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Acute Lymhpocytic Leukemia
New Treatments for Acute Lymphocytic Leukemia
Laura L. Peters, MD
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 therapy? There are three aspects that you have to require. The first one is an appropriate morphologic diagnosis with stain. The second is the full immuno-phenotypic characterization of the blasts of these patients, and the third is the cytogenetic molecular classification.
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 Burkitt’s-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. Here I categorize them as the T-cell markers, which means that the patients will have to have at least two T-cell markers of the CD1 to CD8, then the 3B ALL where the patients are CD19 or CD20 positive, and most of such patients are also CD10 or _ positive, which is about 40% of the total. If they have mature surface immunoglobulin positivity or kappa lambda clonality then they are mature B-cell ALL which is about 5-10% of the patients. Now importantly, people do the myeloid markers and in the past we thought that these had a prognostic implication. Now we know that they do not and I’ll show you the data for that.
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 it’s 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 in excess of 50%.
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 it’s 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 it’s 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 ALL’s. The most frequent molecular abnormality is the P190 which requires PCR analysis. It’s important to recognize the Philadelphia-positive ALL’s because this is the one group that has the worst prognosis with combination chemotherapy and will require either allogeneic or matched unrelated transplant in first complete remission.
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 it’s 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.
I’m 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? It’s 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, it’s 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 it’s not differences in the therapy but differences in the biology of the disease which accounts for most of the prognostic difference.
Next we will talk about the treatment principles in adult ALL and here on this slide I am showing the principles consisting of an induction therapy to induce the patients into complete remission using vincristine, steroids and anthracyclines. Such patients need, unlike adult AML, they need long term maintenance therapy for up to two years and this is traditionally given with 6 mg methotrexate and monthly courses of vincristine and steroids. Different programs use different consolidation approaches with high doses of cyclophosphamide, ara-C, VP16 or the ultimate of intensification which are autologous and allogeneic transplant. Unlike adult AML, these patients need CNS prophylaxis with either radiation therapy or intrathecal chemotherapy. Now these principles have been derived from the childhood experience and when applied to adult ALL it was observed that adults were getting a complete response rate of about 85% and about 40% of the patients were projected to have long term remissions. So this was a very positive thing until people started referring the truly average population of adult ALL. So the older patients and those with Philadelphia-positive disease, and these are the serial studies from Sloan Kettering. This is the well-known L-10 program where it was reported to produce cures in 50% of the patients. And this is the more recent L-17 modified program where the early event-free survival rate had dropped to about 25%. So in fact the initial reports were over-enthusiastic and when the regimen was applied to unselected patients the results were worse. So if you do a review of the literature, as did Dr. Halser in this publication, he looked at about 5,000 patients from 26 large studies. Note the median age of the patients is 30 years and in fact the reality is that the adult ALL median age is probably a decade older. These patients were induced with different regimens and when he looked at the weighted percent of expected complete remission it was 75%, and the weighted percent of leukemia-free survival, it was down to 30%. Which is in fact the reality in adult ALL therapy unless we discover more effective dose-intensive regimens or more selective ALL therapies.
Now then the question is; if we have a patient with adult ALL, what would be our best induction therapy? What is the value of intensifying the patients once they are in remission? When should we perform allogeneic bone marrow transplant in first remission? And is there any role for autologous stem cell transplant? Is there a need and what is the duration of maintenance therapy? And what kind of CNS prophylaxis should we give these patients? Let’s start with the first question of induction therapy. Before the advent of anthracycline, vincristine and prednisone were the standard of care. And when anthracyclines became available the triple threat therapy was compared in a randomized fashion to the classical vincristine/prednisone demonstrating a significant improvement in the complete remission rate. This now has become the standard of care for induction therapy. There were multiple attempts to improve on the induction therapy results, continuing with the vincristine, steroids and anthracyclines, but adding in different regimens asparaginase and cyclophosphamide and in some of the studies, ara-C. None of these studies showed a significant improvement over the average CR rate of 75%. This is a study done by the Italian group where the patients were randomized to a four-drug induction therapy; the triple regimen with asparaginase and with or without cyclophosphamide. In that study there was no difference in either the CR rate or the event-free survival. So one could conclude that there is no point in trying to achieve better remissions, better quality remissions, because there may not be an impact on the event-free survival except that there are studies from the childhood experience, for example, where the patients were randomized to receive either one dose of high dose methotrexate with induction therapy or the conventional induction therapy. When this study matured at seven years there was a significant difference in the leukemia and disease-free survival of the patients. So it is my opinion that we can improve on the induction therapy, perhaps not to improve the complete remission rate but to improve the long term event-free survival rate.
