Click here to view next page of this article

 

New Treatments for Chronic Myeloid Leukemia

The incidence of chronic myeloid leukemia is rare, about 1:100,000 and since the patients live about five years, the prevalence is five times that much. There are no known etiologic factors to cause CML although my suspicion is that in the future we will find probably a viral etiology for that. But the most important thing on this slide is this experiment that was done in looking at the Philadelphia abnormality in a very sensitive technique; looking at 1:100 million cells. And it was found that if you look at normal bone marrows 25% of the normal bone marrows from adult individuals will show the Philadelphia abnormality at the minute amount.

How do we monitor the course of chronic myeloid leukemia? I show here that the classical monitoring is with the cytogenetics but you will see more and more people advising to make a diagnosis or to monitor the course with whatís called the "interface FISH analysis"; fluorescent in situ hybridization. Now what is the FISH analysis, what does it mean? Essentially what we do is find a fluorescent probe that takes up in the area thatís going to break. So here what you see is the two long arms of the two chromosomes and the probe takes in this side.

Now letís talk about the treatment of chronic myeloid leukemia. It is now known that the outcome of CML is not the one thatís described in the classical textbooks, or the one that sometime is told to the patient. That is, you have an average survival of 2-3 years, you have to do something drastic otherwise you are going to die. In fact, with the newer series the average survival is now seven years and thatís because of earlier diagnosis but also because of the new intervention treatments that are improving the outcome of these patients. Now all these treatment interventions have focused on suppressing the Philadelphia chromosome abnormality.

Now what are the modalities that can suppress the Philadelphia chromosome? Hydrea and busulfan really do so, and Iíll show you the role of Hydrea a little bit later on. Allogenic transplant and matched unrelated transplants do so consistently. They produce cures but there is a price to pay in terms of early transplant-related mortality. And then interferon-based therapies do so and Iíll try to discuss some of the updated results and perhaps mention some of the newer strategies, particularly the bcr/abl tyrosine kinase inhibitors. What is the role of busulfan and Hydrea? I think Hydrea is still an excellent tumor-reducing agent.

Now what are the results of allogeneic bone marrow transplantation, which is the known curative modality in CML? We know that the outcome relates to the phase in which the patient is transplanted, the patientís age and possibly better results in early chronic phase - and Iíll show you these data. The first slide shows the results on CML by age and what you see on this slide is that patients who are very young have a very low transplant mortality, and their event-free survival is 60-70%. So for any patient where we anticipate that the one year transplant mortality is under 20% - and these are usually the younger patients with related siblings - then they should go for the transplant. For the older patients, the transplant mortality at one year may be higher so one has to consider the options in terms of early transplant versus interferon-based therapy to select the non-responders.

This slide shows the outcome of allogeneic bone marrow transplantation by the duration of chronic phase and this is the data from the IBMTR that reproduced the initial Seattle study that suggested that if you delayed the transplant after one year there is a significant survival disadvantage. Now this has not been reproduced in the more recent studies. For example, the European bone marrow transplant registry data.

When patients relapse after transplant their outcome is not invariably fatal. In fact, itís very good. So we cannot equate event-free survival with survival, which is much better, and that is because Dr. Kolb in 1979 discovered that if you take a patient who relapses after allogeneic transplant and you give them donor lymphocyte infusions, 80% of them will go back into remission. This is

What about matched unrelated transplant? When is matched unrelated transplant doable? This is a study from 1993 that summarized the results of the matched transplants, and I want to point out the fact that for patients who are in chronic phase and who are young, with a full match or with a one-antigen mismatch, there is still a very high one year mortality, in excess of 30-40%. Now this may get better in time, but at this stage - in most of the centers - unless you do a perfect molecular matching, the mortality is quite excessive. If you take older patients itís even worse, particularly if there is a molecular mismatching. So because of these data, at our

With interferon therapy, when I show you the results, Iím going to discuss cytogenetic responses and here Iím defining them. A complete cytogenetic response is Philadelphia-positive cells going to 0% and the partial cytogenetic response is when they go under 35%. The major cytogenetic response includes both these categories, and in our hands these are the patients that have the best survival advantage. Letís look very quickly at the results up until 1990. In our institution we have a good hematologic response rate, half of the patients with interferon have a cytogenetic

The data with interferon therapy versus conventional therapy has reproducibly shown that interferon therapy is superior. But more importantly, it reproduced the concept that achieving minimal tumor burden, like a complete response for solid tumors, improved survival. So this has consolidated the rationale that we have to continue to develop strategies that increase the proportion of patients who become 0% Philadelphia. How do we do that? In 1986, after multiple failed trials, we finally elected to look at ara-C added to interferon because there was data that showed that ara-C was selective in suppressing the CML clones in vitro, and could

