Lenalidomide Plus R-CHOP (R2CHOP) in Patients with DLBCL Is Associated with a Lower Risk of CNS Relapse: Combined Analysis from Two Phase 2 Studies

Abstract Background Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a devastating event occurring in approximately 5% of patients treated with standard R-CHOP (Thanarajasingam et al, ASH 2015, abs 1456). Isolated CNS relapse is associated with significant morbidity and mortality. New treatment regimens with agents that cross the blood-brain barrier (BBB) are needed. The combination of lenalidomide with R-CHOP (R2CHOP) has shown promising results in activated B-cell (ABC) type DLBCL in phase 2 studies and is currently being evaluated in randomized trials. Lenalidomide crosses the BBB and has been demonstrated to have single-agent activity in relapsed CNS lymphoma. Accordingly, the addition of lenalidomide to R-CHOP may decrease the risk of CNS relapse. Here we characterize the combined incidence of isolated CNS relapse in a population of DLBCL patients who received R2CHOP for induction therapy in two independent phase 2 studies. Methods We analyzed the incidence of isolated CNS relapse in patients with histologically-confirmed DLBCL enrolled in two R2CHOP phase 2 trials - one conducted by Mayo Clinic (MC) and the other by Italian Lymphoma Foundation (FIL) - in the context of clinical variables that included age, gender, disease stage, cell of origin, and administration of CNS prophylaxis. We assessed CNS-International Prognostic Index (CNS-IPI) factors (age, stage, lactate dehydrogenase level, ECOG performance status, extranodal sites, adrenal/kidney involvement) and classified patients into groups of low, intermediate, and high risk of CNS relapse. The risk of CNS relapse in R2CHOP-treated patients was then estimated and compared against published rates in RCHOP-treated patients based on CNS-IPI score. Results One hundred thirty-six patients with DLBCL from both cohorts (87 MC patients, 49 FIL patients) were included in this analysis. Mean age was 65 and median follow-up in 104 patients still alive was 48.2 months (range: 2.1-88.5). 61.8% of patients were male; 86.0% had stage III disease or higher; 44.1% had ECOG performance status of 0; cell of origin phenotype by immunohistochemistry according to Hans algorithm was germinal center B-cell (GCB), non-GCB (ABC), and not available in 43.4%, 36.8%, and 19.8%, respectively; 14.7% received intrathecal (IT) methotrexate for CNS prophylaxis per local practice. No patients received intravenous methotrexate. 10.3%, 71.3%, and 18.4% of patients were classified into low, intermediate, and high-risk CNS-IPI groups, respectively. Only one of 136 patients developed isolated CNS relapse, corresponding to an estimated incidence of CNS relapse of 0.007 (0.7%). Conclusions Despite a large proportion of patients with intermediate and high risk of CNS relapse treated in both phase 2 studies, induction therapy with R2CHOP in patients with DLBCL is associated with a lower-than-expected rate of isolated CNS relapse. The latter is unlikely to be explained by use of IT chemotherapy, which is considered to be marginally effective in this setting and was implemented only in a small proportion of patients. This suggests that addition of CNS-penetrating small molecules, such as lenalidomide, to R-CHOP may decrease the risk of CNS relapse. Disclosures Chiappella: Celgene: Speakers Bureau; Teva: Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Amgen: Speakers Bureau. Nowakowski:Morphosys: Research Funding; Celgene: Research Funding; Bayer: Consultancy, Research Funding. Cavallo:Janssen-Cilag: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Vitolo:Takeda: Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures.

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Evaluation of the m7-FLIPI in Patients with Follicular Lymphoma Treated within the Gallium Trial: EZH2 mutation Status May be a Predictive Marker for Differential Efficacy of Chemotherapy

Blood ◽

10.1182/blood-2019-130208 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 122-122 ◽

Cited By ~ 6

Author(s):

Vindi Jurinovic ◽

Verena Passerini ◽

Mikkel Z Oestergaard ◽

Andrea Knapp ◽

Kirsten Mundt ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Chemotherapy Regimen ◽