Another question that comes about is, do you need to use growth factors with ALL induction therapy? As you know, in adult AML therapy there is more question about the use of growth factor except perhaps as a supportive care measure which will help shorten the duration of neutropenia. But in adult ALL the randomized study from CLCB has shown that not only do you shorten the period of neutropenia but you also reduce the induction mortality. So I think for adult ALL growth factor support may be important. In the bottom of the slide you see the older patients, and these were a much smaller number of patients. About 40 in total but where the induction mortality appeared to be significantly reduced. Even so, the P value was not significant, probably because of the small number of patients.
So are there questions remaining for induction therapy that we could still investigate? I think there is perhaps a role for investigating asparaginase instead of anthracycline, but my personal interest and that of many investigators is to look at more dose-intensive or better quality remissions to try to impact on the long term event-free survival.
How about intensive consolidation therapy? Now in childhood ALL there is no doubt that all the studies that intensified maintenance with either high doses of methotrexate alone or with 6MP, the use of asparaginase therapy has improved the outcome of childhood ALL. This is an example of such studies where high dose methotrexate was given as a consolidation for 15 doses and the investigators were looking as to whether this would replace the CNS prophylaxis, which it did not. But in all the other parameters, including complete remission, durable complete remission at about eight to nine years, whether hematologic, testicular or the event-free survival, the results were improved with the addition of high dose methotrexate therapy. Now in adult ALL there were no such studies that were conducted which looked at the agent that specifically affects ALL. Such as perhaps methotrexate or 6MP or asparaginase. The only two studies that looked at the efficacy of intensive consolidation consisted of two to three months of consolidation with AML-type therapy. So it is not surprising that neither of the two studies showed any benefit. So because of this you have experts that say perhaps that there is no definite benefit, that intensive consolidation therapy in adult ALL is of value, but most of the investigators agree that the more intensive regimens have improved the outcome of adult ALL as they did for childhood ALL.
Now you have a patient who has achieved a complete remission and you wonder, if the patient has a match-related sibling, whether you should send the patient for allogeneic bone marrow transplantation. Now this question has been tackled in numerous studies. The first one that came about was in fact an analysis by Dr. Horowitz from the International Bone Marrow Transplant Registry that took patients who received allogeneic bone marrow transplantation versus patients who were continued on BFM-like chemotherapy. And she accounted for the age so she took patients only between the age of 15-45 and accounted also for the time to transplant. This is the first analysis that did not show an improvement in the outcome, so people said, "Well, maybe if you follow that study longer you will see results" and Dr. Horowitz published an update at eighth year that did not show an improvement in the outcome.
Now the reasons for failures are quite different. In the setting of chemotherapy, the most common reason for failure cumulatively at 60% is leukemia relapse. On the other hand, with allogeneic transplant the most common cause of failure is transplant-related mortality. So this experience has been taken to argue both sides of the coin. The chemotherapists say that if we improve the results of the chemotherapy then we will not need allogeneic transplant. On the other hand, the transplanters say that if we reduce the transplant-related mortality then transplant will work.
Now on the next slide I am showing the results of what’s called the French study, the LILA study, where the investigators assigned patients for allogeneic transplant when available, and if they were under the age of 45, and then they compared the results to the patients who received either chemotherapy or autologous transplant. And, while overall they did not see any difference in the outcome, when they analyzed the subset of the high risk patients there was a significant advantage for allogeneic transplant; arguing that patients who are in complete remission, who have high risk features, maybe should be offered a related allogeneic transplant in first complete remission. This is a similar analysis of the same data but here I’ve divided the patients into the high risk and the standard risk to demonstrate that for the standard risk patient there is no advantage for allogeneic transplant as opposed to the high risk patients where allogeneic transplant will improve the results. Now of course the most obvious candidate for allogenic transplant is a patient with Philadelphia-positive ALL because as I mentioned, there is no potential for a cure for such patients with chemotherapy. While about 30-40% of the patients would be potentially cured with allogeneic bone marrow transplantation. Other indications are definitely the translocation 4-11 which is uncommon, but people could conceive of patients who are identified as potentially having a high risk for relapse. For example, those that take more than one course to achieve complete remission or patients who present with severe leukocytosis. But they should not have T-cell ALL because leukocytosis in T-cell ALL is not an adverse prognostic factor.
