Considering Evidence for a New Drug for Immune Thrombocytopenia Purpura

I’ve been wondering, lately, why so many of the medical blogs cover the same topics, like last week’s lung cancer detection trial, which are often the exact same studies as are reported by conventional news outlets. I’ve been trying, here, to sometimes consider new published articles that seem important to me but, for whatever reasons, don’t get so much attention.

Here’s one:

Yesterday’s NEJM includes an article Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia.* It’s about a drug, manufactured and sold by Amgen as NPlate, that received FDA approval for treatment of chronic immune thrombocytopenia purpura (ITP) in August, 2008. Some consider ITP a rare disease, and I suppose it is; my perception is skewed by the fact that as a practicing hematologist I saw patients with ITP almost constantly in the clinic and hospital. In patients with this autoimmune condition, the body produces pathologic antibodies that bind and lead the tiny, clot-forming blood cells to destruction. Sometimes patients with chronic ITP need treatment, such as steroids, surgical removal of the spleen (splenectomy) or other drugs that raise the platelet count and reduce their risk of bleeding.

The new-ish drug, romiplostim, is effective in raising the platelet count in most patients who are said to have chronic ITP. It’s similar to another platelet-stimulating agent, eltrombopag, that’s manufactured and sold by GlaxoSmithKline under the brand name Promacta. Eltrombopag received FDA approval for the same condition in November, 2008.

So long before reading the thoughtful editorial* by Dr. James George, this hematologist was impressed by the availability of two agents that work by stimulating platelet production in the bone marrow. Dr. George considers the possibility that these new drugs alter the usual but debatable algorithms that most hematologists use in caring for patients for ITP. He acknowledges having consulted to the study’s sponsor, Amgen, on this drug and serving as an investigator in clinical trials, and considers:

…In this randomized study, 85 investigational sites in 14 countries enrolled 234 patients…The conclusions are clear. The outcomes were better in patients receiving romiplostim than in patients receiving standard care (short of splenectomy): romiplostim was associated with a greater incidence of a sustained platelet response, less bleeding and fewer transfusions, a decreased requirement for other treatments (including splenectomy), and greater improvement in quality of life. The side effects of romiplostim therapy were minimal, but …confidence about the safety of the drug requires that more patients be observed for a longer time. Because patients treated with romiplostim had better outcomes, does the work of Kuter and colleagues establish romiplostim as the new standard of care?

As I read the original study results, this issue – of possibly changing the standard of care in this disease – became evident. His question is on-point.

The problem is this: In the study, the authors treat a total of 234 patients who are said to have chronic ITP. But, if you look closely at the eligibility for enrollment, besides having a low platelet count (defined for the study as less than 50,000 platelets per microliter of blood, which in itself is a questionable criterion), examination of a bone marrow-biopsy specimen was required to confirm the diagnosis of immune thrombocytopenia in patients older than 60 years. According to Table 1 in the paper, the median age for study participants was 57 years. This means that more than half of the participants were under 60 years and, as far as we know, they did not have a diagnostic pathology test for ITP. They might instead have a myelodysplastic syndrome or other bone marrow disorder that was missed.

Why this matters, besides to patients who have low platelets and their hematologists, is that it’s really a problem in the practice of evidence-based medicine. If data are derived and published from fundamentally flawed studies, in which the patient groups who respond or don’t to a particular intervention are not well-defined by careful diagnostic parameters, the conclusions we draw from those studies may be incorrect.

I am definitely in favor of evidence based medicine, but we need to be careful in how we evaluate the results of published studies, even in the best of journals, and how we incorporate those findings into recommendations for care.

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A Play About the Life and Work of Dr. Rosalind Franklin

Last weekend I snagged a last-minute ticket to see Photograph 51, a new play about the work and life of Rosalind Franklin. Her data, possibly stolen, enabled Francis Crick and James Watson to decipher and model the double-helix structure of DNA.

The intimate production, enacted by the small Ensemble Studio Theatre on the second floor of a nondescript building on West 52nd Street, affords a fresh look, albeit partly fictionalized, into important moments in the history of science. Most of the scenes take place in a research lab in post-War London, at King’s College, where Franklin took on a faculty appointment.

Franklin’s story starts like this: She was born in 1920 to a Jewish family in London. She excelled in math and science. She studied physical chemistry at Cambridge, where she received her undergraduate degree in 1941. After performing research in photochemistry in the following year on scholarship, she joined the British Coal Utilisation Research Association (BCURA) and carried out basic investigations on the micro-structure of coal and carbon compounds, and so earned a Ph.D. from Cambridge University. She was a polyglot, and next found herself in Paris at the Laboratoire Central des Services Chimique de l’Etat, where she picked up some fine skills in x-ray crystallography.

