Just some of it know it far better than others.
We know it when we look in the mirror.
We know it when we slide a soapy hand over a lump that shouldn't be part of who we are.
We know it when we rifle through our archives of pathology reports and when we hesitate to open letters from our hospitals and insurance companies.
Some of it know it far better than others.
But some of us need a louder signal.
An inconvenience to be ignored and pushed through.
And now, and now, and now ....... it casts long shadows that reach into places that only the darkness can see.
Just some of it handle it far better than others.
We are all mortal in the end. And in the beginning and middle too.
Some of it handle it far better than others.
Not me. I protest against the constraints or more likely try to blow past them at my own peril.
But we are all fragile.
Even those us who don't know it and those who don't want to admit it.
Even those of us who are not incurable today.
Even those of us who harbor no diagnosis today.
So it falls on us that we are challenged to work out a deal with our demons to temper our risk.
Which is so hard when we are all so damned fragile.
On a personal note, I am sicker today, with a painful deep throated cough and a powerful sore throat. Started on Levaquin 500 last night. I will recover.
I am not that fragile.
In Part 5 of my interview from iwCLL 2013, Dr. Jeff Sharman outlines what factors go into deciding how to manage our disease NOW with these new drugs coming, but not here yet.
He lists many of the available trials for both treatment naive and relapsed refractory patients, focusing mostly on the two leading oral CLL drugs, idelalisib and ibrutinib.
As always your best source of finding out about the latest on the status of any clinical trials is visiting clinical trials.gov and don't be afraid to email the trial co-ordinator if you have questions. They want to hear from us. That's how they fill their trials. It is a very user friendly web site and should be part of your life.
There are some great options out there, and we need to know more. Our work is not done. We are not cured with any of these therapies. There are relapses late and early.
We need more clinical research to tell us what works best and most safely, but without us patients enrolling, all research halts. No doubt the lightning fast FDA approval of ibrutinib, going from test tube to prescription pad in under 8 years, was facilitated by the dazzling rapidity of accrual in many of the important trials.
Please carefully consider investigating some of the promising trials of combination therapies with the better known novel agents or one of the newer less studied but very promising novel agents such as ABT-199 and IPI-145 or ONO-4059 and others.
Here is Dr. Sharman. If you haven't seen Parts 1-4 please scroll down or search under Dr. Sharman on my blog.
Part 6 and 7 are on their way.
And so are my interviews with Drs. Kay, Byrd, Kipps, Pagel and Hallek.
On a personal note, I am a touch sick again or still: a deep chesty cough and fatigue. We will see what the morning brings. If I am not better, time to break out for my "just in case" antibiotic.
This is a topic that we all have spent some time on. Do we share our cancer story with friends, relatives, and colleagues? We all have different answers, and different reasons for them.
I believe that my past post and even this much earlier prior post and these poignant comments and these too were among my most provocative of discussion. Worth re-reading.
So finally the main stream press is catching up to us. However, I humbly suggests that our discussions were more erudite and helpful.
The BBC takes a gentler and less probing look at the issue in this still worthwhile article.
I like how the article finishes quoting French minister, Dominique Bertinotti, who recently revealed her battle with breast cancer.
So why has Bertinotti decided to talk after eight months of almost absolute silence?
"To help change the social attitudes towards this disease which is terribly distressing. To show that you can have cancer and still continue to work. So that employers understand that long sick leaves are not necessarily the best solution. So that there is less fear and more understanding," she said.
"Choosing to remain silent is a private matter. As a minister, my only question was to find out if I was able to fulfil my mission. And I have."
Would if it were so for all us. Sadly it isn't always. Sharing our cancer story can be risky business as you can see in some of the comments on my prior posts.
On a different note, expect several video interviews with CLL experts including more of the interview with Dr. Sharman to be posted here over the next week as a warm up to ASH.
I slept well past noon today- one of many things that I am thankful for, and even took a long post meal nap, and except for a sore, slightly pink, and swollen upper arm where I got the vaccine, I am feeling much better. Still tired and a bit achy, but clearly on the mend.
I assume that yesterday's high white count and low blood pressure were an exaggerated response to the PREVNAR 13.
Or perhaps I was about to get sick and the IVIG infusion aborted the pathogen's attack.
I will never know, but I am grateful for feeling much better.
