Leukemia, Lymphoma, and Myeloma PDF

Leukemia, Lymphoma and Myeloma Biology of Lymphomatous Transformation • In Germinal Center: somatic hypermutation failure triggers B cells, leading to translocation of oncogenes • In Marrow: errors in DNA rearrangement occur Where does somatic switching occur for oncogenes? Germinal center CD Surfac...

Leukemia, Lymphoma and Myeloma Biology of Lymphomatous Transformation • In Germinal Center: somatic hypermutation failure triggers B cells, leading to translocation of oncogenes • In Marrow: errors in DNA rearrangement occur Where does somatic switching occur for oncogenes? Germinal center CD Surface Markers of Relevance • T cell Markers o CD2, CD3, CD4, CD5, CD7, CD8, CD25 • NK/Cytotoxic T cell Markers o CD16, CD56, CD57 • CD45 (Leukocyte Common Antigen) o Expressed on nucleated marrow cells (Not platelets, RBCs) o Confirms hematopoietic nature of tumors (if it is a lymphoma or leukemia) • T Lymphocyte Development: o 4 TCR genes: α,β,γ,δ o Mature T-cells express CD4 or CD8 B-lymphocyte development: Goal = Antibodies • Early stage o In bone marrow o Cells express IgM/IgD • Late stage o In germinal centers o Class switching: IgG, IgA, or IgM o Plasma cells or Memory Cells The B Cell Receptor • Surface Ig receptor: CD79a and CD79b • Performs antigen-derived activation signaling (ex. BTK) o Bruton’s Tyrosine Kinase (BTK): a cell signaling enzyme o Targeted inhibition of BTK with Ibrutinib treats inappropriate activation of B-cells • B-Cell Receptor signaling promotes: o Cell proliferation o Adhesion o Survival of B-cell malignancies Lymphoproliferative Neoplasms Staging and Prognosis Stage 0 I II III IV Stage A B C Risk Low Intermediate Intermediate High High Rai Staging (USA) Features at Diagnosis Blood, marrow lymphocytosis Lymphocytosis w adenopathy Lymphocytosis + spleno/hepatomegaly w/wo adenopathy Lymphocytosis and anemia Lymphocytosis and thrombocytopenia Binet Staging (Europe) Features at Diagnosis Blood/marrow lymphocytosis + <3 areas of adenopathy Lymphocytosis + ≥ 3 areas of adenopathy Lymphocytosis + ≥ 3 areas of adenopathy + anemia or thrombocytopenia Only lymphocytosis Involves surrounding structures Involves other blood disorders Involves other blood disorders Chronic Lymphocytic Leukemia (B-CLL, T-CLL) • CLL is defined by monoclonal population of B lymphocytes • CD5, CD19, CD20, CD23 Leukemia or Lymphoma • CLL is blood-born (liquid because leukemia) • SLL-Small Lymphocytic Lymphoma (solid because lymphoma) Clinical Features • “Smudge cells” are common and raise suspicion of diagnosis • Anemia and thrombocytopenia in advanced stages • Posterior iliac crests are common sites for bone marrow aspiration and biopsy • Mature lymphoid cells are present in bone marrow • Patients have low antibodies o Hypogammaglobulinemia o Low on IgG, IgM heavy chain; kappa/lambda light chain • Diagnosis o FISH allows detection of cyto-genetic variants to determine poor prognosis forms (17p and 11q deletions) o Flow Cytometry determines poly or monoclonal: CLL cells express CD19, CD20, and CD5 Immunologic Abnormalities • Hypogammaglobulinemia is common • Imbalance between T4 Helper cells and T8 Suppressor cells in advanced disease • Other autoimmune diseases in CLL: o Rheumatoid Arthritis o Lupus o Hashimoto’s Thyroditis o Grave’s Disease CLL Treatment Indications • Treatment needed in Rai’s high stages III and IV, or Binet stage B or C • Richter Transformation: Evolution of CLL into aggressive leukemias or lymphomas • Specific reasons to treat: o progressive adenopathy o splenomegaly o rapid doubling time of lymphocyte o recurring infections o anemia o thrombocytopenia o autoimmune issues o evolution to PLL or Richter transformation • Treatment: Stem cell transplantation