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Journal of Clinical Pharmacology, 2004; 44:873-880
© 2004 the American College of Clinical Pharmacology

PEDIATRICS

Pharmacokinetics of Gemtuzumab Ozogamicin as a Single-Agent Treatment of Pediatric Patients With Refractory or Relapsed Acute Myeloid Leukemia

Mary Buckwalter, MS, James A. Dowell, PhD, Joan Korth-Bradley, PhD, Boris Gorovits, PhD and Philip R. Mayer, PhD

From Wyeth Pharmaceuticals, Collegeville, Pennsylvania.

Address for reprints: Philip R. Mayer, Clinical Pharmacology, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426.


   ABSTRACT
TOP
 ABSTRACT
METHODS AND MATERIALS
 RESULTS
 DISCUSSION
 REFERENCES
 
Gemtuzumab ozogamicin is currently approved to treat CD33-positive acute myeloid leukemia (AML) in first relapse in patients older than age 60 years. The objective of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin in pediatric patients with relapsed or refractory AML. The study population comprised 29 subjects younger than age 18 with AML in first relapse. Dosages of 6, 7.5, and 9 mg/m2 were administered during the study. Pharmacokinetic parameters were determined following each dose for hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. hP67.6 pharmacokinetic parameters had a consistent and statistically significant change between the first and second doses. Increases in AUC and decreases in both CL and Vss from the first dose to the second dose were consistent with those of the adult population. Changes between dose periods for total calicheamicin derivatives and unconjugated calicheamicin derivatives were consistent with those of hP67.6. Changes in pharmacokinetic parameters between dose periods are attributed to saturation of CD33 binding sites and diminished clearance resulting from a lower peripheral blast burden and antigen. Children receiving 9 mg/m2 had the following hP67.6 pharmacokinetic parameters: Cmax, 3.47±1.04 mg/L; AUC, 136 ± 107 mg•h/L; CL, 0.12 ± 0.15 L/h/m2; Vss, 6.5 ± 5.5 L; and t1/2, 64 ± 44 h after their first dose. Mean pharmacokinetic values are similar to values reported in adults. Individual children demonstrated large intersubject variability, similar to adults. The pharmacokinetics of gemtuzumab ozogamicin in pediatric patients closely follow the profile and variability of adult patients.

Key Words: Gemtuzumab ozogamicin • pharmacokinetics • pediatric • leukemia

Gemtuzumab ozogamicin (Mylotarg®, CMA-676, Wyeth Pharmaceuticals, Collegeville, Pa) is a conjugated monoclonal antibody that selectively targets CD33-positive cells. The drug was given accelerated marketing approval by the U.S. Food and Drug Administration (FDA) for patients older than age 60 with CD33-positive acute myeloid leukemia (AML) in first relapse who are not eligible for cytotoxic chemotherapy.1 Gemtuzumab ozogamicin is composed of a recombinant humanized IgG4, kappa antibody (hP67.6) conjugated with a calicheamicin derivative. Calicheamicins are highly potent antitumor antibiotics that bind to DNA in the minor groove, producing site-specific, double-strand breaks through the formation of a p-benzene diradical.2 Studies of gemtuzumab ozogamicin in adult patients with relapsed AML have shown response rates in approximately 30% of patients. The safety profile established by larger clinical trials in adults is distinct from standard induction chemotherapy.1,3 When compared with conventional chemotherapy, toxicity profiles were relatively mild, but several patients have exhibited serious hepatic abnormalities.1,3,4

AML is a cancer of the blood characterized by an increase in the number of granulocytes produced in the bone marrow. The rise in the number of granulocytes leads to an inhibition of myeloid cell maturation. This often results in hematopoietic insufficiency (granulocytopenia, thrombocytopenia, or anemia), with or without leukocytosis.5 In AML cells, the CD33 antigen is expressed in greater than 90%6 of patients. Normal hematopoietic, nonhematopoietic, or lymphoid cells1,2 do not express this antigen, suggesting that elimination of the CD33-expressed cells would be beneficial in the treatment of AML.1-3,7 AML accounts for approximately 80% of all cases of acute leukemia and for about 20% of the acute leukemias seen in children.8 Over the past two decades, only modest improvements have been made in the cure rate of children with AML, and only limited data are available assessing the use of gemtuzumab ozogamicin in the treatment of relapsed or refractory AML in children.4,9

