Rapid response to obinutuzumab and venetoclax in patients with nephrotic syndrome related to CLL: a report of two cases

1 Introduction

Chronic lymphocytic leukemia (CLL) is derived from neoplastic B-cell lymphocytes mostly involving the bone marrow and lymph nodes. Other lymphatic organs are infiltrated less frequently (1). Moreover, renal involvement in CLL is increasingly recognized as a clinically relevant complication, occurring in approximately 7.5% of patients at diagnosis and more frequently throughout the course of the disease (2–5). The underlying mechanisms of renal impairment are diverse, including direct leukemic infiltration of the renal parenchyma, obstructive uropathy from lymphadenopathy, treatment-related nephrotoxicity, tumor lysis syndrome, and immune-mediated glomerular injury (2–5).

Among renal complications, immune-mediated glomerulonephritis is a particularly important subset. Two large retrospective studies of renal biopsies in CLL and small lymphocytic lymphoma (SLL) have identified membranoproliferative glomerulonephritis (MPGN) as the most frequent histological finding (2, 4, 5).

Due to the rarity of these renal manifestations, treatment recommendations are largely based on individual case reports and small case series, and no standardized therapeutic approach has been established to date. Chemoimmunotherapy with agents such as rituximab, chlorambucil, and fludarabine has previously been reported as an effective treatment option (2, 6). However, data on the efficacy of newer agents routinely used in CLL therapy such as venetoclax or Bruton’s tyrosine kinase (BTK) inhibitors in the management of autoimmune renal complications remain scarce (7–10).

Here, we present two cases of CLL-associated nephrotic syndrome that responded rapidly and completely to treatment with obinutuzumab and venetoclax, without the need for additional immunosuppression.

2 Case description

2.1 Case 1

A 44-year-old patient presented with recurrent lower limb edema and swelling of the arms. Laboratory findings revealed hypoalbuminemia, and reduced blood total protein levels. Urine analysis showed severe proteinuria with a protein level of 5.7 g/gCrea (normal <100 mg/gCrea) and albuminuria with an albumin level of 5 g/gCrea (normal <30 mg/gCrea). At initial presentation, no hematologic findings indicative of CLL were present.

Due to clinical signs consistent with nephrotic syndrome, including edema, hyperlipoproteinemia (cholesterol 364 mg/dL [normal <200 mg/dL], triglycerides 170 mg/dL [normal <150 mg/dL]), hypoproteinemia (serum albumin 28.6 g/L [normal 35–52 g/L]), and proteinuria, a kidney biopsy was performed. Histological examination showed immunocomplex associated membranoproliferative Glomerulonephritis which was interpreted as active diffuse proliferative lupus nephritis class IV, (Figures 1a–c). Consequently, immunosuppressive therapy with mycophenolate mofetil (MMF) and prednisolone was initiated.

After six months of treatment, partial remission was achieved, with a reduction in proteinuria to 1.8 g/gCrea. However, the patient experienced a relapse while tapering prednisolone after 12 months. A differential blood count revealed smudge cells and atypical lymphocytes. Flow cytometry confirmed the presence of B-cell chronic lymphocytic leukemia (B-CLL) with kappa light chain restriction. Abdominal ultrasound showed no evidence of lymphadenopathy or hepatosplenomegaly. The patient was diagnosed with Binet stage A CLL (CLL-IPI score: 0), with no high-risk cytogenetic or molecular abnormalities and without any formal indication for treatment based on hematologic criteria alone.

Given the lack of response of the nephrotic syndrome to immunosuppressive therapy, CLL-induced MPGN was suspected. Therefore, in order to prevent irreversible renal damage, CLL therapy was initiated with obinutuzumab and venetoclax. Six weeks after treatment initiation, the patient reported complete resolution of peripheral edema. Therapy was administered according to the approved treatment protocol consisting of six cycles of obinutuzumab in combination with venetoclax, followed by six cycles of venetoclax monotherapy (11).

