Follicular Lymphoma Grade Research Articles

ZUMA-22: A phase 3, randomized controlled study of axicabtagene ciloleucel (axi-cel) versus standard-of-care therapy in patients with relapsed or refractory (R/R) follicular lymphoma (FL).

TPS7579 Background: Patients with R/R FL experience progressively shorter remissions with each successive line of therapy, and the disease is largely considered incurable (Batlevi et al. Blood Cancer J. 2020). Patients who relapsed < 24 months after initiating first-line chemoimmunotherapy (POD24) have inferior overall survival compared with those who did not experience POD24 (Casulo, Barr. Blood. 2019). However, outcomes of R/R FL have improved with the introduction of novel options including chimeric antigen receptor (CAR) T-cell therapy, a highly effective approach with potential to change the treatment paradigm (Jacobson et al. Lancet Oncol. 2021; Freedman, Jacobson. Am J Hematol. 2020). Axi-cel, an autologous anti-CD19 CAR T-cell therapy, is approved for the treatment of R/R FL. In ZUMA-5, a single-arm, Phase 2 study of axi-cel in indolent non-Hodgkin lymphoma, patients with FL (n = 127) had a median progression-free survival of 40.2 months and median overall survival not yet reached after median follow-up of 41.7 months, with manageable long-term safety (Neelapu et al. ASH 2022. Abstract 4660). In ZUMA-5, POD24 did not adversely affect progression-free survival or overall survival. ZUMA-22 is a Phase 3, open-label, multicenter, randomized controlled trial that will evaluate the efficacy and safety of axi-cel compared with standard-of-care therapy in patients with R/R FL. Methods: The study will enroll approximately 230 adult patients with FL (Grades 1-3a) who have either had 1 prior line of therapy and experienced POD24 or had ≥2 prior lines of systemic therapy. Patients will be randomized 1:1 to receive axi-cel or standard-of-care therapy. Patients in the standard-of-care therapy arm will receive investigator’s choice of either rituximab + lenalidomide, rituximab + CHOP, or rituximab + bendamustine. Patients in the axi-cel arm will undergo leukapheresis, followed by optional bridging therapy, lymphodepleting chemotherapy (fludarabine/cyclophosphamide), and a single axi-cel infusion (2×106 CAR T cells/kg). The primary endpoint is progression-free survival by blinded central assessment per Lugano classification (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete and overall response rates, duration of response, overall survival, event-free survival, time to next treatment, safety, and quality-of-life assessments. Additional key inclusion criteria are ECOG 0-1, presence of ≥1 measurable lesion, and adequate bone marrow and organ function. Those with HIV or hepatitis B or C and an undetectable viral load are eligible. Key exclusion criteria are a history of large B-cell lymphoma or transformed FL, and FL Grade 3b. The study is currently open and actively accruing patients at several sites globally (NCT05371093). Clinical trial information: NCT05371093 .

