Toxicité hématologique des chimiothérapies - afphb.be ?· Toxicité hématologique des chimiothérapies…

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<ul><li><p>Toxicit hmatologique des chimiothrapies</p><p>Dr G. Vanstraelen</p><p>Service dhmatologieCHR Verviers East Belgium</p></li><li><p>Chimiothrapie</p><p>ADN Systme rplicatif cellulaire</p><p>Tissus renouvellementrapide, dont le systmehmatopotique</p></li><li><p>Cintique des cellules sanguines priphriques</p><p> Granulocytes: 6 heures Plaquettes: 10 jours Hmaties: 120 jours </p><p>temps</p><p>leucopnie thrombopnie anmie</p></li><li><p>Physiopathologie</p><p>earlier and lesssevere myelosuppres</p><p>more toxic to maturebut still dividing progenitothan to more primitive and</p><p>mitotically active cells</p><p>Antimetabolites</p><p>delayed and profoumyelosuppression</p><p>not cell cycle dependenactive to primitive stem c</p><p>that have minimal mitotactivity</p><p>Alkylating agents</p><p>Chemotherapy age</p></li><li><p>Pharmacogenetics</p><p> Pharmacogenetics may influence the development of hematologic toxicity</p><p> Metabolic processes for drug inactivation are polymorphic</p><p> Ex: polymorphic deficiency of dihydropyrimidine dehydrogenase results in increased toxicity of 5-FU, including hematologic toxicity</p></li><li><p>A few chemotherapeuty agents result in virtually no myelosuppression</p><p> Bleomycin L-asparaginase Vincristine streptozotocine</p></li><li><p>Modifying the drug administration schedule can reduce the bone marrow toxicity (1)</p><p>5-FU</p><p>IV bolus injection:dose-limiting toxicity:bone marrow suppression</p><p>IV protracted infusion:dose-limiting toxicities:mucositis &amp; hand-and-footsyndrome; myelosuppressionoccurs rarely</p></li><li><p> Neutropnie Risque infectieux</p><p> Anmie Asthnie, dyspne</p><p> Thrombopnie Hmorragie</p></li><li><p>Grade Leucocytes (103/mm3)PNN </p><p>(103/mm3)Lymphocytes(103/mm3) Hb (gr/dl)</p><p>Plaquettes (103/mm3)</p><p>0 &gt;= 4,0 &gt;= 2,0 &gt;= 2,0 N N</p><p>1 3,0 - 3,9 1,5 - 1,9 1,5 - 1,9 10,0 - N 75,0 - N</p><p>2 2,0 - 2,9 1,0 - 1,4 1,0 - 1,4 8,0 - 9,9 50,0 - 74,9</p><p>3 1,0 - 1,9 0,5 - 0,9 0,5 - 0,9 6,5 - 7,9 25,0 - 49,9</p><p>4 &lt; 1,0 </p></li><li><p>Neutropnie</p><p> la neutropnie compromet la rponse inflammatoire linfection, </p><p> en rduisant les signes et symptmes de linfection ( pas de PNN = pas de pus = pas de foyer ) elle attnue la prsentation clinique ( simple fivre),</p><p> malgr le risque de choc septique !</p></li><li><p>Risk-models for predicting chemotherapy-induced neutropenia.</p><p>Lyman et al. Oncologist 2005;10:427-37.</p></li><li><p>Risk of first episode of febrile neutropenia in patients with non-Hodgkins lymphoma treated with CHOP chemotherapy.</p><p>Lyman et al. Oncologist 2005;10:427-37.</p></li><li><p> 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: </p><p>Chimiothrapie Mylosuppressive</p><p>Neutropnie Fbrile (NF)Rductions de dose et dlai </p><p>dadministration de la chimiothrapie</p><p>Diminution de lIntensitDose Relative (RDI)</p><p>Infections et hospitalisations prolonges</p><p>Neutropnie</p><p>Impact sur la survie</p><p>Consquences ngatives sur la survie</p><p>Chimiothrapie moins effiicace avec consequences ngatives </p><p>sur la survie long terme</p><p>Effets Directs de la NeutropnieFbrile</p><p>Effets Indirects </p><p>sur lefficacit</p><p>du