HAEMATOLOGY PRESENTATION

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. 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? CASE 1 -3

5. CASE 1 -4

6. CASE 1 -5 • Bone marrow aspirate and trephine confirmed CLL. • Other tests done include: • Ig levels - Normal • Serum electrophoresis – Oligoclonal banding pattern in the gamma region. • -2 microglobulin -  2.2 (1.3-2.2) • Cytogenetics– Loss of 17p13.1 • 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

16. CLL - BINET

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: • Prednisone • Alkylating agents e.g. chlorambucil or cylcophosphamide (first line) • Fludarabine (need to give co-trimoxazole prophylactically) (second line) • Combination chemotherapy • 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 109/l • Total WBC 200 x 109/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: • Splenomegaly • Leucocytosis – myeloid series: with blasts through to neutrophils • 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.