Performance Status ◽

Predictive Marker ◽

Ecog Performance Status ◽

Advisory Committees ◽

Mutation Status ◽

Prognostic Utility

Introduction : We have previously shown that a clinicogenetic risk model called the m7- Follicular Lymphoma (FL) International Prognostic Index (m7-FLIPI), which includes the mutation status of 7 genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the FLIPI, and the ECOG performance status improves risk stratification in patients with advanced stage FL receiving frontline immunochemotherapy (Pastore, 2015). The m7-FLIPI was trained on a group of patients treated with R-CHOP and validated on an independent cohort treated with R-CVP. The aim of this study was to test the prognostic utility of the m7-FLIPI in patients treated within the GALLIUM trial. The GALLIUM trial enrolled 1202 patients with FL randomized to either receive Rituximab (R)- or Obinutuzumab (GA101, G)-based frontline treatment (Marcus, 2017). The chemotherapy consisted either of CHOP, CVP or Bendamustine and was allocated by the treating study center. All patients had previously untreated FL, advanced stage disease (stage III/IV or stage II with bulky disease) and ECOG performance status 0-2. All patients required treatment according to the GELF criteria. Methods: We performed targeted DNA sequencing of recurrently mutated genes, including the m7-FLIPI genes from diagnostic FL biopsies. We excluded cases with no available biopsies, insufficient DNA quantity/quality, or if patients did not sign informed consent for molecular studies. 418 patients were available for evaluation of the m7-FLIPI. The m7-FLIPI was calculated as previously described (http://www.glsg.de/m7-flipi/). Investigator-assessed progression-free survival (PFS), the primary endpoint in the GALLIUM trial, was the primary endpoint of this analysis. We performed Kaplan-Meier estimation and Cox proportional hazards regression to test the prognostic utility of the m7-FLIPI. The median follow up in the evaluable cohort was 4.7 years. 283 patients (68%) received Bendamustine (140 R, 143 G), 111 (27%) received CHOP (52 R, 59 G), and 24 (6%) received CVP (12 R, 12 G). Results : 104 patients (25%) had high-risk m7-FLIPI. 90 out of 194 patients with high-risk FLIPI (46%) were reclassified as low-risk by the m7-FLIPI. High-risk m7-FLIPI was associated with shorter PFS in the overall cohort (HR 1.52, P=0.030). Likewise, the m7-FLIPI was prognostic in patients treated with R-based regimens (HR 1.67, P=0.037). However, it was not prognostic in patients treated with G-based regimens (HR 1.24, P=0.49). When analyzed by different chemotherapy regimens, the m7-FLIPI was prognostic in patients receiving CHOP/CVP-based treatment (HR 2.05, P=0.013), validating the results from our original publication. The m7-FLIPI outperformed the FLIPI (HR 1.34, P=0.31) and had a significantly higher C-index (m7-FLIPI C=0.69, FLIPI C=0.57, P=0.021). However, the m7-FLIPI was not prognostic in patients receiving Bendamustine-based treatment (HR 1.23, P=0.42). Within the m7-FLIPI, mutations in EZH2 have the highest weight of all gene mutations. In this study, we found EZH2 mutations in 93 cases (22%). EZH2 mutations were associated with longer PFS (HR 0.25, P=0.0036) in CHOP/CVP-treated patients, but not in Bendamustine-treated patients (HR 1.11, P=0.71). Interaction analysis between the chemotherapy regimen and EZH2 mutation status showed a significant interaction term of 1.49 (P=0.011) for EZH2 mutations and Bendamustine. This increased the previously favorable HR in EZH2 unmutated patients (HR 0.55 for Bendamustine vs CHOP/CVP) to an unfavorable HR of 2.42 in EZH2 mutated patients. Overall, patients with EZH2 mutant FL appeared to benefit more from CHOP/CVP, whereas patients without EZH2 mutations had longer PFS with Bendamustine-based regimens, regardless whether chemotherapy was combined with R or G (see Figure). Conclusions: Here, we validated the prognostic utility of the m7-FLIPI for patients treated with R-CHOP/CVP. However, the m7-FLIPI was not prognostic in patients treated with Bendamustine-based regimens. While EZH2 mutation status was associated with longer PFS in patients receiving CHOP/CVP regimens (with either R or G), it did not impact treatment outcome of patients treated with Bendamustine, suggesting that EZH2 mutation status is a predictive marker for differential efficacy of the chemotherapy regimen. If confirmed, the EZH2 mutation status might be a highly useful biomarker to guide the selection of the preferred upfront chemotherapy. Figure Disclosures Oestergaard: F. Hoffmann-La Roche: Employment. Knapp:F. Hoffmann-La Roche Ltd: Employment. Mundt:F. Hoffmann-La Roche: Employment. Fitzgibbon:Gilead: Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Marcus:Roche / Genentech: Honoraria, Speakers Bureau; Gilead: Consultancy. Davies:Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Acerta Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; GSK: Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding. Herold:Roche: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Celgene: Honoraria. Hiddemann:F. Hoffmann-La Roche: Research Funding. Unterhalt:F. Hoffmann-La Roche: Research Funding. Hoster:Roche Pharma AG: Other: Travel support; Janssen: Research Funding. Weigert:Novartis: Research Funding; F. Hoffmann-La Roche: Research Funding.

