Chronic Leukemia

1. Chronic Leukemia Ahmad ShihadaSilmiMsc, FIBMS Staff Specialist in Hematology Medical Technology Department Islamic University of Gaza

2. The definition of chronic leukemia: • Chronic leukemia is thought to arise from genetic defect in a single cell in B.M or in the peripheral tissue. When this cell success to proliferate gives rises to a clonal population that will give mass which when enlarged enough caused a serious disease.

3. What Are the Types of Chronic Leukemia?

4. Classification of CL. • There are two types: 1- chronic myeloid leukemia. 2- chronic lymphoid leukemia.

5. Chronic Myeloid Leukemia.

6. Definition of CML: • CML is defined as a stem cell disorder suggested as Philadelphia chromosome found in all stem cells. So there is replacement of normal B.M cells by cells with an abnormal chromosome – Philadelphia or (ph) chromosome t (9; 22)(q34; q11). • Constitute six different types of leukemia.

7. Types of Chronic CML:

8. Incidence CML comprises <20% of all leukaemia, its rarer than CLL. The incidence rate is 1-2/100,000-1 population; with a peak of incidence in the middle age people. The disease occur in either sex (male: female 1.4:1), however, it may occur in children, neonates and very old people.

9. What Is Philadelphia Chromosome?

10. Philadelphia : • Is the chromosome which result from the t(9;22)(q34;q11)part of the Abelson proto-oncogene ABL is moved to the BCR gene on chromosome 22 & part of chromosome 22 moves to chromosome 9. • The abnormal chromosome 22is the Ph. • See fig.

11. Fig

12. Translocation t(9;22)(q34;q11)

13. Translocation t(9;22)(q34;q11)

14. Pathogenesis • Hematopoietic abnormality • Expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation – increased white cell count • Megakaryocytopoiesis is often expanded • Erythropoiesis is usually deficient • Function of the neutrophils and platelet is nearly normal

15. Pathogenesis • Genetic abnormality • CML is the result of an acquired genetic abnormality • A translocation between chromosome 9 and 22 [t(9;22)] – the Philadelphia chromosome • The oncogene BCR-ABL encodes an enzyme – tyrosine phosphokinase (usually p210) • The function of the normal abl gene product ( p145abl ) is incompletely understood but it is known to have tyrosine kinase activity and may play a role in the regulation of several different growth factor receptors, including those for epidermal growth factor, platelet derived growth factor, and colony stimulating factor receptors.

16. Pathogenesis The normal bcr gene product (p160bcr ) is known to have serine/threonine kinase activity and shows considerable homology to a number of cell cycle proteins. It is thought to play an important role in cellular signal transduction. The chimeric bcr-abl fusion gene produces a chimeric protein of molecular weight 210,000 daltons (p210bcr-abl ). This protein has much more powerful tyrosine kinase activity than p145abl and has been shown to interact with its substrates in an altered manner. (p210bcr-abl ) has a great serine / threonine activity that enhance and push the proliferation and differentiation in a novel manner particularly in chronic phase.

18. P Bcr-Abl Cytoskeletalproteins P SHC DOK GRB-2 CRKL RAS-GAP CRK CBL SOS PI3K P ? P STAT1+5 RAS-GDP RAS-GTP P SAPK RAF-1 P AKT P MEK1/2 P ERK MYC P BAD BAD 14-3-3 BCLXL BCLXL 14-3-3 Mitochondria Nucleus Bcr-Abl Signal Transduction Pathways Adapted from Kantarjian H et al. Hematology. 2000:90-109.

19. How Would the Patient With CML Present?

20. Clinical Presentation of CML • Asymptomatic in ~50% of cases • Common SymptomsCommon Signs – Fatigue – Palpable splenomegaly – Weight loss/anorexia – Abdominal fullness • Common Laboratory Findings – Abnormal differential – Anemia – Leukocytosis – Basophilia – Thrombocytosis

21. How Would You Investigate the Patient With Suspected CML?….

22. Investigation: • CBC: Wbc is usually >50X10/l & some times >500X10/l. Normocytic normochromic anemia. Platelets . • peripheral blood film: • circulating basophil.

