Dr. Furman on genomic testing and MRD negativity in CLL (chronic lymphocytic leukemia)

I am going on radio silence and am writing this from the airport in Qatar so please don’t be upset or worried if I don’t respond to questions or comments.

Betsy Dennison, an oncology RN and NP who handles our website will be posting some interviews from ASH and EHA while I am gone. Today she put up this pretty cool one with Dr. Furman  that really explains the different types of genomic testing and the changing importance  of MRD-  in the era of new therapies.

I must admit for a world traveler, this trip to photo safari in Kenya has me worried. It is a long way aways and it is a long time gone in a poor and dangerous country  in some areas with all kinds of disease that are not a concern here

Once I am there, all should be well. I hear that at the tented safari camps, all is calm and secure if still noisy from all  the nearby animals.

Clothes are sprayed with permethrin, I have a ton of DEET and it is not mosquito season.  I will take Malarone. Kenya does not require a yellow fever vaccine  and risk is very very low and Typhoid can be given as a killed vaccine.  

I am staying away from salads and fruit drinks- that will be hard, and bringing a ton of emergency meds (cipro, immodium, Z-Pak, prednisone, pain meds, anti-histamines, suture kit, disinfectants, and an extra week of all my daily meds including my ibrutinib.)  Sunscreen, N95 masks and hand-sanitizer too.

And I won’t feed the lions, or monkeys or swim with the hippos.

I look forward to catching up when I return.

This is the first trip in years where CLL has not been at the top of the agenda, and where internet is iffy at best.

Stay strong.

We are all in this together.

Brian

The Patients' Perspective on the Changes in CLL (chronic lymphocytic leukemia) Treatment from EHA

If you recall, a month ago I was in Copenhagen for the European Hematology Association  (EHA) meeting and I had the privilege to be asked to speak with a very distinguished panel of CLL experts at a symposium that drew over 1,000 hematologists. Recently in our Conference Coverage section, we have posted a video review by Dr. George Follows of that symposium. You can hear about the highlights here. http://cllsociety.org/2016/07/panel-discussion-management-cll-changing/

Presenting the results of the 350 patients who answered our survey on therapy really added to my credibility in front of my fellow doctors. Thanks to those who helped with that.

If you were on vacation during these first weeks of July, we’d like to call your attention to our quarterly newsletter The CLL Tribune and also request that you take 3 minutes to answer our latest short Reader Poll about what you look for in your CLL physicians. You can access it here. https://asktellq22016.questionpro.com/ Thanks to the 140 CLL patients who have already responded. It really helps. The Tribune is the product of many authors, both patients and doctors. Please enjoy the articles and interviews from the Q2 2016 issue of The CLL Tribune:

· Reading/viewing an interview with Dr. Jeff Jones about Venetoclax from the recent EHA meeting in Copenhagen in Conference Coverage

· Read answers to reader questions by Dr. Rick Furman in Ask the Doctor

· Learn about what bone marrow does in The Basics Section

· In Beyond the Basics, find out about the ASCO sponsored TAPUR trial which is looking for new creative uses for already approved targeted therapies

· Learn new facts about CLL in the Did You Know section

· View some data from our most recent Reader Poll and share with us your opinions on CLL experts and whom you might recommend to other patients in our Ask & Tell section

· In Living Well with CLL, you can read about:

o Why You Should See a CLL Specialist

o How my Support Group Saved my Life

o I Don’t Have CLL. Yes, I Do. Now, I Don’t.

o On Being a Novice Patient

o May I Remember Never To Forget

In the meantime….

Stay strong.

We are all in this together.

Brian Koffman, MD

Volunteer Medical Director of the CLL Society

7/16/16

http://cllsociety.org

Obinutuzumab in CLL (chronic lymphocytic leukemia): Rituximab with an Attitude

This second  OncLive video with Drs. Byrd, Furman, Kipps, and Ma was actually the first, the lead-in to my prior post. In fact the last few minutes of this video are the first few minutes of the video with the same doctors seen on my the recent post discussing ibrutinib.

Obinutuzumab is a powerful antibody directed against CD20 as is rituximab and ofatumumab but it seems to promise better responses as part of a therapeutic combination at least in some circumstances In this case when used with chlorambucil (a gentle form of chemotherapy or alkylating agent similar to cyclophosphamide, the C in FCR), it clearly delivered significantly deeper and longer responses than the other arms of the trial.

