RARE DISEASE
Splenic marginal zone lymphoma
Splenic marginal zone lymphoma
Splenic marginal zone lymphoma
Synonyms: SMZL
Synonyms: SMZL
Synonyms: SMZL
Drug discovery
12
drugs
With orphan designations
Overview
Splenic marginal zone lymphoma (SMZL) is a rare, indolent B-cell non-Hodgkin lymphoma primarily involving the spleen, bone marrow, and peripheral blood. It presents with splenomegaly, cytopenias, and lymphocytosis (often with villous lymphocytes). Diagnosis requires excluding morphologic mimics through immunophenotyping (CD5−, CD10−, CD20+). Approximately 20-30% of cases associate with hepatitis C virus. While median survival exceeds 10 years, 10-20% transform to diffuse large B-cell lymphoma (DLBCL), and 30% experience aggressive disease. First-line therapy typically involves rituximab ± chemotherapy, with splenectomy reserved for select cases [1][3][5][14].
Burden
Prognosis: 5-year survival 77%, declining to 60% at 10 years; DLBCL transformation reduces median survival to <4 years [7][14][17].
Morbidity: Splenomegaly-related complications (pain, cytopenias) in 70% of patients; autoimmune manifestations in 20% [1][5][14].
Challenges: Lack of randomized trials due to rarity, relapse rates >50%, and morbidity risks from splenectomy [3][8][18].
Therapies
Asymptomatic/low tumor burden: Observation with monitoring [5][11][16].
Symptomatic disease: Rituximab monotherapy (90% response rate) ± maintenance; splenectomy for bulky splenomegaly/cytopenias in surgical candidates [3][8][13].
High-risk/transformed disease: Rituximab-chemo combinations (e.g., R-bendamustine) or novel agents (e.g., zanubrutinib for relapsed/refractory cases) [10][11][14].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
350 drug discovery papers about Splenic marginal zone lymphoma, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
350 drug discovery papers about Splenic marginal zone lymphoma, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-06-17 | Splenic Marginal Zone Lymphoma Presenting with Progressive Splenic Infarction and Acute Cholestatic Liver Injury- a Case Report
Abstract Background Splenic marginal zone lymphoma (SMZL) is a rare, indolent non-Hodgkin lymphoma. Progressive splenic infarction and acute cholestatic liver injury are uncommon complications, and their concurrent presentation has not been previously reported. Case Description A 76-year-old woman with remote breast cancer history and chronic splenomegaly with pancytopenia presented with worsening left-sided abdominal pain. Labs revealed pancytopenia and cholestatic liver injury. CT demonstrated a 22-cm spleen with multiple wedge-shaped infarcts and mildly heterogeneous hepatic enhancement. PET/CT showed diffuse splenic hypermetabolism, hypermetabolic periportal lymph nodes, and mildly increased bone marrow FDG uptake. Hemolysis workup including direct antiglobulin test and cold agglutinin titer was negative. Hepatitis B and C serologies were negative. D-dimer was markedly elevated at 3,840 ng/mL. MRCP excluded biliary obstruction. Percutaneous splenic core biopsy revealed nodular and intrasinusoidal infiltration by atypical B lymphocytes. Immunohistochemistry showed CD20, PAX5, and IgM positivity with kappa restriction; CD5, CD10, CD23, CD103, and cyclin D1 were negative. CD21 highlighted follicular dendritic cell meshworks colonized by neoplastic cells. The patient was staged as Ann Arbor stage IV. Rituximab monotherapy was initiated with clinical improvement. At 6-month follow-up, liver function normalized, cytopenias resolved, splenic size decreased from 22 to 17 cm, and PET/CT demonstrated partial metabolic response. Significance This is the first reported case of SMZL with concurrent splenic infarction and cholestatic liver injury. It highlights the diagnostic utility of splenic core biopsy with an expanded immunohistochemical panel and the efficacy of rituximab monotherapy in this clinical context.
2026-05-13 | Beyond Hypersplenism: Splenic Marginal Zone Lymphoma in an Older Adult with Hemoglobin E/Beta-Thalassemia.
