Frontline therapies In CLL (Chronic Lymphocytic Leukemia)

In this lively ONCLIVE multi-part series of polite debates among four world class CLL experts (Drs. Byrd, Furman, Ma, and Kipps), I was struck by the conservative approach of the panelists to frontline therapy.

Almost all the discussion in this 13 minute segment is about chemo-immunotherapy (CIT).

Keep on mind that except for patients with 17p deletion where ibrutinib is approved, chemo-immunotherapy is all that is approved for frontline therapy. That said, we all know that many doctors including several on this panel would discuss with their patients other frontline options besides those they discuss on camera, namely FCR (fludarabine, cyclophosphamide and rituximab) or BR (bendamustine-rituximab) or chlorambucil and obinutuzumab.

Dr. Kipps points out the potential advantages of the chlorambucil and obinutuzumab in elderly patients with a less resilient bone marrow. This relatively gentle approach has achieved a 20% complete response rate and a 26.7 month mean progession free survival, much better than the other arms in the trial that lead to its approval. For the details of the study published in the NEJM please click on this link.

Drs. Byrd and Kipps talk glowingly about the very long term benefits of FCR in a small subset of patients with the best prognostic markers: mutated with no other bad prognostic indicators. This is a subject we have visited frequently visited in the past. Here Professor Hallek and I discussed this topic in this post in the context of the role of chemo-immunotherapy (CIT) way back at iwCLL 2013. I am still waiting for the published material on that low risk subgroup that is looking more and more as if they might be CURED!

In this ONCLIVE video, there is also debate on the need to complete all the cycles of FCR to get the full benefit. I fully agree with Dr. Kipps that the evidence suggests getting to MRD (minimal residual disease) negativity is what determines our prognosis and not the number of cycles it takes to get there. I quote from a Blood editorial by Sebastian Böttcher on the original research: "current investigation suggests that the number of treatment cycles also becomes irrelevant as long as MRD negativity can be attained." 
The full text of the original research is accessible here. The authors state in the abstract that:" MRD-negative patients had comparable PFS ( progression free survival) and OS (overall survival), independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment."

Dr. Furman hastened to point out the potential downside of chemo-immunotherapy and also that the group that did so well is a group that should do well with any therapy.

In this article from the British Journal of Hematology, we learn: "patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5·2%) compared with patients who had not received PNA (1·9%; P = 0·008)"  PNA are drugs such as fludarabine and LPD are lymphoid cancers.  In fact, they go to stated that the only factor found to be associated with an increased risk of a secondary lymphoma for those us with CLL was prior treatment with chemotherapy.

That certainly does give one pause.

There is also some very interesting comparison of BR versus FCR, a subject that we extensively reviewed in this prior blog post with Dr. Jeff Sharman.  I appreciate Dr. Kipps' careful analysis of the different arms of the trial to ensure that we are really comparing apples to apples.

Give a listen and please share your comments.

Again, thank you ONCLIVE for bringing us this great panel discussion.

ASH 2014: Interview with Dr. Susan O'Brien and Dr. Bruce Cheson on CLL (chronic lymphocytic leukemia)

There is much to report from ASH 2014, and this sweet interview from Medscape offers a short synopsis of some of the highlights.

Over the coming weeks I plan to fill in the details with more comments and videos, but this is a nice and succinct place to start.

There are some priceless moments, thanks to the wise and dry humor of Dr. Cheson and the honest and patient centric attitude of Dr. O'Brien.

First, right up front, I really appreciate that Dr. Cheson points out just how out of date are even the most recent CLL guidelines that were developed only a few years ago.

Are you listening, community oncologists? The published CLL guidelines are out of date.

I am glad he also asked about the secondary malignancies with chemo-immunotherapy, a question too often swept under the carpet in many presentation on CLL treatment. We know there is a small but real risk of MDS or myelodysplastic syndrome (for an explanation of the relationship of MDS and CLL from Dr. Steensma, click here), a difficult to treat form of cancer that presents as bone marrow failure, that may come along as a late and serious complication with FCR (fludarabine, cyclophosphamide, and rituximab), but we don't have much data yet on the risk with BR (bendamustine and rituximab).  Because bendamustine is a DNA damaging alkylating agent similar to chlorambucil (Leukeran) and cyclophosphamide (the C in FCR), it is likely that MDS will also present as a late, but hopefully infrequent ugly complication after BR.

What we do know already is that now that we are living longer with our CLL, we are getting more secondary cancers (click here for a reminder of our risks), especially blood cancers.

Don't miss Dr. Cheson's hand gesture when Dr. O'Brien talks about the minority of patients that do so very well on FCR, a topic that we have visited here more than once (click here to hear Dr. Hallek at  iwCLL discuss who gets the most benefit from FCR).

Another highlight comes right after the honest discussion of the follow up important trial of the two old school chemo-immunotherapies that are duking it out for supremacy in the CLL world, namely the  FCR versus BR (for more on this trial from Dr. Sharman click here). After Dr. O'Brien's honest and upbeat response, Dr. Cheson asks her, quite properly in this era of new treatment options: Do we care?

Yet another interesting moment occurs when he asks Dr. O'Brien to choose between ibrutinib, idelalisib, and ABT-199: If they were all available: Which one would you pick?

She refuses to answer.

Their discussion on the meaning of minimal residual disease or MRD negativity in the era of novel therapies is both informative about what we know but even more so about what we don't know.

Only time and trials will help sort al this out.

Dr. O'Brien has her own hand gesture when she describes just how much above 50% was the progression free survival curve for ABT-199 at 18 months. We need more data. And more time to sort this all out.

