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Acute Leukemia Noon Conference April 13, 2016 Why am I giving this talk? • Acute leukemia is an emergency • No one taught me how to manage acute leukemia when I was a resident • Bryan Hambley asked me to Outline • Obligatory pathophysiology/epidemiology discussion • When to suspect acute leukemia • Why is acute leukemia an emergency? • Initial management of the newly diagnosed patient i.e., how to avoid screwing up your admission (and minimize anxiety) • Acute problems in patients receiving chemotherapy VA wards, BMT cross-cover Introduction AML AML AML ALL AML differentiation proliferation CML CLL MM AML Classification FAB M0 AML w/minimal differentiation M1 AML w/o differentiation M2 AML w/differentiation M3 acute promyelocytic leukemia M4 myelomonocytic (AMML) M5 a) monoblastic, b) monocytic WHO AML with recurrent genetic abnormalities AML with MDS-related changes Therapy-related AML/MDS AML NOS Myeloid sarcoma M6 erythroblastic Myeloid proliferation related to Down’s syndrome M7 megakaryoblastic Blastic plasmacytoid dendritic neoplasm Adapted from UpToDate ALL Classification FAB WHO L1 small, monomorphic ALL with recurrent genetic abnormalities L2 large, heterogeneous ALL NOS L3 Burkitt-type T-cell ALL Adapted from UpToDate Acute leukemia statistics Variable AML ALL 4.0 1.7 % new cancer diagnoses 1.3% 0.4% Lifetime risk 0.5% 0.1% 65 39 25.9% 67.5% New cases/year (per 100,000) Average age at presentation 5-year overall survival* SEER Data Diagnosing acute leukemia • Diagnosis is based upon bone marrow analysis (how many blasts?). • A preliminary diagnosis may be made by flow cytometry on circulating blasts (from peripheral blood) if a bone marrow biopsy is not possible. Your job is not to diagnose acute leukemia. Your job is: to suspect acute leukemia in the appropriate clinical setting, to conduct the appropriate workup when you suspect acute leukemia, and to provide the appropriate supportive care to acute leukemia patients. When to suspect acute leukemia • Hematologic abnormalities that may suggest acute leukemia: Presentation Differential Diagnosis Leukocytosis Infection Acute stress “Leukemoid reaction” Medications – which ones? Other hematologic malignancies (CLL, CML, some lymphomas) Bi- or tricytopenias Infection Medications – which ones? Circulating blasts Medications – which ones? Leukoerythroblastic process Leukemic blasts • How to identify blasts – Look at the peripheral smear – Look at the differential for “% blasts” – May be called “atypical lymphocytes” until verified by a pathologist Can AML and ALL be distinguished by morphology alone? Leukoerythroblastic smear • Etiology: release of immature blood cell forms (blasts, nRBCs) due to marrow infiltration, marrow stress, or extramedullary hematopoiesis • Associated disease states: myelofibrosis, metastatic cancer, granulomatous disease (especially with superimposed acute stress) How could you distinguish between a leukoerythroblastic process and acute leukemia? Clinical presentations of acute leukemia Chief complaint is never: “I have an abnormal blood smear.” Chief complaint Reason “Abnormal labs” cytopenias, circulating blasts, sometimes bone marrow Bx Malaise pancytopenia, especially anemia and neutropenia Infection dysfunctional immune system Bleeding thrombocytopenia, DIC Organ failure leukostasis, tumor lysis syndrome, hypoxia Why is acute leukemia an emergency? Tumor lysis Sepsis Leukostasis DIC Tumor Lysis Syndrome (TLS) blast K+ Ca2+ K+ uric acid PO 4 CaPO4 Laboratory Value Ca2+ Direction of change Mechanism K+ tumor cell lysis PO4 DNA release Uric acid DNA release Ca++ PO4 binding TLS: Clinical Features K+ Ca2+ K+ uric acid PO 4 CaPO4 arrhythmias weakness paralysis acute renal failure Ca2+ tetany AMS TLS: Diagnosis TLS Type Definition Primary Spontaneous Secondary Treatment-induced Laboratory ≥ 2 laboratory abnormalities OR ≥ 25% change in 2 values from