Chronic lymphocytic leukemia infiltration of a transplanted kidney successfully treated with venetoclax and obinutuzumab: a case report

Introduction

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the United States comprising 25% to 30% of all adult leukemias (1). CLL mostly involves bone marrow, peripheral blood and lymphoid organs with extra nodal involvement occurring in about 10% of patients. Among patients with extra nodal manifestation, cutaneous manifestations are relatively common at 25% (2). Central nervous system (CNS), cardio-pulmonary, gastrointestinal (GI), hepatic and renal involvement is uncommon at <1% (3,4).

CLL involvement of kidneys histologically appear as diffuse mature lymphocyte infiltration in the renal interstitium replacing the renal tubules and peritubular capillaries and less commonly glomeruli. Membranoproliferative glomerulonephritis (MPGN) is often present with mesangial proliferation and glomerular deposits composed of monoclonal immunoglobulins. Some patients present with paraneoplastic syndrome in the form of minimal change disease which histologically appears normal in light microscopy (5). Autopsy studies indicate that lymphocytic infiltration occurs in 60–90% of CLL patients, though it usually does not lead to renal impairment, necessitating treatment in only a small fraction (1.2%) of cases (6,7).

In this case report we present a patient with CLL and end-stage renal disease (ESRD) who received a deceased donor renal transplant but subsequently developed CLL infiltration of his transplanted kidney, in the absence of systemic progression, successfully treated with venetoclax and obinutuzumab. We present this case in accordance with the CARE reporting checklist (available at https://aol.amegroups.com/article/view/10.21037/aol-23-25/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Our patient is a 71-year-old male with chronic kidney disease (CKD), who first presented in late 2012 with a sensation of a “tickle in the throat” and was found to have bilateral enlarged tonsils. A tonsillectomy was performed and the biopsy revealed bilateral involvement with small lymphocytic lymphoma without large cell transformation. A computed tomography (CT) scan of the chest, abdomen, and pelvis showed diffuse but non-pathological lymphadenopathy. A bone marrow biopsy demonstrated a slightly hypercellular marrow, with 50–65% CLL infiltration. Fluorescence in situ hybridization (FISH) was notable for 13q deletion and trisomy 12. Immunohistochemical staining was positive for CD5, CD19 and CD20. Ki-67 proliferation index was at 10% and staining was negative for cyclin D1. Flow cytometry identified a very prominent neoplastic lymphocyte population representing about 81% of total lymphocyte studied. These neoplastic cells lacked significant CD10 expression and showed dim surface kappa light chain restriction. Following these findings, observation was recommended.

In the interim his CKD progressed to stage 4 due to congenital atrophic kidneys complicated by reflux nephropathy and he was placed on renal transplant list. An interval follow-up bone marrow biopsy in mid-October 2017 showed 85–90% CLL marrow involvement and given concerns for progressive CLL, he was removed from the transplant list. However, he remained clinically asymptomatic with stable mild thrombocytopenia (>100,000/mm³) and was monitored clinically with complete blood count every 2 months and without any treatment. A CT scan of chest, abdomen and pelvis was stable with no lymphadenopathy.

Renal transplant was re-considered since the CLL was stable and the patient underwent a successful deceased donor kidney transplant in late May 2019. He underwent induction with basiliximab, followed by maintenance with mycophenolate, tacrolimus and prednisone. Late August 2019, a kidney biopsy was performed for surveillance purposes, revealing scattered involvement of approximately 5% by CLL (Figure 1). There were no morphological features to suggest an immune complex glomerulonephritis. Immunofluorescence panel demonstrated no significant glomerular staining for IgG, IgA, IgM, C2, C1q, kappa or lambda light chains, or fibrin/fibrinogen. His renal function was stable with creatinine at post-transplant baseline of 1.1–1.2 mg/dL. At the same time, tacrolimus was switched to sirolimus due to his history of skin cancer. He had routine labs in October 2019 where his serum creatinine trended up to 1.58 mg/dL (estimated glomerular filtration rate, EGFR of 44 mL/min). He had a second transplant kidney biopsy early December 2019 where CLL involved approximately 50% of the sampled cortex with evolving tubular atrophy and interstitial fibrosis (Figure 2). Epstein Barr virus (EBV) by in situ hybridization and human herpesvirus 8 (HHV8) immunostaining were negative, providing evidence against a form of post-transplant lymphoproliferative disorder (PTLD). There was no evidence of graft rejection and he had persistently elevated creatinine. Urinalysis was negative for hematuria or proteinuria. Blood pressure was well controlled. His C3, C4, and antineutrophil cytoplasmic antibody (ANCA) levels were within normal limits. Immunofixation testing showed normal pattern with no monoclonal proteins. He did not tolerate the sirolimus well, developing pedal edema and fatigue. He also developed neutropenia felt to be the result of combination of mycophenolate and sirolimus requiring filgrastim-sndz support. Mycophenolate was stopped temporarily and sirolimus was switched back to tacrolimus. Prednisone dosage was increased to 1 mg/kg daily.