What about the role of autologous stem cell transplantation? Here I’m going to show you one of several studies, and this is the one again from the French group that had a high number of patients where they looked at autologous transplant versus chemotherapy. What you see is that also the disease-free survival tends to be slightly better by about 7%. There’s really not much difference and it is certainly not significant for either event-free survival or overall survival. But of course people could argue that autologous transplant is a one-time approach as opposed to two years of chemotherapy. So if you have a patient who is a poor candidate for continuation of maintenance therapy because of intolerance or because of poor compliance, these patients should go for autologous transplant.
The need and duration of maintenance therapy was looked at because some people suggested that perhaps adult ALL, unlike childhood ALL, is more like adult AML where giving 6-12 months of chemotherapy will be enough. So there were at least three studies; one from the CLGB and two from the ECOG that looked at maintenance therapy, ranging anywhere from 7-12 months and in all of these three studies the short term follow-up showed that the event-free survival was quite low particularly under 20%. So now most of the people agree that 6MP methotrexate, even though it looks benign as a treatment, is quite effective in improving the long term event-free survival and should be given for an average of two years.
CNS prophylaxis again was a question because people thought that maybe adult ALL is like adult AML where you don’t need to give them CNS prophylaxis. And if you look at the literature there is one study that looked at the small number of patients, 62 patients, who were randomized to either receive intrathecal methotrexate or no prophylaxis. And that study established that CNS prophylaxis reduced the incidence of relapse significantly and reduced the three year risk of leukemia relapse significantly by about 50%. Now having said this, there are several recent studies that did not use radiation therapy but instead they used intrathecal chemotherapy prophylaxis and on this slide I show the results of the hyper-CVAD regimen that used intrathecal prophylaxis anywhere from 4-16 dosages, depending on the predicted CNS risk, and the incidence of CNS relapse was reduced only 2%. So the summary for CNS prophylaxis is that you do need some form of CNS prophylaxis, that intrathecal chemotherapy - particularly in the setting of high dose systemic chemotherapy - is equivalent to radiation therapy. You usually need on the average 4-8 intrathecals unless a patient has Burkitt or mature B-cell ALL and therefore they need more frequent CNS prophylaxis. Now if you have a patient who presents with CNS leukemia then you have to treat them more intensively, perhaps with twice intrathecals every week until they become negative, and then with an attenuated schedule for about a year. If you have cranial nerve pulses at diagnosis you may want to consider radiation therapy to the base of the skull only.
Now in the next set of slides I am going to talk about tailored therapy for particular subsets. The first one is the adult T-cell ALL, because such patients have improved their outcome only because of the incorporation of cyclophosphamide ara-C pulses into the consolidation therapy. So anytime you have a patient with T-cell ALL you have to remember is that the consolidation therapy in these patients should include cyclophosphamide ara-C pulses. This was established in a pediatric randomized study of the Cytoxan ara-C pulses versus maintenance chemotherapy where the Cytoxan ara-C improved the outcome and in at least three studies in adult ALL - the BFM, the Sloan Kettering and the CLGB - where patients received cyclophosphamide ara-C consolidation, T-cell ALL became a favorable prognostic feature by multi-variant analysis.
The second … this is the data for lymphoblastic lymphoma so your question is, what is lymphoblastic lymphoma? Essentially, lymphoblastic lymphoma is the T-cell variant of T-cell ALL except that it doesn’t involved the bone marrow, and most of the patients present with mediastinal disease. Now lymphoblastic lymphoma has a prognosis which is even better than T-cell ALL if you use adult ALL-type therapy with cyclophosphamide ara-C. This is an update from the hyper-CVAD regimen where I show that 22 of the 23 patients achieved a complete remission and the three year survival rate was 70% with only four relapses. So when you have a patient with lymphoblastic lymphoma you do not treat them as large cell lymphoma. You treat them as ALL and they do need also CNS prophylaxis.
