I spent yesterday wrestling with the CLL Guidelines - both the 1996 and the 2008 versions - trying to evaluate a clinical trial results as part of a Review Panel. It used to be quite easy, though pretty meaningless. To say you had a complete remission (CR) in CLL you had to have disappearance of all disease that could be detected by physical examination, and restoration of the blood count to reasonable levels - neutrophils > 1500/cu mm, lymphocytes <4000/cu mm, platelets >100,000/cu mm and Hb >11 g/dL. This had to last for two months, and at the end of those two months a bone marrow biopsy had to contain fewer than 30% lymphocytes and to be of reasonably normal cellularity.
Of course, the 1996 guidelines were written before imaging became a routine practice, so hepatomegaly meant that you could feel the liver below the edge of the ribs and splenomegaly meant that you could feel the spleen below the edge of the ribs.
If the patient did not fulfill the criteria for a CR the next test was to see if the conditions for a partial remission (PR) were met. These required a >50% decrease in the lymphocyte count, a >50% reduction in the size of the lymph nodes and a >50% reduction in hepatosplenomegaly plus the restoration of (or considerable improvement in) one of the elements of the blood count (ie platelets over 100,000/cu mm, Hb over 11 g/dL and neutrophils over 1500, or if these are not achieved a >50% increase over the baseline levels).
Patients who fail treatment might have progressive disease (PD) which was defined as a >50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations at least 2 weeks apart (at least one node must be > than 2cm) or the appearance of new nodes that could be felt. Or a >50% increase in the size of the liver or spleen below the ribs or the appearance of one of these which was not previously present, or a >50% in the absolute number of circulating lymphocytes (as long as the number is greater than 5000/cu mm.
(It should be noted that all the >50% signs in this essay mean greater or equal to 50%; I don’t know how to make the sign for greater or equal to.)
Those who don’t improve enough to be called a PR or who don’t deteriorate enough to be called PD were designated as having stable disease (SD).
Although this system was fairly easy to operate it was a bit of a joke. This wasn’t a CR like the CRs of acute leukemia where getting a CR is a prelude to a cure. Everybody knew that obtaining a CR in CLL (and that itself was pretty rare) didn’t mean a cure. It was possible that 30% of the cells in the bone marrow were still leukemia cells. And since lymph nodes in the belly couldn’t be felt there could be a couple of kilograms of cancer there undetected. In fat people it’s almost impossible to feel lymph nodes in the armpits and in very thin people you can often feel very small lymph nodes, which may be enlarged because of infection rather than CLL. A spleen has to enlarge threefold to be felt below the ribs, and measuring the liver by physical examination is fraught with difficulties; for example, if the lungs are over expanded, as in emphysema, a normal sized liver can be felt below the ribs.
The new guidelines were prompted by a number of things. It had long been recognized that some patients apparently achieved CR, but their marrow biopsies, while mainly being free of CLL, contained lymphoid nodules. Were these lymphoid nodules foci of CLL or just reactive nodules of normal tissue? They clearly needed to be studied separately and so such patients were designated nPR. We do know that such patients have a shorter time to progression than those with CR. Then there were some patients who seemed to be in CR but their blood counts did not return to normal. It seemed that their bone marrow had been damaged by the CLL. Of course, it could have been the case that residual CLL was suppressing their bone marrow and preventing normalization. The 1996 guidelines regarded this as a controversial issue, but decided that they should be called PR – except that if Hb was still <11 g/dL, neutrophils <1500/cu mm and platelets <100,000 /cu mm they had to be regarded as stable disease.
The other confusing thing about the guidelines was that despite stressing that size measurements are to be determined by physical examination, they add “and appropriate radiographic techniques” for lymph node sizing, and “or appropriate radiographic techniques if in a clinical trial” for liver and spleen measurement, as if physical examination and ‘appropriate radiological techniques’ were interchangeable. We know for certain that radiological techniques will detect disease that is undetectable to the examiner’s hand.
For evaluating clinical trials it turns out that measurements are not noted down in the notes, and investigations are forgotten. There may be ‘after’ CT scans but no ‘before’ or vice versa.
So do the new guidelines help?
Now CR needs all the following criteria as assessed at least three months after the completion of treatment:
1. No clonal lymphocytes. This is more stringent than before – all you needed then was fewer than 4000 lymphocytes.
2. No significantly enlarged lymph nodes. In clinical trials CT scanning is now positively encouraged. So we are talking about the largest diameter of lymph nodes anywhere in the body, not being greater than 1.5 cm.
3. No hepatomegaly or splenomegaly by physical examination. We have now reverted to physical examination even though a CT scan will have been done to look for enlarged lymph nodes. The guidelines advise that if liver or spleen were found to be abnormal before treatment then a scan should be performed at evaluation; this should also be done if the evaluation was inconclusive by physical examination.
4. No constitutional symptoms.
5. Neutrophils >1500 / cu mm, platelets >100,000 /. Cu mm Hb >11 g/dL (untransfused). For more than 20 years I have been protesting that to choose the same Hb level for men and women is insane.
