ASCO 2012
ASCO (American Society of Clinical Oncology) is a big “F” deal. Every year, oncologists from around the world gather together to hear about the latest news in the cancer industry. It is an industry event, with lots of money, reputations and glory riding on the results disclosed at these annual meetings. Unlike ASH (American Society of Hematology – the industry group for blood cancers and diseases), ASCO caters to all cancers. As you can guess, much of the news pertains to the big solid cancers – breast cancer, prostate cancer, lung cancer etc.
But this year we have more than a smattering of important presentations dealing with the new crop of targeted kinase inhibitor trials. While the information is very interesting and I for one am keeping my fingers crossed for the success of these trials, these are all early stage trials – which makes the results not quite something you can hang your hat on. We will have to wait another year or two before we get to see Phase -3 trial results with larger groups of patients.
There were three papers on PCI-32765 (formal name ibrutinib, you might as well start getting familiar with it). After discussing the three abstracts, I decided to write a longish editorial section on stuff I am hearing as anecdotal stories from members. Since some of my concerns arising out of member feedback are not based on official clinical trial results, these are best discussed in an editorial section. As you may have noticed, companies are quick to highlight positive results, not so eager to publicize potential adverse effects.
Single agent PCI-32765 in chemo naive patients
The importance and quality of these papers is to be judged by the high profile researchers who are on the authors list. In this trial, patients who were older than 65 years and who had active CLL that had never been treated before but now needing therapy for the first time were recruited. This is an early stage study trying to determine the right dosage. 26 patients got 420mg per day, while 5 patients got double that, 840mg per day. It seems the higher dose did not show any better response and while they were not clear about it, there may have been some concerns about safety at the higher dose. Whatever, the higher dose was soon discontinued and now the standard dose for PCI-32765 is 420mg per day.
I would describe this patient group as somewhat long in the tooth – you know, the young-at-heart-crowd. Three fourths of the patients were more than 70 years old. Reflecting the need for start of therapy, there were significant percentage with poor platelet counts (less than 100K) and hemoglobin levels not quite in the pink (less than 11.0). A tad under 50% had unmutated IgVH (bad prognostic indication).
Adverse effects reported are moderate. only 10% had Grade 3 or higher infections or cytopenias (drop in platelet counts, red blood cell parameters, reduced neutrophil counts etc). More worrisome, non-blood related adverse effects – Grade 3 or higher – that could have been due to PCI-32765 were seen in 19% of patients. That is roughly one in five, with high grade adverse effects of one kind or another, not even counting the blood related adverse effects. I wish they had spelled out the exact nature of these high grade non-blood related adverse effects.
However, there is no question that PCI-32765 is a relatively easy drug to tolerate, especially when it is compared against chemoimmunotherapy combinations such as FCR or bendamustine combinations. Since a large percentage of CLL patients fall into over 70 crowd, and high impact therapy options such as FCR and B+R may be contraindicated for a variety of reasons, the kinder and gentler nature of PCI-32765 is a huge plus. For that reason, the age group of this particular study cohort is important to note. The researchers were wise in their inclusion criteria choices.
How well did the drug work? After all, kinder and gentler does not impress us unless it actually managed to bring about a good response. These are early days. We have results based on a mere 11 months of patients on the drug. There were 65% partial responses, 8% complete responses with no indication of CLL in the bone marrow either. Another 12% had reduction in the size of their lymph nodes, even if they still showed elevated counts in their blood. Doing the math, that leaves 15% out in the cold. Did these unlucky guys have stable disease or did they have progressive disease while on PCI-32765? We do not know. See what I mean about these abstracts not quite volunteering information about the more squishy side of the results?
The Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study.
ASCO 2012. Abstract No: 6507
Author(s): John C. Byrd, Richard R. Furman, Steven E. Coutre, Jan Andreas Burger, Kristie A. Blum, Jeff Porter Sharman, Ian W. Flinn, Barbara W. Grant, Nyla A. Heerema, Amy J Johnson, Tasheda Navarro, Danelle Frances James, Eric Hedrick, Susan Mary O’Brien; The Ohio State University Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Solove Research Institute, Columbus, OH; Weill Cornell Medical College, New York, NY; Stanford University School of Medicine, Stanford, CA; University of Texas M. D. Anderson Cancer Center, Houston, TX; The Ohio State University, Columbus, OH; Willamette Valley Cancer Institute and Research Center, Eugene, OR; Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; University of Vermont College of Medicine/Fletcher Allen Health Care, Burlington, VT; Pharmacyclics, Sunnyvale, CA; Pharmacyclics, Summit, NJ
Background: Fludarabine based therapy, while effective, carries significant risk of morbidity and mortality in the elderly pts. As such, older CLL pts represent a high priority for new therapeutic approaches. PCI-32765 (P) an oral, selective, irreversible inhibitor of BTK inhibits CLL cell proliferation, migration and adhesion. A multi-cohort Phase Ib/II trial evaluated 2 doses of single-agent P in both TN and relapsed/ refractory (R/R) CLL/SLL pts. Mature follow-up of the TN pts is reported. Methods: Pts >65 yrs old with active CLL requiring Tx by IWCLL guidelines were treated with oral P at doses of 420 mg or 840 mg administered daily for 28-day cycles until disease progression (PD). Response was evaluated according to 2008 IWCLL criteria. Results: 31 pts were enrolled- 26 pts (420mg) and 5 pts (840 mg). The 840 mg cohort was terminated after comparable activity and safety between doses was shown in R/R pts. Median age 71 yrs (range 65-84) with 74% of pts >70 yrs. 19/31 (61%) had baseline cytopenias (Hgb < 11g/dl or plts <100,000). Unmutated IgVH was present in 43% of pts. The majority of AEs have been Gr<=2 in severity, most commonly diarrhea, nausea, and fatigue. Gr >3 non-heme AEs potentially related to P in 19% of pts. 10% of pts experienced Gr >3 infections or cytopenias. With a median follow-up of 10.7 mos on 420 mg cohort 73% (19/26) achieved a response by IWCLL criteria with 65% partial responses (PR) and 8% complete remissions with no morphologic evidence of CLL on marrow. An additional 12% (3/26) of pts achieved nodal responses (NR) with lymphocytosis. Median follow-up in the 840 mg cohort is 4.6 mo, at 2 cycle assessment 2/5 achieved a PR and 1 pt with a NR. ORR was independent of high risk factors. 84% of pts remain on study, reasons for discontinuation = AE (3), investigator decision (1) and PD (1). There have been no deaths. Estimated 12 mo median PFS for the 420 mg cohort is 93%. Conclusions: PCI-32765 is highly active and well tolerated in elderly TN CLL pts. The high ORR, including marrow clearance and very low PD rate with the single agent suggests that P warrants further study as a first-line treatment approach in elderly pts.
Combination of PCI-32765 with ofatumumab
This too is an early stage study, looking to see if combination of PCI-32765 with a second generation monoclonal antibody such as ofatumumab works better; interesting and logical extension of single agent PCI-32765 studies of the type reviewed in the abstract above.
We know now that this kinase inhibitor (similar to the other kinase inhibitor in the news, CAL-101) works by disrupting the signaling pathways of B-cells, thereby kicking them out of their protected niches in swollen lymph nodes, spleen etc. In fact, patients often see higher white blood counts in their blood work soon after start of ibrutinib therapy. So, it makes sense to pair this kinase inhibitor with another drug that does a good job of killing CLL cells once they are out in open blood circulation. Flush the little buggers out of their protective homes, then kill them while they are vulnerable and exposed – that is the game plan.
