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.


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.