The second entity, which is important to recognize because it requires a specific therapy, is the mature B-cell ALL, be it Burkitt type or the non-Burkitt small non-cleaved lymphocytic lymphoma. On the top of the slide I show the conventional approaches that were used in the past which produced CR rates of about 50% but very few patients were cured. So much so that at one point in time we started rejected patients with Burkitt’s leukemia because we thought we had nothing to offer to them. Now Dr. Sharon Murphy first designed the short-term dose intensive therapy with fractionated cyclophosphamide alternating with methotrexate ara-C and subsequently several short term dose intensive regimens were used. In all of them it was shown that now you can cure about half of the patients. Now this next slide again shows the results of the hyper-CVAD, which is similar to the Burkitt childhood treatment experience, in 26 patients.
The point I want to make is that unlike the data which is in the literature, where the median age is reported to be 20-25 years, our experience showed that in fact Burkitt’s leukemia occurs in a very elderly population. You can induce most of the patients into complete remission but when you look at the outcome by age cut-off patients under the age of 60 are like children. You can cure about three-quarters of them. But if they are older, then they die with induction and they relapse. So what we are planning to do for this group of patients is to add monoclonal antibody therapy to the hyper-CVAD intensive chemotherapy to try to improve the results. In this slide I show the outcome of patients by age. The older patients, where we are planning to add monoclonal antibodies to the chemotherapy, and the younger patients; to emphasize the point that the relapses, when they occur, almost always occur within a year except for that particular individual. So the patients with Burkitt’s are either cured within a year or they relapse and die and you can do nothing for them. Therefore it was difficult to incorporate autologous or allogeneic transplant in those treatment strategies.
So here I’m identifying the three probable subsets of ALL that you need to have a different intervention; the Philadelphia-positive and translocation 4-11, where you need allogeneic transplant immediately in complete remission, the Burkitt’s cell disease where you need short term dose intensive therapies, but without maintenance, and the T-cell ALL where you need to include cyclophosphamide ara-C pulses in the consolidation.
The last question is, how do we identify patients that have differences in the outcome? This is summarized on the next slide which shows that the consistent poor risk features have been older age, very high white cell count in patients with non-T-cell ALL, longer time to achieve a complete remission, a non-cell phenotype because they behave like AML, Philadelphia-positive disease and translocation 4-11. These characteristics usually divide the patients into good risk groups. A minority of the patients but where the event-free survival is 60%, and most of the patients have poor risk disease where the event-free survival is about 30%. Can you do anything if the patients relapse? Well, you can do something if their remission duration has been long, longer than a year, but on the average the complete response rate, even though they vary in the literature, from 20-80% they are usually closer to the 20% rate and oftentimes, unless you perform allogeneic transplantation, the outcome is very poor.
The next slide is a summary of about 300 adults with ALL relapse, treated at our institution, demonstrating that the CR rate is low, about 30% and the remission durations and survival are short, about 5-6 months. You can use different regimens. You can use, for example, the classic ALL induction therapy if these patients have had long first remission. If they haven’t been exposed to high dose ara-C you can try a mitoxantrone high dose ara-C regimen and in some of the studies, asparaginase is not used during the induction consolidation and if that’s the case, then you can reintroduce them with that. What you see is that on the average the CR rate is about 30%. Now allogeneic and autologous transplant gives you a higher CR rate but they also offer the chance of event-free survival. Also is it more in the range of 10-20%.How are we going to improve the results? Well, as I mentioned, I believe that a better quality induction therapy, perhaps with a higher dose of anthracycline will improve on the long term event -free survival. Compound 506 which is very effective in T-cell ALL and we’d like to incorporate that into the front line therapy once we know how to deal with the neurotoxicity. If the patients express CD20 or CD52, we are planning to incorporate monoclonal antibody therapy together with chemotherapy like is done with the lymphomas, and we have a few ideas on immune modulation and some of the new agents that could be helpful.
