pp MDS

I am afraid I cannot put a time limit on the risk of MDS or Richter's
syndrome after fludarabine. Generally, MDS occurs in the first 7 years after
chemotherapy, and Richter's syndrome seems to be dependent on imunodeficiency,
which is at its greatest in the first 2 years after fludarabine. It is important
not to exagerate the risk. From the pilot study of autografting in the UK, I
estimate the risk of MDS to be no greater than 8% and from the Catovsky et  al
study in press in Leukemia Research, I estimate the risk of  Richter's
syndrome to be no greater than 12%. Even these high values are  probably not the
result of fludarabine alone, but of the combination of  fludarabine and
alkylating agents

TERRY HAMBlIN	The myelodysplastic syndromes (MDS) are a complex group of conditions that have been lumped together over the past 25 years. In the 1970s French doctors noticed that some chronic anemias did not respond to iron or B12, and some leukemias failed to take off and kill the patient. Both these conditions had similar features in the blood film and bone marrow aspirate. These features, known as dysplasia were found in the granulocytes, the erythrocytes and megakaryocytes. About 30% went on to become acute leukemia. In another third the patient died because of a low white count or platelet count (from infection or bleeding) and in the final third the patient survived to die from natural causes. MDS is is surprisingly common. In the over 80s the incidence is about 1 in 1000. It tends to occur in the same age range as CLL. I think that there is a slightly higher than expected incidence of the two diseases occurring together. We do not know the cause of MDS, but an initiating event is the generation of free radicals, which induce a tendency for mutations to occur in DNA. Agents such as benzene, X-rays, cigarette smoke, certain chemicals like dry cleaning fluid, have all been implicated, as has chemotherapy. Alkylating agents like chlorambucil, melphalan, cyclophosphamide, busulphan and thiotepa have all been known to cause MDS, and there have ben rare reports of fludarabine doing so. I have just returned from Houston where I was lecturing on MDS. There are many new treatments on the horizon. One of the points that I was stressing is how hard it is to diagnose. Hematopathologists fequently get the diagnosis wrong. One common mistake is to misdiagnose the picture produced by treatment with neupogen as MDS. Neutrophils that fail to lobulate properly, but have increased granulation can be produced by both MDS and neupogen treatment. MDS experts who recognise the blood and bone marrow patterns are Dr John Bennett at Rochester, NY and Dr James Vardiman at Chicago.
TERRY HAMBlIN 30 March 2005	I am afraid I cannot put a time limit on the risk of MDS or Richter's syndrome after fludarabine. Generally, MDS occurs in the first 7 years after chemotherapy, and Richter's syndrome seems to be dependent on imunodeficiency, which is at its greatest in the first 2 years after fludarabine. It is important not to exagerate the risk. From the pilot study of autografting in the UK, I estimate the risk of MDS to be no greater than 8% and from the Catovsky et al study in press in Leukemia Research, I estimate the risk of Richter's syndrome to be no greater than 12%. Even these high values are probably not the result of fludarabine alone, but of the combination of fludarabine and alkylating agents
TERRY HAMBlIN 3 April 2005	We are increasingly seeing myelodysplastic syndrome (MDS) in CLL patients. I thougt it might be useful for me to write something on this. MDS is a series of complex conditions of the blood that were first recognised at the end of the 1970s, beginning of the 1980s. Of course they had been around for ever, but nobody had put them together as a single syndrome. What they have in common is low levels of one or all the elements in the peripheral blood - red cells, white cells and platelets - and usually an overactive bone marrow. When the marrow is examined down the microscope the cells look odd. For example, the granulocytes may lack granules, and instead of the nucleus lobulating as it should, it remains circular. The red cell precursors show differing rates of maturation between nucleus and cytoplasm and may have a ring of iron around the nucleus. The platelet precursors - megakaryocytes - are also abnormal with three different abnormal patterns of maturation. I wrote up the first big series of MDS patients in 1985 or 6. If you look me up on PubMed you will find it in Brit J Haematol. First author was my research fellow at the time Mufti GJ. We reported that a third of patients transformed to acute leukemia, a third died of infection or bleeding and a third dies in old age of an unrelated condition. The FAB group (French-American-British) described 5 different types: RA. RAS, RAEB, RAEBt and CMML. More recently MDS has been reclassified by WHO and it is now more complicated. There is a prognostic scoring system IPSS which we published in Blood in 1997 (first author Greenberg P). The main factors in this are the number of cell lineages that are reduced, the percentage of blasts in the bone marrow and the type of chromosomal abnormality (if any). Monosomy 5 or 7 are the bad news chromosomes. WHO have classified treatment-related MDS as a separate category. Chromosome 5 and 7 abnormalities are especially common in this condition which occurs after alkylating agens like cyclophosphamide, though there is a second group that is secondary to drugs known as topoisomerase II inhibitors (etoposide is a good example) where common translocations like t(8:21) and t(15;17) and translocations involving 11q23 are found. It used to be thought that the purine analogues (which include fludarabine, cladrabine and pentostatin) did not cause MDS, but it is becoming clear that this is not true. David Oscier in my group first reported MDS in CLL patients whose only treatment had been fludarabine, and the Don Milligan from Birmingham, UK has reported an 8% incidence of MDS in patients whose initial treatment was fludarabine who went on to have a stem cell autograft. It should not be forgotten that there is a higher incidence of MDS in patients who have any form of lymphoid malignancy, but it is difficult to diagnose in CLL where the marrow is already full of lymphocytes and the rest of the cells are difficult to find. Diagnosis of MDS is difficult in CLL because of this, and anemia or thrombocytopenia due to MDS are often called something else. ITP is a common misdiagnosis. Treatment of MDS is not as hopeless as it was. Revlimid looks to be very promising in the less aggressive forms, and low dose ara-C, azacytidine and decitabine all have their advocates. However, if the blast count in the marrow rises above 10% MDS has to be treated like acute leukemia, which means chemotherapy and sometimes a transplant. There are newer drugs to be tried though such as clofarabine and myelotarg.
TERRY HAMBlIN 4 April 2005	I did a trial of high dose vitamin D in MDS about 5 years ago. The problem with vitamin D is that it causes high blood calcium levels. Different formulations of vitamin D limit this, but the type I used had only minimal effect on the MDS despite pushing the dose to a level that raised the blood calcium. The idea that Vitamin D might help comes from work with the cell line HL60 which can be made to differentiate into mature monocytes with vitamin D and into mature granulocytes with vitamin A. Vitamin A (retinoic acid) has had some success in leukemia treatment (as ATRA in promyelocytic leukemia) and the pharmaceutical industry had hoped that both vitamin A and vitamin D might have a role in MDS. So far there does not seem much success.