Presentation on theme: "Acute Myeloid Leukemia and Acute Complications"— Presentation transcript:
1 Acute Myeloid Leukemia and Acute Complications FARZANE ASHRAFIHematologist & Medical Oncologist
2 Objectives Define AML and recognize the different subtypes Recognize the common clinical presentation of a patient with AMLIdentify various prognostic factors in patients with AMLUnderstand the different complications that are a result of the disease and of treatmentDetermine the therapy for these complicationsBriefly understand the principles of treatment
3 Hematologic Malignancies Lymphoid Cell Line (B or T cells)ALLCLLLymphomaMyelomaMyeloid Cell Line (granulocytes, monocytes, erythrocytes, megakaryocytes)CMLPolycythemia VeraEssential ThrombocythemiaMyelofibrosis with metaplasiaAtypical chronic myeloid disordersAML
4 Acute Myeloid Leukemia What is it?- Clonal expansion of myeloid precursor cells with reduced capacity to differentiate- As opposed to ALL/CLL, it is limited to the myeloid cell linedifferentiated from ALL based on morphology, cytogenetics, cytochemical analysis, cell surface markers
6 Epidemiology Incidence – 2.7 per 100,000 More prevalent: 12.6 per 100,000 in those over 65 yomedian age of presentation : 65 yoMore prevalent:MalesEuropean descentHispanic/Latino background (promyelocytic leukemia (AML M3))
8 Clinical symptomsDue to the excessive proliferation of myeloid precursor cells in bone marrow, certain symptoms/lab findings are expected (e.g. as a result of pancytopenia)Functional neutropenia – fever, chills (INFECTION)Thrombocytopenia – bleeding, bruisingAnemia – weakness, fatigue
9 Clinical symptoms Other findings bone pain (sternum, lower extremities) – infrequent but thought to be secondary to expansion of medullary cavity
10 Physical FindingsGingival involvement (especially in the monocytic variants (M4 or M5))Rare hepatosplenomegaly or LADPallor, petechiae, ecchymosesBone tendernessRetinal hemorrhageCNS infiltration (more common in M4 and M5)Skin, soft tissue infiltration
12 Clinical symptoms/Physical Findings Extramedullary disease (ie, myeloid sarcoma)Can also have involvement of lymph nodes, intestine, mediastinum, ovaries, uterus
13 Diagnosis Previously >30% blasts on BM aspirate (per FAB criteria) Recently changed to > 20% blasts on BM aspirate (per WHO criteria)patients with certain cytogenic abnormalities are considered to have AML regardless of blast percentaget(8;21)(q22;q22), inversion (16)(p13q22)t(16;16)(p13;q22), and t(15;17)(q22;q12)
14 FAB Classification of AML M0 undifferentiated acute myeloblastic leukemia (5%)M1 AML with minimal maturation (20%)M2 AML with maturation (30%)– t(8;21)M3 Acute promyelocytic leukemia (5%)t(15;17)M4 Acute myelomonocytic leukemia (20%)M4 eos Acute myelomonocytic leukemia with eosinophilia (5%)inv (16)M5 Acute monocytic leukemia (10%)t(9;11)M6 Acute erythroid leukemia (3%)M7 Acute megakaryoblastic leukemia (3%)
15 WHO Classification AML with certain genetic abnormalities t(8;21), t(16), inv(16), chromosome 11 changest(15;17) as usually seen with AML M3 AML with multilineage dysplasia (more than one abnormal myeloid cell type is involved)AML related to previous chemotherapy or radiationAML not otherwise specifiedundifferentiated AML (M0) AML with minimal maturation (M1) AML with maturation (M2) acute myelomonocytic leukemia (M4) acute monocytic leukemia (M5) acute erythroid leukemia (M6) acute megakaryoblastic leukemia (M7) acute basophilic leukemia acute panmyelosis with fibrosis myeloid sarcoma (also known as granulocytic sarcoma or chloroma)Undifferentiated or biphenotypic acute leukemias (leukemias that have both lymphocytic and myeloid features. Sometimes called ALL with myeloid markers, AML with lymphoid markers, or mixed lineage leukemias.)
