Case3-present Aml 24.12.08 Update รวม 4 Gr.

CASE 3

CASE 3 • เด็ กห ญิ งอา ยุ 9 ปี มี อา การ อ่อน เพล ีย มา 2 สัปดา ห์ • 2 สัปดา ห์ก่ อนมา โร งพย าบา ล ผู้ ป่ ว ยมี อา กา รอ่ อนเ พลีย มา รดา สั งเก ตว่ า ผู ้ ป่ วยซีด จึงพา ไปต รวจที่อน ามัย แพทย์ บอก ว่า ผู้ป่วยเ ป็ น โร คโล หิตจา ง ให ้ ย าบำา รุ งเ ลือดมา กิ น • 3 วัน ก่อน มา โรง พยา บา ล ผ ู้ป่ว ยมี อา กา รอ่อน เพล ียมา กข ึ้ น ไปโร งเ รี ยน ไม่ไ หว มี จุดแ ดง ขึ้น ตามตัว และแขนข า มา รดา จึง พา มา โรง พยา บา ล • ปฏิ เสธโร คประจ ำา ตัว ไม่ ม ี ถ่า ยดำา ผู ้ป่ว ยยั งไ ม่ ม ี ป ระจำา เดือน

Pertinent Subjective Data • • • • •

อ่อ นเพ ลี ย ซี ด จุ ด แด งขึ้ นตาม ตัวแ ละแ ขน ขา ไม ่ มี ถ่ า ยดำา ยัง ไม ่ม ี ประจ ำา เดื อน ปฏิเ สธโ รคป ระจ ำา ตั ว

2 สั ปดา ห์ ที่ ผ่า นมา

ซีด อ่อน เพล ี ย แพท ย์สง สั ยโลหิตจ าง

ให ้ย าบำา รุง เล ื อด 3 วั นก่อ นม าโรงพ ยา บา ล

อ่อ นเพล ี ย มากขึ้ น + จุด แดง ขึ ้นตา มตั วแล ะแขนขา

ประ วัต ิ -ไม ่ ม ี โร คป ระจ ำา ตั ว -ไม ่ ม ี ถ่ ายดำา -ไม ่ ม ี ปร ะจ ำา เดื อน

Anemia Anemia is defined as a reduction of the RBC volume or hemoglobin concentration below the range of value occuring in healthy persons.

Richard E. Behrman, Robert M. Kliegman, Hal B. Jenson. Nelson textbook of pediatrics. 16th edition. W.B.Saunders company. Pennsylvania. 2000

Minimum of Hct and Hb (WHO) Ages

Hb (g/dL)

Hct (%)

6 mo – 6 yr

11

33

6 – 14 yr

12

36

14 yr up

13

39

Female 14 yr up

12

36

Pregnancy

11

33

Male

Causes of anemia • Blood loss (Acute and chronic) • Excessive destruction of RBCs • Decreased production of RBCs

Causes of anemia  Blood loss • Acute – Trauma, Nosebleeds, Obstetrical complication, etc.

• Chronic – GI bleeding, Vaginal bleeding

Causes of anemia  Excessive destruction of RBCs • Hereditary – Thalassemia, G6PD def, PK def, spherocytosis, elliptocytosis, HbS, etc.

• Aquired – alloantibodies, ( ex. incompat. blood transfusion) – Autoantibodies ( ex. SLE, AIHA, TTP ) – Drug induced antibodies ex. penicillin – Infections, ( ex. malaria )

Causes of anemia  Decreased Production of RBCs • Nutritional deficiency (inadequate intake) o Iron, B12, folate deficiency anemia • Defective absorption: Pernicious anemia • Chronic kidney disease : Decrease EPO • Bone Marrow Failure o Congenital and acquired aplastic anemia o Congenital and acquired pure red cell anemia o Infiltrative (Leukemia, lymphoma) o Myelofibrosis and osteopetrosis

Common causes of anemia in children • • • • • • •

Iron deficiency (most common) Thalassemia Chronic disease Vitamin B12 deficiency Folate deficiency Bone marrow failure G6PD deficiency

