Friday, January 3, 2014

Ibrutinib Update

Dave’s Great Adventure

Book 5, Chapter 2, Verse 6

I’m still doing fine but a lot of news has recently come out about the new, experimental drug called ibrutinib, so much so that I thought an update on it and other related topics is needed. This will be more of a technical update than a personal one.

First, and foremost, the FDA has approved ibrutinib to be sold on the open market and not just to be used in clinical trials. But, quite surprisingly, to many folks at least, it was approved, not for chronic lymphocytic leukemia (CLL) as expected, but rather for a rare and aggressive disease called a mantle cell lymphoma, about which I know very little. Approval of the drug for the treatment of CLL is still expected in the coming months, but with its approval for mantle cell lymphoma (MCL), that is almost a moot point. With the drug on the market now, physicians are pretty much free to use it as they want by using it “off label.” That means they can use any approved drug for other diseases if they feel there is a benefit. There are many examples of off-label use in medicine, such as antidepressants used for peripheral neuropathy, narcotics used to slow down over-active bowel function and many, many other examples. I have already heard of one patient who will now be getting ibrutinib for her Waldenstroms macroglobulinemia, for which the drug is showing great promise. But, I don’t even know if the company has applied for permission to be used for this disease. No matter. It’s now on the market.

And, now that it’s more widely available, it has a trade name. When I first started taking this drug it was still going by its company’s in-house development code, being called PCI 32765. Then, a few months later it was given its current generic name, ibrutinib. But now it has an official trade name of “Imbruvica.” And with that name comes its current marketing price, $91 per capsule. Those of us with CLL take three capsules a day, which comes out to about $8200 a month, or close to $100,000 a year. I believe the folks with MCL actually take four capsules daily but I can’t be sure of that.

And much more specific information is now available about how it, and many other drugs and procedures, are working against so many blood cancers and lymphomas. The American Society of Hematology recently concluded its meeting in New Orleans and all of the abstracts of the hundreds of presentations are now available on-line, for your review. It includes many interesting findings and nuggets of information, with a great deal of information about new and novel treatments for CLL. If you’re interested in taking a look at all or some of the abstracts, look here:

https://ash.confex.com/ash/2013/webprogram/start.html

There is a search function which will allow you to search out the topics of most interest to you. I have to warn you, these are specialized topics written in the lingo of the specialists and some of the data are hard for us amateurs to decipher.

But there are several abstracts (which are just summaries of the presentations, not the entire article) which are of great interest to me. First, Dr. Jan Burger, who is the lead investigator of the study I’m in presented the official findings thus far. You can see it here:

https://ash.confex.com/ash/2013/webprogram/Paper58781.html

I learned a great many things. As I have stated several times in my updates, when in Houston I generally ask how the other 39 folks in the study are doing. I am routinely told that everyone is doing fine. But, I don’t know if I’m asking the question too generally, or if the answers I get are just too general, or if (probably) the folks I’m asking just can’t tell me about the other study participants. But, what I have learned is that all of the other patients in the study are NOT doing just fine. In fact, of the forty original patients in the study, four are now dead. They are reported to have died of unrelated infections; sepsis, pneumonia and cardiovascular failure. Further, four more dropped out of the study for other reasons; two for ibrutinib related complications like mucositis (inflammation of the mucous membranes in the mouth, bowels, etc.) and a subdural hematoma (remember that ibrutinib inhibits platelet function and the clotting process), another with disease progression and one left to have a stem cell transplant. I have to assume, but do not know, that the person who left to have the stem cell transplant must not have been responding well.

However, despite these problems in eight of forty patients in the study, we have to remember that the study recruited the sickest of the sick. All the patients in this study had very bad prognostic indicators. Most had the 17p deletion, the 11q deletion and/or had failed multiple other therapies. Despite the loss of some of our group, the study reported a 95% overall response rate (complete or partial remissions) with 80% of us remaining on the drug without disease progression after 14 months or so. This is still a remarkable response rate in folks who are very high risk and, essentially, have no other options except that of a stem cell transplant.

