A Case of CML

By Dr. P. Arul M 7 Unit

Prof. Dr. P. Vijayaraghavan’s unit

• 45 yr old female, kaveri, from redhills was admitted with complaints of • Abdominal distention – 6 months• Leg swelling – 4 months• urine output – 4 months

• h/o present illness:• Patient was apparently normal 6 months

back• She developed a swelling in the left

hypochondrium that progressed to the present size

• She developed bilateral leg swelling and decreased urine output for the past 4 months

• She gives h/o • Fever – low grade, intermittent, not

associated with chills or rigors, for the past 6 weeks

• Loss of appetite• Loss of weight

• There is no h/o • Nausea, vomiting• Heart burn• Jaundice• Abdominal pain• Hematemesis, melena• Hematochezia or bleeding PR• Alteration in bowel habit• Neuropsychatric manifestation

• Past history:• Patient is not a known case of diabetes,

hypertension, tuberculosis, epilepsy, bronchial asthma

• Personal history:• Not a tobacco chewer• Not a smoker or alcoholic• No h/o chemical/ radiation exposure

• Family history:• No h/o any malignancy among family

members

• Contact history:• No h/o contact with patients with

tuberculosis

• General examination• Conscious • Oriented • Afebrile • Not Dyspnoeic • Hydration Fair • Pallor+ • Pedal edema+• Axillary, cervical, inguinal lymph nodes –

palpable, firm, non tender, size ranging 0.5 to 1 cm

• Vitals• Pulse rate: 80/min• Blood pressure: 100/70 mmHg• Temperature: 98.4 F• Respiratory rate: 16/ min

• Systemic examination• Upper GIT: Normal• Inspection:

• Shape - distended• Flanks - free• Dilated veins - upper part of abdomen• Umblicus - pushed downwards• Skin - normal• Hernial sites - normal• A mass extending from left

hypochondrium to the hypogastric region seen, it moves with respiration

• Palpation• Superficial

• Normothermic• No tenderness, hyperaesthesia• Direction of flow of veins – away from the

umblicus• No divarication of recti• No abnormal pulsation

• Deep• Liver 4.5 cm below RCM, firm, smooth surface,

moves with respiration, non tender• Spleen 19 cm below LCM, towards RIF, firm, non

tender, smooth surface, edges well defined• No other mass palpable

• Percussion• No free fluid• Upper border of liver dullness: 5th ICS• Upper border of spleenic dullness 8th ICS

• Auscultation• Bowel sounds+• No hepatic or spleenic rub• No venous hum• No bruit

• PR – not done

• Blood group – A+ve• Total count – 1,40,000• Differential count – P-98, L-02, E/B-0• Platelets – 34, 000• Sugar 80 mg%• Urea 43 mg%• Creatinine 1.2 mg%• Hiv – neg • Hbsag – neg • Anti HBC – neg

Investigations

• Hb – 5.6 g/dl• PCV – 19.1 • MCV – 84.1• MCH – 24.7 • MCHC – 29.3• ESR 102/hr

• PT • Control – 12-15s• Test 14s• INR 1.0

• APTT • Control – 26s• Test – 26s

• Bilirubin • Total – 1.34• Direct – 0.98

• AST - 23U/L• ALT - 10U/L• GGT - 77U/L• SAP - 567U/L• Proteins

• Total – 5.6 g/dl• Alb – 2.9 g/dl• Glo – 2.7 g/dl

• Na+ 124.6• K+ 5.4• Cl- 95.7

• Urine • colour – pale yellow• Appearance – clear• pH – 6.5• Specific gravity –

1.020• Alb – trace• Sugar – neg• Blood – neg• ketone – neg• Bilirubin – neg• Urobilinogen – N• Nitrite – neg

• Urine microscopy• Leucocytes 1-2/hpf• Epithelial cells –

occasional• RBC – not seen• Other cells – not seen

Peripheral smear

Peripheral smear• RBC

• Normocytic hypochromic• Few cells are microcytic, hypochromic with

anisopoikilocytosis• Few normoblasts seen

• WBC• Increased• Myeloblasts 10%• Promyelocytes 20%• Lymphocyte 40%• Mature neutrophils 20%• Stab form 4%• Basophil 4%• Eosinophil 2%

• Platelets – reduced• No parasites

Bone marrow examination

• Hypercellular marrow – erythroid series normal• Myeloid erythroid ratio 9:1• Megakaryocytes reduced• Myeloid series increased with increase in

lymphoblasts• Lymphoblasts 46%• Myeloblasts 10%• Promyelocytes 24%• Mature neutrophils 16%• Stab forms 2%• Basophil 1%• Eosinophil 2%

