John P. Leonard, MD; Richard M. Stone, MD


June 17, 2011

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John P. Leonard, MD: Hello. I'm John Leonard, Professor of Medicine from Weill Cornell Medical College in New York. Welcome to Medscape Oncology Insights in Blood Cancer.

Today, we are going to discuss several of the significant studies in lymphoma and leukemia that are being presented here at ASCO® 2011. I am very happy to be joined today by Dr. Rich Stone, Professor of Medicine at Harvard Medical School and Director of the Adult Leukemia Program at Dana-Farber Cancer Institute. Welcome, Rich. Thanks for joining me.

ASCO® is a smaller meeting with respect to blood cancers relative to ASH [American Society of Hematology]. Nonetheless, some important studies and updates have been presented here. One of the areas that I think people are interested in is what's happening in acute myelogenous leukemia (AML). What is your take on some of the new developments that people in practice should know about?


Richard M. Stone, MD: As you pointed out, John, a lot of the initial presentations of the interesting studies take place at ASH, but some updates and a few new ones were presented at ASCO® this year. One of the more interesting presentations was the so-called CLASSIC 1 [A Study of Clofarabine and Cytarabine for Older Patients With Relapsed or Refractory Acute Myelogenous Leukemia] trial[1] that was actually presented for the first time here, although a press release preceded it.

This was a trial of cytarabine alone vs cytarabine plus clofarabine in older adults with relapsed AML. So it was a rather selected patient population, one that wouldn't be expected to do very well.

Dr. Leonard: Right.

Dr. Stone: There was a lot of discussion about the optimal control arm -- what to use -- because no one can really agree upon what the optimal relapse regimen in this age group was. But anyway, cytarabine was the control arm and adding clofarabine to cytarabine was the experimental arm.

The press release was kind of sad because there was no difference in overall survival. Survival was 6 months in both arms, which is what you would expect for this difficult patient population. The point of interest was that the response rate was much higher in the experimental arm. The dual drug arm was about 40% compared with about 20%, especially higher in people with relapses compared with some of the other refractory subgroups.

If you wanted to get a response that was important as opposed to survival, then one might consider using those 2 drugs. However, because it did not meet its endpoint, I don't think it will be an approved regimen.

There was also a little bit of emphasis on secondary AML. This is AML that occurs after mild dysplasia or after therapy for other cancers, which sadly is becoming an increasing problem for people who treat leukemia.

Mixed Results in Secondary AML

One trial that I actually was involved in was the largest trial I am aware of (450 patients) performed in people with secondary AML.[2] Half of the patients received standard care, which was daunorubicin and cytarabine, and the other half received a new drug called amonafide. It is actually not so new -- it has been around for years, but it was newly applied in this condition -- amonafide plus cytarabine. So it was amonafide plus cytarabine vs daunorubicin plus cytarabine.

The primary endpoint was complete remission rate. The complete remission rate was exactly the same (45%) in both arms. That was kind of sad. If you look back on it, however, the predicted response rate in the daunorubicin/cytarabine group (the control group) was 30%. So this was a case where the control group did better than expected, which is what sunk the study.

I will end on a happier note, with a trial of a drug called CPX-341.[3] This is daunorubicin and cytarabine just like we normally give, but this is encapsulated in a liposomal matrix. It delivers the daunorubicin and cytarabine in a fixed molar ratio, which in preclinical studies works out pretty well. The company that makes this drug presented an update of the phase 2 randomized trial of daunorubicin/cytarabine given conventionally vs CPX-341.[3]

The complete remission rate was significantly better in people who received the experimental drug. The overall survival in patients with secondary AML (this was a subgroup of the total group of older adults) was a bit longer. So that's promising. They are hopefully going to do a full phase 3 trial of daunorubicin and cytarabine vs the liposomal encapsulated daunorubicin/cytarabine. We will see if that happens.

Dr. Leonard: It seems as though the treatment of older patients with AML has gotten more complicated, but not necessarily better. Is that a fair statement? A lot of regimens seem to be used in different studies, but none that clearly stand out as being dramatically better. Is that accurate?

Dr. Stone: That's certainly true. Yes, in summary, if you look at survival curves in younger adults with AML over the last 30 years, they have improved. If you look at survival curves for older adults with AML, they are all superimposable data back 30 years ago.

Dr. Leonard: Right.

CHOP-R 14 vs CHOP-R 21 for Aggressive Lymphoma

Dr. Stone: John, what about your field? What about aggressive lymphoma? What have you learned at this meeting about that?

