“Soil & Seed”
There is a concept in cancer biology called “soil and seed“. What do you need for plants to grow and flourish? You need healthy and strong seeds with good vigor and pest resistance built into them. But even the strongest seed cannot flourish in bad soil. Both strong seeds and nutritious soil capable of supporting plant growth is needed for plants to grow and flourish. Any gardener can tell you that!
This analogy works in cancer biology as well, it seems. High risk cytogenetics in CLL (unmutated IgVH, 11q and / or 17p deletions, unmutated IgVH etc) are the equivalent of strong cancer seeds, able to resist the damage inflicted on them by chemotherapy. A supportive microenvironment – such as lymph nodes, bone marrow etc – provides the rich soil. Presto, when both of these conditions are met, we have a faster growing and more difficult to control CLL. (Spleen and liver are also considered to be part of the lymphatic system and therefore for the purposes of this discussion, when I write about swollen nodes I am including spleen and liver as possible locations of swelling as well).
As you know by now, CLL comes in a variety of flavors. In some patients, almost all of the disease is seen in peripheral blood. While these guys may have impressively high white blood counts and absolute lymphocyte counts to match, in fact they are the lucky ones and their disease is likely to be the easiest to treat. This is why I caution patients about getting too fixated on white blood counts. It is only a part of the picture, a small part of the picture as it turns out.
On the other hand, people who have large percent of their CLL cells nicely tucked away in swollen lymph nodes and bone marrow, spleen, liver etc have a bigger problem. You see, CLL cells are insecure little buggers. They don’t like being alone, just cruising around in blood circulation all by their lonesome selves. They do much better, live longer and have many more babies when they live in well established colonies of other CLL cells. Also of importance are supportive cells surrounding the CLL clusters, giving the cancer cells much needed approval and survival signals. In fact, some of the interesting papers at the recent ASH2011 report that microenvironment where CLL cells live plays a huge role in the progression of the disease.
Who are most likely to have lymph node centered disease? Typically, people with high risk CLL (FISH deletions of 11q, 17p, 12 trisomy) are most likely to have enlarged nodes. In these patients the lymphocyte count in the blood is nothing more than the tip of the iceberg. As much as 90% of the CLL cells can be safely tucked away in lymph nodes, making these cancer cells hard to get at. As we discussed above, these CLL cells in lymph nodes fit the classic definition of strong seeds in a fertile soil. The cytogenetics makes it hard to kill them, and the cancer friendly microenvironment of the lymph node makes it easier for them to live long and prosper.
It has been a depressing fact of life that many of the drug regimens we had up to now were not very successful at treating patients with high risk CLL, especially if they also had massive lymphadenopathy (fancy word for swollen lymph nodes, or swollen glands if you are a Brit). Important drugs such as Campath are considered useless and contra-indicated if the patient has large lymph nodes. Single agent monoclonal antibodies (Rituxan, ofatumumab) are not of much use either. More aggressive therapies such as FCR and bendamustine combinations may be able to get (most of) the CLL cells lurking in the lymph nodes, thereby giving high response rates. But as we are learning, not everyone can handle FCR and similarly high impact therapies. Elderly and frail patients, folks with other medical issues etc may find such aggressive regimens hard to tolerate. For them, the price tag of therapy toxicity may be more than the remission is worth. People who have relapsed after prior therapies such as FCR or FR are another subset of patients who really needed better salvage therapy options.
This new understanding and emphasis on the microenvironment of CLL cells is fueling a lot of the excitement regarding kinase inhibitors such as CAL-101 and PCI-32765. The science is complex and I will not go into it here. Please read an earlier article titled “Dawn of a new Era” where I discuss a cartoon version of it. In a nut shell, drugs such as PCI-32765 interfere with the cyotokines that act as the cookie crumb trails leading CLL cells home to lymph nodes, as well as the adhesion factors that allow them to stick there. Deprived of their nurturing microenvironment and flushed out into open blood circulation, the soil part of “Seed & Soil” is defeated, making the CLL cells easier targets for therapy.
We discussed the first batch results of PCI-32765 in an earlier report. Here is a followup, with more mature results.
The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study
December 13, 2011
Susan O’Brien, MD1, Jan A. Burger, MD, PhD2, Kristie A. Blum, MD3, Richard R. Furman, MD4, Steven E. Coutre, MD5, Jeff Sharman, MD6*, Ian W. Flinn, MD, PhD7, Barbara Grant, MD8*, Nyla A. Heerema, PhD9, Amy J. Johnson, PhD3, Tasheda Navarro10*, Eric Holmgren, PhD10*, Eric Hedrick, MD10 and John C. Byrd, MD11
1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3The Ohio State University, Columbus, OH
4Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY
5Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA
6US Oncology, Springfield, OR
7Sarah Cannon Research Institute, Nashville, TN
8Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT
9Pathology, The Ohio State University, Columbus, OH
10Pharmacyclics, Inc, Sunnyvale, CA
11Division of Hematology, The Ohio State University, Columbus, OH
Introduction: Btk is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally-administered irreversible inhibitor of Btk which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. An early analysis of the phase Ib/II study PCYC-1102 showed PCI-32765 to be highly active and tolerable in patients with CLL (Byrd, ASCO 2011). Here we report longer-term follow-up of this multicenter phase Ib/II trial.