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Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Treatment in Dual Expressor Diffuse Large B-Cell and Double/Triple Hit Lymphomas: TP53 Mutations Influence on Clinical Outcome

Blood ◽

10.1182/blood-2019-124350 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4116-4116

Author(s):

Anna Dodero ◽

Anna Guidetti ◽

Fabrizio Marino ◽

Cristiana Carniti ◽

Stefania Banfi ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

Tp53 Mutation ◽

Advisory Committees ◽

Tp53 Mutations ◽

Travel Costs ◽

Large B Cell

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

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Variation in Health-Related Quality of Life by ECOG Performance Status and Fatigue Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.4591.4591 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4591-4591 ◽

Cited By ~ 1

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Clinical Practices ◽

Employment Equity ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership ◽

Ecog Ps ◽

The Impact

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Blood ◽

10.1182/blood-2021-152603 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 623-623

Author(s):

Bradley M. Haverkos ◽

Onder Alpdogan ◽

Robert Baiocchi ◽

Jonathan E Brammer ◽

Tatyana A. Feldman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Lymphoma ◽

Phase 2 ◽

Advisory Committees ◽

Phase 1B

Abstract Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from <1 to 90% in 42 tumor biopsies with central lab review. The most common treatment-emergent adverse events (TEAEs) of all grades were nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3/4 TEAEs in >10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

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A Phase IB Study of Blinatumomab (blina) in Patients with B Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (allo-BMT) Remission Maintenance

Blood ◽

10.1182/blood-2019-128255 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 778-778

Author(s):

Jonathan Webster ◽

Richard F. Ambinder ◽

Richard J. Jones ◽

Nina D. Wagner-Johnston ◽

Gabrielle T. Prince ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Phase Ib ◽

Post Transplant ◽

Non Hodgkin Lymphoma ◽

Remission Maintenance

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, long term survival is limited by transplant-related toxicity and particularly by disease relapse. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates the use of alternative allograft sources. Moreover, following PTCy, cellular immune reconstitution is favorable for the integration of strategies to augment anti-tumor immunity. Blina, a CD19/CD3 bispecific T cell engager antibody construct, is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance established posttransplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. Thus, we have undertaken a phase Ib trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL. Methods: Patients ³18 years-old with high risk CD19+ B ALL or NHL who underwent alloBMT using PTCy were eligible including those with prior blina exposure. Patients had to be 60-180 days from transplant with documented count recovery and no evidence of disease progression. Patients had to be off all post-transplant immunosuppression including steroids for the treatment of GVHD for ≥4 weeks prior to treatment initiation, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Patients could receive two cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received only one cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28. Results: As of July 23, 2019, 12 adults (10 males/2 females) have enrolled including 4 patients with B ALL and 8 patients with NHL. Among the B ALL patients, two with known TP53 mutations were transplanted in CR1, while two with relapsed disease were transplanted in CR3. Among the NHL patients, five had large cell transformation (3 from follicular and 2 from CLL); one had relapsed primary CNS lymphoma (PCNSL); one had relapsed mantle cell lymphoma (MCL); and one had diffuse large B cell lymphoma (DLBCL). The median age was 53 (range, 30-73). All patients underwent alloBMT using a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation (TBI). Eight patients received allografts from haploidentical donors, three from matched-unrelated donors, and one from a matched-related donor. Five patients received peripheral blood allografts, and seven bone marrow. Two patients were enrolled after a second alloBMT, and 3/4 ALL patients previously received blina. Baseline characteristics are presented in Figure 1. Patients started blina a median of 144 days post-transplant (range, 90-180). One patient stopped treatment on day 5 due to a grade 2 tremor, and one patient required dose reduction on day 25 due to grade 4 neutropenia. Toxicities were otherwise mild and are presented in Figure 2. There were no exacerbations of GVHD. At a median follow-up of 13.7 months after BMT (range 3.8-23 months), ten patients remain in remission, while one patient suffered a third CNS relapse of ALL at 20.6 months after his 2nd transplant and another had relapse of his transformed lymphoma. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented. Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity. 83% of the very high risk patients treated on study remain in CR at a median of 13.7 months post-transplant. Based on promising safety and efficacy data from the phase IB, the plan is to proceed to the phase II portion of the study. Disclosures Webster: Amgen: Consultancy; Genentech: Research Funding; Pfizer: Consultancy. Wagner-Johnston:Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents & Royalties: Patent holder. Gojo:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Research Funding; Jazz: Consultancy, Honoraria; Amgen Inc: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Amphivena: Research Funding. OffLabel Disclosure: Blinatumomab is not labeled for use as post-transplant maintenance therapy or for use in the non-Hodgkin lymphoma.