Our Thanksgiving vegan feast with family was lovely. I was righteously teased by my wife and my boys for some of my idiosyncrasies, we listened to Klezmer music, lit the menorah, and ate latkes with vegan sore cream and homemade apple sauce, homemade stuffing with homemade vegan gravy, salad, broccoli, stuffed baked pumpkins, seiten with onions, homemade pumpkin pies, and Ben brought his homemade amazing stuffed baked apples served with coconut milk "ice- creme". Sent the boys home with tons of leftovers.
An amazing feast, rightly designed to overwhelm with its abundance this one time a year.
Many of us have much to be thankful for, but until we create the best opportunities for all of us with CLL in particular and cancer in general, until every one of us, has had what I have had, the best chance for a long and meaningful life post diagnosis, our work is not done.
For the first time in years, I have come down with something.
Yesterday I got the relatively new conjugated more antigenic protein based pneumonia vaccine, PREVNAR 13.
My last pneumococcal vaccine, the weaker but broader spectrum Pneumovax, and the older PREVNAR 7 were administered more than seven years ago when I was first diagnosed in the hopes that early in the disease, my immune system had not crumbled too much and I could still mount a protective response.
The new improved PREVNAR 13 made my arm sore, which I took as a good sign, suggesting some immune response. In contrast, the flu jab a few weeks early was a non event.
That night I felt pretty awful- achy, lightheaded, nauseated, chilled, agitated. I slept little.
The next day, today, I went for my every 8 weeks IVIG. This by the way, may also dampen my immune response to the vaccine, but I wanted to get the immunization as far out as possible from the last boost to my passive immunity with the infusion of IVIG.
It was not that long ago that I was getting IVIG every 2 weeks! My veins are much happier.
I still felt terrible this morning.
Although the news was good with my hemoglobin and platelets (both within normal ranges), despite my stretching out the time between the protective dosing with other peoples' antibodies to prevent me from killing my own platelets as I have done so often in the past with my ITP, I got a surprise with the white blood cells.
My lymphocytes were zero, nada, missing in action, on the automated differential although I did have a normal 0.4 count of atypical lymphs.
My lymphs are my cancer cells. I am happy they aren't around.
But they are also my T cells and presumably some healthy non-clonal B cells. Where are they? I need you guys to fight infections and search and destroy any early secondary cancers. Come back!
Strange, but it gets stranger.
My absolute neutrophil count was a very high 16.7, most consistent with a bacterial infection. These are levels one sees in pneumonia or appendicitis or a kidney infection. Serious stuff.
Occasionally however, very early in the course of a viral infection, the neuts will rise. In the past when I was sick, my lymphs shot way up, not the neuts.
And although I had no fever, my blood pressure was as low as 81/45. It was still low, but better by the time I left the cancer center.
Despite the fact my wife was very sick all last week with multiple specific signs and symptoms, I have had no focal problems, just this general overwhelming malaise.
So is it the prodome of a coming illness? The oncologist who saw me at the infusion center wisely wrote a script for a broad spectrum antibiotic just in case, but said to hold it until it is clear I am actually sick with something infectious. Good counsel.
Or was it all just a weird rection to the PREVNAR?
I slept much of the day, and am starting to feel better, so I am betting on the latter. Us CLL patients have pretty weird immune systems.
On a sadder note, another CLL warrior died this week. Ellen Rhudy was a fighter, very actively battling her disease for years in her own unique way with mostly alternative, non allopathic medications. Over the years, we exchange many emails and a few phone calls as she tried to leverage her comprensive knowledge of different nontraditional therapies with the changing and less toxic CLL treatment landscape. We often disagreed, but we were friends because we shared a common enemy.
CLL plays for keeps. I hate it.
I will miss our exchanges, Ellen. Rest in peace.
In Part 4 of my conversation with Dr. Sharman at iwCLL 2013, we start by discussing the lousy tired feeling that sadly so many of us are all too familiar with. And even more sadly, that too many community oncologists seem not to be familiar with or in total denial about our truth that CLL could be the primary source of our achy tired feelings.
When we understand about the cytokines released by our rogue cancer cells, we begin to understand why decreasing our tumor burden with standard therapy such as FCR, or better yet, blocking those cytokines with idelasilib or ibrutinib and others, can give us back out lives.
Many questions. No cookie cutter answers.
Do the new therapies change the threshold to treat?
