Optimal strategies for the safe administration of chemotherapy in patients with chronic kidney disease (CKD) are not well-established, in part due to the exclusion of such patients from most clinical trials (1). At the present time, most recommendations lack strong clinical support and are based predominantly on consensus opinions rather than evidence-based guidelines. Despite attempts to standardize dose adjustments and chemotherapy timing, the absence of substantial pharmacokinetic data along with the development of novel, multi-agent chemotherapy regimens is a persistent obstacle (2, 3). This case report outlines an approach for the administration of fludarabine, idarubicin, and cytarabine (FIA) plus venetoclax in patients receiving intermittent hemodialysis (IHD) for end-stage renal disease (ESRD).

The patient was a 65-year-old woman with hypertension, hyperlipidemia, multi-vessel coronary artery disease, insulin-dependent type 2 diabetes mellitus, renal cell carcinoma status-post left partial nephrectomy, and ESRD requiring IHD three times weekly with associated anemia and mineral bone disorder. She initially sought medical attention due to complaints of fatigue, dyspnea, generalized weakness, and malaise, as well as increasing transfusion requirements for chronic anemia attributed to CKD. Laboratory results on presentation were significant for white blood cell count (WBC) 41.8 × 10⁹/L (absolute neutrophil count 15.59 × 10⁹/L and absolute monocyte count 17.26 × 10⁹/L), hemoglobin 6.4 g/dL, and platelet count 144 × 10⁹/L. Bone marrow biopsy showed 24% blasts and confirmed acute myeloid leukemia (AML) with myelomonocytic differentiation. Bone marrow flow cytometry was notable for 25.3% blasts (CD45 dim with intermediate side scatter) with myelomonocytic differentiation, including a population of myeloblasts (7% of total events) and a population of aberrant monocytic precursors (18% of total events). Next-generation sequencing (NGS) revealed mutations in DNMT3A and PTPN11. FLT3 analysis was negative for internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations. The karyotype was 46,XX[20]; optical genome mapping and RNA gene fusion panel demonstrated intragenic recombination of the KMT2A gene, suggestive of partial tandem duplication of KMT2A.

The patient was also found at presentation to have a large malignant pericardial effusion requiring pericardial drain and subsequent window. She received hydroxyurea 2 g daily for 1 week with adequate cytoreduction to WBC 6.2, and after a multidisciplinary conference weighing risks and benefits of treatment approaches, she was subsequently initiated on renally dosed and attenuated intensive chemotherapy with 3-day FIA plus venetoclax with additional dose reductions due to performance status (Eastern Cooperative Oncology Group Performance Status of 2) and age >65 (Table 1). The patient was transferred out of the intensive care unit but remained hospitalized to allow for the coordination of daily IHD and tumor lysis syndrome (TLS) monitoring. Chemotherapy was scheduled for early morning administration to allow for scheduled IHD approximately 6 hours after the completion of the cytarabine infusion. Volumes of ultrafiltration varied according to patient volume status and laboratory results, ranging from 1,200 to 2,000 mL. An additional IHD session was scheduled in the morning of day 4, following the conclusion of FIA, to adjust the patient back to the previous baseline dialysis cadence. She met laboratory diagnostic criteria for TLS (4) on cycle 1, day 1 (C1D1), but no specific intervention was required, given that she was already scheduled to undergo hemodialysis. She did not experience significant cardiac or neurological toxicities. She had full peripheral blood count recovery by day 26, and a bone marrow biopsy on day 28 confirmed complete remission (CR1) with no evidence of measurable residual disease (MRD) by multiparameter flow cytometry (assay validated to a sensitivity of 0.1%). She has since completed an additional three cycles of consolidation therapy using FIA plus venetoclax with ongoing remission. Anthracycline use was omitted for consolidation courses; fludarabine and cytarabine dosing was maintained, given a positive treatment response and acceptable toxicity of induction cycles.

Review of existing literature confirmed a paucity of evidence for treating AML in patients already requiring IHD at the time of diagnosis; previously published reports are largely limited to either more traditional induction regimens or hypomethylating agents in combination with venetoclax for those who are not candidates to undergo intensive induction (5–7). This report provides an alternative dosing strategy when either continuous cytarabine is not feasible or higher peak concentrations are more desirable. The use of fludarabine-containing regimens, utilizing synergistic sequencing that optimizes the accumulation of active Ara-C triphosphate within AML blasts, may provide additional therapeutic advantage in patients requiring renally dose-adjusted regimens for toxicity mitigation (8). In patients with ESRD on IHD receiving FIA plus venetoclax for newly diagnosed or relapsed or refractory (R/R) AML, we offer the following considerations and recommendations:

With careful dose adjustments and care coordination, we maintain that curative intent therapy using the FIA + VEN regimen remains an achievable goal for patients with ESRD or acute kidney injury requiring IHD at the time of AML diagnosis.