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OP01 Treatment of acute leukemia: 50 years later
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Sessions / Symposia / Special Lectures
Presidential Symposium OP01 Treatment of acute leukemia: 50 years later E. Freireich. UT M.D. Anderson Cancer Center, Houston, TX, USA The advances in therapeutic research in the leukemic disorders have had a profound effect on our understanding of the biology of malignant disease and its treatment. Fifty years ago, the leukemias were uniformly fatal and therapy produced only palliative regression of tumors, which were short-lived and did not affect overall survival. A most significant contribution is the appreciation of the importance of circulating platelets in controlling hemorrhage and the concentration of circulating granulocytes in preventing infection. Developments in supportive therapy with allogeneic platelet transfusion and antibiotic chemotherapy given empirically have dramatically changed the potential for not only the treatment of leukemias but for all myelosuppressive therapy. The development of combination chemotherapy in the late 1950’s, the demonstration of the effectiveness of adjuvant chemotherapy in the 1960’s and the discovery of the importance of both early intensification and intermittent reinduction led to the first cure of a systemic cancer in man, the cure of childhood acute lymphoblastic leukemia described in 1965 more than 40 years ago. The report of a specific cytogenetic abnormality in a malignant disease, that is the Philadelphia chromosome in 1960, sparked a revolution in our understanding of the biology and therapy of cancer. Not only did the study of cytogenetics reveal the enormous heterogeneity of the malignant diseases, particularly leukemias, but it was soon recognized that effective therapy could be evaluated by the effect, not on the clinical and hematological manifestations of disease, but on the cytogenetic and subsequently, the molecular markers of disease. The association of the 15-17 translocation with acute promyelocytic leukemia was a hallmark when the first targeted therapy was introduced in cancer therapy, the use of all transretinoic acid to induce remissions in acute promyelocytic leukemia, and the identification of the rearrangement of the retinoic acid receptor alpha. The demonstration that interferon could induce cytogenetic as well as clinical remissions in CML led to the hypothesis that the protein product of the rearranged gene BCR/ABL was essential for the disease to occur and led to the first small molecule tyrosine kinase inhibitor, Gleevec, which has had a profound impact on research not only in the hematological malignancies, but in solid tumors such as the GI stromal tumors. The development of effective supportive therapy for
myelosuppression allowed Dr. Thomas and his colleagues to accomplish the first successful allogeneic transplants in 1969. This technology has proven extremely important not only for the hematological diseases but for the understanding of anti-tumor immune reactivities. The dramatic change in the natural history of all of the hematological diseases has rapidly impacted on therapeutic research in all of the systemic cancers. As we will hear in the next several days, continued progress in therapeutic research of hematological malignancies will provide fundamental knowledge not only about the biology and control of hematological diseases but of all systemic cancers. References [1] Freireich, E.J and Lemak, N.: Milestones in Leukemia Research and Therapy. Johns Hopkins University Press, Baltimore, Maryland, pp. 1-280, 1991.
OP02 Unrelated cord blood transplantation in children and adults with leukemias and lymphomas E. Gluckman, I. Ionescu, C. Arrais, F. Garnier, S. Chevret, J. Garcia, V. Rocha, on behalf of the Eurocord-Netcord Registry. Bone Marrow Transplant Unit and Department of Hematology, Hôpital Saint Louis, Paris, France We have analyzed 925 patients given a myeloablative single UCBT for malignant disorders from 1994 to 2005 and reported to the Eurocord registry. The median age was 11 years, there were 37% of adults and the median follow-up for survivors was 28 months. Most of the patients (75%) had acute leukaemia; 20% of the patients were transplanted in early phase of the disease, 42% in intermediate phase and 38% in advanced phase. The cord blood graft was HLA matched (6 out of 6) in 9%. Results: Cumulative incidence (CI) of neutrophil recovery (day100) was 77%, and it was 55% of platelets recovery (day 180), 33% of acute GVHD (II-IV) (day 100) and 28% of transplant related mortality (day 100). At 3 years the CI of relapse and chronic GVHD were respectively 23% and 29%. At 3 years estimated OS and DFS were respectively 41% and 37%. In a multivariate analysis; increased early TRM was associated with number of HLA disparities (p=0.0005), nucleated cell dose(>2 × 107 /kg) (p=0.0002) and disease status at transplant (p=0.01), whereas for relapse increasing number of HLA disparities (p=0.0002) decreased incidence of relapse. In multivariate analysis for OS the most important patient-, disease-, donor- and transplant-related factors were 1) recip-
