Raisa Gorbacheva Memorial Lecture Treatment of Acute Myeloid Leukemia: Present Status and New Directions
The article is introduced by a tribute to the huge merits of Mrs. Raisa Gorbacheva's anti-leukemia campaign. Raisa Gorbacheva and her husband, Mr. Michael Gorbachev, have contributed greatly to the arrangement and funding of childhood leukemia treatment in Russia. The review article also covers the basic issues to do with acute myeloid leukemia (AML) treatment, including the general concepts of myeloablative therapy. Over four decades, improvements in therapeutic approaches have resulted in a gradual increase in complete remission rates and general survival of AML patients. However, further intensification of conventional treatments failed to increase the patients' long-term survival. A significantly lower survival rate among older patients (>60 years of age) is found when using this approach. Recent developments are associated with the usage of chromosome and gene aberrations as valuable markers to predict the treatment results and survival in AML. For example, a mutated nucleophosmin 1 gene in the absence of a FLT3 mutation is an age-independent predictor of a favorable outcome in AML. Decisive progress in AML treatment has been achieved when applying intensive chemotherapy followed by allogeneic transplantation of hematopoietic stem cells (allo-HSCT). This approach is clearly superior to conventional therapy in terms of relapse-free survival. However, comparative efficiency for different therapies presents some statistical controversies (e.g., biased patient selection in Matched Pair analysis). Allo-HSCT is still associated with considerable transplant-associated mortality, thus affecting overall survival rates. To avoid early mortality, a reduced-intensity conditioning may be considered, especially for older patients. Most clinical trials in AML are performed as multicentre therapeutic trials (e.g., within the European Leukemia Network): thus providing faster progress in the development of a more efficient AML treatment.
Hematopoietic stem cell transplantation, acute myeloid leukemia, efficiency, gorbacheva, treatment
Prof. Yaitsky, Rector of the University, Prof. Roumiantsev, Prof. Afanasyev, Prof. Zander, Ladies and Gentlemen,
Dear Prof. Afanasyev,
My congratulations for your important achievement, and for the great day you had yesterday with the opening of the new clinic, the Raisa Gorbacheva Memorial Institute of Children Hematology and Transplantation, also for your research team, for all your cooperators, supporters, and sponsors. You do not make much noise, but we all know what you created during the past two years. Thank you, and good wishes for a good cooperation in the future.
Raisa Maximovna Gorbacheva, 1999
I know that this support is continuing until today, as we saw yesterday.
1989 Symposium in Pushkinskie Gory on Acute Leukemia and Lymphoproliferative Diseases
In 1986, the Gorbachevs side by side visited East Berlin. And during the following years, Mikhail Gorbachev pursued the idea of “Glasnost” and “Perestrojka”, that turned out to eventually cause a revolution in our two countries, in Europe and in the world. Three years later, in 1989, I got my first opportunity to visit your country by an invitation to a hematology symposium to be held at “Pushkinskie Gory”. We started our trip in Moscow by bus and we had two excellent Russian piano-players in our group who played Chopin for us and Mussorgsky at the house of Mussorgsky's which we visited before we continued to Pushkinskie Gory. There we had a symposium on Acute Leukemia and Lymphoproliferative Diseases. I was asked to give a lecture on Acute Myeloid Leukemia. I started this lecture by thanking the organisers for inviting me, although I was a German. But they accepted this German and they gave us their friendship.
On the left photo you can see Andrej Vorobiev, actually one of our teachers.
Andrej Vorobiev, Mrs Büchner, Don Thomas (from left to right)
Boris Afanasyev, 1989, another important teacher.
Let us now talk about Acute Myeloid Leukemia (AML), about the disease itself and the problems linked to the disease. AML is characterised by a bone marrow tightly packed with leukemic cells. All cells which produce normal blood cells have disappeared.
Image 1. AML bone marrow
When we remove the leukemic cell burden by chemotherapy until bone marrow gets empty and does not contain any blood forming cells, only some tissue cells are left.
Image 2. AML bone marrow, aplasia after chemotherapy
This is a chance for a normal cell population to recover so that a patient can go into a complete remission where she or he feels well and we are not able to detect leukemic cells any more, and the patient may even be cured, if not relapsing later. In 1969, all patients still died within two years, and half of the patients even died within the first five months.. This was the pre-chemotherapy era, again confirming AML to be a most aggressive and dreadful disease.
Image 3. AML bone marrow, complete remission after chemotherapy
The first of the two tables below shows the results in complete remissions (CR) and 4-5-year continuous complete remissions (CCR) in multicenter randomized trials for younger patients, and the second table represents the results for older patients.
In 1981 and the following years, many reports in multicenter randomized trials were published. And we have to go into all these publications in order to learn our lessons. This is what those 20.000 patients have given us.
Mean percent complete remissions in 31 randomized multicenter trials and 19 882 patients increased over time from 66% to 72% in younger patients, and similarly from 42% to 51% in older patients.
For continuous complete AML remissions at 4-5 years, the cure rate increases from 17% to 34% in younger patients, a double cure rate. In older patients there is an increase from 11% to 15% only. So, in comparison to the younger patients group, older patients do worse.
