The December issue of Oncology & Biotech News featured highlights from the 51st American Society of Hematology (ASH) Annual Meeting and Exposition. We wrap up our ASH coverage this month with interviews on multiple myeloma with Brian G.M. Durie, MD, medical director and co-founder of the International Myeloma Foundation; chronic lymphocytic leukemia (CLL) with Robert J. Kreitman, MD, from the National Cancer Institute; and chronic myeloid leukemia (CML) with Francis J. Giles, MD, Cancer Therapy and Research Center at The University of Texas Health Science Center in San Antonio.
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The annual American Society of Hematology (ASH) meeting takes place each December and draws thousands of hematologists from around the world. Many studies presented at ASH in the past have changed care for patients with hematologic malignancies. We interviewed three experts who presented data at the most recent ASH meeting about advances in care for multiple myeloma, chronic myeloid leukemia, and hairy cell leukemia.
Brian G.M. Durie, MD
Oncology & Biotech News
At the 2009 51st American Society of Hematology Annual Meeting and Exposition in New Orleans, Louisiana, in December, spoke with Brian G.M. Durie, MD, medical director and co-founder of the International Myeloma Foundation (IMF). Durie is also an expert in multiple myeloma and a pioneer in treating blood cancers and chairs three major research groups: the Myeloma Network for Aptium Oncology, the International Myeloma Working Group, and the Myeloma Committee of the Southwest Oncology Group (SWOG).
OBTN: How does IMF work to increase awareness of multiple myeloma in the broader community?
DURIE: IMF is a nonprofit entity based in California and has been in existence now for approximately 20 years and has many tools in place now to raise awareness about myeloma. By telephone and through the Website (www.myeloma.org), we make a lot of information available and alleviate a lot of instant fears that patients might have when they first hear the word myeloma, which they most likely would never have heard of before.
If the word comes up in the diagnostic discussions for a patient, in this electronic age, patients can log myeloma into Google or any one of the search tools and go straight to our Website or call our hotline. We have four hotline staffers in the United States who are well informed about myeloma and can answer questions directly. They can also send published materials or direct people back to the Website to download informational materials. For example, we have booklets about understanding myeloma, understanding anemia, and understanding different drugs that are used to treat myeloma.
One arm of the IMF is the research arm, and one part of that is the International Myeloma Working Group, which is a collaboration of 120 experts form the different major centers working on myeloma around the world. We have worked very hard to take advantage of resources throughout the global myeloma community. The experts in our Working Group provide input from all around the world so that we have appropriate upto- date information. I think that IMF is a tremendous resource.
How is multiple myeloma diagnosed?
We rely these days on the presence or absence of four important features: elevation of calcium, the presence or absence of renal problems, the presence or absence of anemia, and the presence or absence of bone disease. This leads to the acronym CRAB—calcium, renal, anemia, and bone.
The testing for each of those needs to be implemented and the test evaluated to see if there is a problem in any one of those areas, and then seek appropriate consultation about how to start with the treatment paradigm. It’s important to realize that that is the strategy in North America and most of the European nations.
What are some of the challenges in diagnosing multiple myeloma?
There are several challenges in diagnosing multiple myeloma. On the one side, we don’t want to over diagnose and start treatment too soon. But, on the other hand, we want to diagnose and start treatment for those patients who might have serious complications evolving.
Diagnosis can come about through routine testing in which the serum protein or the urine protein level is found to be elevated. The challenge there is to follow through and reach a correct diagnosis. In the one case, it could be a monoclonal gammopathy of undetermined significance, a benign phase of the disease, or there could be truly active multiple myeloma that requires treatment. There needs to be knowledge of what’s necessary to make the diagnosis.
In other parts of the world, such as Latin America and many parts of Asia, this type of routine testing [seen in North America and Europe] has not been carried out…and we find the diagnosis is really, really delayed. When we look at the staging of the disease in Latin America, for example— specifically Brazil—85% to 90% of the patients have stage III disease with high blood calcium and many, many problems. And so the challenges are diverse as we look at this around the world.
How has the care of patients with multiple myeloma and their prognosis changed over the past decade?
This has perhaps been the exciting thing about myeloma therapy, in that we have seen the impact of the novel agents. We have three new drugs that have become available for myeloma in the past decade that many of the investigators refer to as “The Three Musketeers”: thalidomide, Velcade, and Revlimid. These three drugs have really changed the landscape in myeloma therapy.
An important study conducted by a Mayo Clinic team was published in the journal , with Dr Shaji Kumar as lead author. Dr Kumar looked at the survival of patients before and after the introduction of these three drugs. When he looked at the time span between 2001 and 2006, that 5-year time span, he found that for the first time in the last three decades, there was a highly significant jump in the survival expectation for patients with multiple myeloma—that the patients could expect to live at least 2 years longer. And for some groups, the survival has more than doubled.
What do you think about the four-drug regimens being investigated for newly diagnosed multiple myeloma?
Well, there was a lot of excitement and discussion about this [at ASH]…where there were two or three four-drug combinations presented. Perhaps the greatest attention was paid to the EVOLUTION protocol, which is a combination of Revlimid, Velcade, Cytoxan, and steroids. What caught people’s attention is that there is a 100% response rate, so obviously all the patients were responding to this combination. But I also heard a lot of concerns voiced about this, in that yes, this combination works well, but it is not contributing to a cure for myeloma. This was actually a question from the audience, when these data were presented at ASH. A gentleman asked, “Okay, well, what are you going to recommend as a patient goes through this treatment and then is relapsing? How does that constrain your options in the relapse setting?”
