(Idarubicin) with Pharmacokinetic and in Vitro Drug Sensitivity Testing in Children with Refractory Leukemia1

Home , Amsacrine, Idarubicin

(CANCER RESEARCH 48, 5348-5352. September 15. 1988] Phase I Clinical Trial of Orally Administered 4-Demethoxydaunorubicin (Idarubicin) with Pharmacokinetic and in Vitro Drug Sensitivity Testing in Children with Refractory Leukemia1

Ching-Hon Pui,2 Siebold S. N. de Graaf,3 Lois W. Dow, John H. Rodman, William E. Evans, Bruce S. Alpert, and Sharon B. Murphy Departments ofHematology and Oncology [C-H. P., L. W. D., S. B. M.] and Pharmaceutical Division [S. S. N. d. G., J. H. R., W. E. E.], St. Jude Children's Research Hospital, and Divisions of Hematology-Oncology [C-H. P., L. W. D., S. B. M.] and Cardiology [B. S. A.], Department of Pediatrics, University of Tennessee, Memphis, College of Medicine, Memphis, Tennessee 38101

ABSTRACT than that of analogues or i.v. idarubicin (9, 16). However, nausea and vomiting were generally more severe in patients Fifteen children with acute leukemia in relapse, refractory to conven receiving oral idarubicin (16). As a single agent in adults, oral tional therapy, were treated with idarubicin administered orally for 3 consecutive days in dosages ranging from 30 to 50 mg/m2 per day at 19- idarubicin has antileukemic activity at dosages of 45 to 90 mg/ m2 distributed over 3 consecutive days (9, 17, 18). Very little to 21-day intervals. Gastrointestinal complications, including nausea, vomiting, abdominal pain, diarrhea and stomatitis, were the major forms information is available for oral idarubicin treatment in children of dose-limiting toxicity, affecting the majority of patients at all levels of with leukemia. We report here the results of Phase I clinical, idarubicin dosage. Two patients who had received total-body irradiation pharmacokinetic, and drug-sensitivity studies of oral idarubicin for bone marrow transplantation developed life-threatening gastrointes in 15 children with refractory acute leukemia. tinal toxicity suggestive of a radiation "recall" phenomenon. Echocardi- ographic evidence of depressed cardiac function, without clinical symp toms or signs, was noted in six of 11 patients, although the changes were MATERIALS AND METHODS judged to be significant in only one child. The maximal tolerated oral dose of idarubicin was 40 mg/m2 per day. The medium terminal plasma Fifteen children with refractory acute leukemia in hematological half-life of idarubicin was 9.2 h (range, 6.4-25.5 h). Both idarubicin and relapse were enrolled in the study after written informed consent had its metabolite, idarubicinol, accumulated during the 3 days of therapy. been obtained. These 10 boys and five girls ranged in age from 5 to 17 Among the five patients with acute nonlymphoblastic leukemia whose years (median, 9 years). Nine patients had ALL4; three were in first cells were tested for drug sensitivity in vitro, the idarubicin concentration relapse having failed remission reinduction attempts that included resulting in 50% inhibition (ICso) of cluster and colony formation ranged from 1.6 x 10~'Â°Mto 5 x IO"7 M. There was no obvious relationship daunorubicin, two each in second or third relapse, and one each in fourth or fifth relapse. Six patients had ANLL including four with de between the ICso for idarubicin and that for epirubicin or daunorubicin. novo refractory ANLL, one with lineage shift (19) at relapse of ALL Oral idarubicin produced definite antileukemic effects, clearing blast and one with secondary leukemia after therapy for neuroblastoma. Of cells from the circulation in 13 of the 14 Ã©valuablepatients. Future these six patients, four were in first relapse refractory to multiple studies should define an optimal dose schedule to circumvent the limiting reinduction attempts and two were in third relapse. A patient with B- gastrointestinal complications associated with this agent. cell ALL (positivity for surface immunoglobulins) had received five antileukemic drugs, and each of the remaining patients had been given INTRODUCTION 10 to 14 antileukemic agents. Two patients additionally received 12 Gy total-body irradiation for bone marrow transplantation 16 and 21 Idarubicin (4-demethoxydaunorubicin), an anthracycline an months before the study. All patients had received either doxorubicin alogue, was developed in an attempt to reduce the cardiotoxicity or daunorubicin in total cumulative doses of 75-500 mg/m2 (median, 150 mg/m2). They had recovered from the toxic effects of prior therapy, and enhance the therapeutic efficacy of the parent compound had adequate hepatic function (bilirubin <2 mg/dl; normal prothrombin (1). It is 27 to 100 times more potent than daunorubicin in time) and had normal kidney function (creatinine <1.5 mg/dl) as well inhibiting the cloning efficiency of exponentially growing HeLa as normal cardiac function as judged from results of electrocardiogra- cells (2). Against the L1210 and P388 leukemia cell lines, it is phy, echocardiography, and isotope angiocardiography. M-mode ech- more cytotoxic than either daunorubicin or doxorubicin (1-4). ocardiograms were recorded with an Ekoline EK-05500D ultrasoni- Unlike the parent compound which must be administered i.v., scope interfaced to a strip-chart recorder (paper speed, 50 mm/s). The idarubicin can be given orally (5). In contrast to daunorubicin, structures were viewed from the standard parasternal windows, using it is retained selectively in tumor tissue relative to myocardium routine clinical measurements. The shortening fraction of the left (6), and initial data suggest that it has a better therapeutic index ventricle was calculated as: (end-diastolic dimension â€”end-systolic with respect to cardiotoxicity (7, 8). dimension)/end-diastolic dimension. Given i.v., idarubicin has been shown to be an effective Idarubicin hydrochloride was provided by Adria Laboratories (Co antileukemic agent in children and adults (9-15). Phase I and lumbus, OH). It was administered orally for three consecutive mornings after a minimum 8-h fast. Patients took nothing by mouth for at least II studies of oral idarubicin in adults with solid tumors revealed 2 h after each dose. To reduce the potential problem of medication loss that the degree of myelosuppression is comparable to or less from vomiting, we administered chlorpromazine, 25 mg/m2, orally l h