• IMP: CML with lymphoid blast crisis

• ECG – normal• CXR – normal• BT – 2’ 15’’• CT – 3’ • USG abdomen

• Hepatospleenomegaly

• Medical oncologist opinion obtained

• Treatment • symptomatic

Chronic Myeloid Leukemia• Incidence

• 1.5 per 100,000• Men>women• Age usually after middle forties

• Etiopathogenesis• Large doses of radiation can cause CML

• What is CML?• Overproduction of myeloid cells• The myeloid cells retain the capacity of differentiation and

bone marrow function in early phase• Stable for years• Philadelphia chromosome – reciprocal translocation

between long arm of chromosome 9 and 22• Large portion of 22q is translocated to 9q and a smaller

portion of 9q is moved to 22q• 9q has the proto oncogene ‘abl’• Abl is received at a specific site on 22q the bcr (break point

cluster)• Fusion of bcr/abl produces a novel protein that possess

tyrosine kinase activity

• Disease progression is due to • Chromosomal instability of the malignant

clone• Large deletions adjacent to the

translocation break point• Hetrogenous structural alterations of the

p53 gene• Presence of altered ‘myc’ gene

• The disease progress to chronic phase, accelerated phase and blast crisis

• Clinical features• Middle age most affected • Fatigue• Night sweats• Low grade fever• Abdomen fullness• Symptoms of leucostasis

• Blurred vision• Respiratory distress• Priapism

• Physical findings• Spleen enlarged• Hepatomegaly – occationally• Sternal tenderness• Increasing spleen size occurs in accelerated phase

• Investigations• Increase in white cell count• Increase in immature and mature granulocyte• Myelocytes metamyelocytes and band forms are the

majority• Platelets increased• Normocytic normochromic anemia• LAP decreased• Vitamin B12 increased• In bone marrow – cellularity in increased with

increase in myeloid to erythroid ratio. Blast percentage is normal or increased.

• Both in blood and bone marrow – basophils, monocytes, eosinophils are increased in number

• Hall mark is the identification of bcr/abl by PCR

• Disease acceleration• Increasing degrees of anemia• Cytogenetic clonal evolution• Blood or marrow blast between 10-20%• Blood or marrow basophils > 20%• Blood or marrow platelets < 100,000

• Blast crisis• Acute leukemia with blood or marrow blasts

> 20%• Hyposegmented neutrophils may appear• Extramedullary blast proliferation• Large foci of clusters of blasts in marow

Differential diagnosis

WBC Hematocrit PlateletsRed cell

morphology

CML N N or N

Myelofibrosis or N or N or or N or abn

Polycythemia vera

N or N or N

Essential thrombocytosi

sN or N N

• Not usually given till WBC >200,000/cumm• In case of priapism, respiratory distress, visual

blurring emergency leukaparesis done with myelosuppressive treatment

• Imatinib mesylate• Inhibit tyrosine kinase activity• 400 mg/day• Complete hematologic remission after 18 months

was 97%• Cytogenetic remission rate 76%• Progression to accelerated and blast crisis is 3%• ADVERSE EFFECTS: Nausea, fluid retention, diarrhea,

muscle cramp, skin rashes• Other drugs

• Nilotinib• Dasatinib• INF alpha

Treatment

• Allogenic SCT• Indicated for failure to respond to imatinib or when patient

is in accelerated or blastic phase of the disease• Hydroxyurea

• Rapid lowering of WBC, reduction of symptoms and reversal of spleenomegaly

• Busulphan• Not used due to side effects

• Leukapharesis • Inensive leukapharesis may control blood counts in chronic

phase of CML• Used in leucostasis related complications• Rx of pregnant women

• Spleenectomy• Reserved for painful spleenomegaly and spleenomegaly

unresponsive to imatinib chemotherapy or severe anemia, thrombocytopenia associated with hyperspleenism

Treatment cont.

What is hematologic response, molecular response and cytogenetic response

• Hematologic response• Platelet count <450 x 109 /L• WBC < 10 x 109 /L without immature granulocytes

and with less than 5% basophils• Non palpable spleen

• Cytogenetic response• Complete ph+ 0%• Partial ph+ 1-35%• Minor ph+ 36-65%• Minimal ph+ 66-95%

• Molecular response• Complete ph 0%• Partial ph+ non quantifiable and non detectable• Major ph+ <0.10%

What is failure of treatment

Time Criteria

3 months after diagnosis No Hematologic Response

6 months after diagnosisLess than Complete Hematologic

Response, no cytogenetic response

12 months after diagnosisLess than partial cytogenetic

response

18 months after diagnosisLess than complete cytogenetic

response

AnytimeLoss of Complete Hematologic

Response, loss of complete cytogenetic response + mutation

Prognosis

Sokal index Hasford system

Age 0.116 x (age-43.4) 0.666 when age >50 yrs

Spleen 0.0345 x (spleen–7.51) 0.042 x spleen

Platelet count x 109/L

0.188 x [(platelet /700)2

- 0.563]1.0956 when platelet count

>1500 x 109/L

Blood myeloblast %

0.0887 x (myeloblast – 2.10)

0.0584 x myeloblasts

Blood basophils NA 0.20399 when basophils>3%

Blood eosinophils NA 0.0413 x eosinophils

Relapse rate

Low < 0.8 < 780

Intermediate 0.8 – 1.2 781 – 1480

High > 1.2 > 1480