ASCO 2014: Dr. Furman Gives us Perspective on Resistance with Ibrutinib in CLL (chronic lymphocytic leukemia)

More of My Son, Ben's Mural Work

ASCO 2014 was only a few months ago, but happily the CLL world is a fast moving place.

Since this video interview with Dr. Rick Furman of Weill Cornell, recorded and edited by Andrew Schorr and his team at Patient Power, idelasilib has been approved for CLL (see this post for discussion of its labeled indication) as predicted by Dr. Furman, and ibrutinib was approved for frontline therapy in 17p deleted patients (see this post).

YEAH to both!

Also in the intervening months, new mathematical models that consider evolution of resistant sub clones have been published by Dr. Burger out of MDACC and a high powered mathematical team headed by Dr. Natalia Komorova out of UCI. (I plan to interview Dr. Komorova as we are practically neighbors in Orange County, CA). Similar research, but this time using deep genetic analysis of the cancer's evolution over time by Dr. Cathy Wu from Dana Farber was presented at AACR 2014 Hematologic Malignancies Conference last week. (I also plan to post on her important research soon.)

The issue of ibrutinib resistance may be becoming an increasingly important issue. More and more of us are doing great with our BTK inhibited, but we still have residual disease and if you are similar to me with bad markers such as clonal diversity, 17p deletion, 11q deletion, and have a history of having been heavily pretreated (I have the first three for sure and many would say the 4th with my bone marrow transplant), then the fear of a resistant sub clone starting to act out, while still not the case for most of us even with the worst of the worst disease, is based on a growing reality of a droopy Kaplan-Meier (KM) Curve. Below are KM plots from OSU published in NATURE at the start of the year that show the downward drift in progression free and overall survival for those of us that are 17p deleted. As you can see the curves are way better than anything else out there, but they are hardly perfect.

This whole resistance issue might be largely obviated in the future by moving the new therapies up to frontline status. Dr. Furman and I both agree that is the direction we need to encourage with appropriate trials and struggles with insurers to pay for these drugs in all treatment naive patients.

Dr. Furman also mentions two exciting new BTK inhibitors, ACP-196 and ONO-4059. Click on the drugs' names to be linked to their phase 1 trials. We are just in the first chapters, but it is looking that the stories they will tell should have very happy endings. Please consider trials that offer these drugs among your treatment options.

Here is my ASCO 2014 interview with Dr. Rick Furman.



As there is a small but significant cohort of FCR patients that do great for years and years, there is a much much larger cohort of patients taking ibrutinib and other small molecules, now based on more than on more than four years of data, that should continue to do well year after year.

I am so happy for all these patients.

But I worry about the minority who won't do well, who will relapse. I am not giving up on my plea: Don't leave us stranded on 3rd base- Get us to the home plate of a cure with a follow up therapy.

We discuss obinutuzumab and ABT-199 as mop up therapies and I think those are smart choices. Maybe it will be cirmtuzumab, a new ROR1 mAB discussed in my recent post with Dr. Kipps from the very same meeting. We will only find out with clinical trials.

Celebrating My Two Year Anniversary Today on Ibrutinib for My CLL (chronic lymphocytic leukemia)

Much has happened in the last two years, most of it very good.

On a personal note, I swallowed my first 3 battleship grey capsules of PCI-32765 (it wasn't even called ibrutinib yet) on May 7, 2012 in a Phase I/II clinical trial at OSU with Dr. Byrd.

Two years later my lymph nodes have shrunk to less than 1/2 their size with the possibility that all that remains on the CT scans is the scarred shells of what used to be cancerous nodes.

Today, to find any CLL in my blood, you can no longer rely on the standard bloods test but must do the vey sensitive flow cytometry to find the < 0.3% of cells that are still clonal.

My latest bone marrow biopsy was 15 months ago in Feb. 2013 and even back then it showed only 4% CLL by flow cytometry down from between 10%-20% a year earlier.

I am clearly in a very deep and deepening remission.

I am very grateful.

On a community note, ibrutinib, the first in class signal blocker (BTK) for CLL, received breakthrough approval in the USA for anyone who has tried at least one prior therapy based on its outstanding safety and efficacy data in all patient groups, including those with 17p deletions and other hard to treat clones. But it is broadly available to any of us who have tried but not necessarily failed just one prior therapy.

