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BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) exhibited superior modified progression-free survival (PFS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL). Maturing positron emission tomography (PET)-adapted trial data highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET scan after cycle 2 (PET2)-negative (PET2−) patients. We present an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. A total of 1334 patients with stage III or IV cHL were randomized 1:1 to receive 6 cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was required. At median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2−patients aged <60 years were 87.2% vs 81.0%, respectively. A beneficial trend in PET2+patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% vs 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL, consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or bleomycin exposure. This trial was registered at www.clinicaltrials.govas #NCT01712490 (EudraCT no. 2011-005450-60).

The phase 3 ECHELON-1 study demonstrated that brentuximab vedotin (A) with doxorubicin, vinblastine, and dacarbazine (AVD; A+AVD) exhibited superior modified progression-free survival (PFS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for frontline treatment of patients with stage III/IV classical Hodgkin lymphoma (cHL). Maturing positron emission tomography (PET)-adapted trial data highlight potential limitations of PET-adapted approaches, including toxicities with dose intensification and higher-than-expected relapse rates in PET scan after cycle 2 (PET2)-negative (PET2−) patients. We present an update of the ECHELON-1 study, including an exploratory analysis of 3-year PFS per investigator. A total of 1334 patients with stage III or IV cHL were randomized 1:1 to receive 6 cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was required. At median follow-up of 37 months, 3-year PFS rates were 83.1% with A+AVD and 76.0% with ABVD; 3-year PFS rates in PET2− patients aged <60 years were 87.2% vs 81.0%, respectively. A beneficial trend in PET2+ patients aged <60 years on A+AVD was also observed, with a 3-year PFS rate of 69.2% vs 54.7% with ABVD. The benefit of A+AVD in the intent-to-treat population appeared independent of disease stage and prognostic risk factors. Upon continued follow-up, 78% of patients with peripheral neuropathy on A+AVD had either complete resolution or improvement compared with 83% on ABVD. These data highlight that A+AVD provides a durable efficacy benefit compared with ABVD for frontline stage III/IV cHL, consistent across key subgroups regardless of patient status at PET2, without need for treatment intensification or bleomycin exposure. This trial was registered at www.clinicaltrials.gov as #NCT01712490 (EudraCT no. 2011-005450-60).

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Background:There are a lack of clinical prediction tools in early-stage Hodgkin lymphoma (E-HL). We developed and validated a modern-day model, known as E-HIPI, to predict progression-free survival (PFS) within the first 5 years (y) incorporating detailed individual patient (pt) data from international clinical trials and prospective registry data that were standardized, normalized & harmonized as part of the HoLISTIC Consortium (www.hodgkinconsortium.org).

Background:Englumafusp alfa is an antibody-like fusion protein that simultaneously targets CD19 on B cells and 4-1BB on T cells and other immune cells. In the presence of a T-cell receptor signal and strictly dependent on CD19 crosslinking, englumafusp alfa co-stimulates T cells via 4-1BB agonism that boosts T-cell effector functions and prevents T-cell anergy. An ongoing Phase I dose-escalation study (NCT04077723) is investigating the safety, efficacy, pharmacokinetics, and pharmacodynamics (PD) of intravenous administration of englumafusp alfa in combination with glofitamab in patients (pts) with R/R NHL. We recently presented preliminary clinical data demonstrating promising clinical activity and good tolerability in R/R NHL (Hutchings et al, ICML 2023). Here, we report preliminary peripheral blood (PB) and tissue biomarker analyses to demonstrate mechanisms of action (MoA), dose relationship, and baseline features associated with response.

Introduction

Introduction:

Background:Despite recent therapeutic advances, an unmet need exists for efficacious, well-tolerated, and convenient treatment (tx) options for patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL). In particular, pts with high-risk disease, including those refractory to both anti-CD20 tx and an alkylating agent (double refractory) and those with disease progression within 2 y of first-line (1L) immunochemotherapy (POD24), require more effective options. Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, was recently approved by the US FDA for the tx of adults with R/R diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic tx. Here we present initial results from the FL dose-expansion cohort of the EPCORE™ NHL-1 trial (NCT03625037; phase 1/2).

