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)