You get the picture: she was smart, well-educated and totally immersed in physical chemistry before, during and after WWII. Single-minded and focused, you might say –

Franklin in Photograph 51 wears a simple brown dress with large black buttons straight down the middle of her lithe frame. Her lipstick and haircut seem right, but her three inch heels, even after a few years of experiencing the joie de vivre in Paris, or just being holed up in a research institute there, seem a tad too high for such a pragmatic soul. The lab set is perfect with its double-distilling glassware, wooden pegs on racks, tall metal stools with small, flat circular seats, light microscopes, heavy metal desks with file drawers and a contentious cast of characters.

As this narrative goes, Franklin spurns socializing with most of her colleagues. They find her difficult. She spends nearly all of her time and late hours using x-rays to generate crystallographic images of DNA and making detailed notes and related calculations. Eventually a lab assistant gives her key data, Photograph 51, to her colleague, Maurice Wilkins, who is inexpert in crystallography and cannot independently interpret the structure. While Franklin continues working at a measured pace, refusing to rush into publishing a model until she’s sure of her findings and the implications, Wilkins shares the image with Watson and Crick. They move quickly, publish first in Nature and, later, win the Nobel Prize for the discovery. Meanwhile Franklin leaves Wilkins’ lab and starts a new project on the structure of tobacco mosaic virus. She dies at the age of 37 of ovarian cancer, likely caused or effectuated by the radiation to which she exposed herself at work.

It’s a sad story, but instructive, engaging and very well-done, so much that it’s haunted me for days. Hard to know what’s real –

According to a program note from Anna Ziegler, the playwright: “this play is a work of fiction, though it is based on the story of the race to the double helix in England in the years between 1951 and 1953.” Ziegler refers to several books from which she drew material: The Dark Lady of DNA (by Brenda Maddox), The Double Helix (by James Watson) and The Third Man of the Double Helix (by Maurice Wilkins).

My favorite part is Franklin’s statement at the beginning: “We made the visible, visible.”


For a (depressing) counterpoint to this play’s version of events, you can take a look at Nobel Laureate James Watson’s 2007 TED lecture on YouTube. “She was a crystallographer,” he says of Franklin, and other things, before delving into his late-life happiness and current ventures in cancer genetics and autism studies.

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Doctors Singing On YouTube

A few weeks ago I found some doctors singing on YouTube. They made me laugh and perhaps, even, feel better.

Doctors in Cyberspace

I contacted the singing doctors to check, among other things, that they’re still in business. It turns out that Drs. Barry Levy and Greg LaGana both graduated from Cornell University Medical College just a few years back, in 1971. They’ve been performing together for years and still do.

“Why rant and rave when a laugh will do?” said the New York Times about the pair, in 2004.

Now, they have a YouTube channel. Of the five videos available, my preference is Doctors in Cyberspace (above) but that’s probably because I’m partial to the “I Feel Pretty” melody from West Side Story. Health Care Business, to the tune of “There’s No Business Like Show Business” comes in at a close second and, based on the number of YouTube viewings so far, seems to be the public’s favorite.

Their website is called Damaged Care. You can buy a CD for a holiday gift. Or hire the doctors to entertain at a real-life party or other event: they’ve performed for state medical societies, hospital associations, the AMA, pharmaceutical industry associations, the Federal Reserve Bank of Boston and the General Assembly of the Presbyterian Church among other agencies, and at Off-Off-Broadway venues in New York City.

The Damaged Care Doctors

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Noting the Death of Jill Clayburgh Who Lived For 21 Years With a Chronic Form of Leukemia

I was saddened yesterday to learn of the death of Jill Clayburgh. The 66 year old actress died on Friday in her Connecticut home. According to ABC news and the LA Times among other reports, she’d had chronic lymphocytic leukemia (CLL) for 21 years. This means she lived with CLL for nearly a third of her life.

It happens that I used to spend much of my time thinking about CLL; it was the focus of my laboratory’s research program, and I cared for many patients with this particular form of leukemia.

It’s an instructive disease at several levels:

Chronic lymphocytic leukemia is the most common form of leukemia in adults in Europe and North America. The National Cancer Institute reports that there are approximately 15,000 new cases each year in the U.S. Although CLL is not curable, it is an indolent type of tumor, a slow-growing cancer a person might live with for years and even decades. For this reason, it is perhaps the best example of a malignancy for which a “watch and wait” approach is often, but not always, appropriate.

By now, in 2010, it seems the public has a good sense that the big C, i.e. “cancer” is not one disease, but many. For leukemia it’s the same deal: there are at least several dozen forms, perhaps over a hundred identified by now. The nomenclature can be confusing to people who receive a new diagnosis and to doctors, as well, who many not be up-to-date on new molecular classification schemes.