traitement</p><p>NeutropNeutropnienie</p><p>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. </p></li><li><p>NeutropNeutropnienie La NF induite par la chimiothrapie rduit la probabilit de survie</p><p> Pour les patients sous chimiothrapie, la rduction de lintensit de la dose diminue la probabilit de survie: </p><p>Prob</p><p>abilit</p><p>de su</p><p>rvie</p><p>Suivi (mois)</p><p>Patients sans NFPatients avec NF</p><p>Mortalit prcoce chez les patients avec ou sans NF </p><p>Prob</p><p>abilit</p><p>de s</p><p>urvie</p><p>Temps aprs la chimiothrapie par CHOP21 (ans)</p><p>Prob</p><p>abilit</p><p>de s</p><p>urvie</p><p>Temps aprs la chimiothrapie (ans)</p><p>Cancer du seinLymphome non-Hodgkinien</p><p>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</p><p>ARDI (p=0,002)ARDI (p=0,002)</p><p>RDI (p=0,0029)RDI (p=0,0029)</p></li><li><p>Diminution de la </p><p>dure de NS</p><p>100,000</p><p>10,000</p><p>1,000</p><p>100</p><p>500</p><p>100 4 8 12 16 20 24</p><p>Jour (cycle 1)</p><p>filgrastim</p><p>placebo</p><p>Rcupration rapide de lANC*</p><p>Nadir rduit</p><p>Neutropnie svre (SN) ANC &lt; 500 (x 106/L)</p><p>chimiotherapieJours 13</p><p>Initiation filgrastim/placebo</p><p> Lutilisation de G-CSF rduit le dure des pisodes de neutropnie svre (NS) et rduit le nadir: </p><p>Num</p><p>rat</p><p>ion </p><p>abso</p><p>lue </p><p>de </p><p>neut</p><p>roph</p><p>iles </p><p>(x </p><p>106 /</p><p>L)</p><p>Facteurs de Facteurs de croissancecroissance</p><p>Crawford J, et al. N Engl J Med 1991;325:164-170. *ANC: Numeration absolue de neutrophile</p></li><li><p>Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of </p><p>randomized controlled trials.</p><p>Clark et al. J Clin Oncol 2005;23:4198-214.Overall mortality</p></li><li><p>Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of </p><p>randomized controlled trials.</p><p>Clark et al. J Clin Oncol 2005;23:4198-214.Infection-related mortality</p></li><li><p>Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of </p><p>randomized controlled trials.</p><p>Clark et al. J Clin Oncol 2005;23:4198-214.Lenght of hospitalisation</p></li><li><p>Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of </p><p>randomized controlled trials.</p><p>Clark et al. J Clin Oncol 2005;23:4198-214.Time to neutrophil recovery</p></li><li><p>NCCN - National Comprehensive Cancer Network -</p><p>Myeloid Growth Factors in Cancer Treatment -version 1.2005</p><p> The NCCN panel members recommend the routine use of CSFs for high-risk (&gt;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.</p><p>(www.NCCN.org)</p></li><li><p>NCCN - Myeloid growth factors guidelines</p><p>CSF</p><p>High&gt; 20 %</p><p>Consider CS</p><p>Intermediat10 - 20 %</p><p>no CSF</p><p>Low&lt; 10 %</p><p>Risk of FN</p></li><li><p>Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas.</p><p>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.</p><p>Cullen et al. NEJM 2005;353:988-98.</p><p>levofloxacin placebo pn 781 784</p><p>1st cycle-FN (%) 3,5 7,9 </p></li><li><p>A risk model for thrombocytopenia requiring platelet transfusion after cytotoxic chemotherapy.</p><p> Cohort of the 1,051 patients (CLB 1996) treated with chemotherapy In univariate analysis:</p><p> performance status (PS) greater than 1, platelet count less than 150,000/L at day 1 (d1) before the initiation of </p><p>chemotherapy, d1 lymphocyte count </p></li></ul>

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