Talk given at the SIOP meeting in Istanbul 23-27 Sept. 1997 in the PODC Workshop 

Before speaking about our ALL-protocol I would first like to introduce our Pediatric Leukemia Group of the Ukraine (GPLU). This working group, founded in 1993, functions on a voluntary and democratic base with a fixed structure and strict rules of cooperation, corresponding to western models. I have to mention these conditions because they are completely unusual and new for people educated in the Soviet Union and in the successor states. The institution of such kind of cooperative group was not easy and only possible by the continuous intensive support of two experienced German colleagues - Günther Schellong from Münster and Alfred Reiter from Hannover. It was necessary to struggle against a lot of difficulties, psychological and material, and some of them have not been completely overcome. Nevertheless, the group has been working for 4 years now, and we can present some results.

Our group consists of 10 departments of pediatric hematology, which are distributed over the whole country, from Kiev in the north to Simferopol in the south, from L'viv in the west to Donezk in the east. Preconditions for the acceptance of a department as a member were and are basic experience in modern ALL-treatment including MHD-MTX and a sufficient number of trained staff. The 10 centers together treat approximately 30 % of all leukemia children in the Ukraine.

The members of the board of the Pediatric Leukemia Group are elected. The chairperson of the group is Vera Drosdova from the Ukrainian Institute of Hematology. Our two colleagues from Germany, Professor Schellong and Dr. Reiter are regular members of the board. One institution of high importance for the quality of work is the cytologic reference laboratory, headed by Professor Daniil Gluzman who is one of the directors in the Institute of Experimental Pathology, Oncology and Radiobiology of the Ukrainian Academy of Sciences. Bone marrow and peripheral blood smears of all children with leukemia from participating departments are examined in this laboratory morphologically and cytochemically. Due to the limited resources cytoimmunologic examinations can only be done in selected problematic cases.

Until now, detailed protocols were completed for ALL, AML, and ALL-relapses. While all 10 departments participate in the ALL-studies, only 4 fulfill the preconditions for participation in the studies of AML and for ALL-relapse. Thus the patients with these diseases are transferred to those 4 departments. All our protocols are modifications of the respective BFM-protocols adapted to some degree to our special conditions.

Since the foundation of the cooperative group there have been regular meetings of the members twice a year with lectures, discussions of protocols and fatal events, presentation of results by the study chairmen, and so on.

Before focusing on our ALL-projects I have to mention the role of the material aid from abroad. Unfortunately, the financial situation of the hospitals in our country is very, very poor, as in the other successor states of the Soviet Union, depending on the general chaotic economic situation of these countries. Until now, the circumstances in the hospitals became even worse instead of improving. Thus, our rather ambitious projects could never be realized if we did not receive extensive and continuos material help from abroad. Many people and organizations, especially in Germany and Austria, but also in Switzerland, Italy, Canada, USA and other countries support our work in such a splendid way. We want to thank all the physicians and organizations involved in this great humanitarian help. However, in regard to what I want to point out now, I have to mention that the general conditions in our hospitals have remained far from optimal, in spite of the present humanitarian aid. Therefore, our aims have to be realistic and not too high. We want to improve the chances of our leukemic children as much as possible, but until now the conditions are not stable enough to perform, for instance, randomized trials for answering open questions or even for comparing different complex therapy protocols.

The base for our first ALL-protocol was, as I already mentioned, the BFM-90 protocol. At that time, several departments in our country, as in Russia and Belorus, had already started to work with the protocol (or with elements of it), mostly after training of a physician in a German center. We were impressed by the good results of the BFM-group under the chairmanship of Professor Hansjörg Riehm and by the multitude of convincing data gained from the long series of successive trials.

Of course, we had to adapt the original protocol to our conditions. In general, adaptation of a protocol in this context means:
1. To eliminate experimental parts from the protocol, because they produce additional costs, while the effect on the treatment results is completely open.
2. To omit unrealistic and dangerous intensity and duration of the protocol as well as unrealistic costs, if at all possible without major impairment of the treatment results.

In the first ALL-protocol of our group (GPLU-93) the following deviations from the original BFM-90 protocol were made:
# 1g instead of 5g MTX/m² during 24h were given in the M-phase with a leucoverin rescue of 15 mg/m² twice
# patients with initial CNS-involvement received 3 drugs intrathecally instead of 1 drug
# HRG* patients were treated according to the MRG*-strategy, because the very intensive strategy in the original protocol was experimental and previous trials to improve the survival about 40 % had not been successful.
*(HRG= high risk group, MRG= medium risk group)

Prophylactic CNS-irradiation was given as in the original BFM-protocol with 12 Gy in the medium and high risk group to children above 1 year of age. Standard risk group patients and all patients below 1 year were not irradiated.

