aml guidelines rev1

7/31/2019 AML Guidelines Rev1

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ACUTE MYELOID

LEUKEMIA


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Initial Workup

Clinical

H & P

ECHO/MUGA scan

2-lumen mediport

CXR

EKG

BMT Consult (< age70)

Laboratory

CBC, CMP

DIC panel

HLA-typing, CMVserology IgG, IgM( if< 70 y)

Lumbar puncture*

Bone Marrow

Aspirate and core biopsy

Immunophenotyping (flow)

Cytogenetics

Ancillary Studies

FISH MDS panel ( age 60)

PCR ( 50K at diagnosis

If asymptomatic, LP should be deferred until WBC< 20K or CR1 to avoid peripheral blood contamination


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Acute Myeloid Leukemia Acute Promyelocytic Leukemia (M3)

APL

CLASSI FI CATI ON

TREATMENTI NDUCTI ON

M3 morphologyand (+) fort(15;17) byeither

cytogenetics ormoleculartesting; considerpossibility of M3variant

All-trans-retinoicacid (ATRA) and

anthracycline-based(idarubicin ordaunorubicin)chemotherapy1

ATRA + arsenicTrioxide forpatients unable to

tolerateanthracycline-based therapy2

Assess marrow

morphology atcount recoveryfrom start ofinduction

Assess marrowmorphology atcount recovery

from start ofinduction

Completeresponse

Inductionfailure

Consolidate with at least2 cycles ofanthracycline-based(idarubicin ordaunorubicin)chemotherapy + 2 wk

ATRA with each cycle1

Consolidat ion Therapy

Arsenic trioxideor

Matched sibling oralternative donor HSCT

Completeresponse

Inductionfailure

ATRA + arsenicTrioxide x 6 cycles

Clinical trialOrMatched sibling oralternative donor HSCTOrGemtuzumab

ozogamicin3

Or


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Acute Myeloid Leukemia Acute Promyelocytic Leukemia (M3)

Post-Consolidation

Documentmolecularremission onbone marrow

by PCR

PCRnegative

PCR

positive

Maintenance therapy x

1-2 y with ATRA(category 1) +6-mercaptopurine +methotrexate1

Monitor by PCRevery 3 mo for2 y

PCRnegative

PCRpositive

Repeat PCR forconfirmationwithin 4 wks

PCRnegative

PCRpositive

Repeat PCR for

confirmationWithin 4 wks

PCRnegative

PCRpositive

Follow algorithmFor relapsed

APML


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Acute Myeloid Leukemia Acute Promyelocytic Leukemia (M3)Relapsed Disease

FirstRelapse

Arsenic trioxide4

OrGemtuzumabozogamicin3

(If early relapse postarsenic therapy)

No remission

SecondRemission(morphologic)

PCRnegative

PCR

positive

Autologous HSCTOrArsenic consolidation(total of 6 cycles)(if not a transplantcandidate)

Matched or alternativedonor HSCTOrClinical TrialOrGemtuzumab orzogamicin3

Clinical trialOrMatched or alternativedonor HSCTOrGemtuzumab ozogamicin3


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Acute Myeloid Leukemia:

Molecular Risk Categorization

Normal cytogenetics with isolatedFLT3 mutations6

Complex ( 3 abnormalities)-5-75q-7q-

Abnormalities of 11q 23, excluding t(9;11)Inversion 3

t(3;3)t(6;9)

t(9;22)

Poor-risk

C-KIT in patients with t(8;21) orInv(16)

Normal+8 onlyt(9;11)

Other abnormalities not listed with better-risk andpoor-risk cytogenetics and molecular mutations

Intermediate-risk

Normal cytogenetics with isolated

NPM mutation

Inv(16)t(8;21)

t(16;16)

Better-risk

MOLECULAR MUTATI ONS6CYTOGENETI CS5RI SK STATUS


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Acute Myeloid Leukemia Induction (30% blasts: SWOG Regimen9

Ara-C 3 g/m2 days 1-5

Daunorubicin 45 mg/m2

CIV days 6-8CsA CIV days 6-8


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Follow-up

bone marrow

(day 12-16)

< 50% blastreduction

50% blastreductionwithouthypoplasia*

Hypoplasia

(


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Age < 60

Better-riskmolecular profile

Intermediate-riskmolecular profile

AntecedenthematologicDisease, treatment-related disease or poor-risk molecular profile

High-dose cytarabine, 3 g/m over 3 h every 12 h on days 1, 3,5 x 4 courses (OUTPATIENT)11

Or1 to 2 cycles of high dose cytarabine-based consolidation

followed by autologous HSCT (OUTPATIENT)OrClinical trial

Matched sibling or autologous HSCTorHigh-dose cytarabine, 3 g/m over 3 h every 12 h on days 1, 3,