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The Absolute Number of Extranodal Sites Detected By PET-CT Is a Powerful Predictor of Secondary Central Nervous System Involvement in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP

Blood ◽

10.1182/blood.v126.23.3905.3905 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3905-3905 ◽

Cited By ~ 1

Author(s):

Chan Yoon Cheah ◽

Martin Hutchings ◽

Kirsty Rady ◽

Kerry J. Savage ◽

Musa F. Alzahrani ◽

...

Keyword(s):

Regression Analysis ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

B Cell Lymphoma ◽

Absolute Number ◽

Competing Risk ◽

Advisory Committees ◽

Cns Relapse ◽

Pet Ct

Abstract Background Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an infrequent but devastating complication. The German Risk model which includes the 5 IPI risk factors plus involvement of the kidneys has been validated in 2 large independent cohorts (Schmitz, ICML 2013; Savage, ASH 2014; El-Galaly, ICML 2015). In this model, the presence of >1 extranodal site of involvement contributes only 1 point. However, the precise impact of the extent of extranodal disease in PET-CT staged patients is unknown. Patients and Methods We identified patients with newly diagnosed DLBCL presenting to hospitals in Denmark, Canada, the United Kingdom and Australia through systematic searches of national/local lymphoma registries. Inclusion criteria were: staging included PET-CT, primary treatment with R-CHOP or similar regimen ± CNS prophylaxis. Patients treated with high-dose regimens (such as R-HyperCVAD) and those with CNS involvement at diagnosis were excluded. Medical records and PET-CT reports were reviewed for clinical information and outcome. Multiple lesions in one organ or set of paired organs/ tissue were counted as a single extranodal site, and the spleen and Waldeyer's ring were not included as extranodal sites. Time to CNS relapse was determined using the method of Kaplan and Meier, with univariate analysis of absolute number of extranodal sites associated with CNS relapse performed using competing risk regression with death before CNS relapse as competing risk. Multivariate analyses (adjusted for elevated LDH, age>60 y and performance status>1) were performed using Cox proportional hazards to identify the specific increase in risk attributable to the absolute number of extranodal sites of involvement. Involvement of the kidney/adrenals and advanced disease stage were not included in the adjustment because of their intrinsic relationship to number of extranodal sites. Results 1,536 patients meeting the above criteria were included, with the following characteristics: median age 65 y (range 17-92), 63% stage III/IV, 39% B symptoms, 50% elevated LDH, 15% performance status >1 and 39%, 36%, 15%, 6% and 3% had 0, 1, 2, 3 and 4+ extranodal sites of involvement, respectively. 79% received no specific CNS-directed prophylaxis; 8% received intrathecal chemotherapy alone, 5% received systemic high-dose anti-metabolites and 8% received both intrathecal and systemic. After a median follow-up of 41 (interquartile range 28-61) months, 62 (4%) patients developed CNS relapse at a median of 9 (range 4-78) months from initial diagnosis. The 3-y incidence of CNS relapse, unadjusted and adjusted hazard ratios for CNS relapse according to number of extranodal sites of involvement are presented in Table 1. The competing risk regression analysis for CNS relapse using absolute number of extranodal sites of involvement is displayed in Figure 1; >2 vs 2 or fewer extranodal sites was associated with markedly increased risk of CNS progression (P <0.0001). Conclusions In patients with newly diagnosed DLBCL staged with PET-CT and treated with R-CHOP, the presence of 3 or more extranodal sites of involvement is associated with markedly increased CNS relapse risk, even when adjusting for other variables. This finding may reflect the greater sensitivity of PET-CT for detection of extranodal disease compared with CT alone. This population would be suitable for prospective studies evaluating the efficacy of prophylaxis strategies and predictive biomarker studies. Table 1. Risk of CNS relapse according to number of extranodal sites at initial diagnosis. *adjusted for LDH, age>60 y and performance status >1 Number of extranodal sites n (%) 3-year incidence % (95%CI) Unadjusted hazard ratio HR (95% CI) Adjusted hazard ratio* HR (95% CI) 0 602 (39) 1.7 (0.9-3.5) 1.0 (ref) 1.0 (ref) 1 559 (36) 4.0 (2.5-6.4) 3.0 (1.3-6.7) 3.1 (1.3-7.2) 2 230 (15) 4.8 (2.4-9.4) 3.4 (1.3-8.5) 2.8 (1.0-7.5) 3 92 (6) 12.8 (6.6-24.0) 8.1 (3.1-20.9) 6.3 (2.2-17.6) 4+ 53 (3) 32.1 (20.1-48.8) 22.0 (9.0-53.6) 17.2 (6.5-45.8) Figure 1. Competing risk regression analysis depicting cumulative incidence of CNS relapse according to absolute number of extranodal sites of involvement. Figure 1. Competing risk regression analysis depicting cumulative incidence of CNS relapse according to absolute number of extranodal sites of involvement. Disclosures Hutchings: Takeda: Research Funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Seymour:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees. Villa:Roche: Research Funding.

