Kinase inhibitors

Bruton KinaseWe have several kinase inhibitors in the drug pipeline.  A famous one that has seen a lot of publicity in recent months is CAL-101.  PCI-32765 is another.  Both are kinase inhibitors, but they target different cellular pathways.  PCI-32765 is what is called a Bruton kinase inhibitor.  Never mind the jargon, and don’t get your feathers ruffled by all the cool science (which we described in greater detail in the earlier article on CAL-101).  Here is the buzz in a nutshell.  Both of these kinase inhibitors seem to work by flushing out CLL cells from their ever so comfortable homes in the lymph nodes, out into open blood circulation.

Why is this important?  It is important because CLL cells are a lot harder to kill when they are nicely tucked away within the lymph nodes, surrounded by so-called “nurse-like cells” that are nurturing, supportive and providing them soothing feedback, basically telling the cancer cells they should live long and prosper.  Out in the open blood circulation, CLL cells can get very lonely.  And lonely cells without feedback to comfort them are a lot easier to kill.

Majority of chemotherapy drugs and the couple of monoclonal antibodies we have available to us are not very good at killing CLL cells when they are thus protected in lymph nodes (also spleen, liver).  At least, the dosages needed to kill CLL cells in bulky nodes carries with it the penalty of high toxicity to match.  Some drugs cannot do it at any dosage.  For example, people with really bulky nodes (larger than 5 cm diameter) are considered “Campath ineligible” – there is no point subjecting such folks to the toxicity of Campath, it is not going to be able to budge those pesky lymph nodes.

Along come the kinase inhibitors,  and the one thing that they do that captures the imagination is that they are able to kick out CLL cells hiding in lymph nodes.  This is seen in dramatic shrinking of the size of the lymph nodes.  Of course, all those CLL cells kicked out have to go somewhere, and the white blood counts of many patients under going treatment with either of these kinase inhibitors (CAL-101 and PCI-32765) shoot up soon after start of therapy.  This is to be expected and not feared.

Do these kinase inhibitors have the killing power to finish the job and mop up all the CLL cells flushed out into the blood?  To some degree they are able to kill the cancer cells. But that is not really their role, in my layperson opinion.  The early trials focused on single agent therapy, using just the kinase inhibitor, to see what it can (or cannot) do, as well as get a handle on the toxicity side of the equation.  Down the road, I have no doubt these new drugs will be coupled with other drugs to form powerful combinations.  Kinase inhibitors to flush the swollen lymph nodes, another drug (perhaps Rituxan or ofatumumab) to do most of the  killing of the cancer cells in the blood. Perhaps we will need other drug(s) to help clear the bone marrow.  I am a little concerned that neither of these kinase inhibitors seem to be able to do a good job of clearing heavily infiltrated bone marrow.  As we reported in an earlier article, infiltrative late stage CLL defines dangerous scenario.

ASCO Abstracts

ASCO (American Society of Clinical Oncology) has their annual meeting in June of each year. This year is no exception.  Unlike ASH (American Society of Hematology), ASCO deals with all kinds of cancers, solid cancers like breast cancer, lung cancer, prostate cancer etc, along with a smattering of blood cancer studies.  ASH is our dedicated meeting, focused only on blood cancers.  Nevertheless, this years ASCO has several interesting papers and the abstracts are just out.  I am sorry I won’t be able to attend the meeting in person due to health issues.  But the abstracts are the next best thing to being there in person.  Here is the first one, dealing with the latest results from the ongoing early stage  PCI-32765 trials.  My two cent cheat sheet follows the abstract.

2011 ASCO Annual Meeting

Abstract No: 6508 (J Clin Oncol 29: 2011 (suppl; abstr 6508))

Activity and tolerability of the Bruton’s tyrosine kinase (Btk) inhibitor PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim results of a phase Ib/II study.