Received 2/29/88; revised 6/7/88; accepted 6/14/88. before the start of each dose and repeated the dose every 4 h if needed. The costs of publication of this article were defrayed in part by the payment Patients who tolerated a first course without unacceptable toxicity or of page charges. This article must therefore be hereby marked advertisement in progressive leukemia were eligible to receive a second course 16 to 18 accordance with 18 U.S.C. Section 1734 solely to indicate this fact. days later. The starting dosage was 30 mg/m2 per day, and dosages 1Supported in part by Grants CA-20180 and CA-21765 from the National were escalated in subsequent patients to 40 and 50 mg/m2 per day. No Cancer Institute, by the American Lebanese Syrian Associated Charities (ALSAC), and by a grant from Adria Laboratories. dosage escalation in the same patient was attempted. Toxicity and 2To whom requests for reprints should be addressed, at St. Jude Children's Research Hospital. P. O. Box 318, Memphis, TN 38101. 4 The abbreviations used are: ALL, acute lymphoblastic leukemia; ANLL, 3Supported by grants from the European Organization for Research on acute nonlymphoblastic leukemia; ICso, drug concentration inhibiting cell cluster Treatment of Cancer and the Groningen Foundation for Pediatrie Oncology (the and colony formation by 50%; AUC, area under the concentration versus time Netherlands). curve. 5348