With improvements in blood safety and availability, along with broad access to safe and effective iron chelation, outcomes for patients with thalassemia have greatly improved over recent decades. Previously a predominantly pediatric condition, thalassemia is now increasingly encountered in an aging population. We describe an adult man with HbE/β-thalassemia whose course was complicated by progressive splenomegaly and cytopenias, initially attributed to his underlying thalassemia. Further evaluation, however, revealed splenic marginal zone lymphoma. After the initiation of anti-B-cell therapy, he experienced rapid clinical improvement and was able to avoid surgical splenectomy. This case highlights how complications ascribed to thalassemia can overlap with other diagnoses that may become more prevalent with age, and demonstrates the importance of maintaining a broad differential when symptoms progress despite appropriate thalassemia-directed management.
2026-05-01 | B53-11 Refractory Antiphospholipid Syndrome Presenting as a Splenic Infarct and Mesenteric Mass - A Challenging Diagnosis
Abstract Introduction Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder that often affects young women. It is recognized by the presence of antiphospholipid antibodies, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and anti-beta-2-glycoprotein I (aβ2GPI) antibodies in the setting of venous or arterial thrombosis or pregnancy morbidity. APS can be primary or secondary to autoimmune diseases, drugs, infections, or malignancy. Clinicians should maintain a high index of suspicion for secondary APS, especially in older patients or those with progressive thrombosis despite adequate anticoagulation. This report presents an anticoagulant-refractory case of APS in a 60-year-old woman that was ultimately driven by an underlying lymphoproliferative disorder. Case Presentation A 60-year-old woman with hypertension, atrial fibrillation, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), gout, gastroesophageal reflux disease (GERD), and fatty liver disease presented with left upper quadrant abdominal pain associated with nausea, vomiting, and early satiety. A computerized tomography (CT) scan revealed splenomegaly with splenic infarcts. Coagulation studies showed a normal prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), and mild thrombocytopenia. The mixing study demonstrated persistently elevated aPTT. Complete blood count showed anemia and leukopenia. Haptoglobin was low, complement level was normal, and antinuclear antibody (ANA) was elevated. Autoimmune serology confirmed persistently elevated aCL, elevated aβ2GPI antibody, and LA. Since diagnosis, her course was marked by failure to respond to a direct oral anticoagulant and subsequently to warfarin, as evidenced by progressive splenomegaly and the appearance of new splenic infarcts. She was therefore transitioned to subcutaneous enoxaparin, but her symptoms did not improve. Repeat imaging showed a new enhancing right lower mesenteric mass of unclear etiology. Peripheral blood smear showed relative lymphocytosis, although the morphology was not diagnostic for chronic lymphocytic leukemia. Flow cytometry demonstrated involvement by a CD5-negative, CD10-negative kappa-restricted B-cell lymphoproliferative disorder. Bone marrow biopsy confirmed a monotypic CD5-negative, CD10-negative B-cell population most consistent with splenic marginal zone lymphoma. Discussion Late-onset APS that continues to cause recurrent arterial and venous thrombosis with organ infarction despite appropriate anticoagulation should raise suspicion for a secondary driver, including a paraneoplastic process. In this patient, the refractory thrombotic behavior was related to an underlying lymphoproliferative disorder. Adequate anticoagulation could not be achieved without addressing the driving malignancy. She was started on rituximab 375 mg/m² intravenously (IV) weekly in addition to therapeutic enoxaparin 80 mg subcutaneously twice daily and aspirin 81 mg daily, resulting in clinical improvement. This abstract is funded by: None
2026-05-01 | C32-21 Unmasking the Swell: Recurrent Acquired Angioedema as a Manifestation of Marginal Zone Lymphoma