Bleeding Disorders Primary hemostasis (Platelet and vessel)

Secondary hemostasis (Coagulation factor)

Signs

Petechiae, Purpura, Small ecchymosis

Large ecchymosis, Hematoma

Location

Skin, Mucous membrane

Muscle, Intra-articular, Deep connective tissue

Duration

Immediate bleeding

Delayed bleeding

Response when press on

Stop bleeding

Continue bleeding

Petechiae & Purpura

Hematoma

Ecchymosis

Differential Diagnosis 1

Differential Diagnosis From History  Blood loss • Acute – Trauma, Nosebleeds, Obstetrical complication, etc.

• Chronic – GI bleeding, Vaginal bleeding

No melena and history of blood loss

Differential Diagnosis From History  Excessive destruction of RBCs • Hereditary o Thalassemia, G6PD def, PK def, spherocytosis, elliptocytosis, HbS, etc.

• Aquired

ซัก ประวัต ิค รอ บครัวเ พิ ่ม เติม

o Alloantibodies, (ex; incompatible blood transfusion)

No history

o Autoantibodies ( ex; SLE, AIHA, TTP ) o Drug induced antibodies ; penicillin o Infections ( ex ; malaria )

No drug use

No history of camping

Physical Examination : Jaundice, Dark urine

Differential Diagnosis From History  Decreased Production of RBCs • Nutritional deficiency (inadequate intake) o Iron, B12, folate deficiency anemia • Defective absorption: o Pernicious anemia No history of ileectomy • Chronic kidney disease : Decrease EPO

ซักป ระวั ติเ พิ่ มเติ ม : Di et ary beha vior

No history

Phys ical E xami nat ion ; Glo ssit is ,Ko ilo nych ia (Iro n D ef. a nemia ) ,Pe rip hera l Ne uro pathy

glossitis

Koilonychia - spoon shaped nail

Differential Diagnosis From History  Decreased Production of RBCs • Bone Marrow Failure o Congenital and acquired aplastic anemia o Congenital and acquired pure red cell anemia o Infiltrative (Leukemia, lymphoma, Myelofibrosis) o osteopetrosis

Bleeding Disorders Primary hemostasis (Platelet and vessel)

Secondary hemostasis (Coagulation factor)

Signs

Petechiae, Purpura, Small ecchymosis

Large ecchymosis, Hematoma

Location

Skin, Mucous membrane

Muscle, Intra-articular, Deep connective tissue

Response when press on

Stop bleeding

Continue bleeding

Physical examination; Sign of Bleeding

Suspected diseases 1 Anemia & Bleeding disorder Bone Marrow Failure Autoantibodies Anemia Nutritional deficiency Hereditary Excessive destruction of RBCs Bleeding disorder Platelet disorder (Thrombocytopenia & Platelet dysfunction) Vessel disorder Coagulation factor disorder

Physical Examination

Physical Examination • Vital Signs  BT 37 C  Pulse 110/min  RR 20/min  BP 90/60 mmHg Reference value : 6-12 yr (girl)  BT = 37 C  Pulse = 90-110/min  RR = 14-22/min  BP = 100-120/60-75 mmHg Richard E. Behrman, Robert M. Kliegman, Hal B. Jenson. Nelson textbook of pediatrics. 16th edition. W.B.Saunders company. Pennsylvania. 2000

General Appearance : Markedly pale, No jaundice, Petechiae at trunk, arms and legs HEENT : No cervical lymphadenopathy Abdomen : Liver 5 cm. below RCM, Liver span 12 cm, Spleen 2 cm. below LCM Others : Within normal limit

Differential Diagnosis 2

Differential Diagnosis From PE  Decreased Production of RBCs • Bone Marrow Failure o Congenital and acquired aplastic anemia o Congenital and acquired pure red cell anemia o Infiltrative (Leukemia, lymphoma, Myelofibrosis) o osteopetrosis

Lab investigation; CBC, Bone Marrow Examination

Differential Diagnosis From PE  Excessive destruction of RBCs • Hereditary o Thalassemia, G6PD def, PK def, spherocytosis, elliptocytosis, HbS, etc.

• Aquired o Autoantibodies ( ex; SLE, AIHA, TTP ) age group common , Arthritis , Jaundice

Physical Examination : No Jaundice

Lab investigation ; CBC, Special staining, Coomb’s test

Differential Diagnosis From History  Decreased Production of RBCs • Nutritional deficiency (inadequate intake) o Iron, B12, folate deficiency anemia

Lab investigation : CBC, Serum ferritin, TIBC (Total iron binding capacity)

Bleeding disorder •

Platelet disorder (Thrombocytopenia & Platelet dysfunction)

• •

Vessel disorder Coagulation factor disorder Physical Examination : Petechiae

Lab investigation ; CBC, Bleeding time

Suspected diseases 2 Anemia & Bleeding disorder

Bone Marrow Failure Autoantibodies

Anemia Nutritional deficiency Hereditary Excessive destruction of RBCs

Bleeding disorder Platelet disorder (Thrombocytopenia & Platelet dysfunction) Vessel disorder

Bone Marrow Failure • Congenital and acquired aplastic anemia PE : Hepatosplenomegaly

• Congenital and acquired pure red cell anemia Why bleeding ?

• Infiltrative (Leukemia, lymphoma, Myelofibrosis ) • Osteopetrosis (rare)

Laboratory Orders • CBC • BM Examination • Special staining

Laboratory Investigation

Laboratory Investigation 1. CBC 3. Special Staining 5. Bone marrow examination 7. Lactate Dehydrogenase ( LDH )

CBC (complete blood count) : series of test of the peripheral blood

1.Red blood cell count(RBC Count) 2.Hemoglobin(Hb) 3.Hematocrit(Hct) 4.Red blood cell indices -mean corpuscular volume(MCV) - mean corpuscular Hemoglobin(MCH) - mean corpuscular Hemoglobin concentration(MCHC) -Red blood cell distribution width (RDW) 5.White blood cell count and differential count(WBC Count) -lymphocyte -monocytes -eosinophils -basophils 6.Blood smear 7.Platelet count (Plt count)

CBC Red blood cell count Count of the number of circulating RBCs in 1 mm3 of peripheral venous blood. Hemoglobin Measure of the total amount of Hb in the blood Hematocrit Indirect measurement of red blood cell number and volume.

Hb , Hct

Normal value

case

6-18 years old 4.0-5.5x106/microL

-

11.5-15.5 g%

7 g%

35-40%

21%

Anemia

Source :Mosby’s Manual of diagnosis & Laboratory test,United state of america : Mosby Elsevier,2006

CBC

Normal value

case

77-95 fl

85 fl

Mean Corpuscular Hemoglobin (MCH) Measure of the average amount of hemoglobin within an RBC MCH = Hb(g/dL)x10 RBC (million/mm3)

25-33 pg

33.5 pg

Mean Corpuscular Hemoglobin Concentration (MCHC) Measure of the average concentration or percentage of hemoglobin within a single RBC. MCHC = Hb(g/dL)x10 hematocrit (%)

31-37 g%

33.5 g%

Mean Corpuscular Volume(MCV) Measure of the average volume, or size, of a single RBC and is therefore used in classifying anemias. MCV = Hct(%)x10 RBC (million/mm3)

MCV ,MCH ,MCHC

Normocytic,Normochromic

Source :Mosby’s Manual of diagnosis & Laboratory test,United state of america : Mosby Elsevier,2006

CBC White blood cell count and differential count measurement of the total and differential WBC count is a part of all routine laboratory diagnostic evaluation. -neutrophils -lymphocytes -monocytes -eosinophils -basophils -myeloblast

Blood smear examination of the peripheral blood smear can provide a significant amount of information concerning drugs and diseases that affect the RBCs and the WBCs.