The second protocol GPLU-95 adopted two changes which were made in the original BFM-95-protocol.
# For the stratification into risk groups the BFM risk factor was replaced by the criteria age (below or above 6 years) and WBC (below or higher than 20.000/ul) in combination with the initial prednisone response.
# For patients in the standard risk group (SRG) the number of daunorubicin applications in the induction protocol was reduced from 4 to 2.

All other details of our first protocol remained unchanged.

Table 1: Patient Characteristics in 2 Ukrainian ALL-Studies

Table 1 demonstrates some characteristics of the patients in the two Ukrainian ALL-studies. 181 patients were enrolled in the first study between December 93 and May 95, 240 in the second study in the following two years. The recruitment of patients for the second study has not yet been completed. As we have no selection of patients the percentages are quite similar in both groups. We only note relatively high frequencies for severe hyperleucocytosis, initial CNS involvement and mediastinal tumor in the first study. Regarding CNS involvement I have to remark that only some departments of our group have the possibility to make cytospin preparations. Therefore, we defined CNS involvement "at least 10 leukocytes per microliter in the initial spinal fluid sample". Thus, the decreasing number of patients with CNS involvement may be explained by improvement of the lumbar puncture technique.

Table 2: Risk Groups in 2 Ukrainian ALL Studies

In table 2 the distribution of the patients to the 3 risk groups is shown. The higher percentage of standard risk group patients in the second study is the consequence of the changed criteria for allocation of the patients to the risk groups. Nearly one-third of the patients are now treated in the SRG (standard risk group) with reduced cumulative doses of daunorubicin and without cranial irradiation. These are by definition the young patients under 6 years of age with white blood counts below 20.000.
Finally, I will demonstrate some treatment results. Of course we are aware, that the follow-up time is not yet long enough for final conclusions (median follow-up was 31 months in the first study and 11 months in the second one at the time of evaluation in June 1997). 

Table 3: Treatment Failures in 2 Ukrainian ALL Studies (June 1, 1997)

Nevertheless, some trends can be recognized. The treatment failures are listed in table 3. Our main problem in the first study was the relatively high number of deaths due to intercurrent complications, which was also observed in most of the other centers in eastern Europe after the introduction of modern protocol chemotherapy. The number of fatal events was 11.6 %, the causes mostly infections and bleedings. The regular central documentation and the extensive analyses and discussions of the fatal events in our group meetings helped us to understand critical issues and to make attempts for overcoming them. Consequently, the hygienic standards were improved in the departments and strict principles for the prophylaxis were introduced. A special subprotocol for supportive care was prepared by one of our colleagues. Thus we consider the continuous training of the staff to be one of the main benefits of our cooperative work and a chance for further development. After 4 years of such efforts we have registered positive changes. For instance, the frequency of deaths, especially early deaths, has decreased, and we expect that this tendency will continue.

A second problem can also be recognized from table 3: The number of patients lost to follow-up was very high in the first study. The reason was that many parents refused further treatment in a relatively early therapy phase because they were impressed by the toxic side effects. Later on, since the group and our results were recognized in our country the percentage has decreased markedly.
The Kaplan-Meier analysis for event-free survival of both studies is shown in figure 1. In the first study the probability for EFS is 70 % at 42 months, and in the second one 83 % at 24 months. The general trend in the second study is somewhat better than in the first one.

The difference is even more marked in the two survival curves (figure 2). The probability for survival in the second study is 88% at two years.

In conclusion, the results of our studies are quite good and acceptable, especially if our particular working conditions are taken into consideration. It is necessary to remember, that only 7-8 years ago the chances for cure and survival were only 10 % or less in the Soviet Union. Thus, the treatment results have been dramatically improved by our efforts. The attempt to introduce a modern protocol therapy on a multi-center base can be considered successful. Of course, we have to continue our efforts to improve the standards in our departments and we also have to try to achieve some modernization in the neighboring specialties like laboratory and transfusion services, radiology, surgery, and so on.

We hope that the time to include also some experimental approaches in our studies will not be too far away. But we are convinced that only well organized cooperative groups give us the chance to achieve international standards in the pediatric hematology and oncology of our country.