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1988 American Association for Cancer Research. ORAL IDARUBICIN IN CHILDHOOD LEUKEMIA response were assessed by a scalar grading system adopted by the developed after a week, it was uniformly associated with diar Pediatrie Oncology Group (20). rhea. Although none of the courses at the 30 mg/m2-dose level Pharmacokinetic Studies. Pharmacokinetic studies were performed was complicated by mucositis, half of those at levels >40 mg/ for each patient during the first course of oral idarubicin. Heparinized nr resulted in mucositis, including one episode of Grade 4 blood samples, 2 to 3 ml each, were collected before the treatment and toxicity. In summary, at a dosage of 40 mg/m2, three patients at 1,2, 4, 6, 8, 12, and 24 h after the first dose and 24 h after the second and third doses. Each blood sample was centrifuged immedi developed Grade 3 or 4 toxicity after the first course of treat ately, after which the plasma was separated and stored at â€”70Â°Cuntil ment, and none of them was given a second course of treatment. assayed. One child had Grade 4 mucositis with hematemesis and endo Plasma concentrations of idarubicin and its metabolite, idarubicinol, scopie findings of extensive esophageal, gastric and duodenal were measured by reversed-phase high-performance liquid chromatog- ulcers; one had Grade 3 nausea, vomiting and abdominal pain; raphy with fluorescence detection. Briefly, the system included a Nova- and one had Grade 4 diarrhea and Grade 3 nausea and vomiting Pak Phenyl column (15 cm x 3.9 mm; particle size, 4 Â¿im;Waters with gastritis proven by endoscopie examination. Interestingly, Associates, Milford, MA), a Spectroflow 980 fluorescence detector the first two of the three patients with Grade 3 or 4 gastroin (ABO Analytical, Ramsey, NJ) with the excitation wavelength set at testinal complications had received total-body irradiation for 250 nm and a 550-nm emission filter. A loop-column extraction pro bone marrow transplantation. At the 50 mg/m2-dose level, two cedure was used (21). The mobile phase for isocratic elution consisted of 0.2 M sodium phosphate monobasic and acetonitrile (73:27, vol:vol), of the four children had Grade 3 nausea and vomiting. pH 4.0, at a flow rate of 1.4 ml/min. Idarubicin and idarubicinol were Deterioration in cardiac function was noted in the 11 patients quantitated with use of an external standard. The lower limit of sensi tested by serial echocardiogram (P = 0.04 by paired t test). Six tivity of this assay was 0.5 ng/ml. The coefficient of variation was of the patients had 12 to 30% decreases in shortening fraction 12.3% at 0.5 ng/ml and 3.4% at 25 ng/ml. (median, 15%) of the baseline value obtained before idarubicin The AUC was calculated by use of the linear trapezoidal method. treatment. However, only one child had a decrease to below Terminal half-life was estimated for each course of chemotherapy from normal values (29 â€”>20% in shortening fraction by echocar- plasma concentrations measured at 12 and 24 h. diography and 54 â€”Â»47%in left ventricular ejection fraction Clonogenic Assays for Drug-Sensitivity Testing. Leukemic blast cells by radionuclide cineangiography) after receiving 120 mg/m2 of from all six patients with ANLL were studied for growth properties and sensitivity to anthracyclines in clonogenic assays. Low-density idarubicin. This child had congenital heart disease (endocardia! marrow cells (<1.077 g/cc) from each patient were cultured in 0.3% cushion defect) and had previously received daunorubicin and agar in McCoy's medium with 20% fetal calf serum over leukocyte doxorubicin (total cumulative dose, 300 mg/m2). feeder layers, either without drug addition or with increasing concen Hepatic toxicity (Grade 2) manifested by hyperbilirubinemia (peak. 2.7 mg/dl) occurred in one case at the 50 mg/m2 dose trations of idarubicin, epirubicin, or daunorubicin. Cultures were incu bated at 37Â°Cina 7.5% CO2 atmosphere; clusters (3-19 or 20-50 cells) level. No renal toxicity was observed. Two of nine Ã©valuable and colonies (>50 cells) were scored on Days 7,10, and 14 as previously patients had hair loss after treatment. Hematopoietic toxicity reported (22, 23). Cell growth was recorded on Day 7 except for one was not Ã©valuablesinceall patients had leukemia in relapse. All patient, for whom sufficient cell growth was noted only on Day 14. In control cultures, cluster and colony formation per 2 x IO5plated cells patients but one required hospitalization and antibiotic therapy for documented infections or fever developing after treatment. ranged from 40 to 1760 (median, 250). One child who did not have circulating leukemic blast cells was not Ã©valuablefortreatment response because bone marrow RESULTS examination was not performed after the treatment. The re maining 14 Ã©valuablepatients had oncolytic responses charac Twenty-one courses of oral idarubicin were administered to terized by clearance of circulating leukemic cells in 13. Bone the 15 patients, six of whom received two courses. Gastrointes marrow was hypocellular 3 weeks after treatment in seven of tinal complications were the major forms of dose-limiting tox- the 10 patients examined; however, none attained a complete icity in this study; however, no Grade 3 or 4 complications were remission. observed at the 30 mg/m2 dosage level (Table 1). All but two Pharmacokinetic Results. A representative example of the courses of therapy were complicated by nausea and vomiting concentration versus time course of idarubicin and its metabo that developed within 1-14 h (median, 3.5 h). Grade 3 vomiting lite, idarubicinol, in a patient receiving 50 mg/m2 of idarubicin occurred in two of 10 courses at a drug dosage of 40 mg/m2 is shown in Fig. 1. In all patients the plasma concentration of and in two of five courses at 50 mg/m2. Loss of oral idarubicin idarubicinol exceeded the concentration of the parent drug at as a result of vomiting was noted in at least six courses; the all sampling times; clearance of the metabolite was slower than drug was identified in vomitus by its characteristic orange-red that of the parent drug. The AUC for idarubicinol was consist color. Diarrhea, appearing on days 2-6 of treatment, was com ently greater than that for idarubicin. mon at or above the 40 mg/m2 level and persisted from 1 to 33 Pharmacokinetic parameters are summarized in Table 2. days (median, 2 days). Therapy (at the 40 mg/m2 level) was Calculation of the terminal plasma half-life of idarubicin from complicated in one patient by Grade 4 diarrhea. Abdominal plasma concentrations at 12 and 24 h following the first dose pain beginning on Days 1-10 was also common. If the pain of oral idarubicin was based on the assumption that drug

Table 1 Gastrointestinal complications of oral idarubicin toxicity"Dosage Number of courses associated with

and vomitingGl,25 painGl,23 of of (mg/m2)3040 patients3g courses6105Nausea

8 22DiarrheaGl,226 0 10Abdominal7 1 3 00G40 10 50Number 4Number 2G30 4G30 0G40 3G30 0MucositisGl,203G30 ' G, toxicity grade (see Reference 20).

5349

100 drug was above the IC5o in all four patients. At 10 8 M idarub icin, two patients had no growth of clonogenic cells and two others had less than 3% growth compared with control cultures; the remaining child (Patient 4), in third relapse, had fewer idarubicin-sensitive blast cells. Blast cells from four patients 10 were also studied for their sensitivity to epirubicin and daunorubicin. In a comparison of the IC50 results for the three drugs, Ãœ ;,b only Patient 4 had blast cells that were less sensitive to idarub o o Idarubicin icin than to epirubicin or daunorubicin. The blast cells from the Â° Â° Idarubicinol remaining three patients were more (or approximately equally) sensitive to idarubicin than to the other two agents. 246 12 24 Time (hours) DISCUSSION Fig. 1. Time courses of plasma idarubicin and idarubicinol concentrations on Day I of treatment in a patient given oral doses of idarubicin, SOmg/m2. In this study, we found the maximally tolerated dose of oral idarubicin in children to be 40 mg/m2 per day for 3 consecutive Table 2 Pharmacokinetic dala for orally administered idarubicin during the first 24 h after starting treatment (n = 15) days. Gastrointestinal complications were frequent, represent Median values for t*,. fm.,. and dose-normalized AUC were determined from ing the acute dose-limiting toxicity. Of the 21 courses of ida .ill data at all dose levels. For i 'â€ž,.â€ž.onlyconcentrations at the 40 mg/m2 dose rubicin, 19 were complicated by nausea and vomiting, 14 by level are included. abdominal pain, 13 by diarrhea, and seven by mucositis. In at least six courses, the early onset of vomiting resulted in the loss Median(h)RangeMedian *HÂ° available30.2(11.4-42.4)6(2-8)8.2(2.0-14.2)of drug from patients, despite use of antiemetic therapy. Nota bly, the two children who had received total-body irradiation (ng/ml)RangeMedianCâ€žâ€ž.Â«,m. for bone marrow transplantation developed unacceptable gas (h)RangeMedianrâ€žâ€ž trointestinal toxicities. Conceivably, the increased toxicity in them was caused by "recall" of the radiation effect, as has been (ng/h/ml/mgidarubicin)RangeIdarubicin9.2(6.4-25.5)10.6(2.7-16.7)6(1-8)2.4(0.7-3.8)IdarubicinolNotAUCo-24h reported for other anthracycline compounds (24-26). Animal studies have indicated that idarubicin is relatively " i . terminal half-life: (,â€ž.,,.u,â€žâ€ž.peakplasma concentration after an oral dose of 40 mg/m2: (â€ž.,.time of peak concentration following oral administration: less cardiotoxic than the other anthracyclines (8, 27), especially AUCo-Â¡4h,area under the concentration versus time curve, normalized to dose, when given orally (6). In most clinical trials, the patients have for 24 h following oral administration. had refractory malignancies with multiple organ involvement, have received anthracyclines or other cardiotoxic agents, and Table 3 Idarubicin and idarubicinol plasma concentrations 24 hours after three have had limited survival times. Hence, it is very difficult to daily oral doses (n = 15) assess the cumulative cardiotoxic effect of idarubicin. In one Median plasma concentration (ng/ml) study of oral idarubicin in 50 adults with advanced breast cancer Time24 who had not been treated with anthracyclines, none developed h (range, 0.5-4.4) (range, 5.7-22.1) congestive heart failure, including 12 patients with cumulative 48 h 3.1 (range, 0.7-5.6) 18.2 (range. 