (35.8% vs 50.0%), impact on patients’ QoL (37.8% vs 20.0%), and suitability for patients aged over 60 years (10.9% vs 22.0%). Summary/Conclusion: Treatment efficacy and improved survival were the most important attributes for physicians’ 3L FL tx selection whilst safety, impact on patient QoL, frequency of inpatient / outpatient consultations, monitoring requirements, and cost were amongst those attributes considered less important by physicians. Despite literature indicating that patient QoL and cost of tx should both be key considerations for physicians when choosing FL tx, our study highlights these are less commonly reported attributes for treatment selection. Future study is warranted to further explore reasons for physician treatment selection.

P1124: MOSUNETUZUMAB RETREATMENT IS EFFECTIVE AND WELL-TOLERATED IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA

Background: The prognosis for heavily pretreated patients (pts) with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) is poor and there is a need for effective treatment options (Batlevi, et al. 2020; Crump, et al. 2017). Mosunetuzumab (M) is a T-cell engaging CD20xCD3 bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells (Sun, et al. 2015; Budde, et al. 2022). Results from a single-arm, Phase I/II study (NCT02500407) of M in pts with R/R aggressive and indolent NHL showed durable complete responses (CR) and a manageable safety profile (Budde, et al. 2022). Specifically, in pts with R/R follicular lymphoma (FL) after ≥2 prior therapies, M demonstrated a 60% CR rate and an 80% objective response rate with a median duration of response (DoR) of 22.8 months (Budde, et al. ASH 2021). Initial M treatment had a fixed duration (8 cycles for pts who achieved CR; 17 cycles for pts with partial response or stable disease after 8 cycles); however, for pts who achieved a CR but had progressive disease (PD) after initial treatment completion, M retreatment could be provided. We report additional data from this ongoing study to describe the M retreatment experience of pts with R/R NHL. Aims: To evaluate the efficacy and safety of M monotherapy (mono) retreatment in pts with R/R NHL from an ongoing Phase I/II study (NCT02500407). Methods: Pts with R/R NHL who achieved CR after initial treatment with intravenous (IV) M mono but subsequently developed PD after treatment completion were eligible for retreatment. Pts were retreated with IV M mono at a previously tested dose and schedule, which included step-up dosing for cytokine release syndrome (CRS) mitigation. All pts provided informed consent. Results: At the clinical cut-off date, March 15, 2021, 12 pts received M retreatment; 6 pts completed retreatment and 6 pts discontinued retreatment (PD, n=5; start of another anti-lymphoma therapy, n=1). M retreatment step-up dose schedules were as follows (Cycle [C] 1, Day [D] 1/C1D8/C1D15/C2D1/C3+D1): 1/2/13.5mg (n=1), 1/2/20mg (n=1), 1/2/27mg (n=1), 1/2/40.5mg (n=1) and 1/2/60/60/30mg (n=8). Median number of M retreatment cycles received was 8.0 (range, 2–13). Overall, 8 pts with R/R FL, 2 pts with R/R diffuse large B-cell lymphoma (DLBCL), 1 pt with R/R transformed FL (trFL) and 1 pt with R/R mantle cell lymphoma (MCL) were included in the analysis. During retreatment, 9 (75.0%) pts had an objective response (6/8 pts with R/R FL; 2/2 pts with R/R DLBCL; 1/1 pt with trFL; and 0/1 pt with MCL; Table). Six/12 pts achieved a CR (4/8 pts with R/R FL, 1/2 pts with R/R DLBCL; 1/1 pt with R/R trFL; and 0/1 pt with MCL). All pts who received M retreatment were included in the safety population and had ≥1 adverse event (AE). The most common any-grade AE and Grade 3–4 AE was hypophosphatemia (n=7, 58.3% [each]; none were serious and all events resolved with or without treatment). Four pts experienced ≥1 serious AE. No Grade 5 events were reported and no pts had an AE that led to treatment discontinuation. Three pts (25.0%) had low-grade CRS (by Lee, 2014; Grade 1, n=2; Grade 2, n=1) and there were no Grade 3–4 CRS events. Image:Summary/Conclusion: Our results show that IV M mono retreatment was efficacious in heavily pretreated pts with R/R NHL who initially achieved a CR with M treatment, but subsequently developed PD. M retreatment had a manageable safety profile, consistent with the initial treatment.

