“Soil & Seed”
There is a concept in cancer biology called “soil and seed“. What do you need for plants to grow and flourish? You need healthy and strong seeds with good vigor and pest resistance built into them. But even the strongest seed cannot flourish in bad soil. Both strong seeds and nutritious soil capable of supporting plant growth is needed for plants to grow and flourish. Any gardener can tell you that!
This analogy works in cancer biology as well, it seems. High risk cytogenetics in CLL (unmutated IgVH, 11q and / or 17p deletions, unmutated IgVH etc) are the equivalent of strong cancer seeds, able to resist the damage inflicted on them by chemotherapy. A supportive microenvironment – such as lymph nodes, bone marrow etc – provides the rich soil. Presto, when both of these conditions are met, we have a faster growing and more difficult to control CLL. (Spleen and liver are also considered to be part of the lymphatic system and therefore for the purposes of this discussion, when I write about swollen nodes I am including spleen and liver as possible locations of swelling as well).
As you know by now, CLL comes in a variety of flavors. In some patients, almost all of the disease is seen in peripheral blood. While these guys may have impressively high white blood counts and absolute lymphocyte counts to match, in fact they are the lucky ones and their disease is likely to be the easiest to treat. This is why I caution patients about getting too fixated on white blood counts. It is only a part of the picture, a small part of the picture as it turns out.
On the other hand, people who have large percent of their CLL cells nicely tucked away in swollen lymph nodes and bone marrow, spleen, liver etc have a bigger problem. You see, CLL cells are insecure little buggers. They don’t like being alone, just cruising around in blood circulation all by their lonesome selves. They do much better, live longer and have many more babies when they live in well established colonies of other CLL cells. Also of importance are supportive cells surrounding the CLL clusters, giving the cancer cells much needed approval and survival signals. In fact, some of the interesting papers at the recent ASH2011 report that microenvironment where CLL cells live plays a huge role in the progression of the disease.
Who are most likely to have lymph node centered disease? Typically, people with high risk CLL (FISH deletions of 11q, 17p, 12 trisomy) are most likely to have enlarged nodes. In these patients the lymphocyte count in the blood is nothing more than the tip of the iceberg. As much as 90% of the CLL cells can be safely tucked away in lymph nodes, making these cancer cells hard to get at. As we discussed above, these CLL cells in lymph nodes fit the classic definition of strong seeds in a fertile soil. The cytogenetics makes it hard to kill them, and the cancer friendly microenvironment of the lymph node makes it easier for them to live long and prosper.
It has been a depressing fact of life that many of the drug regimens we had up to now were not very successful at treating patients with high risk CLL, especially if they also had massive lymphadenopathy (fancy word for swollen lymph nodes, or swollen glands if you are a Brit). Important drugs such as Campath are considered useless and contra-indicated if the patient has large lymph nodes. Single agent monoclonal antibodies (Rituxan, ofatumumab) are not of much use either. More aggressive therapies such as FCR and bendamustine combinations may be able to get (most of) the CLL cells lurking in the lymph nodes, thereby giving high response rates. But as we are learning, not everyone can handle FCR and similarly high impact therapies. Elderly and frail patients, folks with other medical issues etc may find such aggressive regimens hard to tolerate. For them, the price tag of therapy toxicity may be more than the remission is worth. People who have relapsed after prior therapies such as FCR or FR are another subset of patients who really needed better salvage therapy options.
This new understanding and emphasis on the microenvironment of CLL cells is fueling a lot of the excitement regarding kinase inhibitors such as CAL-101 and PCI-32765. The science is complex and I will not go into it here. Please read an earlier article titled “Dawn of a new Era” where I discuss a cartoon version of it. In a nut shell, drugs such as PCI-32765 interfere with the cyotokines that act as the cookie crumb trails leading CLL cells home to lymph nodes, as well as the adhesion factors that allow them to stick there. Deprived of their nurturing microenvironment and flushed out into open blood circulation, the soil part of “Seed & Soil” is defeated, making the CLL cells easier targets for therapy.
We discussed the first batch results of PCI-32765 in an earlier report. Here is a followup, with more mature results.
