Saturday, April 12, 2014

Mutated vs. Unmutated CLL

I was surprised to realize that I have not posted on the difference between “mutated” and “unmutated” CLL.  This is such a basic characterization of CLL that I assumed I had posted on it previously.

Credit belongs to the late “Terry Hamblin” whose lab actually helped figure this out and created his own CLL blog “mutated/unmutated” that was a valuable source for CLL education prior to his death.  For many insightful articles on CLL I would direct readers to his blog.

Whether a case of CLL is referred to as “mutated” or not is a characterization of the B cell receptor (BCR).  Remember that every B cell has its own unique BCR and it will only have that one BCR for the entire life of the B cell.  When a B cell grows up to full maturity, the BCR becomes a secreted antibody.  You make antibodies to fight off just about every infection out there.  Each infection you can fight off represents the success of a B cell to identify it, go through a bunch of rounds of cell division, then mature to make antibodies.  Each B cell has one and only one unique BCR.

The interaction between B cells and whatever they are trying to fight off is a really important event in B cell biology.  Keep in mind that diseases like lupus and rheumatoid arthritis are really just B cells getting confused between what is normal in your body and what is an invading microorganism.  It is super important that B cells stay properly focused on things that are not you and leave the rest of you alone.

This is where T cells come into play.  T cells are sort of like B cell chaperones.  T cells help determine if the B cell that has received a “signal” through the BCR that is worth fighting off or not.  If the T cell thinks the B cell is on the right track it provides “T cell help.”  If the T cell thinks the B cell is misguided, it can kill the B cell.

When a B cell gets “T cell help,” the B cell goes through a process called “affinity maturation.”  That is just a fancy phrase to describe a set of changes that are designed to “refine” the BCR of the engaged B cell into a more effective antibody.  The B cell literally turns on machinery that induces mutations into the BCR.  Those that do a better job fighting the infection are selected to live and those that do worse get eliminated from the body.  Many of those mutations are in a very specific part of the BCR called the “variable region” aka. IgVH (for the variable region of the heavy chain of the immunoglobulin).

This is where we get the terminology “mutated” BCR, or “mutated “IgVH” or even “mutated CLL.”  So what is “unmutated” then.

Turns out, there are circumstances where a B cell can engage an invading germ and based upon the interaction, can go on to B cell maturity without T cell help.  In these cases there is no “affinity maturation” and no mutations are introduced into the IgVH.  When CLL arises from such cells they are referred to as “unmutated.”  If they go through T cell help they acquire BCR mutations.  At least that is the main theory out there that is somewhat under challenge.

For discussion sake, it is probably fair to say that a particular individual with CLL will have disease that is entirely “mutated” or “unmutated.”  The way we measure this is to compare the genetic sequence of an individuals BCR and compare it to all the known “templates” in the human body.  If it is ≤ 98% identical, we call it mutated where more than that is non-mutated.

So why does it matter?

Turns out that cases with an unmutated IgVH / BCR typically have disease that grows more quickly.  Quite frequently it is associated with other high risk markers like deletion of chromosomes 11Q or 17P.  If you dig deeper than FISH, you also find that many of the high risk mutations such as BIRC3, SF3B1 and NOTCH are also more common in unmutated CLL and help determine prognosis.  In short, it is often worse disease.

In fact, in our recent paper in the New England Journal ofMedicine looking at idelalisib in combination with rituximab, something like 85% of the patients who needed treatment for relapsed disease had an unmutated BCR.  I think that is a fairly dramatic example of who is likely to have problems with their disease and need treatment.  The patients with mutated IgVH didn’t accrue nearly as frequently to the study because they don’t relapse as commonly (it is about a 50/50 split in new cases).

Stopping the discussion at mutated / unmutated also misses some really fascinating information on “stereotyped” B cell receptors which are common in CLL.  I have a prior post on the subject.  In short, stereotypes can happen in about a third of CLL cases and may have very specific prognostic / predictive information for patients that can be good or bad depending on the subtype.

Mutated / unmutated also makes a difference with the new drugs like ibrutinib and idelalisib.  Since these drugs are inhibiting signaling through the B cell receptor, perhaps it is not surprising that there are differences in responses between the two.  In contrast to the general themes of who does better / worse with chemo, it would appear that patientswith unmutated BCR / IgVH actually respond more quickly and deeply to ibrutinib. 

It makes me speculate what will happen when we are finally able to use these drugs in the front line setting.  Would it make more sense to use 6 months of chemoimmunotherapy like FCR or Bendamustine / Rituximab in those patients with a mutated BCR because they are likely to get durable disease control?  Perhaps we would then use the newer drugs in those patients with unmutated IgVH where the long term benefit of chemotherapy is less?  Maybe a test that allowed to us fully remove all the high risk patients with mutations or FISH abnormalities should be the ones to get chemo?  Perhaps taking a pill every day is better even if it has to be taken for many years.  I expect different patients will answer that differently.