Treatment outcomes of Limited Stage Grade 3A Follicular Lymphoma

Introduction: While radiotherapy is an established standard of care for limited stage, low grade follicular lymphoma (FL), the management of localized FL grade 3A (FL3A) disease remains controversial. We reviewed the outcomes of grade 3A patients treated with definitive RT, combined modality therapy (CMT), or systemic therapy (ST) alone. Methods: We retrospectively analyzed a single institution database to identify newly-diagnosed, grade FL3A patients with Ann Arbor stage I/II disease treated between 2000 and 2021. Patients were stratified by definitive treatment modality including RT monotherapy, CMT, or ST. Best post-RT imaging response was evaluated using Lugano criteria for all by CT, and by PET if available. Rate of complete response (CR) was compared between the three treatment modalities. Progression-free survival (PFS) and Overall survival (OS) were calculated using Kaplan Meier from first day of treatment. Univariable Cox regression was used to assess possible clinicodemographic associations with PFS. Results: 84 patients (median age 62, 38% male) were analyzed with median follow-up of 6.9 years from initiation of treatment. Patients were stage I (73%) or II (27%) and 92% were initially PET staged at diagnosis. 29 (35%) had extranodal disease. The median (IQR) maximum SUV and size prior to treatment were 9.8 (5.4, 14.0) and 3.2 (2.0, 4.5) cm respectively. RT was the most common treatment modality (n = 48, 57%), followed by CMT (n = 21, 25%), then ST (n = 15, 18%). For RT/CMT patients the planned RT dose was most commonly 36 Gy (32%, range 4–40 Gy). 2 patients (3%) received very low dose of 4 Gy. Of the CMT/ST patients the most common regimen was 3–4 cycles of R-CHOP (53%). 3 patients (8%) received Rituximab alone. Compared to RT patients, ST patients were most likely to have been diagnosed after 2010 (p = 0.002) and have stage II disease (p < 0.001), while CMT patients were more likely to be female (p = 0.03) and have grade 3 disease not further characterized (p = 0.002). The rates of CR post-treatment were 88% for RT, 100% for CMT, and 87% for ST. Factors significantly associated with PFS univariably included the treatment modality (CMT vs. RT HR 0.30, 95% CI: 0.10–0.91, p = 0.03), and presence of low-grade FL component in the biopsy (HR 3.33, 95% CI: 1.43–7.78, p = 0.005). Age, sex, stage, extranodal status, Ki67 score, size, and SUV were not predictive of PFS. The probability of transformation to DLBCL was 4.2% (95% CI: 1.1%–11%) at 5 years after treatment. Overall survival was excellent for all treatment modalities with median OS of 18 years for CMT, and not reached for RT or ST. Keywords: Combination Therapies, Indolent non-Hodgkin lymphoma, Radiation Therapy Conflicts of interests pertinent to the abstract. A. Zelenetz Consultant or advisory role: ADC Therapeutics, AbbVie, Adaptive Biotechnologies Corp Arvinas, Inc. AstraZeneca BeiGene, Ltd. Bristol-Myers Squibb, Curio Science LLC, Dava Oncology, Genentech, Instituto de Ciencias Integradas, Kyowa Kirin Co., Ltd. MEI Pharma, Inc., Medscape, Oncopeptides, AB Sandoz, Inc., Secura Bio, Inc., Suzhou Liang Yihui Network Science and Technology Company, Limited G. Salles Consultant or advisory role: AbbVie, Aptitude Health, Bayer, BeiGene, Ltd., Bio Ascend, Bristol-Myers Squibb, Celgene, Epizyme, Everest Clinical Research Corporation, GenMab, Genentech, Gilead Pharmaceutical, Incyte, Ipsen, Janssen Pharmaceutical, Nordic Nanovector ASA, s, Inc., Loxo Oncology, Miltenyi Biotec Incorporated, MorphoSys AG, Novartis, Owkin, Inc., Physicians' Education Resource, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Roche, Scientific Education Support Ltd., Takeda Millennium J. Yahalom Consultant or advisory role: Convergent R.N.R Ltd. B. Imber Consultant or advisory role: GT Medical Technologies, Inc.

Real-world early outcomes of axicabtagene ciloleucel for relapsed or refractory (R/R) follicular lymphoma (FL).