I wish I had produced this video. I don't usually see the role of my blog to share what is already available on other websites, but this is good stuff and there was much in it that cried out for commentary and context. I wanted everyone who reads my blog to have the link with it here.

Please enjoy this Medscape Interview:

CLL: It's the Best -- and Most Confusing -- of Times

Thanks for your help and support.

                                          

ASH 2013: Dr. John Pagel Discusses Radio-Immune Therapy (RIT) in Chronic Lymphocytic Leukemia (CLL)

The big buzz at the ASH annual meetings for the last few years has rightly been targeted oral therapies such as ibrutinib and idelasib and other, but one therapy that in my opinion that has received short shrift is radio-immunotherapy or RIT.

In fact, it is so rarely used that since this video was recorded in December, 2013, Bexxar (Tositumomab) was pulled from the market in February, 2014 as it was prescribed fewer than 75 times in 2012.

Zevalin (Ibritumomab Tiuxetan) is still available.

At ASH 2013, I interviewed Dr. John Pagel out of the Seattle Cancer Care Alliance (the union of the Fred Hutchinson Cancer Research Center (the Hutch), UW Medicine, and Seattle Children's) who has a very patient friendly way of explaining how these drugs work and what their role might be. Dr. Pagel is also a kind and wise transplanter and as such has extensive experience with conditioning therapies that often include different forms and dosing of radiation to prepare for the transplant and that is another reason why I wanted to hear about his updated research on this important and neglected corner of CLL research. To understand how much or little we have moved forward in the last year, please check out my interview with Dr. Pagel done a year earlier at ASH 2012. As you can read, we are still dealing with the  some of the same old issues that are slowing our progress.

RIT makes most sense to me as a mop up  or "consolidation" therapy and as I have posted before, we desperately need that. I believe RIT should be explored as a final knockout punch to our CLL when it has been decimated and only a few active cells are hiding out in our marrow and our nodes.

I suspect that this research idea won't get much traction.

Dr. Pagel is too kind when he describes why these antibodies with their toxic payload are underutilized.

True they are expensive and tricky to administer, but they are usually a one or two time treatment. 

Sounds good to me. 

The real reason they are not used as much as they could be is that oncologists can not prescribe them. You need to consult a radiation oncologist and even then, the radiation oncologist you see may not offer that option or have much experience with RIT. It requires specialized set up for its administration and management. 

So basically it is a turf issue. 

Here is a link to the abstract that Dr. Pagel presented at ASH 2013.

And here is the interview. As I said as we talked, I love his analogies.

ASH 2013: Dr. Adrian Wiestner Discusses Prognostic and Predictive Factors, the Nuances of 17p deletion and Residual Disease

Merry Christmas.

In the second part of the interview from ASH 2013 in New Orleans, Dr. Adrian Wiestner from the NIH gives us some very carefully considered reflections on the news from the cutting edge changes in our understanding of CLL.

I first asked him to revisit the important issue of predictive versus prognostic factors that I first discussed at iwCLL with Dr. Sharman.

His review of 17p deletion, particularly for those lucky few who are mutated with 17p is very hopeful and nuanced. Listen carefully.

Dr. Wiestner suggested a cut off of 25% to define high risk 17p deletion. The reality is that it depends. While Dr. Tam's research in Blood on de novo 17p del (from the time of diagnosis and not first appearing after treatment) find prognostic significance only when more than 25% of the nuclei are missing the small arm of one of the 17 chromosome, others suggests a lower cut of 20%, some 10%, and some as low as 5% in looking at all cases, de novo and acquired, of 17p deletion. Like many subjects in CLL, consensus is lacking.

My simple take is the less 17p, the better. None is the best.

And we all know that the less disease, the better. Dr. Wiestner points out the obvious but we we need to hear it: You have to get to MRD (minimal residual disease) negativity to get to cure. What does this mean for the new drugs that rarely seem to get to CR, let alone MRD negative? Dr. Wiestner shares some thoughts.

Keep in mind also that 17p is a bad player in that not only does it not allow apoptosis (cell suicide) in response to most chemotherapy and thus rendering common CLL drugs such as fludarabine and cytoxan most ineffective, it also allows the cancer cells to mutate (genomic instability) with no controls on a clone gone bad. Add this clonal devolution to a significant population of residual cancer cells and we begin to understand why initial responses to the new agents such as ibrutinib and idelalsib are excellent, but sadly late relapses are more likely in those of us with a deleted 17p.

This seems to me to be a strong call for dual therapy for the 17p population, but whether that is the answer will only be answered with clinical trials.

Let's listen to Dr Wiestner.



We are so lucky to have a team of doctors working to solve our issues.

More interviews soon.

iwCLL 2013: Dr. John Byrd Discusses the Role of Novel Therapies versus Standard Chemo-Immunotherapy

In the first part of my interview from iwCLL 2013 in Cologne, Germany, my doctor for my ibrutinib trial out of Ohio State (OSU) gives us his take on two of the pressing questions facing us patients.

First, what is the going forward role of chemo-immunotherapy?

Remember that FRC offers those with specific favorable markers a 60% chance of a greater than a nine years MRD negative survival. That is beginning to smell like a cure, but at what price?

Based on his experience with over 400 ibruitinb patients, listen to Dr. Byrd's take. He calls upon the experience with imatinib (Gleevec) in CML to illustrate his point. Not every agrees with Dr. Byrd, but I do.

Next I ask about the vexing issue of residual disease with these new agents. Dr. Byrd is not worried. Hear his reasoning.



On a personal note, I am off to a very frantic ASH meeting tomorrow. Expect on the fly updates.

Still sick and miserable, but I am not I will recover.  Coughing less with a normal chest and sinus x-rays More of a head cold now. I also have been hampered by a cracked computer screen and broken eyeglasses, but the show must go on.