The objective of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin in pediatric patients with relapsed or refractory AML. Levels of hP67.6 antibody, total conjugated and unconjugated calicheamicin derivatives (total calicheamicin), and unconjugated calicheamicin derivatives were used to characterize the pharmacokinetics of the drug. A comparison was also made between the pharmacokinetics in pediatric patients with those of adult patients.


   METHODS AND MATERIALS
TOP
 ABSTRACT
 METHODS AND MATERIALS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
Patients eligible for the study had CD33+ AML and did not attain remission with primary induction therapy or relapsed after 1 or more remissions. They were required to be younger than 18 years of age at the start of the study. Patients were also required to have a Lansky play index10 or Karnofsky performance status > 60%, negative serum pregnancy test at screening for post-menarchal females of childbearing potential, serum total bilirubin and serum creatinine < 1.5 times the upper limit of normal for age, and adequate pulmonary and cardiac function.

Patients were excluded from the study if they had a history of hematopoietic stem cell transplantation (HSCT) prior to receiving gemtuzumab ozogamicin, prior therapy with anti-CD33 antibodies, AML secondary to chemotherapy or toxins, known central nervous system leukemia or testicular involvement at the time of the study entry, other active malignancy at the time of study entry, uncontrolled infections or known to be HIV positive, unable to obtain bone marrow aspirate, or peripheral white blood count > 30,000/µL. To lower the peripheral blood count, patients were permitted treatment with hydroxyurea. The hydroxyurea was discontinued 24 hours prior to gemtuzumab ozogamicin administration.

Patients in the study were permitted to remain on all medications that were clinically indicated and previously taken for non-AML conditions. This study was conducted according to the Declaration of Helsinki and its amendments as well as good clinical practices regarding drug development. The rationale for the study, procedural details, investigational goals, and potential hazards involving adverse reactions were explained to the patients, and written informed consent was obtained from each patient/parent/guardian prior to enrollment in the study.

Study Design
The study was conducted as a multicenter, dose escalation, open-label, 2-part outpatient study with an observation period following administration of gemtuzumab ozogamicin. Part 1 of the study lasted approximately 42 days (≤ 7 days of screening, 2 doses with a minimum of 14 days and a maximum of 28 days between doses, and a 28-day follow-up following the last administered dose). Pharmacokinetics were collected in part 1 of the study. Part 2 of the study consisted of monthly visits for 6 months. Poststudy follow-up continued for patients who completed part 2 until death or study termination.

Drug Supply
The drug was supplied in amber glass vials as a white, unpreserved, lyophilized powder. Each vial contained 5 mg of test article, which was then reconstituted with 5 mL of sterile water prior to injection. A patient-individualized dose of reconstituted test article was added to 100 mL of 0.9% sodium chloride. The test article was shielded from light during reconstitution and administration.

Dosage and Administration
The original protocol-specified dosages of 6 and 9 mg/m2 were to be administered during the study. These dosages were selected based on the results of a phase 1 ascending-dosage study done to examine dosage levels of 0.25, 0.5, 1, 2, 4, 5, 6, and 9 mg/m2 in adults with AML. Evidence of dose-limiting toxicity (DLT) was observed at the 9-mg/m2 dose. After completion of an additional cohort given 6 mg/m2, an intermediate dosage of 7.5 mg/m2 was added to the protocol by a provision in an amendment.