The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study
December 13, 2011
Susan O’Brien, MD1, Jan A. Burger, MD, PhD2, Kristie A. Blum, MD3, Richard R. Furman, MD4, Steven E. Coutre, MD5, Jeff Sharman, MD6*, Ian W. Flinn, MD, PhD7, Barbara Grant, MD8*, Nyla A. Heerema, PhD9, Amy J. Johnson, PhD3, Tasheda Navarro10*, Eric Holmgren, PhD10*, Eric Hedrick, MD10 and John C. Byrd, MD11
1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3The Ohio State University, Columbus, OH
4Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY
5Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA
6US Oncology, Springfield, OR
7Sarah Cannon Research Institute, Nashville, TN
8Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT
9Pathology, The Ohio State University, Columbus, OH
10Pharmacyclics, Inc, Sunnyvale, CA
11Division of Hematology, The Ohio State University, Columbus, OH
Introduction: Btk is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally-administered irreversible inhibitor of Btk which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. An early analysis of the phase Ib/II study PCYC-1102 showed PCI-32765 to be highly active and tolerable in patients with CLL (Byrd, ASCO 2011). Here we report longer-term follow-up of this multicenter phase Ib/II trial.
Methods and Patients: Two cohorts of CLL patients (previously untreated ≥65 years old and relapsed/refractory [R/R] disease following at least 2 prior therapies, including fludarabine) were treated with oral PCI-32765 administered daily for 28-day cycles until progression of disease. Doses of 420mg (previously untreated and R/R) and 840mg daily (R/R) were examined. The patients with R/R disease are the subject of this report.
Results: Sixty-one R/R CLL/SLL patients were enrolled (420mg cohort n=27, 840mg cohort n=34). The median follow-up time for the 420mg cohort is 10.2 months and for the 840mg cohort is 6.5 months. The median number of prior treatment regimens for the 420mg cohort was 3 (2-10) and for the 840mg cohort was 5 (1-12). Seventy-two percent of patients had at least one poor-risk molecular feature: del(17p) 31%, del(11q) 33%, IgVH un-mutated 57%. Treatment has been well tolerated. Two patients have discontinued for adverse events (AE); 6 patients have required reduction of PCI-32765 dose (420mg cohort 2/27, 840mg cohort 4/34). Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis have been the most frequently reported AEs. Serious AEs (SAEs) have occurred in 38% of patients; SAEs considered potentially related to PCI-32765 have occurred in 10% of patients. Grade ≥3 AEs considered potentially related to PCI-32765 occurred in 21% of patients. A characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of Rx, followed by resolution over time, has been observed in the majority of patients. Objective response (ORR; PR + CR) by IWCLL criteria in the 420mg cohort cohort, previously reported as 48% with 6.2 months median follow-up (Byrd, et al ASCO 2011), is now 70% with 10.2 months median follow-up. ORR in the 840mg cohort is 44% at 6.5 months median follow-up. An additional 19%, and 35% of patients in these cohorts, respectively, have a nodal PR (>50% reduction in aggregate lymph node size) with residual lymphocytosis. ORR appears to be independent of molecular risk features. Eighty-two percent of patients (50/61; 420mg cohort 22/27, 840mg cohort 28/34) remain on PCI-32765. Only 8% (5/61) of patients have had progressive disease (PD); 6-month PFS is 92% in the 420mg cohort and 90% in the 840mg cohort. Treatment cessation not related to PD or AE includes: death (n=2) or investigator discretion (n=3).
Conclusions: The potent Btk inhibitor PCI-32765 is well tolerated and is associated with high rates of 6-month PFS in R/R CLL/ SLL. Phase III trials of PCI-32765 in CLL/ SLL are planned.
Disclosures: O’Brien: Pharmacyclics, Inc: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Burger: Pharmacyclics, Inc: Research Funding. Blum: Pharmacyclics: Research Funding. Furman: Pharmacyclics, Inc: Research Funding. Coutre: Pharmacyclics, Inc: Research Funding. Sharman: Pharmacyclics, Inc: Research Funding. Flinn: Pharmacyclics, Inc: Research Funding. Grant: Pharmacyclics, Inc: Research Funding. Heerema: Pharmacyclics, Inc: Research Funding. Johnson: Pharmacyclics, Inc: Research Funding. Navarro: Pharmacyclics, Inc: Employment, Equity Ownership. Holmgren: Pharmacyclics, Inc: Consultancy. Hedrick: Pharmacyclics: Employment, Equity Ownership. Byrd: Pharmacyclics, Inc: Research Funding.
Judging credibility of research reports is an important part of understanding the results. I discussed some of the issues that go into reading the tea leaves in my last article on CAL-101. Same rules apply here as well. High powered researchers, prestigious institutions, every single one of them with financial connections to the company (Pharmacyclics) that owns the drug. The lead author (Dr. Susan O’Brien, M. D. Anderson) who presented the data at ASH2001 is also on the Board of Directors of the company. Does this mean we throw away the whole report as so much conflicted nonsense? No, that would be throwing the baby out with the bathwater indeed. It just means we keep things in perspective when we read glowing press reports about the new drug.
