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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2001-12-0154.
 Previous Article | Table of Contents | Next Article 
Blood, 15 May 2002, Vol. 99, No. 10, pp. 3854-3856
BRIEF REPORT
Phase 2 trial of imatinib mesylate in myelofibrosis with
myeloid metaplasia
Ayalew Tefferi,
Ruben A. Mesa,
Leigh A. Gray,
David P. Steensma,
John K. Camoriano,
Michelle A. Elliott,
Animesh Pardanani,
Stephen M. Ansell,
Timothy G. Call,
Gerardo Colon-Otero,
Georgene Schroeder,
Curtis A. Hanson,
Gordon W. Dewald, and
Scott H. Kaufmann
From the Mayo Clinic, Rochester, MN; the Mayo Clinic,
Scottsdale, AZ; and the Mayo Clinic, Jacksonville, FL.
 |
Abstract |
In a phase 2 study, 23 patients with myelofibrosis with myeloid
metaplasia were treated with imatinib mesylate at a constant dose of 400 mg/d. Treatment was held in 16 patients (70%), after 1 to
12 weeks, because of side effects (neutropenia, 6 patients; musculoskeletal pain, 5 patients; thrombocytosis, 4 patients; edema, 3 patients; diarrhea and hyperbilirubinemia, 1 patient). Including
patients in whom retreatment at a reduced dose was possible, 11 patients (48%) were able to continue treatment beyond 3 months. None
of the patients experienced a response in anemia, and only 2 had
partial responses in splenomegaly. A greater than 50% increase in
platelet count was documented in 11 (48%) patients, but not in those
with baseline platelet counts of less than 100 × 109/L.
In vitro, imatinib mesylate caused variable degrees of growth suppression of myeloid and erythroid progenitors that unfortunately did
not translate into clinical benefit.
(Blood. 2002;99:3854-3856)
© 2002 by The American Society of Hematology.
| |
Introduction |
Myelofibrosis with myeloid metaplasia (MMM)
is a clonal stem cell disorder that is characterized by anemia, marked
splenomegaly, bone marrow fibrosis, and extramedullary
hematopoiesis.1 Median survival time is estimated at 5 years, and causes of death include transformation to acute myeloid
leukemia and consequences of progressive cytopenia and cachexia.
Conventional treatment provides symptomatic improvement in less
than one third of the patients and does not improve survival.
Promising investigational treatments include allogeneic hematopoietic
stem cell transplantation,2 autologous hematopoietic stem
cell transplantation,3 and drug therapy with
thalidomide4 or etanercept.5
Although the clonal nature of MMM is well established, the
pathogenesis of the florid bone marrow stromal reaction that includes collagen fibrosis, neo-angiogenesis,6 and osteosclerosis
is poorly understood. Current information suggests a pivotal role for
megakaryocyte-monocyte-derived cytokines, such as platelet-derived growth factor (PDGF), transforming growth factor- , and basic fibroblast growth factor, all of which are angiogenic and
fibrogenic.7 This cytokine-mediated bone marrow stromal
reaction may contribute to clinical phenotype and disease progression.
Imatinib mesylate is an orally bioavailable, 2-phenylaminopyrimidine
derivative that inhibits bcr/abl and related kinases.8 This drug has resulted in impressive hematologic and cytogenetic response rates in chronic-phase chronic myeloid leukemia.9 In vitro, imatinib mesylate inhibits the tyrosine kinase activities of
c-kit,10 ARG kinase,11 and
the PDGF receptor.12 In addition, imatinib mesylate
inhibits c-kit or PDGF receptor-dependent cell proliferation ex vivo and in vivo.13,14 Because PDGF and
c-kit15 have been implicated in the pathogenesis
of MMM, we evaluated the efficacy of imatinib mesylate in this disorder.
| |
Study design |
Previously published criteria were used for the diagnosis of
MMM.1,16 In addition to a pretreatment history and
physical examination, all study patients underwent pretreatment bone
marrow examination with cytogenetic and fluorescence in situ
hybridization studies. Oral imatinib mesylate was administered as
single-agent therapy according to a protocol approved by the Mayo
Clinic Institutional Review Board. All patients were started at a dose
of 400 mg/d. The National Cancer Institute-designed Common Toxicity
Criteria Version 2.0 were used to grade toxicity. Imatinib mesylate was held in the event of grade 3 or greater toxicity in neutropenia or
thrombocytopenia and grade 2 or greater toxicity in other parameters. On complete resolution of side effects, the drug was restarted at 200 mg/d. Recurrence of side effects at the reduced drug dose level
required withdrawal from the study.
