An Introduction to

Hematologic Malignancies

Francesco Lo-Coco

Università Tor Vergata, Roma

Summer Medical School

Tor Vergata University, July 2011

Oncohematology

• Dealing with malignant tumors of the hematopoietic system

• Tumors affecting blood and/or bone marrow and/or lymphoid organs

• Synonim: hematologic malignancies

Hematologic Malignancies

• Systemic diseases (with few exceptions)

• Laboratory assessment of paramount relevance for diagnosis and management

Hematologic Malignancies

• Leukemias

• Lymphomas

• Myeloproliferative syndromes

• Multiple myeloma

Leukemia

• Metastatic disease (by definition)

• Early diagnosis (almost) irrelevant

• Etiology mostly unknown

Demographics of Leukemia Types

ALL11%

CLL26%

AML31%

CML15%

others17%

Total Reported Cases = 31,500Sources from Leukemia, Lyphoma, Myeloma Facts 2001

CLL=Chronic Lymphocytic

ALL=Acute Lymphoblastic

CML=Chronic Mylogenous

AML=Acute Mylogenous

Leukemia

• Metastatic disease (by definition)

• Early diagnosis (almost) irrelevant

• Etiology mostly unknown

Leukemia: a paradigm for research

• Tumor cells easily and promptly available

• Can be cultured, manipulated, stored and thawed as viable cells

• Biomarker detection of paramount relevance to guide therapy

Laboratory characterization of blood tumors

• Morphologic exam (blood/marrow smear)

• Immunophenotype

• Cytogenetics

• Molecular biology

Biomarkers in Leukemia

• Diagnostic hallmarks or refinement

• Prognostic markers

• Minimal residual disease (MRD)

• Targeted therapy

Therapeutic targets in APL

AcAcAc

RARa

PMLPML

RARa

CD33

Arsenic trioxide

Anthracyclines

Histone deacetylase inhibitors

FLT3 inhibitors

Gemtuzumab- Ozogamicin (GO)

HuM195

Sin3A

N-CoR/SMRT

HDAC

FLT3

Caspase 3

Caspase 9

ROSApaf

Retinoic Acid

Targeted therapy with retinoic acid for APL

+ All-trans Retinoic Acid

1. Differentiating effect of ATRA

Huang ME, Blood 1988; Castaigne S, Blood 1990; Borrow J, Science 1990; Longo L, J Exp Med 1990; de Thé H, Nature 1990

2. Cloning of PML/RARA

The landmark discoveries that revolutionized APL therapy

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Sanz, M. A. et al. Blood 2004;103:1237-1243

2000-2010

Pre-ATRA era

Outcome results in APL prior and after ATRA

Sanz et al. Blood, 2009

From Confucius to differentiation therapy

ATRA

G. Lo Coco, Westminster School Hook Magazine. May 2011

“If you use laws to direct the people, and punishments to control them, they will merely try to evade the laws, and will have no sense of shame.

But if by virtue you guide them, and by the rites you control them, there will be a sense of shame and of right.”

Confucius

Targeted therapy with imatinib in CML

Outcome of AML in older adults (60+ yrs)

(n=3541)

Outcome of AML in younger adults (15-59 yrs)

(n=7704)

Lymphomas

• Hodgkin’s

• Non Hodgkins (B-cell or T-cell)

Lymphomas

•Highly curable malignancies in oncological practice: 90%of Hodgkin ’s disease 40-50%of high-grade NHL

•Malignant disease of the lymphoid system highly heterogeneous, both histologically and clinically

• 5th most frequently diagnosed cancer in both sexes

• males > females

• incidence– NHL increasing– Hodgkin lymphoma stable

Epidemiology of lymphomas

Frequencies of different lymphomas

HodgkinLymphoma11%

NHL

Diffuse large B-cell

Follicular

Other NHL

Non-Hodgkin Lymphomas

~85% of NHL are B-lineage

Age distribution of Hodgkin lymphoma

Indolent (35%)

Diffuse largeB-cell (31%)

Mantle cell (6%)

Peripheral T-cell (6%)

Other subtypes with a frequency 2% (9%)

Frequency of NHL Subtypes in Adults

Composite lymphomas (13%)

Lymphomagenesis

Chromosomal translocations in NHL

Chromosomal translocations in NHL

• Plasma cell malignancy: clonal proliferation of plasma cells by monoclonal protein

Multiple myeloma

• 1% of all malignancies

• 10% of hematologic malignancies

Epidemiology

Multiple myeloma: hallmarks

Presence of monoclonal protein Anemia Renal failure Bone destruction (lytic lesions) Compressive neuropathy Hypercalcemia Increased risk of infection