Introduction:

Introduction: The documented treatment-induced excess mortality in Hodgkin lymphoma (HL) has led to significant changes in treatment regimens aimed at maintaining efficacy while reducing toxicity. These modifications include the replacement of alkylator-based regimens with anthracycline-based combinations and the adoption of highly conformal radiotherapy. Danish and Nordic radiation oncologists were pioneers in implementing these changes nationwide 10-15 years earlier than most other nations. These early adaptations make Danish HL data uniquely valuable for assessing long-term mortality in a cohort where modern treatment regimens have been implemented nationwide throughout the entire study period. The impact of these treatment modifications on mortality risk in HL survivors remains unclear, therefore, this study aims to assess cause-specific mortality among HL patients treated with contemporary strategies.

Background:Glofitamab is a CD20xCD3 bispecific antibody with a 2:1 (CD20:CD3) format that engages and redirects T cells to eliminate B cells. In a pivotal Phase II study (NCT03075696), fixed-duration glofitamab monotherapy induced high complete response (CR) rates and had a manageable safety profile in patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL; Dickinson et al. N Engl J Med 2022). Here, we present an extended follow up, as well as subgroup analyses in patients with prior chimeric antigen receptor (CAR) T-cell therapy and by baseline total metabolic tumor volume (TMTV).

Background: RO7283420 (RG6007) is a 2+1 TCR-like (TCR-L) T-cell bispecific (TCB) antibody targeting CD3 and the RMFPNAPYL peptide of Wilms Tumor 1 (WT1) protein presented by the major histocompatibility complex-I HLA-A*02 on acute myeloid leukemia (AML) blasts and other antigen presenting cells. The pre-clinical evaluation of RO7283420 in our in vivohumanized AML xenografts and ex vivoAML co-culture models showed strong T-cell mediated AML cell killing (Augsberger C, et al. Blood2021). A Phase 1 dose-escalation (DE) study (NCT04580121) evaluated the safety, tolerability, pharmacokinetics, anti-drug antibodies (ADAs), and anti-leukemic activity of RO7283420 in patients with relapsed/refractory (R/R) AML.

Background

Background:Glofitamab (Glofit) is a CD20xCD3 bispecific antibody which engages and redirects T cells to eliminate B cells. Glofit monotherapy recently received FDA and EMA approval for treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 prior lines of therapy. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate that has a complementary mode of action to Glofit, with little toxicity overlap. In this open-label, multicenter Phase Ib/II study (NCT03533283), Glofit+Pola demonstrated durable responses and a manageable safety profile in patients with R/R DLBCL (Hutchings et al. ICML 2023). We present updated results with longer follow-up in patients with R/R DLBCL, including high-grade B-cell lymphoma (HGBCL), and in patients with prior chimeric antigen receptor (CAR) T-cell therapy.

Background:Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication.

Purpose:Improved predictive tools are desired in classic Hodgkin lymphoma (cHL) to improve prognostication and to better risk stratify patients (pts) for clinical trials. In younger pts who tolerate intensive therapies, focus has been on limiting late treatment toxicity through risk-adapted, PET-guided treatment strategy. In older pts, acute treatment toxicities are limiting factors for optimal disease control. Due to these fundamental differences, predictive tools may perform differently in younger and older pts. In particular, tools developed in younger pts may be suboptimal in older populations and vice versa. The primary objective of this study was to assess the performance of the A-HIPI(development was limited to 18-65 years of age) against the international prognostic score (IPS) for modelling overall survival (OS) and progression-free survival (PFS) in younger and older pts with cHL.

Introduction

Background:While HL is a highly curable cancer, patients (pts) with advanced stage disease experience increased risk of relapse. Delineation of prognosis is desired to compare cohorts and outcomes between trials, and to define groups of pts for whom reduction in treatment may be appropriate or where novel therapeutic approaches are needed. The International Prognostic Score (IPS), which was derived from a discovery set of 1,618 HL pts with complete data, was a seminal publication in the field (Hasenclever and Diehl NEJM1998). However, these data were published >20 years ago with a significant minority of pts having received chemotherapy regimens no longer in clinical use. More contemporary analyses have shown altered utility of the IPS (e.g., Moccia JCO2012; Diefenbach BJH2015). In addition, prior studies identified bulk disease as an adverse prognostic factor in advanced stage HL (Laskar JCO2004; Johnson JCO2010). Our objective was to leverage individual pt data (IPD) from HoLISTIC (www.hodgkinconsortium.com)to discover a new, robust, and modern prognostication index for advanced-stage HL pts applicable to diverse settings across the world.