We did two studies with two different schedules of ara-C. The first one is the well-known intermittent schedule for 7-10 days, but the more recent one - which I think is a better one - is a flat dose of ara-C 10 mg a day, trying to expose the leukemia cells to the effect of the ara-C 100% of the time. In our hands the daily schedule is better because for the first time in the total population it allowed us to have a cytogenetic response in 70% of the patients, and half of the patients for the first time ever had a major cytogenetic response. Not the good risk patients only. And the cytogenetic responses occurred earlier. It takes a median of about nine months to produce a major cytogenetic response at the lower dose of interferon therapy. Now this has been reproduced already in two randomized trials. The first one published by Dr. Gio in the New England Journal of Medicine, 720 patients randomized to interferon alone or with ara-C. And that study showed that the addition of ara-C increased the incidence of major cytogenetic response to 41%, which is very close to our results, and the complete cytogenetic response to 26%. Most important for community practice, it improves the survival significantly and independently by multi-variant analysis. There is a second study which was reported last year as an abstract by Dr. Tura which showed the same thing in 540 patients, randomized to interferon alone or with ara-C. The incidence of major cytogenetic response was significantly better and the survival was better with the addition of ara-C, significant but only for the good risk patients. So in my mind, there are at least two studies now that confirm that the combination of interferon and ara-C in a randomized fashion improves the outcome of the patients and so that has to become the standard of care. So if you look at the sequence of studies with busulfan then Hydrea then interferon, we start having patients with a complete cytogenetic response and now with the combination that proportion of major responders or any cytogenetic response is getting better. So the question is; how can we improve on that degree of complete cytogenetic response?

So in the next set of slides I am going to discuss some investigational therapies which will never come into the Board but I think itís important to realize. After several attempts we found that there is a drug called homoharringtonine that was able to induce hematologic remissions in two-thirds of the patients that were resistant to interferon. And we did two studies with homoharringtonine alone or with ara-C in now about 170 patients. Cytogenetic responses were seen in one-third and to our surprise there was a significant survival advantage when ara-C was added to homoharringtonine. But it told us that HHT is a drug which is a very good one, and how can we exploit that benefit in front line therapy? So what we did was we designed what is now called the triple regimen with interferon/ara-C as the backbone, homoharringtonine added for five days every month and we gave it to front-line, newly diagnosed CML patients. This is the update in the first 56 patients which have received at least three months of therapy, almost everybody has a hematologic remission with a median follow-up of only 11 months we already have three-quarters of the patients having cytogenetic response and 43% having a major cytogenetic response, even with much lower doses of interferon/ara-C and homoharringtonine because of the cumulative myelosuppression. Now your question is; how do we know it is better than ara-C with interferon? We cannot wait ten years to do so, to document this, so what we did was an analysis at six months where we looked at the surrogate markers for survival - which is major cytogenetic response - and what you see is that with the triple regimen the incidence of major cytogenetic response goes from 18% to about 30%. So Iím pretty confidant that the triple therapy is going to be better for the future.

Now you may be saying to yourself, "This treatment is becoming now very cumbersome." We have two shots a day and the homoharringtonine which is given by vein. So is it worth it? Well, first of all, we are working on a subcutaneous homoharringtonine formulation but more important, there is a new formulation of interferon which is put in polyethylene glycol, just like the asparaginase. So the half-life of the interferon is in the order of days. You give it only once a week. The toxicity profile is better. Among the 21 patients that were treated we had five patients that had improved tolerance, but most importantly, of 13 patients that were resistant to interferon five really responded to the PEG interferon. So I think the future is going to be the PEG interferon given once a week, less toxic and more effective.

Now the last treatment that I want to approach is something that I think you must become familiar with, because it is going to change the way we treat CML and the way we view chronic myeloid leukemia. The treatment is called a tyrosine kinase inhibitor which is targeted specifically at the bcr/abl protein message. Now a little bit of a background on the tyrosine kinases, their role in cancer, and what are the kinase inhibitors. This is the product, which is the tyrosine kinase inhibitor for the Philadelphia abnormality. But the background for it is that in cancers there is a family of tyrosine kinases which are not specific for CML but they are specific for other messages produced by each of the specific cancers. Those kinases are what drives the cancer and if you can develop small molecules that suppress those kinases, then you can change the

These are the results of the signal transduction inhibitor in chronic myeloid leukemia. In chronic phase there have been now 40 patients treated, all resistant to interferon, almost every patient achieved a hematologic remission, and at the higher dosages three of nine patients had

Now I am going to discuss a couple of questions which often come into your practice. I get a lot of phone calls, "Well, I made a diagnosis on a CML patient but she is pregnant. Can I give her interferon therapy?" My opinion is that you should not give interferon therapy to these women because even though you may have seen case reports on successful deliveries, the ones which are not successful are usually not published. This is true. Interferon is known to be anti-angiogenic so it can affect the placental blood supply and I am sure there is going to be a higher incidence of abortions or small-for-size delivery. My advice is supportive care or pheresis if

The last question is the most common question asked now. If you have a patient who comes to you with chronic myeloid leukemia how are your going to make the choice of allogenic transplant up front, versus interferon-based therapy. Here Iím giving you a simple algorithm which will apply to the Board. So rather than tell you an age cut-off, which can produce different

Now this is a slide from the Italian study group which was published in JCO. Everybody, when they read the article, they said well itís obvious. If you have a very young patient, go for the transplant. If they are older then do interferon-based therapy. Here Iím showing the results of

So in summary, I hope Iíve given you a good idea about what is happening in chronic myeloid leukemia. It is a disease which has already changed its course significantly from a disease that was incurable, where we sent the patients home to die in three years, to a disease that is highly curable with allogeneic transplant and where also we have multiple modalities that suppress the Philadelphia chromosome, sometimes to a degree where we hope for a long term event-free survival. More importantly, I think the next three years are going to show that the addition of tyrosine kinase inhibitors to interferon/ara-C may increase drastically the proportion of patients who become PCR negative and do not need therapy and will stay without disease outside the setting of allogeneic transplant.