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Old 03-09-2013, 05:09 PM
gdpawel gdpawel is offline
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Default Treatment of MDS is Changing

The treatment landscape for myelodysplastic syndrome (MDS) is changing dramatically.

Not long ago, this bone marrow disorder was an orphan disease with no approved therapies, but research over the past decade has resulted in 3 drugs now approved for MDS: azacitidine (Vidaza), decitabine (Dacogen), and lenalidomide (Revlimid). There are also several in clinical development.

The drugs being tested are not only targeting the disease itself, but also the biology driving the disease and the interaction between the disease and its microenvironment. "I think that we will see in the next 5 years some very effective new drugs entering the marketplace," said Alan List, MD, president and chief executive officer at the H. Lee the Moffitt Cancer Center in Tampa, Florida. Dr. List, who is an expert in MDS and principal investigator of a study of lenalidomide, the first targeted MDS therapy, spoke to Medscape Medical News about recent advances.

He pinpointed a revolutionary moment for MDS in 2007, when improved survival was seen with the azanucleoside azacitidine in a trial known as AZA-001. At the time, as reported by Medscape Medical News, experts in the field hailed the finding as a landmark, and predicted that it would change the treatment paradigm of MDS. This has indeed happened, Dr. List noted.

Azacitidine had already been available for a few years; it was approved by the US Food and Drug Administration (FDA) in 2004 when a clinical trial showed a response in blood cell counts and bone marrow morphology and a decrease in transfusion dependence. Decitabine, another azanucleoside, was approved on a similar basis.

"However, it was unclear whether these drugs had any impact on the natural history of the disease," Dr. List said. This was especially true for the high-risk MDS patient population, where survival is relatively short and the risk for leukemia is high, he explained.

Most patients with high-risk MDS die within 6 to 12 months of diagnosis, he explained; however, in the AZA-001 trial, more than half the patients were still alive after 2 years.

The difference in median overall survival between azacitidine and conventional care was highly statistically significant (24.4 vs 15.0 months; hazard ratio, 0.58; P = .0001). Two-year survival was also better with azacitidine than with conventional care (50.8% vs 26.2%).

This study "was critical because it really opened our eyes to the impact of azacitidine as a disease-altering therapy," he said.

In fact, azacitidine therapy is now the standard of care for all high-risk MDS patients.

A phase 3 trial of the other hypomethylating agent, decitabine, failed to show a survival improvement, Dr. List noted. Those results were presented at a meeting a few years ago, but they have never been published, he said. Decitabine is used clinically, but at a lower cumulative dose than was used in that trial, he reported.

First Targeted Agent

The other breakthrough in MDS, which Dr. List was involved with, was the development of lenalidomide (Revlimid) as the first targeted agent for the disease. Lenalidomide, which is an immunomodulator used in the treatment of multiple myeloma, was approved by the FDA in 2005 for use in a subset of patients with MDS. The specific indication was patients with low-risk or intermediate-1 risk MDS with a deletion 5q cytogenetic abnormality.

Overall, lenalidomide works in about 12% to 15% of all MDS patients (about 50% of MDS patients have a chromosome abnormality, and about 25% to 30% of these have the deletion 5q abnormality), Dr. List explained. In this subgroup, lenalidomide is "extremely effective," he said. It acts as a targeted agent, causing suppression, arresting the autosomal MDS clone, restoring transfusion independence, and normalizing hemoglobin levels. The effects are durable and last beyond 2 years, he noted.

There is hope that new drugs active against other chromosomal abnormalities will be developed. "With exosome and other genetic studies, we now know a lot more about the molecular drivers behind the biology of this disease," Dr. List said.

The most advanced of the new products in development is rigosertib (Estybon), which is being tested in high-risk patients who have become resistant to the hypomethylating agents azacitidine and decitabine. The end point of that phase 3 study is overall survival, and we might have a first glimpse at the data by the end of the year, he said.

"I don't know if it will be successful, but if it is, then we will have a kingpin of new treatment," Dr. List explained.

The biggest clinical need right now is for something to offer patients who have progressed after the azanucleoside therapy, he added.

Another approach under investigation is the use of combinations adding therapies with complementary activity to the azanucleoside. This is being tested in clinical trials; for example, azacitidine is being studied in combination with vorinostat (Zolinza).

Work is also ongoing on an oral formulation of azacitidine, which would be much more convenient than the current parenteral formulations.

Other drugs in development are "exciting in the potential of what they may be able to do, but few are far enough along to be sure that the activity is there," Dr. List explained. One promising area is the use of hedgehog inhibitors to target the disease-initiating malignant MDS stem cells; the investigational agent PF-0444991 could have such activity. Dr. List details this and other investigational agents for MDS in a review published last year in Leukemia Research (2012;36:1470-1474).

"Our paradigm for the approach to treatment of MDS can be expected to evolve with our ever-expanding insight into the disease biology," he concluded.

Citation: Dramatic Changes in Treatment Landscape of MDS. Medscape. Mar 07, 2013
Gregory D. Pawelski
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Old 05-29-2013, 12:13 PM
gdpawel gdpawel is offline
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Default Where we are today in myelofibrosis?

