Acute Leukemia Kylie Lepic BSc, MD, FRCPC CAGPO Conference Oct 19, 2013 1
Disclosures No conflicts of interest 2
Objectives Case presentation Classification of leukemia Clinical manifestations Diagnosis Prognosis Treatment (supportivecare care, chemotherapy) Summary 3
Case Presentation ID: 46 yo F PMHx: Nil Meds: None HPI: Presenting to ER with a fever No focal infectious symptoms Also with a 3 week history of dyspnea and fatigue Hx of nightsweats x 2 weeks, no weight loss No bleeding, occasional spontaneous bruising 4
Case Presentation O/E: Vitals: T 39.0 C, HR 122, BP 110/60, RR 18, O 2 sat 99% RA H&N: +blood blister in oropharynx, gums ok, no LN CVS: N S1,S2, no murmurs, JVP flat, no edema, PPP Resp: Good BS bilaterally to the bases, no adventitious sounds Abdo: +BS, no masses, no HSM Neuro: no focal deficits Derm: +petechiae lower limbs 5
Case Presentation Investigations: CBC: WBC 113, Hb 70, MCV 85, plt 12, ANC 0.3 with circulating blasts INR 1.0, aptt 32, fibrinogen 1.9 Na 135, k 5.2, Cl 98, PO4 2.50, Cr 115, liver enzymes normal, urate 600, LDH 2500, lactate 2.6 Ui Urine dip clear CXR clear Blood cultures pending 6
Case Presentation Investigations: Bone marrow aspirate and biopsy is completed Aspirate hypercellular, 60% blasts, Auer rods Flow cytometry pop n of cells representing 67% that are CD34+/CD117+/CD33+/CD13+/HLA DR+ Core Biopsy blasts accounting for nearly 100% of marrow cells Cytogenetics/Molecular normal karyotype, NPM1 ve/flt3 ITD +ve 7
Leukemia Clonal expansion of myeloid precursors with reduced capacity to differentiate Theseimmature hematopoieticcells cells blasts accumulate in the bone marrow and inhibit normal hematopoiesis causing cytopenias and features of bone marrow failure 8
Classification of Leukemia Leukemia Acute Chronic Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Chronic Myelogenous Leukemia (CML) Chronic Lymphocytic Leukemia (CLL) 9
AML and ALL Features AML ALL Incidence 3.7/100 000 per 1.7/100 000 per year year % Adult Leukemia 80% 20% (80% of childhood) Age of Onset 67 y.o. 14 y.o. (second peak in 60 s) Clinical Features Leukostasis more common Lymphadenopathy Organomegaly CNS involvement 10
AML Classification FAB Classification M0 undifferentiated AML M1 AML with minimal maturation M2 AML with maturation M3 acute promyelocytic leukemia M4 acute myelomonocytic leukemia M5 acute monocytic leukemia M6 acute erythroid leukemia M7 acute megakaryoblastic leukemia 11
AML Classification WHO Classification 2008 AML with recurrent genetic abnormalities AML with myelodysplasia Therapy related myeloid neoplasms AML not otherwise specified Myeloid sarcoma Myeloid proliferations i related to Down syndrome 12
AML Classification WHO Classification 2008 AML with recurrent genetic abnormalities AML with t(8;21)(q22;q22); RUNX1 RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); 1;q22); CBFB MYH11 Acute promyelocytic leukemia with t(15;17)(q22;q12); PML RARA AML with t(9;11)(p22;q23); MLLT3 MLL AML with t(6;9)(p23;q34); DEK NUP214 AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1 EVI1 AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15 MKL1 Provisional entity: AML with mutated NPM1 Provisional entity: AML with mutated CEBPA 13
AML Classification WHO Classification 2008 AML with myelodysplasia y Therapy related myeloid neoplasms 14
AML Classification WHO Classification 2008 AML not otherwise specified AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocyticleukemia Acute monoblastic/monocytic leukemia Acute erythroid leukemia (Pure erythroid leukemia, Erythroleukemia, erythroid/myeloid) Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis 15
AML Classification WHO Classification 2008 Myeloid sarcoma Myeloid proliferations related to Down syndrome transient abnormal myelopoiesis myeloid leukemia associated with Down syndrome 16
ALL Classification WHO Classification 2008 B lymphoblastic leukemia/lymphoma not otherwise specified B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities t(9;22)(q34;q11.2);bcr ABL1 t(v;11q23);mll rearranged t(12;21)(p13;q22);tel AML1 (ETV6 RUNX1) Hyperdiploidy Hypodiploidy t(5;14)(q31;q32):il3 IGH ;q ) t(1;19)(q23;p13.3);e2a PBX1(TCF3 PBX1) T lymphoblastic leukemia/lymphoma 17
Acute Promyelocytic Leukemia (APL) Biologically and clinical distinct Previously M3 (FAB) now t(15;17) with PML RARA fusion product (WHO) Medical emergency high rate of early mortality (DIC) Initiate all trans retinoic acid (ATRA) followed by chemotherapy 18
