CML, MPDs, and MDS - Hotbeds of Activity

By Peter Emanuel, M.D.
No less than three educational sessions, parts of many scien-tific subcommittees, a plenary abstract presenting a clinical study of low dose aspirin in polycythemia vera, and a multitude of other abstracts presented in oral and poster formats, confirm that CML, the other myeloproliferative disorders, and MDS, are brewing a wealth of scientific interest. And that is not just STI-571 for CML, though that story continues to evolve as well.

The Chronic Myeloid Leukemia educational session, offered twice today
(8:00 a.m. – 9:45 a.m. and 2:00 p.m. – 3:45 p.m.), will cover the spectrum of the BCR-ABL oncogene and its role in CML. First, Dr. Junia Melo will recap the history of CML and BCR-ABL. She will cover the evidence of BCR-ABL as an oncoprotein, and the various modalities to potentially attack BCR-ABL. These venues for potential targeted attacks include: inhibiting its tyrosine kinase activity (e.g. imatinib mesylate), blocking oligomerization, destabilizing the BCR-ABL protein, attacking the BCR-ABL mRNA via antisense oligonucleotides or siRNAs, or finally by targeting downstream pathways rather than BCR-ABL itself.

Dr. Tim Hughes will give us a clinical management guide for the monitoring of the molecular response to imatinib mesylate. What should we use for monitoring? Cytogenetics, FISH, quantitative RT-PCR? Should we use combinations? Do the results between techniques always correlate? Do we still need to do marrows or can we just use blood for monitoring? How often should we monitor? What are the definitions of molecular response categories? Should our goals be the same in all patients? What about imatinib-resistance? Is it primary or acquired? What is the evidence and significance for emerging mutations? A ton of questions for Dr. Hughes to shed some light upon.

Finally Dr. Jane Apperley will discuss patient-specific strategies in CML. And this raises even further questions since the reporting of the IRIS trial. Should every patient have a trial of imatinib? In the “young” patient, do you do up-front transplant, or imatinib, or should we combine the therapies? Certainly a session worth attending to get the answers.

The Myeloproliferative Disorders Educational Session will also be presented twice today
(8:00 a.m. – 9:45 a.m and 4:15 p.m. – 6:00 p.m.). Dr. Spivak will discuss diagnostic challenges involving the chronic myeloproliferative disorders (MPDs). Two new molecular assays may prove useful in the diagnosis and classification of MPDs. A few years ago, the overexpression in polycythemia vera (PV) granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Now it appears that overexpression of PRV-1 mRNA appears to be specific for PV and distinguishes PV from secondary erythrocytosis (Klippel et al., Blood 2003;102:3569-74; and accompanying editorial – Blood 2003;102:3464).

Secondly, impaired expression of Mpl, the receptor for thrombopoietin, may be an additional molecular diagnostic marker. Dr. Barbui will discuss the best clinical evidence for treatment strategy design in PV and in Essential Thrombcytosis (ET). What is the current best evidence for cytoreductive therapy in PV and ET? Dr. Tognoni will discuss the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study. This study is also presented as a plenary abstract on Sunday afternoon.

Finally, Dr. Barosi will review the current understanding of the pathophysiology of idiopathic myelofibrosis. The Myelodysplastic Syndromes Educational Session is offered today from
8:00 a.m. – 9:45 a.m. and on Sunday from 9:45 a.m. – 11:30 a.m. Dr. Alan List will present the latest data on the testing of a number of small molecule therapeutics from antiangiogenic agents (thalidomide, CC5013, bevacizumab, arsenic) to kinase inhibitors (SU5416, SU11248, imatinib) to matrix metalloprotease inhibitors (AG3340) to farnesyltransferase inhibitors (R115777, SCH66336) to agents which target genetic integrity (gemtuzumab ozogamicin). Dr. Gore’s presentation will cover therapies targeting epigenetic changes including DNA methyltrans-ferase inhibitors and histone deacetylase inhibitors. Finally, Dr. Mufti will discuss results of stem cell transplantation as well as the use of immunomodulatory agents in MDS. Whoever says there is nothing new to offer MDS patients for treatment options needs to attend this session!