If you look at this paper, it mentions that most of the study subjects were IGVH un-mutated. If you’re looking at this message you likely know that having the IGVH mutation is considered a very good prognostic sign, so it’s not much of a surprise to see that most of these patients in the study, who are generally pretty sick, do not have the mutation. However, note that Dr. Burger says one patient does have the mutation. Hey…that’s me!

This brings up another peripheral study that was presented at ASH. A researcher studied the relationship of the “protective” effects of having the IGVH mutation against the very deleterious effects of having the p53 deletion/mutation (I have both). They found that if you have the p53 deletion, having the IGVH mutation doesn’t seem to confer any protection, the deadly effects of the p53 deletion being the dominant factor. Too bad for folks like me.

Another study of ibrutinib which bears reading and studying is one presented by Dr. Susan O’Brien, also from M. D. Anderson. You can see her paper here:

https://ash.confex.com/ash/2013/webprogram/Paper61648.html

In Dr. O’Brien’s paper, they have apparently combined the results from the Phase 1 study of ibrutinib, which had 108 patients in it, with the forty of us in the Phase 2 study, to give a total of 148 patients. She breaks the data down according to whether the patients had previous treatments and had relapsed or were refractory to treatment (RR) or whether they were getting their first treatments, being “treatment na├»ve” (TN). She further breaks the data down into the patients’ ages, number of previous therapies, time on the drug and more.

They have found that the serious adverse events decline after the first year and that most patients tolerated the drug pretty well. After about two years on the drug, 25 of 31 TN patients were still taking it and only one had shown disease progression, with no deaths noted. On the other hand, of the relapsed patients (RR), only 68 of 117 (58%) were still on the drug and 21 had noted disease progression. Notably, there have been 11 deaths in this RR group of 117 patients. However, the drug shows great promise, as the overall response rate was about 88% for the whole group, with most patients showing a partial response or better. She noted that after more than two years (average 27 months) on the drug, of those patients who had achieved at least a partial response, the median duration of response (DOR--the average time it takes patients to fail on a drug) had not been reached and could not be calculated as 76% of the patients were still alive without disease progression. That’s an amazing statistic. And a very hopeful one. I suggest you take a look at her abstract if you’re on this drug or considering taking it.

One last abstract I’d like to mention is one relating to the upcoming therapy called the Chimeric Antigen Receptor (CAR) procedure which is very exciting and is being studied in many places. It may be able to be a cure for many malignancies and is being studied mostly for leukemias at this point. It enlists the patient’s own immune system to seek out and kill the diseased cells. I won’t describe it here, as I’ve mentioned it previously and much more about it can be found elsewhere on the internet.

This procedure was pioneered by Dr. Carl June’s folks at the University of Pennsylvania. His early study of three patients resulted in two of them apparently being cured of CLL, though they remain immune deficient. In any case, it is interesting to see what percentage of the study patients are responding to therapy. This abstract also comes from Dr. June’s group. You can see his ASH abstract here:

https://ash.confex.com/ash/2013/webprogram/Paper58607.html

This shows that, although the procedure has some excellent results, it doesn’t always work. Of 24 CLL patients who underwent CARs therapy recently, only 5 had complete responses, 7 had partial responses and 12 had no response. The results were a bit better for pediatric patients with ALL. Of 14 patients, 8 had ongoing complete responses and four have relapsed. However, it needs to be remembered that all these patients were desperately ill and essentially had no other options. My point, though, is that for all the excitement surrounding CARs, this procedure is in its early stages and is not a cure for all who enter into these studies, with possible complications, deaths, relapses and such. But, it still holds great promise for the future.

I’m still doing quite well and will be going back to Houston for another check-up and bone marrow biopsy in about six more weeks. Meanwhile the blood counts I have been getting monthly here in Denton are remaining pretty much normal. Hopefully I can give you another good report next month.

Dave