While the video session is clearly aimed at the oncology doctors, and our eyes may glaze over when there is a detailed discussion concerning the choice of the best steroid to use to abrogate the potential severe infusion reactions associated with this potent antibody, it is worthwhile to listen and catch the data on obinutuzumab.

It is nice to listen the experts for once discussing the real world concerns about cost and insurance.

It is also good to hear Dr. Kipps point out the critical role of the infusion nurses in keeping us well and safe.

Here is the results from the abstract published in the NEJM with Valentin Goede as the lead author. It is a study that randomized patients to one of three possible therapies: chlorambucil alone, or combined with either rituximab or with obinutuzumab. The trial patients were all untreated and would generally be considered to be too sick due to renal disease or other problems to risk more robust chemo-immunotherapy such as FCR.

Here is part of abstract results:

Obinutuzumab plus Chlorambucil in
Patients with CLL and Coexisting Conditions 

RESULTS

The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab–chlorambucil or rituximab–chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab–chlorambucil vs. 11.1 months with chlorambucil alone;... and 16.3 months with rituximab–chlorambucil vs. 11.1 months with chlorambucil alone;

Please note that the impressive 10 month improvement in the mean progression free survival noted with obinutuzumab–chlorambucil compared to rituximab- chlorambucil. Comparison to chlorambucil monotherapy is not helpful as it is rarely used this way in the USA because of its known lack of efficacy.

CIRS score is a marker of the degree of co-existing illness.

It is important to remember that a benefit demonstrated with one combination is no guarantee that the antibody would demonstrate a similar benefit in any other combos. Assumptions can be dangerous in cancer care.

I am waiting for the published data that Dr. Kipps that show the results of the combination bendamustine and obinutuzumab.

Lastly, what we all really want (if we can't get a cure) is a durable remission. The mean progression free survival was a little over two years (26.7 months) for the mostly elderly treatment naive patients.

Is that enough for you?  Two years is nice respite, especially for a pretty gentle therapy used in a delicate population, but I wanted a longer time before half the group had to live with the reality of their cancer progressing again.

Initiation and Discontinuation of Ibrutinib in Chromic Lymphocytic Leukemia (CLL)

It is not often one gets this much brain power and experience with ibrutinib around one table so I am very grateful to OncLive for arranging this discussion and wanted to share it here.

I was surprised by Dr. Byrd's hesitancy about using ibrutinib frontline.

I was not surprised by the lack of unaminity among the experts.

Here are some of the key points.

1. The immunological modulation effects of ibrutinib are emphasized by Dr. Byrd. It is doing more than interfering with B cell signaling. Same may be true for idelalisib.
2. The future is combination therapies, but what do we do now? Ibrutinib is approved as monotherapy. (That is why we need more trials.)
3. Dr. Furman points out that some Imbruvica patients are continuing to improve 4 or 5 years down the line, getting to CR and even MRD negative.
4. Dr. Kipps doesn't buy we ever get MRD negative if one uses the most sensitive tests, especially in the bone marrow.
5. No-one really knows when to stop therapy.

There is much more between the lines here. Give a listen.



It seems there are three potential visions of how things may play out.

Below, I have grossly oversimplified the three doctors' nuanced perspectives to highlight the wide spectrum of opinions about what may come to pass with the new CLL agents.

• Dr. Furman talks about a significant subset of patients that tolerate ibrutinib therapy well and continue to improve over long period of time, and so we argues why rock the boat and stop therapy, at least outside a clinical trial.

• Dr. Kipps and I agree that you can't get to CURE without passing by MRD negative first, and he wants to be able to stop therapy because the cancer has been once and for all eradicated.

• Dr. Byrd offers a slightly different possible outcome. Treat to get to MRD negative (likely with a combo), stop therapy, and then a very very long durable remission, maybe never requiring more treatment.

I am sure the difference are matters of emphasis and there is much agreement. And much uncertainty.

As Neils Bohr, the Nobel prize winning quantum physicist said: Prediction is very difficult, especially about the future.