Author(s): J. C. Byrd, K. A. Blum, J. A. Burger, S. E. Coutre, J. P. Sharman, R. R. Furman, I. W. Flinn, B. W. Grant, D. A. Richards, W. Zhao, N. A. Heerema, A. J. Johnson, R. Izumi, A. Hamdy, S. M. O’Brien; The Ohio State University Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Solove Research Institute, Columbus, OH; The Ohio State University, Columbus, OH; University of Texas M. D. Anderson Cancer Center, Houston, TX; Stanford Cancer Center, Stanford, CA; Willamette Valley Cancer Institute, US Oncology, Springfield, OR; Weill Cornell Medical College, New York, NY; Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; University of Vermont College of Medicine/Fletcher Allen Health Care, Burlington, VT; US Oncology Research, LLC, The Woodlands, TX; Texas Oncology, Tyler, TX; Pharmacyclics, Sunnyvale, CA

Background: Btk is essential to B-cell development and function. Btk is highly-expressed in CLL and its inhibition by the potent irreversible inhibitor PCI32765 (P) promotes apoptosis and inhibition of cytokine, chemokine, microenvironment-mediated signaling, proliferation, and chemotaxis ex vivo. We report interim results of a large Phase Ib/II trial of P in CLL/SLL.

Methods: Two cohorts (previously untreated [PU] >65 yrs old and relapsed/refractory [R/R] disease following at least 2 prior therapies [Rx] including fludarabine) of CLL patients (pts) were treated with oral P administered daily for 28-d cycles until progression of disease (PD). Doses of 420mg (24 PU and 27 R/R) and 840 QD (31 R/R) were examined.

Results: Of the 78 pts enrolled, data from the first 39 pts will be sufficiently mature as of May 2011 to assess IWCLL2008/Cheson response criteria. R/R pts had a median age of 64, 37% were Rai III/IV, and median of 3 (range 2-10) prior Rx. 87% had at least one poor-risk molecular feature: del(17p)-30%, del(11q)-21%, IgVH un-mutated 70%. Treatment has been well tolerated with grade >3 AEs potentially related to P in 26% of pts. >Gr 3 cytopenias have been noted in <5% of pts. No pts have had LFT elevations. In evaluable pts with lymphadenopathy, the rate of nodal response (LNR; >50% reduction in target lesions) is 89% (25/28 pts). An increase in absolute lymphocyte counts (ALC) occurred in 75% of pts and has decreased over time in the vast majority. At a median follow-up of 4 months, 17 (44%) have a PR (n=15, 39%) or CR/CRu (n=2, 5%). Response has been similar in all genomic groups. Notably, 4 of 12 pts with del(17p) have responded and 7 others remain on P Rx with improving SD. Mature response data will be updated. At a median follow-up of 4 months, 34/39 pts in the 420 mg cohort remain on P therapy with only one PD. Conclusions: PCI32765 is highly active and well tolerated in CLL/SLL pts irrespective of high risk genomic abnormalities. Although follow-up is short, the high response rate and very low progression rate suggests that PCI-32765 may be an important new targeted treatment approach for CLL pts, including those with del(17p).

Cheat sheet (for what it is worth)