Obinutuzumab, a potent 3rd generation monoclonal antibody (mAb) is now on the market and is getting complete remissions with the wimpy help of a touch of chlorambucil in clinical trials. Clearly it is this new mAB that is doing the heavy lifting.

Idelalisib, another  exciting targeted oral medication, should be approved later this year based on its stellar efficacy results in pivotal trials with few adverse events.

ABT-199 is proving to be perhaps the most potent oral agent yet in difficult to that patients.

ONO (ONO 4059) and Infinity (IPI 145) and others have very promising signal blockers well into development.

ROR1 trials are just beginning and should offer laser like focusing and very little off target damage.

CAR-T therapy has pulled a handful of patients from near death to deep remissions.

I was revising a 2012 CME (continuing medical education) on CLL program that I will be giving in Baltimore in June and realized just how far we (and I personally have) have come.

I am very grateful.

After  all, we are all in this together.

I think I''ll enjoy some  home made coconut milk yogurt to celebrate the amazing progress.

ASH 2013: Dr. Jennifer Brown Discusses the New Data on Obinutuzumab (GA-101 or Gazyva)

At ASH 2013, there was much to celebrate for those us with CLL.

This interview was recorded immediately after Dr. Jennifer Brown of Dana Farber had moderated an exciting CLL press conference in that same noisy press room.

While the small molecules that can be taken orally such as ibrutininb, idelalisib, ABT-199 and even the newer IPI-145 and ONO 4059 may have hogged much of the headlines over the last few year in the CLL world, there was important news about a new and better monoclonal antibody or mAb, namely obinutuzumab.

This one, like rituximab and ofatumumab, is directed against CD20, a surface protein found on all B cells, good and bad.

So like its fellow anti-CD20 mAbs, obinutuzumab knocks out all our B cells, leaving us at an increased risk for new infections and reactivation of old ones such as hepatitis B.

A bit of a background on another mAB first.

I have to say after all the excitement following the the approval of the second generation fully humanized CD20 antibody, ofatumumab, I have been disappointed in the results. Its main advantage seems to be for anyone allergic to rituximab, lovingly called "mouse juice" by the thousands of us who have had it dripped into our arms at infusion centers across the world because of its unholy but magic mix of mouse and human proteins (especially strange to think about if you are vegan like me). Despite high doses of pre-medications with steroids and antihistamines, some of us patients just can't get our bodies to stay calm in the presence of the mouse antigen and let the antibody do its important work. That is where ofatumumab has shined. No mouse proteins, so those who could not tolerate "Vitamin R" had an option. But the impressive improvement in efficacy over rituximab that I and many others were hoping for has not really materialized.

Obinutuzumab tells a different story. People are living longer significantly longer as Dr. Brown will detail on camera. The results are clearly better. The bar with rituximab was already set pretty high. Rituximab might be a lousy CLL drug on its own, but as a dancing partner it makes everyone look like a Fred Astaire (or Ginger Rogers). Its addition to FC forming the "gold standard" of FCR was the first time that any therapy was shown to prolong survival in CLL.

Dr. Brown of Harvard now gives us even better news on obinutuzumab.

But first we review how it was engineered to get these strong results and explains why being the first type 2 anti-CD20 antibody is so important to its efficacy.

And she discusses the management of the higher risk of infusion reactions. Please remember that although these new antibodies have no murine proteins, they can still cause rather severe infusion reactions, precisely because the bind so strongly to our B cells and are such potent killers.

Here is Dr. Jennifer Brown:



Remember too that this drug is already approved for CLL. From the package insert: in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

As I have reviewed in a prior post, this is a very limited indication, and much of its benefit would be expected to come in its use with other more potent combinations than with chlorambucil and for patients who have relapsed or who are refractory to other therapies including other mAbs. I would hope that it appropriate use off label is not rebuffed by the payers.

I expect soon to see a growing number of trials mixing and matching the new TKIs with obinutuzumab to get us that elusive CR. We need more trials. To get to our ultimate goal, a cure, we must first get to and pass CR, and most of the TKIs are leaving stalled on 3rd base with some persistent measurable disease. These new oral wonder drugs still need a teammate to get us home to a cure, and obinutuzumab is a very strong candidate to play that role.

That is the future I want. Rational non-chemo combinations edging us closer to a cure. It can't come soon enough. But we need more creative trials and more brave risk takers to make them happen.