The Improvisational Oncologist

I have been a big fan of Sid Mukherjee ever since we were om training together.   I was a mere intern and he was a Jr. Resident but it is always fun to be in the presence of somebody who is really smart and really humble about it.

He went on to write, "The Emperor of all Maladies" which won the Pulitzer Prize and documents the history of cancer treatment.  If you haven't read it, I highly recommend you read it or watch the six hour documentary that Ken Burns made out of it for PBS.

Sid wrote an article for the New York Times Magazine posted this weekend called "The Improvisational Oncologist."  It is an informative read that describes some of the new medical adventures we have to take with our patients.  If you haven't read it, I would encourage you to do so.

Venclexta

I have never before done a "guest post" on this blog, although I desperately need to do more of it. This year has been very productive for me publishing scientific papers and there is an incredible amount of work that goes into these efforts.  Unfortunately, it has definitely distracted me quite a bit from doing any blog updates.

One of my favorite research colleagues - Tom Boyd from Yakima Washington has an enormous experience with venclexta.  He has treated quite a few patients on research studies with the drug.  I've treated several patients early on in the development.  Unfortunately, shortly after we got started, there were two well documented episodes of fatal tumor lysis syndrome that occurred at other treating institutions that sadly took the lives of two brave research pioneers.

In my position leading a national research organization, I've done countless chart reviews, registry studies, protocol reviews, etc.  I have gained a healthy respect for the ability of doctors to really mess things up.  This drug is unique - the speed with which it works is almost unprecidented.  The potential downside of that can be rapid biochemical shifts as cells die off that require additional medical caution.  While the rate of "low grade" tumor lysis syndrome is about 4% in some studies, clinical trials provide rigorous oversight that may not be as available in the real world experience with the drug.

I am extremely pleased by the length to which Abbvie is extending support to treating doctors to ensure that the drug is used safely.  I cannot recall a drug launch in which the pharmaceutical company made such a strong commitment to physician education.  I would still encourage patients who are going to start this drug to read section 2.3 of the prescribing information.  An educated patient can be an extra set of eyes on the data and provide an additional layer of safety.

I asked Tom if he would be willing to put his thoughts about this drug into a post.  12 hours later he sent me this - thanks Tom.  And oh yeah, by the way, happy birthday old man!  Here is his post:

These are exciting and hopeful times for patients with CLL and physicians treating CLL.

Dr. Sharman asked me to review some of my experience with the recently approved drug VENCLEXTA (venetoclax). I have treated 10 patients with this drug as part of an ongoing Genentech trial. This drug is also known as venetoclax and ABT-199 (generic and research names). It has been under development for about 10 years. The drug was co-developed with Abbvie and Genentech.

The initial approval by the FDA on 4/11/16 was for patients with the 17p deletion in chronic lymphocytic leukemia who have undergone at least one prior therapy. At this point, it is only approved as a single agent (not given with other drugs like Rituxan, chlorambucil or bendamustine). Unlike other oral agents which the FDA recently approved (B-cell receptor drugs such as ibrutinib and idelalisib), this drug works as a bcl-2 inhibitor.

What is bcl-2 and how does VENCLEXTA/venetoclax really work?

The term ‘bcl-2’ refers to an enzyme within the cancer cell that helps keep the cell alive. Almost all CLL cells have a significant ‘overexpression’ of bcl-2. The bcl-2 family of proteins are located in the mitochondria of all cells (including CLL cell). The mitochondria are the energy producing structures which reside in the cytoplasm of all cells. That ‘overexpression’ of bcl-2 means the cells tend to live forever and don’t undergo normal cell death. That is why the white blood count tends to rise and the lymph nodes enlarge steadily during ‘watch and wait.’

VENCLEXTA (ABT-199) is a selective oral medication which inhibits bcl-2. As a result of exposure of CLL cells to VENCLEXTA, there is almost always a rapid apoptosis (rapid death of CLL cells). Most CLL cells have a significant imbalance in their bcl-2 proteins in the mitochondria. There is an interesting video showing the way we believe that VENCLEXTA works on microscopic level (https://www.youtube.com/watch?v=OGvIlvH-ke4).

What does the recent approval mean to patients with CLL?

Since the 17-p deletion only occurs in a small percentage of patients with early CLL, it will have limited use for most patients at this time. If you either have a 17-p deletion at diagnosis (~10% chance) or developed it later on (up to 40% chance), there is a good chance your doctor may consider the option of treatment with VENCLEXTA. In order to receive this drug you will have to have had one or more prior treatments.

Your doctor will have to consider all the options which are useful in patients with CLL and the 17-p deletion. Currently, ibrutinib is the most commonly used medication. Many clinical trials with ibrutinib, ACP-196 and ABT-199 are actively studying patients with this high risk mutations. Some of these studies also incorporate drugs such as Rituxan, Gazyva or bendamustine.

If your doctor believes that you are a candidate for VENCLEXTA, your would need to undergo a number of lab tests, scans to look at the lymph node & spleen size and finally a bone marrow exam. If you have a great deal of disease (high white count, very large lymph node, a big spleen and a ‘packed’ bone marrow), then the risks associated with treatment may be much higher. Some patients with higher risk for tumor lysis will need to spend time in the hospital during their initial therapy. Many of the clinical trials for this drug required admission to a hospital for initiation of treatment.

