Sclerodermatous Chronic Gvhd in Patients Receiving Tyrosine Kinase Inhibitors after Allogeneic Hematopoeitic Stem Cell Transplant

BACKGROUND: Sclerodermatous GVHD (sclerosis) is seen in approximately 20% of patients who received initial systemic treatment for chronic GVHD after allogeneic HCT (Inamoto et al. Blood 2013). Published reports suggest up regulation of PDGFR (platelet derived growth factor receptor) and TGF-β (transforming growth factor-β) pathways in patients with sclerosis. Both pathways are subject to inhibition by imatinib. We probed our database to explore if TKI use post HCT, will reduce the incidence of sclerosis in patients with CML and Ph+ALL.

METHODS: Eighty-nine consecutive patients with CML (n=41) or Ph+ALL (n=48) who underwent allogeneic HCT between 2005 to 2010 were included for analysis. Average age for transplant was 44 years (range 18-62) All patients received GCSF-mobilized PBSC from sibling (n=49) or unrelated donors (n=40). A majority of our patients (n=74) received fully myeloablative conditioning regimens (FTBI with Cytoxan or VP-16: n=56, TMLI based regimens n=3, and Bu/Cy: n=15) while the remaining 15 patients received reduced intensity conditioning (Flu/Mel: n=14, Clo/Mel: n=1). Post transplant GVHD prophylaxis was with sirolimus/tacrolimus in 53 (60%), tacrolimus/MTX in 13 (15%), and tacrolimus/sirolimus/MTX in 11 (12%) patients. Median follow up duration was 30 months (Range 0.03-84.8 months).

RESULTS: 55 patients (62%) received TKI therapy post transplant while 34 patients (38%) did not receive TKI due to- cytopenias (45%), TKI intolerance or resistance (27%), GVHD (9%), infections (6%), and/or LFT abnormalities (6%). Median time to start TKI post-transplant was 1.9 months (range: 0.7 – 17.9 months). The median duration of TKI therapy was 9.1 months (range 0.1- 89.4 months).  Thirteen of 59 surviving patients are currently on TKI therapy at last follow up. 

The cumulative incidence of grade II-IV acute GVHD in this patient cohort was 47% (Grade III/IV: 17%).  The incidence of chronic GVHD in the entire group was 76% (limited: n=6, extensive: n=62).   Eight of 55 patients exposed to TKI therapy post transplant developed sclerosis with the median onset time of 13.8 months (range 10.3-33.1 months). Sclerosis occurred in 5 patients during TKI therapy whereas 3 patients developed sclerosis after discontinuation of TKI. Seven of 34 patients who did not receive TKI post-HCT developed sclerosis with median onset of 17.1 months (range 6.7-53.7 months). The 2-year cumulative incidence of sclerosis was 9.2% (CI: 3.9-21.2%) for the TKI exposed group and 14.8% (CI: 6.6-33.4%) in the non-TKI group (p =0.69).

CONCLUSIONS:  To our knowledge, this is the first cohort study to describe the incidence of sclerosis in patients who received TKI post-HCT. The incidence of sclerosis appeared consistent with the reported rate in the literature. At the power for this analysis, statistical significance- favoring TKI use post HCT to reduce incidence of sclerotic cGVHD, was not achieved.