Hematopoietic Malignacies Plasma Cell dyscrasias (Lymphomas)

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

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

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)

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)

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

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

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

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)

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

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

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

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)

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)

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)