Acute myeloid leukemia

acute myeloid leukemia, blood cancer, prevalance, types, classifications, diagnostics, markers, management, chemotherapy regimen, prognosis

1. ACUTE MYELOID LEUKEMIA SHUMAYLA ASLAM, MD 1 ST YEAR RESIDENCY SOURSE : HARRISON’S INTERNAL MEDICINE 19 TH EDITION CHAPTER 132 [email protected]

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4. Acute myeloid leukemia (AML) is a neoplastic disease characterized by infiltration of the blood, bone marrow, and proliferative, clonal undifferentiated cells of the hematopoietic system. [email protected]

5. I ncidence ~3.5 per 100,000 people per year higher in men than in women (4.5 vs 3.1) increases with age 1.7 in individuals age <65 years 15.9 in those age >65 years The median age at diagnosis is 67 years. [email protected]

6. ETIOLOGY Heredity aneuploidy ( trisomy 21 noted in Down syndrome, Inherited diseases with defective DNA repair ( Fanconi anemia , Bloom syndrome, and ataxiatelangiectasia ) Congenital neutropenia ( Kostmann syndrome) Germline mutations of CCAAT/enhancer-binding protein α ( CEBPA), runt-related transcription factor 1 (RUNX1), and tumor protein p53 (TP53) [email protected]

7. Radiation High-dose radiation atomic bombs ; nuclear reactor accidents, increases the risk of myeloid leukemias that peaks 5–7 years after exposure. Therapeutic radiation alone seems to add little risk Chemical and Other Exposures Exposure to benzene plastic, rubber, and pharmaceutical industries, is associated with an increased incidence of AML. Smoking and exposure to petroleum products paint, embalming fluids, ethylene oxide, herbicides, and pesticides [email protected]

8. Drugs Anticancer drugs are the leading cause of therapy-associated AML. Alkylating agent-associated leukemias occur on average 4–6 years after exposure Topoisomerase II inhibitor–associated leukemias occur 1–3 years after exposure Newer agents for treatment of other hematopoietic malignancies and solid tumors are also under scrutiny for increased risk of AML. [email protected]

9. CLASSIFICATION The current categorization of AML uses the World Health Organization (WHO) classification AML with certain genetic abnormalities AML with a translocation between chromosomes 8 and 21 AML with a translocation or inversion in chromosome 16 AML with a translocation between chromosomes 9 and 11 APL (M3) with a translocation between chromosomes 15 and 17 AML with a translocation between chromosomes 6 and 9 AML with a translocation or inversion in chromosome 3 AML ( megakaryoblastic ) with a translocation between chromosomes 1 and 22 [email protected]

10. AML with myelodysplasia -related changes AML related to previous chemotherapy or radiation AML not otherwise specified AML with minimal differentiation (M0) AML without 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 Myeloid proliferations related to Down syndrome Undifferentiated and biphenotypic acute leukemias   [email protected]

11. FAB subtype M0- Undifferentiated acute myeloblastic leukemia M1- Acute myeloblastic leukemia with minimal maturation M2- Acute myeloblastic leukemia with maturation M3- Acute promyelocytic leukemia (APL) M4- Acute myelomonocytic leukemia M4 eos - Acute myelomonocytic leukemia with eosinophilia M5- Acute monocytic leukemia M6- Acute erythroid leukemia M7- Acute megakaryoblastic leukemia [email protected]

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14. CLINICAL PRESENTATION SYMPTOMS Patients with AML often have several non-specific (general) symptoms. These can include: Fatigue usually the first symptom Fever with or without an identifiable infection is the initial symptom in approximately 10% of patients Night sweats Loss of appetite Weight loss Signs of abnormal hemostasis (bleeding, easy bruising) are noted first in 5% of patients. On occasion, bone pain, lymphadenopathy , nonspecific cough, headache, or diaphoresis are the presenting symptom. [email protected]

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16. Physical Findings splenomegaly , hepatomegaly , lymphadenopathy , sternal tenderness, evidence of infection and hemorrhage are often found at diagnosis. [email protected]

17. Significant gastrointestinal bleeding, intrapulmonary hemorrhage , or intracranial hemorrhage occurs most often in APL. Bleeding associated with coagulopathy may also occur in monocytic AML and with extreme degrees of leukocytosis or thrombocytopenia in other morphologic subtypes. [email protected]

