Safety of nintedanib for treatment of fibrotic lung disease after allogeneic hematopoietic stem cell transplantation

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Graft-versus-host-disease (GVHD) of the lung is most commonly manifested as bronchiolitis obliterans syndrome (BOS) and may occur in up to half of patients with GHVD [1]. Typical treatments include systemic corticosteroids coupled with inhaled steroids, inhaled beta agonists, macrolides, and various other therapies [1,2,3,4,5]. Pro-fibrotic mediators, including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), may play a role in the development of BOS [6, 7].

Nintedanib is a tyrosine kinase inhibitor that mediates multiple pro-fibrotic growth factors, including PDGF, VEGF, and fibroblast growth factor [8]. This drug can slow the rate of disease progression and reduce the risk of exacerbations in idiopathic pulmonary fibrosis (IPF) [9]. Potential side effects of nintedanib include diarrhea, nausea, increased liver enzymes, hemorrhage, and arterial thrombosis.

Because of its mechanism of action, nintedanib may be a potential treatment option for patients with BOS due to pulmonary GVHD. Pirfenidone, an anti-fibrotic agent also approved for treatment of IPF [10], has had preliminary studies showing efficacy in a murine model of chronic GVHD [11].

Based on its favorable side effect profile, we sought to examine the efficacy of nintedanib when utilized in patients with fibrotic lung disease after allogeneic hematopoietic stem cell transplantation (HSCT) and determine whether this drug can be safely used in this patient population. We present two cases of patients treated with nintedanib following allogeneic HSCT.

Patient 1

Patient 1 is a 32-year-old female with history of panniculitis-like peripheral T-cell lymphoma who was admitted to our hospital in March 2015 with pancytopenia and respiratory failure due to severe diffuse alveolar hemorrhage and was subsequently diagnosed with hemophagocytic lymphohistiocytosis (HLH). She was treated with etoposide and dexamethasone, which was completed in May 2015 but developed significant pulmonary fibrosis due to persistent alveolar hemorrhage. She was re-admitted in July 2015 with recurrent HLH and was found on positron emission tomographic scan to have multiple areas of hypermetabolic lesions consistent with T-cell lymphoma, which was later biopsy proven. She was treated with vincristine, cyclophosphamide, daunorubicin, and prednisone followed by romidepsin and etoposide, which was completed in September 2015. She underwent matched sibling donor HSCT on December 1, 2015 with reduced intensity conditioning.

At the time of transplant, the patient was on 3 L/min of continuous oxygen and had significant fibrotic changes on her chest computed tomography (CT) (Fig. 1). Her pulmonary function tests (PFT) revealed a forced vital capacity (FVC) of 1.59 L (42% predicted), forced expiratory volume in 1 s of 1.48 L (48% predicted), total lung capacity (TLC) of 2.42 L (48% predicted), and diffusing capacity of the lung for carbon monoxide (DLCO) of 7.14 (29% predicted). After engraftment, she was started on nintedanib 150 mg twice daily in March 2016. She had an elevation of aspartate aminotransferase (AST) to 316 U/L in May 2016 and nintedanib was held for 1 month, after which time her AST normalized. Nintedanib was resumed at 100 mg twice daily for 2 months until September 2017, at which time it was increased to 150 mg twice daily.

Fig. 1
figure1

Initial chest CT of patient 1 from February 2016 revealing extensive fibrotic changes in both upper lobes

She maintains on nintedanib at 150 mg twice daily currently. Her most recent PFT showed substantial improvement, with a FVC of 2.31 L (60% predicted), TLC of 3.33 L (64% predicted), and DLCO of 12.95 (52% predicted). She also had significant improvement in her CT imaging (Fig. 2). She has had no further side effects from the drug. She has not developed chronic GVHD and is free from other immunosuppressants at this time.

Fig. 2
figure2

Follow-up chest CT of patient 1 from December 2017 showing marked improvement of fibrotic changes in both lungs

Patient 2

The second patient is a 25-year-old without significant past medical history who presented in July 2016 with a new diagnosis of acute lymphoblastic leukemia. She underwent induction chemotherapy along with intrathecal chemotherapy followed by myeloablative conditioning double-cord HSCT in September 2016. Her posttransplant course was significant for cytomegalovirus pneumonia in October 2016 and development of severe-extensive GVHD with pulmonary involvement in February 2017. She underwent fiberoptic bronchoscopy with bronchoalveolar lavage, which did not reveal any infectious pathogens. The patient was subsequently treated with high-dose steroids in addition to azithromycin, montelukast, and inhaled steroids for treatment of suspected organizing pneumonia due to GVHD (supplemental figure 3). Her respiratory status progressed to chronic hypoxemic respiratory failure, significant fibrotic changes in her lung, and spontaneous pneumomediastinum (supplemental figure 4). This occurred in spite of treatment with high-dose corticosteroids, rituximab and ruxolitinib.

The patient was started on Nintedanib 150 mg twice daily in October 2017 and tolerated the drug well. Her liver function tests remained normal and she had normal blood counts as well. Her follow-up CT chest in February 2018 showed significant improvement in her fibrotic lung disease (supplemental figure 5), and the patient subsequently was able to be weaned off of supplemental oxygen.

Based on this experience in our patients, we believe the nintedanib is reasonably safe in the posttransplant patient population without elevated bleeding risk; both of our patients had platelet counts >50,000 at the initiation of nintedanib. One of the patients did have a transient rise in liver enzymes that resolved after the drug was held for a short period and resumed at a lower dose for 3 months before increasing to the standard dosing regimen. No serious side effects occurred at standard dosing of this drug. This should provide a safety basis for the initiation of clinical studies of nintedanib for treatment of BOS due to pulmonary GVHD and further its ongoing use in fibrotic lung disease following HSCT.

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Correspondence to Kyle R. Brownback.

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Dr. Pitts is a paid consultant and speaker for Boehringer Ingelheim. The other authors declare that they have no conflict of interest.

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