P1156: MAGNIFY PHASE 3B STUDY OF LENALIDOMIDE + RITUXIMAB (R2) FOLLOWED BY MAINTENANCE IN RELAPSED/REFRACTORY INDOLENT NON-HODGKIN LYMPHOMA: COMPLETE INDUCTION PHASE ANALYSIS

Background: Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide combined with rituximab (R2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with iNHL (RELEVANCE: N Engl J Med 2018;379:934 and AUGMENT: J Clin Oncol. 2019;37:1188). Aims: These analyses examine the MAGNIFY interim primary endpoint of overall response rate (ORR; 1999 IWG) for induction R2 in efficacy-evaluable patients receiving ≥ 1 treatment and who have available baseline and post-baseline assessments. Methods: MAGNIFY is a multicenter, phase 3b trial in patients with R/R follicular lymphoma (FL) grades 1–3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. In the induction phase, lenalidomide 20 mg PO on days 1–21 of a 28-day cycle + rituximab IV at 375 mg/m2/week cycle 1 and then every 8 weeks starting with cycle 3 (R2) are administered for 12 cycles. Patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) were randomized 1:1 to R2 vs rituximab maintenance for 18 months. Data presented here are the complete analysis from the induction phase in efficacy-evaluable patients with FL grades 1–3a or MZL (FL grade 3b, tFL, and MCL not included). Results: As of March 5, 2021, 394 patients (318 [81%] FL gr1–3a; 76 [19%] MZL) were enrolled. The median follow-up was 40.6 mo (range, 0.6–79.6). Median age was 66 y (range, 35–91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% (n = 279) with 42% (n = 164) CR/CRu (Table). All patients have completed R2 induction (n = 232, 59%) or discontinued study treatment (n = 162, 41%). 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs) (n = 54, 14%) or progressive disease (n = 42, 11%). The majority of patients who have completed induction have been randomized and entered maintenance (n = 217). Median duration of response in the induction period was not reached (95% CI, 43.9 mo–NR), and median progression-free survival in the induction safety population (n = 393) was 50.5 mo (95% CI, 39.5–NR). Efficacy results are reported in the table by histology subgroups (FL vs MZL), and rituximab-refractory, double-refractory, and early relapse statuses. Most common all-grade treatment emergent AEs (TEAEs) were 47% fatigue, 43% neutropenia, 37% diarrhea, 30% nausea, and 30% constipation. Grade 3/4 AEs occurring in ≥ 5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, and 5% fatigue. TEAEs led to discontinuation of lenalidomide in 19% of patients and rituximab in 12% of patients; reduction or interruption of lenalidomide in 64% of patients; and to interruption of rituximab in 30% of patients (dose reduction for rituximab was not allowed). Neutropenia was the most common TEAE leading to lenalidomide discontinuation in 6% and reduction/interruption in 32%, and rituximab discontinuation in 3%. Infusion-related reaction was the most common TEAE leading to rituximab interruption in 8%. Image:Summary/Conclusion: These data represent complete analysis of all patients in the induction phase of MAGNIFY which continue to support that R2 is active with a tolerable safety profile in patients with R/R FL grade 1–3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients.

Anxiety and Depression in Adults With Congenital Heart Disease.

