Andreeff, Michael

Estey, Elihu H.

Kantarjian, Hagop

Keating, Michael

Munker, Reinhold

O'Brien, Susan

English

Reinhold Munker

Hagop Kantarjian

Susan O’Brien

Michael Keating

Michael Andreeff

Elihu H. Estey

Crossref

Phase I Study of Taxol in Refractory Acute Myelogenous Leukemias Using a Weekly Schedule

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Brief CommunicationActa Haematol 1998;99:106–108Phase I Study of Taxol in RefractoryAcute Myelogenous LeukemiasUsing a Weekly ScheduleReinhold MunkerHagop KantarjianSusan O’BrienMichael KeatingMichael AndreeffElihu H. EsteyUniversity of Texas, M.D. Anderson CancerCenter, Department of Hematology,Houston, Tex., USAReceived: March 5, 1997Accepted: June 12, 1997Reinhold Munker, MDMedizinische Klinik III der LMU(Klinikum Grosshadern)D–81377 München (Germany)Tel. +49 89 7095 1, Fax +49 89 7099 400, E-Mail munker@gsf.deABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 1998 S. Karger AG, Basel0001–5792/98/0992–0106$15.00/0This article is also accessible online at:http://BioMedNet.com/kargerTaxol is an antineoplastic drug which targets microtu-bules and which has significant clinical activity in ovarianand breast cancer, and also in lymphomas and non-small-cell lung cancer [1]. In the early clinical trials, a high inci-dence of acute reactions (bronchospasm, hypotension andarrhythmias) was observed due to the vehicle Cremophor[2]. For later clinical trials, taxol was administered withantiallergic premedication. In these trials, neutropeniawas observed as dose-limiting toxicity. In addition, a sen-sory neuropathy, nausea, myalgias, mucositis and alope-cia were common. For phase II studies in solid tumors,210 mg/m2 as a 6-hour infusion and 250 mg/m2 as a 24-hour infusion were recommended [1]. In refractory ovar-ian cancer, taxol could be safely administered at up to250 mg/m2 with G-CSF support; in this study, sensoryneuropathy was the major dose-limiting toxicity [3]. Invitro, several human leukemic cell lines were found to besensitive to taxol [5]. Taxol induces apoptosis in sensitivemyeloid leukemia cell lines [5, 6]. In a phase I study, taxolwas used in refractory acute leukemias. At doses of390 mg/m2, repeated once every 3 weeks, severe mucositiswas observed [7]. At this dose, a clearance of leukemicblasts from blood and bone marrow was observed in 2/6patients. By analogy to vincristine, another agent target-ing microtubules, we hypothesized that weekly adminis-tration of a lower dose repeated 3 times might lead toreduced side effects and enhanced antileukemic activity.We therefore designed a phase I study, in which taxol wasadministered to patients with relapsed or refractory acutemyelogenous leukemia (AML) starting with a dose of80 mg/m2 repeated in 3 weekly intervals.Adults (aged 116 years) were eligible for this phase Istudy if they had relapsed AML or were not in completeremission (CR) after at least 2 courses of induction treat-ment. In addition, the likelihood of remission with stan-dard salvage regimes (high-dose cytosine-arabinoside)had to be !40% as judged by a duration of first remissionof less than 1 year and having received at least one priorsalvage regimen. Other eligibility criteria were: serum cre-atinine and bilirubin each !1.6 mg/ml; Zubrod perfor-mance status !3; no prior cisplatin, or taxotere; no majorcardiac history; at least 2 weeks from last prior therapyand full recovery from any toxic effects. Taxol was sup-plied by the Division of Cancer Treatment of the NationalCancer Institute, Bethesda, Md.The probability of obtaining CR was calculated ac-cording to a statistical model based on 314 patients withrelapsed AML [8]. Details of the patients are given intable 1.Taxol was started in the first 3 patients at a dose of80 mg/m2 over 24 h by intravenous infusion on days, 1, 8,and 15. Premedication consisted of dexamethasone 20mg i.v. 14 and 7 h prior to beginning taxol and diphenhy-dramine and ranitidine 50 mg 30 min prior to taxol. Adose escalation was planned in the steps of 100, 125, 160and 200 mg/m2 (3 doses each) if no excessive toxicitydeveloped in the first 3 patients treated at the previousdosage level. A patient was to be removed from the study1Taxol in Refractory AML Acta Haematol 1998;99:106–108 107Table 1. Patient characteristics, taxol dose, side effects and clearance of leukemic blastsPat. AgeyearsCytogenetics DurationCR 1, weeksSalvagenPred. prob.CR, %Taxoldose, mg/m2Toxicity