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New Treatments for Acute Lymphocytic Leukemia 

What I am going to do is talk about acute lymphocytic leukemia, starting with some aspects related to the diagnosis and then discuss the treatment of ALL. So you are in your clinic and you have a patient with abnormal counts and they do the bone marrow and you find that the bone marrow has more than 30% blasts. So you are stuck with the diagnosis of acute leukemia and the first question is; what kind of studies do you need to require from your hematopathologist to have a very accurate diagnosis, as well as some ideas about the prognosis and the acute lymphocytic anemia.

How does the third diagnosis help? Well, it helps you in making sure that the patient has acute lymphocytic leukemia as opposed to an acute myeloid leukemia. So these patients must be peroxidase-negative and strongly TTD positive. Beyond that all it helps you is identifying the patients with Burkittís-like morphologies because for adults, even though a true morphology is much more frequent than at one, which is the reverse than in childhood ALL. Yet the prognosis is similar. The recognition of the L3 morphology will allow you to select a particular dose-intensive regimen for these patients without any maintenance therapy, which will provide you with a cure rate of about 50%. Now once you know that the patient has acute lymphocytic leukemia the markers on the surface of the cells are very important.

So the immuno-phenotypic classification allows you again to distinguish the mature B-cell ALL, 5-10% of the patients. They are surface immunoglobulin-positive or kappa lambda clonality positive and they look like they are the Burkitt equivalent of the L3, although sometimes they do not have the typical L3 morphology. The immuno-phenotyping also allows you to identify the T-cell ALL which may present with mediastinal disease. It constitutes about 15-20% of the patients. The positive markers include CD1 to CD8 positivity. And itís important to recognize them because in the past T-cell ALL used to have a poor prognosis, but now with the dose-intensive regimens including high doses of cyclophosphamide, ara-C and asparaginase, they have now become in fact the best prognostic category with event-free survival rates.

Now this is the immuno-phenotyping, demonstrating that in several of the recent studies the myeloid marker positivity is not an adverse prognostic feature. So depending on the definitions - and these are the two studies from the CLGB and our institution - the myeloid marker positivity can be anywhere between 20-50%. But in most of the recent studies there is no adverse effect on either complete response, remission duration or survival. So in the past I used to get calls from people saying, "Look, I have a patient with adult ALL and he is myeloid marker positive so he has mixed lineage disease and therefore must have a poor prognosis. Should I send him for transplant?" The point from this slide is that myeloid marker positivity is not an adverse factor and it is not an indication of mixed lineage disease.

How about the cytogenetic molecular classification? Among this long list of cytogenetic abnormalities the ones to remember are the Philadelphia chromosome abnormality, because itís the most frequent one occurring in about 20% of the patients. Now some patients can present with a diploid karyotype of insufficient metaphases and they still will show the molecular abnormality for the Philadelphia. So itís very important among the patients with insufficient metaphases or diploid karyotype to do molecular studies and you cannot do the Southern blot analysis because it will detect the P210 which occurs in only 20% of the Philadelphia-positive ALLís. The most frequent molecular abnormality is the P190 which requires PCR analysis. Itís important to recognize the Philadelphia-positive ALLís because this is the one group.

Now another one of the Board questions is the Burkitt cytogenetic abnormalities and these include translocations 8-14 with the 8 interacting with the heavy chain immunoglobulin. The 8-2 make with the kappa light chain and 8-22 make with the lambda light chain. Lymphoma karyotypes can occur in about 5% of the patients and these usually include the 6Q-, 14Q+ or the known translocations 11-14 and 14-18. There are some rare cytogenetic abnormalities that I show here. The translocation 1-19 which in the past used to be considered a poor prognosis abnormality, but where the prognosis has improved significantly with intensive chemotherapy, so it is not recognized anymore as a bad karyotypic abnormality. But the one which remains in the poor prognosis category is the translocation 4-11, which in fact is a true mixed lineage disease and where the prognosis is poor. So despite itís rarity - under 2% - when you have such a patient you have to do like Philadelphia-positive ALL and try to send them for allogeneic transplant.

Iím going to show you next the importance of this cytogenetic abnormality, the translocation

12-21 which at the cytogenetic level is detected in less than 2% of the patients. But this is where the molecular studies are very important, particularly in childhood ALL, because this cytogenetic abnormality is cryptic. Meaning that it is too subtle to be detected by cytogenetic analysis but 25% of the children will have the molecular rearrangement. Now why is this important in children? Itís important because when you look at the prognosis of these patients, and as I mentioned, by cytogenetics under 2% have it. By molecular studies a quarter of the patients have it. But if you look at their five year event-free survival  is associated with 90% event-free survival compared to 60 or 65% for the regular population of children with ALL. Now why is this important? Well, itís important because in the past people continued to argue that maybe the prognosis of childhood ALL is so good because we are able to give them more dose-intensive chemotherapy. And maybe because they tolerate asparaginase better. In fact now we know that most of the difference between childhood and adult ALL is related to the two chromosomal abnormalities, Philadelphia-positive - which is rare in children, very common in adults, associated with poor prognosis - and the reverse side of the coin is very common in children, rare in adults and is associated with a very good prognosis. So itís not