Many of you are familiar with ofatumumab (also known as Arzerra, or the earlier name Humax-CD20). Think of it as the next generation version of Rituxan. It too target CD20 marker present on all mature B-cells (not just CLL cells). Fortunately for people who develop allergic responses to the mouse component of Rituxan, ofatumumab is fully humanized monoclonal, mo whiff of mouse protein.
Unlike the previous abstract, this study recruited previously treated patients. In fact, all the patients had 2 or more prior therapies under their belt, all of them had exposure to stuff like fludarabine. In addition to garden variety CLL, they also recruited patients with SLL or PLL (prolymphocytic leukemia). There were even 3 patients with the dreaded Richter’s transformation. 10 out of the 27 patients had the high risk (FISH) deletion of 17p deletion, while another 9 had 11q deletion. More than half had bulky lymph nodes, and 11/27 patients were refractory to fludarabine. All in all, about as tough a crowd as one can gather, with not too many good therapy options open to them outside of clinical trials such as this. That must be kept in mind while evaluating results and adverse effects.
Ibrutinib was given at the now standard dose of 420mg daily. Each cycle consisted of 4 weeks. Ofatumumab was initiated in the second cycle, with 2000mg of the monoclonal infused start of each week for the second and third cycles. (The very first infusion of ofatumumab in the first week of the second cycle was a reduced dose of 300mg). After these initial 8 infusions of ofatumumab, infusions were given only once each cycle, on the first day of the cycle.
Impressively, after completion of 6 cycles (24 weeks) all of the CLL/SLL/PLL patients had responded, and even 2/3 Richter’s transformed patients responded. This is truly encouraging news, given the advanced disease status of these patients and their poor prognostic indicators. For the majority of these guys FCR would have been contraindicated and would have done precious little in any case. After 6.5 months, fully 23/24 CLL/SLL/PLL patients are still in the study. Unfortunately, two of the three Richter’s transformed patients had disease progression. Bummer indeed. There were moderate number of high grade (3-4) adverse effects, 11% anemia, 11% pneumonia, 7% urinary tract infections. All in all, encouraging news in a patient cohort with few better options.
A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and related diseases.
ASCO 2012. Abstract No: 6508
Author(s): Samantha Mary Jaglowski, Jeffrey Alan Jones, Joseph M. Flynn, Leslie A. Andritsos, Kami J. Maddocks, Kristie A. Blum, Michael R. Grever, Susan Michelle Geyer, Jennifer Ann Woyach, Amy J Johnson, Nyla A. Heerema, Erin Molnar, Mona Stefanos, Susan Devlin, Tasheda Navarro, Danelle Frances James, Ann M. Lowe, Eric Hedrick, John C. Byrd; The Ohio State University, Columbus, OH; Pharmacyclics, Sunnyvale, CA
Background: Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that is critical for B-cell receptor (BCR) signaling in normal and malignant B lymphocytes. PCI-32765 (P), an oral, potent and irreversible BTK inhibitor, antagonizes BCR signaling in CLL cells and abrogates protective features of the microenvironment. P is highly active as a single agent in CLL/SLL patients (pts), and this phase Ib/II study builds upon single-agent experience by combining P with ofatumumab (O), an anti-CD20 monoclonal antibody. We present initial safety and efficacy data from cohort 1. Methods: Pts with relapsed/refractory (R/R) CLL/SLL following ≥2 prior therapies (Tx), including a purine-nucleoside analog (PA), are treated with 420 mg P daily, in 28-day cycles, until disease progression. O is added at a dose of 300 mg on day (D) 1 of cycle 2, followed by 2000 mg on D8, 15, and 22 of cycle 2, D1, 8, 15, and 22 of cycle 3, and on D1 of cycles 5-8. Results: As of November 2011, 27 patients with either CLL/SLL/PLL (n=24) or Richter’s transformation (RT, n=3) have been enrolled and have received at least 6 cycles of treatment. The median age is 66 (range 51-85), 9 were Rai stage III/IV. Median number of prior Tx is 3 (range 2-10), 15 pts had bulky disease (> 5 cm); 11 pts were PA refractory. Poor-risk molecular features were common (del(17p) 10 pts, del(11q) 9 pts). No grade (G) 3 or 4 infusion reactions, neutropenia, or thrombocytopenia have been observed. The majority of adverse events (AE) were G1/2. G3/4 AE included anemia (11%), pneumonia (11%), UTI (7%), hyponatremia (7%). 24/24 CLL/SLL/PLL pts have achieved PR (100% ORR) within 6 cycles; 2/3 RT pts had PR. With median follow-up of 6.5 mo (range 5.3-10.2 mo), 23 CLL/SLL/PLL pts and 1 RT pt remain on study; 1 CLL/SLL pt went to transplant in PR; 2 RT pts progressed. Conclusions: PCI-32765 combined with ofatumumab is well tolerated and highly active (100% ORR) in pts with heavily pre-treated R/R CLL/SLL. Rapid onset of response, low relapse rate, and favorable safety profile make this combination worthy of further study. Cohorts evaluating other Tx sequences are currently underway.
Combination of PCI-32765 with bendamustine and Rituxan
You could almost have predicted some one would start this clinical trial. If PCI-32765 is good alone, better with a monoclonal thrown in for good measure, would it best when served along with a conventional chemotherapy drug such as bendamustine? True, this would take away some of the “easily tolerable” cachet – since bendamustine packs as much of punch as any other chemotherapy drug out there – but I think most oncologists just cannot resist the temptation of piling on more drugs to increase the impact of their favorite drug regimens. I think FCR + PCI-32765 and similar alphabet soup combinations will soon come to an expert center near you.
Since this article is getting longer and longer, I will not belabor the details – which are highlighted below in the abstract anyway. Basically, the cohort is an older and relapsed or refractory group of patients with late stage CLL with few good therapy options left to them. In addition to the now standard dose of 420mg daily dose of PCI-32765, patients also got the usual doses of bendamustine and Rituxan. Response rate was impressive. But so too was the adverse effect profile, as would be expected from this bendamustine containing regimen. Of note, two out of the 30 recruited patients suffered tumor lysis, an indication of the rate of cell kill with this aggressive therapy combination. “Adverse events (AE) have been consistent with that expected with BR” say the researchers. What else is new. Frankly, addition of BR makes this drug combination not-so-patient-friendly. If you are contra-indicated for BR to begin with, PCI-32765 + BR is not going to be right for you either.
Combination of the Bruton’s tyrosine kinase (BTK) inhibitor PCI-32765 with bendamustine (B)/rituximab (R) (BR) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase Ib/II study.
