BK Virus-Associated Nephropathy (BKVN), an Under-Recognized Cause of Renal Dysfunction in Severely Immunosuppressed Hematopoietic Stem Cell Transplant (HSCT) Patients: Report of 5 Cases of Bkvn and the Potential Role of CMX001 for Treatment

BKVN is reported in 8% of renal transplant (RT) patients (pts) and leads to renal failure/graft loss if untreated. In HSCT BKV is mainly associated with hemorrhagic cystitis (HC), with few BKVN cases reported to-date. In RT, treatment (tx) is primarily immunosuppression reduction, not feasible in HSCT due to the risk of graft versus host disease (GvHD). IV cidofovir (CDV) is used as adjunctive tx, but is associated with significant nephrotoxicity. At MSKCC, we have had 5 HSCT pts with tissue-proven BKVN in past 6 yrs. Diagnosis (dx) was by biopsy in 2, autopsy in 2 and nephrectomy in 1. Three pts received T‑cell depleted (TCD) grafts, 3 had GvHD and 3 CMV disease. Three had severe HC with clot obstruction. Two pts developed end-stage renal disease (ESRD) requiring hemodialysis (HD) despite tx with CDV. ESRD preceded the BKVN dx.  We present 1 HSCT pt treated for BKVN with CMX001 in an open-label, expanded access study (CMX001-350; ClinicalTrials.gov ID: NCT01143181). CMX001 is an orally bioavailable, broad spectrum, lipid acyclic nucleoside phosphonate converted intracellularly into the active antiviral CDV. The pt (58 YO white male) with history of chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL) transformed to a diffuse, large B-cell lymphoma received a TCD graft from a matched, unrelated donor. He had SLL relapse +6 mos post-HSCT (tx with chemotherapy, donor lymphocyte infusion and lenalidomide), complicated by grade IV steroid-refractory acute GvHD (treated with alemtuzumab/mycophenolate mofetil [MMF]). He has remained on sirolimus and MMF. At +16 mos serum creatinine (Cr) was increasing, BKVN was diagnosed by biopsy and he was enrolled in CMX001-350. Methods: CMX001 was given orally at 100 mg twice-weekly for 6 mos (max tx duration under CMX001-350). Pt was assessed weekly (Wks 2-5), biweekly (Wks 7-13), and monthly (Mos 4-6). Results: Baseline (BL) and changes from BL in BK viremia/viruria, Cr, BUN and estimated glomerular filtration rate (GFR, MDRD4) are shown below. No drug-related adverse events (AEs) or serious AEs were reported. The pt continues on CMX001 under separate EIND provisions and has stable renal function and no HD. Conclusions: BKVN may be underdiagnosed in HSCT. In 1 pt treated with CMX001, the drug was well tolerated and controlled the BK viremia. After 6 mos therapy, he has stable renal function without HD. Our data supports a potential role for CMX001 in the tx of BKVN.

Parameter	BL	Change from BL at:
		Wk2	Wk3	Wk4	Wk5	Wk7	Wk9	Wk11	Wk13	Mo4	Mo5	Mo6
BK viremiaa (log10 c/mL)	6.2	-0.6	-1.4	-1.8	-2.1	-2.4	-2.7	-3.0	-3.0	-3.9	-3.9	-3.3
BK viruriaa (log10 c/mL)	8.7	ND	ND	-0.7	-1.0	-1.1	-1.5	ND	-1.9	-2.1	ND	ND
Cr mg/dL)	2.6	+0.5	+0.3	+0.6	+0.5	+1.0	+0.8	+1.1	+1.2	+0.9	+1.0	+1.3
BUN (mg/dL)	39	-2	-3	0	-2	0	-4	-4	-2	+2	-7	-9
GFR (mL/min/1.73m2)	27.1	-5.0	-3.2	-5.8	-5.0	-8.5	-7.2	-9.1	-9.6	-7.9	-8.5	-10.2

^a  Viracor BKV qPCR assays in plasma (LLOD, 2 log₁₀ c/mL) or urine (LLOD = 2.7 log₁₀ c/mL)

ND = not determined