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Report of the eurocord registry
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Abstracts/Experimental Hematology 28 (2000) 31–131
single colony), indicates that hemopoietic cells remain bipotent for the erythroid (E) and Mk pathway after the BFU-E stage. In fact, a cell precursor expressing on the cell surface both E (Ter-119) and Mk (4A5 and 2D5) antigens was identified in the marrow of normal mice and in the marrow and spleen of mice recovering from phenylhydrazine (PHZ)-induced anemia (Vannuchi et al., Blood, in press). Ter-119⫹Ⲑ4A5⫹ cells are candidate as the last bipotent (EⲐMk) cells because they express some E (␣-globin) and Mk (GpIIb) genes by RT-PCR and progress into fully differentiated E and Mk cells when cultured in the presence of either EPO or TPO, respectively. To further understand the biology of Ter-119⫹Ⲑ4A5⫹ cells, their number was measured in mice genetically unable to up-regulate Gata-1 expression (McDevitt et al., PNAS, 1997, 94: 6781). The Gata-1low mice are profoundly thrombocytopenic but have a normal hematocrit (Hct). The spleens of these mice are 2.5-fold bigger than normal and contain many megakaryocytes and erythroid cells at different maturation stages. Also the number of Ter119⫹Ⲑ4A5⫹ cells in these spleens is ⬇5-fold higher than in wild-type animals. Gata1low mice recovered faster than their normal littermate from PHZ-induced anemia (Hct of 48% at day 5 instead than at day 7 from the induction of anemia). They also responded more readily to treatment with EPO (10 UⲐmouse): their hematocrit increased more than the hematocrit of their normal littermate in response to EPO (68% vs 55%). In both cases, the number of Ter119⫹Ⲑ4A5⫹ cells in the spleen increased more than the increase observed in normal mice treated in the same fashion (⬎7 times vs 3–5 times). These results confirm that the block in differentiation of the Gata-1low mice is late and downstream of the bipotent cell and support the concept of Ter119⫹Ⲑ4A5⫹ cells as the last bipotent cell precursor. 150
Sunday, July 9, 2000 (10:30–12:30) Session I-3: Cord Blood Transplantation
COMPARISON OF THE OUTCOME OF UNRELATED BONE MARROW (BM) OR CORD BLOOD (CB) TRANSPLANT IN CHILDREN WITH ACUTE LEUKEMIA (AL) V. Rocha*, J. Cornish*, E. Sievers, A. Filipovich*, O. Ringden*, F. Locatelli*, G. Michel*, W. Arcese*, S. Chevret* and E. Gluckman for EUROCORD With the increased number of CB banks and unrelated BM donors registries, it is very important to compare the outcome of both types of transplants in order to evaluate the strategy of donor search. We analysed a total of 515 children with AL aged ⬍16 y transplanted with unrelated CB (n⫽99) or BM (n⫽416) between 01Ⲑ94 and 05Ⲑ98 in 51 centres, and reported to Eurocord Registry. Results were analysed as of 01Ⲑ99. Overall survival (OS), time to relapse, event-free survival (EFS) and other times to event were estimated using Cox proportional hazards regression to adjust for patient-, disease- and transplant-related factors. Results: Recipients of CB were younger (p⬍0.0001), had more adverse factors: AML (p⬍0.001), previous transplant (p⬍0.001), early relapse after 1st complete remission (CR) (p⬍0.0001). The interval from last CR to transplant was shorter in the CB group (p⬍0.001). the donor was HLA mismatched in 91% CBT and in 29% BMT (p⬍0.0001). The median number of nucleated cells infused was 4⫻108Ⲑkg in BMT and 0.38⫻108Ⲑkg in CBT (p⬍ 0.001). T depletion (TD) was performed in 43% BMT and none in CBT. After adjustment, relative risk [RR] of outcomes showed no difference between both groups for: OS [RR 1.27 p⫽0.16], EFS [RR 1.27, p⫽0.15], acute
GVHDⱖII [RR 0.98, p⫽0.92]. The incidence of grade III–IV GVHD was 9% after TD-BMT, 21% after CBT and 29% after BMT (p⬍0.001). There was no difference in the incidence of relapse [RR 0.79, p⫽0.37]. Neutrophil recovery was significantly delayed after CBT [RR 0.42, p⬍0.001] and this could explain an increased 100 days TRM [RR 2.32, p⫽0.001]. Conclusion: with adjustment for risk factors, we show that, despite an early TRM, probably due to a delayed neutrophil recovery, EFS was comparable between HLA mismatched CBT and HLA-matched or mismatched BMT. GVHD was reduced in CBT when compared to BMT, and finally with a short follow-up the incidence of relapse was identical in the three groups (CBT, TD-BMT and BMT). These results show that unrelated CBT is a reasonable option when there is no HLA identical BM donor available for children with AL. 151
Sunday, July 9, 2000 (18:30–19:30) Poster Session I: Cord Blood Transplantation
