Pathological feature in chronic myeloid leukemia patients with proteinuria receiving olverembatinib therapy Free

Objectives Olverembatinib is a novel 3^rd-generation tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML). However, long-term therapy raises concerns about treatment-related adverse events including proteinuria, hypertriglyceridemia, hyperglycemia, hypoalbuminemia, hypertension, arterial and/or venous obstructive events. To investigate the pathogenesis of proteinuria, we performed renal biopsies in 5 TKI-resistant patients with CML receiving olverembatinib therapy.

Methods Clinical and pathological data on TKI-resistant CML patients with proteinuria receiving olverembatinib therapy were analyzed retrospectively.

Results 5 CML-CP patients who had failed at least one TKI, developed proteinuria during olverembatinib treatment, and performed renal biopsy evaluation were included in this study. Among them, 3 patients developed de novo proteinuria during olverembatinib therapy, while 2 had mild proteinuria prior to olverembatinib therapy and developed nephrotic-range proteinuria during therapy. Median age at the time of renal biopsy was 44 years (range, 31-48 years). None of them had cardiovascular or renal comorbidities before olverembatinib therapy. Median CML history and prior TKI duration before olverembatinib therapy were 119 months (range, 9-189 months) and 29 months (range, 9-101 months), respectively. 2 patients were in MR4, each patient was in CHR, MMR and MR4.5 before renal biopsy. Median interval from starting olverembatinib therapy to renal biopsy was 34 months (range, 25-59 months). Before renal biopsy the median serum creatinine and estimated glomerular filtration (eGFR) was 94 μmol/L (range, 59-101 μmol/L) and 78 ml/min/1.73m² (range, 62-112 ml/min/1.73m²), respectively. All 5 patients developed hypertriglyceridemia during olverembatinib therapy. 4 patients were diagnosed nephrotic syndrome because of nephrotic-ranged proteinuria and hypoalbuminemia; one patient, isolated proteinuria. In renal biopsy, glomeruli ischemic obsolescence was observed in 4 patients; hyperplasia of endothelial cells, in 3 patients; increased intracapillary cellularity and ischemic wrinkling of basement membranes, in one patient each. Microthrombi were noted in 2 patients. Renal tubular epithelial cells displayed vacuolar and granular degeneration with focal atrophy in all 5 patients. Immunofluorescence microscopy examination demonstrated that Complement 1q or Complement 3 deposition was observed in each 3 patients, respectively. Under electron microscopy, thrombotic microangiopathy (TMA) -related renal involvement was observed in 2 patients; endocapillary proliferative glomerulonephritis accompanied by ischemic renal injury, ischemic renal injury, and sclerotic glomeruli, one patient each. The 4 patients diagnosed with nephrotic syndrome received angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and resulted in partial reduction of proteinuria, however none achieved complete normalization of urinary protein.

Conclusion The renal pathology of olverembatinib-associated proteinuria predominantly presented with microvascular occlusion or ischemic injury in CML patients. Proteinuria appears to persist throughout olverembatinib therapy despite optimal therapeutic management. These preliminary findings require validation through future studies with larger sample size.