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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 405-410
A Risk Model for Thrombocytopenia Requiring Platelet Transfusion
After Cytotoxic Chemotherapy
By
J.Y. Blay,
A. Le Cesne,
C. Mermet,
C. Maugard,
A. Ravaud,
C. Chevreau,
C. Sebban,
J.-P. Guastalla,
P. Biron, and
I. Ray-Coquard for the ELYPSE1 Study Group
From the Centre L. Bérard, Lyon, France; the Institut Gustave
Roussy, Villejuif, France; Clinique Sainte-Marie,
Chambéry, France; the Centre R. Gauducheau, Nantes, France; the
Fondation Bergonié, Bordeaux, France; and the Centre Cl. Regaud,
Toulouse, France. For the Elypse Study group, see Appendix for
investigator list.
 |
ABSTRACT |
Severe thrombocytopenia is a rare but life-threatening
side effect of cytotoxic chemotherapy for which risk factors are not well known. Our objective was to delineate a risk model for
chemotherapy-induced thrombocytopenia requiring platelet transfusions
in cancer patients. Univariate and multivariate analysis of risk
factors for chemotherapy-induced thrombocytopenia requiring platelet
transfusions were performed on the cohort of the 1,051 patients
(CLB 1996) treated with chemotherapy in the Department
of Medicine of the Centre Léon Bérard (CLB) in 1996. In
univariate analysis, performance status (PS) greater than 1, platelet
count less than 150,000/µL at day 1 (d1) before the initiation of
chemotherapy, d1 lymphocyte count  700/µL, d1 polymorphonuclear
leukocyte count less than 1,500/µL, and the type of chemotherapy
(high risk v others) were significantly associated (P < .01) with an increased risk of severe
thrombocytopenia requiring platelet transfusions. Using logistic
regression, d1 platelet count less than 150,000/µL (odds ratio
[OR], 4.3; 95% confidence interval [CI], 1.9 to 9.6), d1
lymphocyte counts 700/µL (OR, 3.37; 95% CI, 1.77 to 6.4), the
type of chemotherapy (OR, 3.38; 95% CI, 1.77 to 6.4), and PS greater
than 1 (OR, 2.23; 95% CI, 1.22 to 4.1) were identified as independent
risk factors for platelet transfusions. The observed incidences of
platelet transfusions were 45%, 13%, 7%, and 1.5% for patients with
 3, 2, 1, or 0 risk factors, respectively. This model was then tested
in 3 groups of patients treated with chemotherapy used as validation
samples: (1) the series of 340 patients treated in the CLB in the first 6 months of 1997, (2) the prospective multicentric cohort of 321 patients of the ELYPSE 1 study, and (3) the series of 149 patients with
non-Hodgkin's lymphoma treated in the CLB within prospective phase III
trials (1987 to 1995). In these 3 groups, the observed incidences of
platelet transfusions in the above-defined risk groups did not differ
significantly (P > .1) from those calculated in the model.
This risk index could be useful to identify patients at high risk for
chemotherapy-induced thrombocytopenia requiring platelet transfusions.
| |
INTRODUCTION |
SEVERE THROMBOCYTOPENIA is a rare but
life-threatening side effect of cytotoxic chemotherapy.1,2
Until now, the management of severe thrombocytopenia has been curative,
relying on platelet transfusions when platelet counts are less than
20,000/µL and/or in case of bleeding.3,4 There
are several drawbacks for platelet transfusions, in particular the risk
of viral transmission and resistance to platelet transfusions that
occurs in 0% to 24% of patients requiring frequent platelet
transfusions.5-7
Interleukin-11 (IL-11), thrombopoietin/megakaryocyte growth and
development factor (MGDF), IL-1, IL-3, and
IL-6 have been reported to be capable of increasing platelet
count, reducing platelet nadir, or decreasing the duration of
platelet transfusions, therefore opening the possibility of a
prophylaxis of severe thrombocytopenia in the near
future.8-14 However, the incidence of platelet transfusions is low in a general population of cancer patients treated with conventional chemotherapy.2 It would therefore be useful to identify risk factors for platelet transfusions to select candidate patients for the prophylactic administration of thrombopoietic growth
factors.
We report here a retrospective study of risk factors for
chemotherapy-induced thrombocytopenia requiring platelet transfusions in the cohort of cancer patients treated in the Department of Medicine
of the Centre Léon Bérard in 1996. A risk model for platelet transfusions was delineated and then validated in 3 distinct series of patients.
| |
PATIENTS AND METHODS |
Criteria for patients selection.
