Thursday, March 30, 2006


There has been a bit of discussion about transformation of CLL to PLL. I have been saying that it doesn't happen. This has caused some confusion, so let's see if I can straighten things out.

Prolymphocytic leukemia is quite a different disease from CLL. It has bright surface Ig, it is CD5 negative, CD23 negative, FMC7 positive, CD22 positive and it has more than 55% prolymphocytes on the blood film. Often there is a paraprotein and while the spleen is enlarged, the lymph nodes are not. It is also very rare. I have 7 cases on my books, compared to over 800 CLLs.

Most of the confusion arised from a condition known as CLL/PLL. This condition has between 15% and 55% prolymphocytes in the blood but the cell markers are those of CLL, not PLL. In the 1980s the FAB group (nothing to do with the fab four, it stands for French-American-British) having divided up the acute leukemias and MDS, decided to have a go at the chronic lymphoproliferative disorders. They divided up CLL into typical and two types of atypical CLL. One sort of atypical CLL was CLL/PLL. In a big series of patients, my group and Danny Catovsky's group demonstrated that there was a close correlation between atypical CLL and trisomy 12.

Although people talk about prolymphocytoid transformation of CLL, which seems to imply increasing numbers of prolymphocytes over time, this does not really happen with trisomy 12. There are variable numbers of increased prolymphocytes, but this is a pretty permanent state. I followed one such woman for 20 years with no change in the percentage of prolymphocytes. She had a big spleen, a high white count, a paraprotein, but CLL type cell markers and mutated VH genes. She was non-progressive. If we go back to the papers in Brit J Haem by Junia Melo and David Galton that described CLL/PLL we find that this is just what they descibed.

Here is a section of a paper that I wrote which reviewed the Melo papers:

"Contrary to the common perception, in a study of 55 cases of CLL/PLL half showed a stable picture without a progressive increase in prolymphocytes. The prognosis of this group was similar to that of stable CLL without prolymphocytes. In one third of cases the increase in prolymphocytes was unsustained and in only 18% was there a definite progression towards a more malignant phase of the disease."

In other words a third of patients had a transient increase in prolymphocytes - perhaps triggered by infection or vaccination, and only 18% had a real prolymphocytoid transformation to a more malignant phase. 18% of 55 is 10 cases.

So what was going on with these 10? Trisomy 12 is not the only chromosomal abnormality found in atypical CLL. The very rare t(14;19) translocation involving bcl3 has an excess of prolymphocytes anda poor prognosis. But 80% of patients with p53 mutations or deletions also have atypical morphology. P53 aberrations are likely to occur as a form of chromosomal evolution, and are associated with an increased aggressiveness. I have certainly seen this effect. But note this is not prolymphocytic, but prolymphocytoid transfomation. The cell markers remain typical of CLL.

Part of the confusion lies in the rather atypical immunophenotype of trisomy 12 cells. The surface Ig is rather stronger than normal in CLL and CD20 is also stronger. FMC7 is also moderately positive. These markers have a superficial resemblance to those of PLL but they are quite distinct.

Just to confuse matters more, a minority of PLLs are CD5 positive. We published a paper from my group and the French group from Nantes which exposed these as a variant form of mantle cell lymphoma. They are not the blastic form of MCL that has been described previously, but what appears to be PLL with mantle cell markers including the cyclin D1 and the t(11;14) translocation. They have a dreadful prognosis on the whole.

Is everybody thoroughly confused? Well that's better than being so sure of yourself that you treat zebras like white horses that have caught the sun behind prison bars.


Anonymous said...

Thanks for the explanation. I've seen many papers that discuss transformation from CLL to PLL. They often include this transformation in with Richter's as CLL transformation into a more aggressive state.

You make a persuasive argument, but are the other researchers just clueless, lazy or ill-informed and regurgitating what they've read elsewhere?

Terry Hamblin said...

You would be surpirsed how much cutting and pasting goes on in scientific articles. It is a salutary lesson to acctually read the references quoted in review articles. Often they say something quite different from what they are quotes as saying. A mistake can be perpetuated unnoticed for 50 years

Anonymous said...

Dear Dr. Terry Hamblin!
May I ask something regarding my husband health? He was having FCR for CLL and after 2 rounds and no response he had a FISH done and a lymph gland biopsy and started R-CHOP. The biopsy did not show any change in the CLL, but the FISH showed clonal evolution, it was normal when it was done at the time of the diagnosis three years before, but not they found out p53 deletion in 39% of the nuclei. After two rounds of R-CHOP, the blood counts were almost normal, but the lymph glands of the neck, armpit and abdominal are much worse, too much swollen. The doctors now want to stop R-CHOP and start Rituximab plus high-dose steroids. They told us that even the biopsy did not show any change, there may still be the possibility of Richter Transformation, but the fact that there was not response with R-CHOP makes them believe that there has not happened Richter. At this point I told them about your argument:

There are two types of Richter's syndrome. In one it is a true second
malignancy, unrelated clonally to the CLL. These patients should be treated
conventionally for Diffuse large B cell Lymphoma (DLBCL) with CHOP-R. For those
patients whose aggressive lymphoma develops from the CLL clone the outlook
is more difficult and some form of aggressive treatment CFAR, HyperCVAD
etc is necessary to achieve a remission which if possible should be followed
by an allograft.
Terry Hamblin

I don't know if I got it right(?). I am now concerned if there has happened Richter, and I don't know if knowing it could help in the therapy choices.My husband had anemia during all the time he was having chemotherapy, and he had many blood transfusions. Lately, after the first R-CHOP he started Aranesp. Since then his hematocrit is stable about 31. I am concerned that maybe there has happened a Richter Transformation of a myeloid type and he is continuing to get Aranesp shots that are appropriate for cancer patients with non-myeloid malignancy. The fact that the increased swelling started at the time of starting Aranesp may be a coincidence, but I am not a doctor and I can not know it. I can not understand why the blood counts improved so much and the lymph glands worsened so much during R-CHOP and that doctors can not explain it. I am reading many hours every day in the websites with CLL information, but I can not understand what is happening with my husband's health. Please mind my English (I am a foreigner writing from overseas), and mind my ignorance as I have no connection with the medical field, so my statements and questions may make no sense. But, please read my post and give me some advice.
Best wishes and thank you fr your time.

Terry Hamblin said...

R-CHOP is not an appropriate treatment for del-17p transformation. The drugs that work include high dose steroids, Alemtuzumab, flavopiridol and Revlimid. Probably your husband should also be prepared for an allograft. The doctors ought to be aware of this and if not change doctors. There is no reason to call this Richter's transformation. It is CLL refractory to FCR.