Dr. Leonard: In aggressive lymphoma, some relatively negative but important studies were presented. One of those is an update of a British study[4] that looked at CHOP-R [cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone, rituximab], which is the standard regimen for diffuse large cell lymphoma (the most common type of lymphoma) on a 21-day schedule vs a 14-day schedule. Basically the French group -- the GELA [Groupe d'Etudes de Lymphomes de L'Adulte] -- was the first to do the big study that showed that R-CHOP on a 21-day schedule was better than CHOP alone. The German group has really advocated CHOP-14 on a 14-day schedule with GCSF [granulocyte colony stimulating factor] support.

The question is, now that everybody gets rituximab, does the 14-day vs 21-day schedule matter at the end of the day? This was a huge study, 1000 patients -- younger patients, older patients, all risk groups -- done in Britain. Basically, there was no difference between the R-CHOP 14-day schedule and R-CHOP 21-day schedule, at least in efficacy.

In terms of safety issues, paradoxically, R-CHOP 21 was a little safer. However, that was paradoxic because all of those patients got GCSF; whereas, by ASCO® guidelines, only a minority of the patients getting R-CHOP 14 would have gotten GCSF. So they actually had more myelosuppression and toxicity because they had less support.

The bottom line is, there is no clear advantage. People are left sticking with R-CHOP 21. The question really is, is there any advantage in getting that a little quicker for the patient or anything else? But at the end of the day, it was disappointing that the dose-dense strategy does not represent an advance.

Autotransplant in DLCL: A Disappointment

The other big theme that was presented in diffuse large cell lymphoma [DLCL] relates to intensification with autologous stem cell transplant in first remission for high-risk patients. The IPI [International Prognostic Index], age, performance status, lactate dehydrogenase [level], extranodal disease, and stage have been validated in numerous studies to correlate with outcome.

Probably 10 studies of one form or another have looked at using autologous stem cell transplant as consolidation in high-risk patients, and they differed. All of the trials that were randomized left out rituximab. So they are basically outdated at this point.

This was an SWOG [Southwest Oncology Group] intergroup study[5] that took patients with intermediate- and high-risk IPI and gave them R-CHOP 21. A few of the patients got CHOP because it started before R-CHOP was in vogue and then [they were] randomly assigned to autotransplant in first remission vs just a full course of R-CHOP.

The net result of the study was that there was no difference. The only glimmer of hope in the study was a subgroup analysis of just the high-risk patients, who seemed to benefit. There was a progression-free survival benefit as you would expect, but no overall survival benefit because patients who weren't transplanted could be salvaged with transplant.

The high-risk patients were a small group of patients. You are really getting down to fewer than 50 patients (in that ballpark) who seemed to benefit, but that was an unplanned analysis. So it was interesting in the discussion because the discussant of the abstract suggested that we should be advocating doing autotransplant at first remission in the high- risk patients. That is an opinion that just wasn't shared in talking to people after the meeting and so on. I think that it is not a clear-cut thing and there is a lot of debate there.

It is also disappointing that it didn't demonstrate a more dramatic impact for these patients. We are stuck with R-CHOP 21 for the vast majority.

Dr. Stone: So you think that every high-risk patient should get R-CHOP 21 for 6 cycles?

Dr. Leonard: That's right. If it's a high-risk patient, which is a minority of patients, you could discuss autotransplant, but the data are not clear whether it provides a benefit. We really have to be using new drugs from the beginning. Consolidating somebody 4 months into their treatment for large cell lymphoma is really not going to be the big impact answer. It's coming in on day 1 with a new regimen and a new drug and so on.

Unfortunately, the new regimens that we have used, intensive regimens from day 1, haven't paid off yet. But we'll see. There are some important randomized trials going on.

JAK2 Inhibitors for Myelofibrosis

What about the JAK2 [Janus kinase] area? That's something that we keep hearing about at Cornell -- new drugs that inhibit JAK-2 in myelofibrosis. What do people in practice need to know about that?

Dr. Stone: Right now, those in practice don't need to know too much, except that it's an exciting field and a very crowded one from the developmental standpoint. The point here, John, is that JAK2 mutations were discovered about 10 years ago to be present in about 95% of people with polycythemia vera (PCV) and about 60% of people with essential thrombocytosis (ET) and myelofibrosis.

The JAK2 field really began with all these drugs being tested in people with myelofibrosis because that was felt to be a bad disease -- it does shorten your life expectancy, you can get bad problems with blood counts, hepatosplenomegaly, and even have liver failure due to the extramedullary hematopoiesis. So it's a bad disease, and it was felt that it wasn't really possible to test these drugs first, at least in PCV or ET.

