Mosunetuzumab Successfully Treated Rituximab‐Refractory Lymphoma‐Associated Protein‐Losing Enteropathy With Concomitant Immune Thrombocytopenia in Follicular Lymphoma: A Case Report

ABSTRACT

Protein‐losing enteropathy (PLE) is a rare but potentially severe complication of malignant lymphoma characterized by excessive gastrointestinal loss of plasma proteins, leading to hypoalbuminemia, edema, and serous effusions. We report a case of follicular lymphoma complicated by severe PLE and concomitant immune thrombocytopenia (ITP) without gastrointestinal involvement. A 51‐year‐old man presented with progressive hypoalbuminemia, refractory ascites, thrombocytopenia, and systemic lymphadenopathy. Initial treatment with rituximab monotherapy was selected due to low tumor burden and ITP, followed by rituximab plus lenalidomide (R2), but both resulted in only transient responses. ^99mTc‐labeled human serum albumin scintigraphy confirmed the diagnosis of PLE. Mosunetuzumab was initiated as third‐line therapy. Serum albumin levels increased from 0.7 g/dL to approximately 2.0 g/dL, accompanied by marked improvement in ascites and edema. Platelet counts, which had initially been reduced to approximately 30,000/µL, normalized after rituximab and further increased to 300,000–500,000/µL following mosunetuzumab. Complete remission was achieved and has been maintained for over four months at the time of writing. This case suggests that mosunetuzumab may effectively control both lymphoma‐associated PLE and immune‐mediated cytopenia through deeper and more sustained B‐cell depletion.

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1. Introduction

Protein‐losing enteropathy (PLE) is characterized by excessive loss of plasma proteins into the gastrointestinal tract, resulting in hypoalbuminemia, edema, and serous effusions. It is associated with a wide range of gastrointestinal and systemic diseases, including inflammatory, cardiac, hepatic, and lymphatic disorders.

Malignant lymphoma is a recognized underlying disease that leads to the development of PLE as a secondary manifestation [1]. In many cases, PLE is attributed to direct gastrointestinal infiltration of lymphoma, leading to disruption of the mucosal barrier. However, PLE may also occur in the absence of detectable mucosal lesions, suggesting alternative mechanisms such as lymphatic dysfunction or immune‐mediated processes [2, 3].

Mosunetuzumab is a CD20 × CD3 bispecific antibody that redirects cytotoxic T cells to eliminate CD20‐positive malignant B cells and has demonstrated high clinical activity in relapsed or refractory follicular lymphoma (FL) [4]. However, its role in lymphoma‐associated PLE has rarely been reported.

Here, we describe a case of rituximab‐refractory FL complicated by PLE without gastrointestinal involvement, successfully treated with mosunetuzumab.

2. Case Presentation

A 51‐year‐old man was referred for evaluation of progressive hypoalbuminemia, generalized edema, thrombocytopenia, and lymphadenopathy. He had no significant past medical or family history. Initial laboratory findings revealed total protein 3.6 g/dL, albumin 1.4 g/dL, and platelet count 54,000/µL. Urinalysis showed no proteinuria, and there was no evidence of liver dysfunction. Further evaluation supported the diagnosis of immune thrombocytopenia. Lymph node biopsy demonstrated FL (Grade 1–2). Bone marrow involvement was absent. FDG‐PET/CT demonstrated lymphadenopathy involving the cervical, axillary, supraclavicular, inguinal regions, and right upper lung lobe, consistent with Ann Arbor Stage IV disease. No gastrointestinal or mesenteric involvement was observed. The tumor burden was evaluated as low according to the GELF criteria, as the patient had no bulky lesions (> 7 cm), normal LDH levels, no significant cytopenia related to bone marrow infiltration, and no systemic B symptoms.

Rituximab monotherapy was selected as initial treatment due to low tumor burden and concomitant immune thrombocytopenia, with the expectation of both lymphoma control and platelet recovery. Platelet counts rapidly normalized following treatment, accompanied by improvement in serum albumin levels. However, hypoalbuminemia subsequently recurred along with disease progression, manifested as recurrent cervical lymphadenopathy. A repeat lymph node biopsy was performed. The specimen was independently reviewed by two institutional pathologists and further evaluated by a hematopathology expert (Prof. Naoya Nakamura, Tokai University). A final consensus was reached via a multidisciplinary tumor board. Immunohistochemistry (IHC) revealed that the atypical lymphocytes within the follicles were positive for CD20, CD10, and BCL6, with abnormal, strong expression of BCL2. BCL2 split fluorescence in situ hybridization (FISH) assay was positive for BCL2 rearrangement, confirming a diagnosis of FL. Interestingly, the interfollicular area showed features mimicking angioimmunoblastic T‐cell lymphoma (AITL), including a diffuse proliferation of CD4+ T cells, infiltration of eosinophils, proliferation of collagen fibers, and an increased meshwork of CD21‐positive follicular dendritic cells. Although further molecular studies (such as TCR gene rearrangement, TET2/DNMT3A mutations, or next‐generation sequencing) were not performed, the combination of distinct follicular morphology, characteristic immunophenotype, and BCL2 rearrangement firmly established the diagnosis of classic nodal FL with a prominent AITL‐like reactive microenvironment.

Second‐line therapy with rituximab plus lenalidomide (R2) was initiated and discontinued after 11 cycles due to only transient response.

