ACUTE MYELOID LEUKEMIA

Initial Workup

Clinical
H&P ECHO/MUGA scan 2-lumen mediport CXR EKG BMT Consult (< age 70)

Laboratory
CBC, CMP DIC panel HLA-typing, CMV serology IgG, IgM ( if< 70 y) Lumbar puncture*

Bone Marrow
Aspirate and core biopsy Immunophenotyping (flow) Cytogenetics Ancillary Studies FISH MDS panel ( age 60) PCR (<age 70) FLT3-ITD NPM-1 C-kit (if CBF leukemia) Database Flow Panel (TBD)

* LP should be preformed if patient is symptomatic or if peripheral WBC > 50K at diagnosis If asymptomatic, LP should be deferred until WBC < 20K or CR1 to avoid peripheral blood contamination

Acute Myeloid Leukemia Acute Promyelocytic Leukemia (M3)

Consolidation Therapy TREATMENT INDUCTION All-trans-retinoic acid (ATRA) and anthracycline-based (idarubicin or daunorubicin) chemotherapy1 Assess marrow morphology at count recovery from start of induction Complete response Consolidate with at least 2 cycles of anthracycline-based (idarubicin or daunorubicin) chemotherapy + 2 wk ATRA with each cycle1

CLASSIFICATION M3 morphology and (+) for t(15;17) by either cytogenetics or molecular testing; consider possibility of M3 variant

APL

Induction failure Or ATRA + arsenic Trioxide for patients unable to tolerate anthracyclinebased therapy2 Assess marrow morphology at count recovery from start of induction Complete response

Arsenic trioxide or Matched sibling or alternative donor HSCT ATRA + arsenic Trioxide x 6 cycles Clinical trial Or Matched sibling or alternative donor HSCT Or Gemtuzumab ozogamicin3

Induction failure

Acute Myeloid Leukemia Acute Promyelocytic Leukemia (M3) Post-Consolidation

PCR negative Monitor by PCR every 3 mo for 2y PCR positive Repeat PCR for confirmation within 4 wks PCR positive PCR negative

Document molecular remission on bone marrow by PCR

PCR negative

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

PCR negative PCR positive Repeat PCR for confirmation Within 4 wks PCR positive

Follow algorithm For relapsed APML

Acute Myeloid Leukemia Acute Promyelocytic Leukemia (M3) Relapsed Disease

Autologous HSCT Or Arsenic consolidation (total of 6 cycles) (if not a transplant candidate)

PCR negative

Second Remission (morphologic) Arsenic trioxide4 Or Gemtuzumab ozogamicin3 (If early relapse post arsenic therapy) No remission

PCR positive

First Relapse

Matched or alternative donor HSCT Or Clinical Trial Or Gemtuzumab orzogamicin3

Clinical trial Or Matched or alternative donor HSCT Or Gemtuzumab ozogamicin3

Acute Myeloid Leukemia: Molecular Risk Categorization

RISK STATUS
Better-risk

CYTOGENETICS5
Inv(16) t(8;21) t(16;16) Normal +8 only t(9;11) Other abnormalities not listed with better-risk and poor-risk cytogenetics and molecular mutations

MOLECULAR MUTATIONS6
Normal cytogenetics with isolated NPM mutation C-KIT in patients with t(8;21) or Inv(16)

Intermediate-risk

Poor-risk

Complex ( 3 abnormalities) -5 -7 5q7qAbnormalities of 11q 23, excluding t(9;11) Inversion 3 t(3;3) t(6;9) t(9;22)

Normal cytogenetics with isolated FLT3 mutations6

Acute Myeloid Leukemia Induction (<age 60)

CLASSIFICATION TREATMENT INDUCTION

No antecedent hematologic disease Age < 60 y

Cytarabine 200 mg/m continuous infusion (Cl) x 7 days) + Idarubicin 12 mg/m2 x 3 days)7

See Post-induction Therapy (< age 60)

Clinical trial (incorporating either chemotherapy or low-intensity therapy Antecedent hematologic disease or treatment-related AML Or 30% blasts: Azacitidine 75 mg/m2 x 7 days q 4 weeks8 >30% blasts: SWOG Regimen9 Ara-C 3 g/m2 days 1-5 Daunorubicin 45 mg/m2 CIV days 6-8 CsA CIV days 6-8

Acute Myeloid Leukemia Post-Induction (<age 60)

Complete Response < 50% blast reduction Re-induction Cladribine Cytarabine G-CSF (CLAG)10 Marrow to document remission status upon hematologic recovery Induction failure 50% blast reduction without hypoplasia* Repeat of induction (5 day or 7 day)

Follow-up bone marrow (day 12-16)

Clinical trial Or Matched sibling HSCT or alternative donor HSCT Or Best Supportive Care

Hypoplasia (<5% blasts)*

Await recovery

*Consider repeat bone marrow biopsy 1 week later for patients With minimal disease (i.e. < 20% blasts) at day 12-16 prior to re-induction

Acute Myeloid Leukemia Post-Remission (<age 60)

Better-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 Or 1 to 2 cycles of high dose cytarabine-based consolidation followed by autologous HSCT (OUTPATIENT) Or Clinical trial Matched sibling or autologous HSCT or High-dose cytarabine, 3 g/m over 3 h every 12 h on days 1, 3, 5 x 4 courses11 Or Clinical trial

