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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 notes1750s: 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, 2 -
5 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)
• 4/100 000 (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)
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