When I was practising oncology about 20 years ago lymphomas were divided according what was known as the working formulation. The pathologists had already divided up the lymphomas into more than 20 different types, but to oncologists this was nonsense. They recognized only three types: high grade lymphoma - which was mostly acute lymphoblastic lymphoma and Burkitt's lymphoma, intermediate grade lymphoma - which was mainly what we now call diffuse large cells B-cell lymphoma, and low grade lymphoma - which was mostly follicular lymphoma. There were three treatments: vincristine and prednisone plus head radiotherapy followed by 6-MP and methotrexate maintenance for the high grades, CHOP for the intermediate grades and CVP for the low grades.
We've come a long way since then and there are now more than 40 types of lymphoma, all of which demand separate approach; but in segregating so many, the pathologists have actually lumped two together. Small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL) are regarded by pathologists as a single entity.
From a pathologist’s point of view they are the same disease. When CLL appears in the lymph nodes, the histological pattern is that of SLL, and when SLL eventually appears in the blood, as it does in 25% to 50% of cases, the picture is that of CLL. Diagnostic lymphocyte markers are the same: CD5+, CD19+, CD23+, weak surface Ig, weak CD79b, and FMC7 negative.
However, from the clinician’s viewpoint they are different. By definition, SLL does not appear in the blood. SLL requires enlarged lymph nodes with the same tissue morphology and immunophenotype as CLL with no cytopenias due to bone marrow infiltration and fewer than 5 x 109/L peripheral blood B cells. CLL on the other hand must have more than 5 x 109/L peripheral blood B cells and need not have any lymph node enlargement.
The WHO insists that CLL and SLL are a single disease at different stages. Thus by Ann Arbor staging, CLL is always stage 4, since by definition it is extra nodal. SLL may be stage 4, if there is bone marrow involvement (more than 30% small lymphocytes in the marrow), but may also be stage 1, 2 or 3 depending on how many groups of lymph nodes are involved and whether of not the disease is confined to one side of the diaphragm.
The difference this makes is that stage 1 or 2 lymphomas are potentially curable by involved field or extended field radiotherapy with 80% freedom from relapse in stage 1 and 62% freedom from relapse in stage 2 at 10 years.
For advanced stage SLL treatment recommendations are exactly the same as they are for CLL; the patients should be managed by watchful waiting until certain criteria apply. The only difference from the CLL criteria is the lymphocyte doubling time, which clearly does not apply. Just as with CLL, if the size of the abdominal glands is the criterion for beginning treatment then these need to be measured carefully, which unfortunately means a CT scan. Oftentimes this can be avoided by first attempting to detect them with abdominal ultrasound. Only when they look like having a longest diameter of 10cm need the final decision be made with CT scan measurements.
FCR is now thought to be the best treatment for CLL if the patient is robust enough to manage it. The same is true for SLL.
Is it known why SLL behaves differently to CLL? Not completely, but we do have some clues. Lymphocytes move in response to chemicals called chemokines. We know that CLL cells have more chemokine receptors than SLL cells.
It should not be assumed that all cases of CLL were once cases of SLL. We know that many cases develop from monoclonal B cell lymphocytosis, which is stage 4 from the outset. Probably no more than 10% of cases start in a single lymph node.
19 comments:
I don't think FCR deserves the mention as an initial treatment.
What the pushers of FCR don't point out is that no one is cured of CLL (or SLL) with FCR, yet there are deaths due to treatment.
More importantly, the risk of progression to Richter's is higher in patients with a history of fludarabine, and myelodysplastic syndrome, MDS, can be caused by combination regimes using fludarabine (i.e. FCR).
I've read estimates of up to 10% of the CLL folk treated with FCR will progress to Richter's (median life expectancy six months) and another 10% progressing to MDS, which is itself incurable and often leading to acute myelogenous leukemia, AML.
There are better alternatives around now. UCSD is 'increasingly' using HDMP+R, and R&R (revlimid plus rituximab) is also increasingly being used, the latter in a clinical trial setting.
FCR has a place in CLL therapy, but the drawbacks are real and can be severe.
