LS 2.4 Drugs Used in Hematological Malignancies.pptx

Drugs used in malignancies such as Lymphomas

1. Drugs Used in Hematological Malignancies

2. Objectives Explain the pathophysiology of hematological malignancies and how it informs treatment strategies. Describe the mechanisms of action of key chemotherapeutic agents used in leukemia, lymphoma, and multiple myeloma. Identify and differentiate targeted therapies and immunotherapies used in hematological malignancies, focusing on their molecular targets and mechanisms. Discuss the therapeutic indications for various treatments, including first-line and salvage therapy options for different hematological cancers. Evaluate the side effects and toxicity profiles of chemotherapeutic agents, targeted therapies, and immunotherapies, and their impact on patient management .

3. Introduction Pathophysiology Overview: Hematological Malignancies: Cancers of the blood, bone marrow, and lymphatic systems. Key Cancers: Leukemia, Lymphoma, and Multiple Myeloma. Leukemia : Uncontrolled proliferation of abnormal white blood cells, impairing normal blood function. Lymphoma : Malignant transformation of lymphocytes (B-cells, T-cells), leading to tumor formation in lymphatic tissues. Multiple Myeloma : Abnormal proliferation of plasma cells, leading to bone marrow suppression and osteolytic lesions.

4. Introduction Hematological malignancies refer to cancers that affect the blood, bone marrow, and lymphatic system. These malignancies typically arise from genetic mutations or chromosomal abnormalities that disrupt normal blood cell development and function.

5. Introduction Cellular Origin: Hematological malignancies can originate from myeloid or lymphoid cell lines. Myeloid lineage gives rise to leukemias such as Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML). Lymphoid lineage gives rise to lymphomas (Hodgkin and Non-Hodgkin) and leukemias like Acute Lymphoblastic Leukemia (ALL).

6. Introduction Genetic Mutations: Genetic mutations drive abnormal cell proliferation and block normal cell differentiation. Example: BCR-ABL fusion gene (Philadelphia chromosome) in CML results in uncontrolled tyrosine kinase activity, promoting cell growth. Other mutations include JAK2 mutations in myeloproliferative neoplasms and p53 mutations in various leukemias and lymphomas .

7. Introduction Disruption of Normal Hematopoiesis : Cancerous cells outcompete healthy cells in the bone marrow, leading to decreased production of normal blood cells. This results in anemia (low red blood cells), leukopenia (low white blood cells), and thrombocytopenia (low platelets).

8. Introduction Uncontrolled Proliferation: Malignant cells lose their ability to undergo apoptosis (programmed cell death) and continue to proliferate uncontrollably. This results in the accumulation of abnormal cells in the bone marrow, blood, and lymphatic tissues.

9. Introduction Immune System Dysregulation: Lymphoid malignancies, such as lymphomas and multiple myeloma, affect immune cells (B-cells, T-cells, or plasma cells), leading to immune dysfunction and increased risk of infections. Clinical Manifestations: Patients present with symptoms such as fatigue (due to anemia), recurrent infections (due to leukopenia), bleeding tendencies (due to thrombocytopenia), and organomegaly (enlargement of spleen or liver due to infiltration by malignant cells).

10. Mechanisms of Action of Key Chemotherapeutic Agents Chemotherapy for hematological malignancies targets rapidly dividing cells, including cancerous blood cells, by disrupting processes essential for cell division and survival. These agents fall into several categories based on their mechanisms of action.

11. Mechanisms of Action of Key Chemotherapeutic Agents 1. Alkylating Agents These drugs interfere with DNA replication by forming covalent bonds with DNA strands, causing cross-linking of DNA and leading to cell death. Mechanism of Action: DNA cross-linking: Alkylating agents form covalent bonds with nucleophilic groups on DNA bases, leading to intra- and interstrand DNA cross-linking. This cross-linking prevents proper DNA replication and transcription, triggering cell cycle arrest and apoptosis. Common Drugs: Cyclophosphamide (used in lymphoma, leukemia, and multiple myeloma). Ifosfamide , Melphalan (used in multiple myeloma).

12. Mechanisms of Action of Key Chemotherapeutic Agents 2. Antimetabolites Antimetabolites mimic normal cellular substrates required for DNA and RNA synthesis, thereby inhibiting DNA replication and repair. Mechanism of Action: Folate antagonists: Drugs like methotrexate inhibit dihydrofolate reductase, preventing the synthesis of tetrahydrofolate, a cofactor needed for purine and thymidylate synthesis. Pyrimidine antagonists: Cytarabine ( ara -C) inhibits DNA polymerase, blocking DNA synthesis during the S-phase of the cell cycle. Purine analogs: Fludarabine and 6-mercaptopurine inhibit enzymes involved in purine metabolism, impairing DNA replication. Common Drugs: Methotrexate (used in leukemia, and lymphoma). Cytarabine (used in acute myeloid leukemia).Fludarabine (used in chronic lymphocytic leukemia).