The drug INC-424 is called ruxolitinib. That was the "first guy on the block." The phase 1 and 2 studies showed that this drug, which is a pill, when given to both JAK2-mutant patients and wild-type JAK2 patients who had myelofibrosis (either primary or after PCV or ET developed) caused the pruritus to get better, the constitutional symptoms to get better, and the splenomegaly to decrease in many patients.

It was interesting that you didn't have to have a JAK2 mutation to benefit because this drug is dirty and inhibits other JAKs [that] are involved with inflammation. It is kind of complicated, but nonetheless it seemed to have clinical benefit.

JAK2 Inhibitors Approaching Approval

The big news at this meeting was the 2 randomized trials of this drug. The one that's farthest along is in the same subgroup of people with myelofibrosis with JAK2 wild-type (or not). One trial was mainly in the United States, which was a placebo-controlled trial with the JAK2 inhibitor INC424 vs placebo.[6] The other one was a similarly designed randomized prospective trial of the JAK2 inhibitor vs best care or whatever the patient was going to get from their doctors, conducted largely in Europe.[7]

These 2 abstracts will be presented tomorrow morning. The second one is a late-breaking abstract, and the results are interesting but not surprising. It depends whether you are a glass half-full person or a half-empty person. In both cases, people who received the experimental drug in the study, the JAK2 inhibitor, had at least a 30% reduction in their spleen size by about a year. There were also shorter endpoints.

It didn't seem to matter whether you got placebo or you got whatever was available, nothing else works anyway. There was a nice reduction in the spleen size. So, is that great? Well, it is if you are a patient with a big spleen that hurts. Is it worth it? You pay a price in terms of anemia and some gastrointestinal side effects in both cases, but not intolerable.

I suspect that this drug will get approved on the basis of these prospective randomized trials, which they wouldn't have done unless they thought they could get approval, and it did meet the endpoint of the study. It will be interesting to see how these drugs are used after they get approved. Doctors need to know this is on the horizon.

Other JAK2 inhibitors are coming right behind. Targeson has one. Two were presented. Two more phase 1/2 studies were presented, one with a drug called SB1518[8] and another one with a called drug CYT387 from the Cytopia Corporation.[9] Again the same idea, the spleen shrinks. The CYT387 study was interesting because that was the only one that didn't produce anemia, which is a big problem for a lot of these patients. I would definitely look at that drug, although the drug SB1518 is going to be available first.

Other Drugs on the Horizon

Dr. Leonard: In our last minute or two, people in practice also are interested in what new drugs on the horizon they should monitor beyond what you have mentioned. You gave one great example. One drug that ought to be mentioned, and perhaps patients should even be referred for clinical trials, is a drug that affects diseases we both treat, [and that] is Bruton tyrosine kinase inhibitor, which is important in B-cell signaling and activation.

This drug is really active in chronic lymphocytic leukemia (CLL) and in mantle cell lymphoma as well as in follicular lymphoma. It is a drug that's very well-tolerated. There are some updates on the CLL data at this meeting and for lymphoma and mantle cel, at other upcoming meetings.

How do you see that drug fitting in? It seems to me that for patients with resistant mantle cell and resistant CLL, it is going to have potentially a big impact, and people ought to explore those trials.

Dr. Stone: The abstract that's going to be presented tomorrow[10] suggests that Bruton tyrosine kinase inhibitor seems to have a pretty good response rate in refractory CLL. But just like with indolent lymphoma (and you can comment on this, John), how [do you] fit that in? It's nice to have another drug where there are some responses at the end of the day.

Dr. Leonard: Right.

Dr. Stone: It is really going to be important to move this up front. Where do you see that happening in low-grade lymphoma?

Dr. Leonard: It really comes down to the tolerability and the efficacy in larger numbers of patients. In mantle cell lymphoma, certainly there has been, in a small number of patients, a very high response.

Follicular lymphoma is a little more challenging, given the heterogeneity of the disease. But clearly the drug also has activity. We are moving more and more away from chemotherapy and toward more biologic or target-specific drugs that can hopefully get at the pathogenesis of the disease better.

Closing Remarks

In conclusion, just about everything that we have talked about shows that this is where things are going -- away from kind of the broad-based chemotherapy and more toward targeted therapy, which is obviously a theme in oncology generally speaking.

Well, thanks very much for joining me today -- we have had a nice discussion. Hopefully, the audience has found this to be helpful. We thank the audience for joining us today for this edition of Medscape Oncology Insights. My name is John Leonard and again thank you for joining us here today from ASCO® 2011.


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