Renal Failure in a Patient with Ibrutinib Refractory Chronic Lymphocytic Leukemia

The incidence of a renal lymphocytic infiltration in Chronic Lymphocytic Leukemia (CLL) is a fairly common phenomenon, found in a variable percentage of cases, as a result of autopsy studies. However, it is uncommon the association of the infiltrate with specific renal histopathological alterations, such as a Granulomatous Interstitial Nephritis (GIN), with severe kidney function impairment. We describe a patient with progressive TP53 mutated CLL who developed acute renal failure due to leukemic infiltration associated with GIN during treatment with ibrutinib, the new inhibitor of the Bruton’s tyrosine kinase. After stopping ibrutinib, the patient obtained a complete remission with high doses of prednisone plus chemoimmunotherapy, but recently he underwent relapse treated now with venetoclax plus prednisone. Paola Casciani1, Massimiliano Postorino1, Francesca Rossi2, Sergio Tripodi3, Annalisa Biagi1, Lisa Mercante1, Roberta Laureana1, Enrico Santinelli1, Maria Ilaria Del Principe1, Valter Gattei2 and Giovanni Del Poeta1* 1Department of Biomedicine and Prevention, Università Tor Vergata, Italy 2IRCCS Centro di Riferimento Oncologico, Italy 3UOC Pathological Anatomy, Azienda Ospedaliera Universitaria, Italy Annals of Clinical Case Reports Oncology Remedy Publications LLC. , | http://anncaserep.com/ 2019 | Volume 4 | Article 1749 2 Giovanni Del Poeta, et al., loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay [7]. Variable heavy chain genes of Immunoglobulins (IGHV) status resulted as unmutated, i.e. below the established cut-off of 2% of IGHV mutations (1.7% IGHV3-48*2). In April 2016, the patient presented a rapid increase in peripheral lymphocytosis (100.0 × 109/L), massive increase in mediastinal, abdominal lymph nodes, splenomegaly (24 cm on imaging) and B symptoms. A total Positron Emission Tomography/ Computed Tomography (PET/CT) scan, showing low Standardized Uptake Values (SUV) ruled out Richter’s syndrome transformation. Therefore, the patient started first-line treatment with oral ibrutinib in monotherapy at the dosage of 420 mg/d, according to the ESMO 2016 guidelines [8]. During the first month of treatment the patient showed discrete increase in total lymphocyte count and then a rapid decrease in the following three months. The values of hemoglobin and platelet remained stable as well as the hepatorenal function. A clinical and imaging re-evaluation of the disease carried out in July showed stable disease. In August 2016, the patient suddenly presented fever above 38°C together with lumbago and widespread bone pain. Creatinine (3.57 mg/dl), Azotemia (112 mg/dl), Proteinuria (0.22 gr/ dl) were abnormally increased and the patient was hospitalized for the onset of an acute renal failure. Ultrasonography showed a volumetric increase of both kidneys associated with parenchymal alterations. An immunoassay screening (IgA levels, C3 and C4 complement components) was negative for autoimmune disorders. Therefore, a renal biopsy was performed showing moderate peritubular and intratubular interstitial infiltrates by a clonal subpopulation of small CD20 and CD5 positive B-lymphocytes lacking CD23, Cyclin D1 and CD10 expression (Figure 1A,1B). The histopathology was also characterized by a population of CD3+ T lymphocytes and by a large, non-necrotizing chronic granulomatous phlogosis (Figure 1C,1D). No glomerular or tubulointerstitial immune complex deposits were detected by immunofluorescence (not shown). The peripheral blood immunophenotype performed by flow cytometry showed a CD20+/ CD5+/CD23and CD200+ homogeneous B-lymphocyte population, The FISH analysis and the TP53 mutations confirmed the same picture of the onset. After exclusion of a tuberculous or sarcoidotic nature of renal granulomas [9], the patient stopped ibrutinib and started therapy with methylprednisolone at the dose of 1 mg/Kg body weight obtaining a partial resolution of the renal failure. Afterwards, the patient was discharged from the hospital with prednisone therapy. In September 2016, he resumed oral therapy with ibrutinib at the standard dose of 420 mg per day. However, a certain degree of chronic renal failure (Creatinine 2.4 mg/dL, Azotemia 141 mg/dL), Anemia (Hemoglobin 11 g/dL), peripheral B clonal lymphocytosis (45.0 × 109/L), superficial and inner adenopathies persisted. For this reason, in October 2016, the patient discontinued therapy with ibrutinib and started chemoimmunotherapy according to the R-CHOP scheme (Rituximab 375 mg/m2, Cyclophosphamide 750 mg/m2, Vincristine 1.4 mg/m2, Doxorubicin 50 mg/m2 and Prednisone 40 mg/m2) for a total of six cycles, which was successfully completed in February 2017. During this second-line therapy, the renal function showed a remarkable improvement and creatinine levels were only slightly higher than normal (about 1.5 to 1.7 mg/ dL). The imaging re-evaluation, performed with TC total body, did not show either lymphadenopathies or splenomegaly. Therefore, the patient achieved a complete remission of the disease. In June 2019, the patient showed disease recurrence with increasing lymphocytosis (35.0 × 109/L), numerous superficial and inner lymph node swellings, splenomegaly, fair kidney failure (Creatinine 2.0 mg/dL) and bone marrow lymphocytic infiltrate. For this reason, in July 2019, the patient started treatment with venetoclax, an oral Bcl-2 inhibitor [10], and prednisone, which is ongoing.