Each treatment cycle consisted of 2 doses separated by 14 to 28 days, with doses administered as a 2-hour intravenous (IV) infusion. Regardless of weight changes, the dose administered did not change between dose periods and was based on the observation taken at the screening assessment. To receive a second dose, patients were required to show recovery from reversible nonhematologic toxicities after the first infusion, resolution of any grade 3 or 4 hepatic enzyme elevations (AST, ALT) and bilirubin elevation to grade 1 or 2, no evidence of uncontrolled infection, no evidence of disease progression determined from a bone marrow aspirate performed at day 7 to monitor disease progression, and the time from the previous infusion of ≥ 14 days but ≤ 28 days.

Patients who achieved a complete or morphological remission for at least 1 month after receiving gemtuzumab ozogamicin and later relapsed could be considered for a second treatment cycle as long as the study remained open.

Patients younger than age 3 years were dosed based on a per kilogram basis, as shown in Table I, and their results are included with those dosed on the corresponding mg/m2 basis.


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  		Table I Dose Administration for Patients Younger Than 3 Years of Age

 

Assay Methods
Plasma samples were analyzed for hP67.6 (antibody) and calicheamicin derivatives (total and unconjugated) using validated enzyme-linked immunosorbent assay (ELISA) methods.11 The hP67.6 assay used specific binding of the hP67.6 antibody to the CD33 antigen that is immobilized on the plate surface. Bound hP67.6 antibody was detected by peroxidase-labeled anti-human IgG4 using 3, 3', 5, 5'-tetramethylbenzidine (TMB) as a substrate. The hP67.6 assay had a quantifiable range of 0.18 to 12.38 mg/L in 100% human plasma. The assay did not distinguish between unconjugated hP67.6 antibody, conjugated antibody, or any antibody fragment that was capable of recognizing CD33 antigen and that contained an Fc region. The precision, based on quality control (QC) sample results obtained during the study, ranged from 7% to 25%, and the mean accuracy was within 9% of the expected values. Frozen samples remained stable at -70°C for up to 292 days and through 3 freeze/thaw cycles; all samples were assayed within this time frame.

The unconjugated calicheamicin was detected using a competitive ELISA method that used specific rabbit anti-calicheamicin antibody. The assay had a calibration range of 0.0025 to 0.28 mg/L. Total calicheamicin was analyzed by a competitive enzyme immunoassay following disulfide bond reduction, protein precipitation, and solid-phase extraction. The assay had a calibration range of 0.01 to 1.50 mg/L. The assays for total calicheamicin and unconjugated calicheamicin did not distinguish between various derivatives of calicheamicin. The precision and accuracy based on the performance of the QC samples evaluated during the total calicheamicin assay validation were 10% to 14%, and the accuracy was within 6%. The precision and accuracy based on the performance of the QC samples evaluated during the unconjugated calicheamicin assay validation were 9.8% to 17%, with an accuracy of less than 3%. Frozen samples remained stable for up to 292 days at -70°C and through at least 3 freeze/thaw cycles; all samples were assayed within this time frame.

Pharmacokinetic Sampling and Statistical Analysis
Blood samples (2 mL) were collected in EDTA Vacutainers. Blood was separated using a refrigerated centrifuge (1000g), and plasma was removed prior to freezing at -70°C. Samples were drawn before the infusion; 1, 2, 3, 4, and 6 hours postinfusion; and on study days 3, 5, and 10 of each dose period. Although blood sample collection was required by the protocol at specified time points, the patient population made rigorous adherence to the protocol-specified collection times difficult. Investigators collected as many plasma samples as possible, and actual sample collection times were recorded. Although samples were obtained reasonably close to scheduled sampling times, pharmacokinetic parameters were based on actual sample times.

Pharmacokinetic parameters were derived by standard noncompartmental methods.11,12 The maximum concentration (Cmax) was determined directly from the data. The elimination rate constant ({lambda}z) was determined for each individual from terminal points of the concentration-time profile. The area under the plasma concentration versus time curve (AUC) was determined by the linear-log trapezoidal rule, and half-life (t1/2) was calculated as 0.693/{lambda}z. Clearance (CL) was calculated as a ratio of dose/AUC. Volume of distribution at steady state (Vss) was calculated based on standard equations.11

Pharmacokinetic parameters determined for all 3 assayed species included Cmax, t1/2, and AUC. CL and Vss were estimated for hP67.6. In addition, the AUC ratio of calicheamicin to hP67.6, expressed as a percentage, was calculated for each dose period.

