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acute and chronic Leukemia therapy by irfan hamid
- 1. Presented to: Prof. Dr. Khalid Hussain Janbaz Dean, Faculty of Pharmacy B. Z. University Multan. Presented by: Irfan Hamid Ph.D. Pharmacology 2nd Semester Roll No. 05-PhDL-12 Acute & Chronic Leukemia Therapy
- 3. Leukemia Group of malignant disorders of the hematopoietic tissues characteristically associated with increased numbers of white cells in the bone marrow and / or peripheral blood
- 4. Development of Leukemia in the Bloodstream Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis Legend White Cell Red Cell Platelet Blast Germ Stage 5a- Anemia Stage 4- Worsening Stage 5b- Infection
- 6. Types of Leukemia Acute Lymphoblastic Leukemia (ALL) Acute Myeloblastic Leukemia (AML) Chronic Lymphocytic Leukemia (CLL) Chronic Myelocytic Leukemia (CML)
- 7. Myeloid vs Lymphoid Any disease that arises from the myeloid elements (white cell, red cell, platelets) is a myeloid disease ….. AML, CML Any disease that arises from the lymphoid elements is a lymphoid disease ….. ALL, CLL
- 8. Acute vs. chronic leukemia Leukemias are classified Lymphoid cells ALL - lymphoblasts CLL – mature appearing lymphocytes Myeloid cells AML – myeloblasts CML – mature appearing neutrophils On a CBC, if you see: Predominance of blasts according to cell of origin: in blood consider an acute leukemia Leukocytosis with mature lymphocytosis consider CLL Leukocytosis with mature neutrophilia consider CML
- 9. Chronic and Acute Chronic Leukemia: accumulation of mature granulocytes or lymphocytes longer Progress Not clinical course (several to many years) slowly (runs a slow course) immediately fatal. Acute Leukemia: excess short clinical course (weeks to months) Progress Life myeloblasts or lymphoblasts rapidly (runs a fast course) expectancy short without treatment.
- 10. Acute leukemias Definition: Malignancies of immature hematopoietic cells. (> 20% blast cells in the bone marrow) Types: Acute Myeloid Leukemia (AML) Acute Lymphoblastic leukemia Groups: Childhood (< 15) Adult (> 15) (ALL) > 80% ALL > 80% AML
- 11. Chronic Myeloid Leukaemia The myeloproliferative diseases (MPDs) are clonal stem cell disorders characterised by leukocytosis, thrombocytosis, erythrocytosis, splenomegaly, and bone marrow hypercelularity
- 12. Acute Lymphoblastic Leukemia (ALL) • • • Clonal proliferation and accumulation of blast cells in blood, bone marrow and other organs Disorder originates in single B or T lymphocyte progenitor Incidence in adults : 20% of acute leukemias
- 14. Acute Leukemia accumulation of blasts in the marrow
- 15. Acute leukemias - laboratory findings . Blood examination - anemia, - thrombocytopenia, - variable leukocyte count, usually increased, - blood morphology: presence of blast cells 2. Bone marrow morphology - presence of blast cells, - suppression of normal haematopoiesis
- 16. Acute leukemias - clinical features 1. 2. 3. 4. 5. 6. 7. Bleeding Fever/infection Bone/joint pain Hepatomegaly Splenomegaly Lymphadenopathy CNS involvement
- 17. Acute leukemias - Laboratory findings 1. 2. 3. 4. Cytochemical stains Immunophenotyping Cytogenetics Molecular studies