FDA Approval of Idelalisib (or CAL-101 or GS-1101 or now Zydelig) for CLL (chronic lymphocytic leukemia), SLL (small lymphocytic lymphoma) and FL (follicular lymphoma)

ME AND A GIANT TREE

SEQUOIA NATIONAL PARK

It was another good week for those of us with CLL/SLL and our friends with Follicular Lymphoma (FL).

CAL-101 AKA GS-1101 AKA idelalisib AKA Zydelig (See Dr. Sharman's post on the name game and his positive early experience with the drug) was approved last week by the FDA for relapsed CLL patients who would be consider candidates for rituximab (R) and for FL and SLL patients who have had 2 prior therapies.

I quote from the label:

----INDICATIONS AND USAGE---------------------------

Zydelig is a kinase inhibitor indicated for the treatment of patients with:

            􏰅  Relapsed chronic lymphocytic leukemia (CLL), in combination with 
rituximab, in patients for whom rituximab alone would be considered 
appropriate therapy due to other co-morbidities. (1.1)

            􏰅  Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients 
who have received at least two prior systemic therapies. (1.2)

            􏰅  Relapsed small lymphocytic lymphoma (SLL) in patients who have 
received at least two prior systemic therapies. (1.3)

Let’s pause and consider this.

A few things should catch our attention and this post is about parsing this first part of the label..

First idelalisib is approved as mono-therapy for SLL or small lymphocytic lymphoma (and FL), but not CLL. With CLL it is only approved for use with rituximab. Moreover, for CLL we can use it on label if we have relapsed after one treatment, but for SLL (and FL), idelalisib must be at least our third therapy.

But aren’t CLL and SLL essentially the same disease? Though we may be starting to tease apart the biology of this pairing (see this article expectedly from Serbia: (Possible role of CD22, CD79b andCD20 expression in distinguishing small lymphocytic lymphoma from chroniclymphocytic leukemia; Danijela Jovanovic, Predrag Djurdjevic, Nebojsa Andjelkovic, LjubicaZivic Contemp Oncol (Pozn) 2014; 18 (1): 29–33 DOI: 10.5114/wo.2013.38570), in almost all practical circumstances, there is no distinction between CLL and SLL and we treat the two diseases as one entity. Until now, with perhaps the one exception to consider possibly curative surgery and/or local radiation for SLL when it is only found in a single node, treatment was the same whether our malignant B cell clone was strictly nodal or it had spilled over into the peripheral blood and marrow.

Now, if we are going to strictly follow the language on the Zydelig label, we will have for the first time both a different indication for treatment and a different treatment protocol for CLL and SLL.

While this is an interesting point, it is probably of little clinical import as SLL recurring three times as strictly nodal would be rare. Idelalisib might be a good choice, but ironically this is exactly where I personally would want to use it in combination, likely with antibody or even chemotherapy.

Next point.

For those of us with CLL, idelalisib is approved after our first relapse. This is different than the CLL indication for ibrutinib, where we only need to have received a single prior therapy and due perhaps to an adverse reaction or intolerance, are now looking for another treatment options but may not have relapsed. (The label says: IMBRUVICA™ is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.) Although the most common circumstance leading to a prescription of Imbruvica would still be relapse, it is possible that some of us couldn’t tolerate FCR or Chlorambucil or other treatments and then still needing some sort of therapy for our progressive CLL, but not having relapsed, would now qualify for Imbruvica but not for Zydelig.

This too would be a rare but possible occurrence.

The last item to be considered in the “Indications and Usage” of Zydelig quoting the label again is indicated, for relapsed CLL in combination with Rituximab:

….in patients for whom rituximab alone would be considered 
appropriate therapy due to other co-morbidities.

Who are these patients? What relapsed patient would ever be offered single agent R? Hard to imagine mono-therapy with rituximab where the response rate as a single agent in relapsed disease is dismal, ironically confirmed in the idelalisib pivotal trial where only 13% of those in the rituximab plus placebo arm got any benefit from treatment.

Before dismissing out of hand this possibility, there are several realities to consider.

First and foremost, the FDA approved the drug based on the trial data it was presented.

