Outline

1. Outline • Classification of malignant disease • Myeloid vs lymphoid • Acute vs chronic • The leukemia vs lymphoma question • Lymphoproliferative disorders • Chronic myeloproliferative disorders

2. Classification • Classification system for haematological malignancies is awkward • Names are relics from pre-molecular era when only microscopes mattered • Descriptive but not user-friendly • All sound the same • Considerable overlap and disease features

3. Classification "high-modulus bead apex rubber with spiral-wound, jointless edge and capplies” ??? snow tires • Names are perfectly descriptive, but only if you know what it all means

4. Classification Similar, poorly descriptive names AND Overlapping features EQUALS Some confusion

5. “Myelo” • one of the confusing things is the word part “myelo”: • generally refers to bone marrow in general precedes another descriptor: examples • myelofibrosis = marrow fibrosis • myelosuppression = marrow suppression • myeloablation = marrow ablation…

6. MYELOID • similar to the word myelo • much more specific meaning • usually used in context – myeloid vs lymphoid

7. Proliferation Differentiation

8. Myeloid vs Lymphoid • lymphoid = – B cells – T cells • myeloid = everything else – RBC – Platelets – macrophages/monocytes – granulocytes •neutrophils •basophils •eosinophils

9. Myeloid vs Lymphoid • any disease that arises from the myeloid elements is a myeloid disease – AML, CML, PRV, ET, Myelofibrosis • any disease that arises from the lymphoid elements is a lymphoid disease – ALL, CLL, Hodgkins, Mycosis Fungoides

10. Acute vs. Chronic leukemia • Acute leukemias: • young, immature, blast cells – more fulminant presentation – more aggressive course

11. Acute vs. Chronic leukemia • Chronic leukemias: – accumulation of mature, differentiated cells – often subclinical or incidental presentation – in general, more indolent course • Frequently splenomegaly – accumulation of cells

12. Acute vs. Chronic leukemia • Acute leukemia = blasts in marrow and often blood • Chronic leukemia = mature appearing cells in marrow and blood

13. Acute vs. Chronic leukemia • leukemias are classified according to cell of origin: – lymphoid cells •ALL - lymphoblasts •CLL – mature appearing lymphocytes – myeloid cells •AML – myeloblasts •CML – mature appearing neutrophils

14. leukemia vs lymphoma Reasonably straightforward: • leukemia = increased WBC in blood and marrow – leukemias can be myeloid or lymphoid: • lymphocytosis, neutrophilia, blasts of either origin • lymphoma is always of a lymphoid origin – B cell lymphoma (85%) – T and NK cell lymphoma (15%)

15. leukemia vs Lymphoma • lymphoma of two general types: – Hodgkin’s lymphoma •B cell origin •Reed-Sternberg cells – Non-Hodgkin’s lymphoma •all others •B, T and NK

16. leukemia vs Lymphoma • leukemia presents in blood and marrow • lymphoma most often presents primarily with lymphadenopathy however: one caveat

17. leukemia vs Lymphoma • A few specific entities can present as either lymphoblastic lymphoma and acute lymphoblastic leukemia are the same disease, but named depending on mode of presentation – nodal or leukemic

18. leukemia vs Lymphoma other common example: chronic lymphocytic leukemia and small lymphocytic lymphoma the two best examples: called leukemia vs lymphoma depending on mode of presentation

19. leukemia vs Lymphoma most lymphoid diseases can enter a leukemic phase if advanced enough • high tumor burden, spills out into blood BUT • myeloid diseases very rarely present in lymph nodes

20. Lymphoma Classification • complicated, getting worse – now able to distinguish subtle differences in cells better than ever before – broadly, Hodgkin’s vs non-Hodgkin’s

21. Lymphoma Classification • Old classification: Working Formulation • Classified according to clinical behaviour • Low Grade • Intermediate Grade • High Grade

22. Lymphoma Classification • newer classification: REAL, WHO • take into account – cell type (B vs. T) – disease biology – immunophenotype • Cytogenetics