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Estimated Glomerular Filtration Rate Is an Independent Predictor of Outcome in High-Risk Myelodysplastic Syndrome (MDS) and Low Blast Count Acute Myeloid Leukaemia (AML) Patients Treated with Azacytidine (AZA). a Retrospective Study from the MDS Registry of the Hellenic MDS Study Group

Blood ◽

10.1182/blood-2019-125806 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5423-5423

Author(s):

Sotirios Papageorgiou ◽

Vasileios Papadopoulos ◽

Papoutselis Menelaos ◽

Anthi Bouhla ◽

Argiris Symeonidis ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Performance Status ◽

Univariate Analysis ◽

Advisory Committees ◽

Landmark Analysis ◽

Kaplan Meier ◽

Blast Count

Introduction. Myelodysplastic Syndrome (MDS) is a disease of the elderly. Apart from IPSS, IPSS-R and WPSS, several indexes incorporating patient comorbidities (such as the MDS CI index- Della Porta et al Haematologica 2011, the HCT-CI index - Sorror et al Blood 2005) and performance status (the GFM index- Itzykson et al Blood 2011) have been used to predict outcome in MDS patients treated with azacytidine (AZA). We sought to investigate the effect of comorbidities on the outcome after AZA in a large group of patients from the MDS registry of the Hellenic MDS Study Group. Methods. The present study has been conducted as a retrospective observational cohort one. It included high-risk MDS and low blast count AML patients treated with AZA from 26 centers in Greece from 2007 to 2018. T-test and ANOVA were used to compare scale variables between two or more groups respectively. Univariate analysis of nominal and scale survival data was performed using Kaplan-Meier survival curves and Cox regression respectively. All variables achieving p<0.05 at univariate analysis were considered eligible for multivariate analysis; the latter was based on Cox regression method. Results. We analyzed 536 consecutive patients. Patient characteristics are depicted in Table 1. The median follow-up period was 27.5±4.8 months. 371 patients received at least four cycles of AZA and 165 patients received less than 4 cycles of AZA. Patients who received ≥4 cycles of AZA did not differ from those who received <4 cycles regarding gender, age, estimated Glomerular Filtration Rate (eGFR), cardiovascular, renal, and tumor comorbidities. Significantly higher IPSS-R and GFM scores at baseline were found in the group of patients receiving < 4 cycles of AZA compared to patients who received ≥ 4 cycles of AZA (p=0.042 and 0.05 respectively), while transfusion dependence at baseline occurred more often in patients who received ≥ 4 cycles of AZA (p=0.039). To assess the prognostic significance of risk factors on leukemia free survival (LFS) and overall survival (OS), univariate and multivariate analysis for the whole population was performed, as well as a landmark analysis for patients who were treated with at least 4 cycles of AZA. ECOG performance status and the presence of peripheral blasts were independent prognostic factors for LFS and OS for the whole cohort analysis while response to AZA and the presence of peripheral blasts were independent prognosticators for LFS and OS in the landmark analysis. In addition, prior low dose cytarabine was an independent adverse prognostic factor for LFS in the landmark analysis. As regards comorbidities, neither of MDS-CI, HCT-CI and GFM systems independently predicted LFS or OS in either analysis, but eGFR with a cut-off of 45 ml/min was a strong and independent prognosticator for LFS and OS in both the standard and the landmark analysis. Kaplan-Meier survival curves regarding LFS and OS at AZA initiation and landmark analysis after 4th cycle of AZA in relation with eGFR are shown in Figure 1. Conclusion. This is the first study to demonstrate the importance of eGFR at baseline as a prognostic marker for LFS and OS in high-risk MDS and low-blast AML patients treated with AZA. The role of comorbidities and PS needs to be further evaluated in this patient group. Disclosures Symeonidis: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vassilakopoulos:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Panayiotidis:Bayer: Other: Support of clinical trial. Pappa:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis:Celgene: Research Funding.