The method used in this study was to delineate a risk index for severe
thrombocytopenia requiring platelet transfusions in a retrospective
series and to validate this index in 3 distinct series of patients.
Four distinct cohorts of patients are thus considered in this study.
In all 4 series, the selection criteria for the patients were identical
and as follows. Patients were to be more than 17 years of age. Patients
with leukemia, in particular chronic lymphocytic leukemia, were
excluded, because of the possible contamination of peripheral blood by
malignant cells. Patients receiving chemotherapy regimens administered
daily were excluded. Patients were not to be treated concomitantly with
cytokines (ie, interferon, IL-2, or others). Massive chemotherapy
regimens, ie, regimens requiring bone marrow or peripheral blood stem
cell reinjection, were excluded. Each patient was analyzed for only 1 course of chemotherapy in the 4 series.
The retrospective group of 1996 (CLB 1996) comprised all patients
treated with chemotherapy in the Department of Medicine of the Centre
Léon Bérard in 1996. That year, 3,223 courses of
chemotherapy were administered to 1,116 patients matching the inclusion
criteria. Every patient was analyzed only for his first course of
chemotherapy administered in the Centre Léon Bérard in
1996. Histology, primary tumor site, chemotherapy regimen, sex, age,
performance status (PS), blood cell count at day 1 (d1) just
before the administration of chemotherapy, as well as platelet transfusions after the studied course were collected. Patients with
missing blood cell count at day 1 (n = 65) were excluded. Of the 1,116 patients, 1,051 (94%) were therefore analyzed
(Table 1). The risk model was established
in this retrospective series.
The risk model was then tested in 3 groups used as validation samples.
The first group (CLB 1997) is the retrospective series of 340 patients
treated in the Centre Léon Bérard during the first 6 months
of 1997 and who had not received chemotherapy in the Department of
Medicine of the Centre Léon Bérard in 1996. Every patient
was analyzed only for his first course of chemotherapy administered in
the Centre Léon Bérard in 1997. Only 312 of the 340 patients (92%) were included in the analysis because of missing data
on blood cell count at day 1 (n = 28).
The second group (ELYPSE 1) is a multicentric prospective series of 321 patients treated with conventional chemotherapy in both general
hospital (n = 13) and comprehensive cancer centers (n = 5): 84 patients
(26%) were treated in cancer centers and 237 (74%) in general
hospitals. Every participating physician had to include all his
consecutive patients for 1 month between November 1995 and September
1996. Only 295 of the 321 patients (92%) were analyzed because of
missing data for performance status (n = 24) or blood cell count at day
1 (n = 2). This series has been recently reported.15
The third group (NHL-CLB) is the cohort of 149 non-pretreated patients
with intermediate- or high-grade non-Hodgkin's lymphoma included in
prospective multicentric phase III of the GELA group who received a
first course of conventional chemotherapy regimen in the Centre
Léon Bérard between 1987 and 1995. There were no missing
data in this series and all patients were evaluated.
The characteristics of the patients in the 4 series are listed in the
Table 1.
Indications of platelet transfusions.
Platelet transfusions adminstered for chemotherapy-induced
thrombocytopenia within the 28 days after the course of chemotherapy was chosen as the end-point for this study. Criteria for platelet transfusions in the Centre Léon Bérard as well as for the
physicians who participated to the ELYPSE 1 series were platelet count
less than 20,000/µL or thrombocytopenia less than 50,000/µL with
coagulation disorders and/or heparin therapy and/or
with bleeding complications. Within the database, 4 patients with the
above-described inclusion criteria (all in the CLB 1996 series) were
not transfused with platelets, although they had platelet counts less
than 20,000/µL. In all 4 cases, this decision was made by the
physician because a rapid (<48 hours) death due to tumor progression
was expected (and indeed occurred). The model presented here was not
modified when these patients are considered as having had an event.
Chemotherapy regimens.
The chemotherapy regimens were separated in 2 subgroups according to
the doses and the type of drugs administered. The criteria high-risk
chemotherapy has been previously reported and refers to regimens
containing either greater than 90 mg/m2 doxorubicin,
greater than 90 mg/m2 epirubicin, greater than 100 mg/m2 cisplatin, greater than 9 g/m2
ifosfamide, greater than 1 g/m2 cyclophosphamide, greater
than 500 mg/m2 etoposide, or greater than 1 g/m2 cytarabine per course.15,16 The other
subgroup of regimens included all other chemotherapy regimens.
Statistical analysis.