7509 Background: Axicabtagene ciloleucel (axi-cel) is an autologous CAR T approved for adult patients (pts) with r/r FL after ≥ 2 lines of systemic therapy. In the primary analysis of the pivotal ZUMA-5 trial, 94% of pts who received axi-cel to treat r/r FL achieved an objective response, with a 79% CR rate (Jacobson et al. 2022). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events occurred in 6% and 15% of pts, respectively. Here, we present the real-world outcomes of pts receiving axi-cel for r/r FL, including those who would have been ineligible for ZUMA-5. Methods: A total of 230 pts from 72 US centers receiving first axi-cel for r/r FL in the real-world setting between March 2021 and October 2022 were identified from the CIBMTR registry. The following pts were excluded: no consent, prior non-transplant cellular therapy, and FL grade 3b or 3a/3b unspecified. Of the 230 pts, 151 pts had post-infusion assessments and were included in the analysis of outcomes. Effectiveness outcomes were ORR, CR, DOR, PFS and OS. Adverse events included CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and prolonged cytopenia. Results: Of the 230 pts, median age was 62 years and 60% were male. Prior to infusion, 98% had an ECOG performance score of 0-1, 33% had elevated LDH, and 66% were chemo-resistant. Clinically significant comorbidities were present in 74% of the pts. Ninety-two (40%) pts would have been ineligible for ZUMA-5, mainly due to comorbidities. Pts had a median of 4 (range 1-13) lines of prior therapy including 14% who also underwent prior ASCT. Median time from leukapheresis to infusion was 28 days (IQR 26-34). 9% of pts received bridging therapy. Outcomes were analyzed among the 151 pts with follow-up (median 6.2 mo). ORR and CR rates were 93% (95% CI 88-97%) and 84% (95% CI 77-89%), respectively. Estimated PFS and OS at 6 mo were 88% (95% CI 81-92%) and 96% (95% CI 91-98%), respectively. Grade ≥ 3 CRS (ASTCT consensus) and ICANS (ASTCT consensus) occurred in 2% (95% CI 0-6%) and 13% (95% CI 8-19%) of pts, respectively. Median cumulative incidence estimates of CRS resolution was 5 days and ICANS resolution was 4 days. Among pts alive at Day 30 (n = 150), 11% experienced prolonged cytopenia (4% neutropenia, 9% thrombocytopenia). PFS and OS at 6 mo were comparable regardless of ZUMA-5 eligibility, while pts eligible for ZUMA-5 had fewer Grade ≥ 3 ICANS (10% vs 16%) and more rapid ICANS resolution (92% vs 71% resolved within 2 weeks). Pts aged ≥ 65 vs &lt; 65 years had comparable effectiveness and safety profiles. Conclusions: This is the first report on axi-cel to treat r/r FL in real-world settings. Despite a broader pt population, early results demonstrate effectiveness and safety profiles consistent with those observed in the ZUMA-5 trial. The intent is to present findings from an updated dataset with longer follow-up at ASCO. Overall, these findings support the continued broad use of axi-cel to treat r/r FL.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma. It is typically an indolent entity, however, patients who progress or relapse within 24 months of front-line immunochemotherapy (ICT), have a poor outcome. Tumor mutational burden (TMB) is defined as the number of somatic mutations/megabase (mut/Mb) and has been proposed as a biomarker for predicting response to immune checkpoint inhibitors in some cancers. This study aimed to explore the role of TMB in FL. Methods: The study included 51 patients with FL grade 1–3a treated with first line ICT (rituximab, R-CHOP, R-CVP or R-bendamustine). TMB was determined in diagnostic lymph node biopsies by Next Generation Sequencing (NGS), using the Oncomine Tumor Mutational Load Assay (Thermo Fisher), which covers 409 genes. Sequencing was performed on the Ion GeneStudio S5 system with >300X mean coverage. In addition, the mutational profile of 27 of the 51 patients was analyzed using a QIAgen custom DNA panel which covered 64 genes frequently mutated in FL. Sequencing was performed using MiSeq (Illumina) with >3000X mean coverage. Variants were analyzed and interpreted for pathogenicity using several databases. Results: Median age at time of treatment was 64 years (mean 62; range 24–83), with 84% of patients diagnosed with stage III-IV disease. All patients presented at least one mutation using the custom panel, and showed a median TMB value of 5.22 mut/Mb (range 1.69–14.66 mut/Mb). The number of mutations identified correlated with TMB value at diagnosis (p = 0.003). We did not find statistically significant differences in clinical parameters according to basal TMB. However, patients harboring the t(14;18)(q32;q21) translocation and patients with mutations in genes involved in migration, had a higher TMB at diagnosis (mean 6.57 vs. 4.18 mut/Mb, p = 0.017; 8.52 vs. 4.74 mut/Mb, p < 0.001, respectively). Moreover, patients with mutations in genes involved in the BCR pathway showed a trend towards a higher TMB (6.79 vs. 4.73 mut/Mb, p = 0.061). Patients were then stratified in two groups according to their basal TMB value, with a cutoff of 8 mut/Mb that corresponded to the upper quartile. The high-TMB group was enriched in patients harboring mutations in BCR signaling pathway or migration genes (p = 0.016, p = 0.009 respectively) and showed a trend towards having the t(14;18) translocation or mTORC1 pathway mutations (p = 0.106, p = 0.144 respectively). Patients in the high-TMB subgroup had a trend towards a longer progression free survival (PFS) (p = 0.17) (Figure 1). 5-years PFS was 88.9% (95% CI: 10.5–70.6) in high-TMB patients and 61.1% (95% CI: 46.0–81.2) in low-TMB patients. The research was funded by: FIS/FEDER PI19/00034, ISCIII Spanish Ministry of Education (FPU21/02671) Keywords: diagnostic and prognostic biomarkers, genomics, epigenomics, and other -omics, indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

HIGH RATE OF METABOLIC COMPLETE RESPONSE AFTER LOW DOSE RADIOTHERAPY AND OBINUTUZUMAB IN EARLY STAGE FOLLICULAR LYMPHOMA: INITIAL RESULTS OF THE GAZAI STUDY (GLA 2018‐3)