The FL and SLL gang were two subpopulations of a larger pool of patients with Non Hodgkins Lymphoma (NHL) that were studied. The data that the FDA used was from that lymphoma patient trial where everyone had to have received at least two prior therapies to be included. Of all those studied, these two subgroups, FL and SLL, responded very nicely to single agent idelalisib, hence the language of the approval.

For the CLL trial group, the phase III study was for patients who were considered too frail based on their co-morbidities (chronic kidney disease and others) for chemo-immunotherapy and thus would be considered for rituximab alone. The results of idelalisb with rituximab versus rituximab alone were, as we all would expect, very impressive.

Are the “Indications and Usage” starting to make sense?  This is the same reasoning that that explains why we have Gazyva only approved for use with Chlorambucil.  That's the way it was studied.


The FDA approvals tend to stick pretty closely to the exact way the drug was studied and thus the pharmaceutical companies tend to reap what they sow.

This is not as crazy as it seems on first blush. It can be dangerous to extrapolate data and the FDA has been burnt too often not be conservative. I am in fact impressed with the speed and the use of the new breakthrough pathways has allowed these important novel drugs to get to market so quickly.

In fact the Zydelig label also adds:

Accelerated approval was granted for FL and SLL based on overall response rate. Improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

As to the actual reasons for the pivotal CLL trial design, I discussed with Dr. Sharman and Dr. Furman in this and this past post about the strong trial data that lead to approval for CLL published in the NEJM and presented at ASH 2013. There are times when single agent rituximab might be considered for relapsed disease in the elderly or frail “slow-go” patients that could not tolerate chemo-immunotherapy. While most if not all CLL gurus that you see interviewed here on my blog and quoted elsewhere on the web, would rarely, if ever use single agent R, it is the real world treatment of choice for about 8% of all relapsed patient in the community. Rituximab maintenance which I discussed a few years back in this post, is also frowned upon by most experts, but is used 9% of the time. 

So again, what seems at first to be a strange qualifier on the relapsed CLL indication label, I suspect won’t prove to be much problem to us patients.

Moreover, how the doctors prescribe them and how insurance pays for them is a whole other topic.

Once it is approved, remember that a doctor can use it however he or she wishes.

Which is a good segue to my final subjects for this post.

Before I finish on this very good news, I wanted to share even more good news by means of this link to the Gilead website that will assist any one considering this important new drug. As does Pharmacyclics, Gilead is offering to help commercial and uninsured patients with practical and generous financial support to make this expensive breakthrough drug more affordable. It is also priced a full $1,000 lower per month that ibrutinib, but that doesn’t consider the additional cost of rituximab. Still cheaper is better.

Unfortunately, like all pharmaceutical companies, even if they wanted to, Gilead cannot directly help Medicare Part D patients. They do nice job explaining the financial hit a Medicare patient faces on their website here.

What they can do is support independent non-profit organizations such as LLS that can then offer financial assistance for both eligible federally-insured and privately-insured patients who need help covering out-of-pocket medication costs. On the LLS site, the income must be below 500% of the federal poverty guidelines, but for a family of four, that is anything below $119,250. 

For more details from Gilead and a number to call on how those of us with government insurance might qualify for financial aid, check here: There is of course no guarantee that help will be provided. Resources are limited, but it is certainly worth investigating.

And here is a link to active idelalisib trials. The expanded access program closed for new enrollees in the USA with Zydelig's approval, but will continue for those already enrolled. 

So in the end, good news. We all need more options, and now we have two great oral medications, both with strong help for most of us from their manufacturers to offset the considerable cost.

I will post more soon on how I see Zydelig fitting in, the the black box warnings and its strength and weakness, but for now I am just so happy we have this new weapon in our arsenal.

Thanks to all of you who volunteered for the trials that helped speed its approval. If appropriate, don't forget to consider trials for these two drugs and for several others existing antibodies and TKIs in the pipeline.

It is a good time in the CLL world and it will only continue to get better, quickly.

Only a few days later after this good news, Imbruvica was approved for front line therapy for those of us with 17p deletion. That is giant. More on that important expanded indication in another post soon. 

Much reason to celebrate as we now have two new powerful oral medications to help us live longer and better.

The news from the LRF Conference and the consultations with my NY doctors

What’s new you ask?