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Subcutaneous Epcoritamab in Combination with R-CHOP in Patients with Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma: Preliminary Results from a Phase 1/2 Trial

Blood ◽

10.1182/blood-2021-146569 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1413-1413

Author(s):

David Belada ◽

Jacob Haaber Christensen ◽

Kristina Drott ◽

Sylvia Snauwaert ◽

Joshua Brody ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Metabolic Response ◽

Phase 1 ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Grade 3

Abstract Background: In patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) that is considered high risk (revised International Prognostic Index [R-IPI]: 3-5), standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is associated with a 4-year overall survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab (DuoBody ®-CD3×CD20) is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells to induce T-cell-mediated killing. Single-agent epcoritamab demonstrated a manageable safety profile and substantial antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the first-in-human phase 1/2 trial (EPCORE NHL-1; NCT03625037). Among pts with relapsed/refractory DLBCL treated at the identified recommended phase 2 dose (RP2D) of 48 mg (n=8), the overall response rate was 88% and the complete response rate was 38% (Hutchings, Lancet, in press). These encouraging data supported initiation of the EPCORE NHL-2 phase 1/2 trial (NCT04663347), which is evaluating epcoritamab in combination with various standard of care therapies in pts with B-cell NHL. We present data from arm 1 of this trial, in which epcoritamab in combination with R-CHOP is evaluated in pts with previously untreated high-risk DLBCL. Methods: Adults with previously untreated DLBCL and an R-IPI score ≥3 received flat-dose epcoritamab in combination with standard R-CHOP for 6 cycles followed by epcoritamab monotherapy. The study includes a dose-escalation cohort (epcoritamab doses: dose level 1 = 24 mg; dose level 2 = 48 mg). Step-up dosing of epcoritamab (ie, priming and intermediate doses before first full dose) and corticosteroid prophylaxis were used as previously described (Hutchings, Lancet, in press) to mitigate cytokine release syndrome (CRS). Tumor response was evaluated by positron emission tomography-computed tomography obtained once every 6 weeks for the first 24 weeks. Results: As of July 15, 2021, 9 pts have been treated with the combination of epcoritamab + R-CHOP (4 with epcoritamab 24 mg; 5 with 48 mg). Median age was 66 years (range, 56-78). All pts had stage III-IV disease. At data cutoff, all pts remained on treatment with a median follow-up of 12.2 weeks (range, 2.2-28.2). The most common treatment-emergent adverse events were CRS (56%; all grade 1/2), anemia (56%; grade 1-3), neutropenia (44%; all grade 3/4), fatigue (33%; all grade 1/2), and peripheral neuropathy (33%; all grade 1/2). Notably, no grade ≥3 CRS events or cases of febrile neutropenia were reported. No dose-limiting toxicities have been observed. Four pts have had ≥1 response assessment, with 3 achieving complete metabolic response (CMR; all in the epcoritamab 24 mg dose-escalation cohort) and 1 pt achieving partial metabolic response (epcoritamab 48 mg cohort) by week 6; 2 of the 3 pts with CMR had response assessments at 6 months, and both remained in CMR at that time. Both dose cohorts have been cleared by the Dose Escalation Committee and Safety Committee, and the expansion part has been opened to enroll additional pts. Conclusions: These preliminary data from a small number of pts suggest that epcoritamab in combination with R-CHOP has a manageable safety profile with no new safety signals. Adverse events were similar to those previously reported for epcoritamab and R-CHOP individually. All evaluable pts achieved early responses, and all pts remain on treatment. Updated and additional data from pts treated in the expansion phase will be presented. These findings warrant further evaluation of epcoritamab for the treatment of high-risk, newly diagnosed DLBCL. Disclosures Belada: Genmab: Research Funding. Drott: Roche: Honoraria; Kyowa Kirin: Honoraria; Respiratorius AB: Membership on an entity's Board of Directors or advisory committees. Narkhede: TG Therapeautics: Research Funding; Genmab: Other: Medical writing support, Research Funding; Genentech/Roche: Research Funding; Gilead: Research Funding. Elliot: Genmab: Current Employment, Patents & Royalties: P158-US-PSP3 . Liu: Genmab: Current Employment. Cota Stirner: AbbVie: Current Employment. Abbas: Genmab: Current Employment. Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Phase 2 Study of Tirabrutinib (ONO/GS-4059), a Second-Generation Bruton's Tyrosine Kinase Inhibitor, Monotherapy in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström Macroglobulinemia

Blood ◽

10.1182/blood-2019-124614 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 345-345 ◽

Cited By ~ 10

Author(s):

Wataru Munakata ◽

Naohiro Sekiguchi ◽

Rai Shinya ◽

Kenshi Suzuki ◽

Hiroshi Handa ◽

...

