6. CHRONIC LEUKAEMIAS_Physiotherapy 400L.pptx

Leukemia

1. CHRONIC LEUKAEMIAS

2. What are the Chronic Leukemias? Neoplasms of either the myeloid or lymphoid lineage which are capable of differentiation to mature cells.

3. Types of Chronic Leukaemias Chronic leukaemias are divided into TWO groups: 1. Chronic Myeloid Leukaemia 2. Chronic Lymphocytic Leukaemia Chronic leukaemias unlike acute leukaemias are slower in progression and are usually difficult to cure by chemotherapy

4. Chronic Myeloid Leukaemia Synonyms: - Chronic Myelocytic Leukaemia - Chronic Myelogenous Leukaemia - Chronic Granulocytic Leukaemia Chronic Myeloid Leukaemia (CML) is an acquired clonal disorder of the pluripotent stem cell in the bone marrow CML is also classified among the chronic myeloproliferative disoders (MPDs) – Polycythaemia Rubra Vera, Myelofibrosis , Essential Thrombocythaemia

5. Epidemiology CML is a myeloproliferative disorder which is associated with a specific genetic defect and a very characteristic blood picture It has an annual worldwide incidence of 1 per 100,000 population Commoner in males than females (M:F ratio is 1.4:1) It makes up about 20% of all leukemias CML occurs most frequently in adults between 30-60 yrs, but can occur at any age group including neonates and the very elderly In Nigeria, the median age incidence is 38 yrs compared to 50 yrs in the Western world At presentation, about 50% of patients are diagnosed by routine laboratory tests and 85% will be diagnosed during chronic phase

6. Natural history Basically triphasic disease— 3 recognized phases: chronic phase, accelerated phase blast crisis ( Blastic transformation) phase 50% transform directly from chronic phase to blast crisis. >85% patients are diagnosed in chronic phase (also called stable or indolent phase). Duration of chronic phase varies (typically 3–6 years; median 4.2 years). Accelerated phase is characterized by increasing blood counts and organomegaly , becoming increasingly refractory to therapy; some have constitutional symptoms; this phase is generally brief. Blast crisis ( blastic transformation phase) resembles acute leukemia with >20% blasts and promyelocytes in blood or marrow.

7. Etiology This is unknown but certain factors have been linked to the development of CML - exposure to ionizing radiation which can damage the genetic apparatus - chronic exposure to benzene or other hydrocarbons - Other chemicals and drugs e.g. use of Etoposide (a topoisomerase II inhibitor) has been associated with development of the philadelphia chromosome (t 9,22).

8. Clinical Presentation of Chronic Phase CML Asymptomatic in about 50% of cases Common Symptoms (constitutional or non specific) – due to hypermetabolic state - Fatigue - Weight loss/anorexia - Night sweats Common Signs - Palpable splenomegaly (usually massive) ± hepatomegaly Mild to moderate anaemia ( pallor,dyspnoea , tachycardia) Bleeding disorders ( epistaxis , easy bruising, petechiae , menorrhagia etc) from thrombocytopaenia or abnormal platelet function Gout±renal impairment from excessive breakdown of abnormal WBC and deposition of uric acid crystals in joints and renal tubules Features of hyperleucocytosis (WBC>300x10 9 /L) – dyspnoea , tachypnoea , dizziness, slurring of speech, visual blurring/blindness, tinnitus or deafness

9. Abdominal distension & Massive Splenomegaly In a patient with CML

10. Diagnosis and investigations FBC and peripheral blood film examination show increased WBC (generally >25 x 10 9 /L, often 100- 300 x 10 9 /L) Complete spectrum of myeloid cells in circulation – blasts, promyelocytes , myelocytyes , metamyelocytes , neutrophils , basophils and eosinophils Anaemia is common and platelet count is typically normal or increased Basophilia and/or eosinophilia Low Neutrophil alkaline phosphatase (NAP) score Bone marrow aspiration shows markedly hypercellular marrow due to myeloid hyperplasia Cytogenetic examination of blood or marrow for confirmatory Philadelphia chromosome t(9;22)