Methods and Patients: Two cohorts of CLL patients (previously untreated ≥65 years old and relapsed/refractory [R/R] disease following at least 2 prior therapies, including fludarabine) were treated with oral PCI-32765 administered daily for 28-day cycles until progression of disease. Doses of 420mg (previously untreated and R/R) and 840mg daily (R/R) were examined. The patients with R/R disease are the subject of this report.
Results: Sixty-one R/R CLL/SLL patients were enrolled (420mg cohort n=27, 840mg cohort n=34). The median follow-up time for the 420mg cohort is 10.2 months and for the 840mg cohort is 6.5 months. The median number of prior treatment regimens for the 420mg cohort was 3 (2-10) and for the 840mg cohort was 5 (1-12). Seventy-two percent of patients had at least one poor-risk molecular feature: del(17p) 31%, del(11q) 33%, IgVH un-mutated 57%. Treatment has been well tolerated. Two patients have discontinued for adverse events (AE); 6 patients have required reduction of PCI-32765 dose (420mg cohort 2/27, 840mg cohort 4/34). Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis have been the most frequently reported AEs. Serious AEs (SAEs) have occurred in 38% of patients; SAEs considered potentially related to PCI-32765 have occurred in 10% of patients. Grade ≥3 AEs considered potentially related to PCI-32765 occurred in 21% of patients. A characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of Rx, followed by resolution over time, has been observed in the majority of patients. Objective response (ORR; PR + CR) by IWCLL criteria in the 420mg cohort cohort, previously reported as 48% with 6.2 months median follow-up (Byrd, et al ASCO 2011), is now 70% with 10.2 months median follow-up. ORR in the 840mg cohort is 44% at 6.5 months median follow-up. An additional 19%, and 35% of patients in these cohorts, respectively, have a nodal PR (>50% reduction in aggregate lymph node size) with residual lymphocytosis. ORR appears to be independent of molecular risk features. Eighty-two percent of patients (50/61; 420mg cohort 22/27, 840mg cohort 28/34) remain on PCI-32765. Only 8% (5/61) of patients have had progressive disease (PD); 6-month PFS is 92% in the 420mg cohort and 90% in the 840mg cohort. Treatment cessation not related to PD or AE includes: death (n=2) or investigator discretion (n=3).
Conclusions: The potent Btk inhibitor PCI-32765 is well tolerated and is associated with high rates of 6-month PFS in R/R CLL/ SLL. Phase III trials of PCI-32765 in CLL/ SLL are planned.
Disclosures: O’Brien: Pharmacyclics, Inc: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Burger: Pharmacyclics, Inc: Research Funding. Blum: Pharmacyclics: Research Funding. Furman: Pharmacyclics, Inc: Research Funding. Coutre: Pharmacyclics, Inc: Research Funding. Sharman: Pharmacyclics, Inc: Research Funding. Flinn: Pharmacyclics, Inc: Research Funding. Grant: Pharmacyclics, Inc: Research Funding. Heerema: Pharmacyclics, Inc: Research Funding. Johnson: Pharmacyclics, Inc: Research Funding. Navarro: Pharmacyclics, Inc: Employment, Equity Ownership. Holmgren: Pharmacyclics, Inc: Consultancy. Hedrick: Pharmacyclics: Employment, Equity Ownership. Byrd: Pharmacyclics, Inc: Research Funding.
Judging credibility of research reports is an important part of understanding the results. I discussed some of the issues that go into reading the tea leaves in my last article on CAL-101. Same rules apply here as well. High powered researchers, prestigious institutions, every single one of them with financial connections to the company (Pharmacyclics) that owns the drug. The lead author (Dr. Susan O’Brien, M. D. Anderson) who presented the data at ASH2001 is also on the Board of Directors of the company. Does this mean we throw away the whole report as so much conflicted nonsense? No, that would be throwing the baby out with the bathwater indeed. It just means we keep things in perspective when we read glowing press reports about the new drug.
Here is a bit of a “teaser” for you guys. In the next few days I will be publishing an important new development dealing with ongoing PCI-32765 clinical research. You will not be off the mark if you think of it as a timely Christmas present for the CLL patient community. (Yeah, Happy Holidays present for those of you who do not celebrate Christmas. Sheesh.)
Clinical Trial Design
This clinical trial had two patient cohorts. First one included patients who were chemo-naive (untreated) but older than 65 years. In other words, they are looking at PCI-32765 as a possible frontline drug in older patients for whom combinations such as FCR may be contra-indicated. The second cohort consisted of relapsed / refractory patients who have been through at least two earlier therapy regimens, including fludarabine. In other words, at the other end of the curve, looking at PCI-32765 as a potential salvage therapy for this tough to treat crowd. This report is only about the second cohort, the folks who went into the PCI-32765 after relapse following prior two cycles of therapy.
