AML NCCN guidelines 2009
Presented by CR謝燿宇
Introduction Treatment of AML: age, hx of prior MDS or
cytotoxic therapy and performance status The most predictable factor for disease free
survival: cytogenetic status 60 y/o: divergence point (Frederick R. et. al. Blood 2006 107: 3481-3485.)
P’ts < 60 y/o: induction
Standard induction: < 60 y/o p’ts without antedecent hematologic disease
Anthracycline [daunorubicin or idarubicin (more intracellular retension time)] + Cytarabine, no benefit of adding etoposide
Dose intensive v.s. standard: more treatment related morbidity and mortality, but longer remission duration (SWOG, ALSG)
Neurotoxicity and renal toxocity
SWOG study
SWOG study
SWOG study
SWOG study
SWOG study
SWOG study
CALGB study
CALGB trial: 44% remission rate with SDCA + Daunorubicin plus high dose cytarabine consolidation
High dose cytarabine induction: may be influenced by consolidation strategy, fewer high dose cytarabine consolidation or for early going auto-HSCT (category 2B)
Induction therapy 20-45% p’ts will not enter remission, which is
strongly influenced by cytogenetics
EBMT trial in secondary AML or MDS
45%34%
Post induction therapy
Evaluation: 7~10 days after completion of induction
Both lymphoid and myeloid marker: may response to ALL therapy if failure to induction
Post remission therapy
3-4 courses of high dose consolidation: non-protocol standard for p’ts < 60 y/o and good or intermediate cytogenetic
CALGB trial Robert J. Mayer et. al., N Engl J Med 1995;
332:334-335, 44% 12% severe
neurotoxicity and 5% treatment related mortality, 60% disease free survival in good risk; 30% in intermediate risk; 12% in poor risk
Post remission One or more cycles of high dose
cytarabine followed by auto-HSCT or allo-HSCT?
Consider: expected relapse rate, transplantation related morbidity and mortality, salvage option, features of disease at diagnosis, numbers of cycles of induction to achieve remission
Post remission therapy
Good risk: no single preferred suggestion
Treatment related mortality 8-10%
Clara D. Bloomfield, et. al. CANCER RESEARCH 58. 4173-4179.
CBF: t(8;21) inv(16), t(16;16), and del(16)
50-60%
Post remission therapy
EORTC/GIMEMA-AML10 BLOOD, 2003 VOLUME 102, 1232-1240
No significance
Post remission therapy
Multiple cycles of dose intensive consolidation (category 1), one cycle of dose intensive consolidation followed by auto-HSCT (category 2B)
CBF mutation with c-Kit mutation (20-30%): high risk for relapse (60-70% v.s. 30%), but no impact on remission rate, consider clinical trial
Post remission therapy
Normal risk: transplant based (matched sibling or 1-2 cycles of dose intensive cytarabine followed by auto-HSCT), also multiple courses of high or intermediate dose of cytarabine
Normal karyotype with isolated NPM1 mutation: good prognosis
Normal karyotype with isolated FLT3-ITD mutation: poor prognosis
Post remission therapy
EORTC/GIMEMA-AML10 BLOOD, 2003 VOLUME 102, 1232-1240
No significance
CALGB study Farag SS, et. al. JCO 2005;23:482-193
CALGB study Farag SS, et. al. JCO 2005;23:482-193
Post remission therapy
Poor risk: matched sibling or matched UR-HSCT, as well as clinical trial
Auto-HSCT v.s. chemotherapy: comparable with 18% DFS
EORTC/GIMEMA-AML10 BLOOD, 2003 VOLUME 102, 1232-1240
Significance!
AML in elderly patient: induction therapy
60 y/o as divergence point P’ts > 75 y/o, 60-75 y/o with significant co-
morbidites, PS >2: especially poor
Intensive Chemotherapy in AML and MDS, Kantarjian et al. CANCER 2006;106:1090-1098
British MRC AML14 trial (Burnett et al. CANCER 2007;109:1114-1124)
low dose cytarabine: 30 days mortalities 26%
AML in elderly patient: induction therapy
Pancytopenia with modest marrow infiltration (20-40%): may wait cytogenetic if clinically stable
Remission rate: 25% in poor risk group with 25% mortality rate, highly suggest clinical trial; whereas 40~50% CR rate in normal karyotype (favor idarubicin) ALFA 9801 study, Blood, 2007;110:55a
Phase II Study of Decitabine for Front-line Treatment of Older Patients with AML
Patients age > 60, no prior therapy for AML Primary endpoint: complete remission rate Treatment with decitabine 20 mg/m2 iv x 5 days
q4 weeks All patients will be treated with 2 cycles unless
they have progression of peripheral blast count Patients with a complete or partial response
after 2 cycles can get additional cycles until progression
Phase II Study of Decitabine for Front-line Treatment of Older Patients with AML
Bone marrow collection at baseline, day 5 of cycle 1 and day 28 of cycle 2 for correlative studies RNA profiling as part of the Genomics of AML project DNA methylation profiling Pilot proteomics study
CR rate: 29%3 of 10 poor risk patients also have CR
Clofarabine: previously used in refractory pediatric ALL, proved to use in adult AML as well
Post induction therapy
Evaluation: 7-10 days after completion of induction
Full normalization of PB count often does not occurred in elderly patients due to previous antedecent myelodysplasia
CRi: marrow blast < 5% with mild residual cytopenia
Post induction therapy
ALFA 9803 trial v.s. CALGB trial: dose intensive cytarabine?
Myeloablative HSCT: too risky RIC HSCT: still of interest
28% v.s.17% in 2yrs DFS
Ambulatory better than single dose intensive therapy
ALFA 9803 trial, BLOOD, 2007;109:5129-5135
Elihu Estey et al. BLOOD, 2007;109:1395-1400
Post-remission surveillance and salvage Followed-up: CBC qM-q3M in the first two
years after completion of consolidation then q3M-q6M for total 5 years
BM study: only if abnormal CBC count noted or cytopenia
Transplantation in first CR or first relapse
Post-remission surveillance and salvage Gemtuzumab ozogomicin: single agent use,
29% of p’ts with CD33+ expression obtained marrow clearance and transfusion dependence
Fever, chills, hypotension during infusion, persistent thrombocytopenia without leukemia relapse, hepatotoxicity, increased VOD like syndrome if exposure within 3-4months after HSCT
Auto-HSCT only in non-APL patient with no allogenic donor, no suggested in poor risk patient
CNS leukemia
CNS leukemia: <3% involvement compared with ALL
No routine LP surveillance Neurological symptoms on diagnosis:
imaging for r/o mass effect, if negative, consider LP
May substitute high dose cytarabine for intrathecal
Do not combine R/T with high dose cytarabine!
Supportive care G-CSF: 抽 BM前七天要停 輸血:照光加減白! High dose cytarabine: monitor renal function,
correlated neurotoxiticy (nystagmus, ataxia, dysmetria), change all subsequent high dose to standard dose
Retinoic acid syndrome: fever, fluid retension, WBC > 10000, treat with dexamethasone 10mg bid for 3-5 days taper within 2 weeks, may restart ATRA later
Arsenic trioxide: QT prolong, EKG monitor, keep Ca 9.0, K 4.0, Mg 1.8≧ ≧ ≧