The image to the left, from Wikimedia Commons, reveals a high-power magnification (1000 X) of a Wright’s stained peripheral blood smear from a patient with CLL. The lymphocytes, with the darkly staining nuclei and scant cytoplasm, are CLL cells.

A helpful framework, I find, for understanding leukemia is to think, first, in terms of what kind of cell has become malignant in each case – what an oncologist would call the cell of origin for the tumor. Leukemia is, by definition (from the Greek roots leuk, for white, and haima, of blood) an excess of white cells in the blood. But there are multiple kinds of white blood cells, and each type can form one or more type of leukemia. The most basic leukemia categories are three: tumors of myeloid cells, such as neutrophils and their precursors; tumors of lymphocytes, such as T or B cells; and tumors of other white blood cells that are less common in the circulation. CLL is a tumor of B-lymphocytes, the kind of white blood cells that normally mature to form antibodies.

A second way of classifying leukemia is based on the rapidity of tumor cell growth. In CLL, the malignant B cells tend to divide slowly, rendering this a chronic, i.e. indolent disease in most cases. Now, the disease might be detected in its earliest phases upon routine blood testing, sometimes years before it would become clinically apparent by causing symptoms like uncomfortably swollen glands or fatigue from anemia.

Here are some websites that provide open-access information about CLL:

American Cancer Society

Cancer.net (ASCO)

Leukemia & Lymphoma Society

MedlinePlus

National Cancer Institute

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A Story About A Doctor and His Neighbors

In recent years, some physician authors have wrestled with why doctors might want to think twice before “friending” their patients on Facebook. The usual reasons are to protect the physician’s professional image – that the public might see their weirder, or not-so-polished-as-while-working side and, also, to maintain a certain “distance” – lest doctors become so concerned about their patients’ well-being that they can’t render objective opinions or advice.

Others suggest it’s a good idea for doctors to be socially out there, so to speak. Besides, through most of history, or at least the civilized part in which there have been designated healers, many individuals knew their doctors, who often resided in the same village or region as their patients. People trusted their physicians or didn’t, based on what they knew about their reputations as practitioners and as local denizens.

In the October issue of Harper’s Magazine, T.C. Boyle provides a disturbing portrait of a portly, unkempt doctor who lands a job in small town, presumably in Maine. His unmannerly behavior disturbs some residents. The piece addresses, at least peripherally, some ultra-modern and ancient concerns about relationships between patients and doctors within a community. I don’t wish to give more of this short story away, so I won’t.

I do recommend What Separates Us From the Animals, part of a forthcoming novel, When the Killing’s Done, to my readers. With his frank, absorbing language, Boyle offers insight into human beings as sometimes social creatures who take far-from-perfect care of themselves. Doctor included.

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Wednesday Web Sighting A Blog on Medicine in Art

Some months ago I came upon a unique blog, Ars Medica, by Paul O’Connor. The title means “medical arts” in Latin. O’Connor studied medicine before delving into the humanities. Now he writes and gives a seminar on Literature & Medicine at Trinity College in Dublin.

The site’s theme is portrayals of physicians, medicine and illness. There are short book reviews, essays on film and among other items lately, work posted by students. I am particularly drawn to a recent post on reading poetry to people with dementia.

Worth a visit!

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What Not to Wear In the Hospital While Recovering From a Stroke

Today’s Annals of Internal Medicine includes new results for the CLOTS (Clots in Legs Or sTockings after Stroke) Trial. Not-quite acronyms aside, it’s an interesting study with implications for many patients at risk for deep venous thrombosis (DVT).

compression stockings - NIH image (Medline Plus)

This U.K.-based study, involving 3114 patients in 112 hospitals in 9 countries, used ultrasound to evaluate possible DVTs in legs of people after they’d been immobilized upon suffering strokes. Patients were randomized to receive either thigh-length or below-the-knee compression stockings while recovering in the hospital. The main result was that 98 of 1552 (6.3 %) of patients who received thigh-length stocking and 138 of 1562 (8.8%) of patients with below-the-knee stockings developed DVT. This difference is highly significant (p = 0.008).

The twist is this: in a separate, extensive recent Cochrane review the investigators compiled data from multiple randomized studies of stockings in stroke patients and established that thigh-length stockings were inferior to no stockings, i.e. stroke patients who wore thigh-high compression stockings were more likely to develop DVTs than those who didn’t wear any stockings at all. The authors reconcile these separate results by suggesting that below-knee stockings might increase the risk for DVT after stroke.

Confusing? Yes. The bottom line is that thigh-high compression stockings may not help, based on the Cochrane analysis; below-the knee stockings may hurt.

Why this matters is that the results have implications for other hospitalized patients at risk for DVT, like people who’ve had hip replacements, pelvic or spine surgery. “Unfortunately, no randomized trials have compared below-knee stockings with no stockings,” the authors write.

