Targeting the Source in CML: An Interview With Junia V. Melo, MD, PhD

Sally Church, PhD

Disclosures

March 21, 2005

Editorial Collaboration

Medscape &

Editor's note: Although cancer has been recognized as a malignant disease for centuries, it has only been in the last few decades that the first molecular abnormalities underlying specific tumors have been discovered. One example is chronic myeloid leukemia (CML), which is known to be caused by constitutive activation of a tyrosine kinase (abl) in a fusion oncoprotein (bcr-abl), the end product of a reciprocal translocation (t9;22). Bcr-abl became the paradigm for molecular targeted therapy when it was shown to be effectively inhibited by imatinib mesylate. Dr. Junia V. Melo, from the Imperial College of Medicine in London, chaired the CML Education Session at the 45th Annual Meeting of the American Society of Hematology (ASH) and discussed some of the new developments in CML with Medscape.

Medscape: Which new findings on the management of CML have you found interesting at ASH this year?

Dr. Melo: I think one of the most important things is the further evaluation of trials such as the IRIS trial,[1,2] which compares cytogenetic and molecular responses to imatinib vs interferon-alfa plus low dose ara-C. This is the first time we are seeing longer-term evaluation of these patients. The data from Drs. Radich[1] and Hughes[2] show that it appears that patients are largely responding well to therapy, and a large number of patients are achieving a cytogenetic response, often ≥ 3 log reduction in bcr-abl transcripts as a sign of molecular remission. However, few of those patients have become completely PCR-negative. It may still be early, or it may be that the drug does not completely eradicate the bcr-abl oncoprotein.

Other key data are on the ability of monitoring patients or of predicting disease evolution by microarray or gene expression profile systems. There are a number of groups presenting on this technology at ASH, trying to understand whether there is a signature of gene expression between patients who are going to respond and those who are not going to respond so physicians could forecast individualized therapy for CML patients.[3,4,5,6,7]

Medscape: Resistance to imatinib seems to be a topical issue; could you put it in context and address the strategies that are being used to overcome it?

Dr. Melo: Drug resistance is much talked about, and sometimes it seems that it is more like the rule than the exception. The majority of patients have a good response to imatinib, and those who lose that response are mainly patients with advanced disease. Patients in chronic phase are doing well, and very few experience relapse due to drug resistance.

The other important issue is that resistance is mistakenly thought to be induced by the drug. We have to remember that drug resistance that occurs by the acquisition of point mutations in the kinase domain of abl are random phenomena; it is thought that all cells from every individual who has CML occasionally undergo mutations that are always in the background and nobody knows they are there. When these cells are confronted with a drug, the ones that develop a mutation that prevents binding of the drug are the ones that are going to be selected, and therefore they become evident. So the drug is not inducing the mutation -- the drug is just selecting for a clone that is able to resist the drug.

Medscape: Have there been any developments on a test to detect early drug resistance?

Dr. Melo: Unfortunately, methods currently available to detect point mutations still have a low sensitivity. Dr. Hughes has shown very elegantly that the conventional method of direct sequencing can only detect mutations when the clone is at least 20% of the malignant cells. This is a high proportion of the malignant cells. Ideally, one should develop a technique in which you can screen cells from the patients before treatment to see if you can detect a leukemic clone in smaller proportions. This is still lagging behind, but I forecast that in the next few years, we will hear something related to that.

Another possibility is to develop surrogate tests, so our lab, in collaboration with Dr. Mahon in France, has developed a method whereby we analyze the response in vitro of leukemic cells to a therapy.[7] Patients at diagnosis can be divided into 2 groups: those whose inhibition of phosphorylation is insufficient to completely block the signal, and those in whom we don't see this. When this is correlated with the responses, a clear difference between patients who responded and those who did not can be seen. This needs validation in a larger prospective series, but if proven true, it may be a very simple and useful test to predict responders in the future.

Medscape: The number of patients who attain a complete cytogenetic response is encouraging. Should these patients continue on therapy?

Dr. Melo: This is an important question, and I think we still don't know what to do with the patient who is maintained in cytogenetic response and the one who achieves a good molecular response. After some time, patients do ask, "Can I stop the drug? Am I cured?" This is still an open question -- we don't know the answer. The only clue is what happens when patients have to stop therapy. Dr. Apperley[8] gave an excellent example of female patients who want to get pregnant; it is recommended that they stop therapy before conceiving. We have a period of analysis in these patients in which the drug was stopped and there was an increase in the number of bcr-abl transcripts and an increase in leukemic cells, suggesting that if you stop therapy, you are not going to have the disease controlled and there will be a resurgence of the leukemic clone. One has to be very brave to stop the drug if the patient is responding so well to see what happens, but watch this space!

Disclosures: Dr. Melo has disclosed that she receives grant support for clinical research from Novartis.

References
  1. Radich J, Gathmann I, Kaeda J, et al. Molecular responses to imatinib and interferon ara C in newly diagnosed CML efficacy of imatinib on patients after cross over from interferon therapy and prognostic importance of molecular responses on long term outcomes Blood 2003 102 182a. Molecular responses to imatinib and interferon + ara-C in newly diagnosed CML: efficacy of imatinib on patients after cross-over from interferon therapy and prognostic importance of molecular responses on long-term outcomes. Blood. 2003;102:182a. Abstract 635.

  2. Hughes TP, Branford S, Matthews J, et al. Trial of higher dose imatinib with selective intensification in newly diagnosed CML patients in the chronic phase Blood 2003 102 31a. Trial of higher dose imatinib with selective intensification in newly diagnosed CML patients in the chronic phase. Blood. 2003;102:31a. Abstract 95.

  3. Barnes DJ, Goldman JM, Melo JV. BCR ABL expression levels determine the rate of development of resistance to imatinib mesylate Gleevec Blood 2003 102 415a.BCR-ABL expression levels determine the rate of development of resistance to imatinib mesylate (Gleevec). Blood. 2003;102:415a. Abstract 1508.

  4. Deininger MW, Mori M, Hsieh Y-C, et al. Gene expression profiling of total white cells may not predict complete cytogenetic response to imatinib in patients with chronic myelogenous leukemia CML Blood 2003 102 418a. Gene expression profiling of total white cells may not predict complete cytogenetic response to imatinib in patients with chronic myelogenous leukemia (CML). Blood. 2003;102:418a. Abstract 1521.

  5. Yong ASM, Tipping AJ, Goldman JM, Melo JV. The gene expression profile of CML CD34 cells can predict the duration of chronic phase Blood 2003 102 419a. The gene expression profile of CML CD34+ cells can predict the duration of chronic phase. Blood. 2003;102:419a. Abstract 1522.

  6. Burchert A, Hochhaus A, Rehn M, Schmidt M, Neubauer A.Impaired ICSBP IRF 8 expression persists after remission induction with imatinib in chronic phase CML patients Blood 2003 102 419a. Impaired ICSBP/IRF-8 expression persists after remission induction with imatinib in chronic phase CML patients. Blood. 2003;102:419a. Abstract 1524.

  7. Schultheis B, Fidanis E, Mahon FX, Apperley JF, Goldman FM, Melo JV. Development of a test to predict resistance to imatinib mesylate in the treatment of chronic myeloid leukemia Blood 2003 102 71a. Development of a test to predict resistance to imatinib mesylate in the treatment of chronic myeloid leukemia. Blood. 2003;102:71a. Abstract 241.

  8. Melo JV, Hughes TP, Apperley JF. Chronic myeloid leukemia. Hematology (Am Soc Hematol Educ Program). 2003;:132-152.

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