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case discussion and topic review on acute myleoid leukemia
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Case discussion and topic review
Moderator Dr. Naveen Pandey
Presenter-Dr. Pradip katwal
• 35 years/ Female
• Siraha
• Housewife
• Vegetarian
– Presenting complains-
• Easy fatigability 5 months
• Fever 5 months
HOPI
• Fever, intermittent in nature, associated with chills no rigors, no diurnal variation of fever,no h/o rashes
• Easy fatigability which was progressive associated with shortness of breath, and now shortness of breath present on doing her daily activity.
Past history
• h/o total abdominal hysterectomy 1 years back for menorrhagia
• Tissue biopsy-showed granular tissue wih foreign body gaint cell
• Has received ATT for genitourinany tuberculosis.
Family history
• History of tuberculosis in family +
Examination
• General condition- thin built
• Pallor+ • nails-leukonychia • no petichea/purpura
• Pulse -88/min• Blood pressure -98/60 mmhg• Temperature -102 degree F• Respiratory rate -16/min
Systemic examination
Chest – B/L equal air entry B/L normal vesicular breath sounds
P/A-Soft, non tender -spleen not palpableCVS- S1 + S2 heard no murmurCNS- No neck rigidity WNL
12/24/2011
Differential diagnosis
• Megaloblastic anemia
• Aplastic anemia
• Acute leukemia
• Tuberculosis
• Systemic lupus erythematosus
• Myelodysplastic disorder
Lab investigations
• TLC- 2420 mm3• DLC-N 25% L45% M25% E 05%• HB- 2.74gm/dl• Platelates-2000 mm3• Urine RE/ME- WNL• Blood culture- sterile• Urine culture- sterile• Chest x-ray- wnl
12/24/2011
• RK 39 –ve
• HIV serology –ve
• Ps cytology
• ECG- sinus tachycardia
• Fundoscopy-no evidence of retinal hemorrhage
Ps cytology-
leukocytosis with presence of blast cells. Cells are large N:C ratio is high irregular nuclear membrane. Some of them showing lobulated nuclei prominent 2-3 nucleoli prominent 2-3 nuclei and moderate amount of cytoplasm.
DLC- blast 40% premylocytes-12 % metamylocytes 2%
Management
• Pt received three pints of fresh whole blood transfusion.
• Personal hygeine
• Dental hygeine
During her stay
• After the reports, the nature of illness and treatment options was explained. Patient party wanted to take to bharatpur cancer hospital for further management and was referred.
DIAGNOSIS
• ACUTE MYELOID LEUKEMIA
Epidemiology
• Incidence -3.5 per 100,000 people per year
• Median age at diagnosis- 67 years
• AML incidence increases with age
Hematopoieticstem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloidprogenitor
Lymphoidprogenitor
B-lymphocytesB-lymphocytes
T-lymphocytes
Plasmacells
naïve
ALLALL
AMLAML
Myeloid maturation
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATIONMATURATION
Adapted and modified from U Va website
Acute Leukemia
• Blasts in the marrow
differentiation block
enhancedproliferation
AcuteLeukemia+
Gain of function mutations of tyrosine kinases
eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFR
Loss of function of transcription factors needed for differentiation
eg. AML1-ETO CBF-SMMHC PML-RAR
Two-hit model of leukemogenesis
Etiology
• Heredity– Down syndrome– Fanconi anemia– Bloom syndrome– ataxia-telangiectasia– Congenital neutropenia (Kostmann syndrome)
• Radiation– High-dose radiation (atomic bombs survivors)
• chemical and occupational exposures– Benzene
– petroleum products
– Paint
– embalming fluids
– ethylene oxide
– Herbicides
– smoking
•
• Prospective data suggested an elevated risk of myeloid leukemia associated with cigarette smoking (relative risk, 1.4; 95% confidence interval, 1.2 to 1.6).
• Population-attributable risk calculations suggested that approximately 14% of all US leukemia cases (including 17% of myeloid may be due to cigarette smoking.
