Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia

Eric K. Rowinsky, Alex Adjei, Ross C. Donehower, Steven D. Gore, Richard J. Jones, Philip J. Burke, Yung Chi Cheng, Louise B. Grochow, Scott H Kaufmann

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Purpose: To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. Patients and Methods: Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (C(ss)) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT C(ss) values achieved. Results: Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT C(ss) values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT C(ss) values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multidrug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. Conclusion: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT C(ss) values are achievable, and that further developmental trials are warranted.

Original languageEnglish (US)
Pages (from-to)2193-2203
Number of pages11
JournalJournal of Clinical Oncology
Volume12
Issue number10
StatePublished - Oct 1994
Externally publishedYes

Fingerprint

Topoisomerase I Inhibitors
Topotecan
Leukemia
Type I DNA Topoisomerase
Acute Myeloid Leukemia
Glycoproteins
Blast Crisis
Mucositis
Oropharynx
Daunorubicin
Quinidine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia. / Rowinsky, Eric K.; Adjei, Alex; Donehower, Ross C.; Gore, Steven D.; Jones, Richard J.; Burke, Philip J.; Cheng, Yung Chi; Grochow, Louise B.; Kaufmann, Scott H.

In: Journal of Clinical Oncology, Vol. 12, No. 10, 10.1994, p. 2193-2203.

Research output: Contribution to journalArticle

Rowinsky, EK, Adjei, A, Donehower, RC, Gore, SD, Jones, RJ, Burke, PJ, Cheng, YC, Grochow, LB & Kaufmann, SH 1994, 'Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia', Journal of Clinical Oncology, vol. 12, no. 10, pp. 2193-2203.
Rowinsky, Eric K. ; Adjei, Alex ; Donehower, Ross C. ; Gore, Steven D. ; Jones, Richard J. ; Burke, Philip J. ; Cheng, Yung Chi ; Grochow, Louise B. ; Kaufmann, Scott H. / Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia. In: Journal of Clinical Oncology. 1994 ; Vol. 12, No. 10. pp. 2193-2203.
@article{4f1d360b820b4b6bab79b95ba6b6243a,
title = "Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia",
abstract = "Purpose: To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. Patients and Methods: Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (C(ss)) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT C(ss) values achieved. Results: Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT C(ss) values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90{\%}) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT C(ss) values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multidrug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15{\%}, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. Conclusion: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT C(ss) values are achievable, and that further developmental trials are warranted.",
author = "Rowinsky, {Eric K.} and Alex Adjei and Donehower, {Ross C.} and Gore, {Steven D.} and Jones, {Richard J.} and Burke, {Philip J.} and Cheng, {Yung Chi} and Grochow, {Louise B.} and Kaufmann, {Scott H}",
year = "1994",
month = "10",
language = "English (US)",
volume = "12",
pages = "2193--2203",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "10",

}

TY - JOUR

T1 - Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia

AU - Rowinsky, Eric K.

AU - Adjei, Alex

AU - Donehower, Ross C.

AU - Gore, Steven D.

AU - Jones, Richard J.

AU - Burke, Philip J.

AU - Cheng, Yung Chi

AU - Grochow, Louise B.

AU - Kaufmann, Scott H

PY - 1994/10

Y1 - 1994/10

N2 - Purpose: To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. Patients and Methods: Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (C(ss)) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT C(ss) values achieved. Results: Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT C(ss) values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT C(ss) values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multidrug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. Conclusion: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT C(ss) values are achievable, and that further developmental trials are warranted.

AB - Purpose: To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. Patients and Methods: Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (C(ss)) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT C(ss) values achieved. Results: Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT C(ss) values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT C(ss) values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multidrug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. Conclusion: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT C(ss) values are achievable, and that further developmental trials are warranted.

UR - http://www.scopus.com/inward/record.url?scp=0028090410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028090410&partnerID=8YFLogxK

M3 - Article

VL - 12

SP - 2193

EP - 2203

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 10

ER -