Blasts% in PB·53 i.m. 33 2 1 80!3 0 9/1002 77 diploid 8 3 1 80!3 1 (N, P) 10/153 59 diploid 22 1 20 80!3 0 15/554 35 diploid 43 2 1 100!3 0 59/905 64 –5,–7 20 2 1 100!3 2 (U) 72/9b6 38 diploid 8 1 1 100!3 0 5/nt7 20 diploid NAc 2 1 100!2d 0 93/968 59 i.m. 35 3 10 100!2d 0 10/459 77 diploid 0 2 1 100!3 0 28/8810 50 t(9;11) 43 2 1 125!3 1 (P) nt/nt11 42 diploid 9 2 1 125!3 1 (D) 91/9812 73 +8 0 3 1 125!2e 3 (U) 51/9513 39 –5,–7 6 2 1 125!3 2 (N) 9/63CR = Complete remission; PB = peripheral blood; N = nausea; U = ulcer; D = diarrhea; i.m. = insufficientmetaphases; nt = not tested.a Blasts before/after one course of taxol (percentage).b In this patient, a concomitant decrease in bone marrow blasts from 60 to 15% was noted.c Underwent bone marrow transplantation and relapsed 4 weeks thereafter.d Patient died before 3rd dose could be given.e 3rd dose not given because of grade 3 toxicity (stomatitis).if his marrow was not hypoplastic after 1 course of taxol(3 doses) or if he or she was not in CR after 2 courses oftaxol (6 doses) with 11 week separating courses and nomore than 3 doses given per course or if the patient devel-oped 6 grade 2 extramedullary toxicity with a !50%decrease in the marrow leukemic infiltrate. Toxicity wasevaluated according to common NCI criteria.A total of 13 patients with relapsed or refractory AMLwas treated with taxol. All patients were heavily pre-treated. Most patients had failed several salvage regimensand had a low probability of obtaining CR (!1%) [8]. At80 mg/m2 !3 (3 patients) only minor toxicities wereencountered. Six patients were treated at 100 mg/m2; in 1of 3 evaluable patients a grade 2 stomatitis was recorded.Four patients were treated at 125 mg/m2. All had majortoxicity: 1 patient had a severe buccal ulcer (stomatitis,grade 3), and 1 patient each had grade 2 nausea, grade 1peripheral neuropathy and grade 1 diarrhea. All patientswere severely immunosuppressed: 3/13 had fever of unde-termined etiology, 1 patient each had pneumonia andherpes zoster infection and 5 patients were treated for sep-ticemia and/or fungemia. No patients entered CR. Onlyin 1 of 11 patients some antileukemic activity (decrease ofblasts in blood and bone marrow) could be observed. Tak-ing into account the definite toxicity observed at the doselevel of 125 mg/m2 !3, a further dose escalation does notappear feasible in this group of patients with AML whoare heavily pretreated. Taking into account the modestantileukemic activity observed at this dose level, a furtherdose escalation also would not appear to enter patientsinto CR. We conclude from this study that the scheduleproposed here for taxol (three 24-hour infusions at 1-weekinterval) is no improvement as far as toxicity and antileu-kemic activity are concerned.108 Acta Haematol 1998;99:106–108 Munker/Kantarjian/O’Brien/Keating/Andreeff/EsteyOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOReferences 1 Foa R, Norton L, Seidman AD: Taxol (pacli-taxel): A novel anti-microtubule agent with re-markable anti-neoplastic activity. Int J ClinLab Res 1994;24:6–14.2 Lassus M, Scott D, Leyland-Jones B: Allergicreactions associated with Cremophor-contain-ing antineoplastics. Proc Am Soc Clin Oncol1985;4:268–275.3 Sarosy G, Kohn E, Stone DA, Rothenberg M,Jacob J, Adamo DO, Ognibene FP, CunnionRE, Reed E: Phase I study of taxol and granulo-cyte colony-stimulating factor in patients withrefractory ovarian cancer. J Clin Oncol 1992;10:1165–1170.4 Rowinsky EK, Donehower RC, Jones RJ,Tucker RW: Microtubule changes and cytotox-icity in leukemic cell lines treated with taxol.Cancer Res 1988;48:4093–4100.5 Bhalla K, Ibrado AM, Tourkina E, Tang C,Mahoney ME, Huang Y: Taxol induces inter-nucleosomal DNA fragmentation associatedwith programmed cell death in human myeloidleukemia cells. Leukemia 1993;7:563–568.6 Gangemi RMR, Tiso M, Marchetti C, SeveriAB, Fabbi M: Taxol cytotoxicity on human leu-kemia cell lines is a function of their suscepti-bility to programmed cell death. Cancer Che-mother Pharmacol 1995;36:385–392.7 Rowinsky EK, Burke PJ, Karp JE, Tucker RW,Ettinger DS, Donehower RC: Phase I and phar-macodynamic study of taxol in refractory acuteleukemias. Cancer Res 1989;49:4640–4647.8 Estey E, Kornblau S, Pierce S, Kantarjian H,Beran M, Keating M: A stratification systemfor evaluating and selecting therapies in pa-tients with relapsed or primary refractory acuteleukemias. Blood 1996;88:756.