• Drugs– Alkylating agent– Topoisomerase II inhibitor– Chloramphenicol– Phenylbutazone– Chloroquine– methoxypsoralen
ClassificationWorld Health Organization ClassificationAML with recurrent genetic abnormalities
AML with t(8;21)(q22;q22);RUNX1-RUNX1T1b
AML with inv(16)(pl3.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11b
Acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARAb
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-MKL1Provisional entity: AML with mutated NPM1Provisional entity: AML with mutated CEBPA
AML with myelodysplasia-related changes
Therapy-related myeloid neoplasms
AML not otherwise specified
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
Transient abnormal myelopoiesis
Myeloid leukemia associated with Down syndrome
Blastic plasmacytoid dendritic cell neoplasm
Acute leukemia of ambiguous lineage
Acute undifferentiated leukemia
Mixed phenotype acute leukemia with t(9;22)(q34;q11,20); BCR-ABL11
Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged
Mixed phenotype acute leukemia, B/myeloid, NOS
Mixed phenotype acute leukemia, T/myeloid, NOS
Provisional entity: Natural killer (NK)-cell lymphoblastic leukemia/lymphoma
Clinical Presentation
• Nonspecific symptoms
• Fatigue
• Anorexia
• Weight loss
• Fever
• Bleeding, easy bruising
• Bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis
Physical Findings
• Fever
• Splenomegaly
• Hepatomegaly
• Lymphadenopathy
• Sternal tenderness
• Evidence of infection and hemorrhage
Gum hypertrophy
myeloid sarcoma
• Myeloid sarcoma is a tumor mass consisting of myeloid blasts in which the tissue architecture is effaced, occurring at an anatomical site other than the bone marrow
Leukemia cutis
Hematologic Findings
• Anemia =normocytic normochromic
• The median presenting leukocyte count is about 15,000/L
25 and 40% of patients <5000/L
20% >100,000/L
Fewer than 5% no detectable leukemic cells in the blood
Diagnostic procedure
• Morphology
• cytochemistry
• Immunophenotyping
• Cytogenetics
• Molecular cytogenetics
• Molecular genetics
• The morphology of the malignant cell varies in different subsets– the cytoplasm often contains primary
(nonspecific) granules– the nucleus shows fine, lacy chromatin with one
or more nucleoli– Abnormal rod-shaped granules called Auer rods
are present– neutrophil -abnormal lobulation and deficient
granulation.
Bone marrow in acute leukemia
• Necessary for diagnosis
• Useful for determining type
• Useful for prognosis
• Acute leukemias are defined by the presence of > 20% blasts in bone marrow (% of nucleated marrow cells)
AML
AML
Auer rods in AML
Pretreatment Evaluation Initial Diagnostic Evaluation and Management of Adult Patients with AML
History
Increasing fatigue or decreased exercise tolerance (anemia)
Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)
Fevers or recurrent infections (granulocytopenia)
Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia or bleed)
Early satiety (splenomegaly)
Family history of AML (Fanconi, Bloom, or Kostmann syndromes or ataxia-telangiectasia)
History of cancer (exposure to alkylating agents, radiation, topoisomerase II inhibitors)
Occupational exposures (radiation, benzene, petroleum products, paint, smoking, pesticides
Physical Examination
Performance status (prognostic factor)
Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic leukemia)
Fever and tachycardia (signs of infection)
Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)
Poor dentition, dental abscesses
Gum hypertrophy (leukemic infiltration, most common in monocytic leukemia)
Skin infiltration or nodules (leukemia infiltration, most common in monocytic leukemia)
Lymphadenopathy, splenomegaly, hepatomegaly
Back pain, lower extremity weakness [spinal granulocytic sarcoma, most likely in t(8;21) patients]
Initial Diagnostic Evaluation and Management of Adult Patients with AML
Laboratory and Radiologic Studies
CBC with manual differential cell count
Chemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid, hepatic enzymes, bilirubin, LDH, amylase, lipase)
Clotting studies (prothrombin time, partial thromboplastin time, fibrinogen, D-dimer)
Viral serologies (CMV, HSV-1, varicella-zoster)
RBC type and screen
HLA typing for potential allogeneic HSCT
Bone marrow aspirate and biopsy (morphology, cytogenetics, flow cytometry, molecular studies for NPM1 and CEBPA mutations and FLT3-ITD)
Cryopreservation of viable leukemia cells
Echocardiogram or heart scan
PA and lateral chest radiograph
Placement of central venous access device
Initial Diagnostic Evaluation and Management of Adult Patients with AML
Interventions for Specific Patients
Dental evaluation (for those with poor dentition)
Lumbar puncture (for those with symptoms of CNS involvement)
Screening spine MRI (for patients with back pain, lower extremity weakness, paresthesias)
Social work referral for patient and family psychosocial support
Counseling for All Patients
Provide patient with information regarding their disease, financial counseling, and support group contacts.
Prognostic Factors
• Age at diagnosis
• Chronic and intercurrent diseases
• Performance status
• A prolonged symptomatic interval with cytopenias preceding diagnosis
• A high presenting leukocyte count
• Chromosome findings at diagnosis*
• Achievement of CR
• Secondary AML
Principles of treatment
• Combination chemotherapy– First goal is complete remission– Further rx to prevent relapse
• Supportive medical care– Transfusions, antibiotics, nutrition
• Psychosocial support– Patient and family
Complete remission
CR is defined-
•Blood neutrophil count -1000/L
•Platelet count 100,000/L.
•Circulating blasts - absent.
•The bone marrow <5% blasts
•Auer rods -absent.
