1. HAEMATOLOGY PRESENTATION TZE YENG YEOH MBChB II (2003)

2. CASE 1 -1 Mary, 31 year old lady. Presented to her GP with non- tender lumps in her neck. Otherwise, feeling well. Also feeling very fatigued. What are your differential diagnoses?

3. CASE 1 -2 GP commenced her on oral antibiotics for 3 months. Lumps persisted. In the meantime, bloods were done. Bloods were found to be “abnormal”. Hence, she was referred to the haematologists at MMH.

4. CASE 1 -3 Hb: 132 RCC: 4.33 PCV: 0.38 MCV: 87 MCH: 30.5 Plt: 307 WCC: 19.8 (  ) Neut: 6.7 Monocytes: 0.4 Lymphocytes: 6.9 (  ) Smear cells: 5.7 (  ) Interpret the blood result. What do you think she has? What would you do now?

5. CASE 1 -4

6. CASE 1 -5 Bone marrow aspirate and trephine confirmed CLL. Other tests done include: 1.Ig levels - Normal 2.Serum electrophoresis – Oligoclonal banding pattern in the gamma region. 3.  -2 microglobulin -  2.2 (1.3-2.2) 4.Cytogenetics – Loss of 17p13.1 5.CT scan of neck, chest, abdo and pelvis – Extensive lymphadenopathy in neck (with marked compression of airway), axilla, para-aortic region and around external iliac vessels and in the inguinal region. Also, left lung infiltration and splenomegaly.

7. CASE 1 -6 Commenced on fludarabine PO with co-trimoxazole. Taken for 4 months with no significant change in cervical lymphadenopathy. Had another CT scan which confirmed this. Had one episode of spontaneous bruising on abdomen and upper limbs. Also has frequent bleeding from gums. Had a bout of pneumonia recently. Recovered well with no complications.

8. CASE 1 -7 Treatment changed to prednisone and chlorambucil PO. Again, no significant change in cervical lymphadenopathy. Came to Day Stay to commence on IV chemotherapy. Unfortunately, she developed a significant neutropenia.

9. CLL Accounts for 25% of leukaemias seen in clinical practice. Usually occurs in the elderly (  60 years), with a male proponderance. Etiology is unknown but a familial tendency has rarely been observed.

10. CLL – PATHOLOGY It is known as a lymphoproliferative disorder. Accumulation of small, morphologically mature lymphocytes in bone marrow, lymph nodes, peripheral blood, spleen and liver. These are usually monoclonal B cells. Slow accumulation due to immunological non-reactivity and impaired apoptosis, rather than increased proliferation per se.

11. CLL – CLINICAL FEATURES Lymphocytosis on routine FBC. Symmetrical lymphadenopathy. Discrete and non-tender. Systemic symptoms. Symptoms of anaemia. Splenomegaly and/or hepatomegaly. Infections. (Which infections commonly?) Symptoms of thrombocytopoenia.

12. CLL – LAB FINDINGS -1 FBC   WCC due to lymphocytosis.  Presence of smear cells.  Normochromic, normocytic anaemia.   platelets. Cell markers (from blood film or marrow) - To confirm monoclonal B cells. How?

13. CLL – LAB FINDINGS -2 Bone marrow  Lymphocytic infiltration: 25-95% of all the cells. Biochemistry   Ig.  Paraprotein (rarely).  Hyperuricaemia.

14. CLL – STAGING -1 2 systems: Rai and Binet.

15. CLL - RAI StageFeaturesMedian survival (months) 0 Lymphocytosis  15x10 9 /L 150 + ILymphocytosis + lymphadenopathy105 IILymphocytosis + enlarged spleen and/or liver  adenopathy 71 III Lymphocytosis + anaemia  adenopathy  organomegaly 19 IV Lymphocytosis + thrombocytopenia  adenopathy  organomegaly 19

16. CLL - BINET StageOrgan enlargement Hb (g/L)Platelets (x10 9 /L) A0, 1 or 2 areas B3, 4 or 5 areas≥ 100 CNot considered  100

17. CLL - MANAGEMENT Treat only if symptomatic, complications develop or disease is rapidly progressive. Aim is to control disease and not to cure. Treatment options include: 1. Prednisone 2. Alkylating agents e.g. chlorambucil or cylcophosphamide (first line) 3. Fludarabine (need to give co-trimoxazole prophylactically) (second line) 4. Combination chemotherapy 5. Radiotherapy

18. CLL - COMPLICATIONS Bone marrow failure (pancytopenia) Autoimmune haemolytic anaemia.(How do you diagnose this?) Decreased immunoglobulins – infections. ITP. Splenomegaly. Leukostasis. (rarely)

19. CLL - PROGNOSIS Indolent condition usually. Most patients have a favourable prognosis. Unlike CML, CLL does not transform into an acute leukaemia. However, immunoblastic transformation may occur as a terminal lymphoma (Richter’s syndrome). Many elderly patients with CLL die with CLL rather than from it. Death from CLL usually caused by infection due to bone marrow failure and immune deficiency.