Laura L. Peters, MD
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 therapy? There are three aspects that you have to require. The first one is an appropriate morphologic diagnosis with stain. The second is the full immuno-phenotypic characterization of the blasts of these patients, and the third is the cytogenetic molecular classification.
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 Burkitt’s-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. Here I categorize them as the T-cell markers, which means that the patients will have to have at least two T-cell markers of the CD1 to CD8, then the 3B ALL where the patients are CD19 or CD20 positive, and most of such patients are also CD10 or _ positive, which is about 40% of the total. If they have mature surface immunoglobulin positivity or kappa lambda clonality then they are mature B-cell ALL which is about 5-10% of the patients. Now importantly, people do the myeloid markers and in the past we thought that these had a prognostic implication. Now we know that they do not and I’ll show you the data for that.
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 it’s 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 in excess of 50%.
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 it’s 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 it’s 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 ALL’s. The most frequent molecular abnormality is the P190 which requires PCR analysis. It’s important to recognize the Philadelphia-positive ALL’s because this is the one group that has the worst prognosis with combination chemotherapy and will require either allogeneic or matched unrelated transplant in first complete remission.
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 it’s 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.
I’m 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? It’s 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, it’s 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 it’s not differences in the therapy but differences in the biology of the disease which accounts for most of the prognostic difference.
Next we will talk about the treatment principles in adult ALL and here on this slide I am showing the principles consisting of an induction therapy to induce the patients into complete remission using vincristine, steroids and anthracyclines. Such patients need, unlike adult AML, they need long term maintenance therapy for up to two years and this is traditionally given with 6 mg methotrexate and monthly courses of vincristine and steroids. Different programs use different consolidation approaches with high doses of cyclophosphamide, ara-C, VP16 or the ultimate of intensification which are autologous and allogeneic transplant. Unlike adult AML, these patients need CNS prophylaxis with either radiation therapy or intrathecal chemotherapy. Now these principles have been derived from the childhood experience and when applied to adult ALL it was observed that adults were getting a complete response rate of about 85% and about 40% of the patients were projected to have long term remissions. So this was a very positive thing until people started referring the truly average population of adult ALL. So the older patients and those with Philadelphia-positive disease, and these are the serial studies from Sloan Kettering. This is the well-known L-10 program where it was reported to produce cures in 50% of the patients. And this is the more recent L-17 modified program where the early event-free survival rate had dropped to about 25%. So in fact the initial reports were over-enthusiastic and when the regimen was applied to unselected patients the results were worse. So if you do a review of the literature, as did Dr. Halser in this publication, he looked at about 5,000 patients from 26 large studies. Note the median age of the patients is 30 years and in fact the reality is that the adult ALL median age is probably a decade older. These patients were induced with different regimens and when he looked at the weighted percent of expected complete remission it was 75%, and the weighted percent of leukemia-free survival, it was down to 30%. Which is in fact the reality in adult ALL therapy unless we discover more effective dose-intensive regimens or more selective ALL therapies.
Now then the question is; if we have a patient with adult ALL, what would be our best induction therapy? What is the value of intensifying the patients once they are in remission? When should we perform allogeneic bone marrow transplant in first remission? And is there any role for autologous stem cell transplant? Is there a need and what is the duration of maintenance therapy? And what kind of CNS prophylaxis should we give these patients? Let’s start with the first question of induction therapy. Before the advent of anthracycline, vincristine and prednisone were the standard of care. And when anthracyclines became available the triple threat therapy was compared in a randomized fashion to the classical vincristine/prednisone demonstrating a significant improvement in the complete remission rate. This now has become the standard of care for induction therapy. There were multiple attempts to improve on the induction therapy results, continuing with the vincristine, steroids and anthracyclines, but adding in different regimens asparaginase and cyclophosphamide and in some of the studies, ara-C. None of these studies showed a significant improvement over the average CR rate of 75%. This is a study done by the Italian group where the patients were randomized to a four-drug induction therapy; the triple regimen with asparaginase and with or without cyclophosphamide. In that study there was no difference in either the CR rate or the event-free survival. So one could conclude that there is no point in trying to achieve better remissions, better quality remissions, because there may not be an impact on the event-free survival except that there are studies from the childhood experience, for example, where the patients were randomized to receive either one dose of high dose methotrexate with induction therapy or the conventional induction therapy. When this study matured at seven years there was a significant difference in the leukemia and disease-free survival of the patients. So it is my opinion that we can improve on the induction therapy, perhaps not to improve the complete remission rate but to improve the long term event-free survival rate.
