How Ibrutinib and other perhaps other BTK inhibitor work over time in CLL (chronic lymphocytic leukemia)

At ASH 2016 in San Diego, CA, I had the honor of once again interviewing Dr. Wiestner from the NIH (National Institute of Health) about the prototype BTK inhibitor, ibrutinib and how and why it works so well in CLL.

We have known for a while that for its survival and well-being, our cancer is dependent on BCR (B cell receptor) signaling. Blocking BTK (Bruton’s Tyrosine Kinase), blocks that BCR signaling and that blocking usually leads to our cancer’s retreat.

This is a well-understood critical tenet of why ibrutinib works as well as it does, but it is hardly the whole story as we are learning over time.

At the NIH, Dr. Wiestner and his team not only did some of the earliest clinical research on ibrutinib, but also has been doing the bench science on exactly how it works and its impact changes over time.

Please enjoy the interview here: http://cllsociety.org/2017/02/ash-2016-wiestner-ibrutinib-cll/

Stay strong.

We are all in this together.

Brian

http://cllsociety.org

Dr. Wiestner on Novel Therapies for CLL (chronic lymphocytic leukemia), Oral versus IV therapies, Idelalisib plus Chemo-immunotherapy Update and my Lingering Cold

Our very thin CLL Society team is busy preparing for the ASCO (American Society of Clinical Oncology) 2015 Annual meeting which starts at the end of this week in Chicago, but we still found time to bring three diverse and instructive new topics to our website http://cllsociety.org for this week.

Today, Monday, May 25, 2015, we posted Dr. Adrian Wiestner's thoughtful and well-considered interview from ASH (American Society of Hematology) 2014 on what is known and unknown about novel therapies. You can find that here.

Expect more video interviews and commentaries from ASH 2014 over the next several weeks.

On Wednesday, the camera is turned on yours truly for my personal take on CLL topics of interest. We include the short video and an updated transcript on this week's topic of oral versus IV medications. I think you might be surprised at some of the issues and non-issues in what would seem at first glance to be should be a simple choice. I have posted extensively about the tragedies that were associated with potent oral medications before we knew about the risk of tumor lysis with ABT-199 now known as venetoclax or in the case of lenalidomide (Revlimid), where there is also the risk of tumor flare. These risks have largely been mitigated now with new dosing protocols. Please see this prior blog post for part of the story.

 This new section on the CLL Society website using monologues and text will roll out here.

And this will be only the first in a long series of instructional postings on the various CLL therapies.

On Friday, we will post an up to the minute review of and link to an important ASCO 2105 abstract about the latest data on combining idelalisib with chemo-immunotherapy. You will find it here on Friday.

Please let us know what you think, especially about my reading and the transcripts of my monologues. You can contact the CLL Society here or email directly, but the 1^st method is preferable.

We are constantly working to respond to the unmet needs of the CLL community, so we listen carefully to what you write us and try to respond as best we can.

We don't have a big production budget and team or large institutional backing, but we keep going to offer up the most robust and recent, yet still accessible information with no gloss and no agenda other than to inform our community.

Because we believe that SMART PATIENTS GET SMART CARE™

Switching to a personal update, my wife and I are stilling struggling with a lingering upper respiratory infection aka a cold that my beautiful granddaughter shared when visiting from Chicago. No fever or cough for me. With the frequent use of a Neti pot, normal saline and steroid nasal sprays and a single shot of a decongestant (and no antibiotics), I have managed to control the symptoms and survive the pressure changes in the first of several air flights.  Both of us remain “under the weather” after a full week of symptoms, but we are slowly improving.

For most of my immune-competent patients, I would never recommend an antibiotic in such circumstances, but I am not most patients and either are any of my fellow CLLers. We are all immune comprised. Our immune systems are as dysfunctional as hyperactive adolescents who are asked to focus on a single boring multi-step math problem while the rest of the vibrant world pours on around them. Like those teenagers, my immunity’s focus is weak and easily diverted to the wrong target, having lead in the past to my nasty autoimmune problem of ITP.

Tomorrow I am at Ohio State for my three-month follow up on my ibrutinib trial.

Expecting another good lab report. Usually my neutrophils jump up when I am sick at all, even with a viral illness.