Anyhow, I frequently will test for the IgVH mutation status at diagnosis because it gives me some ability to predict what the future might look like.  I often follow those patients a little more closely in the first year or two to make sure they don’t get into trouble whereas I am a little more relaxed with the patients with a mutated IgVH.  Patients want to know how their disease is likely to behave, this is a test I commonly use.

A few disclaimers are important. 

ZAP-70 is a test we used to use more commonly but for the most part it is merely a proxy for the status of the IgVH mutation status.  Those cases that are unmutated (bad) tend to have high ZAP-70 and vice versa.  Unfortunately testing for ZAP-70 has a lot of technical difficulties and it isn’t nearly as reliable as sending for mutation analysis.  I do not use ZAP-70 in my clinic though there are some selected labs who do a good job (University of California San Diego) and I would trust their results.

Measuring CD38 is an attempt to classify how much the CLL isproliferating.  This can be useful, but other data sets have shown that CLL cells are often dying at the same rate or higher.  Merely knowing the “birth rate”isn’t quite as useful since we don’t have a test to measure the “death rate.”  I like to think of CD38 as “how fast is the treadmill going.”  While you may not be going anywhere, it can be useful to know how quickly you are spinning your wheels trying to get there (see prior posts on clonal evolution).

Finally, we designate mutated versus unmutated based upon the percentage of sequence similarity to known genetic sequences.  2% is the magical number.  If you are greater than 2% different you are“mutated” while those that are less than 2% are “unmutated.”  Occasionally you get a case where you are at 1.9% different.  Once again, this is probably humans trying to make a categorical variable out of continuous data.  Probably safe to say that the more mutated you are the better up to a point.

Anyhow, I hope that is a useful primer on why we get this test.  I always order this and FISH at diagnosis.  Others will argue that you don’t need FISH until you are going to select therapy.  Fine, good people can disagree – I won’t argue that point but I want to know and I think informed patients want to know.  I am looking forward to being able to test for the new molecular markers as well and I suppose it may be the same debate there.

Thanks for reading

Saturday, March 1, 2014

ASH 2013 Video WIth Andrew Schorr

This was a video we did at ASH in December prior to the approval of ibrutinib.  At the time, we didn't know the terminology the FDA would use to describe its "approval."

The main topic of discussion in this video is primarily how a patient goes about choosing a therapy in CLL.  In many cases patients will feel comfortable with a physician recommendation, in other cases they may want to educate themselves about all their options and make their own choice.

In the midst of new treatments like ibrutinib, idelalisib, ABT-199, Gazyva etc. that can be bewildering. Not sure if this video helps sort it out or not, but it is short and hopefully worth your time

Wednesday, February 12, 2014

Irbrutinib has been approved in CLL


Here is the press release from ASCO:

From the American Society of Clinical Oncology
In cooperation with the Food and Drug Administration (FDA), and as a service to our members, ASCO will periodically distribute information about newly approved therapies for cancer patients.  This helps FDA to inform oncologists and professionals in oncology-related fields of recent approvals in a timely manner.  Included in the email from the FDA will be a link to the product label, which will provide the relevant clinical information on the indication, contraindications, dosing, and safety.  In sending this information, ASCO does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.  The following is a message from the FDA's Office of Hematology and Oncology Products Director, Dr. Richard Pazdur:

On February 12, 2014, the U. S. Food and Drug Administration granted accelerated approval to ibrutinib (IMBRUVICA, Pharmacyclics, Inc.) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.  Ibrutinib previously received accelerated approval on November 13, 2013 for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.
The approval in CLL was based on the results of a multi-center, single-arm trial of 48 patients with previously treated CLL. The median age was 67 years (range, 37 to 82 years) and 71% were male. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years and the median number of prior treatments was 4 (range, 1 to 12 treatments).  Ibrutinib was administered orally at 420 mg once daily until disease progression or unacceptable toxicity.

The efficacy results demonstrated a 58.3% overall response rate (95% CI: 43.2, 72.4) as assessed by an independent review committee.  No complete responses were observed. The response duration ranged from 5.6 to 24.2+ months; the median was not reached.

The safety profile of ibrutinib for patients with previously treated CLL was consistent with observations in the mantle cell lymphoma clinical trial.  The most common adverse reactions reported in the CLL clinical trial (occurring in greater than or equal to 20% of patients) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness.

As a condition of this accelerated approval, the FDA required that the sponsor submit results of randomized clinical trial(s.) In January 2014, Pharmacyclics notified FDA of the early stopping of the RESONATE trial by the Data Monitoring Committee (DMC) based on favorable results of a planned interim analysis. RESONATE, a phase 3 clinical trial, randomized patients to either ibrutinib or ofatumumab.  Patients entered on this trial had previously treated CLL or small lymphocytic lymphoma (SLL) and were not considered candidates for treatment with purine analogue-based treatments.  The trial was reported to demonstrate an improvement in progression-free survival and overall survival.  

The recommended dose and schedule of ibrutinib for patients with CLL is 420 mg (three 140 mg capsules) taken orally once daily.
Full prescribing information is available at: