Toxicitй hйmatologique des chimiothйrapies

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Toxicité hématologique des chimiothérapies

• Pr Jean Trédaniel
• Unité de cancérologie thoracique
• Hôpital Saint-Louis

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Chimiothérapie
Système réplicatif cellulaire
ADN
Tissus à renouvellement rapide, dont le
système hématopoïétique
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Cinétique des cellules sanguines périphériques

• Granulocytes 6 heures
• Plaquettes 10 jours
• Hématies 120 jours

leucopénie
thrombopénie
anémie
temps
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Physiopathologie
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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

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A few chemotherapeuty agents result in virtually
no myelosuppression

• Bleomycin
• L-asparaginase
• Vincristine
• streptozotocine

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Modifying the drug administration schedule can
reduce the bone marrow toxicity (1)
5-FU
IV protracted infusion dose-limiting
toxicities mucositis hand-and-foot syndrome
myelosuppression occurs rarely
IV bolus injection dose-limiting toxicity bone
marrow suppression
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Modifying the drug administration schedule can
reduce the bone marrow toxicity (2)

• The myelosuppressive effects of paclitaxel
  consist primarily of granulocytopenia, with an
  increase in the incidence and severity of
  neutropenia observed with increasing doses,
• Identical doses of paclitaxel are markedly less
  myelosuppressive when delivered by 3-hr than by
  24-hr infusion,
• Neutropenia is not related to paclitaxels peak
  concentration or to the AUC but rather to the
  duration that the plasma concentration is aboce a
  certain threshold (gt0,05 µmol/L).

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• Neutropénie
• Risque infectieux
• Anémie
• Asthénie, dyspnée
• Thrombopénie
• Hémorragie

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Neutropénie

• la neutropénie compromet la réponse inflammatoire
  à linfection,
• en réduisant les signes et symptômes de
  linfection ( pas de PNN pas de pus pas de
  foyer ) elle atténue la présentation clinique
  ( simple fièvre),
• malgré le risque de choc septique !

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Neutropénie facteurs de risque dépendants du
patient

• Hémopathie maligne (atteinte intrinsèque du
  système hématopoïétique intensité des
  chimiothérapies) gt tumeur solide
• Âge physiologique élevé
• Taux de LDH élevé
• Fièvre élevée, hypotension à ladmission
• Lymphopénie, hypoalbuminémie
• Conséquence hématologique de la première cure de
  chimiothérapie

Crawford et al. Cancer 2004100228-37.
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Early lymphopenia after cytotoxic chemotherapy as
a risk factor for febrile neutropenia.

• Cohorte rétrospective de 112 patients traités
  consécutivement, avec des régimes divers de
  chimiothérapie
• 2 facteurs de risque identifiés
• taux de lymphocytes lt 700/µl à J5
• type de la chimiothérapie (forte dose versus
  autres)
• Modèle avec 0,1 ou 2 facteurs de risque
• Validation du modèle
• Série du Centre Léon Bérard (Lyon) 3, 19 , 67
• Série de lIGR 6, 19, 75
• Patients traités par ACVBP ( un facteur de
  risque) au CLB 1988-92 33, 72.

Blay et al. J Clin Oncol 199614636-43.
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Incidence of Life-Threatening Neutropenia,
Neutropenic Infection, and Death in Older
Individuals With Large-Cell Non-Hodgkins
Lymphomas Treated With CHOP-Like Regimens
Balducci. J Clin Oncol 2001191583-5.
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Risk-models for predicting chemotherapy-induced
neutropenia.
Lyman et al. Oncologist 200510427-37.
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Risk factors for chemotherapy induced neutropenia

• Disease specific
• Tumor type
• Advanced disease uncontrolled cancer
• Patient specific
• Age
• PS
• Comorbidities
• Laboratory abnormalities
• Treatment specific
• Chemotherapy regimen
• CSF use

Lyman et al. Oncologist 200510427-37.
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Risk of first episode of febrile neutropenia in
patients with non-Hodgkins lymphoma treated with
CHOP chemotherapy.
Lyman et al. Oncologist 200510427-37.
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Risk of Febrile Neutropenia Among Patients with
Intermediate-grade Non-Hodgkin's Lymphoma
Receiving CHOP Chemotherapy.

• 577 intermediate grade NHL patients who received
  CHOP chemotherapy
• 160 patients experienced 224 febrile neutropenia
  events
• The risk of febrile neutropenia was significantly
  associated with
• age 65 years (p0.001),
• cardiovascular disease (p0.020),
• renal disease (p0.006),
• baseline hemoglobin lt12 g/dl (p0.018),
• gt80 planned average relative dose intensity
  (ARDI p0.018),
• and no prophylactic colony-stimulating factor
  (CSF) use (p0.046).
• First febrile neutropenic events occurred by day
  14 of cycle 1 in one-half of patients
  experiencing febrile neutropenia.
• In multivariate analysis, the risk of febrile
  neutropenia remained significantly associated
  with
• age 65 years (HR1.65, 95 CI 1.18-2.32),
• renal disease (HR1.91, 95 CI 1.10-3.30),
• cardiovascular disease (HR1.54, 95 CI
  1.02-2.33),
• baseline hemoglobin lt12 g/dl (HR1.44, 95 CI
  1.04-2.00),
• gt80 planned CHOP ARDI (HR2.41, 95 CI
  1.30-4.47),
• and no CSF prophylaxis (HR2.13, 95 CI
  1.20-3.76).