WBC Blood smear

Normal value

case

Adult/child>2 years 4,500-13,500 /mm3

3,000 /mm3

Absolute lymphocyte = normal 54-62% 25-35% 3-7% 1-3% 0-0.75% 0

20% 50% 8% 2% 20%

-RBC : normochromic normocytic RBC -WBC : N 20% L 40% M 8% E 2% Myeloblast 20% promyeloblast 10% -platelet : 5-6 /oil field

Leukocytopenia Myeloblast,Promyelocyte

Source :Mosby’s Manual of diagnosis & Laboratory test,United state of america : Mosby Elsevier,2006

CBC Platelet count an actual count of the number of platelet per cubic milliliter of the blood. Mean platelet volume (MPV) this test is helpful in the evaluation of platelet disorder, especially thrombocytopenia.

Platelet

Normal value

case

150,000-400,000 /mm3

65,000 /mm3

7.4-10.4 /fL

-

Thrombocytopenia

Source :Mosby’s Manual of diagnosis & Laboratory test,United state of america : Mosby Elsevier,2006

Hb , Hct

Anemia

WBC Platelet

Leukocytopenia Thrombocytopenia

Pancytopenia with Myeloblast,Promyelocyte Bone Marrow Examination

Special staining •Reticulocyte Count •Denatured hemoglobin - Inclusion body - Heinz body

Reticulocyte Count Definition A blood test performed to assess the body's production of immature red blood cells (reticulocytes).

Source :Mosby’s Manual of diagnosis & Laboratory test,United state of america : Mosby Elsevier,2006

Purpose - Diagnosis Provides information about the rate at which the bone marrow is producing red cells . - Monitoring Use to monitor the response of bone marrow response to treatment for anemia.

Source :Mosby’s Manual of diagnosis & Laboratory test,United state of america : Mosby Elsevier,2006

reticulocytes are characterized by a network of filaments & granules.

Interpretation Normal :0.5-2.5%. (reported as a percentage of the total red cells.) In this case : Reticulocyte 0.3% Abnormal : Higher-than-normal percentage - Bleeding,Erythroblastosis fetalis,Hemolytic anemia, Kidney disease with increased erythopoietin production Lower-than-normal percentage - Bone marrow failure,Cirrhosis ,Folate deficientcy ,iron deficiency, Vitamin B-12 deficiency, Radiation therapy, Kidney disease with decreased erythropoietin production Source :Mosby’s Manual of diagnosis & Laboratory test,United state of america : Mosby Elsevier,2006

Special staining •Reticulocyte Count •Denatured hemoglobin - Inclusion body - Heinz body

Inclusion bodies (Hb H Inclusions ) Definition : Oxidised Hb H,precipitated within red blood cells Morphology : greenish-blue inclusion bodies appear in many erythrocytes.

Associated disorder: Hb H disease

Heinz body • Definition : unstable hemoglobin which is denatured & precipitated within red blood cells • Morphology : 1 round body attatching to cell membrane, refractile inclusions (not visible on a Wright stain film) • Associated disorder: - G6PD (Glucose - 6 - phosphatase Dehydrogenase) - α-thalasemia - Chronic liver disease

http://www.vet.uga.edu/vpp/clerk/Tarigo/NMBHzBad.jpg

In this case Denatured hemoglobin - Inclusion bodies negative - Heinz body negative

Exclude Associated disorder: -

G6PD (Glucose - 6 - Phosphatase Dehydrogenase) α-thalasemia Chronic liver disease Hb H disease

Reticulocyte Production Index (RPI) =

reticulocyte(%) x Hct(%) 45 maturation time

=

0.3 x 21 45 x 2.5

=

0.056

Fauci,Braunwalk,Kasper,Hauser,Longo,Jameson et al. Harrison’s principles of internal’s medicine. 17th ed. USA:McGraw-Hill Companies,Inc; 2008

Anemia & Bleeding disorder Bone Marrow Failure » Infiltrative (Leukemia, lymphoma, Myelofibrosis) » aplastic anemia

Autoantibodies Abnormal RBC morphology

Anemia Nutritional (Iron)deficiency Defect only erythroid series Microcytic hypochromic RBC Hereditary Excessive destruction of RBCs Defect only erythroid series

Bleeding disorder Platelet disorder (Thrombocytopenia & Platelet dysfunction) Vessel disorder