I wonder if Dr. Byrd will add an antibiotic and chide me for treating myself, always an ill-advised choice.

Personal confession: I worry about my admittedly relatively mild added illness. Worrying is already too easy to do with CLL, and even more so when we are sick. URIs can lead to chest infections and pneumonia is still the leading cause of mortality in CLL.

I will be much happier when this infection is gone.

I will be home one day this week, long enough to get my every 6 week dose of IVIG.

Late in the week, I will be Orlando for less than 24 hours to lecture on anemia and gout to some 400 primary care providers. Then I fly onto Chicago for the very busy ASCO (American Society of Clinical Oncology) Annual meeting.

Rest is not in the picture. But it is a good busy and I will be with friends everywhere I travel.

I may even get to see the little girl who gave me the cold in Chicago. If we are both well.

Thanks

Stay strong

We are all in this together.

Brian Koffman

Volunteer Medical Director of the CLL Society

ASH 2014: Rough Notes from Dr. Clive Zent and Dr. Wiestner on Prognostic Factors and Resistance in CLL (chronic lymphocytic leukemia)

I found these notes that I had originally planned to use to develop blog posts based on a lecture that I attended at ASH 2014.

I still might do that, but first I am sharing this discovery in its raw form.

I took down all this information live on my laptop as it happened in December 2014 in a lecture hall at ASH, so expect it to be very rough and full of typos and mistakes. 

And don't take it for gospel! I have not done my usual fact checking.

Though it is still mostly unedited, I did try to clean it up a bit. Otherwise it would have been completely indecipherable for most. So I explained a few of the acronyms, improved the grammar, added the occasional punctuation, fixed some of the typos and provided some minimal text to help with context.

I wanted to share a sense of what I try to do at ASH and other cancer meetings. 

I wanted to share the velocity and volume of the information that sometimes comes from the podium. 

This is the raw material that I do my best to unpack, decode, make accessible, explain, contextualize, add relevant references, fact check, and publish here and elsewhere.

So this is hardly my usual blog post. I share it for two reasons:

1. First, it is full of incredibly valuable tidbits of information, albeit in bullet form with almost no explanatory notes.
2. Second, it shares a bit of a peek behind the curtains about what goes on at some of these huge medical conference.

Here goes.

Dr. Clive Zent

In the 1970s, the only testing for genetic testing and prognostic indicators was by karyotype analysis

Major limits- needs metaphase (not that common in CLL), needs BM (bone marrow). Only looks at whole chromosomes

1990s, we get FISH

Limits: can look at specific site only

Now we have a new era of genetic testing

Old school Sanger Sequencing needed 10% of mutation to find it, slow, expensive
PCR amplification needs only 1%
Next generation now look at whole gene- faster, cheaper
SNP arrays (clinical role unclear)
Copy # variations
Loss of heterozygosity

Usually only find 10-20 genes that are mutated
Usually found in " pathways"  controlling DNA repair such as TP53 + ATM
BRC
IGH

DNA damage responses ATM + TP53 related,  eons 4-9 (5-15%)
TP53 usually mono-alelle  5% at time of dx,
11q 10% (exon 68s)

Loss of function

Most common loss of one 17p with 80% of mutation on other gene
In contrast, 11q loss has only about 30% mutation on other gene
Can also have bi-allele losses

What does in mean?

Poor survival

BCR signaling pathways

no known mutations at start (abstract 297 disputes this) but somatic hypermutation, stereotypy

Notch1 10% at dx  in PEST domain
30% of those w RT
up to 20x inc risk of RT
BIRC3 11q22.2  near ATM  6 MB bases from 11q22.3  (asoc w loss of ATM0
significant on its own

RNA editing
SF3B1
splicing factor3 subunit 1
10% at dx
Poor Px dec resp to CIT

Clonal Evolution

No longer believe we develop new clones but start with small one that grow
Freq by FISH  (which is low) 4-5% year, but in next gen 20% after RX
Clinically important for resistance

Does clonal size matter?
Large # of mutations not findable yet, but sub clones of 17p matter even if low #

Comparison of MOLECULAR GENETICS AND PROGNOSIS

13q same as no CLL

TP53 BIRC3  worse

Moving forward

Very high risk-
 P53 and ATM (function testing)
High/intermediate

TP53 - No CIT ( chemo-immunotherapy)

Novel therapies then immune therapies including HSCT or CART1

NOTCH1 targeted theory
SF3B1

Summary Test TP53 and ATM (testing functioning coming soon)

Dr. Adrian Wiestner

Novel therapies in CLL
BCR Pathway
CLL a malignancy of anti-self" B cells
BCR  repertoire is skewed
Stereotyped BCR
often recognizes auto-antigen
Binds self motifs in itself

BCR activation in lymph nodes- CLL dependent on micro-envirnoments

IBRUTINIB NO MTD(maximum tolerated dose)!