Here is a bit of a “teaser” for you guys. In the next few days I will be publishing an important new development dealing with ongoing PCI-32765 clinical research. You will not be off the mark if you think of it as a timely Christmas present for the CLL patient community. (Yeah, Happy Holidays present for those of you who do not celebrate Christmas. Sheesh.)
Clinical Trial Design
This clinical trial had two patient cohorts. First one included patients who were chemo-naive (untreated) but older than 65 years. In other words, they are looking at PCI-32765 as a possible frontline drug in older patients for whom combinations such as FCR may be contra-indicated. The second cohort consisted of relapsed / refractory patients who have been through at least two earlier therapy regimens, including fludarabine. In other words, at the other end of the curve, looking at PCI-32765 as a potential salvage therapy for this tough to treat crowd. This report is only about the second cohort, the folks who went into the PCI-32765 after relapse following prior two cycles of therapy.
There were 61 patients in this group, some were classified as SLL, the lymph node variant of CLL. As you know by now, PCI-32765 is an oral drug, making its administration easy. Dosage varied between 420mg and 840mg per day. Followup (thus far) is between 6-10 months.
Results, Risks, Rewards
Bear in mind this is a tough to treat patient cohort. Besides being relapsed and/or refractory, 44 out of the 61 patients had one or more of the high risk features (17pr or 11q deletion, or unmutated IgVH). “Treatment was well tolerated” – good, but I will take that with a pinch of salt, thank you very much. Amazing how much perspective changes when you are at the pointy end of the stick. Serious adverse effects occurred in 38% of the patients, of which the researchers judge 21% were attributable to the drug in question. I suppose the definition of well tolerated is relative, and in this case it is being used in the context of ‘beggars cannot be choosers’. All the same, I would have preferred more sympathetic language, don’t you think?
Ten months of daily administration of 420mg of PCI-32765 got an overall response rate of 70% of the patients. Overall response rate is the sum of “CR” and “PR”. (Here is an article that describes in detail what CR and PR mean). The abstract does not break out how many CRs there were, and how many PRs. I am willing to bet dollars to donuts the vast majority of these were PR (“partial response”). For starters, I do not really expect to see any full blown CR remissions in this relapsed / refractory crowd. Second, human nature being what it is, I suspect the abstract would have made much of the large number of CR responses, if that had been the case.
The higher dosage (840mg daily) group has been followed for only little over 6 months and in this group the overall response is at 44%. Hopefully, they too will have more and more people getting some sort of a response as time on therapy increases.
Only 8% of the patients seem to have their CLL progress (get worse) while they were on the drug. Two patients died, but the deaths are not considered to be due to PCI-32765.
Here is the most important part of the whole study. Patients’ response to PCI-32765 does not seem to depend on whether or not they had high risk disease. In other words, it did not seem to matter whether they had 17p, 11q deletions, unmutated IgVH etc, they were just as likely to get a response to the drug. That is indeed welcome news. Remember, in our introduction to this article we discussed the need for new therapy options for patients with high risk disease, those unfortunate folks who had both the “good seed and nurturing soil” version of aggressive cancer. This study supports some of the excitement about these new generation of designer kinase inhibitor drugs, in that they seem to be able to do what most other drugs cannot do: treat high risk and relapsed / refractory patients. As with CAL-101, the characteristic feature of kinase inhibitors, their ability to flush CLL cells out of comfortable lymph node cocoons, that seems to be the important feature of how these drugs act.
Notice the silence regarding action on the bone marrow front. As in the previous article on CAL-101, this abstract does not mention the bone marrow microenvironment. Does PCI-32765 do a good job of clearing it? We do not know. Once again, I do not think the bone marrow microenvironment is identical in all ways to the lymph node environment. Is it reasonable to assume / infer / hope / expect that because PCI-32765 works well in flushing out CLL cells from lymph nodes, it will do the same for the bone marrow as well? We do not know – and frankly, I think it is a bit of a stretch to make that assumption. I realize drug companies spend good money getting these important trials done. But how about doing good science while we are about it? Our guys are risking their necks in volunteering for these early stage trials. How about making the best use of their sacrifice, and thanking them too, while we are on the subject?
Are these drugs truly low toxicity? I am not too sure of that. In my layperson opinion, the jury is still out on that. At the same time, please allow me to remind you that we are willing to accept a certain amount of toxicity risk, if the drug in question can actually deliver in terms of deep and lasting remissions. Until better drugs become available with even better responses and fewer adverse effects.
Will the remissions be long lasting? Will the patients have to take PCI-32765 indefinitely, or can they quit after a good long time and still expect to stay in remission? That question has not even begun to be answered, yet. If I were to bet, I would expect patients would not stay in remission for very long after stopping daily use of PCI-32765. But that is just a guess on my part.