23. CML: Peripheral Blood Smear Normal Chronic phase CML

24. Cont: • Neutrophil alkaline phosphatase score is invariably low. • BM: is hyper cellular with granulopoietic predominance. • Cytogenetics: ph chromosome. • Serum vitamin B12 & vitamin b12-binding capacity are. • Serum uric acid is usually.

25. What Are the Phases of CML?…

26. Phases of CML: • Chronic phase : • Accelerated phase: • Blast phase:

27. Chronic phase CML The three defining features of typical chronic phase are: • Raised granulocytes. • The presence of Philadelphia chromosome. • Splenomegaly.

28. Accelerated phase CML The transition to accelerated phase is accompanied by increasing refractoriness to treatment which may be reflected in one or more of the following changes: • >15% blasts in B.M or peripheral blood. • >30% blasts + promyelocyte in peripheral blood. • >20% basophil in peripheral blood. • <100,000/m3 platelet. • Additional chromosome abnormality (+8) trisomy. • Increase B.M fibrosis. • In blastic phase the blast should exceed 30% in the peripheral blood (blastic crisis) , which is an evolution of CML that give rise to acute phase, this is manifested by progression of anaemia , neutropenia and thrombocytopenia.

29. Blastic phase CML • In most cases, establishment of the accelerated phase of CML is followed by a sustained refractory to treatment, the blast cell count rises and physical symptoms are worsening. The diagnostic criteria for blast crisis are that the circulating blast cell counts should exceed 30% of the total leukocyte count. • Progression of chronic phase to blastic phase has been likened to the evolution of chronic leukaemia into acute leukaemia. The accumulation of blast cells which results is accompanied by anaemia, neutropenia and thrombocytopenia

31. DETECTION OF MINIMAL RESIDUAL DISEASE IN LEUKEMIA

32. METHODOLOGIES FOR DETECTING MRD • Conventional cytogenetics • FISH • Nucleic acid amplification techniques • Qualitative RT-PCR • Quantitative RT-PCR

33. DO YOU PREFER QUALITY TO QUANTITY??? Mathematics is the science of pure quantity but what about medicine?

34. METHODS TO DETECT MRD IN LEUKEMIA

35. In the present mangament of leukemias I prefer quantity to quality It is the real time for real-time PCR

36. Changes in Cytogenetic and Molecular Findings in a Patient Responding to Rx.

37. How Would You Treat CML?…

38. Historical Rx. for CML Palliative Arsenic trioxide – 1865 Spleen irradiation - 1903 Busulfan -1953 Hydroxyurea -1966 Interferon alfa+ ARA -C -mid - 1980s Curative BMT - alloBMT - 1970s

39. Treatment: • Chemotherapy: • Tyrosine kinase inhibitor: • Interferon-. • Stem cell transplant.

40. DRUGS DON’T JUST POP OFF THE SHELVES !!!Specificity in drug development

41. P Bcr-Abl Cytoskeletalproteins P SHC DOK GRB-2 CRKL RAS-GAP CRK CBL SOS PI3K P ? P STAT1+5 RAS-GDP RAS-GTP P SAPK RAF-1 P AKT P MEK1/2 P ERK MYC P BAD BAD 14-3-3 BCLXL BCLXL 14-3-3 Mitochondria Nucleus Bcr-Abl Signal Transduction Pathways Adapted from Kantarjian H et al. Hematology. 2000:90-109.

42. Tyrosine kinase inhibitor

43. IMATINIB

44. What Is the Course and Prognosis of CML?..

45. Course & prognosis: • Usually shows excellent response to chemotherapy in the chronic phase. • Death usually occur from terminal acute transformation ,hemorrhage or infection.

46. Take a Break !…

47. Chronic lymphocytic Leukemia:

48. CLL CLL is the most common of the chronic lymphoid leukemias. Is characterised by the accumulation of non-proliferation mature-appearing lymphocytes (Lymphocytosis) in the blood, marrow, lymph nodes, and spleen.

49. CLL In most cases, the cells are monoclonal B lymphocytes that are CD5+ T cell CLL can occur rarely Peak incidence between 60-80yrs. Is the most common form of leukemia in North America and Europe, but is extremely rare in the Orient Affects men twice as often as women Incidence rate: 300 cases / 100,000-1 population/ annually.

50. Etiology Cause is unknown No established viral etiology No link with HTLV, EBV Increased incidence in : farmers rubber manufacturing worker asbestos workers