- 18. Differentiation between AML and ALL Age Blood AML - anemia, neutropenia, thrombocytopenia, myeloblasts and promyelocytes ALL - anemia, neutropenia, thrombocytopenia, lymphoblasts and prolymphocytes Morphology AML - mainly in adults ALL - common in children AML - blasts are medium to large with more cytoplasm which may contain granules, Auer rods, fine nuclear chromatin, distinct nucleoli ALL - blasts are small to medium with scarce cytoplasm, no granules, fine nuclear chromatin and indistinct nucleoli Cytochemistry AML - positive peroxidase and Sudan black, negative TdT ALL - negative peroxidase and Sudan black, positive TdT
- 19. Acute Leukemia: Clinical Manifestations Constitutional Weight & Metabolic effects: loss Fever Hyperkalemia Hyperuricemia
- 20. Acute Leukemia: Clinical Manifestations Marrow replacement, organ infiltration & metabolic effects Marrow replacement Neutropenia: infection Anemia: pallor, fatigue, dyspnea Thrombocytopenia: abnormal bruising and bleeding
- 21. Acute Leukemia: Clinical Manifestations Organ infiltration Bone pain Hepatosplenomegaly Lymphadenopathy Gingival hypertrophy Leukemic meningitis
- 22. AML: FAB classification French American British classification M0-M7 based on morphology, and special cytochemical studies Historically, distinguishing AML M0 from ALL was a major clinical problem
- 23. AML FAB classification M0,M1, M2: Myeloblasts with no, little or some granulocytic maturation M3: Promyelocytic leukemia M4: Myelomonocytic or eosinophilic M5: Monocytic M6: Erythroleukemia M7: Megakaryoblastic Not all that useful except for M3
- 24. AML – M1 Note the myeloblasts and the auer rod:
- 25. AML – M2 Note myeloblasts and hypogranulated PMNs:
- 26. AML – M3 Note hypergranular promyelocytes:
- 27. AML – M4 Note monoblasts and promonocytes:
- 28. AML – M5A Note monoblasts:
- 29. AML – M6 Note M1 type monoblasts
- 30. Morphologic subtypes of acute lymphoblastic leukemias (FAB classification Subtype L1 L2 L3 Morphology Occurrence (%) Small round blasts 75 clumped chromatin Pleomorphic larger blasts 20 clefted nuclei, fine chromatin Large blasts, nucleoli, 05 vacuolated cytoplasm
- 31. FAB Classification L1 Small, uniform lymphoblasts Scant cytoplasm, indistinct nucleoli, occassional clefting of nucleus, chromatin is clumped Affects primarily children
- 32. FAB Classification: L2 L2 Large, pleomorphic lymphoblasts Abundant cytoplasm, predominant nucleoli, nuclear clefting and indentation Affects adults
- 33. FAB Classification: L3 L3: Burkitt’s type Uniform population of large lymphoblasts with deeply basophilic cytoplasm, vacuoles, round to oval nuclei without indentation Affects adults and children
- 35. CHRONIC LEUKEMIAS Definition: Neoplastic proliferations of mature haemopoeitic cells. Types: Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML)
- 36. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) Neoplastic proliferations of mature lymphocytes. Distinguished from ALL by A. B. C. D. Morphology of cells. Degree of maturation of cells. Immunologically immature blasts in ALL. CLL affects mainly elderly.
- 37. SYMPTOMS of CLL Weakness, fatigue, vague sense of being ill Night sweat Infections esp pneumonia
- 38. TREATMENT OF CLL Observation Chemotherapy. Oral chlorambucil Fludarabine, Immunotherapy Anti-CD 20 (rituximab), Anti-CD 52 (Alemtuzumab) Indications for starting chemotherapy a. Progressive Symptoms b. Progressive Anemia or Thrombocytopenia c. Bulky LN, large spleen d. Recurrent Infections
- 39. CHRONIC MYELOID LEUKEMIA CML is a clonal stem cell disorder characterised by increased proliferation of myeloid elements at all stages of differentiation. Incidence increases with age, M > F.