Dr. Sharman touches on the dilemna of mono therapy with rituximab?
If you have not seen Parts 1-3, take the few minutes to acquaint yourself with the first segments of this wide ranging interview.
Start here with Part 1 where we discuss among other things, the emerging importance of pharmacogenetics in medicine in general and cancer in particular.
Part 3, Dr. Sharman managing high risk disease.
And a heads up, Parts 5- 7 are very quickly on their way.
And more from Drs. Byrd and Kipps and Kay and Pagel.
And then on to ASH.
Dr. Sharman was incredibly generous with his time in Germany. I am very grateful and lucky that I get to do this work.
Enjoy listening to a thoughtful expert. I did.
Blessings to all my American friends for Thanksgiving. There really is much to be thankful for in the CLL community this year, but until we all have a seat at the table of deep and durable remissions, we have much hard work ahead of us.
And to all my friends from the Regina and surrounds, how bout them Saskatchewan Roughriders winning the 101st Grey Cup in North America's oldest professional sports league.
Any casual reader of my blog knows that I am a committed vegan.
I love what I eat. Often only raw veggies, but sometimes a plain salad just isn't deeply satisfying. But add some nuts and I get some crunch, some grit, some surprises and some increased nutrition to boot.
I just bought 20 pounds of raw organic nuts: cashews, brazil nuts, pistachios, walnuts, pecans, hazelnuts, macadamia, and pine nuts which are really seeds. Actually all nuts are fruits that have a hard shell and a seed.
Though they vary from nut to nut, most are rich in an antioxidants and other nutrients. Walnuts are especially high in the healthy omega-3 and have been shown to lower our LDL cholesterol. Pistachios are full of lutein and zeaxanthin that may help prevent age related macular degeneration. Each one has its set of particular nutritional assets, and mixed together are delicious.
See this sweet article for a review of some of the nutritions in a few common varieties.
A special shout out and warning to fans like me of brazil nuts ( BTW, more come from Bolivia than Brazil). The USDA National Nutrient Database for Standard Reference, Release 25 tells that as few as 6-8 brazil nuts may contain as much as 10 times the daily recommended dose of selenium, though the amount may vary widely. Getting the right amount of selenium is healthful and I believe may lower cancer risk, but my levels were toxic when I was eating too many tasty brazil nuts. I now restrict myself to 5 or less a day and occasionally check my blood selenium level.
And I choose organic when possible. And never salted or honey coated or spiced or anything. Just raw organic nuts.
I avoid peanuts (not actually a nut but a legume and schizocarpic to boot as I recall from high school biology) because the raw ones are at risk for aflotoxin, a potent poison from the mold aspergilllus flavus that likes to grow on peanuts if they are not properly stored.
I also avoid raw almonds. "Raw" farmed almonds in California may not be actually raw but "pasteurized" usually with the toxic propylene oxide or PPO to prevent a recurrence of the past Salmonella outbreaks. And besides too many of the raw almonds taste awful with a sickly bittersweet aftertaste that I have heard described as "Amaretto gone bad". Not sure why, but spitting out a foul mouthful of nuts is not always possible and is never pleasant, so I sadly just skip them.
The remaining members of the nut are my boon companions when I wander, mixed and packed with great care right next to my other precious travel commodities including my medications and my organic green teabags in my carry-on. I would be lost or more actually hungry without them, especially in the southern US where being a vegan is pretty similar to being some exotic visitor from a faraway planet.
There are too often my breakfast and lunch and late snack snack when I am far from home. They are my manna.
"In two large, independent cohorts of nurses and other health professionals, the frequency of nut consumption was inversely associated with total and cause-specific mortality, independently of other predictors of death."
The news about reducing vascular disease was not a surprise, but the lower risk of cancer and all cause mortality was a happy finding.
As with all retrospective studies, there is the potential for many confounders. Do nuts eaters tend to avoid more junk food, do they make better health and food choices overall and that is the reason for their improved survival?
"Multivariate analyses were adjusted for age; race; body-mass index; level of physical activity; status with regard to smoking, whether a physical examination was performed for screening purposes, current multivitamin use, and current aspirin use; status with regard to a family history of diabetes mellitus, myocardial infarction, or cancer; status with regard to a history of diabetes mellitus, hypertension, or hypercholesterolemia; intake of total energy, alcohol, red or processed meat, fruits, and vegetables; and, in women, menopausal status and hormone use. "
Moreover, the fact that there was a linear inverse relation between nut consumption and mortality indicates that it is a valid correlation, if not necessarily a cause and effect.