An accompanying editorial in the Annals considers the “puzzling” findings of the CLOTS trials and addresses how clinicians might prevent DVT in patients with stroke:

…The unexpected findings that thigh-length stockings are not very effective at preventing venous thromboembolism and that below-knee stockings might increase incidence of thrombosis in patients with stroke should prompt a reevaluation of the role of graduated compression stockings in other groups of patients….Clinicians need to realize that despite the ubiquity of graduated compression stockings in many settings, the net benefits and risks of this seemingly innocuous intervention remain uncertain.

As a hematologist, I see this as a low-tech, big deal because DVTs are a huge source of morbidity and mortality.

In the U.S., the number of clots per year runs in the hundreds of thousands. DVTs tend to arise in people who are immobilized after surgery, with neurological impairment and during travel. The elderly are particularly susceptible, as are pregnant women and people with inherited clotting dispositions. The National Blood Clot Alliance provides an interactive map of the incidence of DVTs, state by state, on its website.

Personally, I love it when the doctors allow me to take off the boots when I wake up after a procedure, so I can kick my feet around and, I hope, reduce my risk of DVT by movement and exercise. Compression stockings feel like corsets on my calves; they’re warm and constraining. On planes, too; I find stockings restrictive.

My own experience aside – the data supporting the use of compression stockings are limited, and this new study suggests they can be damaging.

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No Quick Fix

On History and Health Riffs in the musical, Bloody Bloody Andrew Jackson:

“If it’s chafed, put some lotion on it.”

– some practical advice, offered by the character portraying Andrew Jackson, speaking toward the audience in the last scene of Bloody Bloody Andrew Jackson, a play written and directed by Alex Timbers

Yesterday I had occasion to see the outrageous politicoemo-rock musical, Bloody Bloody Andrew Jackson, which recently moved to Broadway’s Bernard B. Jacobs Theatre. The production focuses on the life and times of the 7th President of the United States.

Now, Old Hickory comes on like a rock star. The story is narrated, in part, by an excitable, graying Jackson groupie who bumps around the stage in a motorized wheelchair. A wild and rattling cast sets the thing’s tone in a startling first number, “Populism, Yea, Yea!” An early review of this musical, toward the end of its early 2008 LA run, cites these lyrics:

Sometimes you have to take the initiative.
Sometimes your whole family dies of cholera.
Sometimes you have to make your own story.
Sometimes you have to shoot the storyteller in the neck.
Sometimes you have to take back the country…

(These words antedate the Tea Party, to which the play vigorously alludes in its current form.)

You get the idea: it’s lively, a bit disjointed and politically relevant. And fun. It messes with the facts, and is tangentially rife with medical topics:

In the play, Jackson’s father, upon witnessing the whoosh and arrow-in-her-back slaying of Jackson’s mother in a backwoods cabin somewhere in South Carolina or Tennessee, immediately and without hesitation attributes her death to cholera. A moment later, he and a cheery cobbler are felled by similar instruments. The future President Andrew Junior, who’s playing with toy cowboys and Indians while both of his parents are shot dead in this life-motivating scene of pseudo-history, refers later to his parents’ deaths from cholera.

Most historical sources and Jackson’s Tennessee home’s current website, attribute the mother’s death to cholera. According to a scholarly review of cholera epidemics in the 19th Century, the disease didn’t appear in North America until after 1831 or so. A fascinating, original New York Times story details the ravaging effects of this illness in Tennessee in 1873, but that would be long after Jackson’s death in 1837.

An unexpected medical writer’s gem of a song, “Illness As Metaphor,” cuts to the heart with a message about blood, symbolism, love and Susan Sontag’s classic essays on the meaning of tuberculosis and cancer in literature and in life. The lyrics of the song from Bloody, Bloody Andrew Jackson are hard-to-find on-line, but you can get it through iTunes, by which I found these words:

A wise woman once wrote that illness is not metaphor.
So why do I feel sick when I look at you?
There is this illness in me and I need to get it out, so when I bleed
It’s not blood, it’s a metaphor for love.
These aren’t veins just the beating of my heart.
This fever isn’t real it represents how I feel…

You can see a Spanish-sung, sickly romantic version on a YouTube video:

I’m not sure how Susan Sontag would feel about emo-rock in general and about this song in particular, but I should save that subject for some intense, future writing project –

A few other medical digs include mention of Jackson’s hepatitis – acquired on “the battlefield,” as he explains to his admirers, syphilis – a killer of Indians and, consistent with the play’s hemi-modern approach, Valtrex – which some of the prostitute-turned government advisees run to get when it’s given for free.

All in all, it’s a terrific play about Americans, Manifest Destiny, populism, anti-elitism, economic frustration, anger toward foreigners, fear of terrorism, emotions and the founding of the Democratic Party.

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Tomorrow is Election Day. Remember to vote!

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