Chemotalk Newsletter

Chemotalk Newsletter, Vol. 96 April 1, 2016

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Well, we never got enough rain...but the rain we got has made this the most spectacular Spring bloom I can remember.  Enough of beauty...

USE YOUR DATA TO CURE DISEASE

By David Augus Professor of medicine & engineering at the University of Southern California

How far would you go to protect your health records?  Your privacy matters, of course, but consider this: Mass data can inform medicine like nothing else and save countless lives, including, perhaps, your own.

Over the past several years, using some $30 billion in federal stimulus money, doctors and hospitals have been installing electronic health record systems.  More than 80% of office-based doctors, including me, use some form of E.H.R.  These systems are supposed to make things better by giving people easier access to their medical information and avoiding the duplication of tests and potentially fatal errors.

Yet neither doctors nor patients are happy.  Doctors complain about the time it takes to update digital records, while patients worry about confidentiality.  Earlier this year, the Association of American Physicians and Surgeons went so far as to warn that E.H.R.s could "crash" the medical system.

We need to get over it.  These digital databases offer an incredible opportunity to examine trends that will fundamentally change how doctors treat patients.  They will help develop cures, discover new uses for drugs and better track the spread of scary new illnesses like the Zika virus. Medicine is famous for serendipity -- scientists coming across important findings when they least expect them, or aren't even looking.  I've often said that we may have all the drugs and therapies we need already to prevent, treat or cure most ailments, but we don't know which ones can be used on which conditions and at which doses.

Case in point: Last year, a team led by researchers at the MD Anderson Cancer Center and Washington University found that a common class of heart drugs called beta blockers, which block the effects of adrenaline may prolong OVARIAN CANCER patients' survival.  This discovery came after the researchers reviewed more than 1,400 patient records, and identified an obvious pattern among those with ovarian cancer who were using beta blockers, most often to control their blood pressure.  Women taking earlier versions of this class of drug typically lived for almost eight years after their cancer diagnosis, compared with just three and a half years, for women not taking any beta blocker.

The researchers are now preparing follow-up clinical trials of ovarian cancer patients.  My guess is they will confirm the connection.

The information was lying in plain sight, no invasive procedures or testing required.  We could have found it years earlier if we had the data.

Here's another example.  In 2015, researchers at Stanford University and the Houston Methodist Research Institute analyzed more than 16 million clinical documents from some 39 million patients and discovered a connection between prescriptions of a certain kind of heartburn drug and heart attacks. One in 15 Americans takes these drugs, the so-called proton pump inhibitors (P.P.I.s) such as esomeprazole (Nexium), omeprazole (Prilosec) and lansoprazole (Prevacid).  The study found that they can increase your risk of a heart attack by about 10%, regardless of whether or not you have an existing heart condition.

This conclusion came from simple data mining, and confirmed earlier research conducted in 2013 and published in the journal Circulation indicating that the P.P.I.s could potentially lead to long-term cardiovascular disease by changing the lining of blood vessels.  Patients who were prescribed another type of heartburn drug, however, had no increased likelihood of heart attack.

I get that patients are nervous about releasing their health records. Studies have shown that even anonymous strings of DNA data can be linked to individuals.  Patients understandably don't want their acquaintances and employers to know all their private health information.  But we cannot let these fears suppress the powerful insights medical data can offer us.  When I explain to my own patients what can be done with their information for the greater good in research, nobody has ever said to me, "Don't use my data."

We all go to a machine on the street where we insert a plastic card and cash comes out; we log into our online accounts to check our balances and pay bills; and we give credit card numbers that contain a key to our financial information to retailers without a second thought.  But if I asked you to put your de-identified personal health information online, or share it and perhaps some bio-specimens with people other than your own doctors, you might panic.  "Health data is not the same as financial data," you might say.

We need to move past that.  For one thing, more debate over data sharing is already leading to more data security.  In January, a bill was signed into law calling for the Department of Health and Human Services to create a health care industry cybersecurity task force, whose members would hammer out new voluntary standards.

New technologies -- and opportunities -- come with unprecedented risks and the need for new policies and strategies.  We must continue to improve our encryption capabilities and other methods of data security and, most important, mandate that they are used.  The hack of the Anthem database last year, for instance, which allowed 80 million personal records to be accessed, was shocking not only for the break-in, but for the lack of encryption.

