RARE DISEASE
Indolent B-cell non-Hodgkin lymphoma
Indolent B-cell non-Hodgkin lymphoma
Indolent B-cell non-Hodgkin lymphoma
Synonyms: Indolent B-cell NHL
Synonyms: Indolent B-cell NHL
Synonyms: Indolent B-cell NHL
Drug discovery
2
drugs
With orphan designations
Overview
Indolent B-cell non-Hodgkin lymphomas (NHLs) are slow-growing malignancies comprising ~40% of NHL cases, including follicular lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma [1][6][16]. Median age at diagnosis is 68, with a 5-year survival rate of 74% [2][5]. Though often asymptomatic initially, these lymphomas are incurable and may transform into aggressive subtypes. Management spans observation (watch-and-wait) for asymptomatic cases to rituximab-based chemoimmunotherapy, targeted agents, and CAR T-cell therapy for advanced/relapsed disease [1][3][8][13].
Burden
Chronic course: Median survival ≈12–14 years, with frequent relapses [11][12].
Leading to 8th highest cancer mortality (5.0 deaths/100,000/year) [2][6].
High healthcare utilization due to lifelong monitoring, treatment-related toxicity risks, and ~20–30% risk of transformation to aggressive NHL (e.g., DLBCL) [6][15][16].
Therapies
First-line: Observation, localized radiation, or rituximab ± chemotherapy (e.g., R-CVP, R-CHOP, bendamustine-rituximab) [1][3][8].
Relapsed/refractory: BTK inhibitors (zanubrutinib), EZH2 inhibitors (tazemetostat), bispecific antibodies (mosunetuzumab), and CAR T-cell therapy [1][6][13].
Maintenance: Rituximab every 2–3 months for 2 years post-remission [1][8].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
898 drug discovery papers about Indolent B-cell non-Hodgkin lymphoma, with 3 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
898 drug discovery papers about Indolent B-cell non-Hodgkin lymphoma, with 3 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-30 | Comparison of H1 versus combined H1/H2 antagonist premedication on incidence of rituximab infusion-related reaction: A retrospective cohort study.
IntroductionRituximab, an anti-CD20 monoclonal antibody used in B-cell malignancies, is associated with infusion-related reactions (IRRs) during the initial infusion. Standard premedication includes acetaminophen, corticosteroids, and a histamine-1 (H1) antagonist, typically diphenhydramine. Second-generation H1 antagonists offer similar efficacy with less sedation. Some institutions also incorporate histamine-2 (H2) antagonists despite limited supporting evidence. This study evaluated whether dual H1/H2 antagonist premedication reduces IRRs compared with H1-antagonist monotherapy when given with standard premedication.MethodsThis retrospective study reviewed health records of adults with a hematologic malignancy who received their first rituximab infusion at Brown University Health system between January 1, 2022 and June 30, 2025. Patients received premedication with either an H1-antagonist alone or dual H1/H2 receptor-antagonists with acetaminophen and a corticosteroid. The primary endpoint was IRR incidence during or within 24 h of infusion initiation. Secondary endpoints included IRR severity, incidence of grade 3-4 IRRs across subgroups, and time to IRR onset.ResultsAmong 299 patients (mean age 65; 55% male), 62% had aggressive lymphoma, 28% indolent lymphoma, and 10% leukemia. Baseline features included bone marrow involvement (38%), bone disease (39%), advanced-stage nodal disease (54%), B symptoms (48%), and >2 extranodal sites (28%). IRRs occurred in 38% of patients receiving dual H1/H2 antagonist premedication versus 36.5% with H1-antagonist monotherapy, with no difference in grade 3-4 IRRs. Most IRRs occurred 30 to 60 min after infusion initiation.ConclusionDual H1/H2-antagonist premedication was not associated with differences in the incidence or severity of rituximab IRRs compared with H1-antagonist monotherapy in addition to standard premedication.
2026-07-23 | Multifunctional CD38 in the pathogenesis and treatment of B-cell lymphomas.