Lyman et al. Leukemia Lymphoma 2003442069-76.
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Risk of Febrile Neutropenia Among Patients with
Intermediate-grade Non-Hodgkin's Lymphoma
Receiving CHOP Chemotherapy.
Cumulative probability of febrile neutropenia, by
number of risk factors.
Lyman et al. Leukemia Lymphoma 2003442069-76.
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2000 update of recommendations for the use of
hematopoietic colony-stimulating factors
evidence-based, clinical practice guidelines.

• Routine use of CSFs for primary prophylaxis of FN
  for any common disease in previously untreated
  patients is not justified,
• The available data indicate that, with a
  sufficiently high incidence of FN ( 40), there
  is strong evidence for the primary administration
  of CSFs to reduce hospitalization for antibiotic
  administration.
• Secondary prophylaxis physicians should consider
  chemotherapy dose reduction after neutropenic
  fever or severe or prolonged neutropenia after
  the previous cycle of treatment,
• CSFs should not be routinely used for patients
  with neutropenia who are afebrile,
• CSFs should not be routinely used as adjunct
  therapy for the treatment of uncomplicated fever
  and neutropenia. Uncomplicated fever and
  neutropenia are defined as follows fever of 10
  days in duration no evidence of pneumonia,
  cellulitis, abscess, sinusitis, hypotension,
  multiorgan dysfunction, or invasive fungal
  infection and no uncontrolled malignancies,
• Certain patients with fever and neutropenia are
  at higher risk for infection-associated
  complications and have prognostic factors that
  are predictive of poor clinical outcome. The use
  of a CSF for such high-risk patients may be
  considered, but the benefits of a CSF in these
  circumstances have not been proven. These factors
  include profound (ANC lt 100/µL) neutropenia,
  uncontrolled primary disease, pneumonia,
  hypotension, multiorgan dysfunction (sepsis
  syndrome), and invasive fungal infection. Age
  greater than 65 years and posttreatment
  lymphopenia may also be high-risk factors but
  have not been consistently confirmed by
  multicenter trials.

Ozer et al. J Clin Oncol 2000183558-85.
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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 (gt20) 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)
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NCCN - Myeloid growth factors guidelines
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NCCN - Myeloid growth factors guidelines
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Colony-stimulating factors for chemotherapy-induce
d febrile neutropenia a meta-analysis of
randomized controlled trials.
Overall mortality
Clark et al. J Clin Oncol 2005234198-214.
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Colony-stimulating factors for chemotherapy-induce
d febrile neutropenia a meta-analysis of
randomized controlled trials.
Infection-related mortality
Clark et al. J Clin Oncol 2005234198-214.
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Colony-stimulating factors for chemotherapy-induce
d febrile neutropenia a meta-analysis of
randomized controlled trials.
Lenght of hospitalisation
Clark et al. J Clin Oncol 2005234198-214.
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Colony-stimulating factors for chemotherapy-induce
d febrile neutropenia a meta-analysis of
randomized controlled trials.
Time to neutrophil recovery
Clark et al. J Clin Oncol 2005234198-214.
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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 2005353988-98.
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Risk model for severe anemia requiring red blood
cell transfusion after cytotoxic conventional
chemotherapy regimens.

• One hundred seven of the 1,051 patients of the
  CLB-1996 cohort (10) experienced SARRT.
• In univariate analysis
• female sex,
• performance status greater than 1,
• hemoglobin level less than 12 g/dL before
  chemotherapy on day 1 (d1),
• d1 lymphocyte count lt 700/µL significantly
  correlated with the risk of SARRT.
• Using logistic regression
• d1 hemoglobin level less than 12 g/dL (OR
  14.0 95 CI, 7 to 30),
• performance status greater than 1 (OR 2.2 95
  CI, 1.4 to 3.5),
• d1 lymphocyte count lt 700/µL (OR 1.7 95 CI,
  1.1 to 2.6) were identified as independent risk
  factors for SARRT.
• These three factors were given arbitrary risk
  coefficients of 3, 1, and 1 respectively, and a
  risk score for each individual patient was
  obtained by adding the coefficients.
• The calculated probability of RBC transfusions
  was 30 for patients with a score 4, and 11,
  4, and 1 in patients with a score of 2 or 3, 1,
  and 0 respectively.

Ray-Coquard et al. J Clin Oncol 1999172840
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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 lt 700/µL,
• d1 polymorphonuclear leukocyte count less than
  1,500/µL,
• and the type of chemotherapy (high risk v others)
  were significantly associated (P lt .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 lt 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 199892405-10.
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Chronic bone marrow damage

• Decreased bone marrow reserve,
• Myelodysplastic syndromes and secondary leukemias.