My guess is that these early trials of kinase inhibitors as single agents will be followed by the inevitable combinations of these drugs with other agents; chemotherapy agents such as F and C come to mind. We may expect to see more full fledged CR responses in such combinations, as well as deeper, longer lasting remissions. Unfortunately, I think most of you can figure out by now, addition of standard chemo agents such as F, C and B(bendamustine) will increase the toxicity of the regimens too. Sigh.
So, what is the Christmas present I promised all about? You will just have to wait a couple of days, no more than a week, I promise. And if you are getting busy making your “nice” and “naughty” lists for holiday giving, I hope you will put us in the “nice” category. Supporting our work through your donations is what keeps us going. It is easy to do. You can do it using your credit cards (through secure PayPal). Or you can put your check in the mail. Hit the “Donate” button below and the page has all the information you need, including our mail address. That’s it folks – that is the sum total of our “donations drive” for the year.
29 comments on "PCI-32765: ASH2011 Update"
Chaya,
Nice review.
I was in San Diego at ASH as a reporter for primary care docs and for my blog. Very exciting time for patients with CLL.
Here’s what I got from questioning O’Brien and Furman and Wiestner and others at ASH about PCI-32765.
One reason given for the little data on the bone marrow is that trial did not call for BMB until the nodes were gone and the blood counts normal as it was only used to check for a CR. Patients don’t like BMB, so let’s only use them when we really need a data point.
The official line on infections is – What do you expect: these are heavily treated CLL patients. And there is no clear evidence of increased infections compared to historic norms.
There is a rebound problem with nodes growing quickly back when you stop the med, but it seems to be less the longer you are on it.
15 of 20 of those with 17p del responded. I think 3 or 4 went on to transplant, but Dr, Wierda wondered out loud to me if this drug might change the paradigm. That you might be able to stay on it for years and avoid the dangers of a transplant.
The doctors are all really high this drug.
O’Brien’s abstract got huge press coverage.
I admit I am also part of the rah rah team for these new drugs and like you I have nothing to disclose other than I am likely betting my health that PCI-32765 is as good or better than its press.
I am encouraged by the improving response rates over time with no new toxicity at least in the short term. I am impressed with the lack of marrow suppression and the relative paucity of other adverse events.
I am less sure about combos. In Gleevec, some combos lowered efficacy. This stuff has not been worked out yet.
Remember too that you are not comparing PCI-32765 to placebo. We would only use it if we need therapy, and our other choices bring their only toxicities and adverse events profile
True that there is more promise that data, but there is real promise. This could be the next big thing.
Or not.
Warm regards
Brian Koffman (bkoffman.blogspot.com)
Hmmm .. I don’t buy that “patients don’t like BMB so let’s not do them”. Patients dislike CT scans even more, yet this trial calls for lots of them. If I do PCI, I will be happy to have a BMB to understand what it is doing to my heavily impacted marrow. Personally, I’ll be looking for a PCI trial in 2012, either single agent or with ofatumumab, rituxan or ..another monoclonal. I’m not interesting in mixing it with chemo. My other choice would be, perhaps, revlimid with or without R .. (better for the Ig’s .. but at what cost? .. another article here?)
Wish there had been some hint at ASH on status of the front line PCI trial for the elderly. I know it had met its enrollment goal a while back. And it looks like some interesting trials with PCI will be available in 2012 .. fortunately, some of them still Phase II so perhaps not with chemo. It does look like PCI brings the Ig’s further down so infection has to be a danger. (These are the things we don’t see in the articles, but learn about from our fellow CLLers who post on various forums.)
Thanks, Chaya, for your great articles. And I look forward to that gift .. perhaps I have a clue .. we’ll see.
All the best,
Lynn
Brian, Lynn:
I too don’t buy that “patients don’t like bone marrow biopsies, so lets not do them” line. Sounds a bit too glib for me, I smell a rat on that one.
Yes, Lynn. I bet you have a pretty good clue on the Xmas gift :)
As for the infections Brian. True, these are heavily pre-treated patients. But I will wait until I see more details before I give PCI-32765 a clean bill of health on that one.
Indefinite maintenance use of PCI-32765 may well depend on its “costs”. Not just the dollar costs, though I expect they would be substantial, but the adverse effect cost as well. If indeed the Ig levels drop with continued use of kinase inhibitors such as this, there is bound to be a price to pay in terms of infections.
