Acute Myeloid Leukemia and Acute Complications Brad Clifford 10/29/08 and 10/31/08

Objectives Define AML and recognize the different subtypes Recognize the common clinical presentation of a patient with AML Identify various prognostic factors in patients with AML Understand the different complications that are a result of the disease and of treatment Determine the therapy for these complications Briefly understand the principles of treatment

Hematologic Malignancies Lymphoid Cell Line (B or T cells) –ALL –CLL –Lymphoma –Myeloma Myeloid Cell Line (granulocytes, monocytes, erythrocytes, megakaryocytes) –CML –Polycythemia Vera –Essential Thrombocythemia –Myelofibrosis with metaplasia –Atypical chronic myeloid disorders –AML

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 line –differentiated from ALL based on morphology, cytogenetics, cytochemical analysis, cell surface markers

Myelopoiesis Myeloid Progenitor cell Myeloblast Promyelocyte Myelocyte Metamyelocyte Band Granulocyte Myeloid Progenitor cell Myeloblast Monoblast Promonocyte Monocyte Myeloid Progenitor cell Proerythroblast Myeloid Progenitor cell Megakaryoblast

Epidemiology Incidence – 2.7 per 100,000 –12.6 per 100,000 in those over 65 yo –median age of presentation : 65 yo More prevalent: –Males –European descent –Hispanic/Latino background (promyelocytic leukemia (AML M3))

Epidemiology Increased incidence –Genetic fragility Bloom syndrome Faconi anemia Wiskott Aldrich Down, Klinefelter, Patau syndromes –tobacco use? –herbicides?, pesticides? –benzene exposure –XRT –Topoisomerase II inhibitors (e.g etopisode), alkylating agents –MDS –other cell proliferation disorders CML, polycythemia vera, primary thrombocytosis, PNH

Clinical symptoms Due to the excessive proliferation of myeloid precursor cells in bone marrow, certain symptoms/lab findings are expected (e.g. as a result of pancytopenia) 1.Functional neutropenia – fever, chills (INFECTION) 2.Thrombocytopenia – bleeding, bruising 3.Anemia – weakness, fatigue

Clinical symptoms Other findings – bone pain (sternum, lower extremities) – infrequent but thought to be secondary to expansion of medullary cavity

Physical Findings Gingival involvement (especially in the monocytic variants (M4 or M5)) Rare hepatosplenomegaly or LAD Pallor, petechiae, ecchymoses Bone tenderness Retinal hemorrhage CNS infiltration (more common in M4 and M5) Skin, soft tissue infiltration

Gingival Infiltration in Monocytic (AML M4 eos) Variant of AML Mani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright ©2008 Massachusetts Medical Society

Clinical symptoms/Physical Findings Extramedullary disease (ie, myeloid sarcoma) –Can also have involvement of lymph nodes, intestine, mediastinum, ovaries, uterus

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 percentage t(8;21)(q22;q22), inversion (16)(p13q22) t(16;16)(p13;q22), and t(15;17)(q22;q12)

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%)

WHO Classification AML with certain genetic abnormalities –t(8;21), t(16), inv(16), chromosome 11 changes –t(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 radiation AML not otherwise specified –undifferentiated 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.)

AML M2 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.

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.

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.

AML M4 eos From 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.

Case #1 52 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 22,000. Chem panel unremarkable. Treatment of this condition would involve: A)Induction chemotx with anthracycline/cytarabine B)Leukapheresis C)Transfusion of platelets, PRBCs followed by leukapheresis D)Running throughout the hospital yelling as loudly as possible

Leukostasis Leukostasis – predominantly in those with WBC counts > 100,000 (10% of patients); can also be seen in patients with WBC > 50,000 –Most common in those with M4 or M5 leukemia –Function 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

Leukostasis in AML Thornton, KA, Levis, M. FLT3 Mutation and Acute Myelogenous Leukemia with Leukostasis. N Engl J Med 2007; 357:1639. Copyright ©2007 Massachusetts Medical Society

Leukostasis Common symptoms –Pulmonary: dyspnea, chest pain –CNS: headaches, altered mentation, CN palsies, ocular symptoms –Priapism –Myocardial Infarction

Leukostasis Treatment –Chemotherapy with induction agents (e.g cytarabine, anthracycline) or with high dose hydroxyurea –Consider 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 hyperviscosity –In patients that are unable to undergo immediate chemotx (e.g renal insufficiency, metabolic derangements, etc), leukapheresis is a 2 nd option

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 response –Should 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

