Efficacy of acetyldinaline for treatment of minimal residual disease (MRD): preclinical studies in the BNML rat model for human acute myelocytic leukemia.
The efficacy of acetyldinaline [4-acetylamino-N-(2'-aminophenyl)-benzamide] for eradication of minimal residual disease (MRD), which is left after bone marrow transplantation, and the risk of a bone marrow graft being jeopardized by this treatment was studied in the Brown Norway rat acute myelocytic leukemia model (BNML). To mimic the clinical situation, MRD induction treatment was given to rats showing clinical signs of leukemia and consisted of 80 mg/kg cyclophosphamide and 7.0 Gy X-rays total body irradiation resulting in a 6-8 log leukemic cell kill leaving 10-1000 leukemic cells in the animals. Treatment was completed with a syngeneic bone marrow transplant. A high dose level (HD) treatment of 23.7 mg acetyldinaline/kg per day and a low dose level (LD) treatment of 11.85 mg/kg per day, each given orally for five consecutive days, were compared. The increase in the survival time, the cure rate, and the toxic death rate were evaluated. One 5-day course of LD treatment, started at a time interval of 10, 17, or 24 days following MRD induction, resulted in 44%, 11% or 0% cures. With two 5-day courses of LD treatment, 89%, 22%, or 0% cures were achieved. With LD treatment, maximally an 8 log leukemic cell kill was obtained and no toxicity-related deaths were observed (only less than a 1 log kill of normal hemopoietic stem cells). In contrast, a single course of HD treatment resulted in 56% of the rats (10/18) dying from intestinal tract toxicity, while from the remaining eight rats at risk for relapse, three (37%) showed a very late relapse and five were cured (63%). It was evident that the leukemic cell load at the start of the acetyldinaline treatment determined the probability of relapse. An important finding was that acetyldinaline did not interfere with bone marrow regeneration. The highly curative potential of acetyldinaline treatment in the BNML model during the phase of MRD warrants the introduction of this compound in clinical phase I/II studies.
el-Beltagi
H M
HM
Hemato-Oncology/TNO, Erasmus University Rotterdam, The Netherlands.
Martens
A C
AC
Dahab
G M
GM
Hagenbeek
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001549:Benzamides; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000628:therapy; D008297:Male; D010655:Phenylenediamines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D012008:Recurrence
D000970:Antineoplastic Agents; D001549:Benzamides; D010655:Phenylenediamines; C081895:tacedinaline