For my money, I really like the potential of this drug to give high risk and relapsed patients a chance of de-bulking their lymph nodes, getting them on track to get a mini-allo stem cell transplant. Transplants work much better when patients do not have bulky nodes going into them. At the same time, it is not very easy to get those damn nodes down in size for potential transplant candidates – who tend to be relapsed patients with aggressive disease.
Thank you Chaya for your excellent review of this drug. I also enjoyed Lynn and Brian’s additional comments. I am following this development very closely since it may well be the drug of choice for my husbands CLL.
I am looking forward to your next article.
Thanks for all you do!
Hope for ‘incurables’ is the best Xmas present ever. Keep it coming Chaya!
As I have mentioned before, I have been on 420 mg/d of PCI since Aug. 2010. At this point I feel better than at any time since a year before my diagnosis. The only significant negative for me is that I have been on IVIG since my IgG levels dropped in Jan ’11. But with this, I have not had to have antibiotics at any time during my treatment. From my single experience and quizzing everyone I talk to, I don’t think the AEs are being underplayed.
I have not had BMB in this trial, but I volunteered. Regarding CT vs. BMB, CT is a nuisance (not so much so since they are recently giving a different cocktail that lacks a laxative) and it is a long-term risk. However, I dread BMB. Last time I had one, I demanded their best technicial – if they don’t do it quite right, it can be truly fearsome.
Thanks Chaya, for a very nice article. You were on target for every issue here.
I don’t understand why there is such concern for the state of the marrow. A BMB is subject to sampling error and the presence of CLL cells in the blood and/or continued presence of lymphadenopathy means that there is still disease, so deferring a BMB until/unless there is a reasonable chance of MRD seems sensible to me, as BMBs do have a cost (both financial and patient discomfort or worse).
The issue of CT vs. BMB is not well understood by some. No one likes frequent CTs for obvious reasons, and we can hope that future trials will decrease their frequency, but the CT scan is the single best modality to accurately follow the status of internal nodes as well as the spleen. This will prove necessary for FDA approval.
As to the issue of what effect PCI 32765 has on infection risk only clinical follow up will yield meaningful information. While the theoretical decrease of Ig levels is real, many patients with CLL do not have undue frequency of infections (I am an example of this phenomenon) despite persistently low Ig levels (my IgG has been less than 200 for over 6 years and now is at 122mg% along with barely measurable IgA and IgM levels).
Clearly there are other factors at play and it may or may not be the case that PCI 32765 has either positive or negative effects upon these as yet unidentified factors.
There does seem to be evidence that the drug adversely affects platelet function (hence the 2 reported cases of intracranial hemorrhage and the observed easy bruising of patients on the drug) so patients who require anticoagulation for other reasons need to be wary.
More than likely this drug (as would any enzyme inhibitor) has effects on other cells and other systems, some of which may only be clinically significant in some people because of biological diversity. We have, for example, already noted the high incidence of inflammatory, non-infectious pneumonitis seen with CAL 101, most likely because of undesired effects of the PI3k delta inhibition on cell systems other than those of CLL cells.
Only with greater use and observation of patients treated with these drugs will we become aware of more “good” and “bad” things about this (and other) drug and it’s utility when used in various combinations with other drugs. For example, if the drug inhibits the action of other cells (eg, NK cells) some combinations utilizing drugs that require other cells to function may be less efficacious that one might otherwise guess.
When Gleevec came on the scene it was initially used to tide CML patients over until they could undergo HSCT. Now CML patients rarely need to undergo HSCT.
Let us hope for the best and certainly let us hope for more data!
Chaya and all. I’m brand new to this CLL stuff. What a great site to learn about it, although my 50 year old knowledge of biology is struggling to catch on to the new language. The initial diagnosis came after my family doctor relentlessly pursued the pneumonia that showed up in early September 2011. One CT led to another and there it was, a grapefruit in my gut. Apart from weariness (read “naps in the afternoon”) I have no external symptoms. Yet. There are several blood tests out there waiting to be reviewed, ZAP-70 being the fanciest, I guess, although I’m reading here that the ZAP may not be all that good. I shall ask Monday about the FISH. At any rate, thanks for doing what you do here. It’s an incredible amount of work you do.
BB
There was a drug called GA-101. Suppose to be much better that Rituxan at sticking to all b-cells. How about a combo of BTK or Cal-101 to flush the cell out and then tag them with GA-101?
