Adulte leucémie myéloïde aiguë Traitement (du PDQ): Traitement - information sur la santé professionnelle [NCI]

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Adulte leucémie myéloïde aiguë Traitement

Incidence et mortalité

Note: les nouveaux cas et de décès de la leucémie myéloïde aiguë (LMA) aux Etats-Unis estimés en 2012: [1]

Nouveaux cas: 13,780.Deaths: 10,200.

Les progrès dans le traitement de la LMA (également appelé la leucémie myéloïde aiguë, la leucémie non lymphocytaire aiguë ou LANL) ont entraîné sensiblement amélioré le taux de rémission complète. [1] Le traitement doit être suffisamment agressif pour obtenir une rémission complète parce rémission partielle ne offre aucun avantage substantiel de survie. Environ 60% à 70% des adultes atteints de LMA peut se attendre à atteindre le statut de rémission complète après un traitement d'induction appropriée. Plus de 25% des adultes atteints de LAM (environ 45% de ceux qui atteignent une rémission complète) peut se attendre à survivre trois ans ou plus et peut être guérie. Les taux de rémission chez les adultes AML sont inversement liés à l'âge, avec un taux de rémission attendue de plus de 65% pour les moins de 60 ans. Les données suggèrent que, une fois atteint, la durée de la rémission peut être plus courte chez les patients âgés. Augmentation de la morbidité et de la mortalité pendant l'induction semble être directement liée à l'âge. Autres facteurs pronostiques défavorables comprennent l'implication du système nerveux central avec la leucémie, l'infection systémique au moment du diagnostic, numération élevée de globules (> 100 000 / mm 3), induite par le traitement AML, et l'histoire des syndromes myélodysplasiques ou un autre trouble hématologique antécédent. Les patients atteints de leucémies qui expriment l'antigène de cellules progénitrices CD34 et / ou de la P-glycoprotéine (produit du gène MDR1) ont un résultat inférieur. [2,3,4] AML associé à une duplication interne en tandem du gène de FLT3 (FLT3 / mutation ITD ) a un résultat inférieur qui est attribué à un taux de rechute ultérieure. [5,6]

Analyse cytogénétique fournit une partie de l'information pronostique la plus forte disponible, prédire les résultats des deux induction de la rémission et la thérapie postremission, comme on le voit dans un procès de la Southwest Oncology Group (SWOG) et l'Eastern Cooperative Oncology Group (ECOG) (E-3489). [ 7] des anomalies cytogénétiques qui indiquent un bon pronostic comprennent t (8; 21), inv (16) ou t (16; 16) et t (15; 17). Cytogénétique normales présagent AML-risque moyen. Les patients atteints de LAM qui se caractérise par des deletions des bras longs des chromosomes ou monosomies 5 ou 7; par translocations ou inversions du chromosome 3, t (6; 9), t (9; 22); ou par des anomalies du chromosome 11q23 ont pronostics particulièrement pauvres avec la chimiothérapie. Ces sous-groupes cytogénétiques, comme on le voit dans le procès du Medical Research Council (MRC-Leuk-AML11), prédire les résultats cliniques chez les patients âgés atteints de LAM ainsi que chez les patients plus jeunes [8] Les gènes de fusion formés dans t (8; 21. ) et inv (16) peut être détectée par transcription inverse-réaction de polymérisation en chaîne (RT-PCR) ou l'hybridation fluorescente in situ (FISH), qui indique la présence de ces altérations génétiques chez certains patients chez qui la cytogénétique standard était techniquement insuffisantes. RT-PCR ne apparaît pas à identifier un nombre significatif de patients présentant de bonnes gènes de fusion de risque qui ont cytogénétique normales [9].

La classification des AML a été révisé par un groupe de pathologistes et cliniciens sous les auspices de l'Organisation mondiale de la Santé (OMS). [10] Bien que les éléments de la classification française-américano-britannique ont été retenus (ce est à dire, la morphologie, immunophénotype, cytogénétique et les caractéristiques cliniques), la classification de l'OMS incorpore les plus récentes découvertes concernant la génétique et les caractéristiques cliniques de AML dans une tentative de définir des entités qui sont biologiquement homogène et qui présentent un intérêt pronostique et thérapeutique. [10,11,12] Chaque critère a pronostique et implications de traitement mais, pour des raisons pratiques, la thérapie anti-leucémique est similaire pour tous les sous-types.

A long terme de suivi de 30 patients qui avaient AML qui était en rémission depuis au moins 10 ans a démontré une incidence de 13% des tumeurs malignes secondaires. Sur les 31 femmes qui ont survécu à long terme de LAM ou leucémie lymphoblastique aiguë moins de 40 ans, 26 reprend la menstruation normale après la fin du traitement. Parmi 36 descendants vivants des survivants, deux problèmes congénitaux eu lieu. [13]

La différenciation de l'AML de leucémie lymphocytaire aiguë a des implications thérapeutiques importantes. Colorants histochimiques et des déterminations d'antigènes de surface cellulaire aider à la discrimination.

Références:

1. Société américaine du cancer .: Faits et chiffres sur le cancer 2012. Atlanta, Ga: American Cancer Society, 2012. Disponible en ligne. Dernière consulté le 14 Juin, de 2012.
2. Myint H, Lucie NP: La signification pronostique de l'antigène CD34 dans la leucémie myéloïde aiguë. Leuk Lymphoma 7 (5-6): 425-9, 1992.
3. Geller RB, Zahurak M, Hurwitz CA, et al .: importance pronostique de immunophénotypage chez les adultes atteints de leucémie myéloïde aiguë: l'importance de la glycoprotéine de cellules souches CD34 (My10) Br J Haematol 76 (3): 340-7, 1990.
4. Campos L, Guyotat D, E Archimbaud, et al .: signification clinique de la multirésistance expression de la P-glycoprotéine sur les cellules de leucémie aiguë non lymphoblastique au moment du diagnostic. Sang 79 (2): 473-6, 1992.
5. Kottaridis PD, Gale RE, Frew ME, et al .: La présence d'une duplication interne en tandem de FLT3 chez les patients atteints de leucémie myéloïde aiguë (LMA) ajoute une information pronostique important de groupe à risque cytogénétique et la réponse à la première cycle de chimiothérapie: analyse de 854 patients du Conseil de recherches médicales Royaume-Uni AML 10 et 12 essais. Sang 98 (6): 1752-9, 2001.
6. Yanada M, Matsuo K, Suzuki T, et al .: importance pronostique de FLT3 duplication interne en tandem et de domaine tyrosine kinase mutations pour la leucémie myéloïde aiguë: une méta-analyse. Leukemia 19 (8): 1345-9, 2005.
7. ML slovaque, Kopecky KJ, Cassileth PA, et al .: analyse caryotypique prédit résultat de preremission et la thérapie postremission chez les adultes leucémie myéloïde aiguë: une étude Oncology Group Southwest Oncology Group / Eastern Cooperative. Sang 96 (13): 4075-83, 2000.
8. Grimwade D, H Walker, Harrison G, et al .: La valeur prédictive de la classification hiérarchique cytogénétique chez les adultes plus âgés atteints de leucémie myéloïde aiguë (LMA): analyse de 1065 patients inclus dans l'essai Medical Research Council Royaume-Uni AML11. Sang 98 (5): 1312-1320, 2001.
9. Mrózek K, Avant TW, Edwards C, et al .: Comparaison de la détection cytogénétique et génétique moléculaire de t (8; 21) et inv (16) dans une série prospective des adultes atteints de leucémie myéloïde aiguë novo: un cancer et la leucémie Groupe Étude B. J Clin Oncol 19 (9): 2482-92, 2001.
10. Brunning RD, Matutes E, Harris NL, et al .: leucémie myéloïde aiguë: mise en place. Dans: Jaffe ES, Harris NL, Stein H, et al, eds Pathologie et de Génétique des tumeurs des tissus lymphoïdes et hématopoïétiques.. Lyon, France: IARC Press, 2001. Classification mondiale de la santé Organisation des tumeurs, 3, pp 77-80.
11. Bennett JM, Catovsky D, Daniel MT, et al .: propositions pour la classification des leucémies aiguës. Français-British American (FAB) groupe coopératif. Br J Haematol 33 (4): 451-8, 1976.
12. Cheson BD, Cassileth PA, chef DR, et al .: Rapport de l'atelier Institut national du cancer parrainé sur les définitions de diagnostic et de réponse dans la leucémie myéloïde aiguë. J Clin Oncol 8 (5): 813-9, 1990.
13. Micallef EN, Rohatiner AZ, Carter M, et al .: résultats à long terme des patients survivants depuis plus de dix ans après le traitement de la leucémie aiguë. Br J Haematol 113 (2): 443-5, 2001.

L'Organisation mondiale de la santé (OMS) la classification de la leucémie myéloïde aiguë (LMA) intègre et il est étroitement morphologie, cytogénétique, génétique moléculaire, et des marqueurs immunologiques dans une tentative de construire une classification qui est universellement applicable et pronostique valide. [1] Dans le plus français (FAB) critères-britannique -American, la classification de l'AML est uniquement basé sur la morphologie telle que déterminée par le degré de différenciation long de différentes lignées cellulaires et la mesure de la maturation de la cellule. [2,3]

Selon la classification de l'OMS, la catégorie «leucémie myéloïde aiguë non classé autrement» est basé sur la morphologie et reflète la classification FAB avec quelques modifications importantes. [2,3] La différence la plus significative entre les classifications de l'OMS et de FAB est la recommandation de l'OMS le pourcentage de souffle nécessaire pour le diagnostic de l'AML soit au moins 20% de blastes dans le sang ou la moelle osseuse. Le régime FAB requis le pourcentage de souffle dans le sang ou la moelle osseuse soit au moins 30%. Cette valeur de seuil pour le pourcentage de l'explosion a éliminé la catégorie «anémie réfractaire avec excès de blastes en transformation» (AREB-T) trouvé dans la classification FAB des syndromes myélodysplasiques (MDS), où AREB-t est définie par un pourcentage de l'explosion de la moelle entre 20% et 29%. Dans la classification de l'OMS, AREB-t ne est plus considéré comme une entité clinique distincte, et est plutôt inclus dans la catégorie plus large "LAM avec dysplasie multilignée» comme «LAM avec dysplasie multilignée la suite d'un syndrome myélodysplasique." [4]

Bien que cet abaissement du seuil de l'explosion a été accueillie avec une certaine critique, plusieurs études indiquent que les modèles de survie pour les cas avec 20% à 29% de blastes sont similaires à des modèles de survie pour les cas avec 30% ou plus de blastes dans la moelle osseuse. [5, 6,7,8,9] Le diagnostic de LAM en elle-même ne représente pas un mandat thérapeutique. La décision de traiter doit être fondée sur d'autres facteurs tels que l'âge du patient, les antécédents de MDS, les résultats cliniques, la progression de la maladie, en plus de le pourcentage de souffle, et, surtout, la préférence du patient.

Plusieurs groupes ont commencé à enquêter sur l'utilisation de profils d'expression génique (GEP) en utilisant des puces pour augmenter les études diagnostiques et pronostiques actuels pour AML. Sous-ensembles distincts peuvent être identifiés en utilisant GEP qui correspondent à cytogénétique et anomalies moléculaires connus. La valeur prédictive positive semble être suffisamment puissant pour être cliniquement utile seulement pour les patients atteints de la translocation t (8; 21) et inv (16) (maintenant appelée noyau facteur de liaison leucémies) et la leucémie aiguë promyélocytaire avec le t (15; 17). GEP a identifié plusieurs cas de leucémies de facteurs fondamentaux contraignant qui ne ont pas été diagnostiqués en utilisant cytogénétique conventionnelle. [10,11,12]

Dans les grandes lignes et la discussion qui suit, les classifications FAB âgées sont notés le cas échéant.

LAM avec anomalies génétiques caractéristiques.

LAM avec t (8; 21) (q22; q22); (AML / ETO) .aml avec inv (16) (p13q22) ou t (16; 16) (p13; q22); (CBFβ / MYH11) .Acute leucémie promyélocytaire (LAM avec t (15; 17) (q22; q12); (PML / RARa) et variantes) .aml avec 11q23 (MLL) abnormalities.AML avec une mutation de FLT3 (pas dans le classification de l'OMS régime) .aml avec dysplasia.AML multilignée et MDS, la thérapie liée.

Alkylation AML liés agent et MDS.Topoisomerase II AML.AML liés inhibiteur non autrement classées.

La leucémie myéloblastique aiguë, peu différenciés (FAB Classification M0) .Acute leucémie myéloblastique sans maturation (FAB classification M1) .Acute leucémie myéloblastique avec maturation (FAB classification M2) .Acute leucémie myélomonocytaire (AMML) (FAB Classification M4) .Acute la leucémie et monoblastique leucémie aiguë monocytaire (classifications FAB M5a et M5b) .Acute leucémies érythroïdes (classifications FAB M6a et M6B) .Acute leucémie mégacaryoblastique (FAB Classification M7).

LBC / syndrome myéloprolifératif transitoire bas syndrome.Acute basophiles leukemia.Acute Panmyélose avec leucémies de la lignée myelofibrosis.Myeloid sarcoma.Acute ambiguë.

La leucémie myéloïde aiguë (AML) avec des anomalies génétiques caractéristiques

Cette catégorie se caractérise par des anomalies génétiques caractéristiques et tarifs souvent élevés de rémission et de pronostics favorables à l'exception notable de ceux avec des anomalies 11q23 [13] Les translocations réciproques t (8; 21)., Inv (16) ou t (16; 16 ), t (15; 17), et translocations impliquant le point d'arrêt 11q23 sont des anomalies génétiques les plus couramment identifiés. Ces réarrangements chromosomiques conduisent à la formation de gènes de fusion qui codent pour des protéines chimères qui peuvent contribuer à l'initiation ou la progression de leucémogénèse. Beaucoup de ces translocations sont détectés par la réaction de la transcriptase inverse chaîne par polymérase (RT-PCR) ou l'hybridation fluorescente in situ (FISH), qui a une sensibilité plus élevée que la cytogénétique. Autres anomalies cytogénétiques récurrentes sont moins fréquentes et décrit ci-dessous dans les LAM non classé autrement.