16 AML M2Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
17 AML M3 (Promyelocytic)Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
18 AML M3 (Promyelocytic)Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
19 AML M4 eosFrom Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
20 Case #152 yo M no significant PMHx presents with general malaise for several days, headache and shortness of breath. Exam reveals palor and scattered petechiae. Found to have 95,000 WBC with HCT of 22 and platelet count of 22, Chem panel unremarkable. Treatment of this condition would involve:Induction chemotx with anthracycline/cytarabineLeukapheresisTransfusion of platelets, PRBCs followed by leukapheresis
21 LeukostasisLeukostasis – predominantly in those with WBC counts > 100,000 (10% of patients); can also be seen in patients with WBC > 50,000Most common in those with M4 or M5 leukemiaFunction of the blast cells being less deformable than mature myeloid cells. As a result, intravascular plugs develop.High metabolic activity of blast cells and local production of various cytokines contribute to underlying hypoxia
24 Leukostasis Treatment Chemotherapy with induction agents (e.g cytarabine, anthracycline) or with high dose hydroxyureaConsider low dose cranial irradiation to prevent cell proliferation in the CNS (can see intracranial hemorrhage in patients with leukostasis)Avoid PRBC transfusion if possible as additional blood elements contribute to the hyperviscosityIn patients that are unable to undergo immediate chemotx (e.g renal insufficiency, metabolic derangements, etc), leukapheresis is a 2nd option
25 Leukostasis Leukapheresis Limited affect on established vascular plugs Limited benefit in those with underlying pulmonary symptoms following chemotx. Symptoms in this case related to leukocyte lysis and subsequent inflammatory responseShould not be used as a single modality agent in patients with leukostasis (unless chemotx is delayed)May consider as adjunct to chemotx in patients with WBC >100,000 and symptoms suggestive of leukostasis
26 LeukapheresisGiles et al (2001) patients with newly-diagnosed AML (APL excluded) and an initial WBC count > 50 x 10(9)/L of whom 71 underwent leukapheresis.Pheresis reduced 2-week mortality rate (p = .006)No evidence that pheresis lengthened longer-term or overall survival; actually data to suggest the opposite (p = .06)
27 Case #272 yo F initiating chemotx with intermediate dose cytarabine. Develops progressive nausea and lethargy with generalized muscle cramps. An ECG is obtained. What diagnosis is concerning?
28 Tumor Lysis SyndromeCharacterized by metabolic derangements caused by massive release of cellular components following lysis of malignant cellsCommonly seen in malignancies with high rates of cell proliferation (esp. ALL, Burkitt’s lymphoma); also can be seen with AML
29 Tumor Lysis SyndromeTumor lysis syndrome - hyperphosphatemia, hyperkalemia, hyperuricemia, hypocalcemia and uremiaRetrospective study of 788 patients (433 adults) found incidence of hyperuricemia and TLS to be 14.7%/3.4% in patients with AML compared to 21.4%/5.2% in patients with ALL and 19.6%/6.1% in patients with NHLElectrolyte abnormalities can occur without the entire spectrum of TLS or even before tx is initiatedHyperuricemiaLactic acidosis
30 Tumor Lysis SyndromeRelease of intracellular proteins →catobilized to hypoxanthine → xanthine → uric acid → Crystalization of uric acid and in renal tubules → impaired renal functionRelease of phosphate from malignant cells → calcium phosphate precipitation and further renal impairment along with hypocalcemia and resultant symptoms from ↓CaHyperphosphatemia: nausea, vomiting, diarrhea, seizures, lethargyHypocalcemia: arrhythmia, hypotension, tetany, crampsHyperkalemia: arrhythmia, cramps, paresthesia
31 Tumor Lysis Syndrome Prevention and management IV hydration : promotes excretion of uric acid and phosphate; improves renal blood flow/GFRAllopurinol → competitive inhibitor for xanthine oxidase. Therefore, ↓ conversion of purine metabolites to uric acidHowever, must consider buildup of xanthine crystals → acute obstructive uropathy (HYDRATE!!!)Recominant urate oxidase (rasburicase)Promotes conversion of uric acid to allantoin (highly soluble; urinary excretion)Indicated in patients at high risk of TLS (Burkitt’s Lymphoma, B-ALL, ALL (WBC >100,000), AML (WBC >50,000)Also indicated in patients that develop hyperuricemia despite allopurinolDialysis can be used in severe casesUrine alkalization is NOT recommended – does not increase solubility of xanthine/hypoxanthine with an increased propensity to develop xanthine-obstructive uropathies (esp with allopurinol use)
33 Case #3A 30-year-old nulliparous female suffered from placental abruption at the 25th week of pregnancy, and emergent cesarean section was done immediately with termination of the pregnancy. Labs were significant for a prolonged PTT/INR, anemia, thrombocytopenia. Peripheral smear as shown. What other tests would you obtain and what is the likely diagnosis?