Raymond
This is good info, thanks for all you do and for everyones posts. I have been on PCI 32765 with Benda + Rituxin since June, finished the chemo and now on maintenance with PCI. I can relate to the IVIG issues as I came down with a Parvo virus and causes extremely inflamation of the joints, hard to say this is PCI related however as I came down with this after my first round of FCR 4 years ago and probably never truly cleared my system but laid in dormant state until this past treatment. Manageable with Advil, but still a pain (pun intended). Outside of that I did develop sinus infection that I am on anti-biotic for, but the pill itsel is manageable and beats the chair. JD
Ia5275 — In response to your “I don’t understand why there is such concern for the state of the marrow” — I would say, if these are clinical trials being conducted in research institutions, then I would expect EVERY significant test to be run before, during and after treatment to yield as much information as possible about the effect of the trial drug. In my case, my mother died of Aplastic Anemia, so I always have marrow impact in the back of my mind. As to the “cost” of a BMB .. I think we do a disservice in the way BMB’s are discussed and I see evidence of readers of various forums becoming BMB-phobic. Mine at NIH was a non-event. I had no pain during, other than a twinge as the local was administered. I had no pain after .. and absolutely no evidence other than a little red dot for a week or so. As these trials are still in research institutions, there should be very experienced BMB staff do do the procedure. As to the sampling error possibility, I’d like to see some numbers on that if possible and then perhaps I’ll rethink my position. How often are two cores taken to avoid that possibility etc?
Finally, limiting the BMB to the MRD- case for this drug seems bizarre as it has been compared to Gleevac, which keeps disease under control but does not eliminate it. Is MRD- really expected? Something is not adding up here in this reasoning and I find it hard to believe that scientists are not extremely curious as to what is happening in the marrow, even if the window into it is imperfect. I know that I am extremely curious and thus am frustrated that the participants are going through all of this without having that final test.
All the best
Lynn
PS — And I am fine if someone just comes out and says “We don’t expect PCI-32765 to clean out CLL in the marrow. But it will make your disease more tolerable and improve your quality of life and longevity”. That is fine .. we just need to share expectations explicitly.
I am in the PCI-32765 monotherapy 420mg group just having completed cycle 6. As you know, I am a discordant patient with good markers that my agressive and heavily node involved CLL fails to appreciate. Although I have a 13q monoallelic deletion Dr. Byrd has suggested that I might have a “point mutation” not picked up by scans on chromosome 11 that is reflected in the clinical manifestation of my disease.
I have had two troubling side effects since starting PCI those being 1)heart issues to include Arrhythmia, tachycardia and right atrial flutter and 2)eye discharge and irritation causing blurred vision as an intermittent or cyclic but chronic problem. The key question is, how much of these problems can be attributed to PCI? in the case of the heart issues, A-fib and Atrial flutter are not uncommon in an aging population of otherwise healthy people. I am genetically Bradycardia (low heart Rate) and am physically active which is a feature of normal heart rate in younger athletes, I am 68. My speculation is that PCI may be inducing a further drop in heart rate triggering (through an escape mechanism) the A-fib, Atrial flutter and Tachycardia. I further speculate that these heart issues originated from my initial 1st treatment with RF in 2009 when 4 days after completing cycle one I had my first ever A-fib tachycardia event. While the eye discharge and irritation first occurred early on in the PCI Trial it is, in my mind, directly tied to the sinus congestion as the right eye is more affected than the left, mirroring the pain/pressure pattern experienced by the sinus at the time of first initiation of the symptoms. While I never had sinus issues in general in my life I did have one acute very painful sinus attack after Rituxan monotherapy that had the same pattern of focus with prominent pressure and dull pain behind the right eye in March of this year.
On the positive side, I have not felt better or more free from dance of the CLL BEAR since taking PCI beginning the first of July. External nodes are not palpable and internal nodes are quite small and continuing to get smaller. RBCs, HCT and HGB are continuing upward, though just under low normal Ref range (MAY INDICATE MARROW IMPROVEMENT) Platelets are stubbornly low at around 87 – 90. WBC has dropped from peak high of 95k but remains for past 3 cycles stalled at 50k.
Although many folks tolerate RF well and some do well even on R-monotherapy for a while, I would characterize my experience on PCI this way: I just returned last night from my 6 cycle monitoring at OSU where I walked a 9 mile return fast paced walk to the scheduled eye exam at the Havener Eye institute doing the 5 story stairs and feeling good. After finishing Clycle 1 of RF in ’09 I had a hard time walking at all and breathing without coughing for a long time. After R- monotherapy in March put me in a wheelchair with side effects best left forgotten, I am part of the patient cheerleading team for PCI and the quality of care received at the JAMES OSU.