Abstract Introduction Acquired angioedema (AAE) due to C1-esterase inhibitor (C1-INH) deficiency is a rare, potentially fatal disorder caused by increased bradykinin activity leading to vascular permeability and submucosal edema. Unlike hereditary angioedema, AAE typically presents later in life, lacks a family history, and is frequently associated with underlying B-cell lymphoproliferative disorders or autoimmune diseases. Among these, splenic marginal zone lymphoma (MZL) is disproportionately represented, highlighting a paraneoplastic link between complement consumption and tumor activity. Because bradykinin-mediated angioedema does not respond to epinephrine, corticosteroids, or antihistamines, recognition and disease-specific management are crucial to avoid airway compromise. Case Description A 65-year-old woman with newly diagnosed splenic MZL presented with her third episode of sudden tongue swelling now accompanied by progressive dysarthria, drooling, and respiratory distress. In the emergency department, she was administered 1g intravenous (IV) Tranexamic acid, 20 mg IV Famotidine, 50 mg IV Diphenhydramine, and 125 mg IV Methylprednisolone without improvement. Worsening edema necessitated emergent endotracheal intubation for impending airway obstruction.In the intensive care unit, she was treated with intravenous corticosteroids, diphenhydramine, famotidine, and received two units of fresh frozen plasma. Complement studies revealed a low C1q level (<2 mg/dL), and markedly reduced C1 esterase inhibitor assay ( 7%), confirming acquired C1-INH deficiency. C4 level was also depressed, and autoimmune serologies were negative. Following stabilization, she self-extubated without rebound swelling and was discharged with hematology follow-up for ongoing lymphoma-directed therapy and referral to Allergy-Immunology. Discussion This case underscores a rare but clinically significant manifestation of AAE in the setting of splenic MZL. Adult-onset, recurrent, non-pruritic angioedema unresponsive to conventional histaminergic therapies should prompt evaluation for bradykinin-mediated etiologies. Diagnostic confirmation relies on complement testing, specifically, low C1q and C1-INH levels with normal C1-INH gene sequence, distinguishing AAE from hereditary forms. Acute management centers on airway protection and targeted therapy such as plasma-derived or recombinant C1-INH, icatibant (a bradykinin B2-receptor antagonist), or ecallantide (a kallikrein inhibitor), when available. FFP remains a pragmatic option in resource-limited settings. Long-term control depends on treating the underlying lymphoproliferative disorder, which can normalize complement levels and prevent recurrence.Heightened clinical awareness of AAE in patients with unexplained angioedema and concurrent B-cell malignancies can prevent morbidity and mortality through timely diagnosis and multidisciplinary management. This abstract is funded by: none
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.
2026-06-17 | Splenic Marginal Zone Lymphoma Presenting with Progressive Splenic Infarction and Acute Cholestatic Liver Injury- a Case Report
Abstract Background Splenic marginal zone lymphoma (SMZL) is a rare, indolent non-Hodgkin lymphoma. Progressive splenic infarction and acute cholestatic liver injury are uncommon complications, and their concurrent presentation has not been previously reported. Case Description A 76-year-old woman with remote breast cancer history and chronic splenomegaly with pancytopenia presented with worsening left-sided abdominal pain. Labs revealed pancytopenia and cholestatic liver injury. CT demonstrated a 22-cm spleen with multiple wedge-shaped infarcts and mildly heterogeneous hepatic enhancement. PET/CT showed diffuse splenic hypermetabolism, hypermetabolic periportal lymph nodes, and mildly increased bone marrow FDG uptake. Hemolysis workup including direct antiglobulin test and cold agglutinin titer was negative. Hepatitis B and C serologies were negative. D-dimer was markedly elevated at 3,840 ng/mL. MRCP excluded biliary obstruction. Percutaneous splenic core biopsy revealed nodular and intrasinusoidal infiltration by atypical B lymphocytes. Immunohistochemistry showed CD20, PAX5, and IgM positivity with kappa restriction; CD5, CD10, CD23, CD103, and cyclin D1 were negative. CD21 highlighted follicular dendritic cell meshworks colonized by neoplastic cells. The patient was staged as Ann Arbor stage IV. Rituximab monotherapy was initiated with clinical improvement. At 6-month follow-up, liver function normalized, cytopenias resolved, splenic size decreased from 22 to 17 cm, and PET/CT demonstrated partial metabolic response. Significance This is the first reported case of SMZL with concurrent splenic infarction and cholestatic liver injury. It highlights the diagnostic utility of splenic core biopsy with an expanded immunohistochemical panel and the efficacy of rituximab monotherapy in this clinical context.