Introduction: The FORT trial demonstrated a higher complete remission (CR) rate using 12 × 2 Gy compared to 2 × 2 Gy in Follicular Lymphoma (FL) (67% vs. 47%). This benefit resulted also in an improved progression free survival (PFS). The TROG 99.03 trial and the MIR study showed an improved PFS with the addition of Rituximab to radiation therapy of 30–40 Gy in early stage FL. Preclinical data suggest that the anti-CD20 antibody may act synergistic with radiation therapy and therefore enhance the radiation effect of low dose radiotherapy. The prospective, multicentric phase II GAZAI study of the German Lymphoma Alliance (GLA) investigated the efficacy of low dose radiation therapy (2 × 2 Gy) in combination with the anti-CD20 antibody Obinutuzumab in early stage nodal FL. The primary endpoint was the metabolic complete remission at the end of therapy. Methods: Patients with early stage FL grade 1/2 were recruited in 11 German centers. Ann Arbor stage I or II was confirmed by FDG-PET/CT. Patients received 1000 mg Obinutuzumab flat dose intravenously in weeks 1, 2, 3, 4, 8, 12 and 16. An interim CT scan was performed in week 7 for response evaluation and subsequent treatment planning. Radiation therapy was applied to the initial involved sites (site of diagnostic surgical intervention and PET positive sites) in week 9. The radiation dose was 2 x 2 Gy on two succeeding days. A FDG-PET/CT was performed at the end of therapy in week 18 for evaluation of the metabolic and morphologic response. Minimal detectable/residual disease (MRD) in peripheral blood was monitored at baseline and at week 18 by allel-specific RQ PCR targeting t(14;18) translocations and clonal immunoglobulin heavy chain (IGH) rearrangements. Results: Of 89 patients included in the study, 54 entered the treatment phase showing FDG-PET-positive lymph nodes qualifying for the primary endpoint. At week 18, metabolic CR (Deauville score (DS) <3) was seen in 46/53 patients (87%; one patient only had a CT without FDG-PET). Partial metabolic remission with a DS 3 was seen in 3 patients (6%) and 3 patients showed a DS 4. Morphologic (CT based) CR/CRu according to Cheson 1999 criteria was seen in 21/54 patients (39%) at week 7 and in 49/54 patients (91%) at week 18. Morphologic PR was seen in 17 patients (32%) at week 7 and in 4 patients (7%) at week 18; one patient (2%) showed progressive disease (metabolic and morphologic) outside of the radiation field. 13/54 patients (24%) were initially MRD positive. All but one patient converted to MRD negativity at week 18. Conclusions: Low dose radiation therapy using 2 × 2 Gy in combination with Obinutuzumab is highly effective in early stage FL. Longer follow-up is necessary to investigate if this effectivity also results in a prolonged PFS. Currently, the FORTplus trial is looking for non-inferiority of this regimen in comparison to a conventional radiation dose (12 × 2 Gy) combined with Rituximab. The research was funded by: Roche Pharma Keywords: combination therapies, indolent non-Hodgkin lymphoma, radiation therapy Conflicts of interests pertinent to the abstract K. Herfarth Research funding: Roche Pharma Educational grants: Roche Pharma C. W. Scholz Consultant or advisory role: Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Educational grants: Roche Pharma K. Hübel Consultant or advisory role: Scientific advisory board Roche Pharma Honoraria: Speaker Honoraria Roche Pharma Research funding: Roche Pharma C. Buske Consultant or advisory role: Roche Pharma Honoraria: Roche Pharma Research funding: Roche Pharma J. Dürig Consultant or advisory role: Scientific advisory board Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Educational grants: Roche Pharma G. Lenz Consultant or advisory role: Advisory board Roche Pharma Honoraria: Speakers honoraria Roche Pharma Research funding: Roche Pharma C. Pott Research funding: Roche Pharma M. Dreyling Consultant or advisory role: Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Research funding: Roche Pharma

MOSUNETUZUMAB DEMONSTRATES DURABLE RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: UPDATED ANALYSIS OF A PIVOTAL PHASE II STUDY

MOSUNETUZUMAB DEMONSTRATES DURABLE RESPONSES IN PATIENTS WITH RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA AND ≥2 PRIOR THERAPIES: UPDATED ANALYSIS OF A PIVOTAL PHASE II STUDY

Six-year safety and efficacy results from the CHRONOS-1 study of the PI3K inhibitor copanlisib in patients with relapsed or refractory follicular lymphoma.

7555 Background: The efficacy of copanlisib, an intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor, was demonstrated in the Phase II CHRONOS-1 study in patients with relapsed or refractory indolent B-cell lymphoma (Dreyling et al. J Clin Oncol 2017). Copanlisib was approved by the US Food and Drug Administration in 2017 for the treatment of patients with follicular lymphoma (FL) who have received ≥2 therapies. Here, we describe updated efficacy and safety data from patients with FL at the 6-year follow-up of CHRONOS-1. Methods: CHRONOS-1 included patients with relapsed or refractory indolent FL (grades 1-3a) who had received ≥2 lines of therapy. Copanlisib 60 mg was administered via intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Objective tumor response rate (ORR) was assessed by independent radiologic review (Cheson et al. J Clin Oncol 2007) as the primary efficacy endpoint. Safety analysis included adverse events graded using CTCAE v4.03. Results: 104 patients with FL were treated in CHRONOS-1, of whom 99.0% ( n= 103) discontinued treatment at the time of database cut-off on June 30, 2022. 72% of patients ( n= 75) received ≥1 line of subsequent systemic anti-cancer therapy during follow-up, with 40% receiving a rituximab-based regimen. At the cut-off, ORR (primary endpoint) was 57.7% ( n= 60), with 19.2% ( n= 20) of patients achieving a complete response. Median duration of response was 12.2 months (range 1.1-48.1). Median progression-free survival (PFS) was 11.2 months (range 0.2-51.5) with a median follow-up of 20.7 months (95% confidence interval [CI] 11.5, 31.5); PFS rate was 32% at 2 years. Median overall survival was 46.3 months (range 0.7-82.9) with a total of 56 events and a median follow-up of 82.4 months (95% CI 79.3, 84.9); survival rate was 43% at 6 years. Median duration of treatment was 6.0 months (range 0.23-80.9). No patients experienced transformation to aggressive lymphoma (diffuse large B-cell lymphoma). The primary reasons for stopping treatment included radiologic disease progression (42.3%; n= 44) and adverse events not associated with clinical disease progression (29.8%; n= 31). The safety profile was consistent with the reported 2-year follow-up data (Dreyling et al. Am J Hematol 2020). The most common treatment-emergent adverse events (all grades/grades 3-4) were infusion-related hyperglycemia (50.0%/39.5%), diarrhea (36.5%/8.7%), hypertension (28.8%/23.1%), pyrexia (27.9%/4.8%), and neutropenia (26.0%/23.0%). Conclusions: Copanlisib continued to induce robust response and durable survival in patients with relapsed or refractory indolent FL at 6 years of follow-up. Copanlisib was well tolerated, with no new safety signals and no evidence of malignant transformation. These results further support the long-term use of copanlisib in this patient population. Clinical trial information: NCT01660451 .

