Tracks 1-19

Track 1 Monitoring patients with chronic myelogenous leukemia (CML) who are receiving tyrosine kinase therapy Track 2 Monitoring patients who have achieved a complete cytogenetic remission Track 3 Rationale for dose escalation of imatinib in CML Track 4 Side effects associated with higher-dose imatinib Track 5 Efficacy and toxicity of dasatinib at 100 milligrams per day Track 6 Utility of FISH in monitoring patients during treatment Track 7 BCR-ABL kinase domain mutation analysis to guide secondary tyrosine kinase inhibitor treatment Track 8 Selection of nilotinib or dasatinib after imatinib failure Track 9 Null association between imatinib and cardiac abnormalities Track 10 IRIS trial six-year follow-up: Sustained survival and declining annual rate of transformation in patients with newly diagnosed, chronic-phase CML treated with imatinib Track 11 Historical rationale for observation of patients with newly diagnosed chronic lymphocytic leukemia (CLL) Track 12 Prognostic factors for the identification of patients with high-risk CLL Track 13 Clinical relevance of prognostic factors to selection of therapy Track 14 Use of consolidation alemtuzumab to eliminate residual disease after response to fludarabine-based therapy Track 15 Side effects and toxicity of alemtuzumab Track 16 Alemtuzumab and cytomegalovirus reactivation Track 17 International Phase III trial of bendamustine versus chlorambucil in treatment-naïve B-cell CLL Track 18 Utility of consolidation therapy for minimal residual disease in CLL Track 19 Future treatment of CML and CLL

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Track 3

DR LOVE: What is the role of dose escalation of imatinib for patients with CML?

DR O’BRIEN: In a recently published trial, patients failing imatinib at 400 or 600 milligrams were randomly assigned to either imatinib at 800 milligrams or dasatinib.

The data were analyzed according to which dose of imatinib the patient had failed (Kantarjian 2007). Patients who failed while they were receiving imatinib at 600 milligrams were better off switching to dasatinib. For those who had failed while on imatinib at 400 milligrams, the response rates between the two arms were similar, and the improvement in progression-free survival with dasatinib was of borderline significance (Kantarjian 2007).

This is why the NCCN guidelines consider dose escalation of imatinib as an option (NCCN 2008). However, if a patient has never had a cytogenetic response to imatinib, it’s better to switch therapy than to increase the dose.

Track 10

DR LOVE: Would you discuss the six-year follow-up data from the IRIS trial, evaluating imatinib in the treatment of chronic-phase CML (Hochhaus 2007)?

DR O’BRIEN: The failure rate continues to be low, showing imatinib to be excellent in the front-line setting (1.1). One of the most interesting findings is that the number of events per year is declining. In fact, during the sixth year, no patients developed accelerated phase or blast crisis.

To some, these data suggest that early on, a clone of imatinib-resistant cells may develop in some patients that is too small to detect with standard techniques. When imatinib eradicates the sensitive clone, the resistant clone emerges and the patients leave the study and experience an event within a year or two. However, patients without a resistant clone have nothing to cause failure — so the failure rate is decreasing.

Track 13

DR LOVE: Let’s talk about CLL. Are we at a point at which we can use a chromosomal abnormality, such as a 17p deletion, to select therapy?

DR O’BRIEN: The simple answer is no. However, we know that patients with 17p deletions don’t respond well to fludarabine-based therapy (Byrd 2006), our mainstay of treatment. Data show that those patients do respond to alemtuzumab. In the trial comparing it to chlorambucil as first-line therapy for CLL, alemtuzumab was better in all groups based on cytogenetic abnormalities (Hillmen 2007; [1.2]).

So patients with 17p deletions fared better on alemtuzumab. Still, their median progression-free survival was 10 months (Hillmen 2007; [1.2]). Alemtuzumab by itself is not the magic bullet for patients with 17p deletions. Steroids also work in these patients, and the British are conducting a Phase II trial combining alemtuzumab with steroids.

Track 14

DR LOVE: Would you discuss some of the ongoing trials with alemtuzumab for the treatment of CLL?

DR O’BRIEN: We are conducting a study combining alemtuzumab with fludarabine, cyclophosphamide and rituximab (FCR) for patients at high risk (2005-0269). We are also conducting a trial using alemtuzumab to treat minimal residual disease, for which I believe it is particularly effective (2003-0834). Alemtuzumab is not great at treating bulky adenopathy, but it’s excellent at clearing bone marrow disease.

Emerging data show that we need a certain period of time — probably three to six months — between treatment with fludarabine and consolidation with alemtuzumab to allow recovery of the immune system (Hainsworth 2008). Patients with a reasonable response to first-line therapy do not experience disease progression that quickly, so we have time to wait, repeat the bone marrow biopsy and then use alemtuzumab if needed to eradicate residual disease. In a German randomized trial, this approach was shown to have a major impact on progression-free survival (Wendtner 2004).

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EDITOR
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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Hematologic Oncology Update:
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