Reflecting on my, as yet early, experience with PCI leaves me with no doubt that the use of kinase inhibitors to best patient advantage will take some sorting out but this is a much more patient friendly therapy in the short term for sure. Concerns over possible increase in viral infections and vulnerability to infections due to lowered Immunoglobulins over time are real but don’t forget, CLL all by itself can lead to hypogammaglobulinemia. Toxic gold-standard chemos and monoclonal antibodies can lead to infections too. Raymond Parker’s suggestion of a novel combo of drugs congers up many possible ways to use the benefits of this powerful new player in the therapy option tool kit. Would alternating less toxic options that included PCI and Cal-101 be a way to keep the cancer from exploiting alternate signaling paths? – Many possibilities.
As a last note: I was told that I was blocked at 100% not too long after beginning PCI on the low dose protocol (420mg). I am one of the ones who have had the dosage reduced (280mg) to see if there would be a positive effect on my eye issue. I am a full cycle out on the 280mg per day with no sign of node enlargement so I may be a useful lab rat in figuring out how LOW a dosage of PCI may remain effective for at least some individuals.
WWW
Thank you all for the PCI comments. I have been holding my breath for a phase III for untreated and under 65 pts. Hope that’s part of your Christmas gift Chaya! Dr. Keating thought it would be this year or next. Everyone I’ve talked with on the drug has said the same thing, “I feel better than I have since I was diagnosed!” For me, that’s worth a substantial amount of risk…
CM
Chaya my husband was given a BMB on the CAL 101 trial, maybe because of his excellent response with cleared nodes (which started out quite huge) and cleared blood. I forget the exact numbers but his BM started out at about 90% in January and dropped to around 50% involvement in July. Unfortuneately he also got the dreaded lung inflammation in August, so has been off the drug since then.
Hi Guys –
Chaya, thank you for another excellent overview. And your sense of humor is priceless. I always find a good chuckle in your articles. I loved your comment about “treatment was well tolerated” and how much perspective changes when you are at the pointy end of the stick.
Brian & Lynn S (& all the posters) thank you for your thoughtful comments! I am always so grateful for the sharing & caring I find in the CLL community.
As someone with w/w CLL I am doing my homework about treatment options. I was dx Oct. 2009 as early stage w/w CLL (IgVH mutated, 13q14 (2x deletion in 71 % of nuclei). ZAP-70 negative).
This past year my WBC/Lymphocytes have increased from 17.1/10.4 to 43.8/39.0 so I am now w/w/w for watch/wait & worry. I feel fine (other than fatigue when I overdo it). I had a mild case of bronchitis last December 2010 after which my WBC/Lymph counts started to climb. However this past year I have been well.
I have a special interest in PCI-32765 as one of my terrific UCSD CLL docs has left UCSD to work for Pharmacyclics. At 69 I’m disappointed the ASH presentation said virtually nothing about the trial findings to date on the chemo-naive >65 group. Hopefully we’ll get some info on them sometime soon.
I’m sure we are all watching these PCI-32765 & CAL-101 trials hoping for an improvement and/or a breakthrough to add to the currently available treatment options.
Thank you again Chaya (Brian, Lynn & everyone). You are all a blessing to this w/w/w Cll gal.
Warm regards – Patti K
Lynn…I don’t think that you are giving enough credit to the very fine researchers behind these studies. If there were indications of an issue in an individual such as severe cytopenia (which might portend a problem such as your mother had) they would surely order a BMB as well as any other appropriate test. In the meantime doing BMBs on everyone when such patients continue to manifest disease (ie, enlarged nodes or CLL in the blood, whether detected by routine CBC or by flow cytometry)would likely cause more harm than good, apart from the financial cost, which, you must remember, is born by the patient and his insurance company.
Finally, let us be honest about this…no one expects these enzyme inhibitors to cure CLL. What we are asking for is a means to control the growth of the CLL clone. If this can be kept in check, we will have achieved a great deal.
Ia5275 .. Oh I have nothing but respect for these researchers and give them all the credit and gratitude I have !! I was just ruminating, putting myself in the researcher’s place, thinking I would want all the information available. I’m part of the NIH Natural History study and gladly have given my CLL and normal blood cells through blood draws, BMB, apheresis .. whatever they ask. I think most participants in trials are grateful to be there and would gladly do procedures for the good of the trial and for the greater good of all CLL-ers.
And as I said, I think we are looking at a new paradigm for these drugs and not the total “cure”. So we are in agreement on that.
Finally, perhaps I’m not understanding the complex relationship between the procedures that are laid out in a drug trial by the drug company and the research work in CLL that is concurrently taking place at these trial institutions. How much leeway does the institution have in adding elective procedures?
If I do participate in a PCI study at one of these institutions, I will ask for a before BMB and then another at a significant milestone and will share it. I’ve seen a post from a front line Revlimid patient who went from (if my memory is correct)83% to 58% CLL involvement in his marrow while his WBC went from 570k to normal. EBW reports a similar reduction in the marrow. So, even if the trials do not officially report marrow change, we can share amongst ourselves.