baseline value Clinical Laboratory TLS + end-organ damage TLS: Prevention & Treatment • Prevention: Fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, allopurinol • Treatment: rasburicase or HD allopurinol K+ purines/pyrimidines uric acid rasburicase allantoin What blood test should you get before administering rasburicase? TLS: Prevention & Treatment Prophylaxis Rasburicase Hemodialysis Clinical tumor lysis syndrome (end-organ damage) Everyone! Limited resources G6PD deficiency Limited time Rasburicase failure TLS: Pearls • 4 laboratory abnormalities: K+, PO4, uric acid, Ca++ (all except Ca++) • Make sure uric acid samples are collected on ice! – values will be falsely low if not…you could miss the diagnosis or be treating ineffectively! • Order G6PD screen early • Look for signs of end organ damage in case treatment is needed • Everyone should get fluids and allopurinol unless contraindicated Leukostasis • High blast count hyperviscosity tissue perfusion • Systems affected: CV (MI), pulm (ARDS), GI (bowel ischemia), CNS (CVA, retinal hemorrhage) Retinal hemorrhage in 49 yo with mantle cell lymphoma s/p filgrastim CT head in pt with AML; Bx showed leukocyte plugs CXR in pt presenting with AML; CT + BAL Dx Algharras et al. (2013) J Clin Diagn Res. 7(12): 3020–3022. Salloum et al. (1998) BMT 21:835-837. Vasquez (2012) FSFB-CIDER Case of the Month. Leukostasis: Diagnosis and Treatment • Leukostasis is a clinical diagnosis. – – – – There is no specific WBC cutoff to establish Dx or decide treatment Pathologic diagnosis is rarely available Rely on clinical judgment and investigation of appropriate DDx Ex: MI could be secondary to anemia, DIC, underlying CAD • Medical management – Steroids, hydrea can rapidly decrease WBC count – Risks: tumor lysis syndrome, hydrea can worsen other cytopenias • Leukapheresis – Requires line placement, transfusion medicine consultation – Contraindicated in APL hematology consultant transfusion medicine consultant Leukostasis: Pearls • Leukostasis is a clinical diagnosis – You may be the first to suspect it! – Consider alternative diagnoses in your differential… • Treatment can be lifesaving, and may be medical or by apheresis – Involve consult teams early! • Leukostasis makes transfusion risky – Transfusion further increases viscosity (but hydration decreases it!) Sepsis • Patients with acute leukemia are immunodeficient – Neutropenic – Dysfunctional bone marrow dysfunctional immune system • Culture on admission, even if asymptomatic and afebrile – Fast fever spikes are common, better to stay ahead of the curve! • Calculate the ANC even in the setting of elevated WBC count – Low ANC may be “hiding” • Fever is an emergency in the neutropenic patient! Neutropenic Fever • Neutropenia – ANC < 500 or ANC < 1000 with expected nadir < 500 • Fever – T > 38°C or T = 38°C x 1h Empiric therapy • Zosyn • Meropenem • Cefepime • Ceftazidime Add vancomycin… Add antifungal… • Hemodynamic instability • PNA • SSTI, CVC infection • +BCx with GP organism • Colonized with MRSA or VRE • Fever 4-7d after initiation of broad abx coverage • no identified source of infxn • Anticipate neutropenia > 7d DIC • Consumptive coagulopathy triggered by release of tissue factor from blasts ICH SDH pulmonary hemorrhage DVT CVA MI Adapted from UpToDate DIC • Occurs in ~10% of patients with acute leukemia – At diagnosis – After initiation of chemotherapy • Screen all patients by sending: – Coags – Fibrinogen – D-dimer • How to manage: – Monitor coags and fibrinogen even after initiation of chemotherapy! – Keep plts > 20-30K (50K if bleeding) – Keep fibrinogen > 150 Recognizing and treating DIC can save a patient’s life! Nur et al. (1995) Eur J Hem 55(2):78-82. DIC in APL (AML M3) • APL has a unique molecular mechanism – t(15;17) PML-RAR fusion protein Nur et al. (1995) Eur J Hem 55(2):78-82. DIC in APL (AML M3) • DIC is more common in APL than in any other acute leukemia – APL blasts