B-cell lymphoma is a group of non-Hodgkin lymphomas with high heterogeneity. Despite advancement in therapeutics, the clinical outcomes of B-cell lymphomas need to be improved. CD38, a transmembrane multifunctional protein, is widely expressed across various B-cell lymphoma subtypes. Research indicates that CD38 plays multiple pathogenic roles in B-cell lymphomas, including regulation of proliferation, apoptosis, immune modulation, primarily through its enzymatic activity and its influence on signaling pathways in malignant lymphoma cells and immunosuppressive cells, making it a valuable therapeutic target. In recent years, CD38-targeted therapies, such as anti-CD38 antibodies and CD38-directed CAR-T cell therapies, have been explored for B-cell lymphomas. This review summarizes the knowledge on CD38 molecular functions, data of CD38 heterogeneous expression and prognostic role in B-cell lymphomas (from indolent to aggressive subtypes), anti-CD38 antibody efficacy and mechanisms of action, current understanding of the treatment resistance mechanisms, frontier advances in CD38-targeted therapies, and the challenges of novel targeted and immunotherapies in clinical applications, thereby seeking to provide a deep understanding of the role of CD38 in the pathogenesis and treatment of B-cell lymphomas. CD38-targed therapy is especially promising as a novel and optional treatment for CD20-negative lymphomas, for which standard treatment has not been established. Although the efficacy of anti-CD38 antibodies in most other B-cell lymphomas is low in previous clinical trials, in contrast to the remarkable efficacy of daratumumab in multiple myeloma, novel therapeutic strategies and combination therapies in ongoing clinical trials have the potential to overcome the counteracting actions and to improve the clinical outcomes of patients with relapsed/refractory B-cell lymphoma.
2026-07-17 | Englumafusp alfa plus glofitamab in B cell non-Hodgkin lymphoma: a phase 1 trial.
There is an unmet need for effective, off-the-shelf therapies for relapsed or refractory aggressive B cell non-Hodgkin lymphoma (B-NHL). Part 2 of the current study was an open-label, nonrandomized, phase 1 study of escalating doses of the CD19-4-1BBL co-stimulatory molecule, englumafusp alfa, in combination with glofitamab in patients with relapsed or refractory B-NHL. Obinutuzumab pretreatment was administered 7 days before the first glofitamab dose. Glofitamab step-up dosing in cycle 1 was followed by 11 cycles of glofitamab plus englumafusp alfa. Englumafusp alfa was administered at escalating doses, with the initial dose on cycle 2 day 8 (C2D8) or cycle 1 day 10 (C1D10). Primary objectives were to establish the maximum tolerated dose, and safety and tolerability. A total of 134 patients were enrolled, including 109 with aggressive B-NHL and 25 with indolent B-NHL. The maximum tolerated dose of englumafusp alfa was not reached; one dose-limiting toxicity occurred (grade 5 Pneumocystis jirovecii pneumonia). Adverse events were reported in 98.5% of all patients, with grade 3/4 adverse events in 59.0%. Grade 5 adverse events occurred in ten patients. In the subgroup of C2D8 patients with aggressive B-NHL (n = 83), overall response and complete metabolic response rates were 68.7% and 56.6%, respectively; among those without previous exposure to chimeric antigen receptor T cell therapy (n = 41), the corresponding rates were 73.2% and 65.9%. Pharmacodynamic changes following englumafusp alfa administration supported its co-stimulatory mode of action. These data demonstrate that the addition of englumafusp alfa to glofitamab is associated with encouraging efficacy and robust pharmacodynamic modulation, as well as a safety profile consistent with glofitamab monotherapy, in patients with relapsed or refractory B-NHL. CTIS identifier: 2022-502616-37-00 ; ClinicalTrials.gov identifier: NCT04077723 .
2026-07-17 | Acquired Hemophilia A Revealing Occult Splenic Marginal Zone Lymphoma.
BACKGROUND Acquired hemophilia A is a rare autoimmune bleeding disorder caused by inhibitory autoantibodies against coagulation factor VIII and is associated with significant morbidity and mortality. Although malignancy-associated acquired hemophilia A is well recognized, its presentation as the initial manifestation of an otherwise clinically subtle indolent B-cell lymphoma, such as splenic marginal zone lymphoma, remains exceedingly uncommon. We report a case highlighting the importance of recognizing acquired factor VIII inhibitors, evaluating for underlying lymphoproliferative disorders, and the potential role of rituximab monotherapy in achieving control of both the inhibitor and the underlying lymphoma. CASE REPORT A 77-year-old man presented with spontaneous bruising and an isolated prolonged activated partial thromboplastin time that failed to correct on mixing studies. Further evaluation demonstrated markedly reduced factor VIII activity, a factor VIII inhibitor, diffuse splenomegaly, and flow cytometry and bone marrow biopsy findings most consistent with splenic marginal zone lymphoma. Treatment with activated prothrombin complex concentrate, corticosteroids, and rituximab resulted in normalization of coagulation parameters, recovery of factor VIII activity, decline in inhibitor titers, resolution of bleeding manifestations, and sustained clinical stability without recurrent bleeding or evidence of lymphoma progression. CONCLUSIONS This case highlights acquired hemophilia A as a rare paraneoplastic manifestation of splenic marginal zone lymphoma and emphasizes the importance of evaluating for an underlying lymphoproliferative disorder in older adults presenting with newly identified factor VIII inhibitors, particularly in the setting of cytopenias or splenomegaly. It also demonstrates that rituximab-based therapy can effectively achieve sustained remission of both the inhibitor and the underlying indolent lymphoma.
