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≧ ≧ ≧