13. Mechanisms of Action of Key Chemotherapeutic Agents 3. Anthracyclines Anthracyclines are potent chemotherapy agents that exert their cytotoxic effects through several mechanisms, including intercalation into DNA and the generation of free radicals. Mechanism of Action: DNA intercalation: Anthracyclines insert between DNA base pairs, disrupting DNA replication and transcription. Topoisomerase II inhibition: These drugs inhibit topoisomerase II, an enzyme that relieves torsional strain in DNA during replication, leading to DNA double-strand breaks. Generation of free radicals: Anthracyclines produce reactive oxygen species (ROS) that cause oxidative damage to cellular components, including DNA, proteins, and lipids. Common Drugs: Doxorubicin (used in lymphoma and leukemia). Daunorubicin (used in acute myeloid leukemia and acute lymphoblastic leukemia). Epirubicin (used in various lymphomas).

14. Mechanisms of Action of Key Chemotherapeutic Agents 4. Topoisomerase Inhibitors These agents inhibit topoisomerase enzymes, which play a critical role in DNA replication and repair, leading to DNA damage and cell death. Mechanism of Action: Topoisomerase I inhibitors: Drugs like topotecan and irinotecan prevent DNA relaxation by inhibiting topoisomerase I, leading to single-strand DNA breaks. Topoisomerase II inhibitors: Etoposide stabilizes the DNA-topoisomerase II complex, leading to double-strand DNA breaks during DNA replication. Common Drugs: Etoposide (used in lymphoma, and leukemia). Topotecan (used in certain leukemias).

15. Mechanisms of Action of Key Chemotherapeutic Agents 5. Proteasome Inhibitors Proteasome inhibitors disrupt the degradation of proteins involved in regulating cell cycle progression and apoptosis, leading to cancer cell death. Mechanism of Action: Proteasome inhibition: Drugs like bortezomib inhibit the 26S proteasome, preventing the breakdown of ubiquitinated proteins. This leads to the accumulation of misfolded proteins, inducing cellular stress and apoptosis, particularly in rapidly dividing cancer cells. Common Drugs: Bortezomib (used in multiple myeloma and mantle cell lymphoma).

16. Mechanisms of Action of Key Chemotherapeutic Agents 6. Monoclonal Antibodies (mAbs) Monoclonal antibodies are designed to specifically target antigens expressed on the surface of malignant cells, leading to direct cytotoxicity, immune-mediated destruction, or blocking of growth signals. Mechanism of Action: CD20-targeting mAbs : Rituximab binds to CD20 on B-cells, inducing antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC). CD38-targeting mAbs : Daratumumab targets CD38 on plasma cells in multiple myeloma, inducing cell death through immune mechanisms. Common Drugs: Rituximab (used in B-cell lymphomas and leukemia). Daratumumab (used in multiple myeloma).

17. Targeted Therapies and Immunotherapies Targeted Therapies : Tyrosine Kinase Inhibitors (TKIs) (e.g., Imatinib, Nilotinib) MOA : Inhibits BCR-ABL kinase, blocking the proliferation of leukemic cells. Indications : CML, Philadelphia chromosome-positive ALL. Monoclonal Antibodies : Rituximab : Targets CD20 on B-cells, inducing cell death (NHL, CLL). Daratumumab : Targets CD38 on plasma cells (Multiple Myeloma).

18. Targeted Therapies and Immunotherapies Immunotherapies : Checkpoint Inhibitors (e.g., Pembrolizumab, Nivolumab) MOA : Blocks PD-1/PD-L1 interaction, enhancing T-cell response against cancer cells. Indications : Relapsed Hodgkin lymphoma. CAR T-Cell Therapy (e.g., Tisagenlecleucel) MOA : Genetically engineered T-cells target specific cancer antigens (e.g., CD19 in ALL). Indications : Refractory B-cell ALL, large B-cell lymphoma.

19. Therapeutic Indications and Treatment Strategies Leukemia: First-line: Chemotherapy (Anthracyclines, Antimetabolites). Targeted Therapy: TKIs for CML (Imatinib). Salvage Therapy: CAR T-cell therapy for relapsed ALL. Lymphoma: First-line: Chemotherapy (CHOP regimen), Monoclonal antibodies (Rituximab). Relapsed: Immune checkpoint inhibitors or CAR T-cell therapy (Hodgkin lymphoma). Multiple Myeloma: First-line: Proteasome inhibitors (Bortezomib), Immunomodulatory agents (Lenalidomide). Relapsed: Monoclonal antibody (Daratumumab), second-generation proteasome inhibitors (Carfilzomib).

20. Side Effects and Toxicity Profiles Chemotherapy : Common Side Effects : Myelosuppression : Neutropenia, thrombocytopenia. Mucositis, alopecia, nausea/vomiting . Specific Toxicity : Cardiotoxicity (Anthracyclines), secondary malignancies (Alkylating agents).

21. Side Effects and Toxicity Profiles Targeted Therapies: TKIs: Cytopenias, edema, fatigue. Monoclonal Antibodies: Infusion reactions, infections (due to B-cell depletion). Immunotherapies: Checkpoint Inhibitors: Immune-related adverse events (colitis, pneumonitis). CAR T-Cell Therapy: Cytokine release syndrome (CRS), neurotoxicity .

22. Management of Side Effects Chemotherapy: Myelosuppression: Use of growth factors (G-CSF), and prophylactic antibiotics. Nausea: Use of antiemetics (e.g., ondansetron). Targeted Therapies: Infusion Reactions: Pre-treatment with corticosteroids, and antihistamines. Immunotherapies: CRS: Managed with tocilizumab (IL-6 inhibitor) and supportive care. Neurotoxicity: Monitoring and early intervention.