Friday, August 7, 2020

ASH 2019: Dr. Jennifer Brown on Using Ibrutinib after progressing on Venetoclax for Ibrutinib-Naïve Patients with Chronic Lymphocytic Leukemia (CLL)

There has been much discussion, but little data on what is the best order of medications to treat CLL and whether combining drugs is better than sequencing them in the long run. In other words, what is the best way to use all this great drugs to keep us alive the longest.


At ASH 2019, in Orlando, FL, I interviewed Dr. Jennifer Brown, Director of CLL Research at Dana Farber Cancer Institute in Boston and a Professor at Harvard Medical School about her real-world research to gather some data to inform these discussions.


Specifically, Dr. Brown looked at the data for those patients who had taken venetoclax, but not ibrutinib, and then relapsed. The basic question she was asking was how well they did.


Take Aways:

·     We have known for some time that venetoclax is a successful salvage therapy for those who fail a BTK inhibitor such as ibrutinib or acalabrutinib. Dr. Wierda was talking about this back in 2017.


·     We have much less data on the other way around. Now that venetoclax is approved frontline and will likely be increasingly used frontline or in later lines of therapy ahead of a BTK inhibitor, we really do need to know.


·    Dr. Brown led a group of researchers that retrospectively looked at 27 patients had never been on ibrutinib but who had received venetoclax, but then relapsed or stopped.


·    On average, venetoclax was the 3rd line of treatment for these patients, so ibrutinib would be the 4th, a tough group to treat.


·     Risk factors for progression on venetoclax were as expected: del 17p (4/10; 40.0%), del 11q (4/9; 44.4%), complex karyotype (8/17; 47.1%) and unmutated IGHV (11/14; 78.6%). For more on these tests, see our Test Before Treat Section.


·     56% or 14 of the 27 patients responded to ibrutinib with one achieving a complete remission.


·     The time to progression on ibrutinib post-venetoclax varied from 3.0 to 53.0 months.


·     Slightly less than half of the ibrutinib patients who stopped did so because of progressive disease (PD). 


Conclusion:


We know there is life after ibrutinib. Now we know that there is at least one good option after ibrutinib, at least for those who have never been on it before.


What we don’t know is what is the best sequencing of the good drugs that we have. All drugs work best when used as the first therapy, but which order is the best.  


For more, please enjoy my interview from ASH 2019 with Dr. Brown here.


For  more of the details, please take a look at the abstract itself: Outcomes of Ibrutinib Therapy in Ibrutinib-Naïve Patients with Chronic Lymphocytic Leukemia (CLL) Progressing after Venetoclax.


For a different perspective on this same sequencing issue, see my interview with Dr. Mato from the same ASH 2019: Dr. Mato on Sequencing of Chronic Lymphocytic Leukemia (CLL) therapies after Venetoclax.


Stay strong, 

We are all in this together

Brian

Sunday, August 4, 2019

ASH 2018: Dr. Neil Kay on how Stromal Cells Keep CLL (chronic lymphocytic leukemia) Cells Alive in the Bone Marrow and How we Can Intervene


At ASH 2018 in San Diego, CA, I interviewed Dr. Neil Kay out of Mayo Clinic, Rochester, MN, an innovative chronic lymphocytic leukemia researcher who besides caring for CLL patients and doing clinical trials, is doing important “bench” science where when we are fortunate we can find insights that can transform how we can best knock out the CLL cells.

Dr. Kay’s research presented at ASH 2018 was on the supportive stromal cells in the bone marrow, formally known as mesenchymal stromal cells (MSCs).

Takeaways:
·       Stromal cells are part of a network of cells in the bone marrow that help keep CLL cells from dying.
·       Dr. Kay’s lab has built a model of MSCs supporting CLL cells for experimentation. 
·      They discovered that the marrow stromal cell mediated increased expression in two enzymes, β-catenin and Axl in CLL B-cells is associated with leukemic cell survival and drug resistance. 
·       The experimental drug, TP-0903 blocks Axl and reduces CLL cells’ survival and their ability to resist chemotherapy.