Figure 1 Surveillance allograft kidney biopsy 3 months post-transplant showed focal (5% of cortex) interstitial infiltrates consistent with CLL/SLL without tubulitis or features of rejection (periodic acid-Schiff stain; magnification, 100×). CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma.

Figure 2 Kidney biopsy performed 6 months post-transplant in the setting of a rising creatinine showed diffuse (50%) cortical involvement by CLL/SLL (periodic acid-Schiff stain; magnification, 100×). The B-cells expressed CD20 (upper inset) with scattered CD3-positive T-cells (lower inset), with co-expression of CD5 (not shown), characteristic of CLL/SLL (immunohistochemical stain; magnification, 100×). CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma.

Given worsening renal function, he met criteria for active disease based on international workshop on CLL (iwCLL) guidelines (8). CLL directed therapy with the fully humanized anti-CD20 monoclonal antibody obinutuzumab was initiated and the bcl-2 inhibitor venetoclax was added on the 8th day of the cycle in December 2019. He initially received venetoclax 20 mg daily, escalating weekly as planned. However, he developed neutropenia at the 400 mg dose, necessitating dose reduction to 200 mg/day initially and eventually to 100 mg/day. Both obinutuzumab and venetoclax were discontinued after the 4th cycle due to ongoing neutropenia.

In May 2020, a third kidney biopsy showed no evidence of CLL with normalization of renal function back to baseline (Figure 3). By November 2020, peripheral blood showed no CLL using multi-color flow cytometry (0.01% sensitivity) consistent with a minimal residual disease (MRD) negative complete remission, a favorable prognostic indicator with normal renal function (Figure 4). Four years later the patient remains MRD negative, off treatment without any indication of recurrent renal CLL involvement.

Figure 3 Kidney biopsy performed at 1-year post-transplant and after four cycles of obinutuzumab and venetoclax was negative for CLL/SLL (periodic acid-Schiff stain; magnification, 100×). CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma.

Figure 4 Creatinine trend.

Discussion

We present a case of ESRD due to congenital atrophic kidneys complicated by reflux nephropathy who underwent renal transplant. Prior to transplant, CLL was being monitored clinically without any treatment. However, post-transplant, the clinical course was complicated by CLL infiltration of the allograft kidney with associated renal impairment. He had difficulty tolerating the treatment for CLL due to neutropenia and did not complete the course. However, his renal function remains stable and he has no evidence of CLL. With ongoing MRD negativity, he continues to do well 4 years post-transplant. To our knowledge, there have been no reports of CLL patients who have undergone renal transplants subsequently treated with venetoclax and obinutuzumab and achieved a durable remission. Our case offers hope for those patients and could inform broader renal transplant eligibility considerations (9).

CLL is a disease of the elderly with median age at diagnosis of about 70 years (10). Given the prevalence of multiple comorbidities in this population, long-term survival exceeding 10 years is possible, making some CLL patients eligible for renal transplant. Multiple studies have shown kidney transplantation is associated with lower mortality and improved quality of life compared to hemodialysis (11). While targeted therapies have significantly improved outcomes of CLL patients, the challenges associated with long-term dialysis may pose a greater barrier to longevity than CLL itself. Nonetheless, genuine concerns have arisen regarding a higher occurrence of complications, including infections (12), graft failure, CLL progression, Richter’s transformation and PTLD (13). Due to these concerns, the presence of CLL is frequently viewed as a contraindication to transplantation (9). Currently American Society of Transplantation recommends no waiting period for monoclonal B-cell lymphocytosis and waiting period of 2 to 3 years after treatment for CLL (14). Consequently, the number of patients with CLL who get kidney transplant remains very small (13).