La leucémie aiguë myéloïde avec t (8; 21) (q22; q22); (AML / ETO)

LAM avec la translocation t (8; 21) (q22; q22) (survenant le plus souvent dans la classification FAB M2) est l'une des aberrations génétiques les plus courantes en matière de LBC et représente 5% à 12% des cas de LAM et 33% des caryotype cas anormaux de leucémie myéloblastique aiguë avec la maturation. [14] sarcomes myéloïdes (de chloromes) peuvent être présents et peuvent être associés à un pourcentage de moins de 20% de l'explosion de la moelle osseuse.

Caractéristiques morphologiques communes sont les suivantes:

Grandes explosions basophiles abondante, contenant souvent de nombreux azurophiles granules.A quelques explosions dans certains cas montrent très gros granules (pseudo Chediak-Higashi granulés) tiges .Auer, qui peuvent être détectés dans les explosions de neutrophils.Smaller matures, principalement dans le sang périphérique .Promyelocytes, myélocytes et les neutrophiles matures avec dysplasie variable dans l'os marrow.Abnormal segmentation nucléaire (pseudo Pelger-Huet noyaux) et / ou une coloration cytoplasmique abnormalities.Increased éosinophiles precursors.Reduced ou érythroblastes et de mégacaryocytes monocytes.Normal absents.

AML avec la maturation (classification FAB M2) est le type morphologique la plus courante en corrélation avec t (8; 21). Rarement, LAM avec cette translocation présente avec un pourcentage de l'explosion de la moelle osseuse inférieure à 20%. [13]

La translocation t (8; 21) (q22; q22) implique le gène AML1, également connu sous le nom RUNX1, qui code pour noyau de liaison du facteur alpha (CBF-alpha), et l'oxyde d'éthylène (de huit à vingt-et-un) gène [13. , 15] La transcription de fusion AML1 / ETO est toujours détecté chez les patients avec t (8; 21) AML. Ce type de AML est généralement associée à une bonne réponse à la chimiothérapie et un taux de rémission complète de haut avec la survie à long terme lorsqu'ils sont traités avec la cytarabine à haute dose dans la phase de postremission comme dans le cancer et la leucémie Groupe B (CLB-9022 et CLB- 8525) essais. [16,17,18,19] anomalies chromosomiques supplémentaires sont communs, par exemple, la perte d'un chromosome sexuel et del (9) (q22). L'expression de la molécule d'adhésion cellulaire neurale CD56 semble être un indicateur pronostique négatif. [20,21]

La leucémie myéloïde aiguë avec inv (16) (p13; q22) ou t (16; 16) (p13; q22); (CBFβ / MYH11)

LAM avec inv (16) (p13; q22) ou t (16; 16) (p13; q22). Se trouve dans environ 10% à 12% de tous les cas de LAM, principalement chez les patients plus jeunes [13,22] Morphologiquement, ce type de AML est associée à la leucémie myélomonocytaire aiguë (FAB classement M4) avec éosinophiles anormaux (AMML Eo). Sarcomes myéloïdes peuvent être présents au moment du diagnostic initial ou à la rechute.

Caractéristiques morphologiques communes sont les suivantes:

Composante des éosinophiles caractéristique anormale Monocytic et differentiation.A granulocytes immatures avec violines éosinophiles granules qui peuvent masquer la morphologie cellulaire se il est présent dans de grandes tiges de numbers.Auer dans les neutrophiles myeloblasts.Decreased dans la moelle osseuse.

La plupart des cas avec cette anomalie génétique ont été identifiés comme AMML Eo, mais des cas isolés ont été rapportés à manquer éosinophilie. Comme on en trouve dans de rares cas de LAM avec t (8; 21), le pourcentage de l'explosion de la moelle osseuse dans ce AML est parfois moins de 20%.

Les deux inv (16) (p13; q22) et t (16; 16) (p13; q22) aboutir à la fusion du facteur bêta de base contraignant (CBFβ) génique à 16q22 à la chaîne lourde lisse myosine musculaire (MYH11) génique à 16p13, formant ainsi le gène de fusion CBFβ / MYH11. [14] L'utilisation de poissons et de méthodes de RT-PCR peut être nécessaire de documenter ce gène de fusion parce que sa présence ne peut pas être fiable documenté par cytogénétique traditionnels de baguage techniques. [23] Les patients avec ce type de AML peut atteindre des taux de rémission plus complets lorsqu'ils sont traités avec la cytarabine à haute dose dans la phase de postremission. [16,17,19]

Leucémie promyélocytaire aiguë [LAM avec t (15; 17) (q22; q12); (PML / RARa) et variantes] (FAB Classification M3)

AML leucémie promyélocytaire aiguë (APL) avec t (15; 17) (q22; q12) est un AML dans lequel promyelocytes prédominent. APL existe que deux types, hypergranular ou APL typique et microgranulaire (hypogranular) APL. APL comprend 5% à 8% des cas de LAM et survient principalement chez les adultes dans la quarantaine. [13] Les deux APL typique et microgranulaire sont couramment associée à une coagulation intravasculaire disséminée (CIVD). [24,25] Dans microgranulaire APL, contrairement APL typique , le nombre de leucocytes est très élevé avec un temps de doublement rapide [13].

Caractéristiques morphologiques communes des APL typique sont les suivantes:

Ou bilobée nuclei.Cytoplasm dense avec de grandes granules (de rose vif, rouge ou pourpre taches Romanowsky) en forme de rein .Bundles d'Auer dans le cytoplasme (cellules faggot) tiges .Larger Auer que dans les autres types de AML.Strongly positif myéloperoxydase (MPO) réaction dans tous les promyélocytes leucémiques promyelocytes.Only occasionnelles leucémiques dans le sang.

Caractéristiques morphologiques communs de microgranulaire APL sont les suivants:

Shape.Apparent nucléaire bilobé granulés rares ou absentes (granules azurophiles submicroscopiques) .Small nombre de promyélocytes anormaux avec des granules visibles et / ou des faisceaux de Auer (cellules faggot) numération leucocytaire .High dans la réaction MPO blood.Strongly positif périphérique en toute leucémique promyélocytes.

En APL, le récepteur de l'acide rétinoïque alpha (RARa) gène sur 17q12 fusibles avec un facteur de réglementation nucléaire sur 15q22 (leucémie promyélocytaire ou le gène PML) résultant en un transcrit de fusion de gènes PML / RARa. [14,26,27] De rares cas de Cryptic ou t masqué (15; 17) manquent cytogénétique typiques et impliquer translocations variantes complexes ou insertion microscopique du gène RARa dans le gène PML conduisant à l'expression de la transcription de fusion PML / RARa [13] méthodes de poisson et / ou de RT-PCR. peut être nécessaire de démasquer ces réarrangements génétiques cryptiques. [28,29]

APL a une sensibilité particulière au traitement par tout-trans acide rétinoïque (ATRA, trétinoïne), qui agit comme un agent de différenciation. [30,31,32] Les taux élevés de rémission complète dans APL peuvent être obtenu en combinant le traitement ATRA avec la chimiothérapie. [ 33] Dans environ 1% des cas d'APL, aberrations chromosomiques variantes peuvent être trouvés dans laquelle le gène RARa est fusionné avec d'autres gènes [34] Variante translocations impliquant le gène RARa comprennent:. t (11; 17) (q23; q21 ), t (5; 17) (q32; q12) et t (11; 17) (q13;. q21) [13]

La leucémie aiguë myéloïde avec 11q23 (MLL) anomalies

LAM avec anomalies 11q23 comprend 5% à 6% des cas de LAM et est généralement associée à des caractéristiques monocytaires. Cet AML est plus fréquente chez les enfants. Deux sous-groupes cliniques des patients ont une fréquence élevée de LAM avec anomalies 11q23: AML chez les nourrissons et AML liées au traitement, survenant généralement après traitement avec les inhibiteurs de la topoisomérase de l'ADN. Les patients peuvent présenter des DIC et les sarcomes extramédullaires monocytaires et / ou l'infiltration tissulaire (gencive, de la peau). [13]

Caractéristiques morphologiques communs de cette AML sont les suivants:

Monoblastes et promonocytes prédominent dans les marrow.Monoblasts osseuses et promonocytes avec de fortes réactions d'estérase non spécifiques positifs.

11q23 anomalies sont associées fréquemment avec myélomonocytaire aiguë, monoblastique et leucémies monocytaires (de classifications FAB M4, M5A et M5B, respectivement) et parfois avec AML avec et sans maturation (classifications FAB M2 et M1, respectivement). [13]

Le gène MLL sur 11q23, un régulateur de développement, est impliqué dans les translocations avec environ 22 chromosomes différents partenaires. [13,14] Les gènes autres que MLL peuvent être impliqués dans 11q23 anomalies. [35] FISH peut être nécessaire pour détecter des anomalies génétiques impliquant MLL . [35,36,37] En général, les catégories de risque et les pronostics pour individuels 11q23 translocations sont difficiles à déterminer en raison de l'absence d'études impliquant un nombre important de patients; Cependant, les patients avec t (11; 19) (q23; P13.1) sont rapportés d'avoir de mauvais résultats [17].

La leucémie myéloïde aiguë avec des mutations de FLT3, NPM1 ou CMBPA

Activation de mutations FLT3 (FMS-like tyrosine kinase-3), présente au moment du diagnostic dans 20% à 30% des LAM de novo, représenter l'anomalie moléculaire la plus fréquente dans cette maladie. [38,39] Le type le plus commun de la mutation ( 23%) est une interne mutation par duplication en tandem (FLT3 / ITD) localisée à la région juxtamembranaire du récepteur, tandis que des mutations ponctuelles dans le domaine kinase sont moins courantes (7%). Caractéristiques cliniques communes de patients atteints de FLT3 / ITD AML sont:

Cytogenetics.Leukocytosis.Monocytic différenciation normale.

Patients présentant des mutations FLT3 / ITD, et peut-être avec ces FLT3 mutations ponctuelles, sont systématiquement signalés à avoir un taux de rechute accrue et réduction de la survie globale. [40,41] Le taux de rémission complète pour les patients atteints FLT3 mutant AML est généralement rapporté avoir aucune différente de celle pour les patients atteints de LAM avec FLT3 non mutant, mais la plupart des études portant sur ce paramètre clinique utilisé les résultats de patients traités avec des régimes de chimiothérapie intensive, et certaines données sont disponibles pour suggérer que le classique 7 + 3 schéma conduit à un taux de rémission réduite dans ce groupe de patients [42] [Niveau de preuve: 3iiiDiv].

Une étude de la myéloïde Groupe d'étude de la leucémie aiguë germano-autrichien a examiné les données sur 872 patients atteints de LAM cytogénétique normale traités avec intensifs induction et postremission régimes sur une période de 11 ans [43] [Niveau de preuve: 3iiiA]. Le groupe d'étude a constaté que les patients avec une alpha / protéine de liaison mutant CCAAT activateur (CEBPA) ou une mutation nucléophosmine (NPM1) sans liés FMS-tyrosine kinase 3 interne duplication en tandem (FLT3-ITD) avaient des taux de réponse plus élevé complets, les taux de survie sans maladie, et la survie globale (OS) taux (avec un taux de 4 ans OS de 62% et 60%, respectivement) que les autres patients atteints de LAM cytogénétiquement normales (qui avaient un taux d'OS 4 ans comprise entre 25% et 30%). Pour l'instant, aucune stratégie claire existe pour améliorer les résultats des patients en FLT3 mutant AML, ou chez les patients présentant des anomalies autres que CEBPA ou NPM1 sans FLT3-ITD, mais inhibiteurs FLT3 petites molécules sont en développement, et le rôle de la greffe allogénique est en cours considéré.

La leucémie myéloïde aiguë Avec multilignée dysplasie

Remarque: Dans la classification de l'OMS, l'anémie réfractaire avec excès de blastes en transformation (AREB-T) ne est plus considéré comme une entité clinique distincte et est plutôt inclus dans la catégorie plus large "LAM avec dysplasie multilignée" comme l'un des éléments suivants:

AML évolution d'un MDS.AML la suite d'une MDS.

LAM avec dysplasie multilignée est caractérisée par 20% ou plus de blastes dans le sang ou la moelle osseuse et de la dysplasie dans deux ou plusieurs lignées cellulaires myéloïdes, y compris généralement mégacaryocytes. [4] pour effectuer le diagnostic, la dysplasie doit être présent dans 50% ou plus les cellules d'au moins deux lignées et doivent être présents dans un échantillon prétraitement de la moelle osseuse. [4,44] LAM avec dysplasie multilignée peut survenir de novo ou à la suite MDS ou myélodysplasique et de syndrome myéloprolifératif (MDS et MPD). (Reportez-vous aux résumés PDQ sur myélodysplasique traitement Syndromes and myélodysplasiques / myéloprolifératifs Tumeurs pour plus d'informations.) La terminologie de diagnostic "LAM avec dysplasie multilignée évolution d'un syndrome myélodysplasique" devrait être utilisée quand une MDS précède AML. [4]

Cette catégorie d'AML se produit principalement chez les patients âgés. [4,45] Les patients atteints de ce type de AML fréquemment présents à une pancytopénie sévère.

Caractéristiques morphologiques communes sont les suivantes:

Multilignée dysplasie dans le sang ou la moelle marrow.Dysplasia à 50% ou plus des cellules de deux ou plusieurs lines.Dysgranulopoiesis de cellules (neutrophiles avec hypogranular cytoplasme, des noyaux ou des noyaux hyposegmented étrangement segmentés) .Dyserythropoiesis (noyaux mégaloblastique, caryorrhexie ou de multinucléation taille précurseurs érythroïdes et sidéroblastes en couronne) .Dysmegakaryopoiesis (micromegakaryocytes et normal ou grands mégacaryocytes avec monolobed ou plusieurs noyaux séparés).