Risk factors for platelet transfusions were tested in univariate and
multivariate analysis using the procedures of the SPSS 6.01 program
(1994; SPSS, Inc, Chicago, IL). The correlation between a clinical or a
biological parameter and the incidence of chemotherapy-induced thrombocytopenia requiring platelet transfusions was performed using
the  2 test or Fisher's exact test. A logistic
regression including the parameters studied in the univariate analysis
was performed using logistic program of SPSS. The forward regression
procedure was used with a P value less than .05 for entry. Risk
factors (eg, PS >1) and end-point (ie, platelet transfusions) were
considered 0 if absent and 1 if present. This multivariate analysis was
performed in the 1,051 patients of the CLB 1996 series. A risk model
was established using the independent risk factors identified in this multivariate analysis. This risk model was then tested on the 3 distinct cohorts of patients.
| |
RESULTS |
Univariate analysis.
Fifty-six of the 1,051 patients (5.3%) of the CLB 1996 series received
platelet transfusions because of severe thrombocytopenia within the 28 days after the administration of the course of cytotoxic chemotherapy.
In univariate analysis, platelet count less than 150,000/µL
immediately before the initiation of chemotherapy (d1), d1
polymorphonuclear leukocyte (PMN) count less than 1.500/µL, d1
lymphocyte count 700/µL, PS greater than 1, and the type of chemotherapy regimen (high risk v others) as previously defined (Patients and Methods) were found to be significantly correlated to the
risk of platelet transfusions (Table 2). In
contrast, age less than 60 years, sex, and number of previous courses
of chemotherapy were not significantly correlated to the incidence of
platelet transfusions (Table 2).
Multivariate analysis.
A logistic regression to identify independent risk factors for platelet
transfusions was performed among all the parameters tested in
univariate analysis. The parameters identified as independent risk
factors for platelet transfusions were PS greater than 1 (odds ratio
[OR], 2.23; 95% confidence interval [CI], 1.22 to 4.11), d1
platelet count less than 150,000/µL (OR, 4.30; 95% CI, 1.93 to
9.61), d1 lymphocyte count 700/µL (OR, 3.37; 95% CI, 1.77 to
6.44), and high-risk chemotherapy regimens (OR, 3.38; 95% CI, 1.77 to
6.46; Table 3).
Risk model.
To construct a simple algorithm for calculating the expected risk of
platelet transfusions for each patient, the parameters PS greater than
1, high-risk chemotherapy, d1 lymphocyte count 700/µL, and d1
platelet count less than 150,000/µL were all given an arbitrary risk
coefficient of 1. The risk index for a given patient was obtained by
summing the coefficients of these 4 risk factors and therefore ranged
from 0 to 4. For example, a patient with PS equal to 1, receiving a
non-high-risk chemotherapy regimen with d1 lymphocyte count 700
/µL and d1 platelet count less than 150,000/µL, has a risk index of
2. Because patients with 4 risk factors represented only 0.17% of
these patients (3 of 1,807), patients with 3 and 4 risk factors were
pooled; 4 risk groups of patients were thus defined
(Table 4). The calculated probability of
platelet transfusions was 44.5% (95% CI, 37.3% to 51.8%) in patients with 3 or 4 risk factors, 13% (95% CI, 10.1% to 16.8%) for
patients with 2 risk factors, 7% (95% CI, 4.9% to 9.9%) for patients with 1 risk factor only, and 1.5% (95% CI, 1.1% to 2.2%) for patients with none of these risk factors (Table 4).
Validation of the model.
This model was then tested in the 3 series of patients used as
validation samples (Table 4).
In the CLB 1997 series, 4.2% (13 of 312) of the patients received
platelet transfusions. The observed incidence of platelet transfusions
was significantly different (P < 10 5) in
patients with 3, 2, 1, or 0 risk factors (33.3%, 9.8%, 2.5%, and
1.5%, respectively; Table 4). A single patient had 4 risk factors and
received platelet transfusions.
In the ELYPSE 1 series, 3.3% (10 of 295) of the patients received
platelet transfusions. The observed incidence of platelet transfusions
was significantly different (P = .001) in patients with 3, 2, 1, or 0 risk factors (0%, 17%, 7%, and 1%, respectively; Table 4).
Of note, although none of the 2 patients with 3 risk factors were
transfused with platelets, their nadir of platelets were 25,000/µL
and 35,000/µL, respectively.
In the CLB-NHL series, 7.4% (11 of 149) of the patients received
platelet transfusions. The observed incidence of platelet transfusions
was significantly different (P < 105) in
patients with 3, 2, 1, or 0 risk factors (50%, 17%, 3%, and 0%,
respectively; Table 4).