According to Research To Practice, hope entered the picture in 2005 when the molecular biology of myelofibrosis (MF) started to become clear.

Most importantly, it was determined that patients with both primary and secondary MF have acquired mutations targeting hematopoietic stem cells, in more than half of cases in the gene encoding the JAK2 tyrosine kinase at position V617F. This abnormality was also determined to be present in the majority of patients with polycythemia vera and many with essential thrombocythemia. These and many other related discoveries quickly led to clinical investigation of JAK inhibitors and to the tandem Phase III COMFORT studies, demonstrating the dramatic benefit of the JAK1/2 inhibitor ruxolitinib (rux).

Some oncologists have witnessed the introduction of many anticancer therapies over the past few years, and perhaps none has had a more dramatic and rapid impact on quality of life than the availability of rux. The truth is this disease is very uncommon and complex and the administration of rux is anything but straightforward. Because of this Research To Practice has spent the past 2 years hounding MF investigators trying to tease out critical practical clinical issues. However, it seems clear that many oncologists remain relatively unfamiliar with and un-COMFORT-able using this drug.

Faculty members provided their perspectives on these challenges:

1. How often is there a significant problem with the diagnosis of MF?

Myeloproliferative neoplasms constitute some of the most complex diagnostic territory in hematology/oncology, and our faculty estimate that perhaps 1 in 6 patients are incorrectly diagnosed at least initially. The most common source of confusion is myelodysplastic syndrome. JAK1/2 testing can be helpful when positive, but MF is primarily a diagnosis of exclusion and because an effective treatment strategy is now available, the implications of delayed diagnosis are much greater.

2. What is the role of cytogenetic analysis?

Although cytogenetic testing is often impossible because many patients have dry bone marrow taps, all of the faculty members generally recommend sending adequate specimens for analysis to both assist in diagnosis, especially in excluding other conditions, and to assess prognosis in younger patients being considered for an allotransplant. In addition, most investigators believe the results can affect clinical decision-making, potentially swaying them to employ, for example, an immunomodulatory agent in patients when a 5q deletion has been detected. Significantly, unlike multiple myeloma, where there is no easy standard to consider, cytogenetics in MF from a practical perspective revolve around the factors identified in the Dynamic International Prognostic Scoring System (DIPSS) Plus, giving oncologists a road map of what should be looked at in this regard.

3. Do patients without JAK mutations benefit from JAK inhibitors?

The December 2012 Patterns of Care data indicated that approximately 47% of US-based medical oncologists are not aware that patients without JAK mutations benefit from JAK inhibitors, including rux, and that the outcomes of therapy are similar regardless of mutational status. The faculty shared their own experiences with general oncologists supporting these findings, which represent an enormous obstacle in establishing the final link between the COMFORT data and clinical practice.

Each investigator has commented on the important and evolving biology underlying this critical point, namely that while only approximately half of patients with MF have JAK2 V617F mutations, virtually all have JAK pathway dysregulation and activation as part of the disease pathogenesis, presumably related to other mutations. In this regard, JAK inhibitors are thought to reduce the symptom burden of the disease by suppressing not only mutated cells but also those without JAK mutations, which likely accounts for much of the beneficial effect of these agents, including the inhibition of cytokine synthesis.

4. How should rux be dosed initially? What is the minimum dose required to observe patient benefit? What is the maximum dose that should be employed?

Like many aspects of oncology, dosing rux is a blend of art and science, and investigators have modified their practices continuously as trial data evolve and they treat patients off study. In terms of the most basic question of initial dosing, for a 65-year-old with symptomatic high-risk MF and normal blood counts, some investigators would start at 20 mg BID, some would start at 10 mg BID and at least one would start at 15 mg BID. Most will increase the dose in patients who are tolerating treatment well but responding suboptimally. However, generally they wont exceed 25 mg BID. The lowest effective dose is considered to be in the 5 to 10 mg BID range, but all agree that the key to success is meticulous follow-up with weekly counts and close monitoring for at least 1 or 2 months.

5. What is the role of splenectomy in the JAK inhibitor era?

Now that an effective systemic, nonsurgical approach to managing splenomegaly has pushed this procedure to the back burner, the question remains, should it be used at all? Interestingly, although all of the faculty state that splenectomy is rarely indicated anymore, six of the eight researchers had in fact sent at least one patient for this procedure in the past year, often patients who were refractory to or could not receive systemic treatment.

Source: Research To Practice
Gregory D. Pawelski
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Old 06-15-2013, 02:22 AM
gdpawel gdpawel is offline
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Default New Dosing, Safety Guidance for ruxolitinib (Jakafi)

An update to the prescribing information for ruxolitinib (Jakafi, Incyte) includes new recommended dosing for patients with low platelet counts and a warning about a possible treatment-related risk for progressive multifocal leukoencephalopathy.

Ruxolitinib, which was approved by the US Food and Drug Administration (FDA) in 2011, is the first and only FDA-approved product for the treatment of patients with intermediate- or high-risk myelofibrosis.

"The expanded dosing guidance provides physicians with important new information intended to help patients with low platelet counts experience the clinical benefits of [ruxolitinib], including meaningful spleen reduction and symptom improvement," said Paul Friedman, MD, president and chief executive officer of Incyte Corporation.