ASCO 2012. Abstract No: 6515
Author(s): Susan Mary O’Brien, Jacqueline Claudia Barrientos, Ian W. Flinn, Paul M. Barr, Jan Andreas Burger, Tasheda Navarro, Danelle Frances James, Eric Hedrick, Jonathan W. Friedberg, Jennifer R. Brown; University of Texas M. D. Anderson Cancer Center, Houston, TX; Long Island Jewish Medical Center, Hyde Park, NY; Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; Case Western Reserve University School of Medicine, Cleveland, OH; Pharmacyclics, Sunnyvale, CA; Pharmacyclics, Summit, NJ; Hematology/Oncology Division, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY; Dana-Farber Cancer Institute, Boston, MA
Background: BTK is an essential mediator of B cell receptor signaling and a critical kinase for lymphoma cell survival. PCI-32765 (P), an oral, selective, irreversible inhibitor of BTK, inhibits proliferation, migration and adhesion in CLL cells, and is highly active as a single agent for the treatment of R/R CLL pts. (O’Brien ASH 2011). BR produces an overall response rate (ORR) of 59% in R/R CLL (Fischer JCO 2011). We report interim data on P combined with BR. Methods: R/R CLL pts received P 420 mg orally daily for 28-day (D) cycles (C) until disease progression (PD). B was administered 70 mg/m2 on D1 and D2 combined with R 375 mg/m2 on D0 for C1 and 500 mg/m2 on D1 for subsequent courses for a maximum of 6 cycles. Response was evaluated according to IWCLL criteria. Results: 30 pts were enrolled. Median age of pts was 62 yrs (range 41-82). 46% of pts were Rai stage III/IV and the median # of prior therapies was 2 (range 1-4). 37% and 13% were considered refractory (treatment free interval <12 mo) to a purine analog containing regimen or BR, respectively. Bulky disease was present in 52%. Adverse events (AE) have been consistent with that expected with BR. Gr 3/4 neutropenia and thrombocytopenia have been noted in 47% and 10% of pts, respectively. Grade >3 non-hematologic AEs potentially related to P included rash (3 pts) and fatigue and tumor lysis reported in 2 pts each. There were no Gr 3/4 infusion reactions. There have been no discontinuations (D/C) due to AE and no deaths on study. At a median follow-up of 4.9 mos (range 2.7-8.3 mo) 16 pts have completed BR and 14 pts are still receiving BR. The ORR is 90% (27/30 pts) (CR 10%, PR 80%). 2 additional pts achieved a nodal response with residual lymphocytosis. Responses appear independent of high-risk clinical or genomic features. 90% of pts remain on study; reasons for D/C include PD (n=2) and 1 pt pursuing SCT. Conclusions: PCI-32765, in combination with BR, is highly active. The high ORR, low rate of PD, and good tolerability compares very favorably with historical controls, warranting additional investigation of this combination.
Editorial
Let us give this new drug its due credit. It has shown remarkable activity in older patients, high risk patients, relapsed and/or refractory patients with bulky disease that is hard to treat. This is precisely what our patient community needs right now, drugs that work well in segments of our community that have run out of other, more conventional therapy options. I have no doubt that PCI-32765 and future generations of other kinase inhibitor drugs will change the paradigm for treating late stage and elderly CLL patients, increasing both quality and quantity of life for this segment of the patient population.
That said, I would like to share some concerns with you. It seems that once the drug is discontinued, relapse happens pretty darned quickly. We are not talking of remissions that last months if not years. People who quit taking the drug start to see their lymph nodes popping back and making their presence felt within a mere week or two. So, basically we are looking at taking drugs such as this daily, on an indefinite basis. Best as I can tell, this is the case both for PCI-32765 as well as CAL-101.
So, that brings us to the next couple of questions. How safe are these drugs as long term maintenance drugs? I will not even attempt to address a very real life concern about the dollar cost of being on these drugs daily, for years and years. We do not know exactly how much they will cost, but I think it is a safe bet they are not going to be cheap. Another question I will not attempt to answer is the long term efficacy of these drugs, since we do not have enough information on which to base even a guess. Cancer cells have a way of learning new tricks, giving them the ability to become drug resistant after some time. Will CLL cells learn to scoff at these new kinase inhibitors? I do not know, I hope that is not the case.
Since I cannot talk about affordability or long term efficacy (yet), I will restrict myself to the safety issues. I have already highlighted the issues recorded in the published abstracts. Let me now focus on one specific concern that has not been talked about much, but one that has caught my attention based on feedback from my members.
Here is the skinny, without a lot of complicated science to confuse things. PCI-32765 is a BTK (Bruton tyrosine kinase) inhibitor. This kinase is important in the way B-cells communicate. Messing up their ability to talk to each other as well as their environment makes the cells isolated and vulnerable, easier to kill. That is the good news.
Now for the bad news. BTK pathways are important not just in B-cell communication, they are are important in a number of crucial other functions of the body as well. We will focus for now on one particular pathway that needs proper function of BTK. It seems platelets need functioning BTK before they can do their job properly. In a nutshell, healthy platelets are able to respond to any injury to blood vessels, seal off the cut with a tiny smidge of clumped platelets or ‘thrombus’. This ability of platelets forming a little clot is essential for the cessation of bleeding. If you nick yourself while shaving, even if you do nothing to stop it, most often the bleeding will stop on its own; that is, it will do so if you have healthy number of platelets and they are functioning properly.
Many of our guys have problems with inadequate numbers of platelets to begin with, courtesy of the underlying CLL. Now on top of that, if there is worry that daily dose of PCI-32765 inhibits BTK function across the board (as it is supposed to do), and this interferes with platelets being able to do their job, we may well have bit of a problem. I am not talking of slightly longer time bleeding when you cut yourself shaving. How about internal bleeding that goes unnoticed? This can happen in your GI tract, in your lungs and throat if you cough violently and last but by no means least, in your brain. Micro ruptures of this sort pose no problem when people have well functioning platelets. But what about the situation when this crucial function is degraded due to BTK inhibition? Most of you are smart enough to keep an eye on platelet counts. But now, we are talking of people with reasonably OK platelet numbers, but who may still be at risk if the platelets they do have are not able to do their job properly, on account of BTK inhibition.
The role of proper BTK function in platelets ability to form necessary clumps and thereby stop bleeding has been reported before, in prestigious journals. I have attached one such report below – there are many others. The science gets a bit hairy, but do read if you are inclined to do so. Importance of BTK pathway in platelet function is sufficiently important that researchers have suggested BTK inhibitors can be used to protect folks from excessive blood clotting and therefore thrombosis risk! Too much clot formation is not a good thing. But so is too little clot formation capability – the ever-present Goldilocks dilemma.
Blood. 2006 Oct 15;108(8):2596-603. Epub 2006 Jun 20.
Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo.
Liu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK.
Department of Biology, University of Memphis, Memphis, TN 38152, USA.
Botrocetin (bt)-facilitated binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein (GP) Ib-IX-V complex on platelets in suspension initiates a signaling cascade that causes alphaIIbbeta3 activation and platelet aggregation. Previous work has demonstrated that bt/VWF-mediated agglutination activates alphaIIbbeta3 and elicits ATP secretion in a thromboxane A2 (TxA2)-dependent manner. The signaling that results in TxA2 production was shown to be initiated by Lyn, enhanced by Src, and propagated through Syk, SLP-76, PI3K, PLCgamma2, and PKC. Here, we demonstrate that the signaling elicited by GPIb-mediated agglutination that results in TxA2 production is dependent on Bruton tyrosine kinase (Btk). The results demonstrate that Btk is downstream of Lyn, Syk, SLP-76, and PI3K; upstream of ERK1/2, PLCgamma2, and PKC; and greatly enhances Akt phosphorylation. The relationship(s), if any, between ERK1/2, PLCgamma2, and PKC were not elucidated. The requirement for Btk and TxA2 receptor function in GPIb-dependent arterial thrombosis was confirmed in vivo by characterizing blood flow in ferric chloride-treated mouse carotid arteries. These results demonstrate that the Btk family kinase, Tec, cannot provide the function(s) missing because of the absence of Btk and that Btk is essential for both bt/VWF-mediated agglutination-induced TxA2 production and GPIb-dependent stable arterial thrombus formation in vivo.