20. CLL – PROGNOSTIC MARKERS Age – Young, good prognosis. Sex – Female, good prognosis. Stage – Early, good prognosis. Disease progression – Slow, good prognosis. Response to treatment – Resistant, bad.  -2 microglobulin – High, bad prognosis. Cell markers – CD 38, bad prognosis Cytogenetics – specific chromosomal mutations predict disease progression and median survival.

22. CASE 2 -1 A 69-year old lady presents with a 3- month history of fatigue and breathlessness. Physical examination revealed splenomegaly. Blood results are as follows:

23. CASE 2 -2 Hb 9.0 g/dl MCV 90 fl Platelets 500 x 10 9 /l Total WBC 200 x 10 9 /l White cell differential count Blasts 3% Promyelocytes 6% Myelocytes 12% Metamyelocytes 6% Neutrophils 55% Eosinophils 4% Basophils 4% Lymphocytes 5% Monocytes 5% What do you think?

24. CASE 2 -3

25. CML - INTRODUCTION Is a myeloproliferative disorder. Comprises  20% of all the leukaemias. Seen most frequently in middle aged people, but can occur at any age. M:F = 1.4:1 No predisposing factors in most cases. 3 cardinal features: 1. Splenomegaly 2. Leucocytosis – myeloid series: with blasts through to neutrophils 3. Bcr-abl gene/Ph chromosome

26. CML – PATHOLOGY -1 Acquired abnormality of haematopoietic stem cells. Myeloid proliferation with expansion of normal marrow, splenomegaly and peripheral blood leucocytosis. Abnormality is due to reciprocal translocation between chromosomes 9 and 22. This leads to formation of a fusion or hybrid gene (bcr-abl), known as the Ph chromosome. (basis of the diagnostic test for CML)

27. CML – PATHOLOGY -2 This new gene codes for an active tyrosine kinase which continuously switches on the haemopoietic stem cell. The Ph chromosome is present in most haemopoietic cell lineages, i.e. RBCs, megakaryocytes, basophils, monocytes and B cells. About 5% of people with CML will lack the Ph chromosome. However, at a DNA, RNA and protein level, the molecular pathology with formation of the bcr-abl gene is still present.

28. CML – PATHOLOGY -3 Ph chormosome can also be found in some ALL and AML.

29. CML – CLINICAL FEATURES 20% asymptomatic. Splenomegaly. Hypermetabolism symptoms e.g. weight loss, lassitude, anorexia or night sweats. Features of anaemia. Features of abnormal platelet function. Gout or renal impairment – hyperuricaemia. Infections – usually when neutropoenic.

30. CML – LAB FINDINGS -1 FBC  Leucocytosis with left shift.   basophils.  Platelets , normal or . Giant platelets.  Normochromic, normocytic anaemia. Bone marrow biopsy  Hypercellular, with granulopoietic predominance.  Ph’ chromosome. NAP score - Low.

31. CML – LAB FINDINGS -2 Cytogenetics  In bone marrow and/or peripheral blood (FISH) – bcr-abl gene/Ph chromosome. Biochemistry   serum B12 and B12-binding capacity.   serum uric acid.

32. CML - PHASES Chronic Accelerated Blast crisis – Transforming to acute leukaemia, usually AML.

33. CML – MANAGEMENT -1 Chronic phase  Hydroxyurea – shorter action. Requires frequent monitoring and continuous therapy.  -interferon – Low platelets, depression.  Cytosine arabinoside.  Glivec (imatinib) – specific inhibitor of abnormal tyrosine kinase. Less useful in blast crisis.

34. CML – MANAGEMENT -2  Allogenic BMT – Potential cure. Only for those ≤ 55 years and with a HLA- matched donor. Accelerated phase and blast crisis  Harder to treat as patient becomes refractory to therapy.

35. CML - PROGNOSIS Chronic phase – 5-6 years, if treated. Usually shows an excellent response to chemotherapy. Accelerated phase – Few months. Blast crisis – Few months. Rough guides to outcome include age, spleen size, platelet count, blast cell percentage on presentation & degree of response to therapy. Death is usually due to terminal acute transformation or from intercurrent haemorrhage or infection.