6. If all these points have been achieved a bone marrow aspirate and trephine biopsy should be performed. The marrow should be examined by flow cytometry and immunohistochemistry to look for clonal B cells. If clonal cells are found then the case is demoted to PR. It must be stressed here that the flow cytometry is not the powerful 4-color flow used to detect MRD, but the simpler 2-color flow that detects one cell in 100.If lymphoid nodules are found in the trephine, then immunohistochemistry should distinguish between CLL and reactive nodules. The nPR category therefore disappears. If the marrow is hypercellular, then it should be repeated in 4-6 weeks, provided the blood counts have recovered. In some cases it is necessary to continue to postpone the marrow, but this time interval should not exceed 6 months.
7. The question of apparent CR with a failure to recover the bone marrow also seems to have been resolved. Those who fulfill all the criteria for a CR including the marrow examination, but who have a persistent anemia, thrombocytopenia or neutropenia unrelated to CLL but related to drug toxicity are designated CRi (‘i’ stands for incomplete marrow recovery). In view of the fact that a PR still requires recovery of at least one of the marrow lineages, I am not clear whether CRi can be applied to a patient with complete pancytopenia.
PR is similar to before – slightly confusing. There are four things that must be achieved:
1. A decrease in blood lymphocytes to fewer than 50% of the starting value.
2. A reduction in the size of the lymph nodes. This has to be assessed by CT in a clinical trial, and is defined as a decrease of 50% or more of the ‘sum products’ of up to six lymph nodes ‘Sum products’ are the figure you get when you multiply the perpendicular diameters of individual lymph nodes. It doesn’t say which six nodes, but most people would take the six biggest ones – of course if only three are enlarged you’d just do it with three. If there is just one big node then you can take a 50% reduction in its diameter. As far as lymph nodes are concerned there must be no increase in size in any of them, though in small nodes of less than 2cm diameter, an increase of less than 25% is not considered significant. There must also be no new enlarged node that wasn’t enlarged before.
3. A decrease in the size of the liver or spleen by 50% or more defined by CT in clinical trials. This is the one I take issue with. Enlarged spleens are often 18 cm long when measured by CT. A 50% reduction in size to 9cm would make it smaller than normal – up to 12 cm – and measurement of livers will have a similar drawback. We don’t want treatment that will make the liver shrink to the size of someone’s with cirrhosis. What they mean is a 50% reduction in the enlargement of either organ, but since we don’t know what the normal was for that patient, we are unable to calculate an answer. Livers and spleens vary with body size – they are certainly larger in men than women. Until this issue is resolved I recommend that any liver or spleen that can’t be felt by clinical examination should be regarded as normal.
4. One of the following should be present: neutrophils >1500 / cu mm, platelets >100,000 / cu mm, Hb >11 g/dL, or if not then at least one should show a 50% improvement over baseline.
A further proviso is that at least one of these parameters should persist for at least 2 months. It is not clear to me from the paper whether this refers to all the 4 measurements or just one of those in section 4. I’m assuming it means any of the four sections.
Systemic symptoms don’t come into it. Although CR requires these to remit, a PR does not, although they have to be noted.
PD is generally obvious from blood counts and therefore need not be looked for by CT scanning, though clearly from the instructions in the paper, it can be. So if any of the following occur PD is said to have occurred:
1. Any new lesions appearing such as an new lymph node enlarged to >1.5 cm diameter, splenomegaly, hepatomegaly or any other organ infiltration.
2. An increase by 50% or more of the greatest diameter of any previous lymph node.
3. An increase of 50% or more of the sum of the product of diameters of multiple nodes.
4. An increase in the size of liver or spleen by 50% or more or the appearance of spleens or livers that can now be felt.
5. An increase of50% or more in the absolute lymphocyte count, as long as it is greater than 5000.
6. Transformation to aggressive histology (eg Richter’s syndrome). This should be confirmed by biopsy.
7. The appearance of cytopenia unrelated to treatment or autoimmunity. This can only be assessed after treatment and so is defined as a fall in Hb by 2g/dL or to less than 10g/dL or by a decrease in platelet count by more than 50% or to below 100,000 per cu mm, that occurs at least 3 months after treatment ends and associated with an infiltrate of clonal lymphoid cells in the marrow. Note, the guidelines say nothing about late neutropenia.
SD is anything between PR and PD.
The duration of a response is measured from the end of the last treatment, but, confusingly, progression-free survival is measured from the first day of treatment.
Trials that are designed to eradicate the CLL should include testing for minimal residual disease (MRD). Either 4-color flow cytometry or allele-specific oligonucleotide PCR should be used using a threshold of one cell in 10,000. It is permissible to use blood for this assay except within 3 months of completing therapy, especially when alemtuzumab, rituximab or other antibodies have been used, in which case, bone marrow should be used.
Although the new guidelines make sense, there are still some ambiguities and in places the application of common sense runs counter to the wording of the document.