Sessions / Symposia / Special Lectures
Presidential Symposium OP01 Treatment of acute leukemia: 50 years later E. Freireich. UT M.D. Anderson Cancer Center, Houston, TX, USA The advances in therapeutic research in the leukemic disorders have had a profound effect on our understanding of the biology of malignant disease and its treatment. Fifty years ago, the leukemias were uniformly fatal and therapy produced only palliative regression of tumors, which were short-lived and did not affect overall survival. A most significant contribution is the appreciation of the importance of circulating platelets in controlling hemorrhage and the concentration of circulating granulocytes in preventing infection. Developments in supportive therapy with allogeneic platelet transfusion and antibiotic chemotherapy given empirically have dramatically changed the potential for not only the treatment of leukemias but for all myelosuppressive therapy. The development of combination chemotherapy in the late 1950’s, the demonstration of the effectiveness of adjuvant chemotherapy in the 1960’s and the discovery of the importance of both early intensification and intermittent reinduction led to the first cure of a systemic cancer in man, the cure of childhood acute lymphoblastic leukemia described in 1965 more than 40 years ago. The report of a specific cytogenetic abnormality in a malignant disease, that is the Philadelphia chromosome in 1960, sparked a revolution in our understanding of the biology and therapy of cancer. Not only did the study of cytogenetics reveal the enormous heterogeneity of the malignant diseases, particularly leukemias, but it was soon recognized that effective therapy could be evaluated by the effect, not on the clinical and hematological manifestations of disease, but on the cytogenetic and subsequently, the molecular markers of disease. The association of the 15-17 translocation with acute promyelocytic leukemia was a hallmark when the first targeted therapy was introduced in cancer therapy, the use of all transretinoic acid to induce remissions in acute promyelocytic leukemia, and the identification of the rearrangement of the retinoic acid receptor alpha. The demonstration that interferon could induce cytogenetic as well as clinical remissions in CML led to the hypothesis that the protein product of the rearranged gene BCR/ABL was essential for the disease to occur and led to the first small molecule tyrosine kinase inhibitor, Gleevec, which has had a profound impact on research not only in the hematological malignancies, but in solid tumors such as the GI stromal tumors. The development of effective supportive therapy for
myelosuppression allowed Dr. Thomas and his colleagues to accomplish the first successful allogeneic transplants in 1969. This technology has proven extremely important not only for the hematological diseases but for the understanding of anti-tumor immune reactivities. The dramatic change in the natural history of all of the hematological diseases has rapidly impacted on therapeutic research in all of the systemic cancers. As we will hear in the next several days, continued progress in therapeutic research of hematological malignancies will provide fundamental knowledge not only about the biology and control of hematological diseases but of all systemic cancers. References [1] Freireich, E.J and Lemak, N.: Milestones in Leukemia Research and Therapy. Johns Hopkins University Press, Baltimore, Maryland, pp. 1-280, 1991.
OP02 Unrelated cord blood transplantation in children and adults with leukemias and lymphomas E. Gluckman, I. Ionescu, C. Arrais, F. Garnier, S. Chevret, J. Garcia, V. Rocha, on behalf of the Eurocord-Netcord Registry. Bone Marrow Transplant Unit and Department of Hematology, Hôpital Saint Louis, Paris, France We have analyzed 925 patients given a myeloablative single UCBT for malignant disorders from 1994 to 2005 and reported to the Eurocord registry. The median age was 11 years, there were 37% of adults and the median follow-up for survivors was 28 months. Most of the patients (75%) had acute leukaemia; 20% of the patients were transplanted in early phase of the disease, 42% in intermediate phase and 38% in advanced phase. The cord blood graft was HLA matched (6 out of 6) in 9%. Results: Cumulative incidence (CI) of neutrophil recovery (day100) was 77%, and it was 55% of platelets recovery (day 180), 33% of acute GVHD (II-IV) (day 100) and 28% of transplant related mortality (day 100). At 3 years the CI of relapse and chronic GVHD were respectively 23% and 29%. At 3 years estimated OS and DFS were respectively 41% and 37%. In a multivariate analysis; increased early TRM was associated with number of HLA disparities (p=0.0005), nucleated cell dose(>2 × 107 /kg) (p=0.0002) and disease status at transplant (p=0.01), whereas for relapse increasing number of HLA disparities (p=0.0002) decreased incidence of relapse. In multivariate analysis for OS the most important patient-, disease-, donor- and transplant-related factors were 1) recip-