I think this is a very important question. We don’t have an exhaustible supply of drugs for myeloma patients, so if you use key drugs as a first step, what is going to be the second step? This opened up a whole discussion about the sequential use of drugs, the idea of, on the one hand, trying to come up with a cure for myeloma by using the best combinations, but then, on the other hand, perhaps being a little more cautious for the standard recommendations of treatment and considering the sequential use of the drugs that we have over time.
How do you see autologous stem cell transplantation fitting into the picture? If the efficacy of the newer treatment holds up in further studies, do you think it might allow delaying the timing of transplantation?
Well, again, this is one of the key aspects that were discussed at this most recent ASH. I think on the one hand, there were follow-up data showing that autologous stem cell transplant with high-dose melphalan is clearly still contributing to excellent outcomes. But, for the first time, there was interest in an abstract in which a novel combination was directly compared to high-dose melphalan, and this was a study from Italy in which [a combination of] melphalan, prednisone, plus Revlimid was compared head-to-head with high-dose melphalan. The follow-up was early, but within the first 2 years, the progression-free survival was equal with the novel combination versus the high-dose melphalan with stem cell transplant. This raised the question that maybe some type of a novel combination could give an equal benefit. I think that because of the long experience with transplant, we’re going to need a lot more data before people would be willing to take that leap. But it was interesting to see this type of randomized study occurring and being presented.
Previously you mentioned that there is a difference in how multiple myeloma is being diagnosed and staged in other countries. Are there also differences in how it is treated in the United States compared with other countries?
Yes, yes. The treatment choices and the strategies for treatment vary quite a bit from country to country. There are complex reasons for that. On the one hand, you have the FDA approval process for the drugs in the United States, so by and large, the new drugs tend to be approved earlier in the United States. In fact, the regulatory agencies in other countries tend to take the lead from the FDA, and so they tend to wait and see if the FDA approves drugs. Then they initiate and move forward with the approval in their country. The only exception to that is probably the European Medicines Agency, which will sometimes approve drugs ahead of the FDA.
The three novel agents are all approved in the United States right now, but there’s a slightly different pattern of approval in Europe. For example, Revlimid is not approved in the front-line setting. Of course, in Latin America and in Asia, Revlimid is not yet approved in most of those countries at all. So based upon the availability of the drugs, there are different choices. Then there is the cost. In Latin America, thalidomide has been available almost for free for the treatment of leprosy. So in Latin America, thalidomide is a cheap drug and has been available widely, and that’s a very important choice to consider. Some of the new drugs with high price tags need to be considered carefully. Based on this, we almost need new treatment guidelines to decide what is appropriate based on what is available.
Has there been a difference in outcomes between different countries in patients with multiple myeloma based on the different treatments available to them?
This is a very interesting point. In a collaborative study with the International Myeloma Working Group, we did an analysis about 5 years ago of the outcomes at the different centers around the world as a basis for a new staging system, the International Staging System (ISS). We found that the staging system did work around the world, but, interestingly enough, the exact outcomes were statistically a little bit better in Europe versus North America and in Asia. This raised some questions about what is happening in the United States, for example, where so much additional healthcare is available. On the converse side, we did find that outcomes in Latin America, particularly in Brazil, were poorer where the myeloma is diagnosed much later.
What efforts are underway to personalize multiple myeloma treatments?
This was another key topic at the ASH meeting. The basis for the personalized approach will most likely be at the molecular level. A whole range of studies was presented talking about cytogenetics, fluorescence in situ hybridization, and other techniques.
Then there were results from gene expression profiling [GEP] of myeloma cells to come up with the profile of patients likely to be sensitive and respond well to available therapies—so-called standard- risk patients—versus the 25% of patients who are high-risk, with more damaged chromosomes and abnormal GEP findings. The idea is that they really should receive alternative approaches to therapy, and the next step would be to do that on a truly individual basis. But we’re not quite there yet in two respects: one, we don’t have the full genetic information; and two, I think most importantly right now, we don’t have the treatment recommendations. In other words, if you are a high-risk patient, what will we recommend differently? We’re not quite sure what is the [best] treatment approach for the high-risk patients.
When do you think that there might be more answers to that?Well, I think the encouraging thing is that there was a lot of discussion about trials, which we desperately need in this setting—trials in which patients with the high-risk, drug-resistant GEP will be directed to new drug approaches in a sequential fashion. In other words, patients in this high-risk group would be amenable to new drug approaches much sooner, with novel agents offered to these patients to really try to test and evaluate several exciting new options rapidly so that we could try to make progress more quickly.
What do you think of the availability and access to clinical trials for multiple myeloma patients? Are there even greater challenges because this is a rare cancer?Well, again, I believe that through the Web and through written materials provided to individual centers, there is a lot of awareness now about clinical trials. For example, the IMF has two tools on the Web. One is called the Myeloma Matrix, which is a complete list of all the drugs going through clinical trials, listed by phase. This listing is now linked to a clinical trials listing, so that if you hear about a particular drug that might be good to consider in your case, it links to a listing of ongoing clinical trials with that drug and where those trials are being conducted.
I think the challenge is, in a variety of ways, for patients who don’t live in a large city or close to a large center. In smaller communities, we are still dependent upon referral perhaps to a larger center, and it can be difficult for a patient in a smaller community to travel to a larger site to gain access to a new drug or to a new trial.
Is it difficult getting patients with multiple myeloma enrolled in clinical trials?I think it depends upon the type of trial. For example, [with] a drug where there’s some evidence of benefit in the relapse setting, it’s relatively easy for a patient who’s received a number of different therapies, let’s say at least three or more different approaches to treatment, to accept the idea of going into such a trial. However, entering randomized trials, particularly early in the disease for a newly diagnosed patient, can be problematic.
For example, right now, [conducting] a randomized study in the United States in which half of the patients will definitely have stem cell transplant and the other half will not can be a problem. Right now, with all of the exciting new information about novel agents, patients are not sure they want to have a transplant. A transplant involves a whole lot more than some of these new drugs, so to have a random allocation to get a transplant can be difficult. Those types of randomized studies, particularly early in the disease, can be more difficult to accrue.
What kind of supportive care measures should be taken to prevent or correct bone damage from multiple myeloma?I think that this is quite interesting in that it has become pretty automatic to recommend some type of bone care for patients with myeloma. The standard of care right now is to use a bisphosphonate, either pamidronate (Aredia) or zoledronic acid (Zometa). And we have clear evidence of benefit with these drugs. They reduce the evidence of bone events, so to speak. But the paradoxical thing is that since we now have such dramatically better treatment for myeloma and the disease is brought under control very quickly, ongoing bone damage in myeloma patients has actually become less of an issue. If you rapidly control the disease, which we were not able to do in the past, there’s less likelihood of new bone damage and there is less of a reliance on this type of supportive care.
The new idea in this area is that we want to have new drugs that will promote bone healing. And so if you can stop new bone damage, the crucial thing is actually to get healing of the site of prior bone damage. Instead of shutting down the osteoclasts, which promote bone damage, we want to stimulate the osteoblast, which can enhance bone healing. This is something that occurs with Velcade, and we’re looking to other new drugs that may enhance bone healing. So this is a new area of research and clinical trials.Which patients might need something more to correct their bone damage, like balloon kyphoplasty, for example?
I’m glad you brought that up. I think that this is a very important intervention. For patients who have had major bone damage, particularly in the spine if a patient has major bone damage to a vertebra or has collapsed a vertebra, injection of cement into the vertebra to stabilize it and correct the deformity can substantially reduce pain and also reduce the deformity and provide mechanical support. I think that, of the techniques that we have available, the balloon kyphoplasty is probably the best in terms of both reducing pain and then, because of the balloon approach, trying to recover the deformity of the collapsed vertebra and then injecting the cement. Again, this is an area of research to look at the benefit with and without the balloon approach [vertebroplasty].
Are there other supportive care options for patients to improve quality of life?
There are other types of approach, obviously, just to relieve pain and to have appropriate strengthening exercises, so broad supportive care approaches. The supportive care for patients with myeloma is actually quite diverse: to recover activities that are related to bone but also to recover activities related to kidneys. If there’s been kidney damage, to maintain a good fluid intake, to protect against anemia or low blood counts, and reduce the risk of infection. So there is a whole menu of supportive care recommendations for myeloma patients, and it’s important that these be carefully implemented.
Are there any situations that patients need to avoid because of their bone health?
Yes. I think that it is important to remember that this is a very individual thing, and so, before embarking on any kind of an exercise program, the patient must talk to their doctor and see if there are any precautions or restrictions in their case…such as avoiding contact sports. Jogging is not a good idea, whereas walking is excellent. Riding a bike is probably not ideal in case a patient would fall off, especially in rough terrain.
I think that there’s a menu of activities—basically more gentle physical activity. Swimming is good. I think that strengthening and flexibility activities with light weights for arms and legs are good. Balance is quite important for myeloma patients, so that they’re less likely to fall. A lot of things to be careful about, too, like no climbing ladders. That would be the worst thing for a patient: to fall off a ladder. And in colder climates, avoid walking on ice.
What are some of the initiatives the IMF has planned for the coming year?
Well, I think it’s an exciting year for us. We are expanding our activities in Europe. For example, we’re planning to open a hotline service in Europe where it will be multilingual and we will refer patients who are calling to the best centers in their own countries, where the key investigators have very nicely agreed to collaborate in providing this type of help and information.
Another initiative that I’m especially pleased about is the investigators from around the world in the Working Group who have agreed to a summit meeting that will be occurring in Barcelona in Spain at the time of the European Hematology meeting. We are going to review the top priorities to come up with better therapies. We really need to have key new drugs that will make a big difference for myeloma, and so the discussion will focus around what more we need to do to identify new pathways, new strategies. This workshop activity is particularly exciting.
We have educational activities that will be going on throughout the United States and around the world. In the current economy, I think that we’re particularly pleased that we have been able to recruit partners and be able to continue and even to expand our activities in some areas.
For more information about the International Myeloma Foundation and the International Myeloma Working Group, visit www.myeloma.org.
When these new drugs were introduced, they were introduced first in patients who had gone through other therapies. And so now the excitement is that these drugs are being introduced as part of the first treatment for myeloma patients, and we’re expecting that there will be an even greater impact in that setting.
Robert J. Kreitman, MD
Oncology & Biotech News
spoke with Robert J. Kreitman, MD, chief, Clinical Immunotherapy Section, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health (NIH), in Bethesda, Maryland. He is an expert on hairy cell leukemia (HCL) and has published several papers on this disease. Kreitman is currently involved in clinical trials investigating the use of various immunotoxins in chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, prolymphocytic leukemia, and other hematologic malignancies.
OBTN: You presented studies at ASH on various immunotoxins being investigated by NIH in HCL and CLL. What is the rationale behind using immunotoxins?
KREITMAN: Immunotoxins are extremely potent targeted molecules. Because they work catalytically once in the cytosol, only a few molecules are needed to kill a cell. They can kill drug-resistant cells because of their unique mechanism of action and ability to target cells with limited numbers of binding sites per cell.
How do these immunotoxins work? Do they all have similar mechanisms of action?
Immunotoxins containing an antibodytargeting molecule fused to a truncated exotoxin work by selectively entering cells with the antibody target and then ADP ribosylation of elongation factor 2, leading to inhibition of protein synthesis and apoptotic cell death.
What are some of the more promising immunotoxins being studied in hematologic malignancies such as HCL and CLL?
CAT-3888 (BL22) has published phase I and II activity, and CAT-8015 (HA22) has phase I activity most recently presented at ASH 2009. The lead agent being developed is CAT-8015, a high-affinity version of CAT-3888.
What are some of the concerns about using immunotoxins?
Immunotoxins targeting CD22 cause hemolytic uremic syndrome (HUS), but it is reversible, and HUS with CAT-8015 is infrequent (<10% to date) and so far not severe.
How has the outlook for patients with HCL changed in the past decade? Has it improved?
With standard treatment introduced in ~1990, HCL is extremely responsive, but there is no evidence of cure and patients continue to relapse at a constant rate. Rituximab can induce complete remission (CR) in a minority of patients with relapsed HCL needing treatment, but these CRs do not appear permanent.
And how about for CLL? Many new treatments can induce CR and partial remission in CLL, but also there is no evidence of cure.
What are common symptoms of HCL and how is the diagnosis made?Common symptoms include low levels of normal blood cells and enlarged spleen. The diagnosis is most accurately made by flow cytometry of the blood or bone marrow.
Have any genes or molecular markers been identified as targets for HCL therapies? CD25, CD22, and CD20 are surface molecules which can be targeted with antibodies or immunotoxins.
What are some of the more promising treatment options available for HCL?Other than the immunotoxins CAT-8015 and CAT-3888, the combination of rituximab and purine analog appears effective and promising, but with significant hematologic toxicity and sometimes neuropathy caused by the purine analog.
Is it true that treatment for HCL can be delayed in some cases and that some patients will never need treatment?
Yes, a minority of patients (~10%) never need treatment.
By low blood counts, large painful spleen, and repeated infections.
There is a variant called HCLv which is usually CD25-negative. VH4-34+ HCL is a recently described variant which only partially overlaps with HCLv.
Other than absence of CD25, CD123 and occasionally CD103, HCLv often has larger malignant cells, presents with higher white counts, is less responsive to purine analog, and has a poorer overall survival compared to classic HCL.
CAT-3888 was reported to induce CR in several patients with HCLv in early clinical studies.
Several years would be needed to complete a large trial to demonstrate benefit sufficient for drug approval.
CAT-8015 is currently enrolling additional patients at a fixed-dose level for relapsed or refractory HCL.
How do you identify those patients for whom treatment can be delayed and is there any risk to delaying treatment? Are there any characteristics of HCL that predict a worse prognosis? What is the difference between HCL and HCLv? When would you test for HCLv and what treatments are effective against HCLv? Do any of the immunotoxins being studied seem to be effective against this more aggressive form of HCL? How far off do you think it is before immunotoxins might be marketable as a treatment option? What trials are being conducted and what patients should physicians consider recommending for trials of immunotoxins in HCL?
For more information on NIH trials involving immunotoxins that are currently enrolling patients with hematologic malignancies such as HCL and CLL, see www.clinicaltrials.gov.
Francis J. Giles, MD
Oncology & Biotech News
Last month, interviewed Francis J. Giles, MD, professor of medicine, Division of Hematology and Oncology, Cancer Therapy and Research Center (CTRC) at University of Texas Health Science Center, regarding the latest data on chronic myeloid leukemia (CML) from the 51st American Society of Hematology (ASH) annual meeting. He also shared his views on the future of treatment for CML. Dr Giles has been involved in CML research for more than a decade and was involved in the early studies on imatinib (Gleevec) and nilotinib (Tasigna).
OBTN: How have things have changed for patients with CML in the past decade?
GILES: Things have changed enormously. Let me give you a statistical answer and then perhaps a more telling day-to-day example. The statistics show that CML has evolved over the last decade from a malignancy that was uniformly lethal unless you had a stem cell transplant—which was still associated with an appreciable mortality—to a situation where we tell patients at their first day of diagnosis that we believe there’s overwhelming odds that we’ll be able to offer them a normal lifespan. It is probably the most dramatic statistical shift in all of oncology in the last 20 years.
For a day-to-day example, as you can imagine, 15 years ago when transplant was just becoming more broadly available and was—as it is now— applicable to only a minority of patients, the longest conversations were the first ones, where you basically had to tell the patient you could use some medications to control the disorder but there was no prospect of a normal lifespan or even significant prolongation of life.
Then came interferon, which prolonged life but at a significant physical- and side-effect cost. The conversations then became, “Well, we can give you interferon and if you’re in a lucky minority, we will be able to prolong your life.”
BCR-ABL—specifically ABL, the kinase part of the driver—is driving this disease, with BCR providing the accelerant. We’ve discovered that the best way to attack CML so far is to go after ABL. Imatinib does this and became the gold standard for front-line patients. It has utterly transformed this disorder.
After imatinib, in particular, and its derivative, nilotinib, the longest conversations I now have in clinic with CML patients are about pregnancy. From a patient perspective, to have gone from a disorder in which you were talking about palliation to having a conversation about when and if it’s safe to attempt to get pregnant puts it in context as to just how dramatic and meaningful the improvements have been.
Imatinib is the gold standard, but it’s not perfect… you have a small percentage of patients who die within the first 10 years of taking the drug. Almost all of those patients die within the first few years, and they almost all die from development of accelerated or blastic phase disease. In other words, biologically at the time of their diagnosis, there’s something different about them and we don’t yet know what, so we cannot pick them out prospectively.
At the recent ASH meeting, we heard a lot about the possibility of using nilotinib as a firstline treatment. Can you tell us more?
It now seems overwhelmingly likely that Tasigna will displace imatinib and that has an enormous number of positive implications. Imatinib works because it is a relatively specific ABL inhibitor. The important word is relatively. It also hits three or four other targets that we’d just as soon leave alone. Early on, even as imatinib’s success was beginning to be appreciated, there was a desire to try to improve upon the chemical structure of imatinib, and this led to the creation of Tasigna.
At the CTRC, we have been involved with nilotinib since it was a chemical, and I was very involved with its design. Imatinib, for all its success, preferentially hits PDGF, as well, before it gets to ABL. Nilotinib is in the inverse of that and was designed to hit ABL above all else.
In an international randomized study, they looked at two dosing regimens of nilotinib and both appear equivalently effective. The side effects for both were absolutely minute, which was also very important, but, to the extent that there is a difference, it favors the lower-dose arm. That’s the dose at CTRC we had already invested in when setting up a single-arm international study, which we’re running with colleagues in Europe. The results are so far perfectly consistent with those from the international randomized study.
The fact that an enormous, very well-conducted international, prospective randomized study proved Tasigna superior to imatinib in front-line patients by every laboratory surrogate marker and clinically significant marker shows the clinical success of this targeted approach to drug development. [Tasigna] was better in terms of cytogenetic remissions and molecular remissions.
A very important measure of whether Tasigna is meaningfully better clinically is whether you can reduce the incidence of blast crisis, for example, or accelerated phase within those first few years. The overwhelming answer is yes, you can. We’re now looking at a possibility that not only are we able to deliver cytogenetic and molecular remission at a speed and degree beyond our imagination 3 years ago, but we also are seeing…that if you get people into the safe haven of a major molecular response, you are protecting them from the risk of disease deterioration.
We’re very interested in the prospect of being able to potentially discontinue nilotinib once you get the great majority of people into this safe haven, and we look forward to conducting studies where we look at whether discontinuation or interruption with careful monitoring is reasonable. Obviously, both for the patient and for society, that’s a fantastic prospect.
It’s going to take time now to recalibrate with nilotinib as the new front-line therapy. What do we require as second-line therapy? How many people will require it? What will be the mechanisms of resistance to nilotinib? Presumably, they will be somewhat different to those of resistance to imatinib…and I think, in fewer patients.
What is very much on our minds now is a simple word: cure. We think CML is now curable. This is not just wishful thinking but is based on principles seen with other hematologic malignancies, where we have managed to get a preponderance of patients into these safe havens, into some objective evidence of a degree of tumor load reduction that’s meaningful, at which point a cure faction has emerged. I’m perfectly confident that will happen in CML now, with a firm basis to either define those patients for whom nilotinib alone is enough or define those who may need other drugs to finish the job. At the CTRC, we’re pretty far ahead in that we already are studying nilotinib as a first-line option and were doing so even before the results of the randomized international study were available.
There has been a clinically meaningful, universally applicable, enormous improvement in the prognosis of patients with CML, and imatinib delivered a lot of that. Now, it seems pretty clear that nilotinib is going to take that one step further. It looks like nilotinib will become a new cornerstone for cure, really.
What implications does the success of nilotinib have for drug development?
The fact that Tasigna has proved overwhelmingly successful has a very important implication for all of medicine because it’s taught us an awful lot about targeting. You have to carefully define your target and decide if that target is druggable and whether you can modulate its behavior. If you can, you probably need to come up with the most specific, sensitive inhibitor or modulator possible. Imatinib transformed our perception of what a drug could do, not just in CML but also in leukemia and in medicine.
Now, within a decade, you’ve got a better drug [Tasigna] that is the first drug deliberately designed for CML. The implications for a drug development program like this, where we’re looking at many different targets and many different drugs, is that you can afford to be quite picky in terms of drug specificity and sensitivity.
As you can imagine, you’ve now thrown the challenge up for all of the other kinase inhibitors and beyond. Now, we’re just as interested in whether you can get a next-generation VEGF inhibitor, Her2Neu modulator, or any of the other targets; can you chemically modify your firstgeneration drug to come up with a better drug? The overwhelming and resounding answer from the imatinib/nilotinib experience is yes, you can.
You know it’s interesting that last year, at least one BCR-ABL inhibitor that had gone all the way into clinical studies was dropped, not because of toxicity but because there was no room for it. It was not predicted to offer a significant advantage over what was already available. I’m quite pleased to see that, both as a physician and as a taxpayer, because we have to see some evidence in developmental therapeutics that both our colleagues and Pharma are learning from lessons of reality—that we’re not really that interested in the third or fourth iteration of a kinase inhibitor any more than we are necessarily in the third or fourth iteration of an antibiotic or an antihypertensive. Simply announcing with a flourish “I’ve discovered a kinase inhibitor,” really doesn’t mean much anymore. We have to have specific hard clinical information that it is beneficial.
I think we really are better primed in this new decade to know, even before the first patient is treated, whether a new kinase inhibitor is going to be good, bad, or indifferent on balance. You are never going to be able to displace the human early clinical studies, of course, because you always encounter issues that you could not have predicted, but our ability to reduce that uncertainty beforehand has improved a lot. We are reducing it, and a lot of the logic that helps to reduce it has come from the CML experience.
What I hear you saying is that as we move increasingly into an era of personalized care, across all cancers, not just CML, we will see the deliberate design of newer drugs with more specific targeting?
I think that’s very well put. Unfortunately, in the history of drug development, what has happened is when a kinase inhibitor emerges, its owners look at what it does and then justify that package, whatever it is, in terms of how that’s the best thing for the disease. That’s neither physiologically nor rationally reasonable.
It’s a matter of deciding a hierarchy: Is there a primary kinase? Are there a number of kinases? Do we need to hit them all together? Do we need to hit them in sequence? What do we not need to hit? The imatinib to nilotinib transition is a testament to positive targeting.
It’s not that the future means we might not add other kinase inhibitors to ABL inhibitors—they just need to be the right ones with the right targets. We’re putting quite a lot of work into defining what those targets and drugs might be. Again, the newer drugs will probably get used in acute myeloid leukemia, myelodysplasia, myeloma, and other malignancies that we’re focused on. They probably will not be as CML-specific as imatinib or nilotinib.
Since the Philadelphia chromosome was discovered, since it was reported in 1960, all of malignancy, and really all of medicine, has learned a lot from CML. I anticipate that’s going to continue, because it is the paradigm for developing these targeted agents.
You have written extensively about your concerns with tyrosine kinase inhibitors (TKIs) that have a broad spectrum of targets in CML. Can you explain your concerns?
We have learned both the upside of very targeted therapy and the downside. For example, if you take a drug like dasatinib, another BCR-ABL inhibitor approved in second-line patients, it hits quite a lot of other kinases aside from ABL, including Src. A doctor’s argument would be, “Well, we know you want to hit ABL, and we know we have a more toxic drug. But surely you would like to hit all these other targets because you’re giving us, at least as currently approved, this drug for somebody with refractory disease and maybe one of these other targets is involved, and maybe it would be a good idea.” In fact, there was some laboratory evidence that Src might matter and that gave people some margin of comfort in going after targets that they might or might not otherwise be interested in.
As time has gone on, we’ve learned that there is a cost to hitting those other kinases; namely, that you have a lot of additional toxicities. One of the most potentially dangerous of these is Src inhibition. Src is critical to our immune surveillance mechanisms and it’s not unpredictable. If you give a Src inhibitor to patients with cancer, you run certain risks. We recently have had reports of opportunistic infection, viral reactivation, and one particularly alarming report about a potentially higher rate of secondary malignancies in patients on dasatinib. One of the main problems with dasatinib is serosal inflammation, which manifests as pleural or pericardial effusions. We believe that’s predominantly attributable to PDGFR inhibition. The great news about the imatinib/Tasigna or imatinib/ nilotinib sequence or succession is we don’t hit Src. In fact, we hit precious few targets other than ABL.
The so-called broad-spectrum agent dasatinib and its very targeted contrast, nilotinib, are equally effective at least in second-line therapy. In fact, nilotinib may be better, so the broad, random targeting approach did not work. It did undoubtedly bring more dangerous, threatening, and unpredictable long-term toxicities, however. We know there are kinases other than ABL that we would like to hit in CML. It’s just that unfortunately dasatinib doesn’t hit any of them.
Bosutinib, another tyrosine kinase under investigation but not yet approved, illustrates the point further. Now, bosutinib does not inhibit PDGFR, so the good news is you don’t get serosal inflammation, as far as we can tell. The bad news is bosutinib is also a Src inhibitor, like dasatinib. Bosutinib is associated with gastrointestinal side effects but not the pleural or pericardial effusions.
We are investigating other kinase inhibitors like the aurora kinase inhibitors. In terms of future patients, even those who don’t have CML, I hope that the medical and commercial brutal realities of what’s gone on in the last 5 years will focus Pharma and our colleagues on developing drugs that really matter.
Dasatinib started life as an immune suppressant drug for patients with solid organ transplants and then it was found to have ABL inhibitory activity. I think we need a little bit more thought to move an immune suppressive medication over to being an anti-leukemia drug. I think there will be more thought about that sort of thing in the future.
Now, that’s not in any way to criticize what went on. When we had dasatinib approved, it was the only drug available. It was a very important drug, and it was necessary for people in whom imatinib had stopped working. But would you do it again? Would you do it now? I would hope not. These are the options and choices we’re going to face.
We have heard a lot about the T315I mutation causing resistance to imatinib and other TKIs. What can you tell us about this mutation?
The T315I mutation is particularly interesting. Within the ABL structure, there’s a narrow channel at one point through which the drug must pass or a portion of the drug must pass. Before we ever identified this mutation in a patient’s cells, the preclinical scientists for imatinib told us if it were their job to make imatinib stop working, that was how they would do it. They said if you create a mutation that puts a large amino acid there, it behaves like a boulder blocking the passage; the drug will be stopped and the drug will be rendered impotent. It will do nothing.
When the first patients—those with very advanced disease—did not respond to imatinib or did so transiently, and we set off looking for why this was happening, we already knew where to look. The T315I mutation was the first mutation discovered. T315I was the initial stimulus to develop nilotinib and yet, ironically is one of the few mutations that nilotinib is not active against.
It’s at such a critical point within ABL. It mediates high-level absolute clinical resistance to imatinib, nilotinib, dasatinib, bosutinib, and nearly everything else we’ve ever tested other than a cou- ple of aurora kinase inhibitors, including MK0457, a highly successful anti-T315I drug that we led the development on. Unfortunately, a commercial decision was made not to develop that drug because T315I was considered too small a population.
What’s interesting is that it does create such high-level resistance but in and of itself, it’s a relatively poor transforming protein. In T315I, you actually have a less powerful transforming protein than the unmutated original protein, so it’s like having a weaker bug displace a stronger one. With our medications, we’ve eliminated the stronger one, and now the weak one can dominate and kill you. It’s very frustrating—like getting rid of the most potent malignant cells and then having a less malignant cell kill the patient anyway. Obviously, we’re not going to allow that to happen.
Now, the ASH data here has a lot of implications. One of our worries was if you introduce a very powerful, specific, safe drug like nilotinib front-line maybe you’ll get a very, very high percentage of people into remission, but those who are doomed to get T315I because of excessive genomic instability or whatever will do so anyway, only earlier. I was really afraid selection pressure would squeeze out the physical manifestation earlier, and I deliberately accelerated our efforts to find a T315I agent as it became clear that nilotinib was going to displace imatinib front-line. I had thought we might need a low dose of an anti-T315I drug with any front-line medication to stop this excess selective pressure.
Our job is to prepare these parachutes and hope they’ll never be necessary. Interestingly enough, from the data presented at ASH, I am really hopeful those parachutes will not be necessary. If you have a reduction in the overall death rate, which we have with nilotinib, and that is predominantly attributable to a reduction in the early development of accelerated phase and blast phase, which it was, then clearly, we’re not seeing an early expression of T315I. If it is not happening [with nilotinib], it’s fantastic news. It basically means we’re killing so many cells there isn’t time for this excess selection pressure to express itself. So now, I feel a little less pressure for the future in terms of developing a T315I medication.
I do need a T315I drug today for people who may still develop T315I mutations following exposure to imatinib, nilotinib, dasatinib, etc, but to what extent we’ll need one in the future is not clear. Dasatinib, particularly in Philadelphia chromosome—positive CML, is associated with a high rate of development of T315I, but I’m not sure that’s drug specific. Nilotinib may be associated with T315I with longer exposure.
It’s not as if T315I can’t be dealt with—it can. We now have a range of drugs active against T315I. One of them, from Millennium, is an oral agent and probably the most powerful and most applicable out there.
We have Millennium’s agents and others that we’re developing here, and Millennium is supporting us in moving that forward very aggressively. We’re still continuing, but without the sense of pressure for front-line.
What are other treatment paradigms you are considering in your quest to cure CML?
I’m a bit influenced here by the HIV model. That’s only partially applicable because, of course, you don’t eradicate HIV with the combination meds. But they have made a dramatic improvement, thankfully, for those patients. So the question is if we’re going to use nilotinib front-line and you want to cure people, does it make sense to add in another mechanism of action early on? Like, would it make sense to add in an aurora kinase ABL inhibitor just to try to nip at any early stage of development, or any other potential mechanism of resistance?
As you can imagine, if the rates of success of nilotinib in the front-line are maintained, the statistical ability to demonstrate further improvement is now beyond our capability. I don’t see how we would ever be able to recruit enough patients under any circumstances, thankfully, to be able to say that we can actually do better than nilotinib front-line. Now, if our preclinical work improves and we manage to predict an event, like who is vulnerable, then we probably will do studies adding a second drug. That drug will probably have an anti-T315I component.
Although we’ve discussed mainly the ABL attack on CML, it’s important to point out that’s not the only one. I mentioned that I now think it’s pretty predictable that nilotinib will be a cornerstone of cure, but that does not mean its partners will also be ABL inhibitors. Vaccination is still worth investigating. T-lymphocytes are extremely important anti-CML weapons and the vaccines need refinement. Our desire, our ability, to eliminate stem cells is also now in flux because I think most of us believe the stem cells are there. Last year, we published some information as to how certain genetic changes might help us objectively identify them. But, again, with the long-term imatinib results, stem cells clearly don’t matter if they exist in quite a lot of patients. In other words, either they’re there or not, and the imatinib kills their progeny as soon as they divide. Clearly, a lot of patients do not need a stem cell activated to have a normal lifespan, and that’s just with imatinib. If you move forward to nilotinib and now see more and earlier responses, well, in whom—if anybody—will the anti-stem cell agents be necessary? Again, the question will shift, because now our target is very firmly cure, not negotiation.
At ASH, there was a beautiful presentation on a combination of nilotinib with a stem cell inhibitor, and there did appear to be a very effective preclinical outcome from that combination. So, for example, a stem cell modifier like a hedgehog inhibitor might be the new partner for nilotinib to go after a cure; that’s if the stem cells have maintained their priority in our hierarchy of development therapeutics right now, which is not clear to me…Then you’ve got others, histone deacetylase inhibitors show activity; epigenetic modifiers have activity.
Once we have a stable baseline with nilotinib, in which we’re confident there is a cure fraction, then you’re basically going to do a lot of parallel studies with potential second partners to try and decide which are the best. And you might say, well, how are you going to design those studies. As you can imagine, we are already well into that process because success breeds ambition.
How do you best measure response in these studies?
Up until now, major molecular responses have been the most ambitious primary endpoint we can look for in CML studies, and that’s a very high power. There you’re talking about multiple log reductions in the CML clone. In March or April, I’ll be helping to lead a very large study with complete molecular response, which is a 4.5 log reduction as the primary endpoint. Now, that’s pushing our ability to detect residual cells right to the limit; that’s as far as we can currently go. Basically, we’re now going to have, as a primary endpoint…that we cannot find the disease with the most sophisticated quantitative PCR available. That’s as close to the laboratory correlate of functional cure as we know how to get.
For our audience of community-based physicians, what do you recommend they do for their patients with CML?
The first thing I would advise my friends out there to do is check that patients are actually taking their drugs, because statistics indicate the majority of them quite a lot of the time are not. We tell people, “We think you’re going to have a normal lifespan, but we need you to keep taking this medication.” Of course, as soon as the terrible shock of having a leukemia diagnosis wears off, they begin to reassess their life and, on any given day, the only reminder that they have CML is when they take this pill. So, for one reason or another…they stop. Adherence with imatinib is a major issue, and it’s the same problem all over the world, regardless of whether it’s the government, yourself, or an insurance company paying for [the drug]. Imatinib is extremely well tolerated and nilotinib is probably at least as well tolerated. It’s not a toxicity issue and it’s not a financial issue—it’s a human nature issue.
We have learned people won’t take a long-term oral medication if they feel well. If community oncologists don’t believe me, they can ask themselves the last time they finished a 5-day or 7-day antibiotic pack, and then realize they didn’t. Make sure patients are taking their Gleevec, if that’s what they’re supposed to be doing.
The second thing, is if you have any reason to believe that Gleevec is not well tolerated or is not working on any level, I advise switching to Tasigna immediately. Up until ASH, we would be appropriately cautious in people with toxicities or suboptimal responses to imatinib. Until we had a large safety database on Tasigna, we’d say, well, you should try to support the medication…see if imatinib dose escalation will make a difference; or you should consider measuring imatinib dose levels— these are all reasonable things to do. However, they’re not what I would do today.
I anticipate that Tasigna will soon be the new front-line medication, so it makes no sense to go to Herculean efforts to preserve a patient on Gleevec when, if the patients were coming in tomorrow, you would give them Tasigna as a frontline agent. The threshold for prescribing Tasigna has gone down enormously.
The third thing is to keep an eye on this disease in general. CML is relatively rare and…it might be very satisfying to take care of it. You might wonder, why spend too much attention with what’s going on because it’s improving already, very well. I can understand that attitude, and I hope one day we can have such optimistic and positive conversations about most cancers.
For patients who do appear to be resistant to nilotinib, would you then advise clinical trials?
It depends on how aggressive the resistance is. If it’s very aggressive resistance, you might want to try dasatinib or bosutinib. Bear in mind, however, that most of the time they’re not going to work if it’s aggressive resistance and exposure to [these drugs] carries long-term consequences. The bottom line is that for anybody today who fails nilotinib, places like the CTRC better come up with better drugs.
When I started getting interested in CML, which is quite a few years ago, you had very depressing conversations with everybody. In other words, there was no need for an individual patient to feel, well, “What’s exceptionally wrong with me?” We had the same conversation with everybody. In 2010, if we have to face a patient with CML and say their future may be compromised, that goes against everything we told them the first day, that we expect them to have a normal lifespan…and they have reason to feel, “I am an unfortunate exception.”
Those patients, thankfully, are very few, but they’re on our minds a lot…If somebody looks at the survival curve and sees 95% or 97% success, people like me say, well, what are we going to do about the remaining 3%? Now, you can’t have a health service operate on that principle, but that’s our job at places like the CTRC, and we desire to fill that gap. Each one of those small gaps represents a patient and their family and their life and their expectations. We would like, someday soon, to be able to promise [a normal lifespan] and deliver on it to everybody with CML, not just 95% to 97% of patients. That’s not to take away from or minimize the phenomenal success the overall endeavor has been.