In May 2025, the patient developed progressive abdominal fullness and dyspnea due to massive ascites and bilateral pleural effusions. Serum albumin levels rapidly decreased to 0.7 g/dL. Although PLE was retrospectively considered to have been present since the initial presentation, contributing to the baseline hypoalbuminemia, it was not clinically suspected during the staging phase because both upper and lower gastrointestinal endoscopies had revealed no remarkable abnormalities, and diarrhea was completely absent. Consequently, fecal alpha‐1 antitrypsin clearance was not evaluated at staging. However, the subsequent development of extreme hypoalbuminemia and progressive serous effusions secondary to lymphoma progression strongly pointed toward the exacerbation of PLE. To establish a definitive diagnosis, ^99mTc‐labeled human serum albumin scintigraphy was performed. The scan clearly demonstrated abnormal tracer accumulation in the intestines (Figure 1), thereby successfully confirming the diagnosis of PLE.

FIGURE 1.

^99mTc‐labeled human serum albumin scintigraphy demonstrating protein leakage into the gastrointestinal tract. Anterior images obtained at 2, 4, 6, and 24 h after tracer administration (A–D) show progressive accumulation of radioactivity in the intestinal lumen (arrows), consistent with protein‐losing enteropathy (PLE).

Mosunetuzumab therapy was initiated. Serum albumin levels gradually increased to approximately 2.0 g/dL, accompanied by marked improvement in ascites and peripheral edema. Platelet counts further increased and stabilized at 300,000–500,000/µL. Complete remission was achieved after eight cycles, and treatment was continued for two additional cycles, for a total of 10 cycles. Treatment was discontinued at this point because the recovery of the serum albumin level had reached a plateau phase by Cycle 10, and completing 10 cycles was deemed optimal to maintain durable efficacy while minimizing potential cumulative toxicities associated with extended dosing.

The patient remains in complete remission with stable albumin levels as of March 2026. Treatment was well tolerated, and no treatment interruptions or significant adverse events were observed (Figure 2).

FIGURE 2.

Clinical course of serum albumin levels and platelet counts during treatment. Serum albumin levels (●, left axis, g/dL) and platelet counts (△, right axis, ×10⁴/µL) are plotted over time. The treatment periods of rituximab (R), rituximab plus lenalidomide (R2), and mosunetuzumab are indicated. Following initiation of mosunetuzumab, both serum albumin levels and platelet counts increased in parallel, accompanied by marked improvement in ascites and peripheral edema. Complete remission was achieved and has been maintained.

3. Discussion

The mechanisms of lymphoma‐associated PLE are generally categorized into three pathways: lymphatic obstruction, mucosal injury, and increased intestinal permeability [1].

In the present case, mechanical lymphatic obstruction was unlikely because tumor burden was low and no mesenteric or retroperitoneal lymphadenopathy was observed. Furthermore, endoscopic evaluation revealed no macroscopic mucosal abnormalities, making mucosal injury an unlikely primary mechanism.

Therefore, increased intestinal permeability due to cytokine‐mediated epithelial dysfunction is the most plausible mechanism. The clinical course supports this interpretation, as hypoalbuminemia closely paralleled lymphoma activity and improved following effective lymphoma treatment.

In lymphoma‐associated PLE, most reported cases are associated with gastrointestinal involvement or bulky disease. In contrast, cases without gastrointestinal lesions and with low tumor burden are rare, highlighting the uniqueness of the present case.

Importantly, the clinical course of platelet counts provides additional insight into the underlying disease biology. The patient initially presented with immune thrombocytopenia, which improved following rituximab therapy and further increased after treatment with mosunetuzumab.

This pattern suggests that B cells played a central role in immune dysregulation, contributing not only to thrombocytopenia but also to PLE. Rituximab achieved only transient control, whereas mosunetuzumab induced a more durable response. This difference may be explained by differences in the depth and sustainability of B‐cell depletion. Rituximab relies on Fc‐mediated cytotoxicity, whereas mosunetuzumab directly engages T cells to eliminate CD20‐positive B cells, potentially achieving deeper and more sustained B‐cell depletion [4, 5, 6].

The parallel improvement in platelet counts and serum albumin levels suggests that both ITP and PLE were driven by shared immune‐mediated mechanisms. More effective disruption of pathological immune interactions by mosunetuzumab may have resulted in simultaneous resolution of these conditions.

In addition, the histopathological finding of FL with AITL‐like features may provide further insight into the immune‐mediated mechanisms observed in this case. Although RHOA mutation was not detected, the presence of such features suggests a background of immune dysregulation. This may have contributed to both PLE and immune thrombocytopenia through cytokine‐mediated mechanisms and abnormal immune interactions. These findings may partly explain why clinical manifestations were not solely dependent on tumor burden but rather on functional immune disturbances.

This case highlights that even low‐tumor burden FL can cause clinically significant immune‐mediated complications and that mosunetuzumab may be an effective therapeutic option in such settings. This report has several limitations. As this is a single case, the generalizability of the findings is limited, and further studies are required to confirm the observed effects of mosunetuzumab.

4. Conclusion

Mosunetuzumab may represent a promising therapeutic option for lymphoma‐associated PLE and immune‐mediated cytopenia refractory to rituximab‐based therapy.

5. Patient Perspective

The patient reported a marked improvement in edema and overall well‐being following treatment with mosunetuzumab. The resolution of ascites and peripheral edema led to a significant improvement in daily activities and quality of life.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.