2026-05-13 | Beyond Hypersplenism: Splenic Marginal Zone Lymphoma in an Older Adult with Hemoglobin E/Beta-Thalassemia.
With improvements in blood safety and availability, along with broad access to safe and effective iron chelation, outcomes for patients with thalassemia have greatly improved over recent decades. Previously a predominantly pediatric condition, thalassemia is now increasingly encountered in an aging population. We describe an adult man with HbE/β-thalassemia whose course was complicated by progressive splenomegaly and cytopenias, initially attributed to his underlying thalassemia. Further evaluation, however, revealed splenic marginal zone lymphoma. After the initiation of anti-B-cell therapy, he experienced rapid clinical improvement and was able to avoid surgical splenectomy. This case highlights how complications ascribed to thalassemia can overlap with other diagnoses that may become more prevalent with age, and demonstrates the importance of maintaining a broad differential when symptoms progress despite appropriate thalassemia-directed management.
2026-05-01 | B53-11 Refractory Antiphospholipid Syndrome Presenting as a Splenic Infarct and Mesenteric Mass - A Challenging Diagnosis
Abstract Introduction Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder that often affects young women. It is recognized by the presence of antiphospholipid antibodies, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and anti-beta-2-glycoprotein I (aβ2GPI) antibodies in the setting of venous or arterial thrombosis or pregnancy morbidity. APS can be primary or secondary to autoimmune diseases, drugs, infections, or malignancy. Clinicians should maintain a high index of suspicion for secondary APS, especially in older patients or those with progressive thrombosis despite adequate anticoagulation. This report presents an anticoagulant-refractory case of APS in a 60-year-old woman that was ultimately driven by an underlying lymphoproliferative disorder. Case Presentation A 60-year-old woman with hypertension, atrial fibrillation, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), gout, gastroesophageal reflux disease (GERD), and fatty liver disease presented with left upper quadrant abdominal pain associated with nausea, vomiting, and early satiety. A computerized tomography (CT) scan revealed splenomegaly with splenic infarcts. Coagulation studies showed a normal prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), and mild thrombocytopenia. The mixing study demonstrated persistently elevated aPTT. Complete blood count showed anemia and leukopenia. Haptoglobin was low, complement level was normal, and antinuclear antibody (ANA) was elevated. Autoimmune serology confirmed persistently elevated aCL, elevated aβ2GPI antibody, and LA. Since diagnosis, her course was marked by failure to respond to a direct oral anticoagulant and subsequently to warfarin, as evidenced by progressive splenomegaly and the appearance of new splenic infarcts. She was therefore transitioned to subcutaneous enoxaparin, but her symptoms did not improve. Repeat imaging showed a new enhancing right lower mesenteric mass of unclear etiology. Peripheral blood smear showed relative lymphocytosis, although the morphology was not diagnostic for chronic lymphocytic leukemia. Flow cytometry demonstrated involvement by a CD5-negative, CD10-negative kappa-restricted B-cell lymphoproliferative disorder. Bone marrow biopsy confirmed a monotypic CD5-negative, CD10-negative B-cell population most consistent with splenic marginal zone lymphoma. Discussion Late-onset APS that continues to cause recurrent arterial and venous thrombosis with organ infarction despite appropriate anticoagulation should raise suspicion for a secondary driver, including a paraneoplastic process. In this patient, the refractory thrombotic behavior was related to an underlying lymphoproliferative disorder. Adequate anticoagulation could not be achieved without addressing the driving malignancy. She was started on rituximab 375 mg/m² intravenously (IV) weekly in addition to therapeutic enoxaparin 80 mg subcutaneously twice daily and aspirin 81 mg daily, resulting in clinical improvement. This abstract is funded by: None
2026-05-01 | C32-21 Unmasking the Swell: Recurrent Acquired Angioedema as a Manifestation of Marginal Zone Lymphoma