2026-07-08 | Pharmacologic activity, safety, and preliminary efficacy of GEN3009, a CD37-targeting DuoHexaBody, in relapsed or refractory B-cell non-Hodgkin's lymphoma.
Tetraspanin CD37, highly expressed in mature B-cells, represents an opportunity for therapeutic targeting in B-cell malignancies. GEN3009 (DuoHexaBody-CD37), a humanized biparatopic IgG1 antibody with an E430G hexamerization-enhancing mutation targeting two non-overlapping CD37 epitopes, was shown to induce potent tumor cell killing through enhanced complement-dependent cytotoxicity (CDC) and other fragment crystallizable-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), in vitro and in vivo. GEN3009 was assessed in non-clinical studies and a phase 1 dose-escalation study of B-cell non-Hodgkin's lymphoma (B-NHL). After a non-clinical toxicity study was conducted in cynomolgus monkeys, a phase 1, first-in-human, open-label, multicenter dose-escalation trial of GEN3009 monotherapy enrolled adults with relapsed/refractory (R/R) B-NHL (NCT04358458). A modified Bayesian optimal interval design informed dose escalation and de-escalation with dose levels ranging from 6 mg to 2000 mg. Primary endpoints were the rate of dose-limiting toxicities (DLTs) to determine the recommended phase 2 dose (RP2D) and safety and tolerability. In the toxicity study, 10 mg/kg GEN3009 weekly was identified as the highest non-severely toxic dose. In the phase 1 study, from March 13, 2020, to July 28, 2023, 46 patients with R/R B-NHL received intravenous GEN3009 infusions. Median duration of treatment was 1.2 months (range, 0.0-14.5). No DLTs were observed up to 1600 mg. The most common treatment-emergent adverse events were neutropenia (n=41 (89.1%)), infusion-related reactions (n=39 (84.8%)), and thrombocytopenia (n=18 (39.1%)). Plasma GEN3009 concentrations increased over time with increasing GEN3009 doses, with no apparent accumulation of GEN3009 observed over the course of treatment. Antitumor activity was observed at dose levels of ≥180 mg in both aggressive and indolent NHL. GEN3009 treatment reduced total hemolytic complement activity (CH50) levels in serum, and peak changes in CH50 levels were significantly correlated with clinical response (p=0.008 by Wilcoxon rank-sum test). Based on safety, efficacy, and pharmacokinetics, the RP2D of GEN3009 was determined to be 1200 mg. Preliminary data suggest that GEN3009 monotherapy demonstrated an acceptable safety profile at the RP2D of 1200 mg, with modest clinical activity. These findings provide the first clinical proof-of-concept for hexamerization-potentiated molecules that induce antitumor activity through enhanced CDC.
2026-07-30 | Comparison of H1 versus combined H1/H2 antagonist premedication on incidence of rituximab infusion-related reaction: A retrospective cohort study.
IntroductionRituximab, an anti-CD20 monoclonal antibody used in B-cell malignancies, is associated with infusion-related reactions (IRRs) during the initial infusion. Standard premedication includes acetaminophen, corticosteroids, and a histamine-1 (H1) antagonist, typically diphenhydramine. Second-generation H1 antagonists offer similar efficacy with less sedation. Some institutions also incorporate histamine-2 (H2) antagonists despite limited supporting evidence. This study evaluated whether dual H1/H2 antagonist premedication reduces IRRs compared with H1-antagonist monotherapy when given with standard premedication.MethodsThis retrospective study reviewed health records of adults with a hematologic malignancy who received their first rituximab infusion at Brown University Health system between January 1, 2022 and June 30, 2025. Patients received premedication with either an H1-antagonist alone or dual H1/H2 receptor-antagonists with acetaminophen and a corticosteroid. The primary endpoint was IRR incidence during or within 24 h of infusion initiation. Secondary endpoints included IRR severity, incidence of grade 3-4 IRRs across subgroups, and time to IRR onset.ResultsAmong 299 patients (mean age 65; 55% male), 62% had aggressive lymphoma, 28% indolent lymphoma, and 10% leukemia. Baseline features included bone marrow involvement (38%), bone disease (39%), advanced-stage nodal disease (54%), B symptoms (48%), and >2 extranodal sites (28%). IRRs occurred in 38% of patients receiving dual H1/H2 antagonist premedication versus 36.5% with H1-antagonist monotherapy, with no difference in grade 3-4 IRRs. Most IRRs occurred 30 to 60 min after infusion initiation.ConclusionDual H1/H2-antagonist premedication was not associated with differences in the incidence or severity of rituximab IRRs compared with H1-antagonist monotherapy in addition to standard premedication.