The numbers were significant too.
The hazard ratio for those us eating nuts 5 x a week was 0.83 compared to those who never had a tasty nut touch their palate. That means almost a reduction of 1/5 in the chance of dying during the study period.
The reductions for heart disease was even bigger, 29% and for kidney disease it was a whopping 39%. Cancer deaths were cut by respectable 11%.
I fully expect that soon we will be able to buy nut extracts to add to our juices or cereals. Or nut pills to avoid all the hard work of buying and chewing those delicious seeds.
Don't fall for it. We have proved over and over again that there a huge danger in assuming that eating the essence or extract of a particular food is the same as eating the food itself.
A de-orderized garlic capsule is not garlic.
Vitamin C is not OJ is not an orange.
Nut extracts are not nuts.
Remember my mantra. Stay close to the soil. The more packaged and processed, the worse it is for you.
As I have said before, I don't for a minute believe eating nuts or any particular diet will cure me or anyone else of cancer, but I do believe that conscious eating can keep us all stronger for the health challenges we face.
In Part 3 of our conversation from iwCLL 2013, Dr. Jeff Sharman talks about how he approaches a patient with 17 p deletion.
This touches on the thorny issue of clonal evolution and the concern that treatment might lead to a Darwinian selection of the fittest, in this case the most resistant and probably the nastiest sub-clone of the CLL bunch.
Still, Dr. Sharman points out how the new biological treatments may force us to reexamine (and I do mean examine in a formal one) our long held beliefs about the inadvisability of early treatment.
Some of the new kinase inhibitors such as ibrutinib and idelalisib seem to have less of this risk, as they seem nearly as active on the high risk clones as in the more wimpy cancer cousins.
But there remains too many gaps in our knowledge to know what is the right thing to do, but we are moving forward at a rapid clip. And what may seem the best choice today, will certainly be different tomorrow.
Here's Dr. Sharman in part 3 from Cologne, Germany. If you haven't seen part 1 and 2 of the interview, please scroll down to the two prior posts.
PS: I love the comment that my tie looks like gene sequencing. That made my day.
In this short but rather technical discussion of the new diagnostic tests that is a follow-up to part one of my interview from iwCLL 2013 in Cologne, Germany, Dr. Sharman shares what he actually tests for in a patient who is considering therapy.
Most of these new prognostic markers have just not yet made it from the research studies into the hematologist's office.
One important point that I want to linger on for a moment is the difference between a prognostic and a predictive marker.
Though the terms are often used rather loosely, and many markers are clearly both, there is a difference.
A predictive marker tells us patients how likely we are to respond to a particular therapy. A 17p or BIR3 or CYP2B6*6 warns us that our chance of a response to FC is markedly diminished.
While there is frequent overlap, it is a helpful distinction to keep in mind when considering our workup in advance of therapy. Obviously a marker that predicts that we won't do well with traditional chemo-immunotherapy carries with a bad prognosis if that is the only therapy our docs could offer.
But as you have heard over and over again, that dangerous bottleneck is rapidly expanding with the new treatments coming into use. Accordingly, the distinction becomes increasingly important and predictive tests may soon help guide choice of our therapy.
One more sad note: I just found out that another CLL warrior lost the fight. George Martinez, whom I met and connected with in Columbus, Ohio, a fellow charter member of Team I (ibrutinib) who like me, flew to Ohio from his home in SoCal to join Byrdland, came to that drug after being badly beaten up by his CLL, its treatment, and multiple horrific infections.
I will miss his kind, funny, warm and generous ways.
We need to be looking at more than kicking the cancer down the road. We need to looking at reconstituting our immunity and preserving our marrow.
I hate this disease and want to see it vanquished!
In this interview from iwCLL 2013 with Dr. Jeff Sharman, a very clear teacher and community based cancer researcher, we learn about what I call the coming third generation of prognostic testing.
The first generation was staging, Rai in the USA, Binet in Europe, plus describing how the bone marrow looked liked under a microscope (degree and pattern of CLL infiltration), and some simple blood tests such as monitoring the rate of the rise in the lymphocyte count (doubling time), and B2M, a marker of disease burden.