Introduction:Glofitamab (RG6026) is a novel T-cell-engaging, bispecific, full-length antibody with a 2:1 molecular configuration that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Preclinically, glofitamab had superior potency compared with other tested bispecifics with 1:1 formats (Bacac, et al. Clin Cancer Res 2018). NP30179 (NCT03075696) is an ongoing multicenter, Phase I/Ib, dose-escalation and dose-expansion trial evaluating the safety, tolerability, pharmacokinetics, biomarker responses, and efficacy of glofitamab in patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). Clinical data from NP30179 demonstrated that fixed dosing of glofitamab (0.6-25mg) induced high and durable complete responses with a manageable safety profile in pts with heavily pre-treated R/R NHL (Dickinson, et al. EHA 2020). Obinutuzumab pretreatment (Gpt) was shown to be effective in mitigating the risk of cytokine release syndrome (CRS), allowing for rapid escalation of glofitamab to clinically active doses (Dickinson, et al. EHA 2020). Step-up dosing of glofitamab was used in addition to Gpt to further reduce the risk of CRS. For the first time, we present clinical data of glofitamab step-up dosing with Gpt in pts with R/R NHL.

Hutchings: Genmab, F. Hoffmann-La Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Genmab, Janssen, Novartis, F. Hoffmann-La Roche, Takeda: Research Funding. Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics and Rhizen Pharmaceuticals: Research Funding; Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca: Honoraria; Boehringer Ingelheim and Sanofi: Consultancy. Bachy:Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Servier: Consultancy; Genentech, Inc.: Consultancy. Crump:Kite/Gilead: Consultancy; Roche: Consultancy; Servier: Consultancy. Iacoboni:Novartis, Gilead, Celgene, Roche: Honoraria. Sureda Balari:BMS: Speakers Bureau; Roche: Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Martinez-Lopez:Novartis: Consultancy; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lundberg:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Dixon:Roche Products Limited: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Perez Callejo:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Relf:Roche Products Ltd: Current Employment. Carlile:AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Piccione:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Humphrey:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Dickinson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy.Glofitamab (RG6026; CD20-TCB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

Parsons: Seattle Genetics: Consultancy. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Federico:Spectrum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mundipharma s.r.l.: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon/Teva: Research Funding. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Bayer: Consultancy; Kite Pharmaceuticals: Research Funding; Portola Pharmaceuticals: Consultancy; Roche: Other: Travel expenses; Seattle Genetics: Research Funding; Astellas: Consultancy. Hutchings:Genmab: Research Funding; Janssen: Research Funding; Roche: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Genmab: Honoraria; Takeda: Honoraria. Johnson:MorphoSys: Honoraria; Kymera: Honoraria; Kite Pharma: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Epizyme: Consultancy, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Oncimmune: Consultancy; Boehringer Ingelheim: Consultancy; Janssen: Consultancy; Oncimmune: Consultancy; Janssen: Consultancy; Genmab: Honoraria; Bristol-Myers: Honoraria; Epizyme: Consultancy, Research Funding. Radford:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Zinzani:MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding. Evens:Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria.

We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P < .0001) and OS (P = .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm3) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (≤147 cm3). In multivariable analysis including iPET2, TMTV was the only baseline prognosticator compared with the current staging systems proposed by the European Organization for Research and Treatment of Cancer/Groupe d’Etude des Lymphomes de l’Adulte, German Hodgkin Study Group, or National Comprehensive Cancer Network. TMTV and iPET2 were independently prognostic and, combined, identified 4 risk groups: low (TMTV≤147+DS1-3; 5-year PFS, 95%), low-intermediate (TMTV>147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV≤147+DS4-5; 5-year PFS, 50%), and high (TMTV>147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well.

We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P< .0001) and OS (P= .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm3) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (≤147 cm3). In multivariable analysis including iPET2, TMTV was the only baseline prognosticator compared with the current staging systems proposed by the European Organization for Research and Treatment of Cancer/Groupe d'Etude des Lymphomes de l'Adulte, German Hodgkin Study Group, or National Comprehensive Cancer Network. TMTV and iPET2 were independently prognostic and, combined, identified 4 risk groups: low (TMTV≤147+DS1-3; 5-year PFS, 95%), low-intermediate (TMTV>147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV≤147+DS4-5; 5-year PFS, 50%), and high (TMTV>147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well.