10.0-36.7) doses >360 mg/m2; changes in cardiac function by isotope 72 hIdarubicin1.63.6 (range, 1.4-4.8)Idarubicinol12.524.2 (range, 11.9-37.0) angiocardiography were minimal (28). In this study, we were unable to evaluate the chronic cardiotoxic effect of oral idarub absorption is completed by 12 h after drug administration. icin. With respect to acute toxic effects, six of 11 children had Elimination rate for the metabolite and total-body clearance a substantial decrease (>12% reduction) in shortening fraction. for both the parent compound and the metabolite cannot be Only one of them had a significant deterioration in cardiac reliably estimated when patients only receive drugs orally. function such that the shortening fraction was below normal, Table 3 shows the median plasma concentrations of drug but this child had underlying heart disease and prior therapy measured 24 h after each of the three daily doses. It is apparent with daunorubicin at a cumulative dose of 300 mg/m2. The that both the parent drug and the metabolite accumulated in relative cardiotoxicity of this agent will need to be addressed in plasma when they were given orally on a daily schedule. The a larger prospective randomized trial. AUC was calculated for 24 h after the first dose of idarubicin. Previous pharmacokinetic data for idarubicin in children has The median ratio of the AUC for parent drug and metabolite been limited to only seven patients who received the intravenous was 3.8 (range, 2.2-6.1). We were unable to demonstrate an form of the drug (11). The terminal plasma elimination half- association between any of the pharmacokinetic parameters and life of idarubicin in this study did not differ substantially from the degree of toxicity. that reported after intravenous administration. However, longer Results of Drug-Sensitivity Assay. Cultures of leukemic blast half-lives have been reported for adults after either oral (mean, cells produced sufficient growth for evaluation of cluster and 34.8 h) (29) or i.v. (mean, 13.9-27 h) (11, 16, 29-33) drug colony formation in five of six patients with ANLL. The ICso administration, suggesting that clearance is faster in children. value or concentration of idarubicin inhibiting cluster and col During the 24 h after the first dose of oral idarubicin, the ony formation by 50% ranged from 1.6 x KT10 to 5 X 10~7 M AUC for the metabolite idarubicinol averaged 3.8 times that of (Table 4). In three patients (nos. 1, 3, and 5), the blast cells the parent compound. This ratio contrasts with the 1.9 calcu were judged to have intermediate sensitivity to idarubicin with lated from the i.v. data provided in the study by Tan et al. (11). IC50 values of 2.7, 3.2, and 3.0 x 10~9 M. The blast cells of First-pass hepatic metabolism is a possible factor contributing Patient 2 were highly sensitive to idarubicin, as demonstrated to this difference. A higher metabolite:parent compound AUC by an IC50 value of 1.6 x 10~'Â°M.The peak plasma concentra ratio following oral versus i.v. administration in adults has been tion of idarubicin and idarubicinol after only one dose of the reported (31). This observation has clinical relevance in view of 5350

