Ask the Doctor Q4 2015

1. Watch and Wait! I keep hearing that it has been shown that there is no benefit for early treatment. However, this attitude is a remnant from the past due to new breakthroughs like Ibrutinib. Because of the age of most CLL patients, wouldn’t it be beneficial to allow this population to receive this medication to improve the quality of life? (i.e. Not being so tired, Reducing the chances for other cancers, etc.) At ages 55 to 70 the active lifestyle becomes more difficult. Why not allow people to live a fuller life and who really cares of about the long term affects?

It is important to remember that if a patient is having an impact upon their quality of life due to the CLL, than that patient has an indication for treatment. Watch and wait was never meant to defer treatment to anyone having symptoms. The most important thing to remember about watch and wait is that it was studied in several trials in the 1970s and 1980s and demonstrated no advantaged to early initiation of treatment with chlorambucil based treatment over deferring therapy until signs of active disease were met.
Several very important caveats regarding this:

First, anytime someone has met criteria as having active disease (hg<11, plt<100, doubling of lymphocyte count in less than 6 months), they qualify as having active disease. These patients may, and usually are, still asymptomatic, but their disease is active, and there is no benefit for further deferring therapy. Many physicians and patients forget this and believe every day a treatment is delayed is another day longer they will live. This is not the correct interpretation. I have seen many patients put off treatment far too long.

Second, there was no benefit to early initiation of treatment, but there was also no harm. Everyone did the same. Using the adage, “above all else, do no harm”, the philosophy was adapted to defer therapy.

Third, it is important to remember how ineffective chlorambucil based therapy is compared with our agents of today. Our newest agents also don’t have the marrow toxicity that chlorambucil has. Since we have more effective and safer therapies, the issue does need to be revisted.

Fourth, in the 1970s and 1980s, we could not differentiate at diagnosis those who were going to progress early from those who could not. With the data now available regarding prognostic markers, we certainly can have a better idea and select a population who are going to have more aggressive disease.

Overall, the issue does need to be revisited, but it is important to remember that almost everyone treated when they met the standard indications for treatment has done remarkably well and not progressed. Therefore, a benefit would only be present if there were groups of patients who might develop changes during the period of watch and wait that would lead to problems and more resistance later.

2. What exactly is a “complex karotype” in CLL? (I have seen it described a few different ways in publications.). How does it relate to treatment choices up front and down the road?

To understand what a complex karyotype is, it is first important to understand what a karyotype is versus an interphase fluorescent in-situ hybridization (iFISH). When chromosomes divide, they condense down into yellow and black banded structures that consist of all of the DNA tightly wounded around proteins (see picture). These structures are call metaphases. The cell then divides and pulls one copy of each chromosome into the respective cell. In karyotyping, the machinery that pulls the chromosomes apart is poisoned, so the cells stop dividing and sit with the chromosomes condensed. These cells are then stained and examined for the yellow and black banding pattern, which is the karyotype. A normal karyotype is 46XX for a woman and 46 XY for a man.

If abnormalities are present where parts of the chromosomes are deleted or duplicated, these extra pieces are seen and the chromosome that is missing or duplicated can often be identified. This could give rise to a complex karyotype.

In iFISH, fluorescent probes are used to bind to chromosomes of cells that are not dividing. Because these probes are very specific, they are very sensitive and accurate for detecting abnormalities.

The two issues between these two methods for looking at the chromosomes are:

1) When you do karyotyping, you might be examining the cells that are more likely to divide, and since CLL cells do not divide frequently, you may be examining other cells from the bone marrow. Whereas, when you do iFISH, you look at all of the cells, regardless of whether or not they are dividing. So you do not select for one cell over another.

2) With iFISH though, you only see what you are probing for. So if you use a 13q14 probe, and the patient has three copies of chromosome 21, you will miss them. Alternatively, with karyotyping, you see all 23 chromosome pairs, and will pick up anything that is substantial.

Complex karyotype is when a cell has multiple abnormalities on karyotyping, even if it is not a recurrent abnormality seen in a disease. This might be a third chromosome 2p and missing a 6q. These abnormalities are not typical in CLL, but indicate that cells that can withstand that much DNA breakage are very aggressive. In essence, complex karyotyping is another form of prognosticating.

3. A year ago, on a Friday, I awakened with what may have been a mosquito bite just above my left eyebrow. There was increased swelling throughout the day. But the next morning my eyelid and surrounding area was noticeably swollen. The swelling slowly moved down to my left clavicle, and my temp rose to 100.3. I wasn’t alarmed; internet sources said to call the doctor if the temp reached 100.4. On Sunday, I woke up at 5:00, nauseous. Shortly I vomited and, according to my husband, appeared to faint. I was seeing a dermatologist Monday. She prescribed an antibiotic. Ironically, my oncologist appointment was Thursday. When I told him what had transpired, he strongly said I should have called him and gone to ER. ·Was I on my way to sepsis? What signs and symptoms should CLLers be aware of? What should we do, and when?

Sepsis, also call blood poisoning, is when bacteria or fungi are in your blood and are growing sufficiently to cause cardiovascular collapse. The bacterial and fungal products usually cause all of the blood vessels to dilate and the blood pool outside of the core of the body, diminishing perfusion to the brain and vital organs. Patients who are septic, are very ill, and usually will not recover without emergency services.

In the above scenario, there are many reasons you might have felt faint, and it is unlikely that you were septic. One reason that we tell neutropenic patients to go to the ER immediately if they have a temperature greater than 100.4 F (38.0 C) is that they are unable to protect themselves from bacteria and fungi adequately, and can become septic very quickly. In patients who are not neutropenic, the neutrophils are usually able to provide sufficient protection, even in CLL patients.

4. Are there any specific blood markers that predict success with ibrutinib?

The only markers that have specifically been found to predict for resistance of CLL to ibrutinib are mutations in the BTK gene that prevents ibrutinib from binding the BTK protein or causes the upregulation of PLC gamma, an enzyme that enables the cell bypass the inhibited BTK. These are the two published thus far and may explain 80% of ibrutinib resistance. When patients with these markers have their pretreatment marrows examined, we have not been able to find these mutations as being present. So they either develop on therapy or are present at such low levels, and then are selected for by the ibrutinib therapy.

5. To date, has ibrutinib ever been successful in patients with a complex karyotype, and if not, what would be the next treatment strategy?

Yes, ibrutinib is successful in patients with complex karyotype.

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Richard Furman, MD is Director of the CLL Research Center at Weill Cornell Medical College and a member of the Lymphoma/Myeloma Service in the Division of Hematology/Oncology. He is a member of the Medical Advisory Board for the CLL Society.

Originally published in The CLL Tribune Q4 2015.