Investigators are at a Loss for Novel
Therapeutics in Myeloid Disorders

By Peter Emanuel, M.D.

The various Educational Sessions dealing with myeloid disorders certainly proved one thing for certain – there is no shortage of novel agents to be tested in clinical trials. And there are also reports of new ways to apply old things. In the AML/APL Education Session, Dr. Lowenberg discussed the revitalized interests in the use of cytokine priming as a strategy of enhancing leukemic cell kill. While some of the predecessor studies employing cytokine priming had negative results, it appears that this may have been largely a mistiming issue. Dr. Griffin outlined the basis for tyrosine kinases as targets in AML, as well as some of the challenges we are faced with in developing specific tyrosine kinase inhibitors. At least four FLT3 inhibitors are under development and entering testing: CEP-701 has completed a phase II trial, and CT53518, PKC412, and SU11248 are in the phase I stage. Most tyrosine kinase inhibitors are oral agents with only mild GI toxicity being the most common problem encountered thus far. In the CML Educational Session, Dr. Melo discussed where we go in the “imatinib plus what?” era. A new intergroup study in the U.S. is gearing up to activate and will examine imatinib in different doses vs. imatinib + combinations, in newly diagnosed CML patients. In terms of new agents, beyond inhibiting the tyrosine kinase activity of Bcr-Abl, we can explore blocking oligomerization of Bcr-Abl or attempt to destabilize the Bcr- Abl protein with agents such as geldanamycin, 17-AAG, or arsenic, or try to interfere with BCR-ABL mRNA by antisense oligonucleotides or small interfering RNA oligonucleotides (siRNAs). Finally, we can investigate other parts of the pathways beyond blocking Bcr-Abl itself, such as farnesyltransferase inhibitors (R115777, SCH66336), mTOR inhibitors (rapamycin), Jak-2 inhibitors (AG490), or cyclin-dependent kinase inhibitors (flavopiridol). In the Myelodysplas-tic Syndrome Educational Session, Drs. List and Gore outlined a dizzying list of novel agents. Their list included some of the agents mentioned above such as the FTIs (R115777, SCH66336) and the tyrosine kinase inhibitors. But there are many other exciting agents in several different classes of molecules.

New antiangiogenic agents include CC5013, CC1088, and bevac-izumab. CC5013 (RevimidTM, Celgene Inc) is a more potent immunomodulatory derivative of thalidomide that lacks the neurologic toxicities of thalidomide. Bevacizumab is a recombinant humanized monoclonal antibody which neutralizes VEGFA. An oral matrix metalloproteinase inhibitor, AG3340, demonstrated some activity in lower risk MDS, but also produced dose-limiting arthralgias and joint stiffness. So maybe we’ll have to wait for the second generation of the matrix metalloproteinase inhibitors. Novel therapies for MDS which target epigenetic changes include the DNA methyltransferase inhibitors (5-azacytidine and 5-aza-2’-deoxycytidine) and the histone deacetylase inhibitors (sodium and arginine butyrate, sodium phenylbutyrate, valproic acid, SAHA, FK228, and MS-275).