For patients with baseline platelet counts from 50 to 100 10⁹/L (50,000 to 100,000/L), the prescribing information now recommends a starting dose of 5 mg twice daily and the flexibility for subsequent dose modifications based on safety and efficacy.

The FDA decision to expand the dosing information comes after a review of the supplemental New Drug Application (sNDA).

The sNDA included data from an ongoing phase 2 trial of patients with baseline platelet counts of 50,000 to 100,000/L. The starting dose in the trial is 5 mg twice daily, but it can be adjusted up or down, according to protocol-defined hematology criteria. The target dose is 10 mg twice daily to achieve clinical response.

The safety and efficacy findings from an interim analysis of Study 258 are generally consistent with the results observed in the pivotal phase 3 COMFORT-I and COMFORT-II program, according to a press statement from the company.

Results from those 2 trials were published last year in the New England Journal of Medicine (2012;366:787-798 and 799-807). At the time, one of the principal investigators told Medscape Medical News that, in her clinical experience, the "vast majority of patients" on ruxolitinib experience meaningful benefits in quality of life and symptom relief. However, another expert, writing in an accompanying editorial (N Engl J Med. 2012;366:844-846), said that ruxolitinib is suitable for only some patients with myelofibrosis, possibly as few as 25%, and has adverse events, including myelosuppression.

The updated prescribing information also has new information on an adverse event. "Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop [ruxolitinib] and evaluate," reads the document.

In addition, the Patient Counseling Information section now advises healthcare professionals to educate patients about the early signs and symptoms of PML.

According to the company, the new warning is based on "1 known case of PML with an undetermined relationship to ruxolitinib in the approximately 9800 myelofibrosis patients treated with ruxolitinib worldwide in clinical trials or with commercial product." The press statement also indicates that patients with myeloproliferative neoplasms, including myelofibrosis, might be at higher risk of developing PML.

Citation: New Dosing, Safety Guidance for Myelofibrosis Drug. Medscape. Jun 14, 2013.
Gregory D. Pawelski
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Old 02-06-2014, 02:51 PM
gdpawel gdpawel is offline
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Default Stomach and colorectal cancers may be treatable with JAK inhibitors

A class of drugs already used to treat a blood disorder could be used to treat stomach and colorectal cancer, according to new research from Australia.

Called JAK inhibitors, the drugs are currently used to treat a cancer-like condition called myelofibrosis. They are also undergoing clinical trials for use as a treatment for leukaemia, lymphoma, lupus, rheumatoid arthritis and other conditions.

In the journal Molecular Cancer Therapeutics, Matthias Ernst, an associate professor at the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, and colleagues report how they found JAK inhibitors reduce the growth of inflammation-associated stomach and colorectal cancer.

The team has been investigating links between inflammation and cancers of the digestive tract for a while.

More recently, they have had some success in unravelling the complex molecular signaling that goes on in inflamed tissue, such as that which occurs in a stomach ulcer or inflammatory bowel disease, and how this might drive cancer development.

That work helped them understand the molecules that help cancer cells grow and survive, and to identify the ones that can be targeted with potential anti-cancer drugs.

JAK proteins are involved in growth of stomach and colorectal cancer

In this new study, they investigated molecules known as JAK proteins, which are involved in the development of cancer in the stomach and bowel.

When they tested the effect of drugs that block the JAK proteins - known as JAK inhibitors - in mouse models of stomach and colorectal cancer, they found they slowed the growth of tumors and killed many of the cancer cells.

Thus the study provides the first evidence, in live mice, of several proteins that could serve as valuable targets for treating cancers of the digestive tract.

This is significant because JAK inhibitors are already available and have been tested in clinical trials for treating cancer-like blood disorders, as Prof. Ernst explains:

"The reason this discovery is particularly exciting is clinical trials have already shown that JAK proteins can be safely and successfully inhibited in patients."

He adds that they hope this will shorten the time it takes to bring their "research to possible clinical trials that may improve the outlook for people with stomach and bowel cancer."

Financial sponsorship for the study came from the Australian National Health and Medical Research Council, the Ludwig Institute for Cancer Research and the Victorian Government.

In December 2013, Medical News Today reported a study where researchers in Canada found a new colorectal cancer target in a stem cell gene. They discovered that switching off the gene stopped the cancer stem cells from renewing themselves, a find that could lead to treatments that shut the cancer down.

Reference: Therapeutic Inhibition of Jak Activity Inhibits Progression of Gastrointestinal Tumors in Mice; Emma Stuart, Michael Buchert, Tracy Putoczki, Stefan Thiem, Ryan Farid, Joachim Elzer, Dennis Huszar, Paul M. Waring, Toby J. Phesse, and Matthias Ernst; Molecular Cancer Therapeutics, online 7 January 2014; DOI:10.1158/1535-7163.MCT-13-0583-T


Citation: Paddock, Catharine. "Stomach and colorectal cancers may be treatable with existing drug." Medical News Today. MediLexicon, Intl., 5 Feb. 2014.
Gregory D. Pawelski
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