18. Retinal hemorrhages are detected in 15% of patients. Infiltration of the gingivae , skin, soft tissues, or meninges with leukemic blasts at diagnosis is characteristic of the monocytic subtypes and those with 11q23 chromosomal abnormalities. [email protected]

19. Hematologic Findings Anemia is usually present at diagnosis and can be severe. normocytic normochromic . Decreased erythropoiesis often results in a reduced reticulocyte count, and red blood cell (RBC) survival is decreased by accelerated destruction. Active blood loss also contributes to the anemia . leukocyte count is about 15,000/ μL . Between 25 and 40% of patients have counts <5000/ μL , 20% have counts >100,000/ μL . Fewer than 5% have no detectable leukemic cells in the blood. Platelet counts <100,000/ μL are found at diagnosis in ~75% of patients, and about 25% have counts <25,000/ μL . [email protected]

20. M orphology In AML, the cytoplasm often contains primary (nonspecific) granules, and the nucleus shows fine, lacy chromatin with one or more nucleoli characteristic of immature cells. Abnormal rod-shaped granules called Auer rods are not uniformly present, but when they are, myeloid lineage is virtually certain. Poor neutrophil function may be noted functionally by impaired phagocytosis and migration and mor - phologically by abnormal lobulation and deficient granulation. Both morphologic and functional platelet abnormalities can be observed, including large and bizarre shapes with abnormal granulation and inability of platelets to aggregate or adhere normally to one another. [email protected]

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24. Diagnosis  20% or more leukemic blasts in the bone marrow Immunohistochemical staining for myeloperoxidase is the best method for determining which cells are committed to the myeloid lineage Immunohistochemical diagnosis of acute myeloid leukemia (AML). (A) Bone marrow aspirate shows increased blasts from a patient with AML with inv(16) (Wright- Giemsa stain, 350). (B) Bone marrow biopsy from the same patient shows 100% cellularity with sheets of blasts ( hematoxylin -eosin stain, 340) [email protected]

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26. Diagnosis the diagnostic work-up for AML    : Complete blood count (CBC) with manual differential and routine chemistry profile (including liver function tests, serum creatinine , lactate dehydrogenase [LDH], and uric acid) Coagulation profile – Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen) Bone marrow aspiration and biopsy, including classical cytogenetics , immunophenotyping , and molecular testing for c-KIT, FLT3-ITD, NPM1, and CEBPA HLA typing of patient and family [email protected]

27. Imaging studies, including dental survey and computed tomography (CT) scan of the chest and abdomen, or chest x-ray and abdominal ultrasound Sperm preservation in men (if desired by patient) Pregnancy test in women [email protected]

28. Treatment newly diagnosed patient with AML is usually divided into two phases, induction postremission management The initial goal is to induce Complete remission based on the patient’s age <60 years - Intensifying therapy with traditional chemotherapy agents such as cytarabine and anthracyclines in younger patients appears to increase the cure rate of AML. >60 years - the benefit of intensive therapy is controversial; [email protected]

29. INDUCTION CHEMOTHERAPY The most commonly used CR induction regimens (for patients other than those with APL) consist of combination chemotherapy with cytarabine and an anthracycline (e.g., daunorubicin , idarubicin , mitoxantrone ). [email protected]

30. <60 years- cytarabine is used either at standard dose (100–200 mg/m2) administered as a continuous intravenous infusion for 7 days or higher dose (2 g/m2) administered intravenously every 12 h for 6 days. anthracycline therapy generally consists of daunorubicin (60–90 mg/m2) or idarubicin (12 mg/m2) intravenously on days 1, 2, and 3 (the 7 and 3 regimen). Other agents can be added (i.e., cladribine ) when 60 mg/m2 of daunorubicin is used. [email protected]

31. ≥60 years- outcome is poor likely due to a higher induction treatment–related mortality rate and frequency of resistant disease, especially in patients with prior hematologic disorders (MDS) or who have received chemotherapy treatment for another malignancy older patients can be also treated with the 7 and 3 regimen with standard-dose cytarabine and idarubicin (12 mg/m2), daunorubicin (45–90 mg/m2)*, or mitoxantrone (12 mg/ m2). *has not shown benefit due to the increased toxicity and is not recommended. [email protected]