And I thank these researchers for moving ahead with this trial and look forward to reports on the untreated elderly arm as well.
To ALL who have posted here that are in clinical trials….THANK YOU! I have have been in several trials and I know that we go there with a large dose of hope in our hearts and brains and sometimes because it is the best option or only option for us.
As Chaya has said repeatedly over the years “there is no free lunch”. We have cancer, there will be a price that goes with that fact. We would all be thrilled with a drug that could stablize our disease without causing damage, long or short term to our other systems. Research and the drugs seem to be getting better and the curve of progress really has gotten steep compared to 2003 when I was first dx. Still for some it is not fast enough.
PCI 32765 is a exciting drug and is tempting. I love Chaya’s picture at the end of the article….fingers crossed. As a CLL’er facing some serious treatment choices (I received a happy but short 14 month remission from FCR) I so very much appreciate hearing from folks who are in these trials! When we can take your experiences and combine them with the abstracts , talk with CLL experts and gather additional information on line we are able to make a well informed
decisions regarding our therapy. You experiences and you willingness to share them is such an important part of this process. With great respect and appreciation, Thank You again!
Finally, if this site has helped you in any way please consider a donation to help support it. For purposes of clarity, I do count Chaya as a friend but beyond that she is one of the few out there who remains committed to our fight. She could of easily walked away years ago and no body would of blamed her but she stayed and works for our benefit. What a gift!
Happy Hoildays!!!
Thanks as always for your excellent work, Chaya. I too will have my fingers crossed!
Just an fyi: Below is the content of the last slide of Dr. O’Brien in the PCI/CLL presentation yesterday at the ASH. These slides are on the Pharmacyclics Web site.
” Acknowledgement
Thank you to all the patients who
participated in the study, their families,
all the clinical institutes and research
staff, and Pharmacyclics.”
Randle:
Thanks for posting Dr. O’Brien’s last slide. I am delighted to see it. Let us hope she sets the trend for other researchers to follow.
WillB425
Chaya, many thanks for the excellent updates. You are the GREATEST.
I almost forgot the time of year…and was about to go out and foolishly spend my annual donation on some expensive wine and a couple six-packs of Guinness (extra stout) beer. Gee…I feel healthier already.
Thanks again for all your helpful research.
Merry Christmas and Jolly Ho Ho Ho’s in 2012.
William Bates
I agree with Brian in his assessment of PCI 32765. I also agree patients don’t like BMB. My first hematolgist I went to see wanted to do an immediate BMB. I told him “Doc I have heard those things are very painful”. He told me it will not hurt HIM a bit, and he was serious. The nurse scheduling the BMB hinted to me I needed to get the BMB done somewhere else. The next place I went, to MAYO didn’t even want to do one. I have had one and wasn’t as bad as I had heard but if I was considering doing a trial, having to have several BMB could sway me. I had my BMB between rounds 5 and 6 of FCR and developed unknown infection with high fever that landed me in isolation hospitalized for 3-4 days-and this was right after the BMB. I have had 5 CT scans and don’t want more of those either. Anyway, looking forward to the Christmas present info.
“Thanks for posting Dr. O’Brien’s last slide. I am delighted to see it. Let us hope she sets the trend for other researchers to follow.”
Chaya:
Do you think all the discussions and mentions of a “simple thank you” to trial participants on this site had anything to do with the O’Brien/Pharmacyclics thank you? I do.
Keep talking and maybe others will listen to what we all have to say!
My husband is in this experimental group (840mg) and has had incredible results with little side effects. However, a minor deal with muscle cramps has progressed to the point where there are severe and frequent. He spent last night sitting up in a chair with bad cramps all night. We think that it must be related to the drug and have told the drs., but they feel it must be something else. I was wondering if anyone else has had these. My husband was told that there had been no reports of this, but my husband met another patient in the waiting room who was experincing the same thing. Anybody else have muscle cramps from this?
Maryheleny:
I will keep an ear to the ground regarding muscle cramps as an adverse effect with this drug. If I hear anything, I will send you a personal email. If there are at least two patients with this adverse effect, how can the researchers say they never heard of it? Makes me hopping mad…
Pharmacyclics has an animation of PCI-32765 at work at http://www.pharmacyclics.com/btk_inhibitors_animation.html
I am impressed with the quality of the posts, for which I am grateful. Hopefully I will not need this until many years to come (wishful thinking does not hurt), and enjoy learning how exciting research has become, only because they are finally closer to management of our disease.
Chaya, thank you forever.
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