PMID: 16788103
Several cases of intra-cranial bleeding in patients taking PCI-32765 have come to my attention. Scary stuff. As you would expect, the risk is highest in people who are on BTK inhibitors such as PCI-32765 as well as blood thinner such as heparin, coumadin etc for other medical reasons. So much so that newer PCI-32765 clinical trials are making this an exclusion factor. If you have an artificial heart valve, for example, that needs daily dose of coumadin, you are likely to be ineligible for PCI-32765 therapy. If you need heparin to treat DVT (deep vein thrombosis), you must wait until the heparin therapy is complete and it can be assumed to be safely out of your system. How about less dramatic blood thinners? How about the daily aspirin, fish oil or green tea extract capsules? All of these are known to decrease – to various degrees – platelets ability to come together and clot as needed, when there is a blood vessel rupture and bleeding starts.
While there is no official word on it, I have begun to encourage members to discontinue (or discuss discontinuing) over the counter supplements such as daily aspirin, green tea and fish oil capsules. How about stuff like Plavix, a drug that is often prescribed to patients at risk of stroke? It too is a “blood thinner”, it is used precisely because it reduces the ability of platelets to clot. Should you be on Plavix if you are going to be on PCI-32765 as well? Talk to your doctor and your clinical trial researcher, before you make decisions on important stuff such as this. I am doing no more than bring the worry to the surface, I am by no means qualified to give you medical advice.
For now, here is my two cents of advice, cheap at the price. Talk to your doctors about each of the blood thinners identified above, if you are taking any of them. Second, try and avoid bruising yourself. You might notice that the bruises are much more dramatic while you are on PCI-32765, since it takes longer for the platelets to stop the bleeding under your skin and the pooling blood forms a bigger and more colorful bruise. This may not be a good time to get truly deep tissue massage. I am not an expert on this since I have never had one, but I would worry about potential micro tears it may cause to blood vessels deep inside. If you do bang yourself up and are inclined to use any of the off-the-shelf potions and ointments on the bruise to ‘make it go away’, please don’t. Most of these ointments work by trying to dissolve the clot – thinning the blood. Who knows if this would make the situation worse, if you already have low platelet counts, and you are on PCI-32765 therapy to boot. (I have heard from one member who did precisely this, you know who you are. Please feel free to kick yourself in the rear-end,ever so gently – so you do not cause additional bruising.)
All in all, I am beginning to be concerned about this – mainly because the value of BTK kinase inhibition by drugs such as PCI-32765 rests with their use on a long term basis. We just don’t know enough about the adverse effect profile of all the things that can go haywire with long term BTK inhibition.
As always, it is important not to throw the baby out with the bathwater. This new generation of kinase inhibitors have given us much needed hope in treating older patients, patients with poor prognosis. I hear people with 17p deletions are responding much better than can be expected to PCI-32765. That is truly wonderful news. But we also need to keep in mind these are early days. We do not know the full adverse effect profile. Degraded platelet function is a serious concern for me, especially if it is enough to trigger significant internal bleeding. Does this adverse effect become worse over time, as patients take the kinase inhibitor drug for longer and longer periods? Do higher doses make the problem more serious? How about people who must be on blood thinners for other medical conditions? How low can the platelet count be before it becomes a real contraindication to take BTK inhibitors?
Keep your eyes peeled, your mind open to both the positive news and reasonable adverse effect concerns. Your best protection is credible information. At this point, they are just my concerns and they have not been officially reported yet in any papers that I am aware of – hence my decision to report them in the editorial section of this article. I will let you be the judge of the credibility of my concerns.
RSS Feed
46 comments on "PCI-32765 (ibrutinib): What We Know Thus Far"
Sounds like so much rat poison. I hope the scientists discover, test and release a gentle effective treatment soon. CLL cells have several Achilles’ heels as does the bone marrow.
Perhaps an aspect of the faulty stem cells can be treated before they turn into CLL cells?
I feel incredibly lucky to have been admitted to the NIH Ibrutinib trial, beginning February 16. Compared to the alternatives I evaluated—pros and cons of each—this option seems miraculous with (in my case) no troublesome or yet-discernible side effects. I offer my own experience (pre- and post-Ibrutinib) at http://alanrknight.blogspot.com with no thought that it would be the same for everyone else.
Good information and a very important reminder that we do not know what the future holds with a brand new drug. Thanks for the heads up. We need to go into these trials with our eyes open.
Wow Chaya!!! What an elucidating description of some possible obstacleHs to completely relying on these new kinase inhibitors. The fact that CLL might be treated as a chronic disease requiring faily meds doesn’t concern me unless the meds themselves become problematic.
As I reach the possible end of watch and wait, with an 11q and unmutated, careful evaluation of the options available has left me confused amd worried. Thinking the NIH study might be the answer and reading your editorial puts me back to rituxan as a single agent. Thanks for such an insightful editorial.
Best wishes…….Linda Q
Donut
No, it is definitely NOT rat poison. For the many patients with poor prognostics and not many good therapy choices, these new kinase inhibitors have been a welcome development. I am very serious when I say please do not throw the baby out with the bathwater. CLL is a nuanced disease and we need to be careful in how we evaluate our options.
By the way, no one has clearly established there is a faulty stem cell that is causing CLL. Devil is in the details!!!
Thanks for the news and your thoughtful comments. PCI-32765 is encouraging to us 17p types but it does have a long way to go in trials. However, Johnson & Johnson has jumped in to the tune of $150M to aid in the development and marketing so I take it to be more than rat poison.
Good to know, Chaya.
Reading or hearing the descriptions of possible side effects of prescription medications often brings that analogy to mind. Prescribing medication is not for amateurs.
Tom has now been on ibrutinib, PCI32765 for 18 months. The one time he had to quit taking his daily pill, his lymph glands everywhere swelled up in 2 days. Not a week, 2 days. MD Anderson will state that there is no remission hold with this treatment. The up side is that he has felt better on ibrutinib than any other treatment. It has done a wondrous job of keeping his lymph glands down. We both feel very lucky to be in this trial. There is a down side though. His platelets are not doing a very good job and he has purpura, petichea and bruises a purple color at the touch of a bump! As time goes on with ibrutinib, we are seeing a slight left shift in his blood counts. By slight, I mean that 2-3 monthly CBC’s will show red counts and platelets trending lower and then a couple of monthly CBC’s will show that they are stable and then the lowering will start again. So, slowly, the left shift is happening.
The other side of down with ibtutinib is his terrible heartburn. Acid reflux to the max. Nothing has seemed to help and this is also getting slightly worse with each continuing month on treatment. Still, quality of life is so much better than before ibrutinib that it is worth the maintenance.
Your article is so timely and I thank you for all the work you are doing for out benefit. I find it difficult to find many articles on Ibrutinib and heartburn. I wonder if some trial patient’s fear rejection from the trial if they voice too many side effects. I know that I have wondered this many times myself.
Jenny Lou Park
Thank you for taking the time and risk to give us your
‘down-low” on this new drug. It comes just before my husband’s next oncology appointment where decisions need to be made. He seems to fit the description for this drug in every way except age – much younger. I’m not sure if long term maintenance would be something the doctors would think feasible. And yet, the lymph nodes are quite large right now and not responding to other drugs we’ve tried.
Thank you again for all you do for the CLL/SLL population. It’s truly a blessing for us.
Debie
Thanks, Chaya, for your hard work and helping to put it all in perspective. Nothing is ever perfect but it seems, for some people, we may be making progress.
Best regards,
Rick
Another Ibrutinib-er aka PCI-32765-er reporting in. Compared to Tom and others, I’m a newbie just about to complete my 2nd cycle on this amazing drug. I entered the NIH mono-therapy trial as an untreated > 65 patient. Knock on wood, my side effects have been minimal so far: easier bruising and mouth sores. I have read of others having the heartburn on various forums, but have not been there myself. However, at the beginning of my treatment, I had to visit the NIH ENT clinic for a cough and bleeding (not because of the drug, but because of a toxic apartment in DC .. another story I won’t bore you with.) Anyway, during my scoping they spotted that I had silent acid reflux and put me on generic prolisec so that may be keeping the heartburn at bay.