Then we got more sophisticated (and expensive) with FISH testing, ZAP 70, CD38, and mutation status.
Dr. Sharman tells us what is coming next. An abstract of the Blood article that reviews some of this topic can be found here.
And the progress is not stopping.
Here's a new word we should all learn: pharmacogenetics or our unique genetic nature or phenotype that is concerned with how we metabolize medications. As we might easily infer, our individual pharmacogenetics has significant consequences on how well we respond to some therapies.
An article published last month in Blood, describes for the first time how this aspect of our genetic make up, specifically the subtype or allele of CYP2B6 that we carry, determines how well we convert a certain chemotherapeutic agent, in this case cyclophosphamide into its active form which in turn influences our response to that chemo. Not unexpectedly, those who have a low conversion rate not only do more poorly, but also have less adverse toxic events.
This whole new area of medicine, pharmacogenomics is already important in cardiac disease where we can measure markers that tells us how and when we doctors should, but sadly too often are not, properly using certain blood thinners based on the patient's measurable genetic make-up.
UPDATE: More on the gathering importance of pharmacogenetics from today's (11/19/13) New England Journal of Medicine (NEJM) here and here and here with an editorial here.
When the conservative and prestigious NEJM devotes most of an entire issue to a topic, we know that is an emerging hot topic. I am certain that this ill become an increasingly important arena in research in oncology precisely because so many drugs have such a narrow range of safety, and how we metabolize them might just determine the difference between toxicity or efficacy or no activity.
Let us return to listen to Dr. Sharman clearly explain some of these new prognostic tests that are emerging. I am particularly interested in his discussion of directly measuring the functionality of p53, rather than just look for a deletion. What matters to us patients is not the presence or absence of part of a single chromosome , but whether the anti--cancer gene is working or not.
ASH is coming so I want to be get most of the iwCLL posted here before.
The world of CLL is unrelenting and demanding.
I tried to step away for a few days, but news, good and bad, swirled into the center of my vision, and if that didn't get my attention, it then whacked me off my seat with its wild and blunt force.
Like my six month old granddaughter saying with her fusses and her smiles, PAY ATTENTION TO ME, CLL craves to be the center of the universe.
We lost another CLL warrior today. A member of our Orange County support group, Susie Vercruse passed from complications from a stroke. This was not likely a direct CLL issue, as even with counts of a million or more lymphocytes, we don't get the dangerous hyperviscosity (the blood gets too thick) seen in other blood cancers than can lead to blood clots, but that doesn't ease the pain. I will miss her easy smile and friendly positive ways. Very sad.
And yesterday we gain a new warrior in our CLL battles. Well sorta.
Ibrutinib or should I say now say Imbruvica was approved for relapsed and refractory mantle cell lymphoma (MCL).
This is very good news. It was as a friend in Houston said: a clean approval: No black box warnings concerning use with blood thinners (an early concern in some trials).
Five percent of patients with MCL had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily.
Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies.
Importantly patients only have had to fail one prior drug before they can have access to Imbruvica (get used to that name). Often new and expensive treatments are held in reserve only for those who have failed all other therapies, not just one.
Also there are no restrictions as far as I can see on how it used, alone or in combination, unlike the more limited recent approval of obinutuzumab.
MCL is much rarer than CLL, less than 3,000 cases a year in the USA, and is generally a much nastier and faster moving cancer than most CLL, with until very recently, fewer good treatment options.
Both obinutuzumab and ibrutinib could benefit a ton of patient of patients "off label", which is an ethical and legal way that many cancer and other drugs are often used.
Of course, cost will be a big issue. At an estimated more than $90 a pill for Imbruvica, the annual price tag for those of us with CLL would be just a tad under $100,000 a year. It is a full third higher in MCL as they take four 140 mg tablets daily. To their great credit, I have read that Pharmacyclics will be offering some medication free to help patients while the insurance is being worked out and will offer co-pay support for others longer term.
These days, this is the typical cost of many new cancer drugs, and is actually lower than some. Some orphan drugs used to treat very rare disorders can cost $200,000 to $400,000 a year, making ibrutinib look like a bargain.
Still 99% of us will not able to pay for that, and insurance will likely balk or in the best case scenario, take a good arm wrestle to consent to lay out that kind of cash.
We need to hope from a very broad approval for Imbruvica for CLL, speedily to minimize these issue.