Table 4 Comparison of the /C5o value for Â¡darubicin,epirubicin, and daunorubicin and peak plasma concentration fC^J ofidarubicin and its metabolite for individual patients (M)EpirubicinNot Patientno.1 growth0140 X 10-' x IO'' x 10-' Â±20 done done 1.6 x IO"10 1.5X 10-' 2.2 x IO'1 2.7 x IO'8 7.8 x 10-' 2 1760 Â±65 3.2 x IO"' 2.6 x IO'' 8.0 x 10-'Â° 1.8 x 10-' 3.2 x 10-' 3 40 Â±5 5.0 x IO'7 4.0 x 10-'Â° 4.0 x 10-' 2.2 x IO'8 5.1 x IO"' 45Control 250 Â±16 3.0 x 10-'IC5o 6.5 x 10-'DaunorubicinNot1.3 x 10-'CÂ».Idarubicin1.21.2 x 10-'.(M)'Idarubicinol3.13.9 x 10-' 110 Â±4Idarubicin2.7 " Number of clusters and colonies formed on Day 7 for Cases 1 to 4 and on Day 14 for Case 5. Values are means Â±SEM. * Peak plasma concentration achieved after the first dose ofidarubicin. the cytotoxic effect reported for the metabolite (34). Penco, S., Casazza. A. M., Franchi, G., Barbieri, B., Bellini, O.. PodestÃ , A., Savi, G., Pratesi, G., Ceroni, C., Di Marco, A., and Arcamone, F. Synthesis, Carella et al. (14) reported that two of eight patients with antitumor activity, and cardiac toxicity of new 4-demethoxyanthracyclines. ANLL refractory to cytarabine, amsacrine, and other anthra- Cancer Treat. Rep., 67:665-673, 1983. 9. Ganzina, F., l'acciarini, M. A., and DiPietro, N. Idarubicin (4-demethoxy cyclines achieved a complete remission after i.v. idarubicin daunorubicin). A preliminary overview of preclinical and clinical studies. treatment, suggesting a lack of cross-resistance between these Invest. New Drugs, 4: 85-105, 1986. drugs and idarubicin. However, in an in vitro study to determine 10. Daghestani. A. N., Arlin, Z. A., Leyland-Jones. B.. Gee, T. S., Kempin. S. J., Mertelsmann, R., Budman, D., Schulman. P., Baratz, R., Williams, L., the drug sensitivity of myeloblasts using clonogenic cells from Clarkson, B. D., and Young, C. W. Phase III clinical and pharmacology six patients, SchÃ¶lzelet al. (35) found no difference in sensitivity study of 4-demethoxydaunorubicin (idarubicin) in adult patients with acute to mitoxantrone, 4'-deoxydoxorubicin, idarubicin, and dauno leukemia. Cancer Res., 45: 1408-1412, 1985. Tan, C. T. C., Hancock, C., Steinherz, P., Bacha, D. M., Steinherz, L., Luks, rubicin. Moreover, cross-resistance was demonstrated in one E., Winick, N., Meyers, P., Mondora, A., Dartis. E., Niedzwiecki, D., and patient refractory to daunorubicin in that study. We found Stevens, Y-W. Phase I and clinical pharmacological study of 4-demethoxy daunorubicin (idarubicin) in children with advanced cancer. Cancer Res., 47: clonogenic cells to be sensitive to idarubicin in vitro at concen 2990-2995, 1987. trations achievable in vivo. The relative sensitivity to idarubicin, 12. Madon, E., Grazia, G., DeBernardi. B., Cornelli. A., Carli, M.. Sainati, L., epirubicin, and daunorubicin varied widely among the four cases Paolucci, G., Canino, R., Colella, R., Bagnulo, S. D., and Pietro, N. Phase II study of idarubicin administered i.v. to pediatrie patients with acute studied. Thus, an in vitro clonogenic assay may be useful in lymphoblastic leukemia. Cancer Treat. Rep., 71: 855-856, 1987. selecting the optimal anthracycline for individual patients. 13. Lambertenghi-Deliliers, G., Pogliani, E., Maiolo, A. T.. Pacciarini, M. A., and Polli, E. E. Therapeutic activity of 4-demethoxydaunorubicin (idarubicin) Although we were unable to induce a complete remission in in adult acute leukemia. Tumori, 69: 515-519, 1983. any of the 15 children, oral idarubicin had definite antileukemic 14. Carella, A. M., Santini, G., Martinengo, M., Giordano, D., Nati. S., Congiu, effects, as shown by the disappearance of circulating leukemic A., Cerri, R., Risso, M., Damasio, E., and Rossi, E. 4-Demethoxydaunorub- icin (idarubicin) in refractory or relapsed acute leukemias. A pilot study. blast cells from 13 of 14 Ã©valuablepatients. To circumvent the Cancer (Phila.), 55: 1452-1454, 1985. problems of vomiting, a major form of toxicity in this study, 15. Harousseau, J. L., Hurteloup, P.. Reiffers, Jâ€žRigal-Huguet, F., Hayat, M., we propose an alternative dosage schedule, such as prolonged Dufour, P., LePrise, P. Y., Monconduit, M., Jaubert, J., and Carcassonne, Y. Idarubicin in the treatment of relapsed or refractory acute myeloid low dose oral idarubicin. That idarubicin and idarubicinol have leukemia (Letter). Cancer Treat. Rep., 7: 991-992, 1987. relatively long half-lives and will accumulate with extended 16. Berman, E., Wittes, R. E., Leyland-Jones. B., Casper, E. S., Gralla, R. J., Howard, J., Williams, L., Baratz, R., and Young, C. W. Phase I and clinical therapy (Table 3) suggest this approach to be rational. Finally, pharmacology studies of intravenous and oral administration of 4-demethox by avoiding high peak plasma concentrations, one might be ydaunorubicin in patients with advanced cancer. 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Ching-Hon Pui, Siebold S. N. de Graaf, Lois W. Dow, et al.

Cancer Res 1988;48:5348-5352.

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