MAHOGANY: A phase 3 trial of zanubrutinib plus anti-CD20 antibodies vs lenalidomide plus rituximab in patients with relapsed or refractory follicular or marginal zone lymphoma.

TPS7590 Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in &gt;15 countries, including the United States and European Union, for pts with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab (ZO) vs obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, ZO in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody vs lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1-3A) or MZL, previously treated with ≥1 anti-CD20–based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to ZO (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 years vs &lt; 60 years), number of prior lines of therapy (1-2 vs &gt; 2) and rituximab-refractory status (yes vs no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC), according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 years vs &lt; 60 years) and number of prior lines of therapy (1-2 vs &gt; 2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Clinical trial information: NCT05100862 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients (pts) with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in >15 countries, including the United States and European Union, for pts with relapsed/refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20–based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, zanubrutinib plus obinutuzumab in pts with R/R FL demonstrated deep and durable responses with a favorable safety profile. Methods: MAHOGANY (BGB-3111-308, NCT05100862) is a phase 3 randomized, open-label trial that compares efficacy and safety of a combination of zanubrutinib plus anti-CD20 monoclonal antibody versus lenalidomide plus rituximab in 2 independent cohorts, for pts with either R/R FL or MZL. Key eligibility criteria include histologically confirmed FL (grades 1–3A) or MZL, previously treated with ≥1 anti-CD20-based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, pts will be randomized 1:1 to zanubrutinib plus obinutuzumab (N = 300) and lenalidomide plus rituximab (N = 300). Randomization is stratified by age (≥60 vs. <60 years), number of prior lines of therapy (1–2 vs. >2), and rituximab-refractory status (yes vs. no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC) according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, pts will be randomized 1:1 to zanubrutinib plus rituximab (N = 75) and lenalidomide plus rituximab (N = 75). Randomization is stratified by age (≥60 vs. <60 years) and number of prior lines of therapy (1–2 vs. >2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: BeiGene Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies Conflicts of interests pertinent to the abstract L. Sehn Consultant or advisory role AbbVie, Seattle Genetics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Kite, a Gilead Company, Merck, Teva, TG Therapeutics, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Honoraria: Amgen, AbbVie, Gilead Sciences, Janssen-ORtho, Kite, a Gilead Company, Merck, Roche/Genentech, Seattle Genetics, Teva, AstraZeneca, Incyte, Sandoz-Novartis, Genmab, Celgene/BMS, BeiGene Research funding: Roche/Genentech, Teva C. Sarkozy Consultant or advisory role Janssen, GSK, Incyte, BMS Honoraria: AbbVie Research funding: Roche Educational grants: Roche, Incyte Other remuneration: Incyte A. Salar Consultant or advisory role BeiGene, Roche Research funding: Roche, AbbVie Other remuneration: Kite, a Gilead Company, Janssen J. Trotman Consultant or advisory role BeiGene WM Advisory Board 2022 (uncompensated) Research funding: BeiGene, Janssen, Pharmacyclics, Roche, Celgene/BMS, Selectar P. L. Zinzani Consultant or advisory role Celltrion, Gilead Sciences, Janssen-Cilag, BMS, Servier, Sandoz, MSD, Roche, EUSA Pharma, Kyowa Kirin, Takeda, Secura Bio, TG Therapeutics, Novartis, ADC Therapeutics, Incyte, BeiGene, Novartis J. Zhang Employment or leadership position: BeiGene Stock ownership: BeiGene P. Fustier Employment or leadership position: BeiGene Stock ownership: BeiGene R. Delarue Employment or leadership position: Celgene/BMS, BeiGene Stock ownership: Celgene/BMS, BeiGene L. Nastoupil Consultant or advisory role Sirpant, Iterus Bios Honoraria: Gilead Sciences, Novartis, Janssen Oncology, TG Therapeutics, BMS, ADC Therapeutics, Morphosys, Epizyme, Genmab, Takeda, Genentech/Roche, Caribou Biosciences Research funding: Janssen Biotech, Genentech/Roche, Epizyme, Novartis, IgM Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda, BMS/Celgene Educational grants: Genentech/Roche