We also must block attempts to discriminate based on health information for work or other pursuits with continued legislation, and portray those who participate in the sharing of health data as heroes.  In fact, they are heroes.  They are part of tomorrow's cures for themselves and their children. We also need to revisit the cumbersome and obsolete privacy rules enacted by the Health Insurance Portability and Accountability Act of 1996 to make it easier for patients to participate.  One idea is to establish a trusted middle "broker", such as a dedicated nongovernmental agency, that can ensure that every effort is made to keep records anonymous before their release for research studies.

Medical research is making progress every day but the next step depends less on scientists and doctors than it does on the public.  Each of us has the potential to be part of tomorrow's cures.

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PHASE-3 DRUG TRIAL FOR REFRACTORY RHEUMATOID ARTHRITIS SUCCEEDS

In a pivotal phase-3 trial led by a Stanford University School of Medicine investigator, a novel drug for RHEUMATOID ARTHRITIS substantially reduced symptoms and improved daily physical functioning in patients for whom other therapies had failed.

A study summarizing the 24-week randomized, double-blind, placebo-controlled trial, which was carried out at 178 centers in 24 countries and involved more than 500 adults who had been living with the painful autoimmune condition for 14 years on average, will be published in the March 31, 2016 issue of The New England Journal of Medicine.

"This is the first drug to demonstrate meaningful clinical benefit in patients who've failed virtually every other commercial drug for rheumatoid arthritis," said Mark Genovese, MD, professor of immunology and rheumatology and the study's lead author. The senior author was Josef Smolen, MD, of the Medical University of Vienna, in Austria.

The drug, baricitinib, belongs to a new category of small-molecule drugs, available in pill form, called Janus-kinase inhibitors. They work by interfering with intracellular enzymes whose signaling action is necessary for various inflammatory substances in the body to be effective.

Pain, stiffness and swelling

Rheumatoid arthritis is a progressive, inflammatory autoimmune disease affecting about 1.5 percent of the population of developed countries. It most commonly manifests between the ages of 30 and 60. It causes pain, stiffness, swelling and eventual destruction of multiple joints, typically smaller ones such as in the hands and feet. About three of every four people with the disease are women. The reasons for this gender skew are unknown.

A diagnosis of rheumatoid arthritis once came hand in hand with a bleak prognosis: a greater than 50 percent likelihood of becoming disabled within 20 years. But advances in treating the disorder since the mid-1990s have made for a much-improved outlook, Genovese said. A major innovation, he said, has been the introduction of several kinds of injectable, bioengineered protein drugs, or biologics, beginning in the latter part of that decade.

Three of the eight top-selling drugs in the United States in terms of dollar sales -- adalimumab, etanercept and infliximab -- are biologics prescribed for rheumatoid arthritis. These three drugs share a common property: They block the action of a substance called tumor necrosis factor, or TNF, secreted by various immune cells, that potently stimulates the immune response and accompanying inflammation. Other biologics prescribed for rheumatoid arthritis -- including abatacept, tocilizumab and rituximab, in whose development Genovese also played a key role -- act through different immune-modulatory mechanisms.

Refractory patients

The success of the plethora of drugs now used for treating rheumatoid arthritis carries a downside: Increasing numbers of patients become refractory. The drugs they're taking no longer provide sufficient benefit, or they produce unacceptable side effects, or both. As a result, Genovese estimates, some 15 to 20 percent of rheumatoid arthritis patients find themselves in the position of having exhausted the current inventory of available medications.  "It's an ever-growing population," Genovese said.

It was these refractory patients who were the focus of the new trial. They had moderate to severe cases of rheumatoid arthritis, with at least six joints affected. All of them had failed at least one anti-TNF biologic, and many had failed two or more. In addition, the trial included a number of patients who had failed other classes of biologics targeting different sources of immune activation. All patients were currently on other medications for their rheumatoid arthritis.

The 527 patients who participated in the trial were randomly assigned to one of three study arms, where they received once-daily regimens of, respectively, 4 milligrams of baricitinib, 2 milligrams of baricitinib or a placebo for 24 weeks.

Reduced symptoms

Some 55 percent of the patients assigned to the higher dose experienced a reduction of at least 20 percent in the number of affected joints at week 12, the primary endpoint of the study. For patients on the lower dose, 49 percent experienced a similar reduction. In contrast, only 27 percent of the patients receiving a placebo saw this effect.  Patients on either dose of baricitinib also had improved physical function and reductions in markers of inflammation, both in absolute terms and in comparison with placebo, the study found.

The improvements in all baricitinib-treated groups largely remained at 24 weeks, said Genovese.

Patients' individual medical histories and prior drug regimens didn't much effect their response to baricitinib treatment, Genovese said. "The drug worked well across all patient subgroups, independently of what they'd been taking before or how long they'd had the disease," he said.