23. B cell Precursor B cell neoplasm Precursor B lymphoblastic leukemia/lymphoma(precursor B cell acute lymphoblastic leukemia) Mature (peripheral) B cell neoplasms B cell chronic lymphocytic leukemia/small lymphocytic lymphoma B cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B cell lymphoma (± villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B cell lymphoma of MALT type Mantle cell lymphoma Follicular lymphoma Nodal marginal zone B cell lymphoma (± monocytoid B cells) Diffuse large B cell lymphoma Burkitt's lymphoma/Burkitt cell leukemia T cell Precursor T cell neoplasm Precursor T lymphoblastic lymphoma/leukemia(precursor T cell acute lymphoblastic leukemia) Mature (peripheral) T cell neoplasms T cell prolymphocytic leukemia T cell granular lymphocytic leukemia Aggressive NK cell leukemia Adult T cell lymphoma/leukemia (HTLV-I+) Extranodal NK/T cell lymphoma, nasal type Enteropathy-type T cell lymphoma Hepatosplenic T cell lymphoma Subcutaneous panniculitis-like T cell lymphoma Mycosis fungoides/Sézary syndrome Anaplastic large cell lymphoma, primary cutaneous type Peripheral T cell lymphoma, not otherwise specified (NOS) Angioimmunoblastic T cell lymphoma Anaplastic large cell lymphoma, primary systemic type Lymphoma Classification

24. For every stage of lymphocyte development, there is a corresponding lymphoid neoplasm

25. B Cell Development Bone Marrow Periphery Antigen-Independent Antigen-Dependent Stem Cell Pro-B Cell Pre-B Cell Immature-B Cell Naïve-B Cell Mature-B Cell Surrogate Light Chain of Pre-BCR Igα/Igß IgM IgM IgM Y Y II II II Y Y II Y IgD Y II II II II II II DHJH µ VHDHJH VLJL Ig Ig gene rearrangement: -ive and +ive selection Pan B Cell Antigens CD19, CD20 CD38 CD22, CD23, CD40 Somatic Hypermutation Precursor B-ALL Burkitt’s CLL, Myeloma, Waldenstroms

26. Acute Lymphoblastic leukemia • 11% of all leukemias • 85% of childhood leukemia • Commonest 2-10 years • 20  after 40 years

27. Aetiology • Chemicals/toxins • Radiation • Viruses • Genetics and congenital factors

28. Presentation • Acute leukemia is always serious and life threatening • Anemia: Pallor, lethargy, dyspnoea • Leucopenia: Infection - mouth, skin, perianal region • Thrombocytopenia: bruising, menorrhagia, gum bleeding • Hepatosplenomegaly is common • Gum hypertrophy, skin infiltration

35. Differential Diagnosis Lymphadenopathy Infectious mono. or other viral infections, Lymphoma, Hepatosplenomegaly Myelo or Lymphoproliferative disorders Autoimmune, Metabolic, storage disorders Pancytopenia Aplastic anemia, Drug related, Hypersplenism, Myelodysplasia

36. Investigations: General FBC: Usually shows  HB and platelets (maybe <20) WCC can vary <1.0 - > 200 x 109/l, Abnormal differential, Film: Blasts Coag. Screening: Maybe abnormal Chemistry: LDH reflects tumor burden, renal failure, hyperuricemia Others: Chest x-ray, USD, Virology, LP, Blood C/S Initial evaluations are not only directed towards diagnosis but to initiate supportive measures for patients with advanced disease (Large mediastinal mass, Renal Failure, Very high WCC)

37. Investigations: Specific • Morphology • Immunophenotype • Cytogenetics • Molecular genetics

38. FAB classification of ALL L1 Small, monomorphic cells L2 Large, heterogenous cells L3 Burkitt-cell type, vacuolated

39. Immunophenotyping: Flowcytometery HLA-DR CD34 Stem cell compartment TdT CD7 CD3 CD19 CD22 CD13 CD33 T-ALL B-ALL AML

40. Abnormalities seen in at least 90 %of cases Karyotype is of major prognostic significance Used in planning Treatment t(9:22), t(1:19), t(4:11), t(8:14)

41. Poor prognostic factors in ALL Age Sex WCC @ DX. CNS disease Immunophenotype Cytogenetics Remission <1 or >10yrs Male > 50x109/l Blasts in CSF B or T, Diff Subtypes Ph+ (9;22) or (4;11) Failure to remit with 1 course of chemo

42. Treatment • Supportive Care • Red cell transfusion for anaemia • Platelets transfusion for thrombocytopenia • Vigorous treatment of infection • Social and psychological support • Hydration and treatment for hyperuricemia

43. Principles of therapy in ALL • Remission induction • Consolidation • CNS prophylaxis • Allogeneic BMT for high risk groups • Maintenance

48. Treatment Outcome The most important factor to influence treatment outcome is AGE • Continuous decline in CR from 95% in children to 40-60% in pts older than 60 • Cytogenetics • Overall CR in adults: 75% (63-86) • leukemia Free Survival: 31% (13-44)

49. Childhood ALL

50. Chronic Lymphocytic leukemia • Commonest leukemia in the western world • Clonal proliferation of the B-Lymphocytes • Disease of the elderly • Younger patients now seen • M:F ratio, 2:1 • CLL is highly variable disorder • 75% cases, diagnosis by chance on a routine blood test