Another question that comes about is, do you need to use growth factors with ALL induction therapy? As you know, in adult AML therapy there is more question about the use of growth factor except perhaps as a supportive care measure which will help shorten the duration of neutropenia. But in adult ALL the randomized study from CLCB has shown that not only do you shorten the period of neutropenia but you also reduce the induction mortality. So I think for adult ALL growth factor support may be important. In the bottom of the slide you see the older patients, and these were a much smaller number of patients. About 40 in total but where the induction mortality appeared to be significantly reduced. Even so, the P value was not significant, probably because of the small number of patients.
So are there questions remaining for induction therapy that we could still investigate? I think there is perhaps a role for investigating asparaginase instead of anthracycline, but my personal interest and that of many investigators is to look at more dose-intensive or better quality remissions to try to impact on the long term event-free survival.
How about intensive consolidation therapy? Now in childhood ALL there is no doubt that all the studies that intensified maintenance with either high doses of methotrexate alone or with 6MP, the use of asparaginase therapy has improved the outcome of childhood ALL. This is an example of such studies where high dose methotrexate was given as a consolidation for 15 doses and the investigators were looking as to whether this would replace the CNS prophylaxis, which it did not. But in all the other parameters, including complete remission, durable complete remission at about eight to nine years, whether hematologic, testicular or the event-free survival, the results were improved with the addition of high dose methotrexate therapy. Now in adult ALL there were no such studies that were conducted which looked at the agent that specifically affects ALL. Such as perhaps methotrexate or 6MP or asparaginase. The only two studies that looked at the efficacy of intensive consolidation consisted of two to three months of consolidation with AML-type therapy. So it is not surprising that neither of the two studies showed any benefit. So because of this you have experts that say perhaps that there is no definite benefit, that intensive consolidation therapy in adult ALL is of value, but most of the investigators agree that the more intensive regimens have improved the outcome of adult ALL as they did for childhood ALL.
Now you have a patient who has achieved a complete remission and you wonder, if the patient has a match-related sibling, whether you should send the patient for allogeneic bone marrow transplantation. Now this question has been tackled in numerous studies. The first one that came about was in fact an analysis by Dr. Horowitz from the International Bone Marrow Transplant Registry that took patients who received allogeneic bone marrow transplantation versus patients who were continued on BFM-like chemotherapy. And she accounted for the age so she took patients only between the age of 15-45 and accounted also for the time to transplant. This is the first analysis that did not show an improvement in the outcome, so people said, "Well, maybe if you follow that study longer you will see results" and Dr. Horowitz published an update at eighth year that did not show an improvement in the outcome.
Now the reasons for failures are quite different. In the setting of chemotherapy, the most common reason for failure cumulatively at 60% is leukemia relapse. On the other hand, with allogeneic transplant the most common cause of failure is transplant-related mortality. So this experience has been taken to argue both sides of the coin. The chemotherapists say that if we improve the results of the chemotherapy then we will not need allogeneic transplant. On the other hand, the transplanters say that if we reduce the transplant-related mortality then transplant will work.
Now on the next slide I am showing the results of what’s called the French study, the LILA study, where the investigators assigned patients for allogeneic transplant when available, and if they were under the age of 45, and then they compared the results to the patients who received either chemotherapy or autologous transplant. And, while overall they did not see any difference in the outcome, when they analyzed the subset of the high risk patients there was a significant advantage for allogeneic transplant; arguing that patients who are in complete remission, who have high risk features, maybe should be offered a related allogeneic transplant in first complete remission. This is a similar analysis of the same data but here I’ve divided the patients into the high risk and the standard risk to demonstrate that for the standard risk patient there is no advantage for allogeneic transplant as opposed to the high risk patients where allogeneic transplant will improve the results. Now of course the most obvious candidate for allogenic transplant is a patient with Philadelphia-positive ALL because as I mentioned, there is no potential for a cure for such patients with chemotherapy. While about 30-40% of the patients would be potentially cured with allogeneic bone marrow transplantation. Other indications are definitely the translocation 4-11 which is uncommon, but people could conceive of patients who are identified as potentially having a high risk for relapse. For example, those that take more than one course to achieve complete remission or patients who present with severe leukocytosis. But they should not have T-cell ALL because leukocytosis in T-cell ALL is not an adverse prognostic factor.