Adverse events, most often in the form of mild upper-respiratory infections, as of 24 weeks into the trial were more common among high-dose and low-dose baracitinib recipients -- 77 percent and 71 percent, respectively -- than among those receiving placebo -- 64 percent. Adverse events deemed serious affected 10 percent of the high-dose group, 4 percent of the low-dose group and 7 percent in the placebo group.

Shingles incidence

At week 12, about 2 percent of patients in the high-dose group, versus 1 percent and 0.5 percent in the low-dose and placebo groups, respectively, had developed herpes zoster, also known as shingles. The disease stems from a reactivation of the latent chicken-pox virus that triggers painful skin eruptions in people whose immune systems have been weakened by, for example, old age or immunosuppressant drugs. At 24 weeks, the corresponding rates were 4 percent, 1 percent and 1 percent.

Baricitinib also appeared to raise both high-density and low-density lipoprotein levels, with unclear clinical implications, Genovese said.

Three other Lilly-sponsored phase-3 trials of baricitinib for rheumatoid arthritis -- one in newly diagnosed patients, another head-to-head versus adalimumab and a third for patients for whom a first-line treatment, methotrexate, proved inadequate -- have shown that the drug reduces symptoms and prevents structural damage.

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NEW DISCOVERY ON HOW BODY ATTACKS CANCER Proteins found in cancer linked to immune response that target tumors

by Kate Lewis

A team of researchers based at University College in London have shed light on a link between cancer neoantigens and the immune response to CANCER. The discovery could influence the nature of future cancer immunotherapy treatments and predict their efficacy on an individual basis, University Microbiology Prof. Victor Engelhard said.  Neoantigens are cell-surface proteins produced by genetic mutations unique to an individual patient¹s cancer cells and are recognizable by human immune cells known as T-cells.

Engelhard, who is also co-director for the immunotherapy department at the University Cancer Center, conducts research on T-cell-mediated immunity to cancer, in the hopes of eventually developing a vaccine for patients already battling the disease.

Engelhard breaks down modern cancer immunotherapy techniques into two categories ‹ adoptive T-cell therapy and checkpoint blockade inhibition therapy.  In adoptive T-cell therapy, T-cells from the tumor are genetically modified to recognize a known neoantigen and then re-introduced to the patient¹s body.

Checkpoint blockade inhibition therapy, the focus of this research, is a little more complex.  Tumors produce a ligand for the T-cell receptor that ³up-regulates² inhibitory molecules on the surface of the T-cell that cause the T-cell to shut down. Checkpoint blockade inhibition therapy disrupts the binding of the tumor-produced ligand by introducing an antibody, allowing for normal T-cell function.

³[Checkpoint blockade inhibition therapy] has been very, very effective in a small number of cancers,² Engelhard said. ³Melanoma is one, non-small-cell lung cancer is another, which is the major focus of the work these folks are doing.²

Engelhard said the research highlights two important principles that positively affect patient survival ‹ a high mutational burden and antigen expression across a high percentage of the tumor cells.  ³Their observation, which is very clear, is that the immune response seems to be primarily directed against the antigens that are expressed in all or most cancer cells and cancer sites in an individual patient,² Engelhard said.

While he is skeptical of the study¹s applicability to other cancer types, since most cancers besides MELANOMA and ADENOCARCINOM have comparatively low mutational burdens, Engelhard sees potential for the research to help predict when and what kind of immunotherapy is right for a cancer patient.

³When you ask about implications for immunotherapy, it gives us insight into another mechanism of the cancer cell evading the immune response,² he said. ³It gives us insight into why checkpoint blockade inhibitor therapy might not work. It also suggests of course that adoptive T-cell therapy wouldn¹t work in those cases either.²

Immunology Prof. David Kittlesen said that clinical applications for the research will take time and extensive testing.  ³Current hurdles include the time required for identifying the relevant targets as well as the expense of what would quite likely be a personalized vaccine,² he said in an email statement.

Kittlesen notes that the study addresses a major challenge of immunotherapy targeting ‹ finding an antigen target widespread enough for T-cells to effectively combat the cancer.  ³As a result of genetic instability and proliferation, the millions of cancer cells within a single patient¹s tumor are not all the same, and if the target recognized by the immune system is present on only some of the cells others will escape being destroyed,² Kittlesen said.

A related treatment method, the combination of radiation or chemotherapy with immunotherapy in an effort to increase mutational load and antigen presentation, was not shown to increase patient survival, according to Engelhard.