Universität München: Elektronischen Publikationen

Brief Communication
Acta Haematol 1998;99:106–108
Phase I Study of Taxol in Refractory
Acute Myelogenous Leukemias
Using a Weekly Schedule
Reinhold Munker
Hagop Kantarjian
Susan O’Brien
Michael Keating
Michael Andreeff
Elihu H. Estey
University of Texas, M.D. Anderson Cancer
Center, Department of Hematology,
Houston, Tex., USA
Received: March 5, 1997
Accepted: June 12, 1997
Reinhold Munker, MD
Medizinische Klinik III der LMU
(Klinikum Grosshadern)
D–81377 München (Germany)
Tel. +49 89 7095 1, Fax +49 89 7099 400, E-Mail munker@gsf.de
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 1998 S. Karger AG, Basel
0001–5792/98/0992–0106$15.00/0
This article is also accessible online at:
http://BioMedNet.com/karger
Taxol is an antineoplastic drug which targets microtu-
bules and which has significant clinical activity in ovarian
and breast cancer, and also in lymphomas and non-small-
cell lung cancer [1]. In the early clinical trials, a high inci-
dence of acute reactions (bronchospasm, hypotension and
arrhythmias) was observed due to the vehicle Cremophor
[2]. For later clinical trials, taxol was administered with
antiallergic premedication. In these trials, neutropenia
was observed as dose-limiting toxicity. In addition, a sen-
sory neuropathy, nausea, myalgias, mucositis and alope-
cia were common. For phase II studies in solid tumors,
210 mg/m2 as a 6-hour infusion and 250 mg/m2 as a 24-
hour infusion were recommended [1]. In refractory ovar-
ian cancer, taxol could be safely administered at up to
250 mg/m2 with G-CSF support; in this study, sensory
neuropathy was the major dose-limiting toxicity [3]. In
vitro, several human leukemic cell lines were found to be
sensitive to taxol [5]. Taxol induces apoptosis in sensitive
myeloid leukemia cell lines [5, 6]. In a phase I study, taxol
was used in refractory acute leukemias. At doses of
390 mg/m2, repeated once every 3 weeks, severe mucositis
was observed [7]. At this dose, a clearance of leukemic
blasts from blood and bone marrow was observed in 2/6
patients. By analogy to vincristine, another agent target-
ing microtubules, we hypothesized that weekly adminis-
tration of a lower dose repeated 3 times might lead to
reduced side effects and enhanced antileukemic activity.
We therefore designed a phase I study, in which taxol was
administered to patients with relapsed or refractory acute
myelogenous leukemia (AML) starting with a dose of
80 mg/m2 repeated in 3 weekly intervals.
Adults (aged 116 years) were eligible for this phase I
study if they had relapsed AML or were not in complete
remission (CR) after at least 2 courses of induction treat-
ment. In addition, the likelihood of remission with stan-
dard salvage regimes (high-dose cytosine-arabinoside)
had to be !40% as judged by a duration of first remission
of less than 1 year and having received at least one prior
salvage regimen. Other eligibility criteria were: serum cre-