32. older patients may be considered for single-agent therapies with clofarabine or hypomethylating agents (i.e., 5-azacitidine or decitabine ) [email protected]

33. Toxicity with high-dose cytarabine also includes pulmonary toxicity and significant and occasionally irreversible cerebellar toxicity. This toxicity occurs more commonly in patients with renal impairment and in those older than age 60 years. [email protected]

34. After one cycle of the 7 and 3 chemotherapy induction regimen, if persistence of leukemia is documented, the patient is usually re- treated with the same agents ( cytarabine and the anthracycline ) for 5 and 2 days, respectively. [email protected]

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36. POSTREMISSION THERAPY without further therapy, virtually all patients experience relapse. Thus, postremission therapy is designed to eradicate residual leukemic cells to prevent relapse and prolong survival. The type of postremission therapy in AML is often based on age and cytogenetic and molecular risk. [email protected]

37. In the postremission setting, high-dose cytarabine for three to four cycles is more effective than standard-dose cytarabine . For younger patients, most studies include intensive chemotherapy and allogeneic or autologous hematopoietic stem cell transplantation (HSCT). Autologous HSCT preceded by one to two cycles of high-dose cytarabine is also an option for intensive consolidation therapy. [email protected]

38. Relapsed or Refractory disease Response rates depend on duration of first remission  Patients in complete remission (CR) longer than 2y have a 60% chance of responding to front-line regimens Patients in CR 1-2y have a 40% chance of responding to front-line regimens; clinical trials are preferred Patients in CR less than 1y are unlikely to respond to front-line regimens and should be referred for clinical trials The prognosis for patients beyond first salvage is very poor  [email protected]

39. Recommended chemotherapy regimens for relapsed or refractory disease: Mitomycin , etoposide , and cytarabine (MEC)    : Etoposide  80 mg/m  2  IV over 1h  plus    cytarabine 1 g/m  2  IV over 6h  plus    mitoxantrone  6 mg/m  2 ; all three drugs should be given daily for 6d  or CLAG-M ( cladribine , cytarabine , mitoxantrone , and filgrastim )    : Cladribine  5 mg/m  2  IV over 2h daily for 5d  plus  cytarabine 2 mg/m  2  IV over 4h daily for 5d, with each dose starting 2h after cladribine   plus  mitoxantrone 10 mg/m  2  IV for 3d  plus    filgrastim  300 µg for 6d starting 24h prior to chemotherapy  or [email protected]

40. FLAG-IDA ( fludarabine , cytarabine , idarubicin , and filgrastim )    : Fludarabine  30 mg/m  2 /day IV over 30min on days 1-5 Cytarabine 2 g/m  2 /day IV over 4h; 4h after fludarabine on days 1-5 Idarubicin 10 mg/m  2 /day IV on days 1-3 Filgrastim 5 µg/kg/day SC to begin on day 6 until neutrophil recovery [email protected]

41. SUPPORTIVE CARE Patients with AML should be treated in centers expert in providing supportive measures. Multilumen right atrial catheters should be inserted as soon as patients with newly diagnosed AML have been stabilized. Platelet transfusions should be given as needed to main- tain a platelet count ≥10,000/ μL . RBC transfusions should be administered to keep the hemoglobin level >80 g/L (8 g/ dL ) in the absence of active bleed- ing , DIC, or congestive heart failure, which require higher hemoglobin levels. Blood products leukodepleted by filtration should be used to avert or delay alloimmunization as well as febrile reactions. [email protected]

42. PROGNOSTIC FACTORS Favorable Translocation between chromosomes 8 and 21 Inversion of chromosome 16 or a translocation between chromosome 16 and itself Translocation between chromosomes 15 and 17 Intermediate-I Mutated NPM1 and FLT3-ITD Wild-type NPM1 and FLT3-ITD Wild-type NPM1 without FLT3-ITD Intermediate-II t(9;11)(p22;q23); MLLT3-MLL Cytogenetic abnormalities not classified as favorable or adverse [email protected]

43. Adverse Deletion (loss) of part of chromosome 5 or 7 (no specific AML type) Translocation or inversion of chromosome 3 Translocation between chromosomes 6 and 9 Translocation between chromosomes 9 and 22 Abnormalities of chromosome 11 (at the spot q23) Complex changes - those involving several chromosomes (no specific AML type) [email protected]

44. That’s All for today ! [email protected]