Limited efficacy of imatinib in severe pulmonary chronic graft-versus-host disease

To the editor:

We read with interest that Olivieri et al¹  observed complete or partial responses to imatinib 100 or 200 mg daily with improvement of lung function in 7 of 11 patients (64%) with pulmonary chronic graft-versus-host disease (cGVHD) of mild severity (lung function score [LFS] of responders, 2-5; percent predicted forced expiratory volume [FEV₁], 44-78).² 

We have conducted a single-center, prospective, open-label, nonrandomized pilot study of imatinib at 100 to 400 mg daily as antifibrotic treatment targeting the platelet-derived growth factor receptor (PDGFR) and transforming growth factor β (TGFβ) pathways^3-5  in patients with refractory cGVHD of the lung. Since November 1995, 9 patients with moderate to severe pulmonary cGVHD have been included (see Table 1). Median age was 45 years (range, 24-50 years); 3 patients were female and 6 male. Peripheral blood stem cell transplantation from sibling (n = 7) or unrelated (n = 2) donors had been performed after myeloablative (n = 7) or reduced-intensity (n = 2) conditioning for acute or chronic myeloid leukemias or lymphomas. All patients had skin, mucosal, visceral, and/or fasciitic manifestations in addition to pulmonary cGVHD; the median duration of pulmonary cGVHD was 6 months (range, 1-28 months). All patients had already received extensive combination therapies with steroids, calcineurin inhibitors, mycophenolate, and/or extracorporeal photopheresis. Additional imatinib was started generally at 100 mg per day and increased monthly up to 400 mg per day, as tolerated. All patients were evaluated monthly for toxicity and response (pulmonary function tests).

Imatinib toxicity (hematologic, nausea, or fluid retention) was mostly mild, except in 2 patients who discontinued the drug due to reversible dyspnea. Dose increase was not possible in a substantial fraction of patients (as has been noted by others^6,7 ): only 3 of 9 reached the target dose of 400 mg. After a median duration of 4 months (range, 1-17+ months) of imatinib treatment, pulmonary function recovered only in 1 patient from severe to moderate. Applying the same response criteria as Olivieri et al, partial responses (ie, possibility of tapering steroids) were found only in 2 patients (22%), whereas 5 patients showed no change, and 2 patients died due to progression of pulmonary GVHD and/or the underlying malignancy.

The patients in our study were older, had all received peripheral blood stem cells, and had much more severe pulmonary cGVHD according to FEV₁,²  which may account for the differences observed, whereas imatinib dosage and duration of exposure were comparable.

Taking together both studies, it appears that imatinib shows best results in mild pulmonary cGVHD, but has limited efficacy in patients with severe, refractory pulmonary cGVHD. Conceivably, a stronger effect might be seen with more potent tyrosine kinase inhibitors. However, it remains unknown to what extent the fibrosis, once established, can be reversed. Further prospective studies are warranted to establish the suggested role of early PDGFR/TGFβ pathway inhibition as antifibrotic treatment in pulmonary cGVHD.