- Email: [email protected]
P-106 Pharmacodynamic study of 5-azacytidine
$64
Posters
Results: The probability of 3 years overall survival and disease-free survival were 62% and 57% respectively. Multivariate analysis (Cox regression) showed that age had effect on probability of overall survival (p 0.049) while sex, source of hematopoietic stem cell, karyotype, chemotherapy before transplantation, FAB classification had no effect on probability of overall survival. Conclusion: We confirm our previous results which showed MDS patients who received Allo-HSCT had higher DFS, especially for younger patients.
Chemotherapy ~ T H E VALUE OF ORAL CYTARABINE OCFOSFATE AND ETOPOSIDE IN THE TREATMENT OF ELDERLY PATIENTS WITH HIGH-RISK MYELODYSPLASTIC SYNDROMES A. Horikoshi*, K. Takei, Y. Nakagawa, Y. Hosokawa, S. Sawada. Internal Medicine, Nihon University
Nerima-Hikarigaoka Hospital, Japan *E-maih [email protected] p Cytarabine ocfosfate (SPAC) is rapidly transformed into cytosine arabinoside (ara-C) when orally administered. We tried to use SPAC combined with oral etoposide (EP) for elderly patients with high risk myelodysplastic syndromes (MDS). Six patients over 65 y were usually treated with SPAC at 300mg/d and EP at 50mg/d for 14 days. One patient with RAEB was treated twice. All patients were hospitalized. Patient's characteristics were as follows: male/female: 2/4; age: 69 86y; RAEB/RAEB-T: 3/3 (FAB classification); IPSS (number): high (3), int-2 (3); performance status (number): 1 (2), 2 (1), 3 (2), 4 (1); leukocyte counts: 2,00028,700; platelet counts: 1.0 55.9 × 104. Patients had such complications as congestive heart failure, hypertension, aneurysm and diabetes mellitus. Two out of 6 patients (7 trials) achieved a complete remission, and 2 patients achieved a partial remission. Two achieved a stable disease and 1 was a failure. The nadir of leukocyte and platelet counts occurred at 8 26 days from the start of therapy. But the durations of leukopenia (<1,000) and thrombocytopenia (<20,000) were not prolonged (0 24 days). Severe side effects were not observed. Five out of 6 patients progressed into overt leukemia later. The durations of survival were 1.5 31 months. Two patients are alive. The association of oral SPAC and EP might be useful for the treatment of high risk MDS in elderly.
•
PHARMACODYNAMIC STUDY OF 5-AZACYTIDINE
R. Khan 1 *, A. Aggerholm2, R Hokland2, M. Hassan 1, E. Hellstr6m-Lindberg1. 1Department of Medicine,
Division of Haematology, Karolinska University HospitalHuddinge, Karolinska Institute, Sweden; :Department of Hematology, Aarhus University Hospital, Denmark *E-maih [email protected] The naRtral history of MDS could be changed by treatment with 5-azacytidine (azacytidine), a drug with favorable toxicity profile. The present subcutaneous dosing schedule, 75 mg/m2 for 7/28 days is based on clinical experience rather than on pharmacodynamic studies. The aim of study was to assess the pharmacodynamic properties of azacytidine by using the myeloid P39 cell line. Cells were incubated with 0.1, 0.5 and 1.0 ~M azacytidine daily for 24 72 hours, followed by 48 hours in drug-free medium. The effects on cell viability, proliferation, apoptosis, cell cycle status and DNA methylation of the surrogate gene, E-cadherin were studied. Azacytidine decreased cell viability and proliferation, increased apoptosis and affected cell cycle status in a dose-dependant manner. However, the length of the exposure time, 24 72 hours, at doses between 0.5 1 ~tM did not significantly affect any of these variables. Using first order exponential pharmacokinetic model, we showed that the effect of 1, 2 or 3 ~tM over 24 hours did not differ from that of 0.5 1 ~tM given over 48 72 hours. Moreover 24, 48 and 72 hours of 1 ~tM azacytidine exposure resulted in the same degree of hypomethylation. Although these experiments must be repeated in models using primary MDS progenitors, they indicate that the dosing schedule of azacytidine could be simplified, and that optimal cellular effects could be achieved with shorter treatment schedules.
•
TREATMENT OF PATIENTS WITH HIGHRISK MDS AND sAML WITH BENDAMUSTIN
S. Knipp*, A. Kuendgen, C. Strupp, M. Aivado, R. Haas, N. Gattermann, U. Germing. Haematology, University
Duesseldo~ Germany *E-maih [email protected] f.de The majority of high-risk MDS patients do not qualify for intensive chemotherapy and allogeneic stem cell transplantation, because of age and concomitant diseases. Older patients with complex karyotype anomalies do not achieve long-term remission. In a phase I/II study, we treated 11 patients aged over 60 years with high-risk MDS or sAML with Bendamustin, administered 100mg/m2 day 1 and 2 once a month in an outpatient setting. There were 3 CMML, 2 RAEB-T and 6 sAML. The patients either were pancytopenic or in 6 cases presented with WBC more than 30,000/ml. 1 patient received 4 cycles, 3 patients 2 cycles,
Posters
Results: The probability of 3 years overall survival and disease-free survival were 62% and 57% respectively. Multivariate analysis (Cox regression) showed that age had effect on probability of overall survival (p 0.049) while sex, source of hematopoietic stem cell, karyotype, chemotherapy before transplantation, FAB classification had no effect on probability of overall survival. Conclusion: We confirm our previous results which showed MDS patients who received Allo-HSCT had higher DFS, especially for younger patients.