2026-07-23 | Multifunctional CD38 in the pathogenesis and treatment of B-cell lymphomas.
B-cell lymphoma is a group of non-Hodgkin lymphomas with high heterogeneity. Despite advancement in therapeutics, the clinical outcomes of B-cell lymphomas need to be improved. CD38, a transmembrane multifunctional protein, is widely expressed across various B-cell lymphoma subtypes. Research indicates that CD38 plays multiple pathogenic roles in B-cell lymphomas, including regulation of proliferation, apoptosis, immune modulation, primarily through its enzymatic activity and its influence on signaling pathways in malignant lymphoma cells and immunosuppressive cells, making it a valuable therapeutic target. In recent years, CD38-targeted therapies, such as anti-CD38 antibodies and CD38-directed CAR-T cell therapies, have been explored for B-cell lymphomas. This review summarizes the knowledge on CD38 molecular functions, data of CD38 heterogeneous expression and prognostic role in B-cell lymphomas (from indolent to aggressive subtypes), anti-CD38 antibody efficacy and mechanisms of action, current understanding of the treatment resistance mechanisms, frontier advances in CD38-targeted therapies, and the challenges of novel targeted and immunotherapies in clinical applications, thereby seeking to provide a deep understanding of the role of CD38 in the pathogenesis and treatment of B-cell lymphomas. CD38-targed therapy is especially promising as a novel and optional treatment for CD20-negative lymphomas, for which standard treatment has not been established. Although the efficacy of anti-CD38 antibodies in most other B-cell lymphomas is low in previous clinical trials, in contrast to the remarkable efficacy of daratumumab in multiple myeloma, novel therapeutic strategies and combination therapies in ongoing clinical trials have the potential to overcome the counteracting actions and to improve the clinical outcomes of patients with relapsed/refractory B-cell lymphoma.
2026-07-17 | Englumafusp alfa plus glofitamab in B cell non-Hodgkin lymphoma: a phase 1 trial.
There is an unmet need for effective, off-the-shelf therapies for relapsed or refractory aggressive B cell non-Hodgkin lymphoma (B-NHL). Part 2 of the current study was an open-label, nonrandomized, phase 1 study of escalating doses of the CD19-4-1BBL co-stimulatory molecule, englumafusp alfa, in combination with glofitamab in patients with relapsed or refractory B-NHL. Obinutuzumab pretreatment was administered 7 days before the first glofitamab dose. Glofitamab step-up dosing in cycle 1 was followed by 11 cycles of glofitamab plus englumafusp alfa. Englumafusp alfa was administered at escalating doses, with the initial dose on cycle 2 day 8 (C2D8) or cycle 1 day 10 (C1D10). Primary objectives were to establish the maximum tolerated dose, and safety and tolerability. A total of 134 patients were enrolled, including 109 with aggressive B-NHL and 25 with indolent B-NHL. The maximum tolerated dose of englumafusp alfa was not reached; one dose-limiting toxicity occurred (grade 5 Pneumocystis jirovecii pneumonia). Adverse events were reported in 98.5% of all patients, with grade 3/4 adverse events in 59.0%. Grade 5 adverse events occurred in ten patients. In the subgroup of C2D8 patients with aggressive B-NHL (n = 83), overall response and complete metabolic response rates were 68.7% and 56.6%, respectively; among those without previous exposure to chimeric antigen receptor T cell therapy (n = 41), the corresponding rates were 73.2% and 65.9%. Pharmacodynamic changes following englumafusp alfa administration supported its co-stimulatory mode of action. These data demonstrate that the addition of englumafusp alfa to glofitamab is associated with encouraging efficacy and robust pharmacodynamic modulation, as well as a safety profile consistent with glofitamab monotherapy, in patients with relapsed or refractory B-NHL. CTIS identifier: 2022-502616-37-00 ; ClinicalTrials.gov identifier: NCT04077723 .
2026-07-17 | Acquired Hemophilia A Revealing Occult Splenic Marginal Zone Lymphoma.