At the end of therapy, proteinuria decreased significantly (from 5.5 g/day to 0.7 g/day). Two years after therapy initiation, the patient remains in remission of the nephrotic syndrome, with albuminuria below 500 mg/day (Figure 2a) and without signs of peripheral edema. During follow-up, no relevant adverse events were observed, and renal function remained stable under regular clinical monitoring.

2.2 Case 2

A 73-year-old male patient presented with fever, lymphadenopathy, deterioration of general condition, edema, and significant mobility impairment (ECOG (Eastern Cooperative Oncology Group) performance status grade 3). Laboratory testing revealed anemia with a hemoglobin level of 8.0 g/dL [normal range 13.5 – 17.2 g/dL], thrombocytopenia with platelets at 64 Gpt/L [normal range 150–370 Gpt/L], and a leukocyte count of 5.91 Gpt/L [normal range 3.9 – 10.2 Gpt/L]. Computed tomography (CT) imaging demonstrated multiple enlarged lymph nodes. A right axillary lymph node excision and bone marrow biopsy were performed. Histological and immunophenotypic analyses confirmed the diagnosis of B-cell chronic lymphocytic leukemia (B-CLL), kappa light chain subtype, classified as Binet stage C and intermediate risk according to the CLL-IPI score (score: 3). Cytogenetic testing, including karyotyping, fluorescence in situ hybridization (FISH), and molecular genetic analyses, revealed no high-risk genetic abnormalities.

At the time of diagnosis, the patient also presented with nephrotic syndrome, characterized by edema, hyperlipoproteinemia (cholesterol 355 mg/dL [normal <200 mg/dL], triglycerides 180 mg/dL [normal <150 mg/dL]), hypoproteinemia (serum albumin 23 g/L [normal 35–52 g/L]), and marked proteinuria (14.7 g/g creatinine [normal <100 mg/g creatinine]). Additionally, the patient showed evidence of renal insufficiency, with a serum creatinine level of 200 µmol/L (normal <107 µmol/L) and an estimated glomerular filtration rate (eGFR) of 28 mL/min/1.73 m² [normal >89 mL/min/1.73 m²]. Renal biopsy revealed histologically MPGN.

We diagnosed secondary MPGN associated with CLL. Immunochemotherapy with obinutuzumab and venetoclax was initiated. In total 12 cycles of therapy were applied: six cycles of obinutuzumab combined with venetoclax, followed by six cycles of venetoclax monotherapy according to the official recommendations (11).

Following the first cycle of therapy, the patient developed tumor lysis syndrome up to CTCAE (Common Terminology Criteria for Adverse Events) grade 3, accompanied by febrile neutropenia. Management was performed according to standard protocols and included intravenous fluids, rasburicase, and antibiotic therapy.

After six cycles, there was a marked improvement in renal parameters. Proteinuria decreased significantly from 14.7 g/g creatinine to 0.2 g/g creatinine, and serum albumin normalized. Serum creatinine levels also improved from 200 µmol/L to 114 µmol/L (normal <107 µmol/L).

After treatment completion, CT and flow cytometry revealed no residual lymphadenopathy and no detectable CLL cells in the peripheral blood. Proteinuria was nearly completely resolved (0.23 g/g creatinine) (Figure 2b).

At three years of follow-up, the patient remains in complete remission of CLL. Proteinuria remains below the nephrotic threshold as well, with less than 250 mg in a 24-hour urine collection. During follow-up, no relevant adverse events occurred, and regular hematologic assessments confirmed sustained complete remission of CLL.

3 Discussion

Glomerulonephritis in chronic lymphocytic leukemia (CLL) is observed in approximately 7.5% of patients at diagnosis, with an increasing incidence over the course of the disease (2, 5). Despite this, clinically relevant renal involvement remains rare and is frequently underrecognized. Nephrotic syndrome may precede the diagnosis of CLL or occur at any stage of the disease and should be suspected in patients presenting with unexplained proteinuria, atypical glomerulonephritis, or disease refractory to standard immunosuppressive therapy, particularly in the presence of discordant serological findings.