35 AML M3 (Promyelocytic)Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
36 DIC (Disseminated Intravascular Coagulation) Seen in AML M3 (promyelocytic)Function of primary granules of promyelocytes → granules contain a thromboplastin-like substance (initiates extrinsic coagulation pathway) and a factor X and Xa activatorInitiation of coagulation cascade → widespread thrombin and fibrin deposition throughout vasculature → microangiopathic vasculopathy and inability of liver/bone marrow to sustain coagulant/platelet levels → multi-organ damage with thrombocytopenia and elevated PT/PTTExcessive production of plasmin as well → breakdown of fibrin/fibrinogen to FDPs
38 DIC Common symptoms/findings Lab findings in addition to weakness (anemia), infections/fever (malfunctioning WBCs)petechiae, ecchymoses, hematuria, bleeding from venipuncture sitesmigratory thrombophlebitis (Trousseau’s syndrome)nonbacterial thrombotic (marantic) endocarditisDVT/PELab findingsProlonged PT/INR, PTTmicroangiopathic anemia (schistocytes)thrombocytopeniaelevated fibrin split productselevated D-dimerlow fibrinogen
39 DIC Treatment Supportive therapy PlateletsCryoprecipitate (fibrinogen)FFPTreatment for obvious thrombosis (e.g thrombophlebitis, mural thrombus)UFH or LMWH; often resistant to coumadinactivated protein CTreatment of underlying malignancyIn the case of AML M3 → All-Trans Retinoic Acid (PML-RARα)Induces differentiation beyond promyelocyte phaseOnly with the more common t(15;17) translocation; t(11;17) and t(5;17) do not respond to ATRARemission rates of greater than 90% with AML M3 patient treated with ATRA and chemotx (eg, anthracyclines (idarubicin)) with 60-70% disease free survivalArsenic trioxide in those that relapse – achieves complete remission in >90%
40 Treatment of DICRandomized prospective double-blind trial (2002) from Japan comparing activated protein C and unfractionated heparin for the treatment of DIC patients with 63 receiving APC and 69 receiving UFH.The effects on DIC-related organ dysfunction were not significantly different between the 2 groups.No significant difference in the rate of complete recovery from DIC between the 2 groups.The rate of death from any cause within 28 days after treatment was 20.4% in the APC group, significantly lower than the 40% death rate observed in the heparin group (P < .05).
41 DIC Side effects of ATRA therapy Headache, bone pain, hypertriglyceridemia, dried mucous membranes and skinRetinoic Acid Syndrome (occur <20% of those tx with ATRA)thought to be caused by cytokine release and/or rapid release of M3 promyelocytes from bone marrow following ATRA therapyfever, respiratory distress, hypotension, pleural and pericardial effusions, LE edema, occasional renal failurehighly elevated WBC count = higher riskprevent by tx with chemotx (eg, cytarabine) at same time; also dexamethasone
42 CNS InvolvementOccurs in less than 5% of AML patients (highest incidence in relapsed promyelocytic (M3) variant)Routine LP is not performed unless symptoms suggestive of CNS pathologyCommon symptomsheadachemental status changesCN palsies (commonly CN III or VI)CSF findingsblast cellsmoderate increase in protein and moderate decrease in glucose
43 CNS Involvement Treatment Intrathecal chemotherapy (methotrexate or cytarabine) +/- whole brain XRTaddition of XRT depends on response to intrathecal chemotx and whether there is cranial nerve involvementhigh relapse rateCommonly administer prophylactic intrathecal chemotx in relapsed promyelocytic disease
44 Ocular Involvement Seen in over 60% of newly diagnosed AML patients Commonly choroid and retina (hemorrhage, cotton wool spots)Can also involve conjunctiva and lacrimal glandsTreatment with common induction chemotherapeutic agents and with platelet transfusions as needed
45 Other ComplicationsNecrotizing enterocolitis – usually at time of neutrophil nadir post chemotxJoint involvement – in setting of leukemic blast synovial membrane infiltration<4% of those with AML
