Magic bullet, part III?

In this issue of Blood, Oliveri and colleagues and Magro and colleagues report pilot trials using imatinib for steroid refractory sclerotic cGVHD, showing response rates of 79% and 50%.^1,2 

Although there have been several phase I/II trials of new therapies for chronic graft-versus-host disease (cGVHD) reporting response rates in the 50% range, none have exclusively enrolled heavily pretreated patients with sclerotic cGVHD, among the most difficult to treat. The toxicity was relatively modest with 7 (out of 33 total) patients discontinued for toxicity, especially when compared to the toxicities of the significantly more immunosuppressive alternatives. These results are quite encouraging, especially considering the late stage patients involved in these trials. Like the initial clinical use of imatinib for chronic myelogenous leukemia (CML)/Philadelphia positive acute lymphoblastic leukemia (ALL) and its subsequent use for GI stromal tumors, the use of this tyrosine kinase inhibitor was based on strong experimental data. Svegliati et al have previously reported in this journal the occurrence of stimulatory autoantibodies to platelet-derived growth factor (PDGF) receptor in patients with extensive cGVHD. They have also demonstrated this in patients with systemic sclerosis, an autoimmune disorder with many clinical similarities to cGVHD.³  Transforming growth factor beta (TGF-beta) may also play a role in systemic sclerosis and cGVHD. Both the PDGF and TGF-beta pathways are inhibited by imatinib, and its clinical use in cGVHD is supported by these 2 trials. Several larger studies are already underway or planned in Europe and the United States. It is hoped that some or all of these studies will include laboratory correlates to better understand response and resistance to this agent.

These 2 pilot trials highlight the resurgence of interest in cGVHD that has occurred after the 2005 NIH-sponsored Consensus Conference in cGVHD. This conference addressed the thorny issues of diagnosis, staging, and response criteria.^4-8  The lack of standardized criteria has significantly inhibited clinical investigation into this disorder and made interpretation of trial results difficult. The current imatinib trials adopted many of the suggestions from this NIH meeting. Although the NIH recommendations are still undergoing critical evaluation and verification, the impact on the field is already substantial, as shown by these trials.

Finally, these 2 trials also address one of the ultimate goals of transplantation-separation of GVHD from graft-versus-tumor effect. What if the dreaded consequences of cGVHD, such as contractures, thickened skin, hair loss, and so forth, were prevented while maintaining the antitumor response? Imatinib is unlikely to be the single magic bullet. It does not correct the immune deficiency and consequent infections seen with cGVHD. However, it is a tantalizing hint that cGVHD may be teased apart, preserving the antitumor benefit while eliminating the debilitating symptoms.