BACKGROUND Acquired hemophilia A is a rare autoimmune bleeding disorder caused by inhibitory autoantibodies against coagulation factor VIII and is associated with significant morbidity and mortality. Although malignancy-associated acquired hemophilia A is well recognized, its presentation as the initial manifestation of an otherwise clinically subtle indolent B-cell lymphoma, such as splenic marginal zone lymphoma, remains exceedingly uncommon. We report a case highlighting the importance of recognizing acquired factor VIII inhibitors, evaluating for underlying lymphoproliferative disorders, and the potential role of rituximab monotherapy in achieving control of both the inhibitor and the underlying lymphoma. CASE REPORT A 77-year-old man presented with spontaneous bruising and an isolated prolonged activated partial thromboplastin time that failed to correct on mixing studies. Further evaluation demonstrated markedly reduced factor VIII activity, a factor VIII inhibitor, diffuse splenomegaly, and flow cytometry and bone marrow biopsy findings most consistent with splenic marginal zone lymphoma. Treatment with activated prothrombin complex concentrate, corticosteroids, and rituximab resulted in normalization of coagulation parameters, recovery of factor VIII activity, decline in inhibitor titers, resolution of bleeding manifestations, and sustained clinical stability without recurrent bleeding or evidence of lymphoma progression. CONCLUSIONS This case highlights acquired hemophilia A as a rare paraneoplastic manifestation of splenic marginal zone lymphoma and emphasizes the importance of evaluating for an underlying lymphoproliferative disorder in older adults presenting with newly identified factor VIII inhibitors, particularly in the setting of cytopenias or splenomegaly. It also demonstrates that rituximab-based therapy can effectively achieve sustained remission of both the inhibitor and the underlying indolent lymphoma.
2026-07-08 | Pharmacologic activity, safety, and preliminary efficacy of GEN3009, a CD37-targeting DuoHexaBody, in relapsed or refractory B-cell non-Hodgkin's lymphoma.
Tetraspanin CD37, highly expressed in mature B-cells, represents an opportunity for therapeutic targeting in B-cell malignancies. GEN3009 (DuoHexaBody-CD37), a humanized biparatopic IgG1 antibody with an E430G hexamerization-enhancing mutation targeting two non-overlapping CD37 epitopes, was shown to induce potent tumor cell killing through enhanced complement-dependent cytotoxicity (CDC) and other fragment crystallizable-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), in vitro and in vivo. GEN3009 was assessed in non-clinical studies and a phase 1 dose-escalation study of B-cell non-Hodgkin's lymphoma (B-NHL). After a non-clinical toxicity study was conducted in cynomolgus monkeys, a phase 1, first-in-human, open-label, multicenter dose-escalation trial of GEN3009 monotherapy enrolled adults with relapsed/refractory (R/R) B-NHL (NCT04358458). A modified Bayesian optimal interval design informed dose escalation and de-escalation with dose levels ranging from 6 mg to 2000 mg. Primary endpoints were the rate of dose-limiting toxicities (DLTs) to determine the recommended phase 2 dose (RP2D) and safety and tolerability. In the toxicity study, 10 mg/kg GEN3009 weekly was identified as the highest non-severely toxic dose. In the phase 1 study, from March 13, 2020, to July 28, 2023, 46 patients with R/R B-NHL received intravenous GEN3009 infusions. Median duration of treatment was 1.2 months (range, 0.0-14.5). No DLTs were observed up to 1600 mg. The most common treatment-emergent adverse events were neutropenia (n=41 (89.1%)), infusion-related reactions (n=39 (84.8%)), and thrombocytopenia (n=18 (39.1%)). Plasma GEN3009 concentrations increased over time with increasing GEN3009 doses, with no apparent accumulation of GEN3009 observed over the course of treatment. Antitumor activity was observed at dose levels of ≥180 mg in both aggressive and indolent NHL. GEN3009 treatment reduced total hemolytic complement activity (CH50) levels in serum, and peak changes in CH50 levels were significantly correlated with clinical response (p=0.008 by Wilcoxon rank-sum test). Based on safety, efficacy, and pharmacokinetics, the RP2D of GEN3009 was determined to be 1200 mg. Preliminary data suggest that GEN3009 monotherapy demonstrated an acceptable safety profile at the RP2D of 1200 mg, with modest clinical activity. These findings provide the first clinical proof-of-concept for hexamerization-potentiated molecules that induce antitumor activity through enhanced CDC.
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Drug Discovery Landscape
2 orphan drug designations for Indolent B-cell non-Hodgkin lymphoma.
2 orphan drug designations for Indolent B-cell non-Hodgkin lymphoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
blinatumomab | antibodies | FDA | 2006-02-06 | — | Amgen, Inc. |
Cladribine [Litak] | small molecules | EMA | 2001-09-18 | — | Lipomed GmbH |
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