5 x 4 courses11

OrClinical trial

Clinical trialOrMatched sibling HSCTOrAlternative donor HSCT

Acute Myeloid Leukemia

Post-Remission (


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Acute Myeloid Leukemia Induction (age 60-75)

Age 60-75

PS > 2

Low-intensity therapy*OrBest supportive care

PS 2

Obtaincytogenetics priorto treatment whenpossible12

Complex

Cytogenetics

Non-complexCytogenetics

Clinical trial (preferred)OrLow-intensity therapy*OrBest supportive careORStandard-dose cytarabine (100

mg/m Cl x 7 days) withidarubicin (7+3)

Clinical trial (preferred)

Or7+3

Age 75 or significant comorbiditieswhich cause organ dysfunction not

directly related to leukemia

Clinical trialOrLow-intensity therapyOrBest supportive care

* Low -int ensit y t herapy may include: azacit idine8, decit abine13, hydroxyurea, low-dose cytarabine14


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Follow-up

bone marrow

(day 12-16)

< 50% blastreduction

50% blastreductionwithouthypoplasia*

Hypoplasia

(


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Complete

Remission


Post-Remission ( age 60)

Clinical trial or

Reduced intensity HSCTin context of clinical trialor

Standard-dose cytarabine(100 mg/m/day x 5-7 dx 1-2 cycles) anthracycline (idarubicinor daunorubicin) or

Consider cytarabine 1-1.5g/m/day x 4-6 doses x1-2 cycles for patientswith good performancestatus


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Acute Myeloid LeukemiaRelapsed Disease

Relapse

Age < 60

Early( < 6 mo)

Clinical trial (strongly preferred) orSalvage chemotherapy (CLAG preferred)10 followed byMatched sibling HSCT or alternative donor HSCT, ifdonor previously identified

Late(> 6 mo) Clinical trial (strongly preferred) or

Salvage chemotherapy (CLAG preferred)10 followed byMatched sibling HSCT or alternative donor HSCT, ifdonor previously identified orRepeat initial successful induction regimen

Age 60

Early( < 6 mo)

Late(> 6 mo)

Clinical trial (strongly preferred)Or Best supportive careOr Gemtuzumab orzogamicin15

Clinical trial (strongly preferred)OrTreatment with initial successful regimenOrGemtuzumab ozogamicin15

OrBest supportive care

I f r elapse into MDS state:Azacitdine

ORDecitabine

CanconsiderAllo-HSCTIf 2nd CRobtained


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SUPPORTI VE CARE (1 OF 4)

There are variations between institutions but the following issues are important to consider in the management ofpatients with AML.

General

Prophylactic antibiotics, including antifungals, are left to the discretion of the individualinstitutions.

Growth factors may be considered in the elderly after chemotherapy is complete. Note thatsuch use may confound interpretation of the bone marrow.

Blood products: Leukocyte-depleted products used for transfusion

Irradiated blood products for patients receiving immunosuppressive therapy

(fludarabine, HSCT).

Transfusion thresholds RBCs for Hgb 8 g/dL or symptoms of anemia; platelets for

platelets < 10,000/mcL or with any signs of bleeding16

CMV screening of potential HSCT candidates may be considered.

Tumor lysis prophylaxis: hydration with diuresis, and urine alkalinization and allopurinol.

Clinical evidence of tumor lysis syndrome and problematic hyperuricemia or inability to

tolerate oral medication: considerrasburicase.


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Saline or steroid eye drops to both eyes four times daily for all patients undergoing high-dose cytarabine therapy until 24 h post completion of cytarabine.

Screening LP for occult CNS disease is a consideration for remission patients who had initial

WBC > 50,000/mcL or monocytic histology.

Patients receiving high dose cytarabine therapy (particularly those with impaired renalfunction or patients > 60 years), are at risk for cerebellar toxicity. Neurologic assessmentsincluding tests for nystagmus, slurred speech, and dysmetria should be performed beforeeach dose of cytarabine.

In patients exhibiting rapidly rising creatinine due to tumor lysis, high-dose cytarabine

should be discontinued until creatinine normalizes.

In patients who develop cerebellar toxicity, cytarabine should be stopped. The patient

should not be rechallenged with high dose cytarabine in future treatment cycles. (Smith

GA, Damon LE, Rugo HS, et al. High-dose cytarabine dose modification reduces theincidence of neurotoxicity in patients with renal insufficiency.

J Clin Oncol 1997;15(2):833-839.


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APL

Clinical coagulopathy and overt bleeding:

Management of clinical coagulopathy and overt bleeding: Aggressive platelet

transfusion support to maintain platelets 50,000/mcL, fibrinogen replacement withcryoprecipitate and fresh frozen plasma to replace clotting factors. Monitor daily until

coagulopathy resolves.