According to current guidelines, treatment of CLL is recommended in cases of symptomatic or progressive disease (1). CLL-associated glomerular disease is not considered an independent criterion for therapy initiation, likely due to its rarity. Nevertheless, it is well established that successful treatment of the underlying leukemia often leads to improvement or resolution of renal involvement (2, 7–9, 12).

In our first case, the patient had an early-stage CLL without any formal indication for treatment based on hematologic criteria alone. However, she presented with a significant nephrotic syndrome that was initially suspected to be associated with lupus nephritis and therefore treated with immunosuppression. Due to insufficient response, CLL-induced MPGN was suspected. Despite Binet stage A/low-risk chronic lymphocytic leukemia, the presence of organ-threatening autoimmune renal disease was considered a sufficient indication to initiate systemic therapy to prevent irreversible renal damage. The iwCLL criteria recommend initiation of therapy in the presence of clinically relevant autoimmune complications, including autoimmune hemolytic anemia and immune thrombocytopenia (1). While severe autoimmune renal involvement is not explicitly addressed, we considered the organ-threatening nature of the disease sufficient justification for systemic treatment to avoid progressive renal impairment.

The second patient had a clear hematological indication for specific CLL therapy in addition to renal complications. Since the CLL did not present with high-risk features in both cases, treatment with obinutuzumab in combination with venetoclax was selected and administered as a time-limited approach with deep hematologic responses, rapid disease control, and a favorable safety profile (11, 13).

In both of our cases, treatment with venetoclax and obinutuzumab resulted in a rapid and profound hematologic and renal response, with complete resolution of the nephrotic syndrome and normalization of proteinuria within weeks of therapy initiation. Notably, this was achieved without the need for additional immunosuppressive therapy.

Historically, treatment strategies for CLL-associated MPGN included immunosuppression or chemoimmunotherapy with agents such as rituximab, chlorambucil, or fludarabine (2, 6). These approaches often resulted in partial or delayed responses and were associated with significant toxicities, especially in elderly or comorbid patients due to prolonged immunosuppression or myelosuppression.

In contrast, modern treatment approaches for CLL increasingly rely on targeted therapies such as Bruton’s tyrosine kinase inhibitors or the BCL2 inhibitor venetoclax, often in combination with monoclonal antibodies like obinutuzumab. However, data on the efficacy of these agents in treating autoimmune renal complications like MPGN remain limited to anecdotal case reports (8–11).

Our observations contribute to the growing body of evidence, suggesting that modern targeted therapies may offer a more effective and better-tolerated treatment option for patients with CLL-associated glomerulonephritis, particularly MPGN (8–11). The rapid clinical improvement observed in our patients highlights the importance of early recognition of renal involvement in CLL and the potential reversibility of kidney injury when appropriate systemic therapy is promptly initiated.

In patients presenting with unexplained nephrotic syndrome, particularly when the clinical course is atypical or refractory to immunosuppressive therapy, CLL should be considered as a potential underlying cause, and careful evaluation including peripheral blood smear and flow cytometry may facilitate early diagnosis.

4 Conclusion

Nephrotic syndrome due to CLL-associated MPGN is a rare but serious complication. In these two cases, treatment with the combination of venetoclax and obinutuzumab was associated with both hematologic response and improvement of renal manifestations. While these observations suggest a potential role for targeted therapies in the management of autoimmune renal complications of CLL, larger studies are required to better define their efficacy and generalizability.

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Footnotes

Edited by: Cherry Bansal, Tantia University, India

Reviewed by: Ya Zhang, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China

Kaushik Muralidharan, Nationwide Children’s Hospital, United States

Nagaishwarya Moka, Lincoln Memorial University, United States