11. WBC x 10 9 /L 122 [4-11] Hb g/L 98.5 [120-160] MCV fl 87 [79-98] Platelets x 10 9 /L 843 [150-450] Neutrophils x 10 9 /L 80 [2-7.5] Lymphocytes x 10 9 /L 2.0 [1.5-4] Monocytes x 10 9 /L 2.0 [0.2-0.8] Eos x 10 9 /L 1.0 [0-0.7] Basophils x 10 9 /L 5.0 [0-0.1] Metamyelocytes x 10 9 /L 4.0 [0] Myelocytes x 10 9 /L 20.0 [0] Promyelocytes x 10 9 /L 4.0 [0] Blasts x 10 9 /L 2.0 [0] Nucleated red cells x 10 9 /L 2.0 [0] Film Comment : appearances suggest CML CML - blood count

12. Peripheral Blood film Source: Postgraduate Haematology 6 th edition NORMAL CML

13. Presence of all forms of myeloid cell series on peripheral blood film

14. Pathogenesis More than 95% of patients with CML have a characteristic genetic abnormality called the Philadelphia chromosome . Peter C. Nowell and David Hungerford were the first to identify the abnormal chromosome in the blood cells and bone marrow of patients with CML in 1960. In Philadelphia chromosome, there is reciprocal translocation of genetic materials between the long arms of Chr. 9 and Chr. 22 with re-arrangement of the bcr and abl oncogenes ( abl on chr . 9 to bcr on chr . 22) The bcr-abl fusion gene encodes for a special mRNA which produces a protein, P 210 P 210 has enhanced Tyrosine Kinase activity thereby leading to excessive cell proliferation and accumulation of immature and intermediates forms in peripheral blood and BM or other tissues The activated Tyrosine Kinase causes loss of cellular growth control and also inhibits apoptosis Less than 5% of patients do not have the Ph chromosome, and this is associated with bad prognosis

15. Melo . Blood . 1996;88:2375. Pasternak et al. J Cancer Res Clin Oncol . 1998;124:643. The Ph Chromosome and the bcr-abl Gene: The t(9;22) Translocation* FUSION PROTEIN WITH CONSTITUTIVE TYROSINE KINASE ACTIVITY bcr-abl bcr Philadelphia Chromosome (or 22q-) Chromosome 9 q+ abl Chromosome 9 Chromosome 22

16. The Philadelphia Chromosome Karyotyping

17. Differential diagnosis Differentiate chronic phase CML from leukaemoid reaction due to infection, inflammation or carcinoma Chronic Myelomonocytic leukaemia (CMML)

18. PROGNOSIS This chronic phase lasts typically 2–7 years but it may, in rare cases, last more than 15 or even 20 years. Even more rarely, spontaneous remissions have been described.

19. Clinical Course of CML Basically biphasic or triphasic - Chronic phase - Accelerated phase - Blastic transformation phase Accelerated phase may be very brief overlaping with the blastic phase In the chronic phase, patients respond well to chemotherapy Patients in chronic phase will eventually progress to the other phases, and may eventually die in the blastic transformation phase.

20. Treatment Both supportive and specific Supportive treatment in the form of : - red cells transfusion for anaemia - treatment of infections Counselling on nature of disease and prognosis

21. Specific Treatment of Chronic phase Treatment aims at reducing the total WBC and keeping the patient symptom free for a long period Allopurinol ( a uricosuric agent) – to prevent tumor lysis syndrome, gout and renal impairment Busulphan (an alkylating agent) – used to be the drug of choice Alpha interferon has also been used. Hydroxyurea – used for immediate cytoreduction Tyrosine Kinase inhibitors – now the mainstay of therapy in Ph+ CML - imatinib ( glivec ), nilotinib or dasatinib ). They can reverse the Ph chromosome positivity. Splenectomy or splenic irradiation in patients with massive splenomegaly not responsive to chemotherapy Autologous or allogeneic HSCT – may be curative in patients below 50 yrs of age

22. Treatment of accelerated phase is to change the drug to another one In blastic transformation phase, treat as for AML or ALL depending on the predominant blasts in blood and marrow

23. Chronic Lymphocytic Leukaemia (CLL) An acquired malignant condition of the B lymphocytes B-CLL is the most common of the chronic lymphoid leukaemias . Peak incidence between 60-80yrs, rare before the age of 40 yrs. More common in males than females M:F ratio = 2:1 It is characterized by chronic persistent lymphocytosis which later infiltrate different organs leading to organ enlargement(spleen, liver , lymph nodes, BM).

