1. Hematopoietic Malignacies Plasma Cell dyscrasias (Lymphomas)

2. Common Issues in HCs HC: ~ 10% of all malignacies (incidence/death) Lymphomas: 4% of all cancers mobility of cells genetic instability clonal expansion potential

3. HC: 45% NHL HC: 12% HL HC: 14% Myelomas HC: 29% Leukemias

4. Historical notes 1750s: Robert Virchow: “leukemia” 1850s: Thomas Hodgkin: H.Disease 1950s: HD as Hlymphoma 1950s:Peter Nowell+David Hungerford: abnormal short chromosome 22 in CML 1970s:Jenat Rowley, Chicago, increased chromosome 9 (22-> 9 translocation) + multiple other defects lymphoblastic lymphomas / lymphocytic lymphomas cancer stem cells (AML, tumor transfer studies)

8. oncogenesis Genetic (translocations / recurring translocations, mutations environmental carcinogens (benzene, radiation) secondary to intensive RxT, ChemoTher (for a primary cancer / in preparation for BMT or HCT)

11. Clinical terms Acute / chronic high grade (transformed precursor cells); T1/2 ~ 24 months medium / low grade (more mature phenotypes, 2 - 5 years) clinical responses: complete remission (>4 weeks) / relapse; refractory to treatment / salvage therapy; LTS/residual disease in > 5 years

12. therapeutics Autologous HCT (G-CSF, leukaferesis, CD34+) allogeneic BM, HLA-matched biologicals: IFNalpha, mAbs anti CD19, CD20, CD22 (ADCC, complement CML), immunotoxins (diphteria toxin - IL2 for IL-2R+ T lymphomas; radiolabelling Yttrium 90, Iodine 131

13. Plasma cell dyscrasias M protein (paraprotein) Monoclonal Gammapathy of Undetermined Significance (MGUS) 1% of age > 40y 70% asymptomatic; transitory 25%: mild anemia => myelomas or B cell lymphomas

14. Waldenstrom Macroglobulinemia large quantities of IgM paraproteins viscous blood => vision / neurologic signs accumulation of tumors BM, spleen, lymph nodes (>40%) anemia hemorrhaging cutaneous lesions (cells / deposits) unlike lymphomas: not producing osteoclast activating factors; BM lesions less than 10% good response to purine analogues (cladribine)

15. Myeloma Often arise from preexisting MGUS by additional mutations anemia state of immunosuppression, infections hypercoagulability circulatory difficulties, pulmonary function reduced neurological signs many cases: excess of Bence Jones proteins

16. Tam-Horshfall protein binding - aggregates promoting hypercalciuria and hypercalcemia; interstitial nephritis (kidney failure) 4/100 000 (age, sex, race); HLA-Cw2 ionizing radiation classification: multiple criteria DEREGULATION in CYTOKINES

18. IL-6 appear to autodrive the cancer STAT-3: upregulation of Bcl-xL; upregulation Myeloid Cell Factor 1 (MCL-1, essential for tumor cell survival) induces VEGF in myeloma cells: promotes angiogenesis, migration of tumor cells, IHIBITS Ag presentation by DCs IL-6+MIP-1a+IL-1b+TNF => BM stromal cells produces OPGL, master regulator of osteoclastogenesis IL-2+IL-7+IL-11+Lta+GM-CSF => suppresses IgG, Th, NK TGFb: autocrine loop for IL-6 secretion IGF-1 of BM stromal cells=> PI3K / PKB(AKT) = > survival

19. Genetics: many abnormalities Trisomy 6, 9(with more favourable prognosis) and 3, 5, 7, 11, 15, 19 13q deletions very poor prognosis 70%: Cdk mutations p15, p16 Cdk inhibitor / hypermethylation Ras oncogene activation (late stages); p53 (late stages)

20. Early: translocation Ig H locus FGFR3 gene, 4p16 => fusion product blocks caspase-3 apoptosis IRF4 gene 67p21 cyclin D3 gene 6p21 Bcl-1 gene at 11q13 common upregulation of Bcl-2, Bcl-xL deletions of 13q14 (Rb tumor suppressor gene)

21. Treatment: difficult 5 years survival < 30% early stages : INDOLENT alkylating agents (melphalan) + prednison alternative: dexamethasone, vincristine, thalidomide, adriamycin Thalidomide: activates caspase 8; blocks IL6, angiogenetic activity BORTEZOMIB (Velcade) proteosomal inhibitor, limits the catabolism of ubiquitinated proteins, including I-kB=> block IL6, induces apoptosis, decreases VEGF IGNa: remission, but not longer survival biphosphonates (osteoclast inhibitors: zolendronate, pamidronate)