RESPONSES WITHIN DAYS

Dramatic shrinkage of nodes but persistent lymphocytosis

With just 1 dose, lymph counts  jumps 50%

Larger patient to patient variability

Different patterns

Unmutated:  high ALC count quick up and downMutated: more SLL like, slower rise and fall- more durable results?

Most of the rise in ALC is from cell redistribution at first, but clear that IBRUT does much more
Measured tumor burden falls by CT and BMB

80-90% reduction: can start with trillion of cells

Cells in peril are not a concern: When you look they have inhibited BCR and NF kappa B and low Ki-67 suggesting no proliferation

Idelalisib PI3K delta  NO MTD!

Unaffected by adverse PX  factors inc 17p especially in first yr

IBR AEs
Diarrhea
AF 5% vs 0.5%  but much longer exposure
Bleeding mostly petechiae- not significant
Grade 3 or higher  no difference in either arm
IDEL AEs
Diarrhea 30%,7% colitis
20% Grade 3 Pneumonia

46% PFS  with 17p deletion

Complex karyotype  are the ones who progress- that is the group that progresses

PFS front line 17p del is >80%

Resistance:

Mutation Cysteine 481 is the problem,- IBRUT can no longer bind covalently (still weakly binds and  has some activity) Two cases of resistance, there was activated in PLC gamma 2 downstream (gain of function)

What about progression due to Richter's transformation?

Q: Is it more or less than without ibrutinib?

In 63 cases of 17p  RT was found in 23% at median of 12 months; risk factor was complex karyotype

Maybe it's actually less risk w Ibrut

Steve Treon

Ibrutinib in WM /LPL (Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma) by 

IGM falls by 75% and Hgb climbs

69% major response in WM

Ibrutinib Research from Dr. Wiestner at the NIH

Below is the press release (PR) from the recent meeting in Washington, DC of the AACR (American Assoc. of Cancer Research) concerning the research by Dr. Wiestner's group at the NIH.

There are a number of things to keep in mind when reading the PR.

First that 29 of 53 patients were 17p del and 30 were relapsed or refractory. These were not the easiest patients to treat.

Second remember this was ibrutinib flying solo. No help from bendamustine or an antibody.

Third this is still early data. We don't know the durability of these fantastic results.

Finally , we learn that the drug is active in all lymphocyte compartments, the blood, the lymph nodes, the spleen, and the marrow.

Please take a look of this data in light of Dr. Wiestner's recent plea that we carefully reassess whether we need to continue with business as usual by insisting more is better and pushing for the "ideal chemo cocktail."

Rather I believe that these new targeted therapies demand that we fully reassess how we treat CLL and we don't just add these molecules to the existing mixes, effective as they are, but  rather we see what they can do on their own, and make slow and logical decisions about what combinations (if any) to consider. 

I like the idea of totally avoiding old school chemo if possible, but only time will tell if that is the wisest approach.

Even mixing two pathway blockers, while mechanistically appealing, is totally unknown territory.

One reason I fear that one reason that chemo or biologicals such as rituximab might get added to these trials (especially true for the very potent and active idelalisib or CAL 101 that where the high counts might linger a bit longer) is that the benign spike seen in the absolute lymphocyte count as the B lymphocyte clone cells exit their protective enclaves in the nodes and marrow and enter the blood stream where they can be counted, may last a long time and makes the early data look weak. Those raised numbers suggest the drug is not working to the uninitiated and it takes works to explain the back story. We all know that is not the case and they are in fact potent therapies, but adding chemo or a mAb solves that short term concern and speeds up the data collection. My questions are: Does it really improve outcome? Does it add unnecessary risk?