Therapy Related AML (t AML) Topoisomerase II Inhibitors I.e. etoposide, doxorubicin 1 3 yr post therapy 11q26 (MLL) or 21q22 (RUNX1) Alkylating agents or Radiation I.e. melphalan, cyclophosphamide 5 7 yr post therapy Often preceding MDS Monosomy 5 or 7 or complex cytogenetics 19
Clinical Manifestations History Constitutional symptoms Symptoms of cytopenias Leukostasis Tissue infiltration (gums) Bone pain Physical Exam Petechiae, blood blisters, bruising Lymphadenopathy/hepatosplenomegaly (ALL) CNS/testicular Myeloid sarcoma (chloroma) Leukemia cutis 20
Clinical Manifestations NEJM, 2008 AJCP, 2008 21
Investigations CBC Coags/DIC screen lytes, extended lytes, Cr, liver enzymes LDH, urate βhcg Lumbar puncture Chest xray Peripheral lblood and BM for flow cytometry, t cytogenetics/molecular Bone marrow aspirate and biopsy HLA typing 22
Bone Marrow Aspirate ASH Image Bank 23
Diagnosis WHO: 20% myeloblasts (or monoblasts/promonocytes/megakaryoblasts) in the peripheral blood or bone marrow Or certain cytogene cs irrespec ve of blast count t(8;21)(q22;q22), inv(16)(p13q22), t(16;16)(p13;q22), 16)(p13 and t(15;17)(q22;q12) 17)(q22 q12) 24
Prognostic Groups AML Blood, 2010 25
Prognosis AML 26
Prognosis ALL Cytogenetics: t(9;22) t(4;11) complex cytogenetics (>5 abnormalities) low hypodiploidy Age >60 WBC>100 for T cell, WBC >30 for B cell B cell phenotype MRD>0.01% 27
Prognosis ALL Blood 2009 28
Initial Treatment ABC Monitoring for: Leukostasis Tumor lysis syndrome DIC Complications of cytopenias (febrile neutropenia, bleeding etc) 29
Leukostasis Generally leukocytes > 50 or 100 x 10 9 /L leukemic cell upregulation of surface adhesion molecules and inflammatory cytokines leading to microinfarction and hemmorhage Pulmonary symptoms, retinal or CNS hemorrhage More common in AML than ALL Treatment: cytoreduction hydroxyurea, definitive chemotherapy, leukopheresis 30
Tumor Lysis Syndrome Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, renal insufficiency IV fluids Close monitoring of lytes and extended lytes, Cr, LDH and urate Allopurinol xanthine oxidase inhibitor Rasburicase converts uric acid to allantoin 31
Tumor Lysis Syndrome Blood, 2001 32
Complications of Cytopenias Transfusion support Hb <80, transfuse 2 units PRBC Plt <10 or <20 if febrile/bleeding, transfuse 1 adult dose plt Coagulopathy cryoprecipitate if fibrinogen < 1.0 Infectious prophylaxis fluconazole +/ bacterial prophylaxis, febrile neutropenia protocol if spikes 33
Treatment of AML Induction Chemotherapy 3+7 Daunorubicin 60 mg/m 2 IV x 3 days Cytarabine 100 mg/m 2 IV x 7 days continuous infusion Consolidation Chemotherapy (generally 3 cycles) HiDAC 3000 mg/m 2 IV Days 1,3,5 (age <60 y.o. otherwise consider intermediate dose infusional Ara C) 34
Treatment of AML Allogeneic Transplant Intermediate or high risk in CR1 All others in CR2 35
Treatment of AML in the Elderly Demethylating agents: Azacitidine Fenaux, P JCO 2010 Intermediate I and high risk MDS patients with a subset of patients with AML with 20 30% blasts (n=113) Azacitidine vs. conventional care Median survival was 24.5 mo in azacitidine group vs. 16 mo with conventional care (P = 0.005) 2 year OS rates were 50% (azacitidine group) and 16% (conventional care) P = 0.001 Clinical trials 36
Treatment of ALL General principles No standard of care, no comparisons between different regimens (Hyper CVAD, CALGB, AL 4) Most contain multiple drugs in combination over 2 3 years and include CNS prophylaxis Consider clinical trial 37
Treatment of ALL Multi agent chemotherapy modeled after pediatric regimens and consisting of multiple phases: Induction CNS phase Intensification Continuation Consider allogeneic stem cell transplant 38
Treatment of Ph+ ALL Addition of Tyrosine Kinase Inhibitor (TKI) Thomas et al, 2008 Comparedto historicalcontrolscontrols without TKI 3 yr disease free survival (DFS) and OS rates were significantly higher for imatinib combination treatment vs chemo alone (Hyper CVAD) at the same institution (DFS, 62% vs. 14%; OS, 55% vs.15%; both P < 0.001) 39
Summary Acute leukemia: 20% blasts AML and ALL WBC can be high with cytopenias in other cell lines or can present with pancytopenia Diagnosis is made using morphology from BM aspirate but flow cytometry and cytogenetics and molecular studies can help In addition to age, cytogenetics and molecular studies are the most important prognostic factors 40
Summary Acute leukemia can be a medical emergency APL requires treatment with ATRA immediately Prompt treatment with supportive care is necessary to prevent complications (leukostasis, coagulopathy, TLS, sepsis etc) 41