It is a brave new world we are entering, and there are no easy answers. Drugs are very very expensive to get to market and for every single chemical that succeeds in making it to market, scores and scores never make it to the pharmacy.
We can't afford it and we can't afford not to do it.
I will post more helpful interviews real soon from iwCLL 2013 (I promise), but as John Lennon said: Life is what happens to you, while you are busy making other plans.
Is there anything better in the world than having a baby fall asleep in your arms?
Maybe if the baby is your granddaughter.
Another reminder of why I am fighting so hard to stay alive myself and help to let others with CLL enjoy a future full of their own sweet moments.
More on ASH and iwCLL soon, but I was way too busy this last weekend with more important business to fuss about that.
Like rocking my infant granddaughter asleep.
Besides addressing our critical importance of needing to understand the biology of our cancer in order to stop it, in Part Two of my interview from iwCLL 2013, Dr. George Calin of MDACC gives us a brief history lesson on micro-RNA and its relevance for us in unlocking the mysteries of CLL.
He also reinforces and enhances our modern understanding that CLL is not just about our stupid clone or clones, but it is all about how that stupid clone or clones prospers and evolves with the support of many helper or nurse cells that have been tricked into coming to the cancer's aid. Micro-RNA is one way all these cells communicate.
Anti-micro-RNA therapies are already being explored in other cancers. See my immediate prior post.
More than that, he touches on one of my favorite themes: the need to have better predictive tests so that we can individualize therapies. He visualizes a time when, by measuring these tiny "non-coding" pieces of genetic material in the blood, we will be able to better predict what therapies will work for which patients, saving much unnecessary treatments with all the attendant risk of collateral damage.
In the second and final part of the interview, Dr. Calin expands on the research that he is doing to help all of with CLL.
The abstracts from ASH have just been released and I am going to be very busy reviewing and digesting and commenting on some of the major ones here, but first, in lead up to ASH in December, I have several more very relevant video interviews including hearing from Dr. Kipps, Byrd, Pagel, Kay, and Sharman from the iwCLL meeting in Cologne to post here over the next few weeks.
This is the last iwCLL interview that is mostly basic science. The rest are more "clinical" and more immediately relevant.
I will be attending ASH again, and welcome your suggestions for questions and concerns for when I meet with the leading researchers. Drop me an email or comment and I'll try to help. After all, we are all in this together.
Dr. George Calin trained in Romania as a gastroenterologist, did ground breaking genetic research in CLL in the lab of the brilliant Italian born geneticist, Professor Carlo Croce, at Ohio State (where as you know I am doing great in my clinical trial), and is continuing to unearth more secrets about our cancer at his lab at MD Anderson by studying what not so long ago was thought to be "too small to be important" tiny chunks of RNA, but that we know realize play a critical role in gene regulation.
In this first part of my two part interview from Cologne, Germany, I will let the "doctor turned scientist" tell his amazing story and begin to explain more of the basic science that will hopefully soon gives us more tools to outsmart our cancer.
We are so lucky to see this type of international and interdisciplinary collaboration. We patients all benefit and must do what we can to encourage more.
Medicinal specialties spend too much time in their own silos, and Dr, Calin's important work reminds us of what can be achieved when we work beyond our national and professional boundaries.
Enjoy and learn as I did.
Obinutuzumab is a third generation monoclonal antibody (mAb) directed against a marker (CD20) sitting on the surface of B cells, including our cancerous CLL cells. Rituximab was the first generation, and it has proven to be a great boon to all of us with CLL. I believe that obinutuzumab will prove to be even more of a friend. It is a type of immunotherapy that has shown its value when added to a chemo backbone to treat CLL. Think of the huge improvement FCR was over FC. The addition of that antibody demonstrated for the first time that we finally had a therapy that could prolong our lives.
A couple of thing to note about the FDA new release that follows.
The approval was based on comparison to chlorambucil alone or chlorambucil with obinutuzumab. That seems like a bit of a fixed race. Single agent chlorambucil is a commonly chosen competitor as it one that is easily beaten. Other drugs such as bendamustine have won approval using a similar trial design. It is rarely used in the USA, especially as a single agent, but might be a good choice for some more fragile elderly patients.
Second, obinutuzumab was approved for frontline therapy in combination with chlorambucil in treatment naive patients. That was the way it was studied, and that's what was okayed. Period.