Truth is we don't know the answers. That is why we need the trials, but the reported 94% event free survival at 1 year as solo therapy is hard to improve on.

Here is the press release from AACR:

Embargoed for Release:                                                    Media Contact:

1 p.m. ET, April 8, 2013                                                      Jeremy Moore

                                                                                               (215) 446-7109

                                                                                               Jeremy.Moore@aacr.org

                                                                                               In Washington, D.C.
April 6-10, 2013:
(202) 249-4005

Ibrutinib Safe, Effective Against Untreated, Relapsed and Unresponsive Chronic Lymphocytic Leukemia

·      Ibrutinib disrupts the CLL-driving B-cell receptor signaling pathway.

·      Phase II trial showed the drug was well tolerated and effective against CLL regardless of del 17p status.

·      The drug was effective against disease in blood, lymph nodes, spleen and bone marrow.

WASHINGTON, D.C. — The novel drug ibrutinib was well tolerated and highly effective in patients with untreated, relapsed and unresponsive chronic lymphocytic leukemia (CLL), according to phase II data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

“The degree of tumor reduction achieved by once-daily oral therapy was impressive,” said Adrian Wiestner, M.D., Ph.D., investigator and head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) in Bethesda, Md. “We have seen patients with more than 90 percent reduction of lymph node disease within just two months.” 

Many elderly patients with CLL are unable to tolerate current aggressive standard therapies, and those with a deletion in the short arm of chromosome 17, referred to as “del 17p,” have particularly poor outcomes with chemotherapy. These two CLL patient populations that are enrolled in the NIH phase II study have the greatest need for novel treatment therapies, according to Wiestner.

Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL. This study confirms the single-agent antileukemia activity seen in prior phase I/II studies and extends this experience, particularly in del 17p CLL, according to Wiestner.

He and his colleagues enrolled 53 patients with CLL into two cohorts — 29 patients with del 17p and 24 patients without del 17p who were aged 65 years or older. They assigned all patients to 420 mg of ibrutinib daily and evaluated response to the drug at six months and every six months thereafter, until disease progression.

Most adverse events were mild or moderate and included diarrhea, fatigue and rash, severe events occurred in less than 13 percent of the patients.

At six months, 95 percent of patients showed at least a 50 percent reduction in lymph node disease, and all showed reduction in spleen enlargement, with a median reduction of 55 percent. In 26 patients for whom a bone marrow biopsy was done, tumor infiltration decreased by 82 percent. Absolute lymphocyte count decreased by a median of 62 percent. Using standard CLL response criteria, 52 percent of patients had a partial response. At 12 months, the estimated event-free survival rate was 94 percent.

Using blood and tissue samples of lymph nodes collected from 15 patients before and during ibrutinib treatment, Wiestner and his colleagues showed effective inhibition of B-cell receptor signaling and tumor proliferation, which was reduced by more than 80 percent, as measured by Ki67 staining.

“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status,” Wiestner said. “Responses appear to be durable, and the drug is effective against the disease in lymph nodes, spleen and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach will greatly improve the lives of patients with this disease.”

This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute at the NIH.

 

# # #

Press registration for the AACR Annual Meeting 2013 is free to qualified journalists and public information officers: www.aacr.org/PressRegistration.

Follow the AACR on Twitter: @aacr #aacr
Follow the AACR on Facebook: http://www.facebook.com/aacr.org

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit www.AACR.org. 

On a personal note, I am just back from a wonderful, meaningful high school reunion held in Vancouver, BC  though we all went to an all boys school in Toronto (UTS) three thousand miles away. I am hoping to do one of my personal reflective posts soon, but  because of the important breaking news and backlog of interviews, I have been weak on telling my CLL and life story that is happily boringly stable these days. 

Later this week I will be lecturing in Orlando, Florida. 

No rest.

ASH 2012: Dr. Adrian Wiestner: Final Thoughts

The thoughtful Dr. Wiestner of the NIH has some provocative things to say in this brief 2 minute wrap up of our interview.

He says that there may be a significant role for chemotherapy in the future for some carefully selected CLL patients.

He reminds us that these new drugs should force us to re-examine our bedrock views about cancer cocktails. They should force us to revisit all our traditional approaches.