The observed incidence of platelet transfusions in the 4 cohorts of
patients studied were not significantly different (56 of 1,051, v 13 of 312, v 10 of 295, v 11 of 149;
2 = 4.01, P = .25). The observed incidences of
platelet transfusions in risk group 3, 2, 1, or 0 were not
significantly different among the 4 series (2 = 2.09, P = .55 for patients with 3 risk factors; 2 = 1.04, P = .79 for patients with 2 risk factors;
2 = 5.77, P = .12 for patients with 1 risk
factor; and 2 = 0.85, P = .83 for patients with
no risk factor; Table 4).
Risk factors for patients not receiving high-risk chemotherapy.
Because it is well established that the risk of thrombocytopenia
correlates to the dose of chemotherapy, we asked whether this model
could be useful in the subgroup of patients who did not receive
high-risk chemotherapy as defined in this study. This subgroup
represented, respectively, 946, 220, 271, and 75 of the patients in the
CLB 1996, CLB 1997, Elypse 1, and NHL-CLB series. Forty-five patients
(4.7%) of the CLB 1996 series (4.7%) received platelet transfusions
because of severe thrombocytopenia. A multivariate analysis was
performed on this subgroup of 946 patients to identify independent risk
factors for severe thrombocytopenia requiring platelet transfusion in
these patients. Logistic regression again identified the same 3 independent risk factors for platelet transfusion: PS greater than 1 (OR, 2.14; 95% CI, 0.87 to 5.3), d1 platelet count less than
150,000/µL (OR, 4.3; 95% CI, 0.6 to 30), and d1 lymphocyte count
700/µL (OR, 3.15; 95% CI, 0.8 to 13). The observed incidences of
platelet transfusions in patients with 0, 1, 2, and 3 of these risk
factors (PS, lymphocyte counts, and platelet counts) were 1.5%, 8%,
13%, and 36%, respectively, in the CLB 1996 series. The observed
incidences of platelet transfusions in risk group 3, 2, 1, or 0 were
not significantly different among the 4 series (2 = 1.5, P = .46 for patients with 3 risk factors; 2 = 1.92, P = .58 for patients with 2 risk factors;
2 = 1.56, P = .66 for patients with 1 risk
factor; and 2 = 0.81, P = .84 for patients with
no risk factor). These results confirm that the general model described
in Table 4 is also efficient for patients not receiving high-risk
chemotherapy.
| |
DISCUSSION |
Severe thrombocytopenia induced by cytotoxic chemotherapy is associated
with a potential risk of toxic death due to bleeding and may require to
delay the administration of chemotherapy. The objective of the present
study was to identify risk factors for chemotherapy-induced
thrombocytopenia requiring platelet transfusions. The number of
platelet transfusions was chosen as the most relevant end-point,
because these patients could benefit the most of a prophylactic
treatment capable to prevent or reduce the incidence of severe
thrombocytopenia.
Little is known on the risk factors for platelet transfusions after
conventional chemotherapy. A search on the electronic database
(Medline) using the MESH terms platelet transfusions, thrombocytopenia,
chemotherapy, toxicity, and risk factors identified no report devoted
to the analysis of individual risk factors for severe thrombocytopenia
induced by conventional cytotoxic chemotherapy. Therefore, it was
chosen to select clinical and biological factors that were potentially
correlated to the incidence of hematological toxicity of chemotherapy
according to our previous studies (age, sex, PS, number of previous
courses, and blood cell counts).15,16 Day-5 lymphocyte
count 700/µL, a major risk factor for febrile neutropenia, was not
available in most patients; hence, the day-1 lymphocyte count
700/µL, which was less strongly correlated to hematological
toxicity in previous studies, was therefore tested.16
The risk model for chemotherapy-induced thrombocytopenia requiring
platelet transfusions was established on the retrospective cohort of
patients treated in the Department of Medicine of the Centre Léon
Bérard in 1996. Each patient was analyzed only for his first
course during the year. As expected, the incidence of platelet
transfusions was low in this series of patients treated with
conventional chemotherapy regimens (n = 56 [5.3%]). Four parameters
were found to have an independent prognostic value for platelet
transfusions, ie, platelet count less than 150,000/µL at d1,
lymphocyte count less than 700/µL at d1, high-risk chemotherapy regimens, and PS greater than 1. It is noteworthy that, when a logistic
regression was applied to all 3,223 chemotherapy courses administered
in the Department of Medicine of the CLB in 1996, the same independent
risk factors with a similar weight were identified, supporting the
validity of this model (data not shown). These results show that 2 categories of parameters influence the incidence of
chemotherapy-induced thrombocytopenia requiring platelet transfusions: (1) parameters reflecting clinical and biological status of patient (ie, PS and day-1 platelet and lymphocyte count) and (2) the type of
chemotherapy regimen (high-risk chemotherapy as defined in our previous
study).15,16 The relative weight of the independent risk
factors being not significantly different, a simple risk model was
established that delineates 4 risk groups with 0, 1, 2, and 3 of
these risk factors. Importantly, this model also proved to be efficient
to identify patients at high risk for severe thrombocytopenia requiring
platelet transfusion among the subgroup of patients not receiving
high-risk chemotherapy. Twenty-nine percent (5 of 17 among the 4 series) of patients not receiving high-risk chemotherapy but with all 3 other risk factors experienced severe thrombocytopenia requiring
platelet transfusion, a notably high incidence for patients receiving
conventional chemotherapy.
