Acute Promyelocytic Leukemia Matthew Volk Morning Report 5/21/2010

Epidemiology Incidence of all AML is 3-5/100k APL represents 5-10% of AML In total 600-800 new ALP cases/year Incidence of APL is highest in young adults

Classification WHO Classification of AML AML with recurrent genetic abnormalities APL with t(15;17)(q22,q12); PML-RARA (previously known as AML M3 by FAB) AML with MDS-related features Therapy-related AML and MDS AML not otherwise specified

Pathogenesis t(15,17)(q22,q12) q12 q22 #15 #17 Chromosome PML PML RARa

Pathogenesis Defining abnormality is a translocation of retinoic acid receptor alpha 95% PML-RARa – t(15;17) <5% PLZF-RARa – t(11;17) Physiologic quantities of retinoic acid no longer sufficient to allow for cell differentiation

Presentation Pancytopenia Coagulopathy Anemia - weakness Neutropenia – severe infections Thrombocytopenia – mucosal or GI bleeding, ecchymosis. Coagulopathy Severe bleeding Promyelocytes in peripheral blood

Peripheral Smear Microgranular varient (25%) Hypergranular morphology (75%)

Bone Marrow Biopsy Aspirate above (hypergranular morphology) shows multiple Auer rods (“faggot cells”)

Cytogenetics Karyotype FISH or immunostaining RT-PCR Detects translocation variant FISH or immunostaining Fast – often within 2-4 hours Immunostaining is inexpensive and can be done at smaller centers RT-PCR Can detect residual disease “Gold Standard”

Supportive Therapy Severe Cytopenias Neutropenic Fever Transfuse irradiated blood products Note: pRBCs can worsen coagulopathy Neutropenic Fever Start broad spectrum abx (vanc/ceftaz) Tumor Lysis - rare with APL replete electrolytes, hydrate, allopurinol, rasburicase

Supportive Therapy Coagulopathy/DIC – very common with APL Maintain platelets >20-30k Maintain fibrinogen >100-150mg/dl Avoid invasive procedures if possible Start ATRA at preliminary diagnosis

Induction Chemotherapy Good functional status – ATRA with an anthracycline + cytarabine Often “7+3” with daily ATRA Elderly/frail patients – ATRA with arsenic trioxide Bone marrow performed either at count recovery or day 90

Hyperleukocytosis Can develop after initiation of ATRA Treatment Develops in 50% of patients induced with single-agent ATRA High risk if initial WBC count >10 Treatment Cytotoxic chemotherapy Hydroxyurea may help Prophylactic steroids to prevent differentiation syndrome

Differentiation Syndrome Develops 2-21 days post induction with ATRA Up to 25% incidence Fever, peripheral edema, pulmonary infiltrates, renal/hepatic failure, serositis with effusions Treatment Dexamathasone 10mg iv q12h x 3 days Hold ATRA for severe symptoms

Consolidation/Maintenance Consolidation – optimal regimen still undefined ATRA + anthracycline +/- cytarabine Additional cycles of arsenic trioxide Goal: negative RT-PCR on marrow Maintenance therapy Intermittent ATRA + 6-MP + MTX (1 yr) Follow with RT-PCR (3 yrs)

Prognosis Chronic remission achieved in 80-95% of patients Platelet count WBC count 3-yr relapse-free survival Low Risk >40 <10 98% Intermediate <40 89% High Risk >10 70%

References Jurcic, J et al. Diagnosis and Treatment of Acute Promyelocytic Leukemia. Current Oncology Reports 2007, 9:337-334 MKSAP14 Hematology/Oncology Sanz, M. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood, 2009, 113:1875-1891 Scaglioni PP et al. The theory of APL revisited. Curr Top Microbiol Immunol. 2007;313:85-100. Uptodate Online – “Clinical manifestations, pathologic features, and diagnosis of APL in Adults” and “Initial Treatment of APL in Adults” 5/2010