The effects of imatinib mesylate on peripheral blood myeloid and
erythroid colony formation were evaluated in 19 of the 23 study
patients. Twenty milliliters peripheral blood (in EDTA) was obtained
from each patient before starting protocol treatment. Peripheral blood
mononuclear cells (PBMCs) were obtained through Ficoll-Hypaque density
centrifugation, washed in Dulbecco phosphate-buffered saline, and
resuspended in Iscoves modified Dulbecco medium. Isolated PBMCs were
then plated in growth factor-containing methylcellulose medium
(Methocult; StemCell Technologies; Vancouver, BC, Canada) in diluent
(0.1% dimethyl sulfoxide) containing 0, 3.125, 6.25, 12.5, or 25 µM
imatinib mesylate. After incubation for 14 days at 37°C in 5%
CO2, myeloid (CFU-GM) and erythroid (CFU-E, BFU-E) colonies
were counted by light microscopy using morphologic criteria established
by the manufacturer.
| |
Results and discussion |
Between May and October 2001, 23 patients (median age, 63 years; range, 37-78 years) with MMM were treated with imatinib mesylate at an initial dose of 400 mg/d. Table 1
outlines the pretreatment clinical and laboratory characteristics of
the patients. Seven patients were in a high-risk prognostic
category,17 9 were red blood cell transfusion-dependent,
11 had substantial constitutional symptoms, and 8 had been previously
treated with chemotherapy. None of the patients underwent splenectomy,
and the median palpable spleen size was 10 cm (range, 0-25 cm) below
the left costal margin. Fifteen (65%) patients had clonal cytogenetic
abnormalities. Fluorescence in situ hybridization studies did not
reveal an abnormal bcr/abl fusion signal in any patient.
Initial treatment with imatinib mesylate at 400 mg/d was held in 16 (70%) patients after 1 to 12 weeks because of side effects. Severe to
moderate neutropenia (absolute neutrophil count less than
1 × 109/L) occurred in 6 patients at a median of 25 days
(range, 15-75 days) from the initiation of treatment. Interestingly,
this side effect was observed in 6 of 10 patients with pretreatment
white blood cell counts (WBCs) of less than 5 × 109/L
but not in any of 13 patients with baseline WBCs of more than 5 × 109/L. Drug-induced neutropenia resolved in all
patients after treatment discontinuation. In contrast to CML, in which
thrombocytopenia is observed with imatinib mesylate,9 a
greater than 50% increase in platelet count was documented in 11 (48%) patients. Of these patients, 4 had thrombocytosis, with platelet
counts (× 109/L) increasing from 436 to 1086 in patient
2, 246 to 610 in patient 4, 848 to 1517 in patient 12, and 343 to 604 in patient 20. Unfortunately, none of the platelet increases occurred
in patients with pretreatment platelet counts below 100. In addition to
these hematologic side effects, nonhematologic side effects included
limb pain or exacerbation of pre-existing joint and muscle pain
(5 patients [patients 7, 15, 16, 18, 22]), peripheral edema
(3 patients [patients 3, 12, 13]), diarrhea (1 patient [patient
6]), and hyperbilirubinemia (1 patient [patient 6]). Fluid retention
and musculoskeletal pain occurred in only those patients with a history
of the same.
Protocol treatment was restarted at the reduced dose of 200 mg/d in 12 of the 16 patients whose treatment was held because of side effects.
The aforementioned side effects recurred and necessitated permanent
cessation of treatment in 9 patients. Overall, 11 (48%) patients,
including those in whom treatment rechallenge at 50% dose reduction
was possible, were able to continue treatment beyond 3 months (7 at 400 mg/d and 4 at 200 mg/d). Of these, 5 patients discontinued treatment
after 3 months because of side effects or personal decision. The
remaining 6 patients either have completed the scheduled 6 months of
treatment or are currently on therapy (3 patients in each group). To
date, none of the patients has experienced a response in anemia, and
only 2 patients have obtained a greater than 50% reduction in spleen
size (patients 4 and 10). Posttreatment bone marrow specimens were
available in 5 patients and showed no change from pretreatment findings.
To determine whether the hematologic side effects of imatinib mesylate
therapy were predicted from in vitro assays, we examined the effects of
imatinib mesylate on colony formation by circulating myeloid (Figure
1A) or erythroid (Figure 1B) progenitor
cells. As a basis for comparison, the peak and trough imatinib mesylate concentrations are estimated to be 4.6 and 1.5 µM, respectively, in
patients receiving 400 mg/d.9 In these assays, the drug demonstrated variable degrees of growth suppression of myeloid and
erythroid progenitors that were more pronounced at higher than
therapeutic concentrations. There was no correlation between in vitro
drug activity and in vivo clinical effects.
View larger version (39K):
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| Figure 1.
Effects of imatinib mesylate on colony formation.
Ex vivo effects of imatinib mesylate on the growth of myeloid (CFU-GM)
and erythroid (BFU-E + CFU-E) progenitors from the peripheral
blood of 19 of 23 study patients with MMM.
|
|
The current study reveals a high incidence of imatinib mesylate
toxicity in MMM and identifies a patient population at risk for
specific side effects. The prevalence of side effects and the strict
protocol requirements may have masked potential activity at higher dose
levels. The observed effect of the drug on platelet count was
inconsistent with the stimulatory effect of PDGF on bone marrow stromal
production of thrombopoietin18 and the expansion of
megakaryocyte progenitors.19 Unfortunately, these effects of imatinib mesylate were not accompanied by any discernible clinical benefit. However, the current study does not rule out the possibility of a favorable drug effect in the context of longer treatment or
imatinib mesylate-based combination therapy.
| |
Footnotes |
Submitted December 3, 2001; accepted January 10, 2002.
Prepublished
online as Blood First Edition Paper, April 17, 2002; DOI
10.1182/blood-2001-12-0154.
Supported in part by Novartis Pharmaceuticals.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Ayalew Tefferi, Division of Hematology, Mayo
Clinic, 200 First St SW, Rochester, MN 55905; e-mail:
tefferi.ayalew{at}mayo.edu.
| |
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Top
Abstract
Introduction