The conference and the meeting with my NY doctors helped clarify my future, even if there was the usual extreme divergence of opinion. Sometimes I think that my survival depends on finding ways to mine the wisdoms of all the different CLL gurus who are often separated by huge chasms in how they approach this illness, a disease so multifaceted that it makes the Hope Diamond look like a glass trinket.

Here is one of the many overly simplistic ways to dice the tomato.

It is fair to say there are two general schools of thought in the CLL community. The futurists and the pragmatists.

The first group’s mantra is that we need to be gentle, we need to avoid risk and toxicity so we can fight again, which we surely need to do.

In the meantime, new wonder drugs are in the pipeline, many of which. like a well scrubbed debutant, had their public coming out at the LRF conference.

They include exciting targeted small molecules that with tight focus interfere with the B cell clone ability to communicate with its neighbors that nourish and protect it from attack and encourage its growth.

New molecules that interfere with its ability to proliferate or with its annoying inability to to die when it gets the signal it is time to self destruct.

New monoclonal that attack more and more specific CLL targets, refusing to say hello and goodbye to even other B cells.

New drugs, often sons and daughters of older ones that modify the immune system in ways not well understood, but that seem to shrink the tumor burden by bringing the cancer to the attention of the authorities.

New gene therapies and vaccines that are finding ways to rekindle the immune systems and getting it to recognize the danger afoot or to resensitize the cancer cells to old killers.

New combinations are being worked out that are smarter with fewer side effects and bigger kill rates.

Watch for more on Cal 101, SYK inhibitors, IMIDs, mTors and others here and at all your favorite CLL haunts.

To these CLL warrior doctors, many of whom split their time between the clinic and the research lab, a stem cell transplant is a blunt weapon, full of certain risk and collateral damage. A must to avoid in all but the most desperate cases. An end game maneuver. If we are smart upfront, we can play this out a long long way. The trick is to avoid drug toxicity and still keep the disease from escaping control.

Don’t let the disease or its treatment kill you with a single fatal blow or a thousand tiny lashes.

Go gently forward. Look at the evidence in the trials and the underlying science. Prod around and don’t always accept the conventional wisdom, but don’t ignore the evidence. Every case is unique.

The brilliant Dr. Furman is of this ilk. He questions everything. He scans the data and needs to be convinced. He is not certain that I even have ITP. Conflicting evidence. He wants to me to hold the IVIG and see what happens. If my platelets fall without the gamma globulin coating to protect them, he recommends Rituxan, but maybe steroids or even a trial of a SYK inhibitor. Works for both CLL and ITP. He is worried about a second transplant and prefers the exciting and cleaner promise of CAL 101 or a revlimid trial. He thinks good old fashion FCR would be a great choice for me with my 11q del. He is not worried about my ITP with the FCR.

The wise and experienced Dr. Rai is more a pragmatist (not that Dr. Furman isn’t practical or Rai isn’t a world class researcher). Last time I saw him he said: DON’T DO ANYTHING STUPID. This time he refused to predict the future. He said every CLL doctor would give you a different opinion. Ain’t that the truth. He said no need to change a winning course. This is definitely ITP because the IVIG is helping. No testing needed. Don’t chase the possible accessory spleens seen on my last CT scans. He says it could be helpful very long term and there are many options if the IVIG stops working. He said I will DEFINITELY need a second transplant. That was as clear as the crystal from which the Queen sips her champagne. He told me that he has had patients that have done very well with a second transplant. He leaves the timing and the path to that to my transplant doctor. That is not his area of expertise, but my tumor load is low now, so there is no urgency. He is strongly against FCR when the time comes to treat the CLL in anticipation of the transplant. He acknowledges that others feel it is safe, but his assessment is that the evidence is weak.

I like most of what Rai has to say. Rai is dealing with what is on the ground now, not what is on the come. The future always looks rosy to the researcher.

I think I will see how long I can ride out the IVIG. Maybe I can stretch the time between treatments to 3 weeks checking Dr. Furman's hypothesis that it may not be ITP by monitoring if my counts falls off a cliff in that extra week without my protein sheath on my platelets.

If it stops working all together, I would like to jump to either HDMP+R for both the CLL and the ITP, then transplant. Or maybe just R to get the ITP whipped into shape, followed by FCR with transplant redux on its heels.

Well, that’s the plan for now.