REPORT OF THE EUROCORD REGISTRY E. Gluckman, V. Rocha*, F. Garnier*, I. Ionescu*, S. Chevret* for Eurocord Transplant group, Hôpital Saint-Louis, Paris, France Eurocord is an international registry operating on behalf of the European Blood and Marrow Transplant Group (EBMT) and supported by a European Concerted Action. Participation is open to both European and non-European centres conducting cord blood transplants. Eurocord Registry works in close collaboration with the Netcord banks, mainly European banks. On July 99, 475 cord blood transplants were reported from 110 transplant centres in 30 countries in Europe (n⫽ 352), North American (n⫽67), South America (n⫽30), Asia (n⫽ 18) and Oceania (n⫽18). The transplants were performed from October 88 to July 99. One hundred twenty six patients, mainly children (n⫽123), received a cord blood from their relatives. Sixty nine children were transplanted for haematologic malignancies, 23 aplastic anaemia, 20 haemoglobinopathies and 11 for metabolic and immunodeficiencies. Unrelated transplants were performed in 349 patients. Two hundred fifty three were children (⬍15 y) and 96 were adults. In the paediatric group, 143 patients received a CBT for leukaemia, 19 for a MDS, 13 for a juvenile LMC, 7 for NHL and other malignancies, 21 for aplastic anaemia and 50 for metabolic and immunodefiencies. In the adult group, 47 patients had acute leukaemia, 6 MDS, 35 CML, 5 lymphoma and 3 aplastic anaemia. Most of the cord blood units (n⫽212) were delivered by European banks: Dusseldorf Cord Blood Bank (CBB) (n⫽79); Milan CBB (n⫽76); Barcelona CBB (n⫽36); French CBB (n⫽9); London CBB (n⫽4); Belgium CBB (n⫽7); and other banks (n⫽2). One hundred thirty units were delivered by American banks (NYCBB⫽115) and seven units from Japanese banks. Other objectives of the Eurocrod group are to analyse clinical results in specific diseases, to compare cord blood transplants with alternative conventional blood and bone marrow hematopoietic stem cell transplants and to study the biology and expansion of cord blood cells. 152
Monday, July 10, 2000 (16:00–17:00) Poster Session II: Immunomodulation
FACTORS CONTROLING THE CATABOLISM OF RADIOLABELED IMMUNOGLOBULINS Vriesendorp HM Marshfield Clinic, Marshfield, WI The pharmacokinetics and biodistribution of radiolabeled immunoglobulins [Ig’s] reactive with tumor associated antigens were
Abstracts/Experimental Hematology 28 (2000) 31–131
single colony), indicates that hemopoietic cells remain bipotent for the erythroid (E) and Mk pathway after the BFU-E stage. In fact, a cell precursor expressing on the cell surface both E (Ter-119) and Mk (4A5 and 2D5) antigens was identified in the marrow of normal mice and in the marrow and spleen of mice recovering from phenylhydrazine (PHZ)-induced anemia (Vannuchi et al., Blood, in press). Ter-119⫹Ⲑ4A5⫹ cells are candidate as the last bipotent (EⲐMk) cells because they express some E (␣-globin) and Mk (GpIIb) genes by RT-PCR and progress into fully differentiated E and Mk cells when cultured in the presence of either EPO or TPO, respectively. To further understand the biology of Ter-119⫹Ⲑ4A5⫹ cells, their number was measured in mice genetically unable to up-regulate Gata-1 expression (McDevitt et al., PNAS, 1997, 94: 6781). The Gata-1low mice are profoundly thrombocytopenic but have a normal hematocrit (Hct). The spleens of these mice are 2.5-fold bigger than normal and contain many megakaryocytes and erythroid cells at different maturation stages. Also the number of Ter119⫹Ⲑ4A5⫹ cells in these spleens is ⬇5-fold higher than in wild-type animals. Gata1low mice recovered faster than their normal littermate from PHZ-induced anemia (Hct of 48% at day 5 instead than at day 7 from the induction of anemia). They also responded more readily to treatment with EPO (10 UⲐmouse): their hematocrit increased more than the hematocrit of their normal littermate in response to EPO (68% vs 55%). In both cases, the number of Ter119⫹Ⲑ4A5⫹ cells in the spleen increased more than the increase observed in normal mice treated in the same fashion (⬎7 times vs 3–5 times). These results confirm that the block in differentiation of the Gata-1low mice is late and downstream of the bipotent cell and support the concept of Ter119⫹Ⲑ4A5⫹ cells as the last bipotent cell precursor. 150
Sunday, July 9, 2000 (10:30–12:30) Session I-3: Cord Blood Transplantation
COMPARISON OF THE OUTCOME OF UNRELATED BONE MARROW (BM) OR CORD BLOOD (CB) TRANSPLANT IN CHILDREN WITH ACUTE LEUKEMIA (AL) V. Rocha*, J. Cornish*, E. Sievers, A. Filipovich*, O. Ringden*, F. Locatelli*, G. Michel*, W. Arcese*, S. Chevret* and E. Gluckman for EUROCORD With the increased number of CB banks and unrelated BM donors registries, it is very important to compare the outcome of both types of transplants in order to evaluate the strategy of donor search. We analysed a total of 515 children with AL aged ⬍16 y transplanted with unrelated CB (n⫽99) or BM (n⫽416) between 01Ⲑ94 and 05Ⲑ98 in 51 centres, and reported to Eurocord Registry. Results were analysed as of 01Ⲑ99. Overall survival (OS), time to relapse, event-free survival (EFS) and other times to event were estimated using Cox proportional hazards regression to adjust for patient-, disease- and transplant-related factors. Results: Recipients of CB were younger (p⬍0.0001), had more adverse factors: AML (p⬍0.001), previous transplant (p⬍0.001), early relapse after 1st complete remission (CR) (p⬍0.0001). The interval from last CR to transplant was shorter in the CB group (p⬍0.001). the donor was HLA mismatched in 91% CBT and in 29% BMT (p⬍0.0001). The median number of nucleated cells infused was 4⫻108Ⲑkg in BMT and 0.38⫻108Ⲑkg in CBT (p⬍ 0.001). T depletion (TD) was performed in 43% BMT and none in CBT. After adjustment, relative risk [RR] of outcomes showed no difference between both groups for: OS [RR 1.27 p⫽0.16], EFS [RR 1.27, p⫽0.15], acute
GVHDⱖII [RR 0.98, p⫽0.92]. The incidence of grade III–IV GVHD was 9% after TD-BMT, 21% after CBT and 29% after BMT (p⬍0.001). There was no difference in the incidence of relapse [RR 0.79, p⫽0.37]. Neutrophil recovery was significantly delayed after CBT [RR 0.42, p⬍0.001] and this could explain an increased 100 days TRM [RR 2.32, p⫽0.001]. Conclusion: with adjustment for risk factors, we show that, despite an early TRM, probably due to a delayed neutrophil recovery, EFS was comparable between HLA mismatched CBT and HLA-matched or mismatched BMT. GVHD was reduced in CBT when compared to BMT, and finally with a short follow-up the incidence of relapse was identical in the three groups (CBT, TD-BMT and BMT). These results show that unrelated CBT is a reasonable option when there is no HLA identical BM donor available for children with AL. 151
Sunday, July 9, 2000 (18:30–19:30) Poster Session I: Cord Blood Transplantation
REPORT OF THE EUROCORD REGISTRY E. Gluckman, V. Rocha*, F. Garnier*, I. Ionescu*, S. Chevret* for Eurocord Transplant group, Hôpital Saint-Louis, Paris, France Eurocord is an international registry operating on behalf of the European Blood and Marrow Transplant Group (EBMT) and supported by a European Concerted Action. Participation is open to both European and non-European centres conducting cord blood transplants. Eurocord Registry works in close collaboration with the Netcord banks, mainly European banks. On July 99, 475 cord blood transplants were reported from 110 transplant centres in 30 countries in Europe (n⫽ 352), North American (n⫽67), South America (n⫽30), Asia (n⫽ 18) and Oceania (n⫽18). The transplants were performed from October 88 to July 99. One hundred twenty six patients, mainly children (n⫽123), received a cord blood from their relatives. Sixty nine children were transplanted for haematologic malignancies, 23 aplastic anaemia, 20 haemoglobinopathies and 11 for metabolic and immunodeficiencies. Unrelated transplants were performed in 349 patients. Two hundred fifty three were children (⬍15 y) and 96 were adults. In the paediatric group, 143 patients received a CBT for leukaemia, 19 for a MDS, 13 for a juvenile LMC, 7 for NHL and other malignancies, 21 for aplastic anaemia and 50 for metabolic and immunodefiencies. In the adult group, 47 patients had acute leukaemia, 6 MDS, 35 CML, 5 lymphoma and 3 aplastic anaemia. Most of the cord blood units (n⫽212) were delivered by European banks: Dusseldorf Cord Blood Bank (CBB) (n⫽79); Milan CBB (n⫽76); Barcelona CBB (n⫽36); French CBB (n⫽9); London CBB (n⫽4); Belgium CBB (n⫽7); and other banks (n⫽2). One hundred thirty units were delivered by American banks (NYCBB⫽115) and seven units from Japanese banks. Other objectives of the Eurocrod group are to analyse clinical results in specific diseases, to compare cord blood transplants with alternative conventional blood and bone marrow hematopoietic stem cell transplants and to study the biology and expansion of cord blood cells. 152
Monday, July 10, 2000 (16:00–17:00) Poster Session II: Immunomodulation
FACTORS CONTROLING THE CATABOLISM OF RADIOLABELED IMMUNOGLOBULINS Vriesendorp HM Marshfield Clinic, Marshfield, WI The pharmacokinetics and biodistribution of radiolabeled immunoglobulins [Ig’s] reactive with tumor associated antigens were