Overall, the treatment with VENCLEXTA has been very well tolerated in research studies, with many patients now on therapy for over two years. However, the initial management (first month of treatment) can be associated with tumor lysis syndrome. That syndrome lead to some deaths and kidney dialysis in the early trials with VENCLEXTA (ABT-199). Therefore the attention and care in starting this drug is MUCH MORE complicated than other oral treatments for CLL. Dr. Sharman discusses the issue of tumor lysis elsewhere.

Should I run off to the nearest major cancer center to be treated with this new agent?

If you do not have the 17-p deletion mutation, then at this time you could only receive this drug, except as part of a clinical trial. However, as with ibrutinib, the indications for treatment will likely broaden to other groups of patients with relapsed (previously treated) and untreated CLL. It is very likely that you will have this treatment option in the next year or two.

If you have been previously treated and you have the 17-p deletion, then you might be a good candidate for treatment with VENCLEXTA. At this point, very few physicians have a lot of experience with this drug. Both Dr. Sharman and I are concerned about the use of this drug by inexperienced physicians and centers. Very careful lab monitoring, hydration and treatment for uric acid levels are critical. You might consider a second opinion before starting this drug, if your situation allows.

If you and your doctor decide to start treatment with VENCLEXTA, then i would encourage you to carefully read everything you can about this agent to understand all the safety issues including a knowledge of tumor lysis syndrome.

Which doctors should treat CLL patients with this new drug?

Technically almost any cancer doctor can write a prescription for this drug. I would strongly recommend that only a doctor who is experienced in CLL treatments should be managing the initial month of therapy. Once the drug is escalated up to full dose than most cancer doctors could easily follow you for longer term monitoring.

How is this oral drug different than ibrutinib? Is it better, safer and better tolerated?

Both ibrutinib and venetoclax are oral drugs. They work in different ways to kill and inhibit CLL cells. As we discussed above, the veneotoclax tends to kill CLL cells quickly and the WBC in many trials is essentially normal within a month. Ibrutinib, on the other hand, results in ‘re-distrubution’ of CLL cells with a rising white count over the first month in most patients. Both drugs result in fairly rapid shrink in the enlarged lymph nodes. VENCLEXTA seems to produce deeper remissions (‘MRD negative’ blood and bone marrow tests).

Sides effects with VENCLEXTA include neutropenia (low white count), anemia and low platelet count. Intestinal symptoms were also fairly common, but could be controlled with lower doses. Most people are able to carry on normal activities. Side effects with ibrutinib include easy bleeding and atrial fibrillation (irregular heart beat).

We do not yet know how long to treat patients with ibrutinib and VENCLEXTA. Dr.Sharman and I both have patients who has been doing well on ibrutinib for over 6 years. A number of patients have been on continous VENCLEXTA for over two years.

If I have a 17p deletion in my CLL how quickly does therapy need to be started?

Some patients may require treatment fairly quickly, but in most cases, reviewing you options and deciding about treatment might go on for a couple months. Some cases of CLL and 17-p deletion will only progress slowly, giving you and your doctor lots of time to look at all the choices carefully (bcl-2 inhibitors, ibrutinib, antibodies and chemotherapy).

If I have a 17p deletion which drug should my doctor be using ibrutinib, acalabrutinib, ldelalisib, or venetoclax?

The good news is that all of these drugs represent major improvements in treatment of 17-p deleted CLL compared to 5 years ago. Your best choice will likely depend on your other medical conditions. Your doctor may be influenced by heart disease, bleeding risk, use of anticoagulants, ….. Your insurance may require you to start with one of these agents initially. Your concern about the small, but very real risk of TLS may affect your choices.

If I do not have 17p deletion can I receive this drug? What if I have other higher risk genetic changes such as 11q deletion or and un-mutated IGHV?

There are a number of active trials looking at use of VENCLEXTA either alone or in combination for other patients with CLL (not just 17p deleted). As mentioned above, if you don’t require treatment immediately, then several additional treatment options with VENCLEXTA and other agents may become available in the next 1-2 years.

What would I do if I had CLL right now?

This is always a tough question to throw back at your doctor. There are so many choices with CLL that it can even be confusing for Hematologists. I just turned 63 years old last week, so I am a very typical age for the initial diagnosis of CLL [but, Dr. Sharman has yet to send me a birthday card ;-) …].

If I had low risk disease that required treatment, then many choices may be very good options such as FCR, BR, and Gazyva (for example). If there was a nearby trial for VENCLEXTA, I would try to learn more about it.

If I had higher risk disease (11q deletion or and unmutated IGVH) then I would explore treatments with the agents such as ibrutinib or trials which incorporated ACP-196 or VENCLEXTA.

If I had CLL with a 17-p deletion I would want to be sure my treatment options included ibrutinib, ACP-196 and VENCLEXTA. We do not have any direct comparisons between these agents, but I am impressed with the ‘depth of response’ seen in many patients following treatment with VENCLEXTA alone or in combination.

Tom Boyd

Venetoclax approved

Venetoclax has been approved!!!

Horray, just came out of a patients room and told her this would be approved by the next time I saw her.  I guess I was wrong, it was already approved!

This is a fantastic drug and one of the most effective agents ever in CLL.  See the press release (click here).  Several years ago, I wrote about BCL-2 as a target (click here)

I have written about tumor lysis previously (click here) and it is worth a read.

This drug is currently approved for patients with relapsed CLL that has 17P deletion - but like ibrutinib will become more and more available as new clinical trials read out.

More later if I can find time to post

Idelalisib - Breaking News

Breaking News: Gilead Sciences Halts Six Idelalisib Combination Trials from Patient Power on Vimeo.