Zanubrutinib plus obinutuzumab versus obinutuzumab in patients with relapsed/refractory follicular lymphoma: Updated analysis of the ROSEWOOD study.

7545 Background: In an early-phase study, the combination of zanubrutinib plus obinutuzumab (ZO) was well tolerated and associated with an early signal of efficacy in patients (pts) with follicular lymphoma (FL) (Tam et al. Blood Adv 2020). ROSEWOOD (NCT03332017) is a phase 2, randomized study designed to assess efficacy and safety of ZO vs obinutuzumab (O) in pts with relapsed/refractory (R/R) FL. Here, we present an updated analysis with a median follow-up of 20.2 mo. Methods: Pts with R/R FL (grade 1–3a) who received ≥2 lines of therapy including an anti-CD20 antibody and alkylating agent were randomized 2:1 to receive ZO or O. Zanubrutinib was given at 160 mg twice daily until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and safety. Results: A total of 217 pts were randomized (145 for ZO; 72 for O). Median age was 64 years. Of the 217 pts, 114 (52.5%) had a high Follicular Lymphoma International Prognostic Index (FLIPI) score at screening and 123 (56.7%) pts had high tumor burden criteria according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Median number of prior lines of therapy was 3 (range, 2–11). A total of 114 (52.5%) pts were refractory to rituximab; 214 (98.6%) pts received prior immunochemotherapy. Prior exposure to anticancer drugs included anthracyclines (80.6%), cyclophosphamide (94.0%), and bendamustine (54.8%). ORR was 69.0% (ZO) vs 45.8% (O) ( P = 0.0012). Complete response rate was 39.3% (ZO) vs 19.4% (O); 18-mo DOR rate was 69.3% (ZO) vs 41.9% (O); median PFS was 28.0 mo (ZO) vs 10.4 mo (O) (hazard ratio [HR], 0.50 [95% CI: 0.33, 0.75]; P = 0.0007). Median TTNT was not evaluable for ZO and 12.2 mo for O (HR, 0.34 [95% CI: 0.22, 0.52]; P &lt; 0.0001). Estimated OS rate at 24 mo was 77.3% (ZO) and 71.4% (O), with median OS not reached in either arm. Nonhematologic treatment-emergent adverse events of any grade that occurred more frequently for ZO vs O ( &gt; 5% difference) were petechiae (6.3% vs 0%) and herpes zoster infection (6.3% vs 0%); in contrast, pyrexia (13.3% vs 19.7%) and infusion-related reaction (2.8% vs 9.9%) occurred more frequently in pts on O. When adjusted for duration of treatment exposure, incidences of infection and cytopenia were similar, and incidence of all grades of hemorrhage was 2.4 (ZO) vs 1.3 (O) persons per 100 person-months. Two pts in each treatment group reported major hemorrhage. Incidences of atrial fibrillation and hypertension were low and similar in both treatment arms. Conclusions: ZO demonstrated meaningful activity and a manageable safety profile in pts with heavily pretreated R/R FL, representing a potential novel therapy. Clinical trial information: NCT03332017 .

Follicular lymphoma grade 3B: low grade, high grade or should we skip the grade?

Not available.

Evaluation of 4 prognostic indices in follicular lymphoma treated in first line with immunochemotherapy.

Several clinical risk models have been proposed to predict the outcome of follicular lymphoma (FL). The development of next-generation sequencing technologies has allowed the integration of somatic gene mutations into clinical scores to build genotyped-based risk models, such as the m7-Follicular Lymphoma International Prognostic Index (FLIPI). We explored 4 clinical or clinicogenetic-risk models in patients with symptomatic FL who received frontline immunochemotherapy. Of 191 patients with FL grades 1 to 3a, 109 were successfully genotyped. The treatment consisted of rituximab (R) plus cyclophosphamide, vincristine, and prednisone (R-CVP)/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (72.5%) or R-bendamustine (R-B) (27.5%). The proportion of cases classified as high risk for FLIPI, FLIPI-2, PRIMA-prognostic index, or m7-FLIPI were 39.3%, 14%, 30.3%, and 22%, respectively. No case with low-intermediate FLIPI was upgraded in the m7-FLIPI, but 18 of the 42 high-risk patients with FLIPI were downgraded to low-risk m7-FLIPI. The sensitivity and specificity for the prediction of POD24 were highest for FLIPI. The discrimination between progression-free survival (PFS) and overall survival (OS) was the best for FLIPI (c-index: 0.644 and 0.727, respectively). When analyzed only in patients treated with R-B, m7-FLIPI showed a higher discrimination between PFS and OS. Thus, the FLIPI remains the clinical risk score with higher discrimination in patients with advanced FL treated with immunochemotherapy; however, the performance of the m7-FLIPI should be further investigated in patients treated with R-B.