Abstract Introduction Acquired angioedema (AAE) due to C1-esterase inhibitor (C1-INH) deficiency is a rare, potentially fatal disorder caused by increased bradykinin activity leading to vascular permeability and submucosal edema. Unlike hereditary angioedema, AAE typically presents later in life, lacks a family history, and is frequently associated with underlying B-cell lymphoproliferative disorders or autoimmune diseases. Among these, splenic marginal zone lymphoma (MZL) is disproportionately represented, highlighting a paraneoplastic link between complement consumption and tumor activity. Because bradykinin-mediated angioedema does not respond to epinephrine, corticosteroids, or antihistamines, recognition and disease-specific management are crucial to avoid airway compromise. Case Description A 65-year-old woman with newly diagnosed splenic MZL presented with her third episode of sudden tongue swelling now accompanied by progressive dysarthria, drooling, and respiratory distress. In the emergency department, she was administered 1g intravenous (IV) Tranexamic acid, 20 mg IV Famotidine, 50 mg IV Diphenhydramine, and 125 mg IV Methylprednisolone without improvement. Worsening edema necessitated emergent endotracheal intubation for impending airway obstruction.In the intensive care unit, she was treated with intravenous corticosteroids, diphenhydramine, famotidine, and received two units of fresh frozen plasma. Complement studies revealed a low C1q level (<2 mg/dL), and markedly reduced C1 esterase inhibitor assay ( 7%), confirming acquired C1-INH deficiency. C4 level was also depressed, and autoimmune serologies were negative. Following stabilization, she self-extubated without rebound swelling and was discharged with hematology follow-up for ongoing lymphoma-directed therapy and referral to Allergy-Immunology. Discussion This case underscores a rare but clinically significant manifestation of AAE in the setting of splenic MZL. Adult-onset, recurrent, non-pruritic angioedema unresponsive to conventional histaminergic therapies should prompt evaluation for bradykinin-mediated etiologies. Diagnostic confirmation relies on complement testing, specifically, low C1q and C1-INH levels with normal C1-INH gene sequence, distinguishing AAE from hereditary forms. Acute management centers on airway protection and targeted therapy such as plasma-derived or recombinant C1-INH, icatibant (a bradykinin B2-receptor antagonist), or ecallantide (a kallikrein inhibitor), when available. FFP remains a pragmatic option in resource-limited settings. Long-term control depends on treating the underlying lymphoproliferative disorder, which can normalize complement levels and prevent recurrence.Heightened clinical awareness of AAE in patients with unexplained angioedema and concurrent B-cell malignancies can prevent morbidity and mortality through timely diagnosis and multidisciplinary management. This abstract is funded by: none
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Drug Discovery Landscape
12 orphan drug designations for Splenic marginal zone lymphoma, including 5 approved therapies.
12 orphan drug designations for Splenic marginal zone lymphoma, including 5 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
odronextamab | antibodies | FDA | 2025-04-16 | — | Regeneron Pharmaceuticals, Inc. |
tafasitamab-cxix | antibodies | FDA | 2024-12-03 | — | Incyte Corporation |
lisocabtagene maraleucel [Breyanzi] | cell therapies | FDA | 2023-04-17 | 2025-12-04 | Juno Therapeutics, Inc., a Bristol-Myers Squibb Company |
zanubrutinib [Brukinsa] | small molecules | FDA | 2020-08-24 | 2021-09-14 | BeOne Medicines USA, Inc. |
parsaclisib | small molecules | FDA | 2019-09-10 | — | Incyte Corporation |
umbralisib [Ukoniq] | small molecules | FDA | 2019-04-11 | 2021-02-05 | TG Therapeutics, Inc. |
obinutuzumab | antibodies | FDA | 2017-08-17 | — | Genentech Inc., a member of the Roche Group |
copanlisib | small molecules | FDA | 2017-02-07 | — | Bayer HealthCare Pharmaceuticals, Inc. |
lenalidomide [Revlimid] | small molecules | FDA | 2017-01-04 | 2019-05-28 | Celgene Corporation |
obinutuzumab | antibodies | FDA | 2015-06-11 | — | Genentech, Inc. |
ibrutinib [Imbruvica] | small molecules | FDA | 2015-02-05 | 2017-01-18 | Pharmacyclics, LLC |
idelalisib | small molecules | FDA | 2013-10-15 | — | Gilead Sciences, Inc. |
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