Hb , Hct

Anemia

WBC Platelet

Leukocytopenia Thrombocytopenia

Pancytopenia with Myeloblast,Promyelocyte Bone Marrow Examination

Bone Marrow Examination

Indications • Virtually pancytopenia in peripheral blood cell • Found blast cell in peripheral blood

Source: Bernadette F. Rodak, Hematology Clinical Principles and Applications, Third edition, Elsevier,USA, 2007

Bone Marrow examination A. Aspirate 1. M/E ratio(ratio of myeloid to erythroid precursors) 2. Cell morphology 3. Iron stain

B. Biopsy 1. Cellularity 2. Morphology 3. Iron stain 4. M/E ratio

Souce : Anthony S. Fauci, Eugene Braunwald, Dennis L. Kasper, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Joseph Loscalzo, Eds : Harrison's Principles ofInternal Medicine, 17th Edition : http://www.accessmedicine.com

Advantage of bone marrow aspiration & biopsy aspiration

biopsy

-appropriate in some clinical settings the -useful for determing cellularity and diagnostic question is very targeted such as anatomic relationship of cell to fat and connective tissue stroma 1. diagnosis of childhood immune thrombocytopenia purpura 2. routine surveillance follow-up of leukemia patients.

-diagnosing infiltrative diseases -diagnosing and following the course of disorders such as 1. reticulin fibrosis 2. hairy cell leukemia 3. chronic myeloproliferative disorders

Sites of bone marrow aspiration Site

Age when practical

Tibia Femur Anterior iliac crest Posterior iliac crest Vertibral spinous process

Birth to 12 mo Birth to 12 mo Any age Any age 2 yr and olde

Source:Robert I,Handi, Samuel E. lux, Thomas P. Stossel,Blood principles and practice of hematology, Philadephia:Lippincoh Williams K Wilkins,2003

Sites of bone marrow examination Strenu m

Posterior iliac crest

Anterior iliac crest

Tibia The patient is prone or in the left or right lateral decubitus position.

Bone marrow examination • Cellularity normal cellurality hypercellularity hypocellularity • M:E ratio ( myeloid : erythroid )

normal ( 3:1 – 4:1 ) • • • •

Erythroid maturation Myeloid maturation Blasts Other Source:Robert I,Handi, Samuel E. lux, Thomas P. Stossel,Blood: principles and practice of hematology, Philadephia:Lippincoh Williams K Wilkins,2003

Normal bone marrow

normal adult marrow (H&E stain) - showing a mix of fat cells (clear areas) & hematopoietic cells. - normal marrow cellularity is 35–40%. - M/E Ratio = 3 : 1

Bone marrow Examination In this case • Bone marrow aspiration – Hypercellurality – increased number of myeloid series – myeloblast 85% with Auer rods

In this case

= Auer rod = Myeloid blast

Pertinent subjective data – Bone Marrow Failure •Leukemia •Aplastic anemia Not found blast cell peripheral blood Low hematopoietic cell in BM • lymphoma Not found increased lymphoid blast cell in BM examination •myelofibrosis Not found increased collagen and fibrosis in BM examination

Leukemi a Acute Leukemi a Blasts predominant Children or elderly Short and drastic course

ALL Lymphoblasts (pre – B or pre – T)

AML - Myeloblasts - Auer rod ->20% of blast cell(WHO criteria) -promyelocyte

Chronic Leukemi Morea mature cells

Midlife age range Longer, less devastating course

CLL -Lymphocytes -Non -Ab- producing B cells

CML Myeloid stem cells “Blast crisis”

Hagop M. Kantarjian, Robert A. Wolff, Charles A. Koller,MD Anderson Manual of Medical

• Bone marrow biopsy – Acute myeloblastic leukemia (Acute non-lymphoblastic leukemia)

Lactate Dehydrogenase ( LDH ) - LDH is found in the cell of many body tissues, especially heart, liver, RBC, kidneys, skeletal muscle, brain and lung - LDH has 5 subtype

- LDH1 - LDH2 - LDH3 - LDH4 - LDH5

mainly from heart mainly from reticuloendothelial sys. come form lungs and the other tissues form kidney placenta and pancreas form liver and striated muscle