Le diagnostic différentiel de LAM avec dysplasie multilignée comprend la leucémie aiguë myéloïde érythroïdes et la leucémie aiguë myéloblastique avec maturation (FAB classifications M6a et M2). Certains cas peuvent se chevaucher deux types morphologiques. [4]

Comme en témoignent plusieurs études Southwest Oncology Group, tels que SWOG-8600 et NCT00023777, les nombreuses anomalies chromosomiques observées dans les LAM avec dysplasie multilignée étaient semblables à ceux trouvés dans les MDS et fréquemment impliqués gain ou la perte des principaux segments de certains chromosomes, les chromosomes principalement 5 et / ou 7. [45,46,47,48] La probabilité d'atteindre une rémission complète a été rapporté d'être affectées par un diagnostic de LAM avec dysplasie multilignée. [45,46,47]

Myéloïde aiguë leucémies et syndromes myélodysplasiques, thérapie connexes

Cette catégorie comprend LAM et MDS qui se posent secondaire à la chimiothérapie cytotoxique et / ou la radiothérapie. [49] Les MDS liées au traitement (ou secondaires) sont inclus en raison de leurs relations étroites clinicopathologic à AML liés thérapie. Bien que ces troubles liées au traitement se distinguent par les agents mutagènes spécifiques impliqués, une étude récente suggère cette distinction peut être difficile à faire parce que de l'utilisation fréquente de chevauchement de multiples agents potentiellement mutagènes dans le traitement du cancer. [50]

Alkylation leucémie myéloïde aiguë liée agent et des syndromes myélodysplasiques

Les agent alkylant / leucémies aiguës liés aux rayonnements et les syndromes myélodysplasiques se produisent généralement 5 à 6 ans après l'exposition à l'agent mutagène, avec une gamme rapporté d'environ 10 à 192 mois. [49,51] Le risque de survenue est liée à la fois au dose totale de l'agent d'alkylation et l'âge du patient. Cliniquement, la maladie présente généralement d'abord comme MDS avec des preuves de l'échec de la moelle osseuse. Cette étape est suivie par des caractéristiques dysplasiques dans plusieurs lignées cellulaires avec un pourcentage de soufflage qui est habituellement inférieure à 5%. Dans la phase MDS, environ 66% des cas satisfaire les critères de cytopénie réfractaire avec dysplasie multilignée (RCMD), avec environ 33% de ces cas présentant sidéroblastes en couronne au-delà de 15% (RCMD-RS). [49] (Voir . le résumé PDQ sur myélodysplasiques Syndromes traitement pour plus d'informations) Un autre 25% des cas répondent aux critères pour l'anémie réfractaire avec excès de blastes 1 ou 2 (AREB-1; AREB-2). La phase MDS peut évoluer à un grade supérieur MDS ou de LAM. Bien qu'une minorité de patients peuvent présenter une leucémie aiguë, un nombre important de patients succombent à la maladie dans la phase MDS. [49]

Caractéristiques morphologiques communes sont les suivantes:

Panmyelosis.Dysgranulopoiesis.Dyserythropoiesis.Ringed sidéroblastes (60% des cas;> 15% dans 33% des cas) .Hypercellular moelle osseuse (50% des cas).

Cas peuvent correspondre à la LBC morphologiquement avec la maturation, la leucémie aiguë monocytaire, AMML, érythroleucémie, ou leucémie aiguë mégacaryoblastique (classifications FAB M2, M5b, M4, M6a, et M7, respectivement).

Des anomalies cytogénétiques ont été observées chez plus de 90% des cas de LAM liés thérapie ou MDS et couramment inclure chromosomes 5 et / ou 7. [49,52,53] anomalies chromosomiques complexes (≥3 anomalies distinctes) sont le résultat le plus commun . AML [50,52,53,54] Therapy-connexe est habituellement réfractaires à la thérapie leucémiques. La médiane de survie après le diagnostic de ces troubles est d'environ 7-8 mois. [50,52]

La leucémie myéloïde aiguë inhibiteur de la topoisomérase II liées

Ce type d'AML se produit chez les patients traités avec des inhibiteurs de la topoisomérase II. Les agents impliqués sont les épipodophyllotoxines étoposide et le téniposide et de la anthracyclines doxorubicine et 4-épi-doxorubicine. [49] La période de latence moyenne à partir du moment de l'introduction de la thérapie étiologique au développement de la LAM est d'environ 2 ans. [55] Morphologiquement , il existe une importante composante monocytaire. La plupart des cas sont classés comme monoblastique aiguë ou de leucémie myélomonocytaire. Autres morphologies signalés comprennent la leucémie aiguë promyélocytaire, les syndromes myélodysplasiques et mégacaryoblastique leucémie aiguë. [49]

Comme agent alkylant / leucémies aiguës liés aux rayonnements et les syndromes myélodysplasiques, les anomalies cytogénétiques sont souvent complexes. [50,52,53,54] La conclusion cytogénétique prédominante implique chromosome 11q23 et le gène MLL. [50,56] Les données actuelles sont insuffisant pour prédire la durée de survie.

La leucémie myéloïde aiguë Non Sinon Catégorisé

Cas de LAM qui ne remplissent pas les critères de LAM avec anomalies génétiques récurrentes, LAM avec dysplasie multilignée, ou de LAM et MDS, liées au traitement, entrent dans cette catégorie. Classification dans cette catégorie est basée sur les caractéristiques de cellules leucémiques de la morphologie, la cytochimie, et la maturation. [57]

La leucémie myéloblastique aiguë, peu différenciés (FAB Classification M0)

Cet AML ne montre aucun signe de différenciation myéloïde par la morphologie et la microscopie cytochimie lumière. [58] La nature myéloïde des explosions est démontrée par immunophénotypage et / ou des études ultrastructurales. [57] IMMUNOPHENOTYPAGE études doit être effectuée pour distinguer cette leucémie aiguë lymphoblastique aiguë à partir leucémie (ALL). [57] cas de LAM, peu différenciés, représentent environ 5% des cas de LAM. Les patients présentant ce AML généralement présente la preuve de l'échec de la moelle, la thrombocytopénie et la neutropénie. [58]

Morphologique et cytochimique caractéristiques sont les suivantes:

Explosions moyennes avec dispersées nucléaires chromatin.Agranular cytoplasm.Occasionally petites explosions qui ressemblent lymphoblasts.Cytochemistry négatif pour la myéloperoxydase (MPO), le Soudan noir B (CFF) et naphtol ASD chloroacétate estérase (<3% de blastes positifs) .Cytochemistry négatifs pour l'acétate d'alpha naphtyle et le butyrate esterases.Markedly moelle hypercellulaire.

L'immunophénotypage révèle cellules blastiques qui expriment un ou plusieurs antigènes panmyeloid (CD13, CD33, et CD117) et qui sont négatifs pour les antigènes T et B lymphoïdes restriction. La plupart des cas expriment des antigènes hématopoïétiques associés primitifs (CD34, CD38 et HLA-DR). Le diagnostic différentiel comprend ALL, leucémie aiguë mégacaryoblastique, biphénotypique / mixte lignée de leucémie aiguë, et, plus rarement, la phase leucémique du lymphome à grandes cellules. études de IMMUNOPHENOTYPAGE sont tenus de distinguer ces troubles. [57]

Bien qu'aucune des anomalies chromosomiques spécifiques ont été trouvées dans la LMA, des mutations ponctuelles minimale dissociés du gène AML1 ont été observées chez environ 25% des cas. Cette mutation semble être en corrélation cliniquement avec un nombre de globules blancs et une plus grande implication de l'explosion de la moelle. [57,59] mutation de FLT3, un gène de la tyrosine kinase du récepteur, se produit dans environ 25% des cas et a été associée à la survie à court. [ 40,59] La survie globale médiane est d'environ 10 mois. [60]

La leucémie aiguë myéloblastique sans maturation (FAB classification M1)

AML without maturation is characterized by a high percentage of bone marrow blasts with little evidence of maturation to mature neutrophils and comprises approximately 10% of cases of AML.[57] Most patients are adults. Patients usually present with anemia, thrombocytopenia, and neutropenia. (Refer to the PDQ summary on Fatigue for more information on anemia.)

Common morphologic and cytochemical features include the following:

Myeloblasts of 90% or more of the nonerythroid cells in the bone marrow.Myeloblasts that may have azurophilic granules and/or Auer rods.Myeloblasts that resemble lymphoblasts.MPO and SBB positivity in blasts of 3% or more.Typically markedly hypercellular marrow.

Immunophenotyping reveals blasts that express at least two myelomonocytic antigens (CD13, CD33, CD117) and/or MPO. CD34 is often positive. The differential diagnosis includes ALL in cases of AML without maturation with no granules and a low percentage of MPO positive blasts, and AML with maturation in cases of AML with maturation with a high percentage of blasts.

Although no specific chromosomal abnormality has been identified for AML without maturation, mutation of the FLT3 gene has been associated with leukocytosis, a high percentage of bone marrow blast cells, and a worse prognosis.[40,57,61]

Acute myeloblastic leukemia with maturation (FAB Classification M2)

AML with maturation is characterized by 20% or more myeloblasts in the blood or bone marrow and 10% or more neutrophils at different stages of maturation. Monocytes constitute less than 20% of bone marrow cells.[57] This AML comprises approximately 30% to 45% of cases of AML. While it occurs in all age groups, 20% of patients are less than 25 years and 40% of patients are 60 years or older.[57] Patients frequently present with anemia, thrombocytopenia, and neutropenia. (Refer to the PDQ summary on Fatigue for more information on anemia.)

Morphologic features include the following:

Myeloblasts with and without azurophilic granules.Auer rods.Promyelocytes, myelocytes, and neutrophils 10% or more of the bone marrow cells.Abnormal nuclear segmentation in neutrophils.Increased eosinophil precursors (frequently).Hypercellular marrow (usually).Blasts and maturing neutrophils reactive with antibodies to MPO and lysozyme.

With immunophenotyping, the blasts typically express one or more myeloid-associated antigens (CD13, CD33, and CD15). The differential diagnosis includes: RAEB in cases with a low blast percentage, AML without maturation when the blast percentage is high, and AMML in cases with increased monocytes.

Approximately 33% of karyotypically abnormal cases of AML with maturation are associated with t(8; 21)(q22;q22). (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information).[14] Such cases have a favorable prognosis. Rare cases with t(6; 9)(q23; q34) are reported to have a poor prognosis.[57,62]

Acute promyelocytic leukemia [AML with t(15; 17)(q22; q12); (PML/RARα) and variants] (FAB Classification M3)

(Refer to the Acute promyelocytic leukemia (FAB Classification M3) section of the Acute Myeloid Leukemia With Characteristic Genetic Abnormalities section of this summary for more information.)

Acute myelomonocytic leukemia (FAB Classification M4)

Acute myelomonocytic leukemia (AMML) is characterized by the proliferation of neutrophil and monocyte precursors. Patients usually present with anemia and thrombocytopenia. (Refer to the PDQ summary on Fatigue for more information on anemia.) This classification of AML comprises approximately 15% to 25% of cases of AML, and some patients have a previous history of chronic myelomonocytic leukemia (CMML). (Refer to the PDQ summary on Myelodysplastic/ Myeloproliferative Neoplasms for more information.) This type of AML occurs more commonly in older individuals.[57]

Morphologic and cytochemical features include the following:

20% or more blasts in the bone marrow.20% or more neutrophils, monocytes, and their precursors in the bone marrow (to distinguish AMML from AML with or without maturation and to increase monocytes).5 x 10 9 /L or more monocytes in the blood.Large monoblasts with round nuclei, abundant cytoplasm, and prominent nucleoli.MPO positivity in at least 3% of blasts.Monoblasts, promonocytes, and monocytes typically nonspecific esterase- (NSE) positive.

Immunophenotyping generally reveals monocytic differentiation markers (CD14, CD4, CD11b, CD11c, CD64, and CD36) and lysozyme. The differential diagnosis includes AML with maturation and acute monocytic leukemia.

Most cases of AMML exhibit nonspecific cytogenetic abnormalities.[57] Some cases may have a 11q23 genetic abnormality. Cases with increased abnormal eosinophils in the bone marrow associated with a chromosome 16 abnormality have a favorable prognosis. (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.)

Acute monoblastic leukemia and acute monocytic leukemia (FAB classifications M5a and M5b)

Acute monoblastic and acute monocytic leukemia are AMLs in which 80% or more of the leukemic cells are of a monocytic lineage. These cells include monoblasts, promonocytes, and monocytes. These two leukemias are distinguished by the relative proportions of monoblasts and promonocytes. In acute monoblastic leukemia, most monocytic cells are monoblasts (usually ≥80%). In acute monocytic leukemia, most of the monocytic cells are promonocytes.[57] Acute monoblastic leukemia comprises 5% to 8% of cases of AML and occurs most commonly in young individuals. Acute monocytic leukemia comprises 3% to 6% of cases and is more common in adults.[63] Common clinical features for both acute leukemias include bleeding disorders, extramedullary masses, cutaneous and gingival infiltration, and central nervous system involvement.

Morphologic and cytochemical features of acute monoblastic leukemia include the following:

Large basophilic monoblasts with abundant cytoplasm, pseudopod formation, round nuclei, and one or more prominent nucleoli.Rare Auer rods.Typically intensely NSE positive and MPO negative.Hypercellular marrow with large numbers of monoblasts.Lysozyme positive.

Morphologic and cytochemical features of acute monocytic leukemia include the following:

Promonocytes with an irregular nuclear configuration with a moderately basophilic cytoplasm and cytoplasmic azurophilic granules.Typically intensely NSE positive.Occasional MPO positivity.Lysozyme positive.Hemophagocytosis (erythrophagocytosis).

The extramedullary lesions of these leukemias may be predominantly monoblastic or monocytic or an admixture of the two cell types. Immunophenotyping of these leukemias may reveal expression of the myeloid antigens CD13, CD33, CD117, CD14 ( + ), CD4, CD36, CD 11b, CD11c, CD64, and CD68.[57] The differential diagnosis of acute monoblastic leukemia includes AML without maturation, minimally differentiated AML, and acute megakaryoblastic leukemia. The differential diagnosis of acute monocytic leukemia includes AMML and microgranular APL.

An abnormal karyotype has been observed in approximately 75% of cases of acute monoblastic leukemia while approximately 30% of cases of acute monocytic leukemia are associated with an abnormal karyotype. Almost 30% of cases of acute monoblastic leukemia and 12% of cases of acute monocytic leukemia are associated with 11q23 genetic abnormalities involving the MLL gene. (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.) Mutation of FLT3, a receptor tyrosine kinase gene, has been observed in about 30% of cases of acute monocytic leukemia (approximately 7% in acute monoblastic leukemia).[64] The translocation t(8;16)(p11; p13) (strongly associated with acute monocytic leukemia, hemophagocytosis by leukemic cells, and a poor response to chemotherapy) fuses the MOZ gene (8p11) with the CBP gene (16p13).[65] Median actuarial disease-free survival for acute monocytic leukemia has been reported to be approximately 21 months.[66]

Acute erythroid leukemias (FAB classifications M6a and M6b)

The two subtypes of the acute erythroid leukemias, erythroleukemia and pure erythroid leukemia, are characterized by a predominant erythroid population and, in the case of erythroleukemia, the presence of a significant myeloid component. Erythroleukemia (erythroid/myeloid; M6a) is predominantly a disease of adults, comprising approximately 5% to 6% of cases of AML.[63] Pure erythroid leukemia (M6b) is rare and occurs in all age groups. Occasional cases of chronic myeloid leukemia (CML) may evolve to one of the acute erythroid leukemias.[57] Erythroleukemia may present de novo or evolve from an MDS, either RAEB or RCMD-RS or RCMD. (Refer to the PDQ summary on Myelodysplastic Syndromes Treatment for more information.) The clinical features of these acute leukemias include profound anemia and normoblastemia. (Refer to the PDQ summary on Fatigue for more information.)