In addition to contributing to scientific knowledge about the overall efficacy of immunotherapy treatments in the context of neoantigen genetics and abundance, the study provides numerous avenues for future biological and clinical research.

³This is a really beautiful study,² Engelhard said.

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A really inspiring piece about blood cancers:

CANCER TREATMENT'S NEW DIRECTION

Genetic testing helps oncologists target tumors and tailor treatments

By RON WINSLOW

Evan Johnson had battled a cold for weeks, endured occasional nosebleeds and felt so fatigued he struggled to finish his workouts at the gym. But it was the unexplained bruises and chest pain that ultimately sent the then 23-year-old senior at the University of North Dakota to the Mayo Clinic. There a genetic test revealed a particularly aggressive form of ACUTE MYELOID LEUKEMIA.

That was two years ago. The harrowing roller-coaster that followed for Mr. Johnson and his family highlights new directions oncologists are taking with genetic testing to find and attack cancer. Tumors can evolve to resist treatments, and doctors are beginning to turn such setbacks into possible advantages by identifying new targets to attack as the tumors change.

Mr. Johnson¹s medical team scrambled to find effective treatments against the genetic mutations driving his disease. His course involved a failed stem cell transplant, a half-dozen different drug regimens, four relapses and life-threatening side effects related to his treatment.

³We truly felt like we were in a war,² his mother, Carol Johnson, recalls. ³We didn¹t know where that enemy was at any given moment and what means he was going to use to attack us next.²

Nine months in, his leukemia had evolved to develop a surprising new mutation. The change meant the cancer escaped one treatment, but the new anomaly provided doctors with a fresh target, one susceptible to drugs approved for other cancers. Doctors adjusted Mr. Johnson¹s treatment accordingly, knocked out the disease and paved the way for a second, more successful stem cell transplant. He has now been free of leukemia for a year.

³You could see the cancer evolution happen,² through regular genetic testing, enabling his treatment to be ³personalized in real time,² says Pashtoon Kasi, an oncology fellow at the Rochester, Minn.-based Mayo Clinic and a member of the team that cared for Mr. Johnson. ³This is where oncology is headed down the line.²

Just a decade ago, ³we were shooting in the dark,² says Jose Baselga, physician-in-chief at Memorial Sloan Kettering Cancer Center in New York. If first- or second-line treatments failed, ³we either had nothing to do [next], or what we did was totally disconnected with the biology of the disease.²

Now patients with advanced cancer who are treated at major centers can expect to have their tumors sequenced, in hopes of finding a match in a growing medicine chest of drugs that precisely target mutations that drive cancer¹s growth. When they work, such matches can have a dramatic effect on tumors. But these ³precision medicines² aren¹t cures. They are often foiled when tumors evolve, pushing doctors to take the next step to identify new mutations in hopes of attacking them with an effective treatment.

³It¹s like a Whac-A-Mole game,² Dr. Baselga says. As soon as a new mutation surfaces, the strategy is to find a new hammer to hit it with.

The approach is challenging. There aren¹t drugs to treat many cancer-causing mutations. When drugs exist, there is no guarantee they will work. A drug that works for a melanoma patient may not succeed in a colon-cancer patient with the same mutation, for example.  Moreover, DNA tests of tumors may lead to a recommendation for a drug that isn¹t approved for the type of cancer being treated, jeopardizing reimbursement for drugs that typically cost $10,000 or more a month.

³It¹s not for every patient or cancer,² Dr. Kasi says. ³But as we develop more drugs and understand more [treatment] pathways, it would be a reasonable option for a lot of our patients.²

EVAN JOHNSON¹S PATH TO REMISSION

February 2014: Diagnosed in Grand Forks, N.D. with acute myeloid leukemia and flown to Mayo Clinic in Rochester, Minn. A genetic test revealed a certain mutation in the FLT3 gene that is a marker of a poor prognosis.

April: Started on sorafenib, a drug that targets FLT3, plus a cancer drug called 5-AZA.

May: Received a stem cell transplant considered a perfect match. He relapsed after 67 days.

August to December: Evan participated in a trial of an experimental AML drug and doctors tried a series of drugs, including a clinical trial. Evan had a sustained response for four months.

November: A test showed initial evidence that Evan¹s cancer was developing a new genetic alteration known as the Philadelphia chromosome, a finding that surprised his doctors. Evan relapsed in January. January 2015 to March 2015: Doctors tried several drugs including ponatinib, which attacks both FLT3 and the Philadelphia chromosome‹further tailoring treatment to the molecular traits of his cancer.