atinine and bilirubin each !1.6 mg/ml; Zubrod perfor-
mance status !3; no prior cisplatin, or taxotere; no major
cardiac history; at least 2 weeks from last prior therapy
and full recovery from any toxic effects. Taxol was sup-
plied by the Division of Cancer Treatment of the National
Cancer Institute, Bethesda, Md.
The probability of obtaining CR was calculated ac-
cording to a statistical model based on 314 patients with
relapsed AML [8]. Details of the patients are given in
table 1.
Taxol was started in the first 3 patients at a dose of
80 mg/m2 over 24 h by intravenous infusion on days, 1, 8,
and 15. Premedication consisted of dexamethasone 20
mg i.v. 14 and 7 h prior to beginning taxol and diphenhy-
dramine and ranitidine 50 mg 30 min prior to taxol. A
dose escalation was planned in the steps of 100, 125, 160
and 200 mg/m2 (3 doses each) if no excessive toxicity
developed in the first 3 patients treated at the previous
dosage level. A patient was to be removed from the study
1
Taxol in Refractory AML Acta Haematol 1998;99:106–108 107
Table 1. Patient characteristics, taxol dose, side effects and clearance of leukemic blasts
Pat. Age
years
Cytogenetics Duration
CR 1, weeks
Salvage
n
Pred. prob.
CR, %
Taxol
dose, mg/m2
Toxicity Blasts
% in PB·
53 i.m. 33 2 1 80!3 0 9/100
2 77 diploid 8 3 1 80!3 1 (N, P) 10/15
3 59 diploid 22 1 20 80!3 0 15/55
4 35 diploid 43 2 1 100!3 0 59/90
5 64 –5,–7 20 2 1 100!3 2 (U) 72/9b
6 38 diploid 8 1 1 100!3 0 5/nt
7 20 diploid NAc 2 1 100!2d 0 93/96
8 59 i.m. 35 3 10 100!2d 0 10/45
9 77 diploid 0 2 1 100!3 0 28/88
10 50 t(9;11) 43 2 1 125!3 1 (P) nt/nt
11 42 diploid 9 2 1 125!3 1 (D) 91/98
12 73 +8 0 3 1 125!2e 3 (U) 51/95
13 39 –5,–7 6 2 1 125!3 2 (N) 9/63
CR = Complete remission; PB = peripheral blood; N = nausea; U = ulcer; D = diarrhea; i.m. = insufficient
metaphases; nt = not tested.
a Blasts before/after one course of taxol (percentage).
b In this patient, a concomitant decrease in bone marrow blasts from 60 to 15% was noted.
c Underwent bone marrow transplantation and relapsed 4 weeks thereafter.
d Patient died before 3rd dose could be given.
e 3rd dose not given because of grade 3 toxicity (stomatitis).
if his marrow was not hypoplastic after 1 course of taxol
(3 doses) or if he or she was not in CR after 2 courses of
taxol (6 doses) with 11 week separating courses and no
more than 3 doses given per course or if the patient devel-
oped 6 grade 2 extramedullary toxicity with a !50%
decrease in the marrow leukemic infiltrate. Toxicity was
evaluated according to common NCI criteria.
A total of 13 patients with relapsed or refractory AML
was treated with taxol. All patients were heavily pre-
treated. Most patients had failed several salvage regimens
and had a low probability of obtaining CR (!1%) [8]. At
80 mg/m2 !3 (3 patients) only minor toxicities were
encountered. Six patients were treated at 100 mg/m2; in 1
of 3 evaluable patients a grade 2 stomatitis was recorded.
