Midostaurin-Related Interstitial Lung Injury in FLT3+ Acute Myeloid Leukemia Post-Allogeneic Transplant

Abstract

A mutation of the FLT3 receptor tyrosine kinase caused by an internal tandem duplication, FLT3-ITD, is the most frequent molecular anomaly found in 28-34% of cytogenetically normal acute myeloid leukemia (AML) patients, and confers a poor prognosis [1]. The drug midostaurin inhibits FLT3 cell signaling, thereby inducing apoptosis of leukemic cells. The agent shows great promise as a multi-targeted therapy in the treatment of a disease with historically dismal outcomes [2, 3]. Schlenk et al (2019) recently reported that although midostaurin as a continued single-agent maintenance therapy results in improved event-free survival (EFS) rates, its associated toxicities, particularly cardiac and pulmonary, need to be further elucidated [4]. One case of midostaurin-induced pneumonitis has previously been reported in an AML patient with FLT3 mutation prior to bone marrow transplant [5]. Three incidents of fatal pulmonary toxicity of unknown etiology were also reported in early studies of the drug [6]. The role of FLT3 inhibitors as post-transplant maintenance therapy is emerging. Here, we describe one case of a FLT3+ AML patient developing interstitial lung disease while on midostaurin therapy post-allogeneic stem cell transplant. To our knowledge, this is the first report of pulmonary toxicity post-allogeneic transplant. Here, we aim to further characterize midostaurin-induced interstitial lung disease and provide insight into its prevention and early detection. A 66-year-old woman with no history of lung disease was diagnosed with AML. Bone marrow biopsy showed myelomonocytic leukemia. Molecular studies confirmed FLT3+ ITD mutation. No tyrosine kinase domain mutation was identified. She completed an induction therapy of 7 days of cytarabine infusion followed by 3 days of daunorubicin infusion (7 + 3) and entered complete remission. She then received two doses of high dose cytarabine, but soon relapsed. Bone marrow biopsy and molecular studies at the time showed FLT3+ ITD AML again. She was then started on salvage induction with cladribine, cytarabine, filgrastim and mitoxantrone (CLAG-M). The safety of midostaurin combined with anthracycline plus cytarabine-based chemotherapy has been investigated thoroughly as a front-line therapy [2]. In a refractory setting, however, midostaurin was shown to have minimal efficacy in a Phase II trial as single agent [7]. Many patients in the trial showed significant blast count reductions, but none achieved complete remission. Our patient received their induction treatment before Food and Drug Administration (FDA) approval of midostaurin as a front-line therapy, not to mention the limited access to midostaurin of their initial treating physician. Thus, upon institutional approval, midostaurin was approved to be used off-label combined with CLAG-M. It was thought that adding an FLT3+ targeted therapy agent would be beneficial. Per the FDA label of the approved front-line therapy, midostaurin was dosed at 50 mg twice daily from day 8 to day 21. A subsequent repeat bone marrow biopsy showed complete molecular remission. Eleven months after initial diagnosis, our patient received a 5/10 haploidentical allogeneic transplant. Post-transplant cyclophosphamide (PTCy) was administered per Hopkins’ haploidentical protocol as prophylaxis for graft-versus-host disease (GVHD). She tolerated the transplant process and continued midostaurin therapy at 25 mg PO daily. Seven months post-transplant, the patient was hospitalized for worsening shortness of breath and worsening hypoxemia without fevers or leukocytosis. Blood cultures were negative and induced sputum grew normal respiratory flora. Infectious workup was also negative for Pneumocystis jirovecii, aspergillus, Epstein-Barr virus, cytomegalovirus, and a respiratory viral panel. Pulmonary function test (PFT) showed no evidence of pulmonary obstruction. At the time of admission, the patient was taking rivaroxaban for pulmonary embolism, but entilation/perfusion (V/Q) scan showed no evidence of new embolus. High-resolution computed tomography (HRCT) of the chest showed bilateral smooth interlobular septal thickening with scattered ground glass opacities and pulmonary interstitial edema (Fig. 1a). Brain natriuretic peptide (BNP) was 140 pg/ mL. Transthoracic echocardiogram (TTE) showed an ejection fraction of 61% and right ventricle systolic pressure elevated to 55 mm Hg. A bubble study did not show evidence of shunting. Midostaurin was stopped due to concern of drug-related interstitial lung disease, and subsequently, the patient’s sympManuscript submitted September 7, 2019, accepted October 7, 2019