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Toxicité hématologique des chimiothérapies
Dr G. Vanstraelen
Service d’hématologieCHR Verviers East Belgium
Chimiothérapie
ADN Système réplicatif cellulaire
Tissus à renouvellementrapide, dont le systèmehématopoïétique
Cinétique des cellules sanguines périphériques
• Granulocytes: 6 heures• Plaquettes: 10 jours• Hématies: 120 jours
temps
leucopénie thrombopénie anémie
Physiopathologie
earlier and lesssevere myelosuppres
more toxic to maturebut still dividing progenitothan to more primitive and
mitotically active cells
Antimetabolites
delayed and profoumyelosuppression
not cell cycle dependenactive to primitive stem c
that have minimal mitotactivity
Alkylating agents
Chemotherapy age
Pharmacogenetics
• Pharmacogenetics may influence the development of hematologic toxicity
• Metabolic processes for drug inactivation are polymorphic
• Ex: polymorphic deficiency of dihydropyrimidine dehydrogenase results in increased toxicity of 5-FU, including hematologic toxicity
A few chemotherapeuty agents result in virtually no myelosuppression
• Bleomycin• L-asparaginase• Vincristine• streptozotocine
Modifying the drug administration schedule can reduce the bone marrow toxicity (1)
5-FU
IV bolus injection:dose-limiting toxicity:bone marrow suppression
IV protracted infusion:dose-limiting toxicities:mucositis & hand-and-footsyndrome; myelosuppressionoccurs rarely
Grade Leucocytes (103/mm3)
PNN (103/mm3)
Lymphocytes(103/mm3) Hb (gr/dl) Plaquettes
(103/mm3)
0 >= 4,0 >= 2,0 >= 2,0 N N
1 3,0 - 3,9 1,5 - 1,9 1,5 - 1,9 10,0 - N 75,0 - N
2 2,0 - 2,9 1,0 - 1,4 1,0 - 1,4 8,0 - 9,9 50,0 - 74,9
3 1,0 - 1,9 0,5 - 0,9 0,5 - 0,9 6,5 - 7,9 25,0 - 49,9
4 < 1,0 <0,5 <0,5 < 6,5 < 25,0
Neutropénie
• la neutropénie compromet la réponse inflammatoire à l’infection,
• en réduisant les signes et symptômes de l’infection (« pas de PNN = pas de pus = pas de foyer ») elle atténue la présentation clinique (« simple fièvre),
• malgré le risque de choc septique !
Risk-models for predicting chemotherapy-induced neutropenia.
Lyman et al. Oncologist 2005;10:427-37.
Risk of first episode of febrile neutropenia in patients with non-Hodgkin’s lymphoma treated with CHOP chemotherapy.
Lyman et al. Oncologist 2005;10:427-37.
La neutropénie peut être induite par la chimiothérapie, et entraîne alors des complications à court terme et à long terme La neutropénie peut réduire la survie des patients:
Chimiothérapie Myélosuppressive
Neutropénie Fébrile (NF)Réductions de dose et délai
d’administration de la chimiothérapie
Diminution de l’IntensitéDose Relative (RDI)
Infections et hospitalisations prolongées
Neutropénie
Impact sur la survie
Conséquences négatives sur la survie
Chimiothérapie moins effiicace avec consequences négatives
sur la survie à long terme
Effets Directs de la NeutropénieFébrile
Effets Indirects
sur l’efficacité
du traitement
NeutropNeutropéénienie
Kuderer NM, et al. Cancer 2006;106:2258-66. Bosly A, et al. Ann Hematol 2008;87:277-83. Chirivella I, et al. Breast Cancer Res Treat 2009;114:479-84.
NeutropNeutropéénienie La NF induite par la chimiothérapie réduit la probabilité de survie
Pour les patients sous chimiothérapie, la réduction de l’intensité de la dose diminue la probabilité de survie:
Prob
abilité
de su
rvie
Suivi (mois)
Patients sans NFPatients avec NF
Mortalité précoce chez les patients avec ou sans NF
Prob
abilité
de s
urvie
Temps après la chimiothérapie par CHOP21 (ans)
Prob
abilité
de s
urvie
Temps après la chimiothérapie (ans)
Cancer du seinLymphome non-Hodgkinien
Lyman GH et al. Cancer 2010; 116(23):5555-5563, Bosly A. et al. Ann Haematol 2008;87:277-283, Chirivella I et al. Breast Cancer Res Treat. 2009; 114(3):479-484
ARDI (p=0,002)ARDI (p=0,002)
RDI (p=0,0029)RDI (p=0,0029)
Diminution de la
durée de NS
100,000
10,000
1,000
100
500
100 4 8 12 16 20 24
Jour (cycle 1)
filgrastim
placebo
Récupération rapide de l’ANC*
Nadir réduit
Neutropénie sévère (SN) ANC < 500 (x 106/L)
chimiotherapieJours 1–3
Initiation filgrastim/placebo
L’utilisation de G-CSF réduit le durée des épisodes de neutropénie sévère (NS) et réduit le nadir:
Num
érat
ion
abso
lue
de
neut
roph
iles
(x
106 /
L)
Facteurs de Facteurs de croissancecroissance
Crawford J, et al. N Engl J Med 1991;325:164-170. *ANC: Numeration absolue de neutrophile
Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of
randomized controlled trials.
Clark et al. J Clin Oncol 2005;23:4198-214.Overall mortality
Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of
randomized controlled trials.
Clark et al. J Clin Oncol 2005;23:4198-214.Infection-related mortality
Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of
randomized controlled trials.
Clark et al. J Clin Oncol 2005;23:4198-214.Lenght of hospitalisation
Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of
randomized controlled trials.
Clark et al. J Clin Oncol 2005;23:4198-214.Time to neutrophil recovery
NCCN - National Comprehensive Cancer Network -
Myeloid Growth Factors in Cancer Treatment -version 1.2005
• The NCCN panel members recommend the routine use of CSFs for high-risk (>20%) patients to prevent the development of FN in patients receiving treatment with curative intent, adjuvant therapy, or treatment expected to prolong survival or to improve QOL.
(www.NCCN.org)
NCCN - Myeloid growth factors guidelines
CSF
High> 20 %
Consider CS
Intermediat10 - 20 %
no CSF
Low< 10 %
Risk of FN
Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas.
Patients who were receiving cyclic chemotherapy for solid tumors or lymphoma and who were at risk for temporary, severe neutropenia (fewer than 500 neutrophils per cubic millimeter).Patients were randomly assigned to receive either 500 mg of levofloxacin once daily or matching placebo for seven days during the expected neutropenic period.
Cullen et al. NEJM 2005;353:988-98.
levofloxacin placebo pn 781 784
1st cycle-FN (%) 3,5 7,9 <0,001
at least 1 FN (%) 10,8 15,2 0,01
probable infection (%) 34,2 41,5 0,004hospitalisation (%) 15,7 21,6 0,004
severe infection (%) 1,0 2,0 0,15
N infection related deaths 4 4
A risk model for thrombocytopenia requiring platelet transfusion after cytotoxic chemotherapy.
• Cohort of the 1,051 patients (CLB 1996) treated with chemotherapy • 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 (OR, 4.3; 95% 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:
Blay et al. Blood 1998;92:405-10.