An illustrative difficult case

This is the first illustrative case report sent in by a reader on which I will attempt to give advice.

Please remember that I am only licensed to treat patients in the UK and I would never give specific advice to a patient without seeing them and taking a full history, completing a full examination and ordering appropriate tests. This post is therefore for illustrative purposes only to show how CLL experts think about difficult cases.

I received a Binet Stage A CLL diagnosis at age 33 with a p53 mutation (although no, 17p-) and unmutated IGVH. My current hematologist is recommending FCR+Campath as a frontline when I come off of W&W.

It seems the FCR portion doesn't work especially well, if at all, with a dysfunctional p53 pathway so does the CFAR treatment make sense?

Would the HDMP+Campath, Revlimid+a CD20 monoclonal, or a BtK Inhibitor treatment be more appropriate prior to looking at a RIC SCT and if so, which of the three is most preferred?

Finally, my WBC is around 48, Hg 15.5 and platelets around 115. My spleen is 14 cm and the other nodes are slightly enlarged, but not very noticeable. I run 10km a day with no fatigue or any other B symptoms. If the platelets go below 100 what is the best way to distinguish between marrow failure and a spleen that is sequestering the platelets--BMB? Would the treatment for thrombocytopenia be the same irrespective of the cause of the platelets going below 100? In other words, failing marrow, I presume would automatically be reason a chemo-immuno therapy right away, but would chemo-immuno therapy be appropriate if the marrow is producing sufficient RBC, but the spleen is keeping those cells from circulating?


The first question to ask is does being diagnosed at 33 make a difference?

The answer is that young people with CLL are likely to live longer than older people but they will die at an earlier age than those who are diagnosed later. This is really obvious since even if a person of 33 lives for 25 years he would still die at 58, whilst the average age of diagnosis for CLL is 69. On the other hand there is on record at least one case diagnosed in his thirties who went for 52 years and never required treatment.

The second question is, given there are bad prognostic markers in this case, should treatment be started now?

The answer is that this question is still moot and clinical trials have been organized to answer it. But the advice being given for now is to watch and wait until the IWCLL/NCR criteria are met; unless you embark on one of the clinical trials designed to answer the question.

The third question is how serious are the poor prognostic markers?

The answer is that IGVH mutations are an index characteristic of the disease. On average people with unmutated IGHV genes require treatment within 2-3 years and are dead within 8 years. Remember, averages don't describe every patient in the cohort and there is considerable variation. In my series some patients with unmutated IGHV genes lived for 15 years and went more than 5 years without starting treatment. I wrote my paper in 1999 and treatment has certainly improved since then. As with all patients, young patients live longer than old patients, so treatment is likely to be an issue at some stage and it is well to think about the future.

TP53 mutations are a different matter. Del 17p is a more certain sign of future danger since some TP53 mutations do not have such a malign effect. We have a small population of patients with TP53 abnormalities who have survived for many years without treatment. However, most of these have mutated IGHV genes.

The next question is about how to treat TP53 abnormal CLL.

This is still difficult. FCR acts poorly and FCM is not that advantageous when used first line although it has a good record second line. CFAR, again does not have a brilliant track record and Bendamustine + R is not useful either. HDMP + Campath has a good response rate, but does induce severe immunodeficiency and the best results are from England. Don't have it unless you get it from an experienced hospital.

Revlimid probably does not have a role, but the BCR inhibitors like CAL 101 and PCI32765 look promising. Stem cell allografting is the most likely to produce a cure, especially at 33, but it has a high mortality and morbidity rate.

All in all, I would say that the field is progressing rapidly and I would hold off treatment until more information is available.

Next question: how important is a spleen of 14cm.

Answer: it is not important at all. This has to be a CT measurement and the normal in a man is 12 cm. This slight increase in size is seen in virtually all CLL patients and it is a good reason not to do CT scans in all patients with CLL. They are expensive, they give you unnecessary radiation and oncologists who are more used to dealing with lymphoma rather than CLL, misinterpret them. In your case the lowered platelet count is almost certainly due to bone marrow infiltration and this could be confirmed by a BMB. Although I don't recommend one; this is an unnecessary investigation in most cases of CLL.

The lowered platelet count is not a reason for starting chemoimmunotherapy straight away; that would be dependent on the rate of fall. At 110 you are not in any danger.