Summary statistics for each pharmacokinetic parameter, including the mean and SD, were reported for each dose period. An analysis of variance was performed to assess statistical differences between the pharmacokinetic parameters of the first and second dose periods. P values less than 0.05 were considered significant. Summary statistics for each parameter were also reported for each age group. Patients were grouped into the following age categories: infants (0-2 years), children (3-11 years), and adolescents (12-16 years). Data from the first dose only from all patients were dose normalized for comparison.


   RESULTS
TOP
 ABSTRACT
 METHODS AND MATERIALS
 RESULTS
DISCUSSION
 REFERENCES
 
Dose-limiting toxicities were observed at the 9-mg/m2 dosage level, and the dose was then lowered to 6 mg/m2 of gemtuzumab ozogamicin. However, preliminary pharmacokinetic data indicated little difference between adult and pediatric patients at the adult dose of 9 mg/m2. The study was amended to allow dose escalation to an intermediate dose level of 7.5 mg/m2 when the 6-mg/m2 dose was well tolerated. However, by this time, the enrollment rate had dropped, and the study was terminated due to lack of enrollment at the 7.5-mg/m2 dose level.

A summary of the patient demographic data is presented in Table II. Pharmacokinetic parameters were determined for a total of 29 patients, 22 of whom also had pharmacokinetic parameters determined after a second dose. One patient received a second cycle of treatment 9 months after his last treatment. The second course of treatment for this patient was received after a considerable washout period, and increased antigen levels were observed. For the analysis of the pharmacokinetic data, this second cycle of treatment was considered as a unique patient profile.


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  		Table II Patient Demographic Summary

 

Figure 1 presents the mean hP67.6 plasma concentrations for the 6- and 9-mg/m2 doses plotted versus time for the first dose period. Concentration-time profiles for the 2 subjects receiving the 7.5-mg/m2 dose were similar to patients receiving the 6- and 9-mg/m2 doses. Mean hP67.6 plasma concentration-time profiles for the first dose period for pediatrics and adults11 are shown in Figure 2. Higher plasma concentrations after the second dose were observed for all 3 dose groups. A statistical summary of the hP67.6 pharmacokinetic parameters for each dose group, as well as the results of statistical comparisons between the first and second dose periods, are presented in Table III.



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  		Figure 1. Mean hP67.6 concentration versus time following dose period 1.

 


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  		Figure 2. Mean hP67.6 concentration versus time following dose period 1 in pediatric and adult subjects.

 

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  		Table III Summary of hP67.6 Pharmacokinetic Parameters by Dose Group for Dose Periods 1 and 2

 

Pharmacokinetic parameters had a consistent change between the first and second doses. Statistically significant changes between dose periods were observed in the 9-mg/m2 group for Cmax. Statistically significant changes between dose periods were observed for AUC for both the 6- and 9-mg/m2 groups. AUC increased by 63% and 77%, with a corresponding decrease in CL, with or without normalization for body surface area, for the 6- and 9-mg/m2 groups, respectively. The volumes of distribution also decreased from the first to second dose period, whereas the half-lives increased following the second dose. The intersubject variability within dose period was large for most parameters. A decrease in the volume of distribution was also observed as the dosage increased from 6 to 9 mg/m2, with an associated decrease in drug clearance.

The concentration-time profiles of total calicheamicin were similar in shape to the profiles of hP67.6 for most patients. A statistical summary of the total calicheamicin parameters for each dose group, as well as the results of a statistical comparison between the first and second dose periods, is presented in Table IV.


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  		Table IV Summary of Total Calicheamicin Pharmacokinetic Parameters by Dose Group for Dose Periods 1 and 2

 

Changes in pharmacokinetic parameters of total calicheamicin from dose period 1 to dose period 2 were consistent with those of hP67.6. Increases in t1/2 and AUC were observed in the second dose period. The ratio of AUC values for the total calicheamicin to hP67.6 was approximately 3% for all dosage levels. An increase in AUC was also observed as the dosage increased from 6 to 9 mg/m2.

