Date: November 9, 2005
by Chaya Venkat
Perhaps one of the most read articles on our website is What Type of CLL Do You Have? Rightly so, in my opinion. How can we make informed therapy decisions if we do not have a good handle on the nature of our disease? That is like shooting in the dark. You might get lucky and hit the target, but equally likely that you will shoot yourself in the foot, or some place even more painful.
I cannot overemphasize this point: it is very important to know the name and face of your enemy. This aspect of living with CLL has become of personal interest to me and PC. After a routine blood test in 2001 showed my husband had higher than normal WBC, we were referred to a local oncologist (one of two in this small town in Arizona). He promptly had PC get a CT scan, an ultrasound scan, and a lymph node biopsy. The biopsy was a full blown surgical procedure, with full anesthesia, the works. We waited with bated breath for the next week while the samples from the biopsy were examined. The oncologist called us in to review the results. The pivotal phrase was “some sort of lympho-proliferative disease”. Heck, I could have said that, just looking at his higher than normal WBC, it was obvious his lymphocytes had proliferated! Without inviting any further discussion, the oncologist went on to say that PC had Stage-4 non-Hodgkin’s lymphoma, we were looking at a possible survival of 2 years or thereabouts. There was no time to waste and PC had better start fludarabine therapy the very next day. He had his hand on the door knob all the time he spoke, shutting out any discussion. It was your proverbial bum’s rush.
That was in the spring of 2001. To make a long story short, it turned out PC had Stage-1 CLL, a much more benign diagnosis. More than four years later he has not yet had to resort to standard chemotherapy. Annual Rituxan therapy seems to hold the CLL at bay, and we are just as happy that he had not started fludarabine therapy on that fateful day (Fludarabine Monotherapy Is No Longer the Gold Standard). I lost a lot of my naiveté over those frantic and terrifying early days and weeks. Judging by what we went through as a family, patient education and empowerment became a very personal crusade for us. Ignorance can kill you, whether the ignorance is yours or your oncologist’s (What You and Your Oncologist Need to Know). It pays to remember you have more skin in this game than any one else.
An incident happened just a few days ago that brought this issue of accurate diagnosis back into stark focus for me.
This time around, the problem was distinguishing CLL from Mantle Cell Lymphoma (MCL). In its early “leukemic” phase when the lymphoma cells are circulating in the blood, MCL is very hard to distinguish from CLL. However, this distinction is crucial because MCL is a heck of a lot more aggressive disease than CLL. Typically, it has a shorter fuse and requires a different approach to therapy. (There is a version of MCL that is also indolent, but this is not very common). Someone with MCL which is incorrectly diagnosed as CLL can be lulled into a false sense of security and stay in Watch & Wait mode for too long.
I received an email from a member whose father had just been diagnosed with CLL. After reading our many articles on the importance of getting prognostic testing done early in the game (Prognosis at Diagnosis), the patient had a FISH analysis done (FISH-ing for Answers). To make a long story short, the FISH results showed her father had no abnormalities detected in his 13q, 11q, 12, or 17p chromosomes. Good news! Right? Hold your horses. There was a little something else in the report. It said her father was positive for “Cyclin D1 / IGHG”. What the heck is that? I remembered vaguely reading something about this. Fortunately I have become pretty good at data-mining, and soon I located a bang-on-target article, published in a 2005 issue of the British Journal of Hematology. The icing on the cake — the authors were the CLL team at the Mayo Clinic, many of whom I knew personally. Incidentally, if you want to read the full text of the article all you have to do is write to us and we will help you locate it. My bullet point list below gives the bare bones of some of the differences between CLL and its more dangerous cousin MCL.
Br J Haematol. 2005 Jul;130(1):36-42.
Interphase fluorescence in situ hybridization with an IGH probe is important in the evaluation of patients with a clinical diagnosis of chronic lymphocytic leukaemia.
Nowakowski GS, Dewald GW, Hoyer JD, Paternoster SF, Stockero KJ, Fink SR, Smoley SA, Remstein ED, Phyliky RL, Call TG, Shanafelt TD, Kay NE, Zent CS.
Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN
Translocations involving IGH are common in some lymphoid malignancies but are believed to be rare in chronic lymphocytic leukaemia (CLL). To study the clinical utility of fluorescence in situ hybridization (FISH) for IGH translocations, we reviewed 1032 patients with a presumptive diagnosis of CLL. Seventy-six (7%) patients had IGH translocations. Pathology and clinical data were available for the 24 patients evaluated at the Mayo Clinic. Ten (42%) patients had IGH/cyclin D1 fusion and were diagnosed with mantle cell lymphoma (MCL). The immunophenotype was typical of MCL in three of these patients and atypical for MCL in seven patients. One patient had biclonal disease with typical MCL and CLL with IGH/BCL-2. Eleven (46%) patients had IGH/BCL-2 fusion including the patient with biclonal disease. Two of these patients had leukaemic phase follicular lymphoma and nine patients had CLL. The median progression-free survival of patients with CLL and IGH/BCL-2 translocation was 20.6 months. The two patients with IGH/BCL-3 fusion (one of these also had IGH/BCL-11a) had rapid disease progression. The IGH partner gene was not identified in two patients. We conclude that use of an IGH probe in FISH analysis of monoclonal B-cell lymphocytosis improves diagnostic precision and could have prognostic value in patients with CLL.
Important, as in it can make a life-or-death difference. Here is the skinny on MCL, how to distinguish it from CLL and why it is important to make this distinction. I gathered these bullet points from the article as well as the informative emails I received from the Mayo team in response to my query.
After exchanging a couple of emails with the Mayo folks, I began to appreciate the significance of our patient testing positive of IGH / Cyclin D1 (also known as t(11;14) in shorthand notation), that this could be a tell-tale marker of MCL, rather than CLL. With zero pressure on my part, Dr. Clive Zent (one of the Mayo authors on the paper cited above) agreed to take a phone call from our member. Below is an excerpt from her letter back to me (I took out the personal bits in the letter). As you can see, getting an accurate diagnosis is at the heart of making smart therapy choices. The game strategy is quite different for MCL patients, compared to CLL patients. How many of us would consider removal of the spleen as a frontline option, so soon after diagnosis? Yet, it might very well be the way to go for this patient.
I spoke with Dr. Zent last night. He gave me some great information about CCND1/IGHG t(11:14) translocation which produces the cyclin D1 protein so we now know that we are actually dealing with Mantle Cell Lymphoma in the leukemic phase, presuming the test was done accurately.
Some other diagnostic factors, like my father's massive spleen, all other lymph nodes being clear, bright CD20, would further support that. Dr. Zent has a close colleague practicing locally. I spoke with her office this morning and we have an appt scheduled for Nov. 15.
I think our first step will be to repeat the FISH analysis to confirm the diagnosis. Dr. Zent spoke also about frontline purine analog therapy with fludarabine and Rituxan (less toxic than R-CHOP) and then dependent upon response to that looking into allogeneic transplant. Of course we will know more and have a more accurate idea once we meet with Dr. Zent’s colleague. Due to the splenomegaly, the first response could quite probably be splenectomy.
Speaking with Dr. Zent was extremely helpful and quite reassuring, given the situation, to be able to have that contact with someone at the forefront of this disease.
By now we should all be familiar with FISH analysis. If you are not, I suggest you remedy that right away! This blood test looks for specific chromosomal abnormalities that are common in CLL, by means of using specific probes sensitive to each abnormality. Typical CLL FISH panel includes 13q, 11q, 12 trisomy and 17p abnormalities. If none of these abnormalities are seen, the patient is reported to have “normal” cytogenetics. Frankly, I find this name tag deceptive. When a patient has none of the common abnormalities tested for by the FISH probes used, it is probably more accurate to call it “none of the above” or "unknown". What you see depends on what you test for. If you don’t test for a given abnormality, with a specific probe for that abnormality, you will not be able to see it.
I was very pleased that we were able to field this fly ball for our member, help her get an accurate diagnosis of her father’s illness. We were no more than the intermediaries in this case, the real thanks goes to the experts we were able to reach right away, and who were willing to provide their guidance on a pro-bono basis. CLL Topics is now about 3 years old. We think one of our biggest success stories is the number of CLL experts we now have on our informal advisory board. These experts answer our phone calls and emails, often taking time out of their busy lives to guide patients we introduce to them. Believe you me, their generosity has been a tremendous help in several cases.
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Topic: Prognostic Indicators