Chemotherapy ~ T H E VALUE OF ORAL CYTARABINE OCFOSFATE AND ETOPOSIDE IN THE TREATMENT OF ELDERLY PATIENTS WITH HIGH-RISK MYELODYSPLASTIC SYNDROMES A. Horikoshi*, K. Takei, Y. Nakagawa, Y. Hosokawa, S. Sawada. Internal Medicine, Nihon University
Nerima-Hikarigaoka Hospital, Japan *E-maih [email protected] p Cytarabine ocfosfate (SPAC) is rapidly transformed into cytosine arabinoside (ara-C) when orally administered. We tried to use SPAC combined with oral etoposide (EP) for elderly patients with high risk myelodysplastic syndromes (MDS). Six patients over 65 y were usually treated with SPAC at 300mg/d and EP at 50mg/d for 14 days. One patient with RAEB was treated twice. All patients were hospitalized. Patient's characteristics were as follows: male/female: 2/4; age: 69 86y; RAEB/RAEB-T: 3/3 (FAB classification); IPSS (number): high (3), int-2 (3); performance status (number): 1 (2), 2 (1), 3 (2), 4 (1); leukocyte counts: 2,00028,700; platelet counts: 1.0 55.9 × 104. Patients had such complications as congestive heart failure, hypertension, aneurysm and diabetes mellitus. Two out of 6 patients (7 trials) achieved a complete remission, and 2 patients achieved a partial remission. Two achieved a stable disease and 1 was a failure. The nadir of leukocyte and platelet counts occurred at 8 26 days from the start of therapy. But the durations of leukopenia (<1,000) and thrombocytopenia (<20,000) were not prolonged (0 24 days). Severe side effects were not observed. Five out of 6 patients progressed into overt leukemia later. The durations of survival were 1.5 31 months. Two patients are alive. The association of oral SPAC and EP might be useful for the treatment of high risk MDS in elderly.
•
PHARMACODYNAMIC STUDY OF 5-AZACYTIDINE
R. Khan 1 *, A. Aggerholm2, R Hokland2, M. Hassan 1, E. Hellstr6m-Lindberg1. 1Department of Medicine,
Division of Haematology, Karolinska University HospitalHuddinge, Karolinska Institute, Sweden; :Department of Hematology, Aarhus University Hospital, Denmark *E-maih [email protected] The naRtral history of MDS could be changed by treatment with 5-azacytidine (azacytidine), a drug with favorable toxicity profile. The present subcutaneous dosing schedule, 75 mg/m2 for 7/28 days is based on clinical experience rather than on pharmacodynamic studies. The aim of study was to assess the pharmacodynamic properties of azacytidine by using the myeloid P39 cell line. Cells were incubated with 0.1, 0.5 and 1.0 ~M azacytidine daily for 24 72 hours, followed by 48 hours in drug-free medium. The effects on cell viability, proliferation, apoptosis, cell cycle status and DNA methylation of the surrogate gene, E-cadherin were studied. Azacytidine decreased cell viability and proliferation, increased apoptosis and affected cell cycle status in a dose-dependant manner. However, the length of the exposure time, 24 72 hours, at doses between 0.5 1 ~tM did not significantly affect any of these variables. Using first order exponential pharmacokinetic model, we showed that the effect of 1, 2 or 3 ~tM over 24 hours did not differ from that of 0.5 1 ~tM given over 48 72 hours. Moreover 24, 48 and 72 hours of 1 ~tM azacytidine exposure resulted in the same degree of hypomethylation. Although these experiments must be repeated in models using primary MDS progenitors, they indicate that the dosing schedule of azacytidine could be simplified, and that optimal cellular effects could be achieved with shorter treatment schedules.
•
TREATMENT OF PATIENTS WITH HIGHRISK MDS AND sAML WITH BENDAMUSTIN
S. Knipp*, A. Kuendgen, C. Strupp, M. Aivado, R. Haas, N. Gattermann, U. Germing. Haematology, University
Duesseldo~ Germany *E-maih [email protected] f.de The majority of high-risk MDS patients do not qualify for intensive chemotherapy and allogeneic stem cell transplantation, because of age and concomitant diseases. Older patients with complex karyotype anomalies do not achieve long-term remission. In a phase I/II study, we treated 11 patients aged over 60 years with high-risk MDS or sAML with Bendamustin, administered 100mg/m2 day 1 and 2 once a month in an outpatient setting. There were 3 CMML, 2 RAEB-T and 6 sAML. The patients either were pancytopenic or in 6 cases presented with WBC more than 30,000/ml. 1 patient received 4 cycles, 3 patients 2 cycles,