Keyword(s):

Research Funding ◽

Kinase Inhibitor ◽

Performance Status ◽

Phase 2 ◽

Ecog Performance Status ◽

Advisory Committees ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Phase 2 Study ◽

Treatment Naïve

BACKGROUND Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma in which bone marrow is infiltrated by immunoglobulin M (IgM)-producing clonal lymphoplasmacytic cells. Tirabrutinib (ONO/GS-4059) is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. We performed a prospective, multicenter phase 2 study of tirabrutinib in patients with treatment-naïve (TN) or relapsed/refractory (R/R) WM. METHODS Patients with TN or R/R WM, serum IgM ≥500 mg/dL, ECOG performance status ≥1, and normal end-organ function were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR, ≥ partial response [PR]) assessed by an independent review committee (IRC) according to the criteria of the VIth International Workshop on Waldenström Macroglobulinemia (IWWM) (Owen RG et al. Br J Haematol. 2013). Secondary endpoints included overall response rate (ORR, ≥ minor response [MR]), time to major response (TTMR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Twenty seven patients (18 TN and 9 R/R) were treated as of July 3, 2019, and the median follow-up duration was 6 months. The median age of patients was 71 years (range 50-83), and 20 patients (74.1%) had ECOG performance status 0. Median serum IgM was 3600 mg/dL (range 730-6930). Median number of prior therapies among R/R patients was 2 (range 1-7), and 8 patients had received prior rituximab monotherapy or rituximab-containing chemotherapy. IRC-assessed MRR was 77.8% (95%CI: 52.4-93.6) in TN and 88.9% (95%CI: 51.8-99.7) in R/R. IRC-assessed ORR was 94.4% (95%CI: 72.7-99.9) in TN and 100% (95%CI: 66.4-100.0) in R/R. Median TTMR was 1.9 months (range 1.0-5.7) in TN and 2.1 months (range 1.0-3.7) in R/R. Median DOR, PFS, and OS were not reached. The most common adverse events (AEs) at any grade were rash (41%), neutropenia (22%), and leukopenia (15%), of which most were grade 1 or 2. Grade ≥3 AEs were neutropenia (7.4%), leukopenia, lymphopenia, atypical mycobacterial infection, rash erythematous, and erythema multiforme (3.7% each); there was no grade 4 or 5 AE. There were 4 bleeding events and all events were grade 1: mouth hemorrhage, petechiae, anal hemorrhage, and hematoma (3.7% each). Rash-related events occurred in 56% of patients and 2 events were grade 3: erythema multiforme and rash erythematous (3.7% each) which were manageable. CONCLUSION Although the follow-up time was relatively short, the results of this phase 2 study showed that tirabrutinib monotherapy is a highly effective treatment option for patients with TN and R/R WM, with a manageable safety profile. Disclosures Munakata: Ono: Research Funding. Sekiguchi:Ono, A2 Healthcare, Astellas, Janssen, Merck Sharp & Dohme. Otsuka, Pfizer, PPD SNBL, Sumitomo Dainippon Pharma, Daiichi Sankyo Company, Bristol-Myers Squibb: Research Funding. Shinya:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Handa:Ono: Research Funding. Shibayama:Astellas, Teijin, MSD, Shionogi, Eisai, Sumitomo Dainippon, Taiho, Nippon Shinyaku: Research Funding; Takeda, Novartis, Janssen, Chugai, Eisai, Mundi Pharma, Ono, Otsuka, Kyowa Kirin, Sumitomo Dainippon, AstraZeneca, Avvie, DaiichiSankyo, Fujimoto, Nippon Shinyaku, Sanofi, Bristol-Myers Squibb, Pfizer: Honoraria; Celgene, Chugai, Eisai, AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Endo:Ono: Research Funding. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria. Iwaki:Ono: Research Funding. Fukuhara:AbbVie: Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinkyaku: Honoraria; Mundi: Honoraria; Celgene Corporation: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Zenyaku: Honoraria; Gilead: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Bayer: Research Funding; Solasia Pharma: Research Funding. Tatetsu:Ono: Research Funding. Iida:Astellas: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding; Teijin Pharma: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Research Funding. Shiibashi:Ono: Employment. Izutsu:Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria; Celgene: Consultancy; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for WM/LPL.

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Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.

