fludarabine

Overview

Purine nucleoside analog; historical backbone of CLL chemoimmunotherapy. RRM1 (ribonucleotide reductase) is a direct target.

Evidence in the corpus

  • In the 1,148-patient CLL map, RRM1 — the molecular target of fludarabine — was nominated as a novel U-CLL-specific driver PMID:35927489.
  • In the contemporary era of ibrutinib/venetoclax (replacing fludarabine-based chemoimmunotherapy), isolated TP53 mutation without 17p deletion was no longer associated with adverse outcome in U-CLL PMID:35927489.
  • SF3B1 and other recurrently mutated genes identified in CLL tumors from patients treated with fludarabine-based regimens in the Broad/DFCI cohort PMID:23415222
  • Component of the FC/FCR chemoimmunotherapy regimens evaluated in the CLL8 trial (n=538 CLL patients); prognostic biomarkers under fludarabine-based therapy identified as mutated TP53, SF3B1, and RPS15; subclonal driver burden predicted shorter PFS (HR 1.6) in both FC and FCR arms PMID:26466571.
  • Listed as part of conditioning/preparative regimens for allogeneic stem-cell transplantation (SCT) — the treatment modality associated with the largest survival improvement in the WashU AML/MDS decitabine trial (n=116); allogeneic SCT vs no SCT was the dominant Cox predictor (P<0.001) irrespective of TP53 status PMID:27959731
  • Severe neurotoxicity (progressive muscle atrophy → tetraparesis) occurred in a pediatric patient (LPP_07, de novo TP53 c.586C>T LP/PV, T-cell ALL with lineage switch) during HSCT conditioning with fludarabine; the patient died one month later, illustrating the chemotoxicity risk in carriers of DNA-damage-response gene LP/PVs PMID:29489754

Resistance mechanisms

Cancer types (linked)

Sources

  • PMID:35927489
  • PMID:23415222
  • PMID:26466571 — Landau et al. (Nature 2015). CLL8 trial genomics; FC/FCR regimen prognostic landscape in 538 CLL patients.
  • PMID:27959731 — Welch et al. 2016, NEJM. WashU AML/MDS decitabine trial; fludarabine referenced as SCT conditioning context; allogeneic SCT was the dominant survival predictor.
  • PMID:29489754 — Briese et al. 2018. Germline LP/PVs in 25 HBOC genes across 372 pediatric cancer patients (Düsseldorf); fludarabine HSCT conditioning associated with fatal neurotoxicity in TP53 LP/PV carrier.

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