Tracks 1-14

Track 1 AZA-001: Azacitidine prolongs overall survival in higher-risk myelodysplastic syndrome (MDS) compared to conventional care regimens Track 2 Clinical trials evaluating azacitidine in combination with histone deacetylase inhibitors Track 3 Counseling patients about the similarities and differences between MDS and cancer Track 4 Common questions about the treatment of MDS Track 5 Treatment algorithm for patients with newly diagnosed MDS Track 6 Newly recognized cytogenetic abnormalities not included in the International Prognostic Scoring System Track 7 Incidence of MDS in the US Track 8 Case discussion: A man in his seventies with high-risk (INT-2) platelet transfusion-dependent MDS Track 9 Case follow-up: Complete remission and freedom from transfusion after treatment on a demethylating agent Track 10 Case discussion: A 75-year-old woman with isolated del(5q) syndrome Track 11 Case follow-up: Two-year response to lenalidomide on a clinical trial Track 12 Case discussion: A 60-year-old man with high-risk MDS Track 13 Case follow-up: Azacitidine followed by umbilical cord transplantation Track 14 Emerging treatment options in MDS

Select Excerpts from the Interview

Track 1

DR LOVE: Where are we right now in terms of therapy for myelodysplastic syndrome (MDS)?

DR STEENSMA: The biggest news, which came from the 2007 ASH meeting, was the presentation of data from a study comparing azacitidine to the conventional care regimens of best supportive care, low-dose cytarabine or standard chemotherapy. Azacitidine was shown to improve overall survival by about nine months and delay transformation to leukemia. It was also well tolerated (Fenaux 2007; [3.1]). Patients received an average of nine cycles of therapy, so they were able to receive the drug for a longer period than we’ve seen in the past.

Another drug in the same class, decitabine, is approved for myelodysplasia. A multicenter study with a five-day outpatient regimen of decitabine — which is more convenient than the regimen on the package labeling — demonstrated a 32 percent complete response rate. That is better than what we have seen before azacitidine and decitabine were available (Steensma 2007).

DR LOVE: How would you compare the available data for azacitidine and decitabine?

DR STEENSMA: We have survival data for azacitidine (Fenaux 2007; [3.1]) but not yet for decitabine. EORTC-06011 is an ongoing study of decitabine in which survival is the endpoint. We’re likely to hear those results later this year or perhaps in early 2009. The trial is taking place in Europe, with a study design similar to the azacitidine trial. Azacitidine and decitabine have never been compared directly, so we have to extrapolate by comparing studies side by side.

Track 2

DR LOVE: What current clinical research for MDS do you expect to have the greatest impact on clinical practice during the next three to five years?

DR STEENSMA: One interesting area is combining azacitidine or decitabine with other classes of drugs. People are most excited about the combinations with the histone deacetylase (HDAC) inhibitors. One of those, vorinostat, is already approved for cutaneous T-cell lymphoma. Several others are being evaluated specifically in MDS. ECOG-E1905 is comparing azacitidine to azacitidine with an HDAC inhibitor called MS-275. A Phase II multicenter trial is evaluating another HDAC inhibitor, belinostat. If it shows efficacy as a single agent, we may have a good rationale to combine it.

Combining azacitidine and decitabine with the HDAC inhibitors is attractive because the side-effect profiles are different. With the HDAC inhibitors, cytopenias don’t seem to be an issue as much as QT-interval prolongation and fatigue (Byrd 2005). Perhaps we could use the agents together and not find much overlap of the adverse events.

DR LOVE: What do we know about the side effects and toxicities of azacitidine and decitabine?

DR STEENSMA: With azacitidine, the biggest issue has been cytopenias. Neutropenia is manageable for some patients, but it lands others in the hospital with febrile neutropenia. In the Phase II multicenter study of decitabine, 17 percent of the patients had febrile neutropenia (Steensma 2007). That was not as high as with some of the leukemia induction regimens, but it’s not negligible either.

The other adverse events associated with azacitidine and decitabine, which are similar, are mild: Gastrointestinal toxicities and rash.

Track 5

DR LOVE: Would you discuss your clinical approach to the treatment of patients with MDS?

DR STEENSMA: I start by risk stratifying. Is the patient at high or low risk of progression to leukemia and death? If the patient is at low risk, you have time to try different approaches, such as growth factors. If the patient is at high risk, then the question is whether he or she is a transplant candidate. I find that assessment difficult.

The transplant centers are accepting sicker and older patients now. I don’t automatically rule out someone who is 63 or 64 years old. I send them to the transplant physician to hear the specialist’s opinion.

If the transplant physician recommends it, then for higher-risk disease, transplant is the treatment of choice. We may need to prepare the patient for the transplant and decrease the blast count with azacitidine, but transplant is the definitive therapy.

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Neil Love, MD

INTERVIEWS
Susan M O’Brien, MD
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Robert Z Orlowski, MD, PhD
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David P Steensma, MD
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David G Maloney, MD, PhD
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