Morphologic and cytochemical features of erythroleukemia include the following:[57]

50% or more erythroid precursors in the entire nucleated cell population of the bone marrow.20% or more myeloblasts in the nonerythroid population in the bone marrow.Dysplastic erythroid precursors with megaloblastoid nuclei.Multinucleated erythroid cells.Myeloblasts of medium size, occasionally with Auer rods.Ringed sideroblasts.Positive PAS stain in the erythroid precursors.Hypercellular bone marrow.Megakaryocytic dysplasia.

Morphologic and cytochemical features of pure erythroid leukemia include the following:

Medium- to large-sized erythroblasts with round nuclei, fine chromatin, one or more nucleoli, deeply basophilic cytoplasm, and occasional coalescent vacuoles.Erythroblasts reactive with alpha-naphthyl acetate esterase.Acid phosphatase.PAS.

Immunophenotyping in erythroleukemia reveals erythroblasts that react with antibodies to glycophorin A and hemoglobin A and myeloblasts that express a variety of myeloid-associated antigens (CD13, CD33, CD117, c-kit, and MPO). Immunophenotyping in acute erythroid leukemia reveals expression of glycophorin A and hemoglobin A in differentiated forms. Markers such as carbonic anhydrase 1, Gero antibody against the Gerbich blood group, or CD36 are usually positive. The differential diagnosis for erythroleukemia includes RAEB and AML with maturation with increased erythroid precursors and AML with multilineage dysplasia (involving ≥50% of myeloid or megakaryocyte-lineage cells). If erythroid precursors are 50% or more and the nonerythroid component is 20% or more, the diagnosis is erythroleukemia, whereas, if the nonerythroid component is less than 20%, the diagnosis is RAEB. The differential diagnosis for pure erythroid leukemia includes megaloblastic anemia secondary to vitamin B 12 or folate deficiency, acute megakaryocytic leukemia, and ALL or lymphoma.[57]

No specific chromosome abnormalities are described for these AMLs. Complex karyotypes with multiple structural abnormalities are common. Chromosomes 5 and 7 appear to be affected frequently.[57,67,68] One study indicates that abnormalities of chromosomes 5 and/or 7 correlate with significantly shorter survival times.[69]

Acute megakaryoblastic leukemia (FAB Classification M7)

Acute megakaryoblastic leukemia, in which 50% or more of blasts are of the megakaryocyte lineage, occurs in all age groups and comprises approximately 3% to 5% of cases of AML.[57] Clinical features include cytopenias; dysplastic changes in neutrophils and platelets; rare organomegaly, except in children with t(1; 22); lytic bone lesions in children; and association with mediastinal germ cell tumors in young adult males.[57,70,71]

Morphologic and cytochemical features include the following:[57,70,72]

Medium- to large-sized megakaryoblasts with round or indented nucleus and one or more nucleoli.Agranular, basophilic cytoplasm with pseudopod formation.Lymphoblast-like morphology (high nuclear-cytoplasmic ratio) in some cases.Circulating micromegakaryocytes, megakaryoblastic fragments, dysplastic large platelets, and hypogranular neutrophils.Stromal pattern of marrow infiltration mimicking a metastatic tumor in infants.Negative stains for SBB and MPO.Blasts reactive with PAS, acid phosphatase, and nonspecific esterase.

Immunophenotyping reveals megakaryoblast expression of one or more platelet glycoproteins: CD41 (glycoprotein IIb/IIIa) and/or CD61 (glycoprotein IIIa). Myeloid markers CD13 and CD33 may be positive; CD36 is typically positive. Blasts are negative with the anti-MPO antibody and other markers of myeloid differentiation. In bone marrow biopsies, megakaryocytes and megakaryoblasts may react positively to antibodies for Factor VIII.[57] The differential diagnosis includes minimally differentiated AML, acute panmyelosis with myelofibrosis, ALL, pure erythroid leukemia, and blastic transformation of chronic myeloid leukemia or idiopathic myelofibrosis and metastatic tumors in the bone marrow (particularly in children). (Refer to the PDQ summary on Chronic Myeloproliferative Disorders Treatment for more information on chronic myeloid leukemia or idiopathic myelofibrosis).

No unique chromosomal abnormalities are associated with acute megakaryoblastic leukemia in adults.[57,73] In children, particularly infants, a distinct clinical presentation may be associated with t(1:22)(p13; q13).[70,72] The prognosis for this type of acute leukemia is poor.[74,75]

Variant: Acute myeloid leukemia/transient myeloproliferative disorder in Down syndrome

Individuals with Down syndrome (trisomy 21) have an increased disposition to acute leukemia, primarily the myeloid type.[76,77] The primary subtype appears to be acute megakaryoblastic leukemia. In cases in which the leukemia remits spontaneously, the process is referred to as transient myeloproliferative disorder or transient leukemia. Clinical features include presentation in the neonatal period (10% of newborn infants with Down syndrome), marked leukocytosis, blast percentage in the blood greater than 30% to 50%, and extramedullary involvement.

Morphologic and cytochemical features include the following:

Blasts with round to slightly irregular nuclei and a moderate amount of basophilic cytoplasm.Coarse azurophilic granules in the cytoplasm that resemble basophil granules.Promegakaryocytes and micromegakaryocytes.Dyserythropoiesis.MPO-negative and SBB-negative blasts.

Immunophenotyping reveals markers that are generally similar to those of other cases of childhood acute megakaryoblastic leukemia.

In addition to trisomy 21, some cases may show other clonal abnormalities, particularly trisomy 8.[77,78] Spontaneous remission occurs within 1 to 3 months in transient cases. Recurrence followed by a second spontaneous remission or persistent disease may occur. Treatment outcomes for pediatric patients with Down syndrome and persistent disease may be better than those for pediatric patients with acute leukemia in the absence of trisomy 21.[75]

Acute basophilic leukemia

Acute basophilic leukemia is an AML that exhibits a primary differentiation to basophils. This acute leukemia is relatively rare, comprising less than 1% of all cases of AML.[57] Clinical features include bone marrow failure, circulating blasts, cutaneous involvement, organomegaly, occasional osseous lytic lesions, and symptoms secondary to hyperhistaminemia.

Morphologic and cytochemical features include the following:

Medium-sized blasts with a high nuclear-cytoplasmic ratio and an oval, round, or bilobed nucleus with one or more nucleoli.Moderately basophilic cytoplasm containing a variable number of coarse basophilic granules.Sparse numbers of mature basophils.Dysplastic erythroid features.Blasts with metachromatic positivity, with toluidine blue.Blasts with acid phosphatase positivity.Negative by light microscopy for SBB, MPO, and nonspecific esterase.Hypercellular bone marrow.

Immunophenotypically, the blasts express the myeloid markers CD13 and CD33 and the early hematopoietic markers CD34 and class-II HLA-DR. The differential diagnosis includes: blast crisis of CML, other AML subtypes with basophilia such as AML with maturation (M2) associated with abnormalities of 12p or t(6;9), acute eosinophilic leukemia, and, rarely, a subtype of ALL with prominent coarse granules.[57]

No consistent chromosome abnormality has been identified for acute basophilic leukemia.[57] Due to its rare incidence, little information regarding survival is available.

Acute panmyelosis with myelofibrosis

Acute panmyelosis with myelofibrosis (also known as acute myelofibrosis, acute myelosclerosis, and acute myelodysplasia with myelofibrosis) is an acute panmyeloid proliferation associated with fibrosis of the bone marrow. This disorder is very rare and occurs in all age groups.[57] The disorder may occur de novo or after treatment with alkylating-agent chemotherapy and/or radiation (Refer to the section on Acute myeloid leukemias and myelodysplastic syndromes, therapy related of this summary for more information). Clinical features include constitutional symptoms such as weakness and fatigue. (Refer to the PDQ summary on Fatigue for more information.)

Morphologic and cytochemical features include the following:

Marked pancytopenia.Anisocytosis.Dysplastic changes in myeloid cells.Hypercellular bone marrow (biopsy).Variable degrees of hyperplasia of erythroid precursors, granulocytes, and megakaryocytes in the bone marrow.Increased number of small- to large-sized megakaryocytes with dysplastic features in the bone marrow.Marked increase in reticulin fibers in the bone marrow.

Immunophenotypically, blasts may express one or more myeloid-associated antigens (CD13, CD33, CD117, and MPO). Some cells may express erythroid or megakaryocytic antigens. The major differential diagnosis includes acute megakaryoblastic leukemia, acute leukemias with associated marrow fibrosis, metastatic tumor with a desmoplasmic reaction, and chronic idiopathic myelofibrosis.[57] (Refer to the PDQ summary on Chronic Myeloproliferative Disorders Treatment for more information.)

No specific chromosomal abnormalities are associated with acute panmyelosis with myelofibrosis. This AML is reported to respond poorly to chemotherapy and to be associated with a short survival.[57]

Myeloid sarcoma

Myeloid sarcoma (also known as extramedullary myeloid tumor, granulocytic sarcoma, and chloroma) is a tumor mass that consists of myeloblasts or immature myeloid cells, occurring in an extramedullary site;[57] development in 2% to 8% of patients with AML has been reported.[79] Clinical features include occurrence common in subperiosteal bone structures of the skull, paranasal sinuses, sternum, ribs, vertebrae, and pelvis; lymph nodes, skin, mediastinum, small intestine, and the epidural space; and occurrence de novo or concomitant with AML or a myeloproliferative disorder.[57,79]

Morphologic and cytochemical features include the following:

Granulocytic sarcoma composed of myeloblasts, neutrophils, and neutrophil precursors with three subtypes based on degree of maturation (ie, blastic, immature, and differentiated).Monoblastic sarcoma preceding or occurring simultaneously with acute monoblastic leukemia.Tumors with trilineage hematopoiesis occurring with transformation of chronic myeloproliferative disorders.Myeloblasts and neutrophils positive for MPO.Neutrophils positive for naphthol ASD chloroacetate esterase.

Immunophenotyping with antibodies to MPO, lysozyme, and chloroacetate are critical to the diagnosis of these lesions.[57] The myeloblasts in granulocytic sarcomas express myeloid-associated antigens (CD13, CD33, CD117, and MPO). The monoblasts in monoblastic sarcomas express acute monoblastic leukemia antigens (CD14, CD116, and CD11c) and usually react with antibodies to lysozyme and CD68. The main differential diagnosis includes non-Hodgkin lymphoma of the lymphoblastic type, Burkitt lymphoma, large-cell lymphoma, and small round cell tumors, especially in children (eg, neuroblastoma, rhabdomyosarcoma, Ewing/primitive neuroectodermal tumors, and medulloblastoma).

No unique chromosomal abnormalities are associated with myeloid sarcoma.[57,79] AML with maturation and t(8; 21)(q22; q22) and AMML Eo with in (16)(p13; q22) or t(16;16)(p13; q22) may be observed and monoblastic sarcoma may be associated with translocations involving 11q23.[57] The presence of myeloid sarcoma in patients with the otherwise good-risk t(8; 21) AML may be associated with a lower complete remission rate and decreased remission duration.[80] Myeloid sarcoma occurring in the setting of MDS or MPD is equivalent to blast transformation. In the case of AML, the prognosis is that of the underlying leukemia.[57] Although the initial presentation of myeloid sarcoma may appear to be isolated, several reports indicate that isolated myeloid sarcoma is a partial manifestation of a systemic disease and should be treated with intensive chemotherapy.[79,81,82]

Acute Leukemias of Ambiguous Lineage

Acute leukemias of ambiguous lineage (also known as acute leukemias of undetermined lineage, mixed phenotype acute leukemias, mixed lineage acute leukemias, and hybrid acute leukemias) are types of acute leukemia in which the morphologic, cytochemical, and immunophenotypic features of the blast population do not allow classification in myeloid or lymphoid categories; or the types have morphologic and/or immunophenotypic features of both myeloid and lymphoid cells or both B and T lineages (ie, acute bilineal leukemia and acute biphenotypic leukemia).[83,84,85,86,87] These rare leukemias account for less than 4% of all cases of acute leukemia and occur in all age groups but are more frequent in adults.[83] Clinical features include symptoms and complications caused by cytopenias, ie, fatigue, infections, and bleeding disorders. (Refer to the PDQ summary on Fatigue for more information.)

Morphologic and immunophenotypic features of these acute leukemias include the following:[83,84,86,87]

Undifferentiated acute leukemia in which the leukemic cells lack any differentiating characteristics and lack markers for a given lineage.Bilineal acute leukemia in which a dual population of blasts exhibits morphologic features and markers of two distinct lineages, ie, myeloid and lymphoid or B and T.Biphenotypic acute leukemia in which the blasts exhibit the morphological features of only one lineage but express markers of more than one lineage.

The differential diagnosis includes myeloid antigen-positive ALL or lymphoid-positive AML (from which biphenotypic acute leukemia should be distinguished) and minimally differentiated AML (from which undifferentiated acute leukemia must be distinguished).