What has amazed me is the almost immediate reduction of my WBC and ALC. I started with 342k and 331k and two weeks ago my labs showed WBC = 207k and ALC = 201k. So that reduction was achieved in 6 weeks. My platelets went from just over 100k to 146k, but as Chaya points out, we don’t know about their functioning. NIH however is doing a platelet function measurement each month, with an ADP and EPI measurement. Mine is still in the normal range. My BMB has gone from 2.6 to 1.8.
On Wednesday I will get my end of cycle 2 labs and have also volunteered for another BMB so well report back on that as well as my CT scan. I’m very curious how the drug is affecting my marrow, so will have the “on entry” result to compare with my cycle two result. More to follow.
I think it’s very important that we lab rats share our stories with other CLL patients and with each other as this provides an important anecdotal qualitative view of this experimental drug.
I’m thrilled to be on this trial and to have been on the Natural History Study at NIH before this. I have Chaya to thank for letting me know about the initial study that then allowed me to segue into the trial. I see too many of my CLL brothers and sisters having bone marrow challenges after chemo and, given my late mom’s aplastic anemia, I knew I would take an alternative if offered.
Not only may platelets be involved as BTK is expressed on reticulocytes, the progenitors of RBCs as well.
I am a part of the R/R lab-rat crowd and started on 420mg of PCI – monotherapy June 2011. Soon after starting I had a major dry eye condition begin and 2 months into the Trial I was experiencing A-Fib and right atrial flutter to the degree that put me into the hospital for an ablation of the right atria. In the hospital I consulted with DR. Byrd and stopped taking PCI, prior to the ablation. I was put on Heparin and given a lovenox shot upon leaving the hospital. All toll I was off PCI for 4 days. OK – is everybody scared enough yet? Let’s develop some context and perspective.
My real “rat poison” was Rituximab and Fludarabine. I had little choice in options that I liked after nearly dying from RF and R monotherapy. My heart problems were part genetic and part I believe induced by Fludarabine and Rituximab. The severe dry eye was not seen in other of my fellow lab rats and coincidentally or maybe not, it manifested acutely in my right eye which had been where a post Rituxan infusion acute sinus attack had put me on a couch for a couple of days. Both on the right side with the same sinus pressure as with the Rituxan related incident.
When leaving the hospital from my right atrial ablation I was urge by my cardio docs to go on a bloodthinner with Coumadin being mentioned. At that time no patient had died from hemorrhage but I was aware that bruising and lowered platelets were being seen. There were 27 patients in my arm of PCI Trial. I declined bloodthinners except for taking one 325mg Aspirin for every day of the first month post ablation when the risk of clotting is highest. I had no problem with any bruising or bleeding that I could notice. One patient in a PCI Trial that I briefly met had had a CMV activation which altered the prophylaxis part of the protocol to include the taking of 1 gram Valtrex daily. I was also put on a cyclosporin based eye drop “Restasis” for the dry eye. A-Fibs persisted and became worse to the point of my nearly passing out every other day this May. Dr. Byrd indicated that I might have to go off PCI unless I got the heart to straighten out.
I was between a rock and a heart place:-). An ablation of the left atria would have necessitated longterm anti-coagulation with Coumadin forcing me off Trial. Given my generally low risk for clotting risk and my history for surviving my Sept. ablation I opted for an AV node ablation and a Pacemaker. Dr. Byrd helped to get me an interview with the head of the electrophysiology dept. at OSU and again I was taken off PCI for a few days until the procedure was completed. Again I went on 325mg of aspirin and took it almost one month but noticed a bruise i did not remember getting on my right elbow. I reduced my aspirin to 81mg per day and may continue that as the left A-Fibs are still ongoing.
Chaya, you have often told us that there is no free lunch and I would agree. My experience with PCI has so far been an easy to say ‘glad I did it’. The drug for me was an easy to take therapy that made me feel free of an aggressive CLL for the first time since 2006. My dry eye has resolved to the point where I have not used Restasis in almost two weeks. If I had a choice to redesign my therapy strategy from the git-go, given the hindsight of my experience to include the dry eye and heart dysfunction possibility, I would opt for PCI as a frontline option in a heart beat, my tachycardia not withstanding.
By a math formula given to me by Dr. Byrd, we rats on PCI monotherapy could expect to see numerically normal lymphocyte counts happen on a schedule of 11% per month drop, calculated from the time of first taking PCI and using the highest ALC count (lymphocytosis occurs on PCI) as a starting level. I was a concern in that scenario, for awhile, after my first ablation last Sept. as my ALC just hung in at around 50K for several months but then it began to drop and put me squarely on track with the formula. As I write this, I am half way through my 14th 28 day cycle and if the formula plays out, I should be in numerically normal ALC counts by end of cycle 17. But to be honest, I don’t care. I began feeling good regarding the symptoms of having CLL after a very short time on PCI when my ALC was climbing! As my ALC approaches normal counts is it a coincidence that my dry eye is now resolved? Are many of our condiment ills as opposed to the main course of CLL “B” symptoms caused by the cancer cells activities in the peripheral blood? What will be the longterm judgment on PCI? who knows? I’ll take the “Free-of-cancer-feeling” as long as I can and hope there will be a better rock to jump on when and if the time comes.
great review,
Hope this finds you and Radha doing well,
WWW
Jlou:
It probably wont surprise you to hear your husband Tom is not the only one to experience massive problems with heart-burn. No official explanation of this adverse effect, yet.
If I may be so bold, I have a possible explanation / hypothesis for the heart-burn. This too can be a consequence of poor platelet function. All of us have micro tears in our GI tract, including our stomachs, part of normal wear and tear. If these micro ruptures are not quickly repaired, allowing gastric acid to seep into the surrounding tissues and further irritate them, we are looking at micro lesions – think of them as tiny little ulcers – that can cause massive amounts of pain. This type of heart burn is not likely to respond to conventional heartburn medications, which are all geared to trying and reducing the amount of acid produced. If there are micro lesions, even the smallest amount of stomach acid will be enough to set it off. Any one who has Crohn’s disease or ulcerative colitis (I am one of them) is only too familiar with the pain of unhealed ulcers in the stomach and GI tract.
Another area of concern is that I am beginning to hear from several patients with mouth sores. Some of these guys are already on Acyclovir or some other such anti-herpes medications. So, there seems to be something different about these mouth sores, they are not quite like the garden variety Herpes sores. Again, the explanation could be micro tears in the lining of the mouth that are not fixed soon enough by platelet clumping, allowing infection of the tiny wound with one the zillions of pathogens in our mouths. Scrupulous oral hygiene and using a soft toothbrush that does not cause scratches seems to be indicated.
As I said, these are just some ideas I have been mulling around in my head – nothing to guarantee they are right.
