case discussion and topic review on acute myleoid leukemia

1. Case discussion and topic
review
Moderator Dr. Naveen Pandey
Presenter-Dr. Pradip katwal

2. • 35 years/ Female
• Siraha
• Housewife
• Vegetarian
– Presenting complains-
• Easy fatigability 5 months
• Fever 5 months

3. 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.

4. 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.

5. Family history
• History of tuberculosis in family +

7. 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

8. Systemic examination
Chest – B/L equal air entry
B/L normal vesicular breath sounds
P/A-Soft, non tender
-spleen not palpable
CVS- S1 + S2 heard
no murmur
CNS- No neck rigidity
WNL
12/24/2011

9. Differential diagnosis
• Megaloblastic anemia
• Aplastic anemia
• Acute leukemia
• Tuberculosis
• Systemic lupus erythematosus
• Myelodysplastic disorder

10. 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

11. • RK 39 –ve
• HIV serology –ve
• Ps cytology
• ECG- sinus tachycardia
• Fundoscopy-no evidence of retinal
hemorrhage

12. 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%

13. Management
• Pt received three pints of fresh whole
blood transfusion.
• Personal hygeine
• Dental hygeine

14. 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.

15. DIAGNOSIS
• ACUTE MYELOID LEUKEMIA

16. Epidemiology
• Incidence -3.5 per 100,000 people per
year
• Median age at diagnosis- 67 years
• AML incidence increases with age

17. ALL
naïve
B-lymphocytes
Plasma
Lymphoid cells
progenitor T-lymphocytes
AML
Hematopoietic Myeloid Neutrophils
stem cell progenitor
Eosinophils
Basophils
Monocytes
Platelets
Red cells

18. Myeloid maturation
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATION
Adapted and modified from U Va website

19. Acute Leukemia
• Blasts in the marrow

20. Two-hit model of
leukemogenesis
Loss of function of Gain of function mutations of
transcription factors tyrosine kinases
needed for differentiation
eg. FLT3, c-KIT mutations
eg. AML1-ETO N- and K-RAS mutations
CBFβ-SMMHC BCR-ABL
PML-RARα TEL-PDGFβR
differentiation enhanced Acute
block + proliferation Leukemia

21. Etiology
• Heredity
– Down syndrome
– Fanconi anemia
– Bloom syndrome
– ataxia-telangiectasia
– Congenital neutropenia (Kostmann syndrome)
• Radiation
– High-dose radiation (atomic bombs survivors)

22. • chemical and occupational exposures
– Benzene
– petroleum products
– Paint
– embalming fluids
– ethylene oxide
– Herbicides
– smoking

23. • 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.

24. • Drugs
– Alkylating agent
– Topoisomerase II inhibitor
– Chloramphenicol
– Phenylbutazone
– Chloroquine
– methoxypsoralen

25. Classification
World Health Organization Classification
AML 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-MKL1
Provisional entity: AML with mutated NPM1
Provisional entity: AML with mutated CEBPA
AML with myelodysplasia-related changes

26. 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

27. 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

28. Clinical Presentation
• Nonspecific symptoms
• Fatigue
• Anorexia
• Weight loss
• Fever
• Bleeding, easy bruising
• Bone pain, lymphadenopathy, nonspecific
cough, headache, or diaphoresis

29. Physical Findings
• Fever
• Splenomegaly
• Hepatomegaly
• Lymphadenopathy
• Sternal tenderness
• Evidence of infection and hemorrhage

30. Gum hypertrophy

31. 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

32. Leukemia cutis

33. 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

34. Diagnostic procedure
• Morphology
• cytochemistry
• Immunophenotyping
• Cytogenetics
• Molecular cytogenetics
• Molecular genetics

35. • 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.

36. 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)

37. AML

38. AML

39. Auer rods in AML

40. 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

41. 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]

42. 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

43. 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.

44. 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

45. 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

46. 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

47. Management: Acute Myeloid
Leukemia

48. Dan Longo, Anthony Fauci, Dennis Kasper et al Harrison's Principles of Internal
Medicine 18th Ed. 2011

49. 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

50. Postremission Therapy
• Postremission therapy is designed to
eradicate residual leukemic cells to
prevent relapse and prolong survival

51. • Intensive chemotherapy
– High-dose cytarabine 4 cycles of HiDAC
(3 g/m2 per q12h on days 1, 3, and 5)
• Allogeneic or autologous HSCT

52. • Patients who fail to attain CR after two
induction courses should be treated with
an allogeneic hematopoietic stem cell
transplant (HSCT)

53. 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

54. 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.

55. Treatment of Promyelocytic
Leukemia
• Tretinoin
– APL differentiation syndrome
• anthracycline-based chemotherapy
• Arsenic trioxide
• Gemtuzumab ozogamicin

56. Management of special situations

57. 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

58. Cns involvement
• Less than 5% of patient
• Intrathecal cytarabine
• Dexamethasone to prevent arachnoiditis

59. Supportive Care

60. 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.

61. 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

62. 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.

63. Selected New Agents under Study for the Treatment of
Adults with AML
Class 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

64. 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