24. Aetiology Unknown but certain factors have been implicated - Chronic stimulation of the immune system with lymphoid hyperplasia which may accompany poverty related chronic infections - Familial predisposition

25. Clinical Features Many cases are discovered routinely. Systemic symptoms such as fever, night sweats and weight loss are less common compared with CML Symmetrical enlargement of superficial lymph node is the most frequent clinical sign. LN are discrete and non tender Normocytic normochronic anaemia Splenomegaly and/or hepatomegaly

26. Laboratory Diagnosis Full Blood count - lymphocytosis >15.0 x 10 9 /L (occasionally >300x 10 9 /L) ; anaemia , thrombocytopenia and neutropenia are absent in early stage CLL PBF will show small matured lymphocytes, with smear (smudge or basket) cells Autoimmune haemolysis may occur at any stage and can be detected by a positive direct Coomb’s test (DCT) Bone marrow aspiration will show a hypercellular marrow with diffuse or nodular lymphoid infilteration .

27. lymphocytes ‘smudge’ cells Chronic Lymphocytic Leukaemia

28. Classification and Staging in CLL There are two methods of staging or classification: Rai classification Binet classification (IWP classification) Rai divides CLL into 5 stages while Binet divides CLL into 3 stages

29. Rai Staging Level of risk Stage Median survival Low 0 Absolute Lymphocytosis alone >13 yrs Intermediate I Absolute Lymphocytosis & lymphadenopathy II Absolute Lymphocytosis , splenomegaly or hepatomegaly 8 yrs 5 yrs High III Absolute Lymphocytosis , anaemia ( Hb <10.0g/ dL ) IV Absolute Lymphocytosis , thrombocytopenia (<100 x10 9 /L) 2 yrs 1 yr ** Absolute Lymphocytosia is Lymphocyte count ≥ 15 x 10 9 /L

30. Binet clinical staging Stage Clinical features Median survival A ( Rai O) Absolute Lymphocytosis , No anaemia or thrombocytopenia but presence of <3 lymphoid regions enlargement 12 yrs B ( Rai I-II) Absolute lymphocytosis , No anaemia or thrombocytopenia but presence of 3 or more lymphoid regions enlargement 5 yrs C ( Rai III-IV) Absolute lymphocytosis + Anaemia ( Hb ≤10g/ dL ) and/or thrombocytopenia (≤100 x109/L) irrespective of organ enlargement 2 yrs

31. In Binet staging, each of the following is taken as an area of organ enlargement lymph nodes > 1cm in the neck, axillae or groin Splenomegaly Hepatomegaly

32. Clinical management Patients with asymptomatic lymphocytosis Binet stage A) simply require monitoring, no drugs – so called smouldering CLL Chemotherapy is reserved for patients with symptomatic or progressive disease i.e anaemia ( Hb <10g/ dL ) or thrombocytopenia (<100 x10 9 /L), constitutional symptoms due to CLL

33. Drug Treatment First line therapy generally uses the alkylating agent chlorambucil or Cyclophosphamide Purine analogue e.g Fludarabine and 2,Chlorodeoxy Adenosine (CDA) Monoclonal antibodies in combination with chemotherapy – Rituximab (anti CD20) and Alemtuzimab (anti CD52)

34. Other forms of Treatment Allopurinol to reduce risk of developing gout/renal impairement Splenectomy for massive splenomegaly , hypersplenism , or AIHA not responding to chemotherapy Radiotherapy – local irradiation of lymph nodes or spleen Intravenous Immunoglobulins – reduce risk of severe infections from atypical organisms Supportive measures – red cell transfusion, platelet concentrates transfusion and antibiotics, liberal oral fluid intake

35. Prognosis CLL remains an incurable disease with current therapy, apart from a few allografted patients. Most patients with early stage or asymptomatic CLL may die of other, unrelated causes Infection is major cause of morbidity and mortality in symptomatic patients. Advanced stage patients eventually develop refractory disease and bone marrow failure. Terminally, some refractory patients show prolymphocytic transformation, or immunoblastic transformation – so called Richter’s syndrome

36. Prognostic Factors in CLL GOOD BAD Stage of disease Binet A Rai stage 0-I Binet B and C Rai stage II-IV Sex female male Lymphocyte doubling time slow rapid BM biopsy appearance Focal/nodular diffuse LDH level in serum normal raised CD 38 expression negative positive