Classification of indolent B-cell lymphomas

The 5th edition of the WHO classification (WHO-HAEM5) and the International Consensus Classification (ICC) have considerable overlap but also some distinct differences in categorizing indolent B‑cell lymphomas. Most differences with the expected impact on the daily diagnostic routine relate to follicular lymphoma (FL). Grading of FL remains mandatory only in the ICC; adiffuse growth pattern in anFL with > 15 blasts per high-power field (FL grade 3A) is not automatically classified as DLBCL according to WHO-HAEM5, and anFL subtype with unusual morphology (blastoid or large centrocyte) and biology is recognized as an entity only in the WHO-HAEM5. With the exception of B‑prolymphocytic leukemia, which is no longer acknowledged in WHO-HAEM5, there are only minor differences between both classifications and include updated names of entities, improved diagnostic criteria, and upgrades from provisional to definite entities.

Obinutuzumab Can Be Administered as a 90-minute Short Duration Infusion in Patients With Previously Untreated Follicular Lymphoma: GAZELLE End of Induction Analysis.

Obinutuzumab Can Be Administered as a 90-minute Short Duration Infusion in Patients With Previously Untreated Follicular Lymphoma: GAZELLE End of Induction Analysis.

Comparison of first-line treatment with bendamustine plus rituximab versus R-CHOP for patients with follicular lymphoma grade 3A: Results of a retrospective study from the Fondazione Italiana Linfomi.

In the setting of follicular lymphoma (FL), frontline therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) has represented for many years the standard of care for patients with symptomatic advanced disease. More recently, the combination of bendamustine plus rituximab (R-B) has emerged as an alternative therapeutic option. We present a retrospective, multicenter, observational study aimed at comparing outcomes and toxicities observed in 145 patients diagnosed with grade 3A FL treated with a first line therapy in 15 Italian Fondazione Italiana Linfomi centers between the 1st of January 2014 and the 30th of May 2018. Seventy patients were treated with R-B and 75 with R-CHOP. In the R-B group, the median age at the time of diagnosis was 67 years compared with 59 years in the R-CHOP group. Patients in R-B group achieved a similar overall response rate (96% vs. 99%) and a better complete remission rate (87% vs. 80%, p=0.035) compared with patients in R-CHOP group. Progression free survival (PFS) was similar between individual treated with R-CHOP and R-B (48- month PFS 77.7% vs. 76.6% respectively, p=0.745). The overall survival was significantly longer with R-CHOP treatment (HR=0.16; 95% IC, 0.04-0.74; p=0.007); however, no statistical significant difference was observed after adjustment for age. With the limitations of the study design, our results suggest that both R-B and R-CHOP seem to be valid first-line treatment options in FL3A.

Differences in clinical characteristics and outcomes between patients with grade 3a and grades 1–2 follicular lymphoma: a real-world multicenter study

BackgroundThe difference between clinical characteristics and outcomes between follicular lymphoma grade 1–2 (FL1-2) and FL3a defined pathologically remains unclear, resulting in uncertainty how to treat FL3a. However, it may be crucial for clinicians to discriminate grade 3a and grade 1–2 for predicting prognosis and thus making treatment decisions.MethodsWe compared 1403 patients with FL1-2 and 765 patients with FL3a diagnosed between January 2000 and December 2020 from fifteen centers nationwide in China to describe differences in clinical characteristics and outcomes.ResultsCompared with FL1-2 patients, FL3a subgroup had a higher percentage of elderly patients (P = 0.003), and relatively more FL3a patients presented with increased levels of LDH (P < 0.0001) and higher Ki-67 indexs greater than 30% (P < 0.001). More FL3a patients were treated with CHOP ± R (P < 0.0001), and fewer were treated with the watchful-waiting approach (P < 0.0001). The results showed a higher incidence of relapse among FL3a patients, in which more patients underwent histological transformation (HT) when compared to FL1-2 (P = 0.003). 1470 (76.2%) patients of the entire cohort received R-CHOP therapy; survival analysis revealed that FL3a patients had a worse progression-free survival (PFS) rate than FL1-2 patients. Survival of FL3a patients with respect to FLIPI showed an inferior PFS in the intermediate and high-risk groups than FL1-2 patients. FL3a patients had a much worse prognosis than FL1-2 with or without progression of disease within 24 months (POD24). FL3a patients had higher likelihood of lymphoma-related death (LRD, P < 0.05), whereas the rates for non-LRD were comparable.ConclusionIn conclusion, this study demonstrates a marked difference in clinical features and outcomes in FL3a patients compared with FL1-2 patients. The results highlight the need for applying therapeutic approaches distinct from FL1-2 when treating FL3a patients.