•Extramedullary leukemia -absent
Management: Acute Myeloid Leukemia
Dan Longo, Anthony Fauci, Dennis Kasper et al Harrison's Principles of Internal Medicine 18th Ed. 2011
Induction Chemotherapy
• Cytarabine is usually administered as a continuous intravenous infusion for 7 days
• Anthracycline therapy generally consists of daunorubicin intravenously on days 1, 2, and 3 (the 7 and 3 regimen).
• Etoposide
Postremission Therapy
• Postremission therapy is designed to eradicate residual leukemic cells to prevent relapse and prolong survival
• Intensive chemotherapy– High-dose cytarabine 4 cycles of HiDAC
(3 g/m2 per q12h on days 1, 3, and 5)
• Allogeneic or autologous HSCT
• Patients who fail to attain CR after two induction courses should be treated with an allogeneic hematopoietic stem cell transplant (HSCT)
Hematopoietic stem cell transplantation
• Permits “rescue” from otherwise excessively toxic treatment
• Additional advantage of graft-vs-leukemia effect in allogeneic transplants
• Trade-off for allogeneic transplantation: greater anti-leukemic effect but more toxic
Molecularly targeted therapy
• Gemtuzumab ozogamicin
• Anti-cd33 antibody
• Chemically linked to the cytotoxic agent calicheamicin
• Inhibits DNA synthesis andinduces apoptosis
Zein N, Sinha AM, McGahren WJ, Ellestad GA. Calicheamicin gamma 1l: an antitumor antibiotic that cleaves double-stranded DNA site specifi-cally.Science.1988;240(4856):1198-1201.
Treatment of Promyelocytic Leukemia
• Tretinoin– APL differentiation syndrome
• anthracycline-based chemotherapy
• Arsenic trioxide
• Gemtuzumab ozogamicin
Management of special situations
Hyperleukocytosis
• Hyperleukocytosis with leukostasis immediate medical treatment.
• Leukapheresis • Hydroxyurea, given at dosages up
– 50 to 60 mg/kg per day.– Until the wbc has been reduced.
• Prevention of tumor lysis syndrome– Hydration,
– Control of uric acid production using allopurinol or rasburicase
– Control of urine ph
Cns involvement
• Less than 5% of patient
• Intrathecal cytarabine
• Dexamethasone to prevent arachnoiditis
Supportive Care
Prophylactic anti-infectious treatment
• Personal hygiene
• Dental hygiene
• Vigorous hand washing
• Anti-fungal prophylaxis
• Antibiotic prophylaxis
Leibovici L, Paul M, Cullen M, et al. prophylaxis in neutropenic patients. New evidence, practical decisions.Cancer.2006;107(8):1743-1751.
Growth factors
• GM-CSF or G-CSF*– Accelerate neutrophil recovery by 2 to 5 days– Reduce antibiotic use– Reduce duration of fever– Number of days spent in hospital– Do not retard platelet recovery– Do not have a detrimental effect by
stimulation of leukemic cell growth*Estey EH. Growth factors in acute myeloid leukaemia.Best Pract Res Clin Haematol. 2001;14(1):175-187
Transfusion support
• Prophylactic platelet transfusions-• hemoglobin level above 8 g/dL
• Prevent alloimmunization• Gamma irradiation (at least 25 Gy)
Schiffer CA, Anderson KC, Bennett CL, et al. transfusion for patients with cancer: clini-cal practice guidelines of the American Clinical Oncology.J Clin Oncol.2001;19(5):1519-1538.
Selected New Agents under Study for the Treatment of Adults with AMLClass of Drugs Examples of Agents in Class
Tyrosine kinase inhibitors PKC412, MLN518, SU11248, CHIR-258, imatinib (STI571, Gleevec), dasatinib, AMN107
Demethylating agents Decitabine, 5-azacytidine
Histone deacetylase inhibitors Suberoylanilide hydroxamic acid (SAHA), MS275, LBH589, valproic acid
Heavy metals Arsenic trioxide
Farnesyl transferase inhibitors R115777, SCH66336
HSP-90 antagonists 17-allylaminogeldanamycin (17-AAG), DMAG, or derivatives
Cell cycle inhibitors Flavopiridol, CYC202 (R-Roscovitine), SNS-032
Toxin-conjugated antibodies Gemtuzumab ozogamicin
Proteasome inhibitors Bortezomib
Aurora inhibitors AZD1152, MLN-8237, AT9283
Immunomodulatory Lenalidomide, IL-2, histamine dihydrochloride
Refrences
• Dan Longo, Anthony Fauci, Dennis Kasper et al Harrison's Principles of Internal Medicine 18th Ed. 2011
• Current Medical Diagnosis and Treatment 2012
• Boblöwenberg et al, acute myeloid leukemia, review article, www.nejm.org
• Hartmut Döhner et. Al, recommendations from an international expert panel, on behalf of the Diagnosis and management of acute myeloid leukemia in adults:European LeukemiaNet