- This enzyme used to supportive diagnosis of injury or disease involving the heart, liver, red blood cell, kidneys, skeletal muscle, brain, and lung - In this case : serum LDH 2480 U/L (Normal 150-500 U/L)

Source :Mosby’s Manual of diagnosis & Laboratory test, United state of america : Mosby Elsevier,2006

CBC Hb , Hct WBC Platelet

Anemia

Conclusion

Leukocytopenia Thrombocytopenia

Myeloblast

Bone marrow aspiration Hypercellurality increased number of myeloid series myeloblast 85% Bone marrow biopsy Acute myeloblastic leukemia (Acute non-lymphoblastic leukemia) with Auer rods

Lactase Dehydrogenase ( LDH ) serum LDH 2480 U/L

Acute myeloblastic leukemia (AML)

Basic Science

Haematopoiesis

Robbins and Cotran. Pathologic basis of disease. 7th edition.Elsevier Saunders.2005

http://content.answers.com/main/content/wp/en-commons/thumb/0/0d/400px-Hematopoiesis_(human)_diagram.png

Granulocytic series

Leukemia General concepts 1. Malignancies of hematopoietic cell origin. 2. Infiltrated with leukemic cells in - BM

failure of normal haematopoiesis

- Other organs: Liver, Spleen, Lymph nodes

Arthur S. Schneider, Philip A. Szanto. Pathology. 3rd edition. Lippincott Williams& Wilkins. 2006.

Classification of Leukemia Classification : according to cell lineage Cell type

Acute

Chronic

Myelogenous leukemia ( "nonlymphocytic")

Acute myelogenous leukemia (AML)

Chronic myelogenous leukemia (CML)

Lymphocytic leukemia ( "lymphoblastic")

Acute lymphoblastic leukemia (ALL)

Chronic lymphocytic leukemia (CLL)

Characteristic AML: Accumulation of immature myeloid forms in the BM and the suppression of normal hematopoiesis. ALL: Predominance of lymphoblasts (pre-B and pre-T cell) in the blood circulation and BM. CML: Increased production of terminally differentiated myeloid cells CLL: Proliferation of lympoid stem cell that is capable of giving rise to mature cells (almost always B-cell) but less capable of differentiating into plasma cell

Incident of Leukemia • The most common childhood cancers, account for one third of pediatric malignancies.

ALL Incident

AML

CML

<10 yrs.

Peak incident in adult between15-39 yrs.

25-60 yrs.

~75% of all cases in children and has a peak incidence at age 4 yr.

~20% of leukemias, with 5% an incidence that is stable from birth through age 10

CLL >60 yrs.

rarely affects children.

Richard E. Behrman, Robert M. Kliegman, Hal B. Jenson. Nelson textbook of pediatrics. 16th edition. W.B.Saunders company. Pennsylvania. 2000

ALL

AML

http://www.accessmedicine.com/loadBinary.aspx?name=licha&filename=licha_VII.G.011.jpg

CML

CLL

http://medicineworld.org/images/blogs/12-2007/chronic-lymphoid-leukemia.jpg

Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia (AML) Classification

World Health Organization Classificationa  I. AML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22);RUNX1/RUNX1T1b AML with abnormal bone marrow eosinophils [inv(16)(p13q22) or t(16;16)(p13;q22);CBFB/MYH11]b Acute promyelocytic leukemia [AML with t(15;17)(q22;q12) (PML/RAR    ) and variants]b AML with 11q23 (MLL) abnormalities II. AML with multilineage dysplasia

Following a myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative disorder Without antecedent myelodysplastic syndrome III. AML and myelodysplastic syndromes, therapy-related

Alkylating agent–related Topoisomerase type II inhibitor–related Other types IV. AML not otherwise categorized

AML minimally differentiated 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 French-American-British (FAB) Classificationc 

