Hematologic Malignancies 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 CLL=Chronic Lymphocytic ALL=Acute Lymphoblastic CML=Chronic Mylogenous AML=Acute Mylogenous Sources from Leukemia, Lyphoma, Myeloma Facts 2001 Total Reported Cases = 31,500

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 Retinoic Acid Arsenic trioxide Anthracyclines Gemtuzumab- Ozogamicin (GO) HuM195 ROS Apaf Caspase 9 CD33 Caspase 3 FLT3 FLT3 inhibitors Sin3A RARa RARa N-CoR/ SMRT HDAC PML PML Histone deacetylase inhibitors Ac Ac Ac

Targeted therapy with retinoic acid for APL + All-trans Retinoic Acid

The landmark discoveries that revolutionized APL therapy 1. Differentiating effect of ATRA 2. Cloning of PML/RARA Huang ME, Blood 1988; Castaigne S, Blood 1990; Borrow J, Science 1990; Longo L, J Exp Med 1990; de Thé H, Nature 1990

Outcome results in APL prior and after ATRA 2000-2010 Pre-ATRA era Sanz, M. A. et al. Blood 2004;103:1237-1243 Sanz et al. Blood, 2009 Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

From Confucius to differentiation therapy “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 ATRA G. Lo Coco, Westminster School Hook Magazine. May 2011

Targeted therapy with imatinib in CML

Outcome of AML in older adults (60+ yrs) 18

Outcome of AML in younger adults (15-59 yrs) 19

Lymphomas Hodgkin’s Non Hodgkins (B-cell or T-cell)

Lymphomas Malignant disease of the lymphoid system highly heterogeneous, both histologically and clinically Highly curable malignancies in oncological practice: 90%of Hodgkin ’s disease 40-50%of high-grade NHL

Epidemiology of lymphomas 5th most frequently diagnosed cancer in both sexes males > females incidence NHL increasing Hodgkin lymphoma stable

Frequencies of different lymphomas Non-Hodgkin Lymphomas Diffuse large B-cell Hodgkin Lymphoma 11% NHL Follicular Other NHL ~85% of NHL are B-lineage

Age distribution of Hodgkin lymphoma

Frequency of NHL Subtypes in Adults Mantle cell (6%) Peripheral T-cell (6%) Indolent (35%) Other subtypes with a frequency 2% (9%) Key Point: The REAL/WHO classification system makes it possible to define clinically distinct types of NHL.1,2 This is a clinical evaluation of the REAL classifications in 1403 cases of NHL at 9 study sites worldwide.2 For most subtypes, diagnostic accuracy and reproducibility were ≥85%.2 The most common NHL subtypes2 Indolent lymphomas 35% Follicular lymphoma 22% Small lymphocytic lymphoma 6% Marginal zone B-cell MALT 5% Marginal zone B-cell nodal 1% Lymphoplasmacytic 1% Mantle cell lymphoma 6% Peripheral T-cell lymphoma 6% Diffuse large B-cell lymphoma 31% Composite lymphomas 13% The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89:3909–3918. Armitage JO, Weisenburger DD, for the Non-Hodgkin’s Lymphoma Classification Project. New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. J Clin Oncol. 1998;16:2780–2795. Composite lymphomas (13%) Diffuse large B-cell (31%)

Lymphomagenesis

Chromosomal translocations in NHL

Chromosomal translocations in NHL

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