- 40. CML is characterised by 3 distinct phases a) Chronic Phase:Proliferation of myeloid cells, which show a full range of maturation. b) Accelerated Phase decrease in myeloid differentiation occurs. c) Blast crisis (acute leukemia)
- 41. CLINICAL PRESENTAITON OF CML Symptoms Asymptomatic (50% of patients) Fatigue Weight loss Abdominal fullness and anorexia Abdominal pain, esp splenic area Increased sweating Easy bruising or bleeding
- 42. CYTOGENETICS OF CML Philadelphia (Ph) chromosome is an acquired cytogenetic abnormality in all leukaemia cells in CML Reciprocal translocation of chromosomal material between chromosome 22 and chromosome 9. t(9;22)
- 44. Treatment
- 45. ACUTE LYMPHOBLASTIC LEUKEMIA ( ALL) DOSE ROUTE REGIMEN Induction ( 4 weeks) Vincristin Prednisolone L- Asparaginase Daunorubicin 1.5 mg/m2 40mg/m2 6000u/m2 45mg/m2 I.V Oral I.M I.V Weekly for 4 weeks Daily for 4 weeks 3xWeekly for 3 weeks Daily for 2 days Intensification(1 week) Vincristin Daunorubicin Prednisolone Etoposide Cytarabine Thioguanine 1.5mg/m2 45mg/m2 40mg/m2 100mg/m2 100mg/m2 80mg/m2 I.V I.V Oral I.V I.V Oral 1 dose Daily for 2 days Daily for 5 days Daily for 5 days 2x daily for 5 days Daily for 5 days CNS Prophylaxis( 3 weeks) Cranial irradiation Methotrexate 24 Gy I.T weekly for 3 weeks Oral Oral Oral I.V Weekly Daily 5days/ Month Monthly Maintenance Therapy ( 2 years) Methotrexate 6-Mercaptopurine Prednisolone vincristine 20mg/m2 75mg/m2 40mg/m2 1.5mg/m2
- 46. (Treatment of acute leukemias)Induction Obtained by using high doses of chemotherapy 1 Severe bone marrow hypoplasia 2 Allowing regrowth of normal residual stem cells to regrow faster than leukemic cells. Remission Normal neutrophil count Normal platelet count Normal hemoglobin level Remission defined as < 5% blast in the bone marrow
- 47. (Treatment of acute leukemia) Consolidation • Different or same drugs to those used during induction • Higher doses of chemotherapy • Advantage: Delays relapse and survival improved
- 48. (Treatment of acute leukemias) Maintenance • Smaller doses for longer period • Produce low neutrophil counts & platelet counts • Objective is to eradicate progressively any remaining leukemic cells.
- 49. (Treatment of acute leukemias) Supportive Care Vascular access (Central line) Prevention of vomiting Blood products (Anemia, ↓Plat) Prevention & treatment of infections (antibiotics) Management of metabolic complications
- 50. ALL vs AML ALL AML Induction Induction Consolidation Consolidation Maintenance No maintenance CNS prophylaxis all CNS – Selected group only patients
- 51. DRUGS USED TO TREAT ACUTE MELOBLASTIC LEUKEMIA ( AML) Anthracycline Daunorubicin Doxorubicin Idarubicin Mitoxantrone Antimetabolite Cladribine Cytarabine Fludarabine Hydroxyurea Methotrexate 6-Mercaptopurine 6-Thioguanine
- 52. DRUGS USED TO TREAT ACUTE MYELOBLASTIC LEUKEMIA ( AML) TOPOISOMERASE INHIBITORS ETOPOSIDE TOPOTECAN DNA DAMAGING ( ALKYLATING AGENT) o CYCLOPHOSPHAMIDE CARBOPLATIN TEMOZOLOMIDE CELL MATURING AGENT ALL-TRANS RETIONIC ACID (ATRA) ARSENIC TRIOXIDE o HYPOMETHYLATING AGENT AZACITIDINE DECITABINE
- 53. Treatment of Chronic Lymphoblastic Leukemia (CLL) Alkylating agents : Chlorambucil intermittently (10 mg/m2 x 7 days, monthly ) or continously ( 5 -10 mg / day ) Combinations : COP : Cyclophosphamide, Oncovin, Prednisolone( 5 day – monthly course ) Chlorambucil + Epirubicin CHOP : COP + Doxorubicin
- 54. Treatment of Chronic Lymphoblastic Leukemia (CLL) Corticosteroids : Prednisolone : 30 mg / m2 for 3 weeks + 1 week tailing off for initial treatment of pts with Stage C disease. High – dose Methylprednisolone IV at 1 g/m2 ( 5-day monthly course ) Nucleoside analogues : Fludarabine ( 25 mg / m2 IV daily as 30 min infusion for 5 days every 28 days ) Fludarabine + Cyclophosphamide Pentostatin ( 2 mg/m2/day IV for 5 days every 28 days) Cladribine ( IV infusion over 2 hrs dose of 0.12 mg/kg/day for 5 consecutive days )
- 55. Nucleoside analogues Studies have shown FLUDARABINE superior to Chlorambucil in CLL with higher clinical response rates, superior time to treatment failure, better tolerance in pts > 65 yrs. FLUDARABINE – Currently 1st line of treatment in CLL
- 56. Monoclonal Antibodies Alemtuzumab ( monoclonal antibody directed at CD 52 ) : 1st line agent For salvage in pts with fludarabine refractory disease Effective in CLL with p53 mutations Very effective in clearing Bone Marrow disease Limited activity in clearing bulