Acute myeloid leukemia (AML) is a truly nasty disease and one I hope never to have the misfortune to be diagnosed with.
Last month, at the Chemotherapy Foundation in New York, Dr Norman Wolmark gave an entertaining lecture on what he called the "Decade of Discontent" in colorectal cancer, a bleak period where no new therapies or stunning ideas emerged and the researchers bogged themselves in answering minutiae rather than focusing on the bigger picture.
He could well have been describing AML.
Take a look at this slide that was shown at the AML Super Friday educational symposium (the reference is from Dohner et al., (2009), published in Blood and how complex the disease has become with a myriad of phenotypes being described:
Which of these mutations or phenotypes are actually relevant and what is driving the cancer's survival and ability to outwit treatment?
No one really knows and thus it illustrates the frustration inherent in making a nasty disease ever more complex. Just because a mutation exists or a pathway is overexpressed does not mean that it is critical to the survival of the leukemia cells! Sometimes the mutations occur as artifacts, a function of a generally increasing leukemic burden over time as the disease gets more established.
Image via Wikipedia
Undoubtedly, the 14% of AML patients who have no additional mutation beyond the t(9,11) translocation that defines the disease, probably do best and at least attain a complete response (CR). The issue of how to keep them there, thus preventing relapse from occurring is an entirely different matter. We need more smart young researchers like Dr Gail Roboz in New York who asked the Chemotherapy Foundation audience what can be done to keep more AML patients in remission?
In ALL, which is more common in children than adults, there are well accepted maintenance therapy strategies for maintaining remission. In AML, post transplant or chemotherapy, there are none. Why it is not clear, but certainly something that can be easily tested with the plethora of targeted agents we have available on the market or in the clinic.
At the American Society of Hematology meeting in New Orleans this week, we attended a number of education and oral sessions discussing AML and read many posters on the topic too. What was startling was how little real progress has been made over the last five years… there were numerous versions of induction and conditioning regimens associated with stem cell transplantation, a general agreement that using the current targeted agents in late stage relapsed or refractory disease is doomed to failure because the leukemic burden is too high…
Dr Wolmark's 'decade of discontent' comment rang loudly in my ears while walking around a huge cold hangar on Monday reading poster after poster with little positive news to inspire or encourage. Skipping to the CML, CLL or NHL poster sections brought cheer and hope by comparison.
Part of the problem with AML is that many of the patients are diagnosed in the elderly, thereby limiting options either because the regimens are highly toxic and less well tolerated, transplant is not an option (survival decreases in the over 55 yo) or they have co-morbidities and multiple mutations, reducing the effectiveness of therapy.
There is, therefore, a clear need for alternative approaches in this population as well as better therapies for the very young who at least have a chance of cure by preventing relapse.
At ASH, some abstracts did catch my eye. Genzyme's clofarabine (Clolar) is one such interesting drug, currently approved for acute lymphocytic leukemia (ALL) and being tested in elderly AML patients. FDA's ODAC recently declined to approve clofarabine in elderly AML patients in the relapsed/refractory setting because the trial was compared to placebo. The same thing happened with Vion's laromustine (Onrigin) in the elderly AML setting. We will probably have to wait until the comparative trial data is available for clofarabine in 2010 before any major decision can be made as to the drug's safety and efficacy in the elderly population. There were no new abstracts on laromustine at this ASH meeting.
Meanwhile, some other interesting companies with early phase I/II data in AML included Sunesis and Cyclacel, both of which have seen their stock price rise since ASH on publication of the data.
Sunesis are developing voreloxin, a chemotherapy given as an infusion and used either alone or in conbination with cytarabine (araC) in heavily pre-treated AML. In the combination study (#645), the researchers found that:
"Among evaluable first relapse (n=36) and primary refractory patients (n=28), preliminary median overall survival is 7.8 months and the remission rate is 31% (complete remission [CR] 27%, complete remission without full platelet recovery [CRp] 2% and complete remission with incomplete recovery [CRi] 2%).
Historical median overall survival data in primary refractory and first relapse patients on currently available chemotherapies range from Voreloxin in combination with either bolus or continuous infusion cytarabine was generally well-tolerated. Infection-related toxicities were the most common Grade 3 or higher non-hematologic adverse events. In addition, Grade 3 or higher oral mucositis was observed."
A poster (#1037) was also presented on voreloxin in elderly AML, and while the data looks interesting initially, I would have major concerns about the registerability of the data given that it is a single arm study of the sort that the FDA and ODAC has repeatedly baulked at:
"Median survival was 8.7 months in Schedule A; 5.8 months in Schedule B; and 7.3 months (preliminary) in Schedule C (72 mg/m2 on days one and four).
Median duration of remission was 10.7 months and one year survival was 38% for Schedule A. For the other schedules, median duration of remission has not been reached and one year survival is too early to evaluate.
Patients age 75 or older (N=49) with at least 1 additional risk factor at diagnosis, a population identified by the National Comprehensive Cancer Network (2010) AML Guidelines as having poor outcome to standard treatment,experienced a CR rate of 30% and a 30-day all-cause mortality of 5%.
Survival in these patients was too early to evaluate.
Based on trial results, Schedule C has been determined to be the recommended pivotal dose regimen. For Schedule C, response rates (CR and CRp) are 38%; 30- and 60-day all-cause mortality are 7% and 17% with improved tolerability over Schedule A."
Cyclacel is a NJ biotech developing an oral prodrug for AML, MDS and CTCL called sapacitabine, a nucleoside agent that targets DNA synthesis and cell cycle arrest. Several phase II studies were presented at ASH, including interesting data on long term follow up in elderly AML patients from an MD Anderson study (#1061) and another in MDS (#1758).
It should be noted that while the one-year follow up data looks promising in AML, the study design suffers from the same issue as tipifarnib, clofarabine, laromustine, and voreloxin in that there is no comparator arm from which to compare and determine if the investigational agent is actually significantly prolonging life in AML.
Overall, it was a disappointing meeting in AML and I sincerely hope that some mre enlightening data emerges in 2010 rather than face the dreaded precipice that Wolmark so pithily described.