April: After achieving a remission with no evidence of leukemia cells, Evan underwent a second stem cell transplant from an unknown matched donor. The procedure worked.

March 2016: Nearly one year out from the second transplant and two years after his initial diagnosis, he is in remission.

Dr. Kasi and his Mayo colleagues‹Naseema Gangat, a hematologist, and Shahrukh Hashmi, a transplant specialist‹are among the authors of an account of Mr. Johnson¹s case published in January in the journal Leukemia Research Reports.

Mr. Johnson¹s first genetic test at Mayo, in February 2014, revealed that his cancer was driven by a mutation in a gene, called FLT3, that is usually associated with a poor prognosis. His best chance at survival was a stem cell transplant. More than 50% of the blood cells in his bone marrow were myeloblasts, or blasts for short, dysfunctional immature cells that are a hallmark of the disease. Before qualifying for a transplant, a patient¹s blasts need to be under 5%.

To get under 5%, he started on a standard chemotherapy regimen and almost immediately, things went south. His blast cells plummeted, but ³the chemo just wiped out my immune system,² Mr. Johnson says, likely opening the doors to a mysterious fungal infection that attacked his throat and nearby soft tissue. Emergency surgery failed to help.

Just 10 days after his arrival at Mayo, a surgeon tearfully told the family that Mr. Johnson had a 10% chance of surviving the next 48 hours, Ms. Johnson says.  The next day Mr. Johnson¹s three brothers bought an expensive golf driver he¹d been eyeing and placed it in his hands as he lay tethered to tubes in the ICU. They sensed he responded with a faint smile.

Then as mysteriously as it began, the infection stopped. But Mr. Johnson couldn¹t tolerate the chemo, and his blast cells were on the rise. A two-drug combination that included the liver cancer drug Nexavar, which targets the FLT3 mutation, knocked back the blast cells. But the stem cell transplant in May, which came from one of his brothers, failed to take, and he relapsed after 67 days, around late July.

By then, his ordeal had taken a toll: the throat surgery left him unable to swallow and he weighed just 120 pounds, some 55 pounds less than the day he arrived.

He was put into a clinical trial of an experimental AML drug being developed by Astellas Pharma of Japan. To participate, Mr. Johnson had to be able to swallow a pill. It took weeks of exercises with a swallowing coach and bags of M&Ms, but he succeeded just before the trial opened at the clinic in September.

The trial was almost a respite for Mr. Johnson. Free of toxic chemotherapy, his hair came back. He started to regain weight, an important consideration, as his doctors wanted him healthy enough to eventually try a second transplant. His blast cells were responding well to the medicine.

In November 2014, doctors spotted the initial signs in blood tests that Mr. Johnson¹s cancer was evolving to acquire a new mutation. By late January, he relapsed again.  To the doctors¹ surprise, the culprit was the Philadelphia chromosome, a well-known genetic alteration associated with chronic myeloid leukemia. It also is a target of the blockbuster cancer drug Gleevec and several other medicines.  Armed with new options, the Mayo team revamped Mr. Johnson¹s treatment, starting with a regimen that included CHEMOTHERAPY and Sprycel, a next-generation version of Gleevec.

His fight wasn¹t over. He developed lung inflammation and other side effects on the new medicine and relapsed yet again. Taking a suggestion from a national expert panel on AML, doctors switched to a regimen including Iclusig, a drug that hits both FLT3 and the Philadelphia chromosome.

The total cost of Mr. Johnson¹s care was $4 million, says Ms. Johnson, adding that the copayments for his treatment were manageable. None of the key drugs given to Mr. Johnson are approved for AML, meaning most were used off-label. That is a deal breaker for many insurers, who balk at paying for expensive drugs for nonapproved uses. But Dr. Kasi says the Johnsons¹ health insurer was ³responsive² to Mr. Johnson¹s needs.

Tests using the most sensitive instruments showed Mr. Johnson had no blast cells, which Mayo¹s transplant experts set as a prerequisite before performing another transplant. This time the donor was an anonymous person from Germany, under a program called Be the Match that keeps a global registry of willing stem cell donors. He got his second transplant last April. After he recovered from several weeks of severe side effects including pancreatitis, recent tests suggest he has a good chance of a sustained, durable remission.

Mr. Johnson finally returned home last summer after 17 months at the Mayo Clinic. He is now finishing his senior year in college. He says he was too weak last year to give his new driver a good test on the golf course. He expects a better chance this summer.

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Until next month...

 

And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.

Elaine Jesmer

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