Concentrations of unconjugated calicheamicin were low and were only measurable for a relatively short time after the end of drug infusion. Concentration versus time profiles of unconjugated calicheamicin were similar in shape to those of hP67.6 and total calicheamicin for most patients. Statistical summaries of the unconjugated calicheamicin parameters for each dose group, as well as the results of a statistical comparison between the first and second dose periods, are presented in Table V. Changes in pharmacokinetic parameters of unconjugated calicheamicin from dose period 1 to dose period 2 were consistent with those of hP67.6. Statistically significant changes from dose period 1 to dose period 2 were only observed for AUC.


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  		Table V Summary of Unconjugated Calicheamicin Pharmacokinetic Parameters by Dose Group for Dose Periods 1 and 2

 

A statistical summary of the hP67.6 pharmacokinetic parameters for each age group is presented in Table VI. Pharmacokinetic parameters were consistent across all age groups for dose period 1. Differences in pharmacokinetic parameters across the pediatric age groups were not statistically significant. Pharmacokinetic data from 59 adult subjects are included in Table VI for comparison. Comparisons of clearance versus body weight and clearance versus age are presented in Figure 3 and Figure 4, respectively. There were no special circumstances surrounding the 1 outlier in Figure 3 and Figure 4.


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  		Table VI Summary of hP67.6 Pharmacokinetic Parameters by Age Group for Dose Period 1

 


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  		Figure 3. hP67.6 clearance versus body weight for dose period 1.

 


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  		Figure 4. hP67.6 clearance versus age for dose period 1.

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS AND MATERIALS
 RESULTS
 DISCUSSION
REFERENCES
 
The overall safety profile of gemtuzumab ozogamicin in pediatric patients was similar to the safety profile in adult patients. The most common treatment-emergent adverse events were leukopenia, thrombocytopenia, sepsis, fever, hypokalemia, hypochromic anemia, pleural effusion, and pneumonia. All patients had myelosuppression, which was expected because of the known mechanism of action of gemtuzumab ozogamicin. Almost all patients had transient and reversible elevations in liver function test results. There were fewer cases of clinically important mucositis events than are usually observed in patients with AML undergoing chemotherapy.

Concentrations of hP67.6 and calicheamicin were at the highest levels for all patients shortly after the end of the infusion. The mean increase in Cmax for hP67.6 between the first and second doses was 14.7% and 35.0% for the 6- and 9-mg/m2 groups, respectively. Considering the high interpatient variability, this increase is relatively small. Increases in AUC by 63% and 77%, with a corresponding decrease in CL for the 6- and 9-mg/m2 groups, respectively, were also observed between dose periods. The volumes of distribution also decreased for all dose groups. Changes in the pharmacokinetic parameters between dose periods for the pediatric patients are consistent with those of the adult patients.11 Changes in the pharmacokinetic parameters between dose periods, as well as the changes observed with increased dosage from 6 to 9 mg/m2, are most likely related to saturation of CD33 binding sites and diminished clearance resulting from a lower peripheral blast burden and antigen.

The terminal phase half-lives for hP67.6 following the first dose were 43.1 and 63.7 hours for the 6- and 9-mg/m2 dose groups, respectively. Following the second dose, the mean half-lives were 49.4 and 57.8 hours for the 6- and 9-mg/m2 dose groups, respectively, similar to values observed with the first dose.

For most patients, concentration versus time profiles for total and unconjugated calicheamicin were similar in shape to those of hP67.6. On average, concentrations for the total calicheamicin derivatives were higher after the second dose of treatment. Greater AUC values with the second dose were the only statistically significant pharmacokinetic parameters between dose periods 1 and 2. By comparison of AUC values, the ratio of exposure of total calicheamicin to hP67.6 is approximately 3%. Calicheamicin exposure is rate limited by hP67.6 and dependant on the retention of calicheamicin on hP67.6. Concentrations of unconjugated calicheamicin in plasma were measurable for only a short time after the end of drug infusion, were relatively low, and had high interpatient variability. These observations are also consistent with those in the adult population.11 CL in adults is 0.27 L/h,11 which is in the same range as CL in the pediatric population, whose overall mean across all dose groups is 0.36 L/h.