Incidence 

M0: Minimally differentiated leukemia

5%

M1: Myeloblastic leukemia without maturation

20%

M2: Myeloblastic leukemia with maturation

30%

M3: Hypergranular promyelocytic leukemia

10%

M4: Myelomonocytic leukemia

20%

M4Eo: Variant: Increase in abnormal marrow eosinophils

 

M5: Monocytic leukemia

10%

M6: Erythroleukemia (DiGuglielmo's disease)

4%

M7: Megakaryoblastic leukemia

1%

Fauci,Braunwalk,Kasper,Hauser,Longo,Jameson et al. Harrison’s principles of internal’s medicine. 17 ed. USA:McGraw-Hill Companies,Inc; 2008 th

World Health Organization Classification I. AML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22);RUNX1/RUNX1T1b AML with abnormal bone marrow eosinophils [inv(16)(p13q22) or t(16;16) (p13;q22);CBFB/MYH11]b Acute promyelocytic leukemia [AML with t(15;17)(q22;q12) (PML/RAR    ) and variants]b AML with 11q23 (MLL) abnormalities II. AML with multilineage dysplasia

Following a myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative disorder Without antecedent myelodysplastic syndrome III. AML and myelodysplastic syndromes, therapy-related

Alkylating agent–related Topoisomerase type II inhibitor–related Other types IV. AML not otherwise categorized

AML minimally differentiated 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

Conditions Predisposing to Development of AML Environmental Factors

Inherited Conditions

Radiation Benzene Alkylating agents and other cytotoxic drugs Tobacco smoke

Sibling with AML Amegakaryocytic thrombocytopenia, congenital Ataxia-pancytopenia Bloom syndrome Congenital agranulocytosis (Kostmann syndrome) Diamond-Blackfan syndrome Down syndrome Dubowitz syndrome Dyskeratosis congenita Pure (nonsyndromic) familial AML Familial platelet disorder Fanconi anemia Naxos syndrome Neurofibromatosis 1 Noonan syndrome Poland syndrome Rothmund-Thomson syndrome Seckel syndrome Shwachman syndrome Werner syndrome (progeria) Wolf-Hirschhorn syndrome WT syndrome

Acquired Diseases Clonal myeloid diseases Chronic myelogenous leukemia Idiopathic myelofibrosis Primary thrombocythemia Polycythemia vera Clonal cytopenias Paroxysmal nocturnal hemoglobinuria Other hematopoietic disorders Aplastic anemia Eosinophilic fasciitis Myeloma

http://www.accessmedicine.com/content.aspx?aID=2148252

Molecular Pathogenesis AMLs are associated with acquired genetic alterations Translocation t(8;21) & inv(16) Affected CBF1α/CBF1β

Point mutation t(15;17)

RARα fuse to PML protein

block terminal differentiation RARα,normally activates transcription, is converted (but not sufficient to cause to a repressor leukemia)

Point mutation of FLT3 (tyrosine kinase) that result in its constitutive activation

Promote cellular proliferation and survival

Turn off genes required for complete myeloid differentiation

AML Robbins and Cotran. Pathologic basis of disease. 7th edition.Elsevier Saunders.2005

Hypothesis: Case3 genetic alterations

AML

Serum LDH

Proliferation of neoplastic cell in BM suppress normal hematopoietic stem cells Peripheral blood: Erythropenia Thrombocytopenia Neutropenia

Hypercellularity wt myeoblast 85% wt Auer rods Found in peripheral blood

Hct , Hb , Reticulocyte count

Pale, Fatique

Platelet

Petechiae

Neutrophil

Risk for opportunistic infection

compensate

Extramedullary hematopoiesis

Hepatosplenomegaly

AML treatment •

Immediate treatment at diagnosis

•

Induction of remission

•

Continuation or post-remission therapy

1) Immediate treatment at diagnosis Bleeding •

Transfusion therapy: RBC Platelet

Fever and Infectious •

Antibiotic

Tumor Lysis Syndrome • • •

Fluid Sodium bicarbonate >>> Increase pH Allopurinol >>> Decrease Uric acid

Leukostasis = WBC > 200,000/cu.mm. >>> Blast cell aggregation • • •

Hydroxyurea Leukapheresis Exchange transfusion

2) Induction of remission • •

to stop the growth of cancer cells to quickly induce complete remission (CR)