Four patients were treated at 125 mg/m2. All had major
toxicity: 1 patient had a severe buccal ulcer (stomatitis,
grade 3), and 1 patient each had grade 2 nausea, grade 1
peripheral neuropathy and grade 1 diarrhea. All patients
were severely immunosuppressed: 3/13 had fever of unde-
termined etiology, 1 patient each had pneumonia and
herpes zoster infection and 5 patients were treated for sep-
ticemia and/or fungemia. No patients entered CR. Only
in 1 of 11 patients some antileukemic activity (decrease of
blasts in blood and bone marrow) could be observed. Tak-
ing into account the definite toxicity observed at the dose
level of 125 mg/m2 !3, a further dose escalation does not
appear feasible in this group of patients with AML who
are heavily pretreated. Taking into account the modest
antileukemic activity observed at this dose level, a further
dose escalation also would not appear to enter patients
into CR. We conclude from this study that the schedule
proposed here for taxol (three 24-hour infusions at 1-week
interval) is no improvement as far as toxicity and antileu-
kemic activity are concerned.
108 Acta Haematol 1998;99:106–108 Munker/Kantarjian/O’Brien/Keating/
Andreeff/Estey
OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO
References 1 Foa R, Norton L, Seidman AD: Taxol (pacli-
taxel): A novel anti-microtubule agent with re-
markable anti-neoplastic activity. Int J Clin
Lab Res 1994;24:6–14.
2 Lassus M, Scott D, Leyland-Jones B: Allergic
reactions associated with Cremophor-contain-
ing antineoplastics. Proc Am Soc Clin Oncol
1985;4:268–275.
3 Sarosy G, Kohn E, Stone DA, Rothenberg M,
Jacob J, Adamo DO, Ognibene FP, Cunnion
RE, Reed E: Phase I study of taxol and granulo-
cyte colony-stimulating factor in patients with
refractory ovarian cancer. J Clin Oncol 1992;
10:1165–1170.
4 Rowinsky EK, Donehower RC, Jones RJ,
Tucker RW: Microtubule changes and cytotox-
icity in leukemic cell lines treated with taxol.
Cancer Res 1988;48:4093–4100.
5 Bhalla K, Ibrado AM, Tourkina E, Tang C,
Mahoney ME, Huang Y: Taxol induces inter-
nucleosomal DNA fragmentation associated
with programmed cell death in human myeloid
leukemia cells. Leukemia 1993;7:563–568.
6 Gangemi RMR, Tiso M, Marchetti C, Severi
AB, Fabbi M: Taxol cytotoxicity on human leu-
kemia cell lines is a function of their suscepti-
bility to programmed cell death. Cancer Che-
mother Pharmacol 1995;36:385–392.
7 Rowinsky EK, Burke PJ, Karp JE, Tucker RW,
Ettinger DS, Donehower RC: Phase I and phar-
macodynamic study of taxol in refractory acute
leukemias. Cancer Res 1989;49:4640–4647.
8 Estey E, Kornblau S, Pierce S, Kantarjian H,
Beran M, Keating M: A stratification system
for evaluating and selecting therapies in pa-
tients with relapsed or primary refractory acute
leukemias. Blood 1996;88:756.


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Phase I Study of Taxol in Refractory Acute Myelogenous Leukemias Using a Weekly Schedule

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