What about the role of autologous stem cell transplantation? Here I’m going to show you one of several studies, and this is the one again from the French group that had a high number of patients where they looked at autologous transplant versus chemotherapy. What you see is that also the disease-free survival tends to be slightly better by about 7%. There’s really not much difference and it is certainly not significant for either event-free survival or overall survival. But of course people could argue that autologous transplant is a one-time approach as opposed to two years of chemotherapy. So if you have a patient who is a poor candidate for continuation of maintenance therapy because of intolerance or because of poor compliance, these patients should go for autologous transplant.
The need and duration of maintenance therapy was looked at because some people suggested that perhaps adult ALL, unlike childhood ALL, is more like adult AML where giving 6-12 months of chemotherapy will be enough. So there were at least three studies; one from the CLGB and two from the ECOG that looked at maintenance therapy, ranging anywhere from 7-12 months and in all of these three studies the short term follow-up showed that the event-free survival was quite low particularly under 20%. So now most of the people agree that 6MP methotrexate, even though it looks benign as a treatment, is quite effective in improving the long term event-free survival and should be given for an average of two years.
CNS prophylaxis again was a question because people thought that maybe adult ALL is like adult AML where you don’t need to give them CNS prophylaxis. And if you look at the literature there is one study that looked at the small number of patients, 62 patients, who were randomized to either receive intrathecal methotrexate or no prophylaxis. And that study established that CNS prophylaxis reduced the incidence of relapse significantly and reduced the three year risk of leukemia relapse significantly by about 50%. Now having said this, there are several recent studies that did not use radiation therapy but instead they used intrathecal chemotherapy prophylaxis and on this slide I show the results of the hyper-CVAD regimen that used intrathecal prophylaxis anywhere from 4-16 dosages, depending on the predicted CNS risk, and the incidence of CNS relapse was reduced only 2%. So the summary for CNS prophylaxis is that you do need some form of CNS prophylaxis, that intrathecal chemotherapy - particularly in the setting of high dose systemic chemotherapy - is equivalent to radiation therapy. You usually need on the average 4-8 intrathecals unless a patient has Burkitt or mature B-cell ALL and therefore they need more frequent CNS prophylaxis. Now if you have a patient who presents with CNS leukemia then you have to treat them more intensively, perhaps with twice intrathecals every week until they become negative, and then with an attenuated schedule for about a year. If you have cranial nerve pulses at diagnosis you may want to consider radiation therapy to the base of the skull only.
Now in the next set of slides I am going to talk about tailored therapy for particular subsets. The first one is the adult T-cell ALL, because such patients have improved their outcome only because of the incorporation of cyclophosphamide ara-C pulses into the consolidation therapy. So anytime you have a patient with T-cell ALL you have to remember is that the consolidation therapy in these patients should include cyclophosphamide ara-C pulses. This was established in a pediatric randomized study of the Cytoxan ara-C pulses versus maintenance chemotherapy where the Cytoxan ara-C improved the outcome and in at least three studies in adult ALL - the BFM, the Sloan Kettering and the CLGB - where patients received cyclophosphamide ara-C consolidation, T-cell ALL became a favorable prognostic feature by multi-variant analysis.
The second … this is the data for lymphoblastic lymphoma so your question is, what is lymphoblastic lymphoma? Essentially, lymphoblastic lymphoma is the T-cell variant of T-cell ALL except that it doesn’t involved the bone marrow, and most of the patients present with mediastinal disease. Now lymphoblastic lymphoma has a prognosis which is even better than T-cell ALL if you use adult ALL-type therapy with cyclophosphamide ara-C. This is an update from the hyper-CVAD regimen where I show that 22 of the 23 patients achieved a complete remission and the three year survival rate was 70% with only four relapses. So when you have a patient with lymphoblastic lymphoma you do not treat them as large cell lymphoma. You treat them as ALL and they do need also CNS prophylaxis.