release tissue factor, cancer procoagulant, annexin II • Without treatment, APL patients die of bleeding complications in < 1 week • APL patients are often treated empirically prior to definitive diagnosis – Benefits outweigh risks (“nothing to lose”) • When to suspect APL: Clinical presentation: • hemorrhage, DIC Blast morphology: • abnormal promyelocytes, prominent cytoplasmic granules, bilobed nuclei, Auer rods DIC and APL Pearls • Evaluate coags and fibrinogen on every suspected acute leukemic patient and replete aggressively! – Continue to monitor during chemotherapy • APL patients classically present with DIC and are at high risk of bleeding complications • Treatment with ATRA may be initiated prior to confirmation of diagnosis – Involve hematology consult service early if any suspicion of APL • Invasive procedures (e.g., central lines) and leukapheresis are contraindicated in APL – Procedures excessive bleeding – Leukapheresis is associated with sudden death Acute leukemia: Admission Orders Diagnostic workup CBC, peripheral smear, flow rule out/work up other conditions Tumor lysis K+, PO4, uric acid, Ca++, LDH ECG, BUN/Cr, physical exam Leukostasis CBC/diff CT head, CXR, eye exam Sepsis Blood cultures, neutropenic fever tx low threshold for prophylactic abx DIC Coags Fibrinogen Acute leukemia: Initial Management Diagnostic workup Flow cytometry, bone marrow biopsy Ancillary studies to r/o other diseases Tumor lysis Tumor lysis labs TID, prophylaxis for everyone, treatment if indicated Leukostasis Monitor CBC Monitor for ischemia Sepsis Frequent VS, f/u cultures, ANC daily, rapid abx for neutropenic fever DIC Daily coags, fibrinogen Keep plts > 20-30, fibrinogen > 150 Treatment complications: common • Volume overload – – – – Pts are aggressively hydrated during chemotherapy for 2 reasons: _______, _______ Continuation of hydration + diuresis preferred over stopping fluids Prevention: DAILY WEIGHTS DAILY WEIGHTS DAILY WEIGHTS DAILY WEIGHTS Treatment: diurese (may need a drip), hold fluids if necessary • Electrolyte wasting – K, Mg, PO4 – May require repletion multiple times per day – Monitor lytes frequently and don’t forget to check Mg (especially when repleting K) • Infection – Work up and treat promptly – Neutropenic patients may not show signs of infection (e.g., pulmonary infiltrates) – Don’t forget viral workup: respiratory antigens, CMV, EBV Differentiation Syndrome (APL) • Mechanisms – Cytokine release from differentiating APL blasts – “cytokine storm” – Migration and tissue deposition of differentiating APL blasts – Increased integrin expression endothelial adhesion capillaritis leak • Presentation – Associated with WBC > 10K (especially > 30K) – Symptoms: fever, hypoxia, pleural or pericardial effusion, renal failure, hypotension • Treatment – Dexamethasone 10 mg BID x3-5 days with taper – Consider holding ATRA Call the hematology fellow with any concerning symptoms in an APL patient! Dr. Carlos Silva, UpToDate Summary • Acute leukemia is an emergency – Blasts may not be recognized when pathologists are sleeping…YOU may be the first to recognize and treat acute leukemia! • If you know the 4 emergent syndromes, management becomes manageable! – – – – Tumor lysis: prophylaxis for everyone, treatment for some Leukostasis: look for signs of end-organ ischemia (it’s a clinical diagnosis!) Sepsis: ANC can hide in high WBC counts, treat fever early DIC: coags and fibrinogen for everyone • Leukemia treatment can be complicated by volume overload, electrolyte wasting, and infection – daily weights, DIURESIS, daily BMPs, daily Mg, prompt treatment of neutropenic fever • If you feel overwhelmed, call hematology (it’s our job to help you!) Acknowledgments • BMT faculty – – – – – – – Paolo Caimi, MD Brenda Cooper, MD Marcos de Lima, MD Hillard Lazarus, MD Jane Little, MD Ehsan Malek, MD Benjamin Tomlinson, MD • Hem/onc fellows – – Carlos Silva, MD Masumi Ueda, MD • BMT patients