Within Hours: A Catastrophic Reaction to Fludarabine in Fanconi Anaemia

Introduction

Fanconi anaemia (FA) is an autosomal recessive or X-linked disorder caused by mutations in genes responsible for deoxyribonucleic acid (DNA) repair. This condition leads to progressive bone marrow failure, congenital anomalies, and an increased risk of cancer. Allogeneic haematopoietic stem cell transplantation (HSCT) remains the primary curative treatment for the haematological complications of FA. However, the use of conventional myeloablative conditioning regimens has historically resulted in high rates of toxicity and mortality due to the underlying cellular hypersensitivity of FA patients to DNA-damaging agents.^1,2 Reducedintensity conditioning (RIC) regimens utilising agentslike fludarabine have improved outcomes, but toxicity concerns persist. Fludarabine-induced pulmonary toxicity is a recognised adverse event, typically manifesting as a later-onset interstitial pneumonitis or acute respiratory distress syndrome (ARDS) with a median onset of 21 days.³ We report an exceptionally rare case of immediate, fata ARDS onset within hours of initial fludarabine exposure in a patient with FA, underscoring a unique and heightened susceptibility to this agent.

Case Report 

A patient diagnosed with FA, confirmed by the identification of a pathogenic FA complementation group A (FANCA) mutation and presenting with severe pancytopenia, was admitted to the Department of Haematology-Oncology and Bone Marrow Transplantation for a planned allogeneic HSCT. The donor was a fully human leukocyte antigen (HLA)-matched sibling. A standard RIC regimen, which included fludarabine, was initiated. Figure 1 shows the initial chest X-ray (CXR) taken after insertion of the peripherally inserted central catheter (PICC) line. 
Approximately three hours following the administration of the initial dose of fludarabine, the patient experienced abrupt and rapid clinical deterioration. This acute event was characterised by the onset of recurrent high-grade fever, systemic hypotension, and profound hypoxia that necessitated immediate high-flow oxygen support and escalation of care. A CXR was performed, which revealed widespread bilateral diffuse haziness consistent with ARDS (Figure 2), whereas the CXR prior to fludarabine administration was normal (Figure 1). Despite aggressive resuscitation efforts and intensive supportive care, the patient's condition rapidly progressed to irreversible respiratory failure. The patient expired within 24 hours of receiving the initial fludarabine dose.

Discussion

This case highlights the extreme and immediate vulnerability of patients with FA to the severe toxicities of conditioning agents, even those typically considered less myeloablative or associated with later-onset toxicities.Fludarabine pulmonary toxicity is a known, albeit generally uncommon, adverse event following HSCT, usually developing one to two weeks after the final course of chemotherapy or a median of 21 days post-transplant. ^3,4 The temporal association of drug administration and the development of acute respiratory failure in a patient with normal lungs points towards a drug-induced idiosyncratic reaction. The underlying genetic defect in DNA repair widespread bilateral diffuse haziness consistent with ARDS (Figure 2), whereas the CXR prior to fludarabine administration was normal (Figure 1). Despite aggressive resuscitation efforts and intensive supportive care, the patient's condition rapidly progressed to irreversible respiratory failure. The patient expired within 24 hours of receiving the initial fludarabine dose.mechanisms specific to FA as a likely predisposing factor cannot be excluded.This critical outcome underscores a vital clinical necessity:the implementation of hyper-vigilant monitoring protocols for FA patients during the administration of all conditioning agents. At the earliest sign of pulmonary compromise,fever, or any Worsening clinical status due to infection,immediate cessation of potentially causative agents must be considered. This case serves as a stark reminder of the unique high-risk profile of the FA patient group, where standard drug kinetics and toxicity profiles may not apply.