IntroductionAnxiety and depression can worsen outcome in patients with heart disease. We elucidate the prevalence of anxiety and depression in a cohort of adults with congenital heart disease (ACHD).Materials and MethodsProspective screening for anxiety or depression was performed in 204 consecutive patients of the outpatient clinic of our tertiary care center using the Hospital Anxiety and Depression Scale (HADS) questionnaire and the distress thermometer (DT) as a potential ultra-short screening test. Functional data were assessed at liberty of the responsible physician. HADS scores ≥ 8 were considered doubtful and scores ≥ 11 as confirmed cases of anxiety or depression, respectively. HADS results were compared with a historical group of 100 patients with non-Hodgkin Lymphoma (NHL) as well as German reference values from the literature.ResultsPatients from the ACHD cohort were 28 ± 10 years old (mean ± SD, 54% male), 34% had a simple, 51% a moderate, including 52 patients with transposition of the great arteries after arterial switch operation, and 15% a heart defect of severe complexity. Prevalence of depression in ACHD was comparable to the German normal population (5.9% ACHD vs. 5.4% control). In contrast, prevalence of anxiety was higher than expected from reference values (12.7% ACHD vs. 5.6% control). There was a positive association between psychological distress and NYHA class [anxiety: OR 2.67 (95% CI, 1.50–4.76) p = 0.001; depression: OR 2.93 (95% CI, 1.60–5.35) p = 0.0005], but not with age, gender, or heart defect severity. Percentages of patients with ACHD with anxiety were significantly higher than in a cohort of patients with indolent non-Hodgkin lymphoma (NHL) but comparable to those with aggressive NHL (HADS-A ≥ 11: ACHD 12.7%, indolent NHL 2.2%, aggressive NHL 13.2%; p = 0.037 ACHD vs. indolent NHL; p = 0.929 ACHD vs. aggressive NHL). The distress thermometer screening test had only a fair discriminatory ability (AUC 0.708; p = 0.002) and is therefore of limited usability.ConclusionAdults with congenital heart disease exhibit an increased risk for anxiety disorders independently of the severity of the underlying heart defect. Anxiety prevalence was comparable to a historical cohort of patients with aggressive NHL underlining the importance of a routine screening for psychosocial distress in adults with congenital heart disease.

Abstract LB523: Biomarker assessment of PTEN protein expression and gene expression profiling (GEP) in a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL)

Abstract Introduction: The combination of the PI3K inhibitor copanlisib (C) plus the anti-CD20 antibody rituximab (R) has been shown to be superior to R plus placebo (P) in patients with relapsed iNHL (Matasar et al. Lancet Oncol 2021). We report here the biomarker analysis to assess correlation with response of baseline samples for PTEN expression and GEP signatures. Methods: Adult patients with relapsed B-cell iNHL were randomly assigned 2:1 to either C + R or P + R; standard dosing on a 28-day cycle applied. Either fresh or archival tumor tissues were collected for central pathology review and biomarker analysis. Extraction of the formalin-fixed, paraffin-embedded (FFPE) tissue slides was performed using the Qiagen AllPrep DNA/RNA FFPE Kit, where quality was assessed using a combination of Agilent TapeStation for integrity and ThermoFisher NanoDrop for quantity and purity. Immunohistochemistry (IHC) for PTEN expression was performed by Mosaic Laboratories (Lake Forest, CA, USA) and RNA sequencing analysis was performed by Almac Diagnostics (Durham, NC, USA). GEP was also conducted using claraT pathway signatures provided by Almac. Results: Patients with complete, very good partial, and partial objective responses were combined in a “responders” group and compared against all other patients (“non-responders” group). Data from PTEN IHC were available for 222 patients (149 for C + R; 73 for P + R). There was no statistically significant difference in response with PTEN presence or absence for the 3 subgroups - total iNHL, follicular lymphoma (FL), and non-FL. Also, baseline PTEN expression did not show significant correlation with best overall response. C + R treatment improved median progression-free survival (PFS) for all patients, with a statistically significant benefit to those with PTEN presence in all 3 subgroups. For patients treated with P + R, Kaplan-Meier plots and log-rank tests showed statistically improved median PFS in patients with PTEN absence vs PTEN presence in overall iNHL (p=0.031) and FL (p=0.0021). Data from GEP were available for 202 patients (133 for C + R; 69 for P + R). The association with best overall response and PFS was analyzed using specific biomarker gene sets and/or 23 preselected clinical parameters. Association of GEP analysis based on hypothesis-based modeling, single-gene hypothesis-free modeling, and claraT pathway signatures showed no predicted responsiveness or PFS that was statistically significant. Conclusions: C + R improved median PFS in the overall iNHL, FL, and non-FL groups, with a statistically significant improvement in the PTEN-positive population. In the P + R group, PTEN-positive patients had worse PFS in all 3 subgroups. Data from GEP and pathway analysis did not show correlation with overall response or PFS. Citation Format: Shalini Chaturvedi, Anke Schulz, Lidia Mongay Soler, Barrett H. Childs, Matthew Matasar, Pier Luigi Zinzani. Biomarker assessment of PTEN protein expression and gene expression profiling (GEP) in a phase III study of copanlisib in combination with rituximab in patients with indolent non-Hodgkin lymphoma (iNHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB523.