Cytogenetic abnormalities are observed in a high percentage of bilineal and biphenotypic leukemias.[84,85,88,89] Approximately 33% of cases have the Philadelphia chromosome, and some cases are associated with t(4; 11)(q21; q23) or other 11q23 abnormalities. In general, the prognosis appears to be unfavorable, particularly in adults; the occurrence of the translocation t(4; 11) or the Philadelphia chromosome are especially unfavorable prognostic indicators.[83,85,90]

Références:

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51. Ellis M, Ravid M, Lishner M: A comparative analysis of alkylating agent and epipodophyllotoxin-related leukemias. Leuk Lymphoma 11 (1-2): 9-13, 1993.
52. Olney HJ, Mitelman F, Johansson B, et al.: Unique balanced chromosome abnormalities in treatment-related myelodysplastic syndromes and acute myeloid leukemia: report from an international workshop. Genes Chromosomes Cancer 33 (4): 413-23, 2002.
53. Mauritzson N, Albin M, Rylander L, et al.: Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5098 unselected cases reported in the literature 1974-2001. Leukemia 16 (12): 2366-78, 2002.
54. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, et al.: Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 99 (6): 1909-12, 2002.
55. Leone G, Voso MT, Sica S, et al.: Therapy related leukemias: susceptibility, prevention and treatment. Leuk Lymphoma 41 (3-4): 255-76, 2001.
56. Bloomfield CD, Archer KJ, Mrózek K, et al.: 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer 33 (4): 362-78, 2002.
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59. Roumier C, Eclache V, Imbert M, et al.: M0 AML, clinical and biologic features of the disease, including AML1 gene mutations: a report of 59 cases by the Groupe Français d'Hématologie Cellulaire (GFHC) and the Groupe Français de Cytogénétique Hématologique (GFCH). Blood 101 (4): 1277-83, 2003.
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61. Abu-Duhier FM, Goodeve AC, Wilson GA, et al.: FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol 111 (1): 190-5, 2000.
62. Alsabeh R, Brynes RK, Slovak ML, et al.: Acute myeloid leukemia with t(6;9) (p23;q34): association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype. Am J Clin Pathol 107 (4): 430-7, 1997.
63. Stanley M, McKenna RW, Ellinger G, et al.: Classification of 358 cases of acute myeloid leukemia by FAB criteria: analysis of clinical and morphologic features. In: Bloomfield CD, ed.: Chronic and Acute Leukemias in Adults. Boston, Ma: Martinus Nijhoff Publishers, 1985, pp 147-74.
64. Haferlach T, Schoch C, Schnittger S, et al.: Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients. Br J Haematol 118 (2): 426-31, 2002.
65. Panagopoulos I, Isaksson M, Lindvall C, et al.: Genomic characterization of MOZ/CBP and CBP/MOZ chimeras in acute myeloid leukemia suggests the involvement of a damage-repair mechanism in the origin of the t(8;16)(p11;p13). Genes Chromosomes Cancer 36 (1): 90-8, 2003.
66. Fenaux P, Vanhaesbroucke C, Estienne MH, et al.: Acute monocytic leukaemia in adults: treatment and prognosis in 99 cases. Br J Haematol 75 (1): 41-8, 1990.
67. Cigudosa JC, Odero MD, Calasanz MJ, et al.: De novo erythroleukemia chromosome features include multiple rearrangements, with special involvement of chromosomes 11 and 19. Genes Chromosomes Cancer 36 (4): 406-12, 2003.
68. Domingo-Claros A, Larriba I, Rozman M, et al.: Acute erythroid neoplastic proliferations. A biological study based on 62 patients. Haematologica 87 (2): 148-53, 2002.
69. Olopade OI, Thangavelu M, Larson RA, et al.: Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia. Blood 80 (11): 2873-82, 1992.
70. Bernstein J, Dastugue N, Haas OA, et al.: Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from at(1;22) study group. Leukemia 14 (1): 216-8, 2000.
71. Nichols CR, Roth BJ, Heerema N, et al.: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 322 (20): 1425-9, 1990.
72. Carroll A, Civin C, Schneider N, et al.: The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study. Blood 78 (3): 748-52, 1991.
73. Dastugue N, Lafage-Pochitaloff M, Pagès MP, et al.: Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood 100 (2): 618-26, 2002.
74. Pagano L, Pulsoni A, Vignetti M, et al.: Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 16 (9): 1622-6, 2002.
75. Athale UH, Razzouk BI, Raimondi SC, et al.: Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience. Blood 97 (12): 3727-32, 2001.
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There is no clear-cut staging system for this disease.

Untreated

Untreated adult acute myeloid leukemia (AML) is defined as newly diagnosed leukemia with no previous treatment. The patient exhibits the following features: abnormal bone marrow with at least 20% blasts and signs and symptoms of the disease, usually accompanied by an abnormal white blood cell count and differential, an abnormal hematocrit/hemoglobin count, and an abnormal platelet count.

In Remission

Adult acute myeloid leukemia (AML) in remission is defined as a normal peripheral blood cell count (absolute neutrophil count >1,000/mm 3 and platelet count >100,000/mm 3 ) [1] and normocellular marrow with less than 5% blasts in the marrow and no signs or symptoms of the disease. In addition, no signs or symptoms are evident of central nervous system leukemia or other extramedullary infiltration. Because the vast majority of AML patients meeting these criteria for remission have residual leukemia, modifications to the definition of complete remission have been suggested, including cytogenetic remission, in which a previously abnormal karyotype reverts to normal, and molecular remission, in which interphase fluorescence in situ hybridization (FISH) or multiparameter flow cytometry are used to detect minimal residual disease. Immunophenotyping and interphase FISH have greater prognostic significance than the conventional criteria for remission.[2,3]

Les essais cliniques actuels

Check for US clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute myeloid leukemia. La liste des essais cliniques peut être encore réduit par emplacement, la drogue, l'intervention, et d'autres critères.

Informations générales sur les essais cliniques est également disponible sur le site Web du NCI.

Références:

1. Cheson BD, Cassileth PA, Head DR, et al.: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8 (5): 813-9, 1990.
2. Cheson BD, Bennett JM, Kopecky KJ, et al.: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21 (24): 4642-9, 2003.
3. Bacher U, Kern W, Schoch C, et al.: Evaluation of complete disease remission in acute myeloid leukemia: a prospective study based on cytomorphology, interphase fluorescence in situ hybridization, and immunophenotyping during follow-up in patients with acute myeloid leukemia. Cancer 106 (4): 839-47, 2006.

Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[1,2,3]

Treatment is divided into two phases: remission induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States, other than for acute promyelocytic leukemia. (Refer to the Adult Acute Myeloid Leukemia in Remission section of this summary for more information.) Other studies have used more intensive postremission therapy administered for a shorter duration of time after which treatment is discontinued.[4] postremission therapy appears to be effective when given immediately after remission is achieved. [4]

Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions, as well as for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm 3 rather than 20,000/mm 3 .[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony-stimulating factors, eg, granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage colony–stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in a randomized trial of AML in patients aged 55 to 70 years (median survival was 10.6 months vs. 4.8 months). In this Eastern Cooperative Oncology Group (ECOG) (EST-1490) trial, patients were randomized to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow;[9] however, GM-CSF did not show benefit in a separate similar randomized trial in patients aged 60 years and older.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a Southwest Oncology Group (NCT00023777) randomized trial of G-CSF given following induction therapy to patients older than 65 years, complete response was higher in patients who received G-CSF, due to a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11,12] Because the majority of randomized clinical trials have not shown an impact of growth factors on survival, their use is not routinely recommended in the remission induction setting.

The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and postremission therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[13,14][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML aged 55 to 75 years showed improved disease-free survival in the group receiving GM-CSF (median disease-free survival for patients who achieved complete remission was 23 months vs. 11 months; 2-year disease-free survival was 48% vs. 21%), with a trend towards improvement in overall survival (2-year survival was 39% vs. 27%, P = .082) for patients aged 55 to 64 years.[15][Level of evidence: 1iiDii]

Références:

1. Kebriaei P, Champlin R, deLima M, et al.: Management of acute leukemias. Dans: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principes et pratique de l'oncologie. 9e éd. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1928-54.
2. Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3e éd. New York, NY: Churchill Livingstone, 1996, pp 283-302.
3. Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6 (7): 708-14, 1992.
4. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992.
5. Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3e éd. New York, NY: Churchill Livingstone, 1996, pp 779-967.
6. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337 (26): 1870-5, 1997.
7. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997.
8. Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996.
9. Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86 (2): 457-62, 1995.
10. Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 332 (25): 1671-7, 1995.
11. Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 332 (25): 1678-83, 1995.
12. Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 91 (10): 3607-15, 1998.
13. Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. [Abstract] Blood 84 (10 Suppl 1): A-95, 27a, 1994.
14. Löwenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15 (12): 3496-506, 1997.
15. Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91 (8): 2722-30, 1998.

The two-drug regimen of daunorubicin given in conjunction with cytarabine will result in a complete response rate of approximately 65%. Some physicians opt to add a third drug, thioguanine, to this regimen, though little evidence is available to conclude that this three-drug regimen is better therapy. One study suggested that the addition of etoposide during induction therapy may improve response duration.[1] Idarubicin appeared to be more effective than daunorubicin, particularly in younger adults, though the doses of idarubicin and daunorubicin may not have been equivalent.[2,3,4,5] No significant survival difference between daunorubicin and mitoxantrone has been reported.[6]

The role of high-dose cytarabine in induction therapy is controversial; randomized trials have shown prolongation of disease-free survival [7,8] or no effect [9,10] compared with conventionally dosed cytarabine-based induction chemotherapy. Post hoc analyses of two negative trials suggested potential benefit for the intensified therapy in subsets of patients at high risk for treatment failure;[9,10] however, an analysis of a subset of patients with complex cytogenetic abnormalities treated in a randomized multicenter trial in Germany showed improvement in complete remission (CR) rate with minimal improvement in event-free survival (EFS) (CR = 56% vs. 23%; P = .04; median EFS = 1 month vs. 2 months; P = .04).[11][Level of evidence: 1iiDii]

AML arising from myelodysplasia or secondary to previous cytotoxic chemotherapy has a lower rate of remission than de novo AML. A retrospective analysis of patients undergoing allogeneic BMT in this setting showed that the long-term survival for such patients was identical regardless of whether or not patients had received remission induction therapy (disease-free survival was approximately 20%). These data suggest that patients with these subsets of leukemia may be treated primarily with allogeneic BMT if their overall performance status is adequate, potentially sparing patients the added toxic effect of induction chemotherapy.[12][Level of evidence: 3iiiDii]

Older adults who decline intensive remission induction therapy or are considered unfit for intensive remission induction therapy may derive benefit from low-dose cytarabine, administered twice daily for 10 days in cycles repeated every 4 to 6 weeks. The complete remission rate using this regimen was 18% compared to 1% for patients treated with hydroxyurea ( P = .006).[13] Survival with low-dose cytarabine was better than survival was with hydroxyurea (OR = 0.60; 95% confidence interval, 0.44–0.81; P = .009).[13][Level of evidence: 1iiA]

Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate.[14,15] Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[16,17] Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities (including filtered air, sterile food, and gut flora sterilization) are not routinely indicated but may benefit transplant patients.[18,19] Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm 3 for 2 weeks).[20] Norfloxacin and ciprofloxacin have been shown to decrease the incidence of gram-negative infection and time to first fever in randomized trials. The combination of ofloxacin and rifampin has proven superior to norfloxacin in decreasing the incidence of documented granulocytopenic infection.[21,22,23] Serial surveillance cultures may be helpful in such patients to detect the presence or acquisition of resistant organisms.

A long-term follow-up of 30 patients who had AML that was in remission for at least 10 years has demonstrated a 13% incidence of secondary malignancies. Of 31 long-term female survivors of AML or acute lymphoblastic leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, 2 congenital problems occurred.[24]

Acute Promyelocytic Leukemia

Special consideration must be given to induction therapy for acute promyelocytic leukemia (PML). Oral administration of tretinoin (all-trans-retinoic acid (ATRA); 45 mg/mm 2 /day) can induce remission in 70% to 90% of patients with M3 AML. (ATRA is not effective in patients with AML that resembles M3 morphologically but does not demonstrate the t(15;17) or typical PML-RARα gene rearrangement.)[25,26,27,28,29,30,31] ATRA induces terminal differentiation of the leukemic cells followed by restoration of nonclonal hematopoiesis. Administration of ATRA leads to rapid resolution of coagulopathy in most patients, and heparin administration is not required in patients receiving ATRA. However, randomized trials have not shown a reduction in morbidity and mortality during ATRA induction when compared with chemotherapy. Administration of ATRA can lead to hyperleukocytosis as well as a syndrome of respiratory distress now known as the differentiation syndrome. Prompt recognition of the syndrome and aggressive administration of steroids can prevent severe respiratory distress.[32] The optimal management of ATRA-induced hyperleukocytosis has not been established; neither has the optimal postremission management of patients who receive ATRA induction. However, two large cooperative group trials have demonstrated a statistically significant relapse-free and overall survival (OS) advantage to patients with M3 AML who receive ATRA at some point during their antileukemic management.[33,34]

A randomized study has shown that the relapse rate was reduced in patients treated with concomitant ATRA and chemotherapy compared with ATRA induction followed by chemotherapy given in remission (relative risk [RR] of relapse at 2 years, 0.41; P = .04).[35][Level of evidence: 1iiDii] This trial also showed a disease-free survival benefit to maintenance therapy, which consisted of either 6-mercaptopurine plus methotrexate (RR of relapse, 0.41), intermittent ATRA (RR of relapse, 0.62), or a combination of all three drugs. The use of 6-mercaptopurine and methotrexate also produced an improvement in OS (RR of relapse, 0.36; P = .005). Two concurrent clinical trials separately conducted in Italy and Spain included ATRA plus anthracycline induction followed by three cycles of postremission and maintenance therapy. The two treatment protocols differed only in the addition of nonanthracycline drugs during postremission therapy cycles in the Italian study; doses of anthracyclines were identical between the two trials. Essentially identical relapse-free survival suggests that the nonanthracycline drugs (ie, cytarabine, etoposide, and 6-thioguanine) may not contribute significantly to the outcome of patients with acute promyelocytic leukemia induced with ATRA plus anthracycline.[36][Level of evidence: 3iiiDii]

In contrast, a trial randomly assigned low-risk patients (age < 60, white blood cell count [WBC] < 10,000/mm 3 ) to receive all- trans -retinoic acid (ATRA) and daunorubicin as induction therapy, followed by daunorubicin consolidation and ATRA plus mercaptopurine plus methotrexate as maintenance therapy.[37] Patients were randomly assigned to receive cytarabine in the induction and consolidation modules, or not. The trial was stopped at an early interim analysis following randomization of 172 patients. The cytarabine group demonstrated a superior 2-year relapse rate (4.7% vs. 15.9%, P = .011), 2-year EFS (93.3% vs. 77.2%, P = .002), and 2-year OS (97.9% vs. 89.6%, P = .007).[37][Level of evidence: 3iiiA] The latter study used a different chemotherapy platform than the one used by the Italian and Spanish groups, which reported no benefit to cytarabine.

