Prognostic Indicators el pt

MCL — A Wolf in CLL Clothing

Date: November 9, 2024

by Chaya Venkat

Know the Name of Your Enemy

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 2024 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 2024. 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.

Mantle Cell Lymphoma (MCL)

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 2024 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.

Abstract:

Br J Haematol. 2024 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.

PMID: 15982342
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MCL versus CLL: the Difference Is Important

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.

• The initial misdiagnosis of the leukemic phase of MCL as CLL is not uncommon and probably accounts for a small percent of the patients Mayo sees after an initial diagnosis as CLL elsewhere. Although the percentage is small, it obviously makes a huge difference for these individuals and there is no reason why these patients cannot be diagnosed correctly the first time.
• MCL is a more aggressive cancer and it usually has a poorer prognosis than CLL. The game plan for treating MCL is quite different.
• Patients with the IgH/Cyclin D1 fusion gene (also known as t(11;14) ) are more likely to have Mantle Cell Lymphoma. (Editor’s note: t(11:14) stands for ‘translocation’, where a bit of chromosome 11 is broken off, and reattaches itself to chromosome 14. The “IGH/Cyclin D1 probe” can be used as part of the FISH panel, along with the other probes presently used.
• Today, MCL is probably the disease most likely to be misdiagnosed as CLL. Mayo is on the record as stating that the FISH test for the t(11:14) should be performed in all newly diagnosed CLL patients to answer this question with certainty. Smart therapy decisions cannot be made without accurate diagnoses!!
• It is true patients can have both CLL and MCL — but few patients seem to be thus doubly blessed. Thank Providence for small mercies.
• MCL patients typically have massive enlargement of their spleens, even though the rest of their lymph nodes may be unremarkable in early stages of the disease. Compared to CLL patients, they also do not develop very high WBC in their peripheral blood.
• Another tell-tale marker is “bright” CD20 expression. As you know, CD20, the marker targeted by Rituxan, is only dimly expressed by classic CLL cells. Lymphomas express it at higher intensity, and a high intensity “bright” expression of this marker suggests the underlying cancer may be a lymphoma, such as MCL, rather than a leukemia, such as CLL.
• Removal of the spleen is often a viable frontline therapy choice for MCL patients.
• Stem cell transplant should be considered in MCL patients — and given the aggressive nature of this disease, perhaps sooner rather than later. Both allogeneic and autologous stem cell transplants are done in MCL patients. The choice depends upon the age and relative fitness of the patient, as well as the availability of a well matched donor (Only Real Cure, Matching Made Simple).
• Given the importance of Auto-stem cell transplants for MCL patients, it is important to recognize that prior fludarabine therapy may make it harder to collect stem cells from the patient. It would be a shame if the patient had been through extensive fludarabine therapy, only to find the underlying disease is MCL and an autologous stem cell transplant would have been his best choice.
• On a happier note, some of the other diseases confused with CLL could have a better prognosis — for example, marginal zone lymphomas.

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.

Editorial

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.

• Several of the experts at the Mayo Clinic are on record recommending that all newly diagnosed CLL patients should have the IGH/Cyclin D1 probe included in their FISH panel, to distinguish between CLL and MCL. Additional tests may be done if the probe tests positive.
• Following up on my conversations with the Mayo folks, we contacted Quest Diagnostics, the company we have worked with in the past to provide cost-effective prognostic testing packages for CLL patients (Prognostic and Monitoring Test Packages). We sent them the Mayo paper quoted above, and asked if they would include the IGH/Cyclin D1 probe along with their present list of probes in the CLL FISH panel.
• Quest answered that they do not see the need for adding this addition probe to their FISH panel. They can certainly do the test, but only if they are specifically asked to do it by the referring oncologist or pathologist. In other words, it has to be a special request, not a routine part of the CLL FISH panel in their prognostic packages.
• But what if your local oncologist happens to belong to be a little behind the times and as far as he is concerned FISH is no more than a type of seafood? Chances are good this subtle distinction between CLL and MCL will not be captured, because no one will think to ask for the IGH/Cyclin D1 test.
• That puts you squarely on the pointy horns of dilemma. What to do? If you have a straightforward or garden variety of CLL, you do not have to worry about this additional wrinkle. But if you are newly diagnosed and your CLL seems to be of an unusual type, such as
  • Swollen spleen, but not too many enlarged lymph nodes to match;
  • Your WBC never gets up very high, even though you clearly have heavy tumor load in terms of swollen spleen etc.;
  • If your flow cytometry lists CD20 expression as “bright” (or 3+);
  • If your disease is progressing at a much faster clip than anticipated by you or your oncologist, given your prognostic indicators, and there are no other contributing factors.
  • If your situation fits this pattern, the next step might be to get your oncologist to ask for tests of CD23 and surface immunoglobulins.  Unlike classical CLL, MCL patients typically do not express CD23 on their cancer cells, and often have high a level of expression of (“bright”) surface immunoglobulin.
• Under these circumstances I would advice you to make the effort to get yourself to one of the top rated research institutions such as the Mayo Clinic, get a second opinion and a rock-solid diagnosis.

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.