I do appreciate this site very much and the provocative discussions and comments. It really is a good complement to the oncologists who work so hard for so many that they can’t possibly explain all of this to everyone. I am getting very familiar with this subject from a biological as well as psychosocial perspective. The articles have addressed both aspects of the disorder. Certainly, we see less of a focus on psychosocial manifestations of the disorder which is a reflection of our society at large, which pays less attention to the psychosocial components of all disorders (unless they manifest themselves in primarily psychiatric ways) than to the biological components. We certainly have seen where there is no gross sign that a psychological approach could alter the course of many biological processes such as CLL, but I can’t help but wonder whether there might not be some central signalling process that has yet to be uncovered. Since we now know that 96% of the universe is hidden from view, why should we not expect our brains with 10 billion neurons to have some control over whether a gene turns on or off? Of course, there are reports of people’s cancers beginning or relapsing under stressful circumstances. That is not to say that the underlying biology was not present. But, latent and manifest are two different things, and there could be huge differences in outcomes if what was latent never became manifest in the first place, i.e Chaya; does every single person with the CLL genetic makeup manifest the disease? Are there studies on this? Oh well. Some musings which most people will definitely reject, but which nevertheless might interest a few.
Still on W & W and getting educated. Thanks to you and all responders and active testers. You are my heros and teachers.
I always feel a little guilty asking naive questions as a ‘watch and wait’ patient when so many people here are obviously facing very heavy-duty challenges and choices but I woud be interested to hear a little more on your thoughts about discontinuing green tea and fish oils. I have been investing in quality green tea extracts over the past few years and they certainly seem to help keep the white cell counts relatively steady, compared with a six-month period when I experimented with discontinuing. I also take fish oils to help a troublesome neck vertebra (and because they are always promoted as so good for health in a number of ways). Are you suggesting they may be a problem for all or only for those on active treatments?
Thanks for featuring this, Chaya.
I’ve been on the ibrutinib-ofatumumab trial at OSU since last May, currently in Cycle 15 – which means that since December I’ve been on ibrutinib-only. ALC has changed from about 180K at the start, a climb for several weeks, then steady drop and has been below normal since December. Have had some neutropenia but not serious enough to discontinue drug. Hgb has been steadily OK. My platelets have been below normal for years and I barely had enough to qualify for the trial (minimum 30K) at the start so I was elated when they rose to normal after two months (about midway through the weekly ofat infusions). But… then they dropped steadily, back to where they started, before returning and stabilizing in the 70s. Spleen which had bothered me for years has shrunk to near normal size. Side effects have included some diarrhea and the bruising that others have mentioned. As Jenny Lou observed, it takes the merest scrape or bump to produce a deep and lasting bruise. I have not been troubled with heartburn except a bit at the start and recently when a new gastroenterologist recommended I switch from generic prevacid to OTC Zantac. After experiencing heartburn like I’d never known, I switched back to prevacid, twice a day, and the heartburn is gone (but the risk of long-term prevacid use remains).
Overall, it’s been a relatively easy course (other than the commute to Columbus!) and the results are remarkably good. I do hope they figure out what the story is with ibrutinib and platelets.
Betsy
juliah1:
The concern about taking baby aspirin, fish oil or green tea extracts is only if the patient has (1) low platelet counts (2) and /or is contemplating therapy with a drug such as ibrutinib that may reduce the proper function of platelets as well. If you are still in W&W and your platelet counts are in healthy range, no reason to worry. In any case, you should be checking with your oncologist to make sure each and every supplement you are taking is OK with him/her. Don’t feel in the least bit guilty about asking questions. All of us started early stage at one point or the other and as we progressed, we learned more about the disease by asking questions.
I am a 72 year old male who was diagnosed with CLL at Christmas 2007, went through chemo and was in remission until July, 2010. Lucky for me I found Dr. Byrd and PCI. Tuesday, July 10 will complete 2 years on PCI and things are great. I also have A-Fib and take one aspirin a day. I have bruising but can’t tell if it’s from the PCI or the aspirin. It looks bad but seems to have now lasting problems. Have minor heartburn which is very manageable.
My understanding is that I will be on the next phase of testing for another 2 years.
This is day 10 for me on the NIH Ibrutinib trial. I am happy to report that my lymph nodes began to reduce in size in mere hours after taking the first dose of 3 capsules daily. From the third day on, I have unexpectedly experienced significant pain. A small localized area becomes warm to the touch, swollen, and progressively painful over about a 2- or 3-day period, then slowly returns to normal, only to be followed by the cycle repeating itself in another random area. So far, both wrists, various fingers, right ankle, left knee, and now left foot have been affected. I spoke with a hematology fellow two days ago who said this is unrelated to Ibrutinib. True, I’ve read nothing of this AE in the abstracts, but have read posts from another patient in the trial who endured muscle and join pain, and have heard of yet another patient with similar issues. Despite the discomfort, I am still grateful to be participating in the trial!
Thank you so much, Chaya, for your clear explanations and educated guesses. Thank you, too, commenters, on your experiences and side effects.
Carter
Dear Chaya,
Thank you very much for more homework,thought i had left all that behind. As usual a concise, informative and humourous update, you make a difficult subject a good read. Thanks again for your hard work
Just wanted to add to my PCI post .. within 5 days on PCI, my large neck node cluster had disappeared. At the end of cycle 1, spleen that had been 16 cm and “three fingers palpable” was no longer palpable. All this coupled with my dramatic WBC reduction which certainly was more than the 11% per month that Wayne mentioned. I’m wondering if that was because mine was not a very nodal disease when I began to take PCI. Early days for me, so we will see what this coming week reveals.
Hi Chaya and All
Thank you for such an interesting article, just how many other BTK mediated functions are halted by use of ibrutinib?. Reading this thread quite a few others are suggested too? Until reading your article I had only heard about accompanying self limiting diarrhea as a side effect in some of the treatment population (or was that GAL1101?). I have been awaiting someone willing to address side effects and risk..
I am a current Plavix(clopidogral) and asprin user, but have been on other antiplatelet combos now long terms as I have overactive platelets. I have always been concerned about the difficulties in decisions about juggling prophylaxis and any treatments. From what I understand about CLL treatments, there are increased clotting risks involved in conventional immunochemotherapy use and modulating therapies such as Revlamid. Now it would appear that BTK inhibiters may bring exclusions to the table from the opposite end of the spectrum. The Ying and Yang of treatment risk.. Chaya as you always say there is no such thing as a free lunch.
Your article does encourage us to consider risk in our decision making when weighing our treatment choices up. (these trials are invaluable to those who have few alternative choices). They are so new, there are so many unknowns and the interactions so complex, I salute all you brave trail blazers who are taking part in the US, you will allow more information to become available for those following you or joining other countries’ trial programmes when they commence next year.
I will continue to follow you all, and it is good to read that all this anecdotal evidence is being corralled by someone that is able to consider it and disseminate it to the rest of us to consider and discuss.
Best wishes
Nick
Is it also Ibrutinib for which has been reported atypical grade 3-4 pneumonia – not bacterial and not viral? Or am I thinking of GS1101?
mrblot
That is indeed GS1101 (earlier known as CAL-101) that you are thinking of.
My husband Bill has been on Ibrutinib/Ofatumumab trial at OSU and is also on cycle 15. After one month of Ibrutinib alone Bill’s WBC and ALC doubled to 335 and 331 respectively. After four treatments of the combination of Ibrutinib and O, his WBC and ALC were in the normal range. He also started with low platelets (63) and they have never reached the norm of 150 but have hovered between 110 and 125 so far.
The only side effect that he has had was a soft stool and this has been very manageable. He says that for the first time in years he has a sense of well being.
His final BMB showed less than (.1% ) residual disease. The CT showed all lymph nodes were less than 1.5cm and his spleen is normal.
Bill is 67 years old and has other co-morbidities, diabetes II and heart disease (triple bypass in 2010). He went into cardiac arrest at home 4/10. He had no pulse or breathing. I was able to do CPR until the EMT’s came and defibbed him. He was put into an induced coma and his temperature was kept low in a device called “The Arctic Sun” for 24 hours to protect his brain and vital organs. After six weeks in the hospital he came home with a triple bypass. He also had AIHA in 2009 and therefore cannot have Fludarabine again.