Studies are beginning to examine the inclusion of arsenic trioxide (ATO) in the management of previously untreated patients. In one trial, 85 newly diagnosed patients were treated with ATRA plus ATO until remission; hydroxyurea or idarubicin and cytarabine were added if the WBC was greater than 10,000/mm 3 .[38] This was followed by three cycles of consolidation (ara-C plus daunorubicin, plus cytarabine, and ara-C plus homoharringtonine) and maintenance with five cycles of sequential ATRA (1 month), ATO (1 month) and 6-mercaptopurine plus methotrexate (1 month). Eighty patients achieved remission with five induction deaths. Four relapses developed between 8 months and 39 months following remission attainment, all of which were in the central nervous system. Five-year event-free survival (EFS) was 89%.[38]

In another trial, investigators used an ATO-based regimen, which included gemtuzumab ozogamycin (GO) as the only cytotoxic drug.[39] Patients received ATRA plus ATO induction; patients also received a dose of GO if the WBC was greater than 10,000/mm 3 on presentation or rose to over 30,000/mm 3 during induction. Patients in remission received alternating months of ATO and ATRA for a total of seven cycles; GO was substituted if either ATO or ATRA were discontinued as a result of toxicity. Eighty-two patients were treated; seven patients died during induction, the remainder achieved remission. Three patients relapsed and four patients died during remission; thus EFS was approximately 76%.

Presence of the unique fusion transcript PML-RARα (measured in bone marrow by polymerase chain reaction) in patients who achieve complete remission may indicate those who are likely to relapse early.[40] In addition, a retrospective review of randomized trials from the Southwest Oncology Group suggested that the dose-intensity of daunorubicin administered in induction and postremission chemotherapy may significantly impact on remission rate, disease-free survival, and OS in patients with M3 AML.[41] Although most patients currently receive ATRA in their induction therapy, for patients who do not, careful management of coagulopathy is required. Coagulopathy is occasionally a problem in patients undergoing induction with ATRA plus chemotherapy. This coagulopathy can lead to catastrophic intracranial bleeding but can be well-controlled with low-dose heparin infusion (in the setting of clotting) or with aggressive replacement of platelets and clotting factors.[42]

Treatment options for remission induction therapy:

1. One of the following equivalent combination chemotherapy regimens:

Cytarabine plus daunorubicin.[43,44]Cytarabine plus idarubicin.[2,3,4,5]Cytarabine plus mitoxantrone.[45]Dose-intensive cytarabine-based induction therapy.[7,8]Cytarabine plus daunorubicin plus thioguanine.[46]
2. Treatment of central nervous system leukemia, if present:

Intrathecal cytarabine or methotrexate.
3. Les essais cliniques.

Les essais cliniques actuels

Check for US clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated adult acute myeloid leukemia. La liste des essais cliniques peut être encore réduit par emplacement, la drogue, l'intervention, et d'autres critères.

Informations générales sur les essais cliniques est également disponible sur le site Web du NCI.

Références:

1. Bishop JF, Lowenthal RM, Joshua D, et al.: Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group. Blood 75 (1): 27-32, 1990.
2. Wiernik PH, Banks PL, Case DC Jr, et al.: Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79 (2): 313-9, 1992.
3. Vogler WR, Velez-Garcia E, Weiner RS, et al.: A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol 10 (7): 1103-11, 1992.
4. Berman E, Heller G, Santorsa J, et al.: Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77 (8): 1666-74, 1991.
5. Mandelli F, Petti MC, Ardia A, et al.: A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. A multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer 27 (6): 750-5, 1991.
6. Arlin Z, Case DC Jr, Moore J, et al.: Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group. Leukemia 4 (3): 177-83, 1990.
7. Bishop JF, Matthews JP, Young GA, et al.: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87 (5): 1710-7, 1996.
8. Geller RB, Burke PJ, Karp JE, et al.: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74 (5): 1499-506, 1989.
9. Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996.
10. Büchner T, Hiddemann W, Wörmann B, et al.: Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 93 (12): 4116-24, 1999.
11. Schoch C, Haferlach T, Haase D, et al.: Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients. Br J Haematol 112 (1): 118-26, 2001.
12. Anderson JE, Gooley TA, Schoch G, et al.: Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood 89 (7): 2578-85, 1997.
13. Burnett AK, Milligan D, Prentice AG, et al.: A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109 (6): 1114-24, 2007.
14. Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980.
15. Murphy MF, Metcalfe P, Thomas H, et al.: Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization. Br J Haematol 62 (3): 529-34, 1986.
16. Hughes WT, Armstrong D, Bodey GP, et al.: From the Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 161 (3): 381-96, 1990.
17. Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988.
18. Armstrong D: Symposium on infectious complications of neoplastic disease (Part II). Protected environments are discomforting and expensive and do not offer meaningful protection. Am J Med 76 (4): 685-9, 1984.
19. Sherertz RJ, Belani A, Kramer BS, et al.: Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 83 (4): 709-18, 1987.
20. Wade JC, Schimpff SC, Hargadon MT, et al.: A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia. N Engl J Med 304 (18): 1057-62, 1981.
21. Karp JE, Merz WG, Hendricksen C, et al.: Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. A, en double aveugle, randomisée contrôlée par placebo. Ann Intern Med 106 (1): 1-7, 1987.
22. Prevention of bacterial infection in neutropenic patients with hematologic malignancies. A randomized, multicenter trial comparing norfloxacin with ciprofloxacin. The GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. Ann Intern Med 115 (1): 7-12, 1991.
23. Bow EJ, Mandell LA, Louie TJ, et al.: Quinolone-based antibacterial chemoprophylaxis in neutropenic patients: effect of augmented gram-positive activity on infectious morbidity. National Cancer Institute of Canada Clinical Trials Group. Ann Intern Med 125 (3): 183-90, 1996.
24. Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001.
25. Huang ME, Ye YC, Chen SR, et al.: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72 (2): 567-72, 1988.
26. Castaigne S, Chomienne C, Daniel MT, et al.: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 76 (9): 1704-9, 1990.
27. Warrell RP Jr, Frankel SR, Miller WH Jr, et al.: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 324 (20): 1385-93, 1991.
28. Chen ZX, Xue YQ, Zhang R, et al.: A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood 78 (6): 1413-9, 1991.
29. Muindi J, Frankel SR, Miller WH Jr, et al.: Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia. Blood 79 (2): 299-303, 1992.
30. Licht JD, Chomienne C, Goy A, et al.: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85 (4): 1083-94, 1995.
31. Gallagher RE, Li YP, Rao S, et al.: Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid. Blood 86 (4): 1540-7, 1995.
32. Frankel SR, Eardley A, Lauwers G, et al.: The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med 117 (4): 292-6, 1992.
33. Fenaux P, Le Deley MC, Castaigne S, et al.: Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 82 (11): 3241-9, 1993.
34. Tallman MS, Andersen J, Schiffer CA, et al.: Phase III randomized study of all-trans retinoic acid (ATRA) vs daunorubicin (D) and cytosine arabinoside (A) as induction therapy and ATRA vs observation as maintenance therapy for patients with previously untreated acute promyelocytic leukemia (APL). [Abstract] Blood 86 (10 Suppl 1): A-488, 125a, 1995.
35. Fenaux P, Chastang C, Chevret S, et al.: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 (4): 1192-200, 1999.
36. Sanz MA, Lo Coco F, Martín G, et al.: Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96 (4): 1247-53, 2000.
37. Adès L, Chevret S, Raffoux E, et al.: Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol 24 (36): 5703-10, 2006.
38. Hu J, Liu YF, Wu CF, et al.: Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 106 (9): 3342-7, 2009.
39. Ravandi F, Estey E, Jones D, et al.: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27 (4): 504-10, 2009.
40. Lo Coco F, Diverio D, Pandolfi PP, et al.: Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia. Lancet 340 (8833): 1437-8, 1992.
41. Head D, Kopecky KJ, Weick J, et al.: Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood 86 (5): 1717-28, 1995.
42. Stone RM, Mayer RJ: The unique aspects of acute promyelocytic leukemia. J Clin Oncol 8 (11): 1913-21, 1990.
43. Yates J, Glidewell O, Wiernik P, et al.: Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 60 (2): 454-62, 1982.
44. Dillman RO, Davis RB, Green MR, et al.: A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 78 (10): 2520-6, 1991.
45. Löwenberg B, Suciu S, Archimbaud E, et al.: Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol 16 (3): 872-81, 1998.
46. Gale RP, Foon KA, Cline MJ, et al.: Intensive chemotherapy for acute myelogenous leukemia. Ann Intern Med 94 (6): 753-7, 1981.

Although individual patients have been reported to have long disease-free survival (DFS) or cure with a single cycle of chemotherapy,[1] postremission therapy is always indicated in therapy that is planned with curative intent. In a small randomized study conducted by the Eastern Cooperative Oncology Group (ECOG), all patients who did not receive postremission therapy experienced a relapse after a short median complete remission duration.[2] Current approaches to postremission therapy include short-term, relatively intensive chemotherapy with cytarabine-based regimens similar to standard induction clinical trials (postremission chemotherapy), postremission chemotherapy with more dose-intensive cytarabine-based treatment, high-dose chemotherapy or chemoradiation therapy with autologous bone marrow rescue, and high-dose marrow-ablative therapy with allogeneic bone marrow rescue. While older studies have included longer-term therapy at lower doses (maintenance), no convincing evidence is available with acute myeloid leukemia (AML) that maintenance therapy provides prolonged disease-free survival (DFS) beyond shorter-term, more dose-intensive approaches, and few current treatment clinical trials include maintenance therapy.

Nontransplant postremission therapy using cytarabine-containing regimens has treatment-related death rates that are usually less than 10% to 20% and have yielded reported long-term DFS rates from 20% to 50%.[3,4,5,6] A large randomized trial that compared three different cytarabine-containing postremission therapy regimens showed a clear benefit in survival to patients younger than 60 years who received high-dose cytarabine.[3] Intensification of cytarabine dose or duration of postremission chemotherapy with conventionally dosed cytarabine did not improve disease-free or OS in patients aged 60 years or older, as evidenced in the Medical Research Council (MRC-LEUK-AML11) trial.[7,8] The duration of postremission therapy has ranged from one cycle [4,6] to four or more cycles.[3,5] The optimal doses, schedules, and duration of postremission chemotherapy have not been determined. Therefore, to address these issues, patients with AML should be included in clinical trials at institutions that treat large numbers of such patients.

Dose-intensive cytarabine-based chemotherapy can be complicated by severe neurologic [9] and/or pulmonary toxic effects [10] and should be administered by physicians experienced in these regimens at centers that are equipped to deal with potential complications. In a retrospective analysis of 256 patients who received high-dose bolus cytarabine at a single institution, the most powerful predictor of cytarabine neurotoxicity was renal insufficiency. The incidence of neurotoxicity was significantly greater in patients treated with twice daily doses of 3 g/m 2 /dose when compared with 2 g/m 2 /dose.

Allogeneic bone marrow transplantation (BMT) results in the lowest incidence of leukemic relapse, even when compared with BMT from an identical twin (syngeneic BMT). This has led to the concept of an immunologic graft-versus-leukemia effect, similar to (and related to) graft-versus-host disease. The improvement in freedom from relapse using allogeneic BMT as the primary postremission therapy is offset, at least in part, by the increased morbidity and mortality caused by graft-versus-host disease, veno-occlusive disease of the liver, and interstitial pneumonitis. The DFS rates using allogeneic transplantation in first complete remission have ranged from 45% to 60%.[11,12,13] The use of allogeneic BMT as primary postremission therapy is limited by the need for a human leukocyte antigen (HLA)-matched sibling donor and the increased mortality from allogeneic BMT of patients who are older than 50 years. The mortality from allogeneic BMT that uses an HLA-matched sibling donor ranges from 20% to 40%, depending on the series. The use of matched, unrelated donors for allogeneic BMT is being evaluated at many centers but has a very substantial rate of treatment-related mortality, with DFS rates less than 35%.[14] Retrospective analysis of data from the International Bone Marrow Transplant Registry suggests that postremission chemotherapy does not lead to an improvement in DFS or OS for patients in first remission undergoing allogeneic BMT from an HLA-identical sibling.[15][Level of evidence: 3iiiA]

A common clinical trial design used to evaluate the benefit of allogeneic transplant as consolidation therapy for AML in first remission is the so-called donor-no donor comparison. In this design, newly diagnosed AML patients who achieve a complete remission (CR1), have one or more siblings, and are deemed medically eligible for allogeneic transplant undergo HLA typing. If a sibling donor is identified, the patient is allocated to the transplantation arm. Analysis of outcome is by intention to treat; that is, patients assigned to the donor arm who do not receive a transplant are grouped in the analysis with the patients who did actually receive a transplant. Relapse-free survival (RFS) is the usual endpoint for this type of trial. Overall survival (OS) from the time of diagnosis is less frequently reported in these trials. Results of these trials have been mixed, with some trials showing a clear benefit across all cytogenetic subgroups, and others showing no benefit.

Investigators attempted to address this issue with a meta-analysis using data from 18 separate prospective trials of AML patients using the donor-no donor design, with data from an additional six trials included for sensitivity analysis.[16] The trials included in this meta-analysis enrolled adult patients aged 60 and younger during the years 1982 to 2006. Median follow-up ranged from 42 months to 142 months. Preparative regimens were similar among the different trials. Allogeneic transplant was compared to autologous transplant (6 trials) or to a variety of consolidation chemotherapy regimens with high-dose cytarabine being the most common.

Treatment-related mortality ranged from 5% to 42% in the donor groups compared with 3% to 27% in the no-donor group. Of 18 trials reporting RFS across all cytogenetic risk groups, the combined hazard ratio (HR) for overall RFS benefit with allogeneic transplant was 0.80, indicating a statistically significant reduction in death or relapse in CR1. Of the 15 trials reporting OS across all cytogenetic risk groups, the combined HR for OS was 0.90, again indicating a statistically significant reduction in death or relapse in CR1.