The much bigger issue is that if this is only way its use will be covered by insurance plans, then we are leaving the real power of this potent medication in many other life saving setting sorely neglected. That would be a real disservice to us patients. It remains to be seen how this will play out, but I am dismayed about the limited indication granted by the FDA and frankly worried about how that bodes for ibrutinib and idelalisib. Will their indications also be as tightly focused?
The reality is that many cancer drugs are widely or even mostly used off label, and if there is evidence, usually in the form of published research, then insurance can often be arm wrestled into paying. Once a drug is approved, the options for patients should greatly expand beyond the narrow boundaries of the inclusion/exclusion criteria set forth in a clinical trial. But they are no guarantees.
Does this make pharmaceutical companies rethink how they design trials if the indications approved by the FDA will only reflect the exact manner in which the drug was studied? Those more expert than me in knowing how these processes unfold will need to answer that thorny question. I suspect we will have some more approval news soon on ibrutinib that should give us a clearer indication of how the FDA is handling these issues.
Finally, a reminder that at least to the the FDA's eyes, the concerns with hepatitis B reactivation and the very rare but devastating brain infection, progressive multifocal leukoencephalopathy, are risks for all the CD20 monoclonal antibodies (mAb) such as rituximab and ofatumumab. I am not sure that those unusual complications were even seen in the trials with obinutuzumab, but the black box warning is there nevertheless. I am OK with that. Logically it makes sense, and it is better to err on the side of safety, though I doubt this is an error.
Still is very good news to have this new and more potent option. There are many reasons to believe that this third generation monoclonal antibody obinutuzumab will prove to be a much better CLL killer than rituximab. It got 30% of the patients to MRD (minimal residual disease, that is an important surrogate marker for length and depth of remission) negativity in combination with chlorambucil in the trial that got it approved. And you can bet it did the heavy lifting, because in the arm with chlorambucil alone, the MRD rate was zero.No surprise there. Image what magic it will wrought when matched with an equally potent fighter such as ibrutinib or idelalisib. And now that it is approved, setting up such trials will be much easier. it is already being studied with ABT-199, a trial that I have recommended for many to consider.
Side effects were generally pretty minimal. Except for the nasty infusion reactions common with many mAbs, most of those listed below in the news release were more likely from the effects of chlorambucil on the bone marrow than from the obinutuzumab.
Here is my prayer: That this powerful and important new mAb will be available to all those who might benefit and that means many more than those specified in the narrow indication.
I plan to be at ASH 2013 to hear the details of the phase 3 trial data and will share it all here.
The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
CLL is a blood and bone marrow disease that usually gets worse slowly. According to the National Cancer Institute, 15,680 Americans will be diagnosed and 4,580 will die from the disease this year.
Gazyva works by helping certain cells in the immune system attack cancer cells. Gazyva is intended to be used with chlorambucil, another drug used to treat patients with CLL.
Gazyva is the first drug with breakthrough therapy designation to receive FDA approval. This designation was requested by the sponsor and granted soon after the biologic license application to support marketing approval was submitted to the FDA. The FDA can designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases.
The FDA also granted Gazyva priority review because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. And the FDA granted Gazyva orphan product designation because it is intended to treat a rare disease.
Gazyva’s approval for CLL is based on a study of 356 participants in a randomized open-label multicenter trial comparing Gazyva in combination with chlorambucil to chlorambucil alone in participants with previously untreated CLL. Participants receiving Gazyva in combination with chlorambucil demonstrated a significant improvement in progression free survival: an average of 23 months compared with 11.1 months with chlorambucil alone.
The most common side effects observed in participants receiving Gazyva in combination with chlorambucil were infusion-related reactions, a decrease in infection-fighting white blood cells (neutropenia), a low level of platelets in the blood (thrombocytopenia), low red blood cells (anemia), pain in the muscles and bones (musculoskeletal pain), and fever (pyrexia).
Gazyva is being approved with a boxed warning regarding Hepatitis B virus reactivation and a rare disorder that damages the material that covers and protects nerves in the white matter of the brain (progressive multifocal leukoencephalopathy). These are known risks with other monoclonal antibodies in this class and rare cases were identified in participants on other trials of Gazyva. Patients should be advised of these risks and assessed for Hepatitis B virus and reactivation risk.
Gazyva is marketed by Genentech, a member of the Roche Group, based in South San Francisco, Calif.