Toxicité hématologique des chimiothérapies - afphb.be .Toxicité hématologique des chimiothérapies

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  • Toxicit hmatologique des chimiothrapies

    Dr G. Vanstraelen

    Service dhmatologieCHR Verviers East Belgium

  • Chimiothrapie

    ADN Systme rplicatif cellulaire

    Tissus renouvellementrapide, dont le systmehmatopotique

  • Cintique des cellules sanguines priphriques

    Granulocytes: 6 heures Plaquettes: 10 jours Hmaties: 120 jours

    temps

    leucopnie thrombopnie anmie

  • 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

  • Neutropnie Risque infectieux

    Anmie Asthnie, dyspne

    Thrombopnie Hmorragie

  • 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

  • Neutropnie

    la neutropnie compromet la rponse inflammatoire linfection,

    en rduisant les signes et symptmes de linfection ( pas de PNN = pas de pus = pas de foyer ) elle attnue la prsentation clinique ( simple fivre),

    malgr 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-Hodgkins lymphoma treated with CHOP chemotherapy.

    Lyman et al. Oncologist 2005;10:427-37.

  • La neutropnie peut tre induite par la chimiothrapie, et entrane alors des complications court terme et long terme La neutropnie peut rduire la survie des patients:

    Chimiothrapie Mylosuppressive

    Neutropnie Fbrile (NF)Rductions de dose et dlai

    dadministration de la chimiothrapie

    Diminution de lIntensitDose Relative (RDI)

    Infections et hospitalisations prolonges

    Neutropnie

    Impact sur la survie

    Consquences ngatives sur la survie

    Chimiothrapie moins effiicace avec consequences ngatives

    sur la survie long terme

    Effets Directs de la NeutropnieFbrile

    Effets Indirects

    sur lefficacit

    du traitement

    NeutropNeutropnienie

    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.

  • NeutropNeutropnienie La NF induite par la chimiothrapie rduit la probabilit de survie

    Pour les patients sous chimiothrapie, la rduction de lintensit de la dose diminue la probabilit de survie:

    Prob

    abilit

    de su

    rvie

    Suivi (mois)

    Patients sans NFPatients avec NF

    Mortalit prcoce chez les patients avec ou sans NF

    Prob

    abilit

    de s

    urvie

    Temps aprs la chimiothrapie par CHOP21 (ans)

    Prob

    abilit

    de s

    urvie

    Temps aprs la chimiothrapie (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

    dure de NS

    100,000

    10,000

    1,000

    100

    500

    100 4 8 12 16 20 24

    Jour (cycle 1)

    filgrastim

    placebo

    Rcupration rapide de lANC*

    Nadir rduit

    Neutropnie svre (SN) ANC < 500 (x 106/L)

    chimiotherapieJours 13

    Initiation filgrastim/placebo

    Lutilisation de G-CSF rduit le dure des pisodes de neutropnie svre (NS) et rduit le nadir:

    Num

    rat

    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

  • 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/L at day 1 (d1) before the initiation of

    chemotherapy, d1 lymphocyte count