Conclusions:

It is easy to forget that ibrutinib was only developed as the amazing breakthrough for chronic lymphocytic leukemia it is when the importance of the B-cell receptor (BCR) to CLL cells survival was recognized, in other words when that biology was cracked.

Dr. Kay and his team is trying to do the same kind of thing with this research and it has quickly gone from bench to bedside in a clinical trial using TP-0903 alone or in combination with ibrutinib: Phase 1/2 Study of TP-0903 (an Inhibitor of AXL Kinase) in Patients With Previously Treated CLL.

It is an intriguing direction, attacking the soil, not just the seed of cancer. For more of the importance of cancer micro-environment, see my interview with Dr. Wang, also from Mayo.

While the science may be less accessible than we talk about clinical trial results, there would be no new drugs for clinical trials without this basic laboratory research.

Here is my ASH 2018 interview with Dr. Kay.



Here is the actual abstract.

Thanks for reading


Brian Koffman

Saturday, July 13, 2019

So tired

So tired.

I have been tired and sleepy for weeks now. Which is weird as my CLL is in a deep deep deep remission.

I first blamed it on stress- have a googol of problems weighing on me, but I usually cope well with pressure. 

Been traveling >100,000 miles in the last 6 months including 2 hectic sleep robbing trips to Europe to lecture on chronic lymphocytic leukemia or CLL in June so I thought maybe jet lag. But I’ve been home for 10 days now, so that should have resolved by now.

Have an 18-wheeler full of to -dos ahead of me, but that isn’t all that unusual. One at a time is my mantra.

Been in increased pain due to my bone on bone osteoarthritic knees. I had a scare yesterday when I developed increased right calf pain and swelling in my foot. A quick Doppler showed no blood clot, but I do have significant excess fluids in my calf likely due to my arthritis and swelling around the knee. Pain can wear anyone down, but I am used to low grade pain.

Blood pressure and pulse are low normal and I don’t feel sick.

My labs are all great, not anemic, CLL is no where to be seen in the blood and no enlarged nodes. Blood chemistries are fine except for low protein. I do have some elevated inflammatory markers that don’t help my energy.

Checked my thyroid and it’s normal too. I don’t snore, so I doubt I have sleep apnea.

Tried my usual remedies- sleeping in, naps, dark chocolate, more exercise, less food, change of scenery. No help. Some ice coffee helps for a few hours.

Now I switching to less swimming and more weight training, no naps and going to bed early.

And working anyway. 

This too will pass.

Wednesday, May 22, 2019

May 15, 2019: FDA approved venetoclax in combination with obinutuzumab for the treatment of people with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

This is very big news.
This is the first non-chemotherapy based fixed duration treatment for CLL in treatment naïve patients.
Until this approval, the only viable approved treatments were fixed duration chemotherapy or taking ibrutinib until progression or side effects force you off.
Of course, venetoclax and obinutzumab could have been and have been used together “off label” as they are both already approved medications, but now insurance will have no excuse not to pay for it.  And doctors less familiar with treating CLL should feel comfortable with an another strong option for a first therapy.
The Phase III study was done by the well-respected German CLL study group lead by Prof. Hallek out of Cologne.
Here is a link to the Abbvie press release.
Below is part of the press release from Genentech who is co-developing venetoclax with Abbvie
About the CLL14 Study
CLL14 (NCT02242942) is a randomized Phase III study evaluating the combination of fixed-duration venetoclax plus obinutuzumab compared to obinutuzumab plus chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL) and co-existing medical conditions. 432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venetoclax alongside six-month duration of Obinutuzumab (Arm A) or six-month duration of obinutuzumab plus chlorambucil followed by an additional six-month duration of chlorambucil (Arm B). Arm A started with an initial cycle of obinutuzumab followed by a five-week venetoclax dose ramp-up to help reduce tumor burden. The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints include PFS assessed by Independent Review Committee (IRC), minimal residual disease (MRD) status, overall response (OR), complete response (with or without complete blood count recovery, CR/CRi), overall survival (OS), duration of response (DOR), event-free survival (EFS), time to next CLL treatment (TTNT), and safety. The CLL14 study is being conducted in cooperation with the German CLL Study Group (GCLLSG), headed by Michael Hallek, M.D., University of Cologne.
The most common adverse reactions with Venetoclax plus Obinutuzumab were low white blood cell count (neutropenia), diarrhea, fatigue, nausea, low red blood cell count (anemia), and upper respiratory tract infection.
Comments:
This is a powerful new option for patients to consider. Just how durable these responses will be remains to be determined, but the depth of the remissions with ¾ of patients reaching U-MRD (undetectable minimal disease or less than one CLL cell per 10,000 white blood cells) in the peripheral blood and 56% in the bone marrow bodes well for lengthy responses. For more on MRD from Prof. Hallek , see this interview from ASH 2017. What we patients want to see if very durable PFS (progression fee survival) and OS (overall survival), and the early results are promising.
Moreover, hopefully this is the first of many such approvals of fixed duration combinations that will be coming over the next few years that could revolutionize how CLL is treated. And of course, the approval raises the question as to which combos and sequences are best.
Exciting times for us patients.
Brian Koffman, Chief Medical Officer, CLL Society

Sunday, May 12, 2019

Acalabrutinib Phase III ASCEND trial met primary endpoint at interim analysis in relapsed or refractory chronic lymphocytic leukemia and will stop early

This trial in previously treated CLL patients showed a clinically significant progression free survival when compared to a combination regimen of rituximab plus physician’s choice of idelalisib or bendamustine. No new side effects or problems were noted.
While not unexpected, it is important to have this trial confirmation that another BTK inhibitor, like ibrutinib has proven to save lives.
This is more good news for CLL patients. Acalabrutinib is already approved for mantle cell lymphoma (MCL) and hopefully will be soon approved for us CLL patients based on this and Phase 3 trials that should have positive results soon.
While not approved for CLL, because it is approved for MCL and is part of the NCCN guidelines for CLL, it is already an option today for appropriate CLL patients if your doctor pushes for it.
Here is a link to a nice review of the data we have so far and more trial news.
Here is the official press release.
It is good to have more choices of all these great drugs. Can’t wait for approval to make it easier to access.
Stay strong,
Brian
Brian Koffman MDCM DCFP, DABFM, MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.

Tuesday, March 26, 2019

One Year CAR-T Anniversary to Treat my CLL and an Interview with Dr. Siddiqi about how chronic lymphocytic leukemia treatment has change since ASH 2018

Hi
March 22, 2019 was my one year anniversary of receiving my experimental CAR-T cells in Seattle.
About a month earlier, I got the great news that I remain U-MRD4 in the peripheral blood- no CLL to be found. Read more here: https://cllsociety.org/2019/03/one-year-anniversary/
Also this week, I posted a brief ASH 2018 interview with Dr. Siddiqi that hits the important practice changing data that emerged from ASH 2018. See: https://cllsociety.org/2019/03/ash-2018-dr-siddiqi-on-the-practice-changing-lessons-for-treating-cll/
Enjoying a total of two weeks at home before I head to Bethesda for our educational forum at the NIH on April 5. Hope to see some of you there.
Stay strong.
We are all in this together.
Brian
Brian Koffman MDCM DCFP, DABFM, MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.
PO Box 1390
Claremont, CA 91711

Saturday, February 16, 2019

CMS Approval of CAR-T Therapy

CMS approves CAR-T therapy payment, but with significant strings attached. For more details see: https://cllsociety.org/2019/02/cms-approves-car-t-therapy-payment/
This is a positive first step, but only the first step. We will be interviewing experts on funding over the next few weeks.
I am proud of the small role I played in this by going to CMS and lobbying on behalf of future CAR-T patients.
If you want a personal response, or just want to stay in touch, please email me at bkoffmanMD@gmail.com. I have no other way of contacting. 
Thanks. Stay strong. After all, we are all in this together. 
And please visit our website: http://cllsociety.org for the latest news and information.
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