Concentration versus time profiles of hP67.6 were similar between age groups for the first dose period. The mean Cmax for infants was only slightly lower than the adolescent age group, and the mean Cmax for the children was 22.8% higher than the adolescent age group. Adolescents had slightly lower AUC in comparison with infants (2.3% higher) and children (33.5% higher). CL among infants and children was 80.9% lower and 72.0% lower, respectively, than among the adolescents. However, no statistically significant relationships were observed between hP67.6 CL and body weight or CL and age. Volume of distribution was also lower among infants and children. Intersubject variability within age groups was large for most parameters.

Concentration versus time profiles for both total and unconjugated calicheamicin were similar between age groups for dose period 1 and were similar in shape to that of hP67.6. Individual subjects also demonstrated large intersubject variability, comparable to hP67.6.

In conclusion, the pharmacokinetic profile of gemtuzumab ozogamicin in pediatric patients closely follows that of adult patients. Preliminary clinical outcomes4 indicate that similar efficacy would result following the 7.5-mg/m2 dose in pediatric subjects.


   FOOTNOTES
 
DOI: 10.1177/0091270004267595

Submitted for publication February 22, 2004; Revised version accepted May 23, 2004.


   REFERENCES
TOP
 ABSTRACT
 METHODS AND MATERIALS
 RESULTS
 DISCUSSION
 REFERENCES
 

1. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, et al: Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001;7(6): 1490-1496.[Abstract/Free Full Text]

2. van Der Velden VH, te Marvelde JG, Hoogeveen PG, Bernstein ID, Houtsmuller AB, Berger MS, et al: Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 2001;97(10): 3197-3204.[Abstract/Free Full Text]

3. Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H, et al: Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001;19: 3244-3254.[Abstract/Free Full Text]

4. Zwaan CM, Reinhardt D, Corbacioglu S, van Wering ER, Bokkerink JP, Tissing WJ, et al: Gemtuzumab ozogamicin: first clinical experiences in children with relapsed/refractory acute myeloid leukemia treated on compassionate-use basis. Blood 2003;101(10): 3868-3871.[Abstract/Free Full Text]

5. Lowenberg B, Downing JR, Burnett A: Acute myeloid leukemia. N Engl J Med 1999;341: 1051-1062.[Free Full Text]

6. Legrand O, Perrot J-Y, Baudard M, Cordier A, Lautier R, Simonin G, et al: The immunophenotype of 177 adults with acute myeloid leukemia: proposal of a prognostic score. Blood 2000;96: 870-877.[Abstract/Free Full Text]

7. Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, et al: Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjugate Chem 2002;13(1): 47-58.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

8. Ebb DH, Weinstein HJ: Diagnosis and treatment of childhood acute myeloid leukemia. Pediatr Clin North Am 1997;44(4): 847-862.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Sievers EL, Arceci R, Franklin J, Lange B, Shannon K, Smith F, et al: Preliminary report of an ascending dose study of gemtuzumab ozogamicin (Mylotarg, CMA-676) in pediatric patients with acute myeloid leukemia [abstract]. Blood 2000;96: 217b.

10. Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR: The measurement of performance in childhood cancer patients. Cancer 1987;60(7): 1651-1656.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Dowell JA, Korth-Bradley J, Liu H, King SP, Berger MS: Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse. J Clin Pharmacol 2001;41(11): 1206-1214.[Abstract]

12. Gibaldi, M, Perrier D: Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982.
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R. J. Arceci, J. Sande, B. Lange, K. Shannon, J. Franklin, R. Hutchinson, T. A. Vik, D. Flowers, R. Aplenc, M. S. Berger, et al.
Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia
Blood, August 15, 2005; 106(4): 1183 - 1188.
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