BRAFV600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAFV600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAFV600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAFV600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAFV600E mutation–positive HCL. This trial is registered at www.clinicaltrials.govas #NCT02034110.

The guanosine triphosphatases (GTPases) of the immunity-associated protein (GIMAP) family of putative GTPases has been implicated in the regulation of T-lymphocyte development and survival. A mouse conditional knockout allele was generated for the immune GTPase gene GIMAP1. Homozygous loss of this allele under the influence of the lymphoid-expressed hCD2-iCre recombinase transgene led to severe (> 85%) deficiency of mature T lymphocytes and, unexpectedly, of mature B lymphocytes. By contrast there was little effect of GIMAP1 deletion on immature lymphocytes in either B or T lineages, although in vitro studies showed a shortening of the survival time of both immature and mature CD4+ single-positive thymocytes. These findings show a vital requirement for GIMAP1 in mature lymphocyte development/survival and draw attention to the nonredundant roles of members of the GIMAP GTPase family in these processes.

The guanosine triphosphatases (GTPases) of the immunity-associated protein (GIMAP) family of putative GTPases has been implicated in the regulation of T-lymphocyte development and survival. A mouse conditional knockout allele was generated for the immune GTPase gene GIMAP1. Homozygous loss of this allele under the influence of the lymphoid-expressed hCD2-iCrerecombinase transgene led to severe (> 85%) deficiency of mature T lymphocytes and, unexpectedly, of mature B lymphocytes. By contrast there was little effect of GIMAP1deletion on immature lymphocytes in either B or T lineages, although in vitro studies showed a shortening of the survival time of both immature and mature CD4+single-positive thymocytes. These findings show a vital requirement for GIMAP1 in mature lymphocyte development/survival and draw attention to the nonredundant roles of members of the GIMAP GTPase family in these processes.

Russell bodies (RBs) are intracellular inclusions filled with protein aggregates. In diverse lymphoid disorders these occur as immunoglobulin (Ig) deposits, accumulating in abnormal plasma or Mott cells. In heavy-chain deposition disease truncated antibody heavy-chains (HCs) are found, which bear a resemblance to diverse polypeptides produced in Ig light-chain (LC)–deficient (L−/−) mice. In L−/− animals, the known functions of LC, providing part of the antigen-binding site of an antibody and securing progression of B-cell development, may not be required. Here, we show a novel function of LC in preventing antibody aggregation. L−/− mice produce truncated HC naturally, constant region (C)γ and Cα lack CH1, and Cμ is without CH1 or CH1 and CH2. Most plasma cells found in these mice are CD138+ Mott cells, filled with RBs, formed by aggregation of HCs of different isotypes. The importance of LC in preventing HC aggregation is evident in knock-in mice, expressing Cμ without CH1 and CH2, which only develop an abundance of RBs when LC is absent. These results reveal that preventing antibody aggregation is a major function of LC, important for understanding the physiology of heavy-chain deposition disease, and in general recognizing the mechanisms, which initiate protein conformational diseases.

Introduction:Despite advances in the treatment of B-cell non-Hodgkin lymphoma (B-NHL), more efficacious, less toxic, off-the-shelf therapies are needed for patients (pts) with relapsed or refractory (R/R) disease. Epcoritamab is a novel, subcutaneously (SC) administered bispecific antibody (bsAb) that simultaneously binds to CD3 on T cells and CD20 on B cells, inducing activation and cytotoxic activity of T cells for killing of target lymphoma cells. In an open-label, phase 1/2 trial (NCT03625037), initial data demonstrated an encouraging safety profile and potent single-agent clinical activity, even at low doses, in heavily pretreated pts with R/R B-NHL (Hutchings M. EHA 2020, Poster EP1218). Herein, we present updated dose-escalation data, including initial results for the 48-mg recommended phase 2 dose (RP2D) and for pts with mantle cell lymphoma (MCL).

Background: Up to 50% of patients suffering from Non-Hodgkin's lymphoma (NHL) become refractory to or relapse after treatment (M. Crump, Blood 2017). With this, the lack of curative outcomes for patients with both indolent and aggressive NHL subtypes remains an unmet medical need. The CD20 CD3 T cell bispecific antibody glofitamab induces specific T-cell activation and has demonstrated significant single agent activity in r/r NHL patients (NP30179 study, M. Dickinson, EHA 2020, Abstract S241).