(4) Combination chemotherapy (6) Bone marrow transplantation > Esp. CA Drug resistance > Relapse

(3) Radiation Therapy > With or after chemotherapy > Found Leukemic cells in CNS or CSF

Mechanism of action Doxorubicin •Inhibition of DNA and RNA synthesis by intercalation between DNA base pairs •inhibition of topoisomerase II •iron-doxorubicin complex can bind DNA and cell membranes and produce free radicals that immediately cleave the DNA and cell membranes

Etoposide

Idarubicin • inhibition of DNA and RNA synthesis by intercalation between DNA base pairs

•

delay transit of cells through the S phase and arrest cells in late S or early G2 phase

•

inhibit mitochondrial transport at the NADH dehydrogenase level

•

inhibit uptake of nucleosides into HeLa cells

•

topoisomerase II inhibitor

ADRs • Myelosuppression (Anemia, Leukopenia, Thrombocytopenia) • GI disturbances, N/V, Alopecia • Cardio toxicity (Tachycardia, arrhythmias, dyspnea, Hypotension, CHF) • Cerebella toxicity

3) Continuation / post-remission therapy • to kill any remaining leukemia cells that may not be active but could begin to regrow and cause a relapse. • to prolong the duration of the initial remission

3) Continuation / post-remission therapy (1) Combination chemotherapy • Maintenance therapy Low Dose + Long time • Consolidation therapy In Dose Similar to given initially + Short time • Intensification High Dose/ Change CA Drug (2) Bone marrow transplantation

Side effects of conditioning therapy • • • • • • • • • • • •

Nausea and vomiting Diarrhea Mucositis Hair loss Loss of blood cell formation Pneumonitis (pneumonia) Occlusion (blockage) of veins in liver Congestive heart failure Premature menopause* Infertility* Growth retardation* Cataracts* * These effects are more likely to occur if total body irradiation is required for conditioning.

Psycho-Social Psycho - Anxiety - Depression - Loss of self-confidence

Social - Isolation - Loss of self-confidence

Counseling - ให้กำำลังใจผู้ป่วย - ให้ผู้ป่วยคิดในแง่บวก - ให้ผู้ป่วยดูแลตัวเอง - สร้ำงควำมมั่นใจให้กบั ผู้ป่วย Counseling - ครอบครัวและคนใกล้ชิดเข้ำใจ และให้กำำลังใจผู้ป่วย - หำกผู้ปว่ ยมีปัญหำด้ำนควำม สวยงำมและบุคลิกภำพ ให้ปรึกษำ ผู้เชี่ยวชำญด้ำนควำมงำม

References •

Richard E. Behrman, Robert M. Kliegman, Hal B. Jenson. Nelson textbook of pediatrics. 16th edition. W.B.Saunders company. Pennsylvania. 2000 • Fauci,Braunwalk,Kasper,Hauser,Longo,Jameson et al. Harrison’s principles of internal’s medicine. 17th ed. USA:McGraw-Hill Companies,Inc; 2008 • Robbins and Cotran. Pathologic basis of disease. 7th edition.Elsevier Saunders.2005 • Mosby’s Manual of diagnosis & Laboratory test,United state of america : Mosby Elsevier,2006 • Hagop M. Kantarjian, Robert A. Wolff, Charles A. Koller,MD Anderson Manual of Medical Oncology • Robert I,Handi, Samuel E. lux, Thomas P. Stossel,Blood principles and practice of hematology, Philadephia:Lippincoh Williams K Wilkins,2003 • http://www.vet.uga.edu/vpp/clerk/Tarigo/NMBHzBad.jpg • http://www.medindia.net/animation/bone-marrow-transplantation.asp • http://www.leukemia-lymphoma.org/attachments/National/br_1203086953.pdf • http://www.med.cmu.ac.th/dept/pediatrics/04-divisions_home_thai/08-hemaonco-home/Panja-book/chapter5.htm • http://www.cancer.gov/cancertopics/pdq/treatment/childAML

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