Cladribine-based low-intensity therapy is safe and effective in patients with newly diagnosed Acute Myeloid Leukemia (AML) and renal impairment

Abstract

Abstract Background: Despite a recent emphasis on developing regimens for patients (pts) with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy, pts with baseline kidney dysfunction are often underrepresented. A concern for increased toxicity due to inadequate renal elimination often precludes these pts from receiving effective chemotherapy or participating in clinical trials altogether. Cladribine has demonstrated efficacy and survival benefit in patients with AML as part of both higher- and lower-intensity combination regimens. Neurologic and renal toxicity have been reported in pts receiving cladribine at doses 4-9x the recommended dose. As a result, clinical drug references empirically recommend dose reduction of cladribine for pts with a creatinine clearance (CrCl) <50 mL/min; however little data is available regarding the adverse event (AE) profile and clinical outcomes of pts with kidney impairment who receive cladribine-based therapy. Methods: Pts with newly diagnosed AML or high-risk myelodysplastic syndrome (MDS) treated with cladribine and low-dose cytarabine as part of an ongoing clinical trial (NCT01515527) between 3/2016 through 4/2025 were evaluated. While standard clinical trials exclude pts with impaired renal function, this study included a specific cohort that allowed the enrollment of pts with renal dysfunction (serum creatinine [Scr] >2 mg/dL). Pts received cladribine 5mg/m2 IV D 1-5 and cytarabine 20 mg subcutaneously twice daily D1-10. CrCl was calculated by the Cockroft-Gault equation and those with CrCl<50 mL/min on Cycle 1 Day 1 were included in this analysis. AEs were evaluated for all pts. Time to blood count recovery during Cycle 1 was calculated from Cycle 1 Day 1 for pts who achieved a complete response (CR) or CR with incomplete count recovery (CRi). Results: Fifteen pts with newly diagnosed AML (n=14) or high-risk MDS (n=1) were identified, with a median age of 75 years (range, 43-89) and median ECOG performance status of 2 (1-3). Pts presented with a median of 6 comorbidities (range, 2-11) including hypertension (n=12; 80%), type 2 diabetes (n=9; 60%), coronary artery disease (n=3; 20%), and atrial fibrillation (n=3; 20%). Two pts (13%) had a history of stroke and 1 had a previous MI. Ten pts (67%) had a prior (n=8; 53%) or concurrent active malignancy (n=2; 13%). Four pts (27%) had a diagnosis of chronic kidney disease (CKD). The median Scr was 1.61 mg/dL (range, 0.91-3.86) and CrCl was 42 mL/min (range, 32-49) at baseline. All pts received the complete course of cladribine without dose reduction. Nine pts (60%) achieved a CR (n=6, 40%) or CRi (n=3, 20%) after Cycle 1. Median time to best response was 1 cycle (range, 1-4). Among the 9 responders, the median time to ANC >500 cells/µL was 25 days (95%CI: 19-31) and ANC >1000 cells/µL was 25 days (95%CI: 24-26). Median time to PLT >50 K/µL was 28 days (95%CI: 22-34) and PLT >100 K/µL was 30 days ( 95%CI: 24-36). One pt with a FLT3-ITD mutation also received concomitant gilteritinib and achieved a CRi with full ANC recovery at 37 days and PLT > 50 K/µL at 36 days. The median overall survival among responders was 12.3 months (95%CI: 4.4-20.3) in this cohort of high-risk pts with comorbidities that precluded them from standard trials. AEs were as expected for an older population with AML receiving induction chemotherapy. No neurotoxicity was observed. Two pts (13%) experienced laboratory tumor lysis syndrome (TLS) and 6 pts received rasburicase to prevent or treat TLS. Eight pts (53%) experienced neutropenic fever, with documented infection in 4 (27%). Among pts treated on study in a cohort with normal renal function, the rates of TLS and infection were 2% and 28%, respectively. Three pts (20%) died during induction due to sepsis (n=2) and multiorgan failure in the setting of cardiogenic shock (n=1). Conclusions: The presence of renal dysfunction in pts with newly diagnosed AML can pose a major challenge, often limiting the optimal use of highly effective therapies based on inadequate data. Treatment with cladribine, without dose modifications, did not result in significant or unanticipated toxicities among pts with impaired kidney function and may be considered as part of the treatment backbone for these pts. Close monitoring of kidney function and TLS management is necessary. Future clinical trials confirming these findings in pts with impaired kidney function are warranted to help expand availability of effective therapy.