The German Acute Myeloid Leukemia Cooperative Group started its work in 1978. Our first observation was that patients who did not receive any post-remission chemotherapy have no chance of a longer relapse-free survival. In the following years we intensified our chemotherapy step-by-step by giving consolidation and maintenance. By double induction and maintenance, the cure rate of these patients was raised to 35%, which was, however, not enough. Yet the good point about this is that these are the results for patients of all age groups.
We tried to improve the results by further intensifying chemotherapy. By HAM-HAM induction, randomised against TAD-HAM, representing a difference in dosage of factor 2 there was no difference in the overall survival. And this lesson shows us that once a certain intensity of chemotherapy has been reached, we may not be able to further improve the results. Those may in fact be the limits of cytotoxic treatment. So we have to look for alternatives. This is true for patients of all ages.
The overall survival of older patients amounts to only half of the overall survival of younger patients. So the situation for older patients is two times worse. This is a very important finding because two thirds of our patients are 60 years of age or older.
AML is a disease of older people. The treatment of older age AML is a challenge for the future. The challenge is to improve the results not only in the children, but also in the grandparents.
We also have to look at the chromosomes that show typical abnormalities in AML. These abnormalities give predictions for different outcomes in patients.
A favorable cytogenetic group is associated with a relatively long overall survival on the top and unfavorable cytogenetics predict for a short survival (on the bottom). And in between, three other groups of outcome in AML (AMLCG). So we can establish a hierarchy of classification on the basis of cytogenetics.
This slide shows that this classification is maintained in both age groups, in the younger patients on the left and also in the older patients on the right. But you see that in the older patients the general survival is significantly lower, which proves that the situation for older patients is worse.
We also have to look at the genes and their mutations as discovered more recently. We are in a position to find out particular genes and their mutations. This is especially important in the patients with normal karyotypes. Since half of the patients have normal karyotypes, we cannot classify them by cytogenetics.
There are some important mutations, such as mutations of the nucleophosmin1 gene in an acute myeloid leukemia (NPM), particularly when combined with the absence of an FLT3 mutation.
This combination really predicts a favorable outcome for patients of all ages.
In contrast to other combinations of the two genes, we need this again for classification. And we need the mutations in the future for therapeutic targets, of course.
This slide shows the steps of improvement of chemotherapy together with allogeneic transplantation. Allogeneic transplantation represents the most important alternative to chemotherapy. Moreover, allogeneic transplantation appears superior to chemotherapy. However, it is difficult to measure it. There are different approaches. One approach is Match Pair analysis. You see 84 transplantations compared to 84 chemotherapy patients in the Matched Pair system. And you see some superiorities which are not quite significant.
Furthermore, here, allogeneic transplantation appears highly superior to chemotherapy. However, you have to keep in mind that transplant patients are positively selected patients. In addition, they are younger than 60, in contrast to the chemotherapy patients, who are of all ages. However, allogeneic transplantation looks promising.
Here we did additional comparisons and analyses of allogeneic transplantation. The slide presents Matched Pair Analysis of 98 chemotherapy patients. A transplant is highly superior in the probability to remain without relapse.
Those patients mostly do not relapse. However, if you look at the overall survival of these patients they become superimposable. This teaches us that allogeneic transplantation in all adults is associated with considerable mortality. We need to find out how transplant associated mortality can be overcome. This would really bring us much forward.
This could be done for instance by reduction in the Total Body Irradiation here at 8 Gy instead of 12 Gy. In this study it led to a high cure rate for the transplant patients, even in their overall survival. It looks like the transplant associated mortality was overcome in this study. And this is very encouraging. I heard from Hans-Jochem Kolb that this is also possible by reduction in chemotherapeutic conditioning of patients with similar results.
It is very promising also for our older patients. Patients even over 60 years old and even over 70 years old may be treated by allogeneic transplantation in the future.
We also need better cooperation and we try to have it in the European Leukemia Network which is being funded by the European Commission in Brussels. In this network we combine a huge number of centres, of countries and of investigators.
We also created a network of multicenter therapeutic trials for AML. For such trials, researchers normally don't cooperate but rather compete with each other. But here they are cooperating using the instrument of a common standard arm.
The first symposium of the European Leukemia Network was in 2004. President Mikhail Gorbachev sent us a greeting address.
The next annual meeting will be in January 2009. We are hoping for Mikhail Gorbachev to join us in this meeting and to speak to us. We like to learn from paediatricians.
My colleague, Professor Ritter, from our university, gave me this slide about AML-multicenter-BFM trial, the Berlin/ Frankfurt/ Munich trial. And you see a stepwise improvement of the results according to the optimisation. A similar picture as in the adults.
Paediatricians have a lot to teach us and we appreciate learning from them. More than 15 years ago, while in St. Petersburg with Boris Afanasyev, Edith and I met a family, with a little girl just undergoing allogeneic transplantation from her sister. She is now a medical student.
Ladies and Gentlemen, I hope I could give you a taste of the efforts required for helping patients with Acute Myeloid Leukemia, efforts of investigators, efforts of clinicians, and efforts of dedicated persons, their sponsorship, their organisation, their political work, let me say, their spirit. And this is the contribution of Raisa Gorbacheva. We will never forget Raisa Gorbacheva. We, our children, our grandchildren, and even history will not forget Raisa.