The Nazli Gad-el-Mawla Award Recipient: Federico Sackmann-Muriel, MD

Historical development of Pediatric clinical trials in Hematological malignancies in Latin American Countries

Between 1950 and 1960, all children with acute lymphoblastic leukemia (ALL) died, with a median survival of between 12 and 18 months, even though several drugs, such as 6-mercaptopurine, corticosteroids and methotrexate, were able to produce temporary remissions in some patients. In 1960, an important advance, the foundation of modern risk-adapted therapy, was made by a German hematologist practicing in the USA, Wolf Zuelzer, with whom I studied. He and his colleagues observed that the level of the initial leukocyte count correlated with the length of survival. With the increasing effectiveness of chemotherapy, particularly using drug combinations, the importance of leukemic infiltration of the CNS became apparent, and by the early 1960s the basic pattern of therapy—remission induction, intensification, preventive treatment of meningeal leukemia and prolonged maintenance therapy—had been established. By the late 1960s and early 1970s, Pinkel and his colleagues at St Jude, Memphis, and Riehm and his colleagues in Berlin, had been able to demonstrate long-term survival in 50-55% of children with ALL.

At about this time (1967), the Grupo Argentino de Tratamiento de Leucemias Agudas (GATLA) was founded in Buenos Aires by Drs Santiago Pavlovsky, Marion Eppinger and myself. Initially there were three member institutions, including the founding institution, Hospital de Niños, Ricardo Gutierrez. At that time, survival rates in ALL were only 1% at 4 years, but the discipline and focus created by the cooperative effort, and the use of recent treatment approaches, resulted in an improved survival rate at 4 years of 21% in patients treated between 1967 and 1972. Among those in continuous remission at 4 years, 80% achieved long-term survival. These promising results led to the rapid expansion of the group, and by 1990, there were 32 members. Now, almost all Argentinean cities have a GATLA member institution. In 1973, following the success of GATLA, an international cooperative group was founded—Grupo Latino-americano de Tratamiento de Hemopatias Malignas (GLATHEM)—which eventually included Chile, Costa Rica, Cuba, Brazil and Uruguay. In some studies, GATLA and GLATHEM have used the same treatment protocols.

Between 1967 and 1994, 3,576 patients with ALL were entered into nine different joint GATLA/GLATHEM studies in which various remission induction, CNS prophylaxis and maintenance regimens were tested. During four chronologically sequential periods, event-free survival rates (EFS) improved steadily, being successively 11%, 24%, 46% and 55%. Over a similar timeframe, 497 patients with AML were treated. EFS at 5 years improved from 1% between 1967-80, to 21% between 1983-90. Similar success was achieved in 423 children with non-Hodgkin’s lymphoma, EFS improving from 35% for children treated from 1973-83 to 60% for children treated from 1984-88. With Hodgkin’s disease 497 children were treated in two main periods—1968-84 and 1986-92. EFS rose from 50% in the first study to 84% in the second. These were gratifying results, but still not as good as those being achieved in Europe and the USA. By now, I was the Chief of Oncology at the Garrahan Hospital for Children in Buenos Aires, which had opened in 1987. We decided to see whether we could improve upon the GATLA results for ALL by using protocols based on the Berlin-Frankfurt-Münster group regimens. In three successive protocols, ALL97, ALL90 and ALL96, we achieved EFS rates of 64%, 65% and 75% at 5 years—similar to those being achieved anywhere in the world.