  • The author list is literally a who’s-who of CLL experts.  Rock stars each and everyone of them!
  • Bruton kinase (“Btk”) is involved in the ability of B-cells to talk to other cells, have babies and move around, homing in to comfortable niches in the lymph nodes.  Shutting this pathway makes life a lot more uncomfortable for B-cells.  (All B-cells need Btk functioning, not just cancerous CLL cells. In other words, PCI-32765 targets healthy B-cells too, not just CLL cells).
  • This study looked at two groups of patients.  Previously untreated as well as relapsed / refractory patients. Drug was given as an oral pill in 28 day cycles for as long as the patients’ CLL did not progress.
  • Early stage trials are all about finding the right dose.  The previously untreated folks got 420mg each day.  The relapsed / refractory folks were split into two groups, getting 420mg or 840mg of the drug.
  • 78 patients are enrolled, but only the first 39 patients have been in the trial long enough and the report is limited to them. The relapsed/refractory group was suitably tough group, high Rai stage, lots of guys with 17p or 11q deletions, a whopping 70% were unmutated IgVH.
  • Adverse effects greater than grade 3 were seen 26% of patients. That is not trivial!  Remember, “greater than grade 3″ means grade 4.  That is as high as it gets, without the patient actually being dead.  Some researchers use the cute phrase of “grade 5 adverse effect” to avoid using the phrase “dead”.  So, a quarter of the folks had the highest grade adverse effects. That was a bit of a shock to me, I expected far lower toxicity.
  • On a positive note, there was very little liver toxicity and grade-4 cytopenias were seen in less than 5% of patients.  (I wish they gave the percentages for lower grade adverse effects!  How about how many adverse effects were seen that were higher than Grade 2? )
  • 25 out of 28 patients with swollen lymph nodes had better than 50% shrinkage of nodes. Way to go!  This was much hoped for and the drug did not disappoint on this front.
  • As expected, white cell count increased in the blood as the lymph nodes shrank, but this too gradually came down as the lonely CLL cells in the blood got killed. Not a big deal folks, this is not to worry about.
  • These are early results, only 4 months or so of follow-up.  It does not help to get fixated on response statistics this early.  But the interesting thing is that patients across all prognostic risk groups responded.  In particular, 4 out of the 12 people with 17p deletion responded  – thus far.  Others may join them over time – we can only hope.
  • All in all, these are encouraging results. With more late stage trials and especially in well designed drug combinations, PCI-32765 may prove to be an important drug for our guys. Keep your fingers crossed!
  • But the results are early.  Details are sketchy.  For example, there is no mention of bone marrow disease.  Did PCI-32765 do a better job of clearing the bone marrow than CAL-101? Inquiring minds want to know.  Also, I would like greater detail in that scary 26% of patients with grade 4 adverse effects.  Exactly what kind of adverse effects are we talking about? Did they resolve over time?  Were they more pronounced in the group that got 840mg of the drug – was it a matter of tweaking the drug dosage down a bit?

Site News:

Guys, as I read through all the ASCO abstracts, I will be reviewing some of them as full-length articles such as this one.  Others will be reviewed only as short “Tidbits“. You just have to get into the habit of visiting the homepage ( updates.clltopics.org ) and click on the tasty looking bruschetta  Tidbits logo if you don’t want to miss this stuff.  I notice very few of you have found your way there.  Did you know I posted an interesting tidbit last night, about a clinical trial that wants to control early stage CLL with nothing more than a cocktail of broad spectrum antibiotics?  And it is not a crazy idea either! You won’t know about this and all the ASCO stuff I will be publishing there, unless you get into the habit of visiting – I will not be sending out emails every time I have a new tidbit to report.

Different subject, several of you wrote and asked for the date of our Fall CLL Workshop, so you can plan your schedules.  It is going to be on the second Saturday in August, on the 13th.  As for the topic of our workshop, again based on feedback I got, it will be all about CLL complications:  infections, second cancers, autoimmune diseases, B-symptoms, cytopenias. Quite a lot of ground to cover and I expect we will be busy for the the duration of the workshop, 1:00pm through 5:00pm.  We will send out driving directions later on to folks who wish to attend, as we get closer to the date.

I would like to thank all the folks who have written to ask about my pesky knee problem. It seems I am not yet far enough along to justify a full fledged knee replacement.  And yet, the damage is extensive enough after four decades of neglect and abuse that the surgeon did not hold much hope for a simple arthroplasty to clean up the mess inside just a bit.  So, I get to do the middle path: exercise, pain medication, ugly looking knee brace and weight loss.  Uggh.  The good news is that the surgeon turned out to be an old student of mine, back when I was teaching freshman chemistry at Princeton.  I was relieved when he told me he had aced my course.  I would not want a surgeon who held a long standing grudge because I had flunked him!

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