hematopoietic malignacies n.
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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.

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hematopoietic malignacies

Hematopoietic Malignacies

Plasma Cell dyscrasias

(Lymphomas)

common issues in hcs
Common Issues in HCs
  • HC: ~ 10% of all malignacies (incidence/death)
  • Lymphomas: 4% of all cancers
  • mobility of cells
  • genetic instability
  • clonal expansion potential
slide3
HC: 45% NHL
  • HC: 12% HL
  • HC: 14% Myelomas
  • HC: 29% Leukemias
historical notes
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
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
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
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
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
slide14

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
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
slide16
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
slide18

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

slide19

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)

slide20

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)

slide21

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)