Azacitidine induced lung injury: report and contemporary discussion on diagnosis and management

Abstract

Azacitidine, a hypomethylating agent, has caused a paradigm shift in the outcomes of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who are not eligible for stem cell transplantation, particularly in combination with BCL2 and IDH inhibitors. Azacitidine and Azacitidine-based combinations have been widely considered a safe low-intensity therapy when compared to traditional conventional treatments. The development of lung toxicity from azacitidine is not a well-characterized adverse event. However, if it happens, it can be fatal, especially if not recognized and treated promptly. In this review, we aim to familiarize the reader with the presentation of azacitidine-induced lung injury, provide our suggested approach to management based on our experience and the current understanding of its mechanism, and review the literature of 20 case reports available on this topic.

Keywords: acute lung injury; acute myeloid leukemia; azaciditine; azacitidine induced lung injury myelodysplastic syndrome; hypomethylating agents; pneumonitis.

Figure 1

CT chest images. (A) After the first cycle of azacitidine, at that time, the patient was treated for invasive fungal infection. Imaging shows significant improvement of previous bilateral ill-defined nodular opacities with residual GGOs and micronodules. (B) Imaging was done at the time of the development of respiratory symptoms after the second cycle of azacitidine. Imaging showed worsening diffuse GGOs with smooth interlobular septal thickening and centrilobular nodules with bilateral bronchial wall thickening and small bilateral pleural effusions.

Figure 2

Suggested mechanisms of azacitidine-induced lung injury. (A) Direct toxicity to the lungs through damage to the capillary endothelial cells, causing fluid leakage and pulmonary edema, leading to respiratory distress syndrome and interstitial pneumonitis, disturbs the normal production of surfactant. (B) Type I hypersensitivity reaction; azacitidine activates the IgE on mast cells, leading to IgE aggregation and release of histamines, leukotrienes (LT), prostaglandins (PG), and tryptase, which lead to vasodilation, increased vascular permeability, and tissue damage. (C) Hypomethylates DNA, leading to a recovery in normal hematopoiesis in the bone marrow and immune system recovery. (D) Type IV hypersensitivity reaction and azacitidine's ability to augment IFN- ɣ intracellularly, which increases macrophage activation and, as a result, granuloma formation. (E) Recovery of hematopoiesis leads to increased neutrophil production, which increases neutrophil elastase and collagen type I production, leading to fibrosis, and can also damage the type II pneumocytes responsible for the repair process.

Figure 3

Suggested algorithm for managing azacitidine-induced lung injury. *Steroids type and dose depends on availability, severity of illness and comorbidities that can limit the use of steroids. We generally recommend 1mg/kg as starting dose. Gradual tapering of steroids is preferred if feasible. While patient is on steroids, especially if will be on it for a prolonged time, prophylaxis against pneumocystis jiroveci pneumonia (PJP) and fungal infections, along with protein-pump inhibitors (PPIs) as prophylaxis against gastric ulcers if indicated and vitamin D replacement.