APL differentiation syndrome:

Maintain a high index of suspiciaon of APL differentiation syndrome (fever, often

associated with increasing WBC > 10,000/mcL usually at initial diagnosis or relapse,

shortness of breath, hypoxemia, pleural or pericardial effusions). Close monitoring of

volume overload and pulmonary status is indicated. Initiate dexamethasone at first

signs or symptoms of respiratory compromise (hypoxia, pulmonary infiltrates,

pericardial or pleural effusions) (10 mg BID for 3-5 days with a taper over 2 wks).

Consider interrupting ATRA therapy until hypoxia resolves.

Patients with relapsed APL or with hyperleukocytosis after ATRA may be at increased risk ofCNS disease. Prophylactic intrathecal therapy (IT) is being evaluated in this group.


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Leukapheresis is not recommended in the routine management of patients with a high WBCcount in APL because of the difference in leukemia biology; however, in life threatening caseswith leukostasis that is not responsive to other modalities, leukapheresis can be consideredwith caution.

Arsenic trioxide monitoring

Prior to initiating therapy

ECG for prolonged QTc interval assessment Serum electrolytes (Ca, K, Mg) and creatinine

During therapy

Maintain K concentrations above 4 mEq/dL Maintain Mg concentrations above 1.8 mg/dL Reassess patients with absolute QTc interval > 500 millisec

(weekly during induction therapy and before each course of post-remission therapy)


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Reference List

(1) Sanz MA, Vellenga E, Rayon C et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly

patients with acute promyelocytic leukemia. Blood. 2004;104:3490-3493.

(2) Estey E, Garcia-Manero G, Ferrajoli A et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to

chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;107:3469-3473.

(3) Lo-Coco F, Cimino G, Breccia M et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acutepromyelocytic leukemia. Blood. 2004;104:1995-1999.

(4) Soignet SL, Frankel SR, Douer D et al. United States Multicenter Study of Arsenic Trioxide in Relapsed Acute Promyelocytic

Leukemia. J Clin Oncol. 2001;19:3852-3860.

(5) 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.2000;96:4075-4083.

(6) Schlenk RF, Dohner K, Krauter J et al. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid

Leukemia. N Engl J Med. 2008;358:1909-1918.

(7) Pautas C, Thomas X, Merabet F et al. Randomized Comparison of Standard Induction with Daunorubicin (DNR) for 3 Days vsIdarubicin (IDA) for 3 or 4 Days in AML pts Aged 50 to 70 and of Maintenance with Interleukin 2. Final Analysis of the

ALFA 9801 Study. ASH Annual Meeting Abstracts. 2007;110:162.

(8) Silverman LR, McKenzie DR, Peterson BL et al. Response Rates in Patients with Acute Myeloid Leukemia (AML), Treated

with Azacitidine, Using WHO and International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS). ASH

Annual Meeting Abstracts. 2005;106:1848.


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(9) List AF, Kopecky KJ, Willman CL et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute

myeloid leukemia: a Southwest Oncology Group study. Blood. 2001;98:3212-3220.

(10) Wrzesien-Kus A, Robak T, Lech-Maranda E et al. A multicenter, open, non-comparative, phase II study of the combination of

cladribine (2-chlorodeoxyadenosine), cytarabine, and G-CSF as induction therapy in refractory acute myeloid leukemia - areport of the Polish Adult Leukemia Group (PALG). European Journal of Haematology. 2003;71:155-162.

(11) Mayer RJ, Davis RB, Schiffer CA et al. Intensive Postremission Chemotherapy in Adults with Acute Myeloid-Leukemia. NEngl J Med. 1994;331:896-903.

(12) Farag SS, Archer KJ, Mrozek K et al. Pretreatment cytogenetics add to other prognostic factors predicting complete remission

and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia

Group B 8461. Blood. 2006;108:63-73.

(13) Lubbert M, Ruter B, Claus R et al. Continued Low-Dose Decitabine (DAC) Is an Active First-Line Treatment in All

Cytogenetic Subgroups of Older AML Patients: Results of the FR00331 Multicenter Phase II Study. ASH Annual MeetingAbstracts. 2007;110:300.

(14) 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. 2007;109:1114-1124.

(15) Larson RA, Sievers EL, Stadtmauer EA et al. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in

patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer. 2005;104:1442-1452.

(16) Rebulla P, Finazzi G, Marangoni F et al. The Threshold for Prophylactic Platelet Transfusions in Adults with Acute MyeloidLeukemia. N Engl J Med. 1997;337:1870-1875.

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