Thanks Terry. I have had SLL for 10 years, and watch and wait. Probably stage 3 by now. Have head sweats only, which can be drenching, especially with a little exertion. Have been told that treatment will be CVP, so was interested to hear FCR best treatment for both CLL/SLL.
Cheryl.
No-one has been more hesitant about using FCR than I. However, despite the risks which I have drawn attention to (and the risks of MDS are certainly not 10%), people who have FCR live longer than those who don't. HDMP + R is an interesting development, but it has not been tested against FCR so we do not know whether it has a place. Revlimid +R is at a much earlier stage of development.
Cheryl
Don't let them give you CVP. V stands for vincristine which causes peripheral neuropathy to some degree in everybody who has it. I have had peripheral neuropathy from oxaloplatin for about 8 months now and it is very nasty. FCR is the treatment of choice for people with CLL or SLL, but even plain chlorambucil is to be preferred to CVP. (there has been a head-to-head comparison between CVP and chlorambucil, back in the 1980s, both are equally effective, but chlorambucil is less toxic).
As a longtime reader, I am surprised at your remarks about FCR. My understanding is that once treated with FCR there are limits as to what can be given when it fails. Beginning with chlorambucil (if it seems viable for our treatment) gives us options, does it not - including FCR? I know several people who have been on Chlorambucil for years with very little side effects. I had always read that FCR might give longer remissions but does not increase life span. That's not true anymore? My father probably had CLL with Richter's transformation (1969) so I am nervous to use FCR.
Thank you for sharing all your knowledge with us. Deb
The German CLL8 trial changed everything. FCR causes people to live longer than FC. There is no difference between overall survival whetrher you have FC, F alone or chlorambucil. Therefore FCR is the treatment of choice unless FCR is contraindicated.
Further analysis may pick out subgroups that should be treated differently.
The REACH trial which was also reported at ASH last year demonstrated that FCR is less effective when given second line than first line.
as a sll patient living in the UK radiotherapy and cure were never discussed with me as a possiblilty. I have bilateral lymphnodes in axilla and neck but CT scan showed nothing below the diaphragm. My BM biopsy showed less than 30% effected lymphocytes.
I have been told my condition is incurable and W&W is the option being given to me.
Do I have any other options or is that correct?
I think it really depends on how much the marrow is involved. Radiotherapy will not clear the marrow. I do think that it is worth speaking to a radiotherapist about it. I shall be writing a piece for the UK CLL Forum website, so that UK CLL doctors are educated on this.
as a cll patient ,i would like to ask that if we go for less toxic treatment at first stage ie chlorambucil initially,then wait and if relapse use other treatment as FCR
with this we can have a better quality of life
sanesh
Yes, that may be an option for those with good markers.
Terry,
If CLL cells do not die, and, therefore, inevitably keep increasing in number, and if the total lymphocyte count has effectively plateaued for a period of two years or more after the inital increase, does it mean the CLL must be starting to build up in the lymph nodes and/or spleen?
Barry
No. CLL cells do die, but slowly. The ALC is a balance between production and destruction. It does not imply that nodes are increasing, though the bone marrow could be gradually filling up without a change in ALC.
Terry,
Thanks for your explanation that CLL cells do die off slowly. Are any of the tests that are included in the normal WBC panel indicative of a build up of CLL in the bone marrow over a period of time?
Barry
Only a repeat bone marrow trephine, and even that is only semi-quantative.
Terry, sorry to harp on this, but after the initial increase in ALC after diagnosis it plateaued (or perhaps increased more slowly) in the 50 to 57 range for the past two years and the RBC, HG & HCT have dropped in the last two years (though not dramatically). Would these drops not be related to build up in the bone marrow?
Barry
Possibly, but so small an increase could not be measured by looking at a bone marrow trephine.
Hi Terry
Are you inferring that early stage SLL could potentially be cured?
Yes, precisely that.
SLL patient 2yrs. Nodes above and below diaphragm. Blood counts still good. WBC ranges between 9-15k. Offered to continue on W&W or first line double dose Rituxan protocol once a week for 4 weeks @ 750 then once every 3 months for 2yrs for a 375 maint. dose. Thoughts?
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