Age < 60

Intermediate-risk molecular profile

Antecedent hematologic Disease, treatmentrelated disease or poorrisk molecular profile

Clinical trial Or Matched sibling HSCT Or Alternative donor HSCT

Acute Myeloid Leukemia Induction (age 60-75)

Low-intensity therapy* Or Best supportive care Complex Cytogenetics Obtain cytogenetics prior to treatment when possible12 Clinical trial (preferred) Or Low-intensity therapy* Or Best supportive care OR Standard-dose cytarabine (100 mg/m Cl x 7 days) with idarubicin (7+3)

PS > 2

Age 60-75 PS 2

Non-complex Cytogenetics

Clinical trial (preferred) Or 7+3

Age 75 or significant comorbidities which cause organ dysfunction not directly related to leukemia

Clinical trial Or Low-intensity therapy Or Best supportive care

* Low-intensity therapy may include: azacitidine8, decitabine13, hydroxyurea, low-dose cytarabine14

Acute Myeloid Leukemia Post-Induction ( age 60)

< 50% blast reduction Clinical Trial OR Re-induction Cladribine Cytarabine G-CSF (CLAG)10 OR Best supportive care Complete Response Marrow to document remission status upon hematologic recovery Induction failure 50% blast reduction without hypoplasia* Repeat of induction (5 day or 7 day) Clinical trial or Reduced intensity HSCT in context of clinical trial or Best supportive care

Follow-up bone marrow (day 12-16)

Hypoplasia (<5% blasts)*

Await recovery

*Consider repeat bone marrow biopsy 1 week later for patients With minimal disease (i.e. < 20% blasts) at day 12-16 prior to re-induction

Acute Myeloid Leukemia Post-Remission ( age 60)

Clinical trial or Reduced intensity HSCT in context of clinical trial or Standard-dose cytarabine (100 mg/m/day x 5-7 d x 1-2 cycles) anthracycline (idarubicin or daunorubicin) or Consider cytarabine 1-1.5 g/m/day x 4-6 doses x 1-2 cycles for patients with good performance status

Complete Remission

Acute Myeloid Leukemia Relapsed Disease

Early ( < 6 mo) Age < 60 Late (> 6 mo) Clinical trial (strongly preferred) or Salvage chemotherapy (CLAG preferred)10 followed by Matched sibling HSCT or alternative donor HSCT, if donor previously identified Clinical trial (strongly preferred) or Salvage chemotherapy (CLAG preferred)10 followed by Matched sibling HSCT or alternative donor HSCT, if donor previously identified or Repeat initial successful induction regimen Clinical trial (strongly preferred) Or Best supportive care Or Gemtuzumab orzogamicin15

Relapse Early ( < 6 mo)

Age 60 Late (> 6 mo) Clinical trial (strongly preferred) Or Treatment with initial successful regimen Or Gemtuzumab ozogamicin15 Or Best supportive care Can consider Allo-HSCT If 2nd CR obtained

If relapse into MDS state: Azacitdine OR Decitabine

Acute Myeloid Leukemia

CNS Leukemia
Lumbar puncture LP negative CT/MRI to Rule out bleed or mass effect Negative Mass effect Observe and repeat LP if symptoms persist Intrathecal chemotherapy 2x/wk until clear, then weekly x 4-6 wk

At diagnosis, neurological symptoms

LP positive

Neuro-oncology consultation

Positive mass effect or increased intracranial pressure

Consider needle aspiration or biopsy

Strongly consider RT followed by intrathecal chemotherapy 2x/wk until clear, then weekly x 4-6 wk

First CR screening, no neurological symptoms

LP negative Lumbar puncture LP positive

Observe and repeat LP symptoms present Intrathecal chemotherapy 2x/wk until clear or If patient to receive high-dose cytarabine, follow-up with LP post completion of therapy to document clearance

Acute Myeloid Leukemia

SUPPORTIVE CARE (1 OF 4)
There are variations between institutions but the following issues are important to consider in the management of patients with AML. General Prophylactic antibiotics, including antifungals, are left to the discretion of the individual institutions. Growth factors may be considered in the elderly after chemotherapy is complete. Note that such 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.

Acute Myeloid Leukemia

SUPPORTIVE CARE (2 OF 4)
Saline or steroid eye drops to both eyes four times daily for all patients undergoing highdose 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 renal function or patients > 60 years), are at risk for cerebellar toxicity. Neurologic assessments including tests for nystagmus, slurred speech, and dysmetria should be performed before each 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 the incidence of neurotoxicity in patients with renal insufficiency. J Clin Oncol 1997;15(2):833-839.

Acute Myeloid Leukemia

SUPPORTIVE CARE (3 OF 4) 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 with cryoprecipitate 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 of CNS disease. Prophylactic intrathecal therapy (IT) is being evaluated in this group.

Acute Myeloid Leukemia

SUPPORTIVE CARE (4 OF 4)
Leukapheresis is not recommended in the routine management of patients with a high WBC count in APL because of the difference in leukemia biology; however, in life threatening cases with leukostasis that is not responsive to other modalities, leukapheresis can be considered with 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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(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 - a report 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. N Engl 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 Meeting Abstracts. 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 Myeloid Leukemia. N Engl J Med. 1997;337:1870-1875.