Leukapheresis Bug G et al (2007) - Retrospective study from Germany of 53 newly diagnosed cases of AML and hyperleukocytosis. Cohort A – Chemotx without leukoreduction (28 patients). Cohort B – Chemotx followed by leukapheresis (25 patients). –By day 21 -> 13 of 53 patients had died with a lower risk of early death in Cohort B compared to Cohort A (16% vs. 32% respectively; p = 0.015). –Dyspnea (p = 0.005), elevated creatinine (p = 0.028), and higher lactate dehydrogenase serum levels (p = 0.021) were independent risk factors for early death. –At a median follow-up of 24.2 months, the overall survival was similar in both cohorts (Cohort A, 7.5; Cohort B, 6.5 months). (eg, Leukapheresis had no impact on long term survival)

Leukapheresis Giles 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)

Case #2 72 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?

Tumor Lysis Syndrome Characterized by metabolic derangements caused by massive release of cellular components following lysis of malignant cells Commonly seen in malignancies with high rates of cell proliferation (esp. ALL, Burkitts lymphoma); also can be seen with AML

Tumor Lysis Syndrome Tumor lysis syndrome - hyperphosphatemia, hyperkalemia, hyperuricemia, hypocalcemia and uremia –Retrospective 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 NHL Electrolyte abnormalities can occur without the entire spectrum of TLS or even before tx is initiated –Hyperuricemia –Lactic acidosis

Tumor Lysis Syndrome Release of intracellular proteins catobilized to hypoxanthine xanthine uric acid Crystalization of uric acid and in renal tubules impaired renal function Release of phosphate from malignant cells calcium phosphate precipitation and further renal impairment along with hypocalcemia and resultant symptoms from Ca –Hyperphosphatemia: nausea, vomiting, diarrhea, seizures, lethargy –Hypocalcemia: arrhythmia, hypotension, tetany, cramps –Hyperkalemia: arrhythmia, cramps, paresthesia

Tumor Lysis Syndrome Prevention and management –IV hydration : promotes excretion of uric acid and phosphate; improves renal blood flow/GFR –Allopurinol competitive inhibitor for xanthine oxidase. Therefore, conversion of purine metabolites to uric acid However, 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 (Burkitts Lymphoma, B-ALL, ALL (WBC >100,000), AML (WBC >50,000) Also indicated in patients that develop hyperuricemia despite allopurinol –Dialysis can be used in severe cases –Urine alkalization is NOT recommended – does not increase solubility of xanthine/hypoxanthine with an increased propensity to develop xanthine-obstructive uropathies (esp with allopurinol use)

Case #3 A 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?

Greer JP, Kinney MC. Acute nonlymphocytic leukemia. In: Lee GR, Bithell TC, Foerster J, et al, eds. Wintrobe s Clinical Hematology. 9th ed. Philadelphia, Pa: Lea & Febiger;1993:

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.

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 activator –Initiation 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/PTT –Excessive production of plasmin as well breakdown of fibrin/fibrinogen to FDPs

Coagulation cascade en.wikipedia.org/wiki/Tissue_factor

DIC Common symptoms/findings – in addition to weakness (anemia), infections/fever (malfunctioning WBCs) –petechiae, ecchymoses, hematuria, bleeding from venipuncture sites –migratory thrombophlebitis (Trousseaus syndrome) –nonbacterial thrombotic (marantic) endocarditis –DVT/PE Lab findings –Prolonged PT/INR, PTT –microangiopathic anemia (schistocytes) –thrombocytopenia –elevated fibrin split products –elevated D-dimer –low fibrinogen

DIC Treatment 1.Supportive therapy Platelets Cryoprecipitate (fibrinogen) FFP 2.Treatment for obvious thrombosis (e.g thrombophlebitis, mural thrombus) UFH or LMWH; often resistant to coumadin activated protein C 3.Treatment of underlying malignancy In the case of AML M3 All-Trans Retinoic Acid (PML-RAR α) –Induces differentiation beyond promyelocyte phase –Only with the more common t(15;17) translocation; t(11;17) and t(5;17) do not respond to ATRA Remission rates of greater than 90% with AML M3 patient treated with ATRA and chemotx (eg, anthracyclines (idarubicin)) with 60-70% disease free survival Arsenic trioxide in those that relapse – achieves complete remission in >90%

Treatment of DIC Randomized prospective double-blind trial (2002) from Japan comparing activated protein C and unfractionated heparin for the treatment of DIC. 132 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).