In subgroup analysis according to cytogenetic risk category, there was no RFS or OS benefit of allogeneic transplant for patients with good-risk AML (RFS: HR, 1.07; 95% confidence interval [CI], 0.83–1.38; P = .59; OS: HR, 1.06; 95% CI, 0.64–1.76; P = .81). However, a transplant benefit was seen for patients with intermediate (RFS: HR, 0.83; 95% CI, 0.74–0.93; P < .01; OS: HR, 0.84; 95% CI, 0.71–0.99; P = .03) or poor-risk cytogenetics (RFS: HR, 0.73; 95% CI, 0.59–0.90; P < .01; OS: HR, 0.60; 95% CI, 0.40–0.90; P = .01). The conclusion from this meta-analysis was that allogeneic transplant from a sibling donor in CR1 is justified on the basis of improved RFS and OS for patients with intermediate- or poor-risk, but not good-risk, cytogenetics.[16][Level of evidence: 2A]

An important caveat to this analysis is that induction and postremission strategies for AML among studies included in the meta-analysis were not uniform; nor were definitions of cytogenetic risk groups uniform. This may have resulted in inferior survival rates among chemotherapy-only treated patients. Most US leukemia physicians agree that transplantation should be offered to AML patients in CR1 in the setting of poor-risk cytogenetics and should not be offered to patients in CR1 with good-risk cytogenetics.

The use of matched, unrelated donors for allogeneic BMT is being evaluated at many centers but has a very substantial rate of treatment-related mortality, with DFS rates less than 35%.[14] Retrospective analysis of data from the International Bone Marrow Transplant Registry suggests that postremission chemotherapy does not lead to an improvement in DFS or OS for patients in first remission undergoing allogeneic BMT from an HLA-identical sibling.[15][Level of evidence: 3iiiA]

Autologous BMT yielded DFS rates between 35% and 50% in patients with AML in first remission. Autologous BMT has also cured a smaller proportion of patients in second remission.[17,18,19,20,21,22,23] Treatment-related mortality rates of patients who have had autologous peripheral blood or marrow transplantation range from 10% to 20%. Ongoing controversies include the optimum timing of autologous stem cell transplantation, whether it should be preceded by postremission chemotherapy, and the role of ex vivo treatment of the graft with chemotherapy, such as 4-hydroperoxycyclophosphamide (4-HC) [21] or mafosphamide,[22] or monoclonal antibodies, such as anti-CD33.[23] Purged marrows have demonstrated delayed hematopoietic recovery; however, most studies that use unpurged marrow grafts have included several cycles of postremission chemotherapy and may have included patients who were already cured of their leukemia.

In a prospective trial of patients with AML in first remission, City of Hope investigators treated patients with one course of high-dose cytarabine postremission therapy, followed by unpurged autologous BMT following preparative therapy of total-body radiation therapy, etoposide, and cyclophosphamide. In an intent-to-treat analysis, actuarial DFS was approximately 50%, which is comparable to other reports of high-dose postremission therapy or purged autologous transplantation.[24][Level of evidence: 3iiDii]

A randomized trial by ECOG and the Southwest Oncology Group (SWOG) compared autologous BMT using 4-HC-purged bone marrow with high-dose cytarabine postremission therapy.[25] No difference in DFS was found between patients treated with high-dose cytarabine, autologous BMT, or allogeneic BMT; however, OS was superior for patients treated with cytarabine compared with those who received BMT.[25][Level of evidence: 1iiA]

A randomized trial has compared the use of autologous BMT in first complete remission to postremission chemotherapy, with the latter group eligible for autologous BMT in second complete remission. The two arms of the study had equivalent survival.[26] Two randomized trials in pediatric AML have shown no advantage of autologous transplantation following busulfan/cyclophosphamide preparative therapy and 4HC-purged graft when compared with postremission chemotherapy including high-dose cytarabine.[27,28] An additional randomized Groupe Ouest Est d'etude des Leucemies et Autres Maladies du Sang trial (NCT01074086) of autologous BMT versus intensive postremission chemotherapy in adult AML, using unpurged bone marrow, also has shown no advantage to receiving autologous BMT in first remission.[29] Certain subsets of AML may specifically benefit from autologous BMT in first remission. In a retrospective analysis of 999 patients with de novo AML treated with allogeneic or autologous BMT in first remission in whom cytogenetic analysis at diagnosis was available, patients with poor-risk cytogenetics (abnormalities of chromosomes 5, 7, 11q, or hypodiploidy) had less favorable outcomes following allogeneic BMT than patients with normal karyotypes or other cytogenetic abnormalities. Leukemia-free survival for the patients in the poor-risk groups was approximately 20%.[30][Level of evidence: 3iiiDii]

An analysis of the SWOG/ECOG (E-3489) randomized trial of postremission therapy according to cytogenetic subgroups suggested that in patients with unfavorable cytogenetics, allogeneic BMT was associated with an improved relative risk of death, whereas in the favorable cytogenetics group, autologous transplantation was superior. These data were based on analysis of small subsets of patients and were not statistically significant.[31] While secondary myelodysplastic syndromes have been reported following autologous BMT, the development of new clonal cytogenetic abnormalities following autologous BMT does not necessarily portend the development of secondary myelodysplastic syndromes or AML.[32][Level of evidence: 3iiiDiv] Whenever possible, patients should be entered on clinical trials of postremission management.

Because BMT can cure about 30% of patients who experience relapse following chemotherapy, some investigators suggested that allogeneic BMT can be reserved for early first relapse or second complete remission without compromising the number of patients who are ultimately cured;[33] however, clinical and cytogenetic information can define certain subsets of patients with predictable better or worse prognoses using postremission chemotherapy.[34] Good-risk factors include t(8; 21), inv(16) associated with M4 AML with eosinophilia, and t(15; 17) associated with M3 AML. Poor-risk factors include deletion of 5q and 7q, trisomy 8, t(6; 9), t(9; 22), and a history of myelodysplasia or antecedent hematologic disorder. Patients in the good-risk group have a reasonable chance of cure with intensive postremission therapy, and it may be reasonable to defer transplantation in that group until early first relapse. The poor-risk group is unlikely to be cured with postremission chemotherapy, and allogeneic BMT in CR1 is a reasonable option for patients with an HLA-identical sibling donor. However, even with allogeneic stem cell transplantation, the outcome for patients with high-risk AML is poor (5-year DFS of 8% to 30% for patients with treatment-related leukemia or myelodysplasia).[35] The efficacy of autologous stem cell transplantation in the poor-risk group has not been reported to date but is the subject of active clinical trials. Patients with normal cytogenetics are in an intermediate-risk group, and postremission management should be individualized or, ideally, managed according to a clinical trial.

The rapid engraftment kinetics of peripheral blood progenitor cells demonstrated in trials of high-dose therapy for epithelial neoplasms has led to interest in the alternative use of autologous and allogeneic peripheral blood progenitor cells as rescue for myeloablative therapy for the treatment of AML. One pilot trial of the use of autologous transplantation with unpurged peripheral blood progenitor cells in first remission had a 3-year DFS rate of 35%; detailed prognostic factors for these patients were not provided.[19] This result appears inferior to the best results of chemotherapy or autologous BMT and suggests that the use of peripheral blood progenitor cells be limited to clinical trials.

Allogeneic stem cell transplantation can be performed using stem cells obtained from a bone marrow harvest or a peripheral blood progenitor cell harvest. In a randomized trial of 175 patients undergoing allogeneic stem cell transplantation, with either bone marrow or peripheral blood stem cells, for a variety of hematologic malignancies using methotrexate and cyclosporine to prevent graft-versus-host disease, the use of peripheral blood progenitor cells led to earlier engraftment (median neutrophil engraftment = 16 vs. 21 days, median platelet engraftment = 13 vs. 19 days).[36] The use of peripheral blood progenitor cells was associated with a trend toward increased graft-versus-host disease but comparable transplant-related death. The relapse rate at 2 years appeared lower in patients receiving peripheral blood progenitor cells (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.24–1.00); however, OS was not significantly increased (HR for death within 2 years, 0.62; 95% confidence interval, 0.38–1.02).[36]

Les essais cliniques actuels

Check for US clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute myeloid leukemia in remission. La liste des essais cliniques peut être encore réduit par emplacement, la drogue, l'intervention, et d'autres critères.

Informations générales sur les essais cliniques est également disponible sur le site Web du NCI.

Références:

1. Vaughan WP, Karp JE, Burke PJ: Long chemotherapy-free remissions after single-cycle timed-sequential chemotherapy for acute myelocytic leukemia. Cancer 45 (5): 859-65, 1980.
2. Cassileth PA, Harrington DP, Hines JD, et al.: Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia. J Clin Oncol 6 (4): 583-7, 1988.
3. Mayer RJ, Davis RB, Schiffer CA, et al.: Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 331 (14): 896-903, 1994.
4. Champlin R, Gajewski J, Nimer S, et al.: Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment. J Clin Oncol 8 (7): 1199-206, 1990.
5. Rohatiner AZ, Gregory WM, Bassan R, et al.: Short-term therapy for acute myelogenous leukemia. J Clin Oncol 6 (2): 218-26, 1988.
6. Geller RB, Burke PJ, Karp JE, et al.: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74 (5): 1499-506, 1989.
7. Stone RM, Berg DT, George SL, et al.: Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 98 (3): 548-53, 2001.
8. Goldstone AH, Burnett AK, Wheatley K, et al.: Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 98 (5): 1302-11, 2001.
9. Baker WJ, Royer GL Jr, Weiss RB: Cytarabine and neurologic toxicity. J Clin Oncol 9 (4): 679-93, 1991.
10. Haupt HM, Hutchins GM, Moore GW: Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia. Am J Med 70 (2): 256-61, 1981.
11. Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987.
12. Reiffers J, Gaspard MH, Maraninchi D, et al.: Comparison of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission: a prospective controlled trial. Br J Haematol 72 (1): 57-63, 1989.
13. Bostrom B, Brunning RD, McGlave P, et al.: Bone marrow transplantation for acute nonlymphocytic leukemia in first remission: analysis of prognostic factors. Blood 65 (5): 1191-6, 1985.
14. Busca A, Anasetti C, Anderson G, et al.: Unrelated donor or autologous marrow transplantation for treatment of acute leukemia. Blood 83 (10): 3077-84, 1994.
15. Tallman MS, Rowlings PA, Milone G, et al.: Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 96 (4): 1254-8, 2000.
16. Koreth J, Schlenk R, Kopecky KJ, et al.: Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301 (22): 2349-61, 2009.
17. Chao NJ, Stein AS, Long GD, et al.: Busulfan/etoposide--initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood 81 (2): 319-23, 1993.
18. Linker CA, Ries CA, Damon LE, et al.: Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81 (2): 311-8, 1993.
19. Sanz MA, de la Rubia J, Sanz GF, et al.: Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. J Clin Oncol 11 (9): 1661-7, 1993.
20. Cassileth PA, Andersen J, Lazarus HM, et al.: Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol 11 (2): 314-9, 1993.
21. Jones RJ, Santos GW: Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging. In: Gale RP, ed.: Acute Myelogenous Leukemia: Progress and Controversies: Proceedings of a Wyeth-Ayerst-UCLA Symposia Western Workshop Held at Lake Lanier, Georgia, November 28-December 1, 1989. New York: Wiley-Liss, 1990, pp 411-419.
22. Gorin NC, Aegerter P, Auvert B, et al.: Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging. Blood 75 (8): 1606-14, 1990.
23. Robertson MJ, Soiffer RJ, Freedman AS, et al.: Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia. Blood 79 (9): 2229-36, 1992.
24. Stein AS, O'Donnell MR, Chai A, et al.: In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission. J Clin Oncol 14 (8): 2206-16, 1996.
25. Cassileth PA, Harrington DP, Appelbaum FR, et al.: Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 339 (23): 1649-56, 1998.
26. Zittoun RA, Mandelli F, Willemze R, et al.: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 332 (4): 217-23, 1995.
27. Ravindranath Y, Yeager AM, Chang MN, et al.: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med 334 (22): 1428-34, 1996.
28. Woods WG, Neudorf S, Gold S, et al.: Aggressive post-remission (REM) chemotherapy is better than autologous bone marrow transplantation (BMT) and allogeneic BMT is superior to both in children with acute myeloid leukemia (AML). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-1091, 368, 1996.
29. Harousseau JL, Cahn JY, Pignon B, et al.: Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 90 (8): 2978-86, 1997.
30. Ferrant A, Labopin M, Frassoni F, et al.: Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation study. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood 90 (8): 2931-8, 1997.
31. Slovak ML, Kopecky KJ, Cassileth PA, et al.: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96 (13): 4075-83, 2000.
32. Imrie KR, Dubé I, Prince HM, et al.: New clonal karyotypic abnormalities acquired following autologous bone marrow transplantation for acute myeloid leukemia do not appear to confer an adverse prognosis. Bone Marrow Transplant 21 (4): 395-9, 1998.
33. Schiller GJ, Nimer SD, Territo MC, et al.: Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission. J Clin Oncol 10 (1): 41-6, 1992.
34. Edenfield WJ, Gore SD: Stage-specific application of allogeneic and autologous marrow transplantation in the management of acute myeloid leukemia. Semin Oncol 26 (1): 21-34, 1999.
35. Witherspoon RP, Deeg HJ, Storer B, et al.: Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol 19 (8): 2134-41, 2001.
36. Bensinger WI, Martin PJ, Storer B, et al.: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344 (3): 175-81, 2001.