The cohort of high-risk patients (3 risk factors) represented less
than 3% of all patients in these 4 series and comprised 19% (17 of
90) of the patients who required platelet transfusions in the 4 series.
The intermediate-risk group (2 risk factors) with a 13% calculated
incidence of platelet transfusions comprised 29% (26 of 90) of the
patients transfused with platelets in the 4 series. Patients with a
risk index ranging from 2 to 4 included, therefore, 48% (43 of 90) of
the patients who require platelet transfusions after chemotherapy
administration in the 1,807 patients of the 4 series, although they
represented only 13% (239 of 1,807) of all patients.
A potential limit of this study is the heterogeneity of these series in
terms of disease types and chemotherapy regimens. Indeed, the CLB 1996 and CLB 1997 series included patients with similar clinical
characteristics. In contrast, the CLB-NHL series comprised only
patients with non-Hodgkin's lymphoma receiving their first course of
chemotherapy, and the ELYPSE 1 series was a multicentric prospective
cohort of patients. Despite the differences in the characteristics of
patients, the risk index proved efficient to distinguish patients with
a high risk of platelet transfusions. The reproducibility of the
results in the 3 groups used as validation samples as well as the large
number of patients analyzed (n = 1,807) suggest that the risk model may
be useful to identify patients at high risk for chemotherapy-induced
thrombocytopenia requiring platelet transfusions in the general
population of patients treated with conventional chemotherapy.
This model could distinguish a cohort of patients with such a high risk
of platelet transfusions that a prophylactic administration of a
platelet growth factor, such as MGDF or IL-11, could be both clinically
justified and cost-effective.13,14 Randomized phase III
studies could focus on the subgroup of high-risk patients (with or
without the subgroup of 2 risk factors) to evaluate the prophylactic
use of these platelet growth factors versus placebo.
| |
FOOTNOTES |
Submitted April 9, 1997;
accepted March 13, 1998.
Supported by a grant from Roche (Neuilly, France) and from the
Programme Hospitalier de Recherche Clinique (France).
Address reprint requests to J.Y. Blay, MD, Centre Léon
Bérard, 28, rue Laënnec-69008, Lyon, France; e-mail:
blay{at}lyon.fnclcc.fr.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors are indebted to Frederic Bouanchaud for his assistance.
| |
APPENDIX Investigator List for the ELYPSE 1 Study |
Dr Jean C. Balzon (CH, Saintes); Dr Jean-Yves Blay (CLB, Lyon); Dr A. Boutan-Laroze (CH, Argenteuil); Dr Jacques Brunot (Hôpital Desgenettes, Lyon); Dr Laurent Cany (Clinique de Francheville, Périgueux); Dr Capdeville (CH, Foix); Dr Y. Caudry (Clinique Tivoli, Bordeaux); Dr D. Celerier (CH, Bayonne); Dr Zahia Haddad/Dr Bruno Salles (CH, Châlon); Dr A. Le Cesne/Dr K. Fizazi (IGR, Villejuif); Dr M. Malet (CH, Pau); Dr Maugard (Centre R. Gauducheau, Nantes); Dr Mayeur (CH, A.Mignot, Le Chesnay); Dr Jean
Mermet (Clinique Sainte-Marie, Chambery); Dr B Mongodin/Dr M. Zouai
(CH, Montelimar); Dr Hubert Orfeuvre (CH, Bourg en Bresse); Dr
Pierre-Yves Peaud (CH, Valence); Dr Ravaud (Institut
Bergonié, Bordeaux); Dr D. Sevin (Polyclinique Ste
Marguerite, Auxerre); Dr Jean-Philippe Suchaud (CHG, Roanne); Dr Song
Vu Van (Lyon)
| |
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Abstract
Introduction
Abstract