DIC Side effects of ATRA therapy 1.Headache, bone pain, hypertriglyceridemia, dried mucous membranes and skin 2.Retinoic 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 therapy –fever, respiratory distress, hypotension, pleural and pericardial effusions, LE edema, occasional renal failure –highly elevated WBC count = higher risk –prevent by tx with chemotx (eg, cytarabine) at same time; also dexamethasone

CNS Involvement Occurs in less than 5% of AML patients (highest incidence in relapsed promyelocytic (M3) variant) –Routine LP is not performed unless symptoms suggestive of CNS pathology Common symptoms –headache –mental status changes –CN palsies (commonly CN III or VI) –CSF findings blast cells moderate increase in protein and moderate decrease in glucose

CNS Involvement Treatment –Intrathecal chemotherapy (methotrexate or cytarabine) +/- whole brain XRT addition of XRT depends on response to intrathecal chemotx and whether there is cranial nerve involvement high relapse rate –Commonly administer prophylactic intrathecal chemotx in relapsed promyelocytic disease

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 glands Treatment with common induction chemotherapeutic agents and with platelet transfusions as needed

Other Complications Necrotizing enterocolitis – usually at time of neutrophil nadir post chemotx Joint involvement – in setting of leukemic blast synovial membrane infiltration –<4% of those with AML

Treatment of AML Goal for complete remission –platelet count greater than 100 –neutrophil count greater than 1000 –BM with 5% or less blasts Molecular 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)

Treatment Assess need for emergent therapy –APL with blast > 50,000 and evidence of DIC –leukemic crisis with organ dysfunction (pulmonary, CNS) – seen most often with M4 or M5 variant

Prognostic Factors in AML Favorable –younger age (<50) –WBC <30,000 –t(8;21) – seen in >50% with AML M2 –inv(16) – seen in AML M4 eos –t(15;17) – seen in >80% AML M3 Unfavorable –older age (>60) –Poor performance status –WBC >100,000 –Elevated LDH –prior MDS or hematogic malignancy –CD34 positive phenotype, MRD1 postive phenotype –del (5), del (7) –trisomy 8 –t(6;9), t(9;22) –t(9;11) – seen in AML M5 –FLT3 gene mutation (seen in 30% of patients)

Treatment Remission induction 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 remission Postremission therapy 1.Consolidation –longer survival than maintence alone –typically high dose cytarabine 2.Maintenance – continue chemotx monthly for 4-12 months –nonmyelosuppressive doses

Treatment Increasingly, hematopoietic cell transplantation is used in patients with AML after 1 st remission in those with poor/intermediate prognostic factors. Also allogenic/autologous transplant in those with relapse or 2 nd remission –autologous with higher relapse rates. Used in those without HLA matched donor

Disease Free Survival (EORTC/GIMEMA trial) Zittoun, RA, Mandelli, F, Willemze, R, et al, N Engl J Med 1995; 332:217

Overall Survival (EORTC/GIMEMA trial) Zittoun, RA, Mandelli, F, Willemze, R, et al, N Engl J Med 1995; 332:217

Treatment Standard therapy remission rates of 60-80% with median remission durations of 1 yr –less than 20% achieve long-term remission free survival Therapy 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 survival –low dose cytarabine +/- hydroxyurea –investigational therapy –palliative care

Survival in AML Jabbour EJ, Estery E, Kantarjian HM. Adult Acute Myeloid Leukemia. Mayo Clin Proc. 2006;81:

Treatment in Refractory or Relapsed AML Most important predictive factor for outcome in relapsed/refractory AML = duration of 1 st remission Relapse is defined by >5% blasts in bone marrow –Salvage therapy produces remission rates of 40-60% in pts with remission rates >1 yr, but only 10-15% in those with shorter remission Allogenic transplant appears superior to cytarabine based chemotx in those with remission <1 yr –Gentuzumab (anti-CD33 Ab linked to antitumor antibiotic calicheamicin) – only approved tx for relapsed AML in pts >60 yo with remission > 3 months

Treatment Supportive care –G-CSF –platelet transfusions –PRBCs (leukodepleted, irradiated) –Prophylactic antibiotics fluconazole (candidiasis) acyclovir (HSV, VZV)

Future Therapeutic Targets Surface antigens – using monoclonal antibodies Signal transduction targeting (eg, FLT3, methylation, angiogenesis) Multidrug resistance reversing agents Gene expression profiling

Resources Andreoli 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): Bernard et al. Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An Evidence Based Review. Journal of Clinical Oncology. Vol 26. June Bug 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. May Giles et al. Leuk Lymphoma Jun;42(1-2): 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, 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, Zittoun, RA, Mandelli, F, Willemze, R, et al, NEJM 1995; 332:217.