Follicular Lymphoma in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms-Updated Classification and New Biological Data.

The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has undergone significant revision. The vast majority of FL (85%) with a follicular growth pattern are composed of centrocytes and centroblasts, harbor the t(14;18)(q32;q21) translocation and are now termed classic FL (cFL). They are set apart from three related subtypes, FL with predominantly follicular growth pattern, FL with unusual cytological features (uFL) and follicular large B-cell lymphoma (FLBCL). In contrast to the revised 4th edition of the WHO classification of haematolymphoid tumors (WHO-HAEM4R), grading of cFL is no longer mandatory. FL with a predominantly diffuse growth pattern had been previously recognized in WHO-HAEM4R. It frequently occurs as a large tumor in the inguinal region and is associated with CD23 expression. An absence of the IGH::BCL2 fusion and frequent STAT6 mutations along with 1p36 deletion or TNFRSF14 mutation is typical. The newly introduced subtype of uFL includes two subsets that significantly diverge from cFL: one with "blastoid" and one with "large centrocyte" variant cytological features. uFL more frequently displays variant immunophenotypic and genotypic features. FLBCL is largely identical to WHO-HAEM4R FL grade 3B and renaming was done for reasons of consistency throughout the classification. In-situ follicular B-cell neoplasm, pediatric-type FL, duodenal-type FL and primary cutaneous follicle center lymphoma are categorized as discrete entities. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of early and systemic follicular lymphoma will be presented.

Lisocabtagene maraleucel in the treatment of relapsed/refractory large B-cell lymphoma.

Lisocabtagene maraleucel (liso-cel) is one of the three US FDA-approved chimeric antigen receptor T-cell therapies for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). TRANSCEND is the landmark trial that led to the approval of liso-cel in the third-line setting for R/R diffuse LBCL, primary mediastinal B-cell lymphoma, follicular lymphoma grade 3B and transformed lymphoma. The TRANSFORM and PILOT studies evaluated the use of liso-cel in the second-line treatment of R/R LBCL. This review details the structure and manufacturing process of liso-cel that make it distinct from other approved chimeric antigen receptor constructs, outlines results from landmark trials of liso-cel in LBCL and discusses liso-cel toxicity.

Progression of follicular lymphoma grade I in the central nervous system

Progression of follicular lymphoma grade I in the central nervous system

Efficacy Analysis of Bendamustine-Based Combination Regimen in Treatment of Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

To investigate the efficacy and safety of bendamustine combined with gemcitabine, vinorelbine，glucocorticoids (BeGEV)±X regimen in treatment of patients with relapsed/refractory non-Hodgkin lymphoma. A total of 18 relapsed/ refractory non-Hodgkin lymphoma patients at the age of 18 years or older hospitalized in the First People's Hospital of Changzhou from March 2020 to March 2021 were selected. They received two or more cycles of BeGEV±X regimen. X could be anti-CD20 monoclonal antibody, PD-1-blocking antibodies, lenalidomide, BTK inhibitor, Bcl-2 inhibitor and so on according to patients' disease feature. The clinical efficacy and adverse effects were observed. In total, 18 patients completed two or more cycles of BeGEV±X regimen, including 14 with diffuse large B-cell lymphoma, one with low-grade follicular lymphoma, one with follicular lymphoma grade 3b, one with angioimmunoblastic T-cell lymphoma and one with peripheral T-cell lymphoma, not otherwise specified. 11 patients were male. The median age of the patients was 64 years old. 17 patients had modified Ann Arbor stage Ⅲ/Ⅳ disease. 13 patients had high- intermediate risk or high risk IPI score, while 15 patients had high-intermediate high risk or high risk NCCN-IPI score. 14 cases had extranodal sites of disease. And 6 cases had bulky disease. 12 patients experienced refractory disease, while 8 patients had received 3 line or more prior treatment. After two or three cycles of chemotherapy, the complete response rate was 6/18, the partial response rate was 3/18, and the objective response rate was 9/18. From the beginning of salvage chemotherapy to the end of follow-up, the median progression-free survival time was 130 days, and the median overall survival was 152 days. The most common grade 3 to 4 adverse events were hematologic toxicities, infection and febrile neutropenia. BeGEV±X is an effective salvage regimen in treatment of patients with relapsed/refractory non-Hodgkin lymphoma, while adverse events such as hematologic toxicities and infection should be closely monitored.