I am explaining all this so you understand why Dr. Byrd said, “We have to treat you with a more gentle treatment.” We knew this was a trial and many unknowns but Bill knew his choices were limited. Also, he honestly felt that he had survived something that most don’t survive and wanted to try to help not only himself but others as well. So far, so good as they say. He just keeps plugging along.
Again, thank you Chaya for all your knowledgeable articles.
Cheryl
Chaya, thanks again for all the information.
These new ‘kids’ on the block (kinase inhibitor drugs)certainly seem like a roller coaster ride so far. They go from miraculous to possibly very scary side effects and back again within the same article! Hearing from the people actually at the trials coal face is so interesting, knowing exactly what their anecdotal experience is like, positive and negative.
At Barts hospital here in London, patients are given fresh grapefruit juice to prevent sore mouths from chemo but that might not be so good for heart burn – here we go again on the roller coaster!
“Sense of well being.” That is the common thread that most applies to my own case. I’ve been on single-agent PCI since August, 2010, and all indicators are good. Regarding concerns expressed in this discussion, I experience very minor bruising around wounds and the healing seems a little slow. Very minor heatburn and diarrhea are almost fully controlled by one Pepcid and Imodium each, daily. I get mouth sores about once per month, but these are controlled by upping the daily valecyclovir dose from 1 g to 3 g for three days – so this seems like a viral effect. My fear, so far not realized, is pneumonia/respiratory infection. Of course, this, and viral infections are the constant risk for all CLL patients – e.g., I spent 4 days, while on w&w, in the hospital in 2007 with pneumonia, and fought shingles in 2006 (6 months after diagnosis) for four painful months with valecyclovir and pain medications – have been on 1 g/day of valecyclovir ever since.
I have to pipe up and say I don’t agree that PCI is a “roller coaster ride”. In fact, from everything I’ve read and heard about chemo, that is the true roller coaster. And, let’s face it, isn’t CLL one as well? I’m surprised that people are having such an extreme reaction to this article, reading it as a cautionary “No go”. I don’t believe that is Chaya’s intent. Certainly we need to go into trials with new powerful drugs with our eye wide open and perhaps there has been a lot of hype on this drug. However, I’ve been surprised to read on other forums that some who have read this article have now ruled out Ibrutinib.
Randle .. did you enter the single agent trial as a relapsed or refractory? I’m also interested in whether there are some who are part of the original untreated > 65 arm of the first trials.
I guess I need to reaffirm what LynnS said above. This is not (repeat, NOT) intended to be a “no go” evaluation of ibrutinib (PCI-32765). I have no idea where people are getting that from. I worked hard to ramp up recruitment for the NIH trial using this drug because I believe it may prove to be a valuable addition to our drug lineup. Here are some quotes from my review above:
“For the many patients with poor prognostics and not many good therapy choices, these new kinase inhibitors have been a welcome development.”
“Let us give this new drug its due credit. It has shown remarkable activity in older patients, high risk patients, relapsed and/or refractory patients with bulky disease that is hard to treat.”
“I have no doubt that PCI-32765 and future generations of other kinase inhibitor drugs will change the paradigm for treating late stage and elderly CLL patients, increasing both quality and quantity of life for this segment of the patient population.”
These snippets are a mere sampling of all the positive things I have had to say about this drug.
Are there issues to be wary about, things to keep an eye on? YES. I am not the only one who is aware of potential platelet issues – I am merely the one who is giving it some publicity in the patient community. You see, I believe very strongly that you are best served when you have all the information, as much as we have at this point, both the positive and potential negative effects. As for physicians and researchers, they seem to have more constraints on what they can say, more conflicts of interest that keeps them circumspect. How I miss Dr. Terry Hamblin!!!
Is the possibility of adverse effect due to platelet function trivial? No, I do not think it is a trivial issue (notwithstanding a rather flip and condescending comment from a CLL expert on one of the Yahoo group sites). Nor do I think this is only in my own head. Why else would recent trials with PCI-32765 have exclusion criteria for anyone on blood thinner medications such as heparin and coumadin? It seems to me this is something the researchers are concerned about as well.
Only time will tell how much of an issue this is going to be, especially for patients who stay on this drug for extended periods of time. In the meantime, you should continue to make therapy choices with your eyes wide open – both to the positive aspects of this drug, of which there are many, as well as newly surfaced concerns regarding platelet function.
Lynn,
I was 64 and a veteran of FR immunochemo in 2008 and lenalidomide in 2010. I nearly failed fR with low ANC did fail lenalidomide for the same reason. I would face very difficult choices if this PCI were to fail, save very rapid development of the new T-cell protocol.
I try to ask everyone I encounter at the clinic about their impression of the success of this trial. They all seem very positive. They have seemed maybe more wary about platelet issues recently – at my last visit, my number was 103, down from 115. They expressed concern about that even though it has been fluctuating in this range for the last two years. It will be a discussion topic for my next visit – I always take a note card with bullet points on it to make sure I don’t forget items of concern.
To me, Chaya’s article and her note just above are on target.
Thanks Chaya. I appreciate the update and truly appreciate everyone’s comments. The trial participants are the real heroes — a heartfelt THANK YOU!! to each and everyone of you.
It’s great to see input from Chaya and trial participants because, sometimes, the koolaid that the researchers serve up in their reports isn’t what everyone wants to drink. ;-) With input from many, trial participants can be aware of side effects others might also be experiencing.
Here’s hoping for some great success stories in the months and years to come!
Chaya,
Thanks. Again
As those who follow my blog ( Bkoffman.blogspot.com ) know, I have done well in the OSU trial of PCI-32765 and ofatumumab. After 8 weeks of ofa infusions I am now 9 weeks into the ibrutinib
My counts were never an issue, but my ALC did float up a bit for a few weeks. My Hg is 12.8. lower than when I started but not bad. Retics are normal. My platelets are in the high 300,000 but I have had a splenectomy for my ITP.
My palpable nodes began to shrink in less than a week. The are not all gone yet but the largest is about 1 x 1 cm. After one month of ibrutini, the nodes on my CT scan all are about 50% smaller, but at least two cluster were >5 cm. tells how big they were before!
I feel well, better energy. No sores or bruises. Did have heartburn and some mild GI issues in the first few weeks, and some annoying myalgias that might be related to the ofa that I still getting once a month.
Really the PCI-32765 is nearly free of adverse events for me.
A few points.
The nodes returning so quickly after stopping the med. Could that be a compartment shift in the opposite direction, from blood to nodes? Does it happen to those very few in CR MRD neg? Is it less likely the further out you are?
Life long meds. They are just starting to study stopping the poster child for targeted therapies, imatinib (Gleevec) and it has been out since 2001. A life of expensive meds is not my 1st choice, but it sure beats any of the existent alternatives out there, especially for high risk disease.
Brain hemorrhage. Anemia. Bruising. Very concerning. I suspect the variable levels of expression of BTK in platelets and retics is the reason for the range of results we are experiencing. This needs more research.
The infection rate is less worrisome to me. It it better than with most chemos and most of the trials were as you said a tough crowd. Two-armed trials should tease out those facts.
Richter’s Transformation. This scares me too. I sure want more details. I am sure some of these can be blamed on prior mutagenic therapy, but is that the whole story? Abstracts at society meetings are not enough.
That said, I believe these new drugs are game changers, the best thing to come along in CLL to date. The combination of low toxicity and high efficacy and in most cases, improved disease control over time recommends them.
I fought hard to get into this trial and feels very lucky indeed.
Be well
Brian
Brian Koffman MD CM
bkoffman.blogspot.com
Just an anecdotal addition .. had my end of cycle 2 labs today and I continue to be amazed. From my WBC “before” of 342k, I am now 159k. That is over a 100% reduction in 8 weeks. My B2M is now in the normal range, at 1.7. Today I had a BMB and will report on that when I get the results. I know I’m only one of many, but feel so fortunate to be on this drug.
Oops .. I’m a mathematician and what have I just posted !! It is NOT a 100% reduction .. it’s over 50%. Wish there were some way of editing, LOL. Oh well, let’s blame it on my giddiness at the results.
Chaya-
I too, am rather baffled by some of the posts “out there” in the other CLL sites. I wondered at first what article they had read. Surely, it wasn’t the same one that I read from you!
Yes, ibrutinib is a game changer. It is a wonderful drug to have Tom take. He has NO palpable nodes. Tom is relapsed and refractory and so I suppose that puts him into that “hard to treat” group. Sometimes I have to remind myself that he is in that group. I read an article by a well known CLL specialist who stated that the trial of Ibrutinib for relapsed/refractory patient’s was fantastic because almost all of these patient’s would no longer be with us today if not for long term use of ibrutinib. WOW–that made me sit up and take notice! At first, I was shaking my head – that didn’t sound right to me to put Tom in that group. But, when I remember how he didn’t get close to a CR with Revlimid or Humax or Rituximab combo’s and how he was so sick before starting Ibrutinib and it just made sense. This stuff is wicked good! The side effects that Tom is having are a million times better than what he was going through before starting this trial. BUT–I am interested in long term use. Watching the platelets and the immunoglobulin serums. And once you are termed, “relapsed/refractory”, I find that I am always waiting for that other shoe to drop when it comes to treatment.
I miss Dr. Hamblin also. He was always so willing to step over that medical line and speak some truths to us, the patient.
JLOU
Thank you all for being open and honest and sharing information on your personal experiences. I am just beginning the CLL journey and find comfort in being part of your journey. I hope that as I continue I can post information that will be helpful to someone.
I was just doing some browsing and came across a wonderful last page “thank you” from the ASH 2011 poster on PCI and the mouse model. Chaya .. I think we have you, and I would imagine your chat with Dr. Wiestner who is one of the researchers on this, to thank. I’m thrilled.
“Special Thanks: NIH study patients, for their
participation and willingness to undergo
additional procedures – without which this
research would not be possible”
I gave them billions of cells via apheresis so felt especially thanked.
Thank you for this article. I have stage iv SLL/CLL and have been putting off chemo (BR)for almost a year now. I am 68 years old, have 17p deletion and have not seen any trial results using BR, that have any effect on 17p.
I tried to get into a PCI-32765 trial but was to late, as it filled before I could get all my tests updated.
I found it very interesting concerning platelets, as mine go from 53,000 to 59,000 every month. Maybe it wasn’t so bad that I missed out on the trial, but I would have really liked to be in it.
The other reason I keep putting off chemo, is that I feel really good. Not tired, other CBC readings holding steady, just platelets and enlarged spleen is reason my doctor wants chemo for me.
Still hoping to see Ibrutinib approved by FDA, before I have to start any chemo.
Nobody knows how long it will be for the proper clinical trials to be completed before ibrutinib can be evaluated by the FDA for approval. There is a critical Phase 3 trial NCT01578707 comparing ofatumumab to ibrutinib in relapsed CLL patients. That trial is not scheduled for completion until 2015.
Oh friends. What a tough almost two weeks it’s been. I was doing so well on PCI .. WBC had gone from 342k to 114k, Hgb and dropped but was coming back up, platelets from around 100k to the 140k’s. Then the BMB and CT scan about two weeks ago and whammoo. BMB was great — CLL from 80-90% down to 50% in only two cycles but then I got the call ..”We see a mass in your CT scan” and it’s been down hill ever since. First bronchoscopy under conscious sedation couldn’t get enough cells as the mass in my upper right lung lobe airway (bronchus) was bleeding too much to use the needle core approach. So then when that news comes, it’s a broncoscopy in the OR with complete sedation and they got the cells needed. That and my Thursday PET scan confirmed non-small cell lung cancer.
I met yesterday with the wonderful NIH team and turned in my meds. Then had a consult downstairs with the thoracic surgeon, Dr. David Schrump who has taken me on, if all goes as planned. I will be giving my cancer cells to two research projects that are studying lung cancer, one looking a anti-lung cancer vaccine. I am thrilled to be able to stay at NIH for this most frightening phase. I know I will get great care and can’t imagine how I would pull together such a team in a hurry in San Francisco. The tumor was not visible in my baseline March CT scan, but the team feels there may have been a tiny something hidden by my nodes. Whatever .. I don’t think PCI caused the tumor as I had strange bronchitis just before coming to NIH in May, and coughing and bleeding 10 days into the trial. Could PCI had encouraged growth (to 2.5 cm in the ct scan)? We will never know. This doesn’t seem to have happened to anyone else so let’s just write it off as “shit happens”.
I didn’t want to post earlier until I knew more and I was very hesitant as I also didn’t want to freak people out about the wonderful PCI drug.
The plan is lots of tests this coming week and surgery August 9th. Dr. Schrump had already sketched me into his schedule before seeing me .. or before seeing me awake. Evidently the wonderful pulmonologist who did my bronchoscopy had him visit me while I was sedated in the OR so he could view the tumor as she thought this might be my path. The tumor is in the bronchus for the upper right lung lobe so I will be getting at least one lobectomy, losing that upper right lobe. There are other lobes so I’m hopeful that I will still be able to do some hula down the road. Fingers are crossed that he only needs to take one lobe, but we won’t know until he gets in and sees the exact location and if he can get margins. This week I’ll see a world recognized lung cancer expert at NIH, Dr. Giaconne who will know more about the details of my tumor.
Dr Farooqui, my NIH trial doc, has done a fabulous job pulling all this together .. all the various tests and scans and then introducing my case to the NCI folks, where lung cancer and thoracic oncology reside. I love NIH. I love my CLL docs and hope to learn to love these new members of my team.
So .. CLL is in the background. Hopefully it won’t roar back too soon and will allow me to address the new cancer.
And to all my PCI family .. please stay in touch !! I will be following your wonderful success, hoping that I will be able to get PCI when the FDA approves it. The trial excludes anyone with another cancer, so no chance I’ll return.
And finally .. I think my experience demonstrates the incredible support one gets as an NIH patient. As Dr. Farooqui said, “Once an NIH patient, always an NIH patient”. Thank you Chaya for starting me down the NIH path with the Natural History Study.
LynnS:
I am heartbroken to hear this news. I guess I will never gain enough wisdom to answer the question “why?”. If anyone can handle this tough situation, it is you. Grace under fire – that is how I see you.
All the best my friend. Please keep in touch and do remember you have many friends in the CLL patient community. Thank you for sharing your situation with such honesty.
LynnS,
I am so sorry to hear of your news. However, after reading your posts these past couple of years, you’re definitely one to kick butt and take names. So, when you’re finished kicking the crap out of lung cancer, you’ll back on the path to deal with the pesky CLL stuff.
I’m so thankful that the wonderful folks at NIH were there for you at every turn. You couldn’t ask for a better team anywhere! Peace of mind that comes with the confidence of your medical team is priceless. Please take care of yourself — I’ll be watching for the new CLL posts from you.
Leave a Comment