There were 61 patients in this group, some were classified as SLL, the lymph node variant of CLL. As you know by now, PCI-32765 is an oral drug, making its administration easy. Dosage varied between 420mg and 840mg per day. Followup (thus far) is between 6-10 months.
Results, Risks, Rewards
Bear in mind this is a tough to treat patient cohort. Besides being relapsed and/or refractory, 44 out of the 61 patients had one or more of the high risk features (17pr or 11q deletion, or unmutated IgVH). “Treatment was well tolerated” – good, but I will take that with a pinch of salt, thank you very much. Amazing how much perspective changes when you are at the pointy end of the stick. Serious adverse effects occurred in 38% of the patients, of which the researchers judge 21% were attributable to the drug in question. I suppose the definition of well tolerated is relative, and in this case it is being used in the context of ‘beggars cannot be choosers’. All the same, I would have preferred more sympathetic language, don’t you think?
Ten months of daily administration of 420mg of PCI-32765 got an overall response rate of 70% of the patients. Overall response rate is the sum of “CR” and “PR”. (Here is an article that describes in detail what CR and PR mean). The abstract does not break out how many CRs there were, and how many PRs. I am willing to bet dollars to donuts the vast majority of these were PR (“partial response”). For starters, I do not really expect to see any full blown CR remissions in this relapsed / refractory crowd. Second, human nature being what it is, I suspect the abstract would have made much of the large number of CR responses, if that had been the case.
The higher dosage (840mg daily) group has been followed for only little over 6 months and in this group the overall response is at 44%. Hopefully, they too will have more and more people getting some sort of a response as time on therapy increases.
Only 8% of the patients seem to have their CLL progress (get worse) while they were on the drug. Two patients died, but the deaths are not considered to be due to PCI-32765.
Here is the most important part of the whole study. Patients’ response to PCI-32765 does not seem to depend on whether or not they had high risk disease. In other words, it did not seem to matter whether they had 17p, 11q deletions, unmutated IgVH etc, they were just as likely to get a response to the drug. That is indeed welcome news. Remember, in our introduction to this article we discussed the need for new therapy options for patients with high risk disease, those unfortunate folks who had both the “good seed and nurturing soil” version of aggressive cancer. This study supports some of the excitement about these new generation of designer kinase inhibitor drugs, in that they seem to be able to do what most other drugs cannot do: treat high risk and relapsed / refractory patients. As with CAL-101, the characteristic feature of kinase inhibitors, their ability to flush CLL cells out of comfortable lymph node cocoons, that seems to be the important feature of how these drugs act.
Notice the silence regarding action on the bone marrow front. As in the previous article on CAL-101, this abstract does not mention the bone marrow microenvironment. Does PCI-32765 do a good job of clearing it? We do not know. Once again, I do not think the bone marrow microenvironment is identical in all ways to the lymph node environment. Is it reasonable to assume / infer / hope / expect that because PCI-32765 works well in flushing out CLL cells from lymph nodes, it will do the same for the bone marrow as well? We do not know – and frankly, I think it is a bit of a stretch to make that assumption. I realize drug companies spend good money getting these important trials done. But how about doing good science while we are about it? Our guys are risking their necks in volunteering for these early stage trials. How about making the best use of their sacrifice, and thanking them too, while we are on the subject?
Are these drugs truly low toxicity? I am not too sure of that. In my layperson opinion, the jury is still out on that. At the same time, please allow me to remind you that we are willing to accept a certain amount of toxicity risk, if the drug in question can actually deliver in terms of deep and lasting remissions. Until better drugs become available with even better responses and fewer adverse effects.
Will the remissions be long lasting? Will the patients have to take PCI-32765 indefinitely, or can they quit after a good long time and still expect to stay in remission? That question has not even begun to be answered, yet. If I were to bet, I would expect patients would not stay in remission for very long after stopping daily use of PCI-32765. But that is just a guess on my part.
My guess is that these early trials of kinase inhibitors as single agents will be followed by the inevitable combinations of these drugs with other agents; chemotherapy agents such as F and C come to mind. We may expect to see more full fledged CR responses in such combinations, as well as deeper, longer lasting remissions. Unfortunately, I think most of you can figure out by now, addition of standard chemo agents such as F, C and B(bendamustine) will increase the toxicity of the regimens too. Sigh.
So, what is the Christmas present I promised all about? You will just have to wait a couple of days, no more than a week, I promise. And if you are getting busy making your “nice” and “naughty” lists for holiday giving, I hope you will put us in the “nice” category. Supporting our work through your donations is what keeps us going. It is easy to do. You can do it using your credit cards (through secure PayPal). Or you can put your check in the mail. Hit the “Donate” button below and the page has all the information you need, including our mail address. That’s it folks – that is the sum total of our “donations drive” for the year.