Haematological Malignancyleukaemia and

lymphoma,myelomaConcepts and principles

Medical Students

2010

Haematological Malignancies concern blood and lymphoid

tissue

• Myelodysplasia (pre malignant)

• Acute leukaemia

• Chronic leukaemias

• Lymphoma

• Myeloma

Cancer cells Normal cells

Different growth patterns

Hahn, W. C. et al. N Engl J Med 2002;347:1593-1603

Acquired Capabilities, Molecular Pathways, and the Transformation of Human Cells: Emerging Rules That Govern Cancer Formation

Naparstek, E. N Engl J Med 1995;333:516-518

A Possible Mechanism of Leukemic Transformation

apotosis

• Cells cycle and turn over

• Malignant cells

• Normal cells

Autophagy

• An concept of cell death avoidance

Chronic leukaemia

• Chronic myeloid leukaemia

• Chronic lymphatic leukaemia

Chronic Lymphatic Leukaemia (CLL)

• May present with mild lymphocytosis

• May have lymphadenopathy

• Hb 13.5g.dl, WCC 15x109/l, platelets normal. Neutrophils 4x109/l, lymphocytosis of 10x109/l

• Immunophenotyping on peripheral blood is diagnostic

• Uniquely –biopsy not required

Mature B lymphocytes

Therapy for CLL

• No therapy• Chemotherapy• Steroids• Immunotherapy: • Rituximab is a monoclonal antibody to CD20

which is expressed on all CLL cells. It is less toxic than chemotherapy and is effective in combination with chemotherapy drugs

• Ofatumumab

Chronic Myeloid leukaemia

• Typical count

• Hb 14.0g/dl

• WCC 120x109/l

• Platelets 560x109/l

• Neutrophils 114x109/l

In CML raised WBC with some immature forms in the blood and often increased eosinophils and basophils . The predominant cell is the neutrophil.

Neutrophil Alkaline Phosphatase (NAP) low or absent

Marrow hypercellular with gross myeloid hyperplasia. Why is there so much growth? What’s driving it?

•Translocation of long arm of 22 to long arm of 9.

•This results in activation of a hybrid bcr-abl proto-oncogene which can be detected by reverse transcriptase PCR

•This oncogene is critically dependant on thyrosine kinase to transmit its intracellular message

Imatinib (Gleevec )….Time May 2001

Staying on Gleevec for life could cost a patient as much as $30,000 per year, though the mag predicts insurance companies will probably pick up the tab now that Gleevec's off the experimental list.

THYROSINE KINASE INHIBITORS

Imatinib

Desatinib

Nilotinib

All licenced in Ireland

Goldman, J. M. et al. N Engl J Med 2003;349:1451-1464

Signal-Transduction Pathways Affected by BCR-ABL

Savage, D. G. et al. N Engl J Med 2002;346:683-693

Mechanism of Action of BCR-ABL and of Its Inhibition by Imatinib

Lymphoma

• Non Hodgkin’s Lymphoma

• Hodgkin’s Disease

NHL

• T cell

• B cell

• Histology/biopsy of node

• Radiology for staging

• Bone marrow for staging

NHL

• WHO and other classifications

• Aggressive –often curable

• Low grade-incurable but reasonable prognosis…

Treatment of Lymphomas

• Chemotherapy• Steroids• Immunotherapy: • Rituximab is a monoclonal antibody to CD20 which

is expressed on all CLL cells. It is less toxic than chemotherapy and is effective in combination with chemotherapy drugs

• Radiotherapy• Radio-immunotherapy (Yttrium-90)• Novel agents, lenalidomide,bortazemib

Also ofatumumab – a fully humanised anti- CD20 in trials in CUH and elsewhere

Myeloma

• The malignant cell is the plasma cell

• Plasma cells secrete…..

• The malignant cell is clonal…

• Therefore the paraprotein is clonal…– A monoclonal gammopathy

Plasma cells in myeloma

Therapy of myeloma

• Chemotherapy

• Prednisolone and other steroids

• Thalidomide (angiogenesis inhibitors)

• Proteosome inhibitors Bortazemib

• Lenalidomide

• Experimental agents – include monoclonal antibodies

Tansey, W. P. N Engl J Med 2004;351:393-394

Prodding the Proteasome

Myeloproliferative disorders

• Chronic myeloid leukaemia (CML)

• Polycythaemia rubra vera (PRV)

• Essential thrombocytosis (ET)

• Myelofibrosis (MF)

MYELOFIBROSISMYELOFIBROSIS