The second entity, which is important to recognize because it requires a specific therapy, is the mature B-cell ALL, be it Burkitt type or the non-Burkitt small non-cleaved lymphocytic lymphoma. On the top of the slide I show the conventional approaches that were used in the past which produced CR rates of about 50% but very few patients were cured. So much so that at one point in time we started rejected patients with Burkitt’s leukemia because we thought we had nothing to offer to them. Now Dr. Sharon Murphy first designed the short-term dose intensive therapy with fractionated cyclophosphamide alternating with methotrexate ara-C and subsequently several short term dose intensive regimens were used. In all of them it was shown that now you can cure about half of the patients. Now this next slide again shows the results of the hyper-CVAD, which is similar to the Burkitt childhood treatment experience, in 26 patients.
The point I want to make is that unlike the data which is in the literature, where the median age is reported to be 20-25 years, our experience showed that in fact Burkitt’s leukemia occurs in a very elderly population. You can induce most of the patients into complete remission but when you look at the outcome by age cut-off patients under the age of 60 are like children. You can cure about three-quarters of them. But if they are older, then they die with induction and they relapse. So what we are planning to do for this group of patients is to add monoclonal antibody therapy to the hyper-CVAD intensive chemotherapy to try to improve the results. In this slide I show the outcome of patients by age. The older patients, where we are planning to add monoclonal antibodies to the chemotherapy, and the younger patients; to emphasize the point that the relapses, when they occur, almost always occur within a year except for that particular individual. So the patients with Burkitt’s are either cured within a year or they relapse and die and you can do nothing for them. Therefore it was difficult to incorporate autologous or allogeneic transplant in those treatment strategies.
So here I’m identifying the three probable subsets of ALL that you need to have a different intervention; the Philadelphia-positive and translocation 4-11, where you need allogeneic transplant immediately in complete remission, the Burkitt’s cell disease where you need short term dose intensive therapies, but without maintenance, and the T-cell ALL where you need to include cyclophosphamide ara-C pulses in the consolidation.
The last question is, how do we identify patients that have differences in the outcome? This is summarized on the next slide which shows that the consistent poor risk features have been older age, very high white cell count in patients with non-T-cell ALL, longer time to achieve a complete remission, a non-cell phenotype because they behave like AML, Philadelphia-positive disease and translocation 4-11. These characteristics usually divide the patients into good risk groups. A minority of the patients but where the event-free survival is 60%, and most of the patients have poor risk disease where the event-free survival is about 30%. Can you do anything if the patients relapse? Well, you can do something if their remission duration has been long, longer than a year, but on the average the complete response rate, even though they vary in the literature, from 20-80% they are usually closer to the 20% rate and oftentimes, unless you perform allogeneic transplantation, the outcome is very poor.
The next slide is a summary of about 300 adults with ALL relapse, treated at our institution, demonstrating that the CR rate is low, about 30% and the remission durations and survival are short, about 5-6 months. You can use different regimens. You can use, for example, the classic ALL induction therapy if these patients have had long first remission. If they haven’t been exposed to high dose ara-C you can try a mitoxantrone high dose ara-C regimen and in some of the studies, asparaginase is not used during the induction consolidation and if that’s the case, then you can reintroduce them with that. What you see is that on the average the CR rate is about 30%. Now allogeneic and autologous transplant gives you a higher CR rate but they also offer the chance of event-free survival. Also is it more in the range of 10-20%.How are we going to improve the results? Well, as I mentioned, I believe that a better quality induction therapy, perhaps with a higher dose of anthracycline will improve on the long term event -free survival. Compound 506 which is very effective in T-cell ALL and we’d like to incorporate that into the front line therapy once we know how to deal with the neurotoxicity. If the patients express CD20 or CD52, we are planning to incorporate monoclonal antibody therapy together with chemotherapy like is done with the lymphomas, and we have a few ideas on immune modulation and some of the new agents that could be helpful.
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