Saturday, February 28, 2015

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.

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Blogger Bryan Sentes said...

Thanks for these clarifications and amplifications, especially re FCR and MRD. FCR is the frontline protocol here in Quebec and if/when it comes time for me to undergo an FCR regimen, I'll be sure to pass this research on to my oncologist--unless even newer data comes to light!

March 1, 2015 at 3:43 AM  
Anonymous Anonymous said...

Thanks Brian. I praise the doctors for having that kind of frank dialogue on that phenomenal video series... So helpful for patients to see true experts with differing opinions.

Nearing frontline treatment I am kicking the can as far out as possible given the precision designed agents being combined in new trials. Seems difficult for Drs to prescribe something new against a regimen w/15 yrs of good data (FCR). It seems the FCR data doesn't encapsulate secondary cancer risk which has impacted so many with FCR. Great that a person who is mutated Trisomy 12 with good markers has a 60% shot at remission from CLL 15 yrs, but what about other cancers, including MDS and AML? The cause and effect from FCR and the 2nd cancer is impossible to prove so it's not in the data.

It seems difficult for a doctor to recommend even these disease-engineered combo trials instead of comparatively "dumb" carpet bombing with FCR for frontline... Yet I suspect many wish they could. And with such long follow up on FCR I fear it will take many more years for novel agent combos to prove their advantage enough to give cover to prescribing doctors. I suspect if the docs had treatment naive CLL many would opt for some of these trials and avoid the chemo complications and DNA damage. After all DNA damage is essentially our problem to begin with in CLL!

It's easy for me to say because I don't have to take the Hippocratic oath or deal with malpractice complications... But I am hoping a different standard will apply given the science behind these new agents which were specifically engineered to our disease. I am a student of this disease and can make that determination for myself. But I am probably the minority as are probably most who read your blog.

March 1, 2015 at 7:31 AM  
Blogger Jeffrey Zuckerman said...

Wow that reply was well written.

March 1, 2015 at 8:28 AM  
Anonymous Anonymous said...

Thanks for this, Brian. Another excellent post.

I commented on an earlier post of yours regarding FCR. At the time I was really struggling with whether or not to use FCR as front line. I have since decided against using FCR, even though I have good markers (mutated, 13q only). Instead, I've enrolled in the ACP-196 trial at OSU. It will mean many of trips to and from Columbus, OH (14 hours round trip), but I feel much more comfortable going this route. The main reason? — that 4-6% (and in one report 10%) chance of acquiring MDS/AML with FCR. Too big of a gamble for me!

March 1, 2015 at 9:38 AM  
Anonymous Anonymous said...

Now if they could figure out who among us is high risk re MDS/AML/Richter's(?) that might change the calculus for this younger untreated 13 q mutated physically fit individual... until then I would remember what Chaya told me: always try and keep another arrow ready to go- thus not likely FR or FCR or BR for me unless the last arrow or new facts?

March 1, 2015 at 3:57 PM  
Anonymous Anonymous said...

A great post! Clearly, these physcians are caring and committed to eradicating CLL. However, to echo the previous sentiments about FCR, there is a real probability of getting into a worse spot.

As someone schooled in numbers and making choices with that information, I am troubled by the steadfast stance that FCR is the starting point. The data on BR and the newer novel agents suggests that these are much less toxic than FCR.

As somebody who may need FCR because I am "young and fit," this choice is not an academic exercise. I wonder how many of these physcians would change their tune if they were in the patients shoes.

Keep up a great blog. I check daily for new updates.

March 2, 2015 at 7:27 AM  
Anonymous Anonymous said...

As Chaya always told us, CLL is not "one size fits all". For those who are eligible for FCR the choice is not easy, as many of you have said. Yes, it would be nice if we knew that several rounds of FCR would buy 10 years or more of remission, but that is not a given. For those of us with 17p, FCR isn't even an option. At least with FCR there is some long term data. With Ibrutinib it's all conjecture.

March 6, 2015 at 10:48 AM  

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