46 Treatment of AML Goal for complete remission platelet count greater than 100neutrophil count greater than 1000BM with 5% or less blastsMolecular complete remission : no evidence of leukemic cells in BM even with sensitive tests (eg, PCR, flow cytometry)If in complete remission for >3 yrs without relapse → potentially cured (<10% chance of relapse)
47 Treatment Assess need for emergent therapy APL with blast > 50,000 and evidence of DICleukemic crisis with organ dysfunction (pulmonary, CNS) – seen most often with M4 or M5 variant
48 Prognostic Factors in AML Favorableyounger age (<50)WBC <30,000t(8;21) – seen in >50% with AML M2inv(16) – seen in AML M4 eost(15;17) – seen in >80% AML M3Unfavorableolder age (>60)Poor performance statusWBC >100,000Elevated LDHprior MDS or hematogic malignancyCD34 positive phenotype, MRD1 postive phenotypedel (5), del (7)trisomy 8t(6;9), t(9;22)t(9;11) – seen in AML M5FLT3 gene mutation (seen in 30% of patients)
49 Treatment Remission induction therapy Postremission therapy Commonly anthracycline (ie, daunorubicin, idarubicin) and cytarabine → (“3+7 regimen”)Cytarabine has ample CNS penetration so no need for prophylactic intrathecal chemotx (also, ↓ risk in patients with AML compared to ALL)60-80% achieve complete remissionPostremission therapyConsolidationlonger survival than maintence alonetypically high dose cytarabineMaintenance – continue chemotx monthly for 4-12 monthsnonmyelosuppressive doses
50 TreatmentIncreasingly, hematopoietic cell transplantation is used in patients with AML after 1st remission in those with poor/intermediate prognostic factors.Also allogenic/autologous transplant in those with relapse or 2nd remissionautologous with higher relapse rates. Used in those without HLA matched donor
51 Disease Free Survival (EORTC/GIMEMA trial) Zittoun, RA, Mandelli, F, Willemze, R, et al, N Engl J Med 1995; 332:217
52 Overall Survival (EORTC/GIMEMA trial) Zittoun, RA, Mandelli, F, Willemze, R, et al, N Engl J Med 1995; 332:217
53 TreatmentStandard therapy → remission rates of 60-80% with median remission durations of 1 yrless than 20% achieve long-term remission free survivalTherapy is altered in older individuals (esp. those with poor performance status)AML believed to be a clinically/biologically distinct entity in older individuals → remission rates of 45% in those > 60 yo with less than 10% long-term remission free survivallow dose cytarabine +/- hydroxyureainvestigational therapypalliative care
54 Survival in AMLJabbour EJ, Estery E, Kantarjian HM. Adult Acute Myeloid Leukemia. Mayo Clin Proc. 2006;81:
55 Treatment in Refractory or Relapsed AML Most important predictive factor for outcome in relapsed/refractory AML = duration of 1st remissionRelapse is defined by >5% blasts in bone marrowSalvage therapy produces remission rates of 40-60% in pts with remission rates >1 yr, but only 10-15% in those with shorter remissionAllogenic transplant appears superior to cytarabine based chemotx in those with remission <1 yrGentuzumab (anti-CD33 Ab linked to antitumor antibiotic calicheamicin) – only approved tx for relapsed AML in pts >60 yo with remission > 3 months
58 ResourcesAndreoli et al. Acute Myelogenous Leukemia. Cecil Textbook of Medicine. 2004;Aoki N et el. A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation. Int J Hematol Jun;75(5):540-7.Bernard et al. Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An Evidence Based Review. Journal of Clinical Oncology. Vol 26. JuneBug G et al. Impact of leukapheresis on early death rate in adult acute myeloid leukemia presenting with hyperleukocytosis. Transfusion Oct;47(10):Estey E. Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Patients. Journal of Clinical Oncology. Vol 25. MayGiles et al. Leuk Lymphoma Jun;42(1-2):67-73.Jabbour EJ, Estery E, Kantarjian HM. Adult Acute Myeloid Leukemia. Mayo Clin Proc. 2006;81:Larson RA. Treatment of Acute Myeloid Leukemia in Younger Adults. Up to Date Online. June 11, 2008.Lowenberg B, Downing J, Burnett A. Acute Myeloid Leukemia. NEJM. 1999;341:Randolph T. Acute promyelocytic leukemia (AML M3) – part 1. Clinical Laboratory Science, Spring 2000; 13(2):Schiffer C. Complications of Acute Myeloid Leukemia. Up to Date Online. June 11, 2008.Zittoun, RA, Mandelli, F, Willemze, R, et al, NEJM 1995; 332:217.