Phase i trial of 7-hydroxystaurosporine and fludararbine phosphate

In vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia

Gerald E. Marti, Maryalice Stetler-Stevenson, Nicole Drbohlav Grant, Therese White, William D. Figg, Tanyifor Tohnya, Elaine S. Jaffe, Kieron Dunleavy, John Edward Janik, Seth M. Steinberg, Wyndham H. Wilson

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 26. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.

Original languageEnglish (US)
Pages (from-to)2284-2292
Number of pages9
JournalLeukemia and Lymphoma
Volume52
Issue number12
DOIs
StatePublished - Dec 1 2011

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
Phosphates
Apoptosis
Lymphocytosis
7-hydroxystaurosporine
Lymphocytes
Circulating Neoplastic Cells
Stevens-Johnson Syndrome
Lymphoma
Cell Death
Pharmacokinetics
Pharmacology

Keywords

  • CLL
  • Cell death
  • Flow cytometry
  • Protein kinase inhibitor

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Phase i trial of 7-hydroxystaurosporine and fludararbine phosphate : In vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia. / Marti, Gerald E.; Stetler-Stevenson, Maryalice; Grant, Nicole Drbohlav; White, Therese; Figg, William D.; Tohnya, Tanyifor; Jaffe, Elaine S.; Dunleavy, Kieron; Janik, John Edward; Steinberg, Seth M.; Wilson, Wyndham H.

In: Leukemia and Lymphoma, Vol. 52, No. 12, 01.12.2011, p. 2284-2292.

Research output: Contribution to journalArticle

Marti, GE, Stetler-Stevenson, M, Grant, ND, White, T, Figg, WD, Tohnya, T, Jaffe, ES, Dunleavy, K, Janik, JE, Steinberg, SM & Wilson, WH 2011, 'Phase i trial of 7-hydroxystaurosporine and fludararbine phosphate: In vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia', Leukemia and Lymphoma, vol. 52, no. 12, pp. 2284-2292. https://doi.org/10.3109/10428194.2011.589547
Marti, Gerald E. ; Stetler-Stevenson, Maryalice ; Grant, Nicole Drbohlav ; White, Therese ; Figg, William D. ; Tohnya, Tanyifor ; Jaffe, Elaine S. ; Dunleavy, Kieron ; Janik, John Edward ; Steinberg, Seth M. ; Wilson, Wyndham H. / Phase i trial of 7-hydroxystaurosporine and fludararbine phosphate : In vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia. In: Leukemia and Lymphoma. 2011 ; Vol. 52, No. 12. pp. 2284-2292.
@article{6b295f1b585e4dd5979d8d65a12b6a06,
title = "Phase i trial of 7-hydroxystaurosporine and fludararbine phosphate: In vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia",
abstract = "This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 26. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.",
keywords = "CLL, Cell death, Flow cytometry, Protein kinase inhibitor",
author = "Marti, {Gerald E.} and Maryalice Stetler-Stevenson and Grant, {Nicole Drbohlav} and Therese White and Figg, {William D.} and Tanyifor Tohnya and Jaffe, {Elaine S.} and Kieron Dunleavy and Janik, {John Edward} and Steinberg, {Seth M.} and Wilson, {Wyndham H.}",
year = "2011",
month = "12",
day = "1",
doi = "10.3109/10428194.2011.589547",
language = "English (US)",
volume = "52",
pages = "2284--2292",
journal = "Leukemia and Lymphoma",
issn = "1042-8194",
publisher = "Informa Healthcare",
number = "12",

}

TY - JOUR

T1 - Phase i trial of 7-hydroxystaurosporine and fludararbine phosphate

T2 - In vivo evidence of 7-hydroxystaurosporine induced apoptosis in chronic lymphocytic leukemia

AU - Marti, Gerald E.

AU - Stetler-Stevenson, Maryalice

AU - Grant, Nicole Drbohlav

AU - White, Therese

AU - Figg, William D.

AU - Tohnya, Tanyifor

AU - Jaffe, Elaine S.

AU - Dunleavy, Kieron

AU - Janik, John Edward

AU - Steinberg, Seth M.

AU - Wilson, Wyndham H.

PY - 2011/12/1

Y1 - 2011/12/1

N2 - This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 26. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.

AB - This is a phase I study of 7-hydroxystaurosporine (UCN-01) and fludararbine monophosphate (FAMP) in relapsed lymphoma. UCN-01 alone was administered in cycle 1 and with FAMP in cycles 26. FAMP was escalated in cohorts from 1 to 5 days. UCN-01 and FAMP pharmacokinetics and apoptosis of malignant lymphocytes was evaluated. Eighteen patients were enrolled. Standard FAMP with UCN-01 was tolerated without dose-limiting toxicity (DLT) and those seen were common to either agent alone. One patient died due to Stevens-Johnson syndrome. Seven of 18 patients responded. No pharmacological effect of UCN-01 by FAMP was noted. Lymphocytosis occurred in 15 of 18 patients following UCN-01 to paradoxically increase circulating tumor cells. UCN-01 induced apoptosis in six of eight patients with chronic lymphocytic leukemia (CLL). UCN-01 does not increase FAMP toxicity. Transient lymphocytosis followed by apoptosis occurs with UCN-01. Mobilization from tissue reservoirs may play a role in the induction of cell death in malignant lymphocytes.

KW - CLL

KW - Cell death

KW - Flow cytometry

KW - Protein kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=82255193028&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=82255193028&partnerID=8YFLogxK

U2 - 10.3109/10428194.2011.589547

DO - 10.3109/10428194.2011.589547

M3 - Article

VL - 52

SP - 2284

EP - 2292

JO - Leukemia and Lymphoma

JF - Leukemia and Lymphoma

SN - 1042-8194

IS - 12

ER -