Blood ◽

10.1182/blood.v114.22.933.933 ◽

2009 ◽

Vol 114 (22) ◽

pp. 933-933 ◽

Cited By ~ 4

Author(s):

Nathan Fowler ◽

Brad S Kahl ◽

Peter Rosen ◽

Jeffrey Matous ◽

Amanda Cashen ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

Clin Oncol ◽

Board Of Directors ◽

Research Funding ◽

High Risk Population ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Grade 3

Abstract Abstract 933 Follicular lymphoma (FL) is an incurable, indolent B-cell non-Hodgkin lymphoma. Although survival has improved with the introduction of rituximab (Rituxan®, R), relapse is inevitable and new therapies are needed. Bortezomib (Velcade®, V) plus rituximab is active in relapsed or refractory (rel/ref) FL (de Vos et al, ASH 2006). Bendamustine (Treanda®, B) plus R has also shown activity in rel/ref FL (Robinson et al, J Clin Oncol 2008), and V has been safely combined with B in patients (pts) with advanced multiple myeloma (Fenk et al, Leuk Lymph 2007). The single-arm, multicenter, phase 2 VERTICAL study was conducted to determine the efficacy and safety of V and R in combination with B (VBR) in pts with rel/ref FL. Here we report preliminary phase 2 efficacy and safety findings from pts treated with VBR at doses determined in the dose-escalation phase of this study (Matous et al, ASCO 2009). Pts with rel/ref FL who had received ≥4 prior doses of R (no prior V or B), and had ≥1 measurable tumor mass, no active central nervous system lymphoma, Karnofsky Performance Status (KPS) ≥50%, adequate hematologic, renal, and hepatic function, and no grade ≥2 peripheral neuropathy (PN) were eligible. Pts could receive up to five 35-d cycles of V 1.6 mg/m2 (d 1, 8, 15, 22), B 90 mg/m2 (d 1, 2), and R 375 mg/m2 (d 1, 8, 15, 22, cycle 1; d 1, cycles 2–5). Response was assessed by the investigator using International Working Group criteria (Cheson et al, J Clin Oncol 2007). Adverse events (AEs) were graded using the CTCAE v3.0, and by laboratory assessment of hematologic toxicity. Sixty-three pts received VBR; median age was 58 years, 63% were male and 25% had KPS ≤80%. At diagnosis, 47% had grade 1, 26% grade 2, and 8% grade 3 histology, and 18% unknown histology; 35% had high-risk Follicular Lymphoma International Prognostic Index score. Pts had received a median of 2 prior therapies (range 1–11), and 39% were refractory to their last prior rituximab-containing therapy. The median time from diagnosis was 48 months. As of data cut-off (14 Aug 2009), pts had received a median of 3 cycles (range 1–5); 29 pts remain on therapy and 10 have completed treatment. In the 49 pts with at least one post baseline response assessment, to date, the overall best response rate was 84%; 23 (47%) pts achieved a complete response (CR) and 18 (37%) a partial response (PR). VBR was generally well tolerated, with manageable toxicities. The most common treatment-related AEs were primarily grade 1 and 2 and included nausea (79%; 3% grade 3), fatigue (65%; 10% grade 3), diarrhea (57%; 3% grade 3), and vomiting (44%; 5% grade 3). Other non-hematologic grade 3/4 AEs that occurred in more than one pt included syncope (n=2; 3%) and PN (see below). Grade 3/4 neutropenia, thrombocytopenia, and anemia were seen in 25%, 6%, and 3% of pts, respectively. Treatment-related serious AEs were reported in 17 (27%) pts, including 3 (5%) with febrile neutropenia and 1 (2%) with grade 3 herpes zoster who did not receive antiviral prophylaxis and discontinued therapy. Of the 17 (27%) pts with treatment-related PN, only 4 (6%) had grade 3 (2 discontinued therapy; no grade 4); PN has resolved in 5 (29%) pts to date. There was one on-study death (cardiac arrest) that was considered treatment-related. Additional follow-up is required to assess long-term outcomes, including progression-free and overall survival. VBR is active in this heavily pre-treated, high-risk population, with high CR rates, and was generally well tolerated. Efficacy and safety data will be updated and reported at ASH. Disclosures: Fowler: Millennium Pharmaceuticals, Inc.: Research Funding. Kahl:Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rosen:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Southern California Lymphoma Group, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tower Cancer Research Foundation: Employment. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Amin:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncotype DX: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Milllennium: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Shi:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Milllennium: Employment. Cheson:Millennium Pharmaceuticals, Inc.: Consultancy, Speakers Bureau; Cephalon: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau.

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