No standard regimen exists for the treatment of patients with relapsed acute myeloid leukemia (AML), particularly in patients with a first remission duration of less than 1 year.[1]

A number of agents have activity in recurrent AML.[2,3] A combination of mitoxantrone and cytarabine was successful in 50% to 60% of patients who experienced relapse after initially obtaining a complete remission.[4] Other studies using idarubicin and cytarabine or high-dose etoposide and cyclophosphamide reported similar results.[3,5,6,7] Mitoxantrone, etoposide, and cytarabine (MEC) demonstrated a complete remission induction rate of 55% in a population including 30 patients with relapsed AML, 28 patients with primary refractory AML, and 16 patients with secondary AML.[8][Level of evidence: 3iiiDiv] However, in a phase III Eastern Cooperative Oncology Group (ECOG) (E-2995) trial of MEC with or without PSC388, a multidrug resistance modulator, complete response (CR) was only 17% to 25% in a population including relapse at less than 6 months after first complete remission, relapse after allogeneic or autologous bone marrow transplantation (BMT), second or greater relapse, primary induction failures, secondary AML, and high-risk myelodysplastic syndromes.[9][Level of evidence: 1iiDiv] Thus, treatments with new agents under clinical evaluation remain appropriate in eligible patients with recurrent AML.[10]

The immunotoxin gemtuzumab ozogamicin has been reported to have a 30% response rate in patients with relapsed AML expressing CD33. This included 16% of patients who achieved CRs and 13% of patients who achieved a CRp, a new response criteria defined for this trial. CRp refers to clearance of leukemic blasts from the marrow, with adequate myeloid and erythroid recovery but with incomplete platelet recovery (though platelet transfusion independence for at least 1 week was required). Unclear is whether the inadequate platelet recovery is due to megakaryocyte toxic effects of gemtuzumab or to subclinical residual leukemia. The long-term outcomes of patients who achieve CRp following gemtuzumab are not yet known. Gemtuzumab induces profound bone marrow aplasia similar to leukemia induction chemotherapy and also has substantial hepatic toxic effects, including hepatic venoocclusive disease.[11,12] The farnesyltransferase inhibitor tipifarnib (R115777) demonstrated a 32% response rate in a phase I study in patients with relapsed and refractory acute leukemia (two CRs and six partial responses in 24 patients treated) and has entered phase II trials.[13] Clofarabine, a novel purine nucleoside analogue, induced complete remissions in 8 out of 19 patients in first relapse as a single agent [14] and in 7 out of 29 patients when administered in combination with intermediate-dose cytarabine.[15][Level of evidence: 3iiiDiv]

A subset of relapsed patients treated aggressively may have extended disease-free survival (DFS); however, cures in patients following a relapse are thought to be more commonly achieved using BMT.[7][Level of evidence: 3iDii] A retrospective study from the International Bone Marrow Transplant Registry compared adults younger than 50 years with AML in second complete remission who received HLA-matched sibling transplantation versus a variety of postremission approaches.[16] The chemotherapy approaches were heterogeneous; some patients received no postremission therapy. The transplantation regimens were similarly diverse. Leukemia-free survival appeared to be superior for patients receiving BMTs for two groups: patients older than 30 years whose first remission was less than 1 year; and patients younger than 30 years whose first remission was longer than 1 year.[16][Level of evidence: 3iDii]

Allogeneic BMT from an HLA-matched donor in early first relapse or in second complete remission provides a DFS rate of approximately 30%.[17][Level of evidence: 3iiiA] Transplantation in early first relapse potentially avoids the toxic effects of reinduction chemotherapy.[3,17,18] Allogeneic BMT can salvage some patients whose disease fails to go into remission with intensive chemotherapy (primary refractory leukemia). Nine of 21 patients with primary refractory AML were alive and disease free at 10 years following allogeneic BMT.[7][Level of evidence: 3iiiA] Randomized trials testing the efficacy of this approach are not available. Autologous BMT is an option for patients in second complete remission, offering a DFS that may be comparable to autografting in first complete remission.[19,20,21]

Patients who relapse following an allogeneic BMT may undergo an infusion of lymphocytes from the donor (Donor Lymphocyte Infusion or DLI), similar to the therapy patients with relapsing chronic myelogenous leukemia (CML) undergo. (Refer to the Relapsing Chronic Myelogenous Leukemia section of the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.) There are no published studies of any prospective trials examining the role of DLI for patients with AML who relapsed following allogeneic BMT. A retrospective study of European patients found that, out of 399 patients who relapsed after an allogeneic BMT, 171 patients received DLI as part of their salvage therapy.[22] A multivariate analysis of survival showed a significant advantage for the 171 DLI recipients, who achieved a 2-year overall survival from the time of relapse of 21%, compared to 9% for the 228 patients who did not receive DLI ( P < .04; RR, 0.8; 95% confidence interval, 0.64–0.99).[22][Level of evidence: 3iiiA] The strength of this finding is limited by the retrospective nature of the study, and the possibility that much of the survival advantage could have been the result of selection bias. Furthermore, the remission rate of 34% reported in this study was considerably less than the 67% to 91% reported for CML.[23] Therefore, even if the survival advantage conferred by DLI is real, the fraction of relapsed AML patients who might benefit from this therapy appears to be quite limited.

Arsenic trioxide, an agent with both differentiation-inducing and apoptosis-inducing properties against acute promyelocytic leukemia (APL) cells, has a high rate of successful remission induction in patients with relapsed APL. Clinical complete remissions have been reported in 85% of patients induced with arsenic trioxide, with a median time to clinical complete remission of 59 days. Eighty-six percent of evaluable patients tested negative for the presence of PML-RARα transcript after induction or postremission therapy with arsenic trioxide. Actuarial 18-month relapse-free survival was 56%. Induction with arsenic trioxide may be complicated by APL differentiation syndrome (identical to ATRA syndrome), prolongation of QT interval, and neuropathy.[24,25] Arsenic trioxide is now being incorporated into the postremission treatment strategy of de novo APL patients in clinical trials.

Les essais cliniques actuels

Check for US clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult acute myeloid leukemia. La liste des essais cliniques peut être encore réduit par emplacement, la drogue, l'intervention, et d'autres critères.

Informations générales sur les essais cliniques est également disponible sur le site Web du NCI.

Références:

1. Ferrara F, Palmieri S, Mele G: Prognostic factors and therapeutic options for relapsed or refractory acute myeloid leukemia. Haematologica 89 (8): 998-1008, 2004.
2. Hiddemann W, Kreutzmann H, Straif K, et al.: High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia. Blood 69 (3): 744-9, 1987.
3. Brown RA, Herzig RH, Wolff SN, et al.: High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood 76 (3): 473-9, 1990.
4. Paciucci PA, Dutcher JP, Cuttner J, et al.: Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia. Leukemia 1 (7): 565-7, 1987.
5. Lambertenghi-Deliliers G, Maiolo AT, Annaloro C, et al.: Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refractory patients with acute non-lymphoblastic leukemia. Eur J Cancer Clin Oncol 23 (7): 1041-5, 1987.
6. Harousseau JL, Reiffers J, Hurteloup P, et al.: Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine. J Clin Oncol 7 (1): 45-9, 1989.
7. Forman SJ, Schmidt GM, Nademanee AP, et al.: Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia. J Clin Oncol 9 (9): 1570-4, 1991.
8. Spadea A, Petti MC, Fazi P, et al.: Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia. Leukemia 7 (4): 549-52, 1993.
9. Greenberg PL, Lee SJ, Advani R, et al.: Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol 22 (6): 1078-86, 2004.
10. Estey E, Plunkett W, Gandhi V, et al.: Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Leuk Lymphoma 9 (4-5): 343-50, 1993.
11. Sievers EL, Larson RA, Stadtmauer EA, et al.: Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 19 (13): 3244-54, 2001.
12. Giles FJ, Kantarjian HM, Kornblau SM, et al.: Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer 92 (2): 406-13, 2001.
13. Karp JE, Lancet JE, Kaufmann SH, et al.: Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 97 (11): 3361-9, 2001.
14. Kantarjian H, Gandhi V, Cortes J, et al.: Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 102 (7): 2379-86, 2003.
15. Faderl S, Gandhi V, O'Brien S, et al.: Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 105 (3): 940-7, 2005.
16. Gale RP, Horowitz MM, Rees JK, et al.: Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia 10 (1): 13-9, 1996.
17. Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987.
18. Clift RA, Buckner CD, Appelbaum FR, et al.: Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. J Clin Oncol 10 (11): 1723-9, 1992.
19. Meloni G, De Fabritiis P, Petti MC, et al.: BAVC regimen and autologous bone marrow transplantation in patients with acute myelogenous leukemia in second remission. Blood 75 (12): 2282-5, 1990.
20. Chopra R, Goldstone AH, McMillan AK, et al.: Successful treatment of acute myeloid leukemia beyond first remission with autologous bone marrow transplantation using busulfan/cyclophosphamide and unpurged marrow: the British autograft group experience. J Clin Oncol 9 (10): 1840-7, 1991.
21. Gorin NC, Labopin M, Meloni G, et al.: Autologous bone marrow transplantation for acute myeloblastic leukemia in Europe: further evidence of the role of marrow purging by mafosfamide. European Co-operative Group for Bone Marrow Transplantation (EBMT). Leukemia 5 (10): 896-904, 1991.
22. Schmid C, Labopin M, Nagler A, et al.: Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 25 (31): 4938-45, 2007.
23. Dazzi F, Szydlo RM, Craddock C, et al.: Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 95 (1): 67-71, 2000.
24. Soignet SL, Frankel SR, Douer D, et al.: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19 (18): 3852-60, 2001.
25. Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89 (9): 3354-60, 1997.

Les information sur le cancer résumés PDQ sont revus régulièrement et actualisés si de nouvelles informations deviennent disponibles. Cette section décrit les dernières modifications apportées à ce résumé à la date ci-dessus.

Les modifications rédactionnelles ont été apportées à ce résumé.

But de ce résumé

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of acute myeloid leukemia. Il est conçu comme une ressource pour informer et aider les cliniciens qui soignent les patients atteints de cancer. Il ne fournit pas de directives ou de recommandations officielles pour prendre des décisions de soins de santé.

Les examinateurs et mises à jour

Ce résumé est révisé régulièrement et mis à jour au besoin par le comité de rédaction Adult Treatment PDQ, qui est l'indépendance éditoriale de l'Institut national du cancer (NCI). Le résumé reflète un examen indépendant de la littérature et ne représente pas un énoncé de politique de NCI ou de la National Institutes of Health (NIH).

les membres de la Commission de révision a récemment publié des articles chaque mois pour déterminer si un article doit:

être discuté lors d'une réunion, être cité avec le texte, orreplace ou mettre à jour un article existant qui est déjà cité.

Les modifications apportées aux résumés sont faites à travers un processus de consensus dans lequel les membres du Conseil d'évaluer la force de la preuve dans les articles publiés et de déterminer comment l'article devrait être inclus dans le résumé.

The lead reviewers for Adult Acute Myeloid Leukemia Treatment are:

Steven D. Gore, MD (Johns Hopkins University)Mark J. Levis, MD, PhD (Johns Hopkins University)Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)

Des commentaires ou des questions sur le contenu de résumé doivent être soumis à Cancer.gov à travers le formulaire de contact du site Web. Ne pas communiquer avec les membres du Conseil individuels avec des questions ou des commentaires concernant les résumés. Les membres du Conseil ne seront pas répondre aux demandes individuelles.

Niveaux de preuve

Certaines des citations de référence dans ce résumé sont accompagnées d'une désignation au niveau de la preuve. Ces désignations visent à aider le lecteur à évaluer la force de la preuve à l'appui de l'utilisation des interventions ou des approches spécifiques. Le comité de rédaction Adult Treatment PDQ utilise une preuve formelle système de classement dans le développement de ses désignations niveau de la preuve.

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PDQ est une marque déposée. Bien que le contenu des documents PDQ peut être utilisé librement sous forme de texte, il ne peut être identifié comme une NCI PDQ résumé de l'information sur le cancer que si elle est présentée dans son intégralité et est régulièrement mis à jour. Toutefois, un auteur serait autorisé à écrire une phrase comme «PDQ information sur le cancer du résumé du NCI sur la prévention du cancer du sein indique les risques de façon succincte: [inclure extrait du résumé]."

La citation préférée pour ce résumé PDQ est:

National Cancer Institute: PDQ® Adult Acute Myeloid Leukemia Treatment. Bethesda, MD: National Cancer Institute. Date de la dernière <JJ / MM / AAAA> modifié. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional. Consulté <JJ / MM / AAAA>.

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Désistement

Sur la base de la force de la preuve disponible, les options de traitement peuvent être décrits comme «standard» ou «en cours d'évaluation clinique." Ces classifications ne doivent pas être utilisés comme base pour la détermination de remboursement de l'assurance. Plus d'informations sur la couverture d'assurance est disponible sur Cancer.gov sur la face au cancer: financière, assurance, juridique et la page d'information.

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Pour plus d'informations, les résidents américains peuvent appeler de l'Institut national du cancer (NCI) Service d'information sur le cancer au 1-800-4-CANCER (1-800-422-6237) sans frais du lundi au vendredi 08h00-8h00 h, heure de l'Est. Un spécialiste de l'information sur le cancer formé est disponible pour répondre à vos questions.

Chat en ligne

LiveHelp® service de chat en ligne du NCI offre aux internautes la possibilité de discuter en ligne avec un spécialiste de l'information. Le service est disponible 8:00-à-23h00 heure de l'Est, du lundi au vendredi. Spécialistes de l'information peuvent aider les internautes à trouver des informations sur les sites Web du NCI et répondent aux questions sur le cancer.

Écrivez-nous

Pour plus d'informations de la NCI, se il vous plaît écrire à cette adresse:

NCI Bureau des enquêtes publiques
Suite 3036A
6116 Boulevard exécutif, MSC8322
Bethesda, MD 20892-8322

Recherche sur le site Web du NCI

Le site Web du NCI offre un accès en ligne à l'information sur le cancer, les essais cliniques, et d'autres sites et d'organismes qui offrent un soutien et des ressources pour les patients atteints de cancer et leurs familles sur le Web. Pour une recherche rapide, utiliser la boîte de recherche dans le coin supérieur droit de chaque page Web. Les résultats pour un large éventail de termes de recherche incluront une liste de «meilleurs résultats», pages Web éditorial choisis qui sont le plus étroitement liés au terme de recherche saisi.

Il ya aussi beaucoup d'autres endroits pour obtenir des matériaux et des informations sur le traitement et les services cancer. Hôpitaux dans votre région peuvent avoir des informations sur les agences locales et régionales qui ont des informations sur les finances, pour se rendre et d'un traitement, de recevoir des soins à la maison et faire face aux problèmes liés au traitement du cancer.

Trouver Publications

Le NCI a brochures et autres matériaux pour les patients, les professionnels de santé et le public. Ces publications traitent types de cancer, les méthodes de traitement du cancer, faire face au cancer, et des essais cliniques. Certaines publications fournissent des informations sur les tests pour le cancer, les causes de cancer et la prévention, statistiques sur le cancer, et les activités de recherche du NCI. NCI sur ces matières et d'autres sujets peuvent être commandés en ligne ou imprimées directement à partir du NCI Locator Publications. Ces matériaux peuvent également être commandés par téléphone du au 1-800-4-CANCER (1-800-422-6237) sans frais Service d'information sur le cancer.

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