Autopsy studies indicate frequent lymphocytic infiltration of kidneys in CLL patients, often asymptomatic, with only a small percentage (1.2%) requiring treatment (6,7). Renal complications in CLL often manifest as membranoproliferative glomerulonephritis, presenting as acute kidney injury or nephrotic syndrome which is thought to be paraneoplastic phenomenon (15). The data on patients with CLL developing renal infiltration is limited to a handful of cases (6,13).

Strati et al. reported four patients with CLL who underwent renal transplant. After a median follow-up of 52 months, none of these patients developed progressive disease or Ritcher’s transformation. Serious infections necessitating hospitalization occurred in two patients. Two of these patients experienced graft failure and required hemodialysis. None of these patients required any therapy for CLL (13). Historically, before the incorporation of targeted agents, CLL patients with renal transplants have done poorly, so in many cases, CLL patients are excluded from transplant. d’Ythurbide et al. reported a case series of four patients with CLL who subsequently received renal transplant (6). Authors found two had rapid worsening of renal function with finding of CLL infiltrates in the kidneys and one patient had recurrence of glomerulonephritis. One of these patients was treated with chlorambucil and the other with radiotherapy with overall poor response and no improvement in renal function (6). All patients suffered severe infectious complications. In addition to worsening renal function, CLL progression was another issue related to immunosuppression regimen following the transplant. Two of the patients had CLL progression and were treated with chlorambucil and mini-CHOP. These patients tolerated additional chemotherapy for CLL very poorly and 3 out of 4 patients died from complications related to CLL progression. The likelihood of disease progression in CLL is determined by a range of factors such as clinical staging at diagnosis, genetic and biological attributes, and whether the patient is new to the treatment or has relapsed/refractory disease (13). Although few cases have been described, there does appear to be predilection for CLL infiltration in the kidneys post-transplant. Any etiology is speculative but could be the result of immunosuppression. Given asymptomatic CLL infiltration of kidneys are fairly common based on autopsy studies, addition of immunosuppressant can indirectly increase cancer risk by hindering immune surveillance and promoting oncogenic viruses (16). Recent studies have shown that the allograft immune microenvironment plays a key role in graft rejection and can contribute to progression of CLL in transplanted kidney (17). This includes complex interaction between chronic antigenic stimulation by graft kidney, immunosuppression and donor derived immune cells accompanying the graft (17). Although other targeted regimens including Bruton’s tyrosine kinase (BTK) inhibition could be considered in this setting, we opted to treat with obinutuzumab and venetoclax, which is associated with rapid disease clearance and high rates of MRD negativity using a fixed duration regimen (18). Notably, the study by Fischer et al. excluded patients with Creatinine clearance of <30 mL/min (18). To our knowledge, this is the first reported case of CLL in transplant recipient that was successfully treated with targeted therapy.

Conclusions

In conclusion, our case suggests that CLL infiltration and progression remains a concern in patients who have received renal transplant with risk amplified by immunosuppression. Our case also highlights the efficacy of venetoclax and obinutuzumab in treating CLL post renal transplant and supports the idea that appropriately selected patients can be suitable candidates for renal transplant. More studies are needed to further define the incidence of CLL renal infiltration post-transplant and best treatment approaches.

Take home points

• CLL patients who receive kidney transplantation can have CLL progression with infiltration of the kidneys. These patients need careful monitoring of their renal function.
• Historically these patients had poor prognosis but with advent of targeted therapy they can achieve deep and long-lasting remission.
• Appropriately selected CLL patients can be candidates for kidney transplant.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://aol.amegroups.com/article/view/10.21037/aol-23-25/rc

Peer Review File: Available at https://aol.amegroups.com/article/view/10.21037/aol-23-25/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aol.amegroups.com/article/view/10.21037/aol-23-25/coif). S.S. is a Distinguished Scholar in Leukemia and Lymphoma Research which provides support for research projects. Expert testimony: Abbvie. Program Research Support: Acerta Pharma, Gilead Sciences, Celgene-BMS, Janssen, Profound Bio, Genentech, Beigene, Verastem, Pharmacyclics. Paid Consultancy: ADCT Therapeutics, Genentec. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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