That is a hard thing to do, but a good thing. Doctors are by nature conservative and slow to change.

But there is a sea change coming and Dr. Wiestner suggests that this is a time to really consider what  old baggage can be tossed and what we might need on this voyage.

IMPORTANT: Dr. Wiestner's trial at the NHLBI still has openings for treatment naive 17p del patients. Check out http://www.clinicaltrials.gov/ct2/show/NCT01500733?term=CLL+17p+Ibrutinib&recr=Recruiting&rank=2 . This is a great opportunity at the NIH for those who qualify and I understand a number of fellow Canadians have already enrolled.

Soon I will share his updated data on this research.

Right now, here is the second part of the ASH 2012 interview:



I still have a few surprises from ASH 2012, before I start posting from ASCO 2013 later this month.

I am happy to share that my good friend and fellow CLL survivor and patient advocate, Andrew Schorr of Patient Power and I will be combining forces to offer up several interviews on CLL and other blood and solid cancer from ASCO in Chicago.

I am looking forward to working with Andrew and his professional and pro-patient team.

I have so much I want to share here: more on non-chemo approaches, important discussions on the place of cross-overs in clinical trials, new data from the AACR meeting, what we can learn from the death and autopsy of those who didn't make it, new trials starting up and old trials closing down.

So much to share.

On a personal note, May 7th marked my one year anniversary of my taking ibrutinib. I still remember my disbelief that my nodes seemed to be shrinking in those first few days, but they were. And still are. a year later, albeit, in a less dramatic fashion.

So much has happened in this last year. My mission here and elsewhere is push that we patients can get the best possible care, and that involves more research, great doctors, and wise and brave patients.

We have all those and we sure have moved the bar forward in the last year!

Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in CLL/SLL Patients and Has Minimal Effects On Platelet Aggregation

Apparently, judging by some of the emails that I received, my epistaxis (bloody nose) generated some general concern, so I am glad to be able to say that I am no longer walking around with a tissue at the constant ready, and more importantly, I have some reassuring research to share from an ASH 2012 abstract.

No less an expert than Dr. Mohammed Farooqui from the NIH did the study titled Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) Patients and Has Minimal Effects On Platelet Aggregation without any pharma support that looked at not only at platelet counts, but also how well they actually function or aggregate, a critical step in clot formation, and other measures of their activity. He found what yours truly had suggested in my last post.

Although grade 1 or 2 (mild or moderate and not dangerous or disabling) bruising is a known adverse event seen with an ibrutinib, Dr. Farooqui found in looking at 25 volunteers in the NIH trial who were taking 420 mg a day that " This preliminary report does not identify any significant ibrutinib effect on platelet function." Equally important, platelet counts rapidly improved. He concludes by saying something very similar to what I gathered from the old literature that I referenced in my last post:  A rough day: Bloody nose times two and a tender rash minutes before my CLL and MDS lectures in Chicago. I quote the last line of the ASH abstract: "The apparent functional tolerance of BTK inhibition in platelets is likely attributable to redundancy in the affected signaling pathways." What I said was "there are also clearly redundant pathways and signaling to get a healthy thrombus going in response to an arterial injury."  Like minded, except Dr. Farooqui has the lab data to support his finding.

Here's another thing I really liked about his abstract beside the reassurance on the platelet issue.


"This work was supported by the Intramural Research Program of NHLBI, NIH. We thank our patients for participating in these research studies." 

They not only funded the research themselves because they thought it was important, but they thanked the patients. That is so rare and so welcome. I would have to call Dr. Mohammed Farooqui and his team at the NIH (including my old friend, Dr. Wiestner) mensches (Yiddish for a good people).

Now you might argue that I should have read all the ASH abstracts that mention ibrutinib by now and you would make a good point. I am therefore most grateful to the reader who pointed me to this particular research after reading my last post. In my defense, I have been a tad busy with travel and teaching. I guarantee that all the ASH abstracts that mention CLL will be read with more than a few reviews presented here over the next few weeks.

As my more constant reader can perhaps tell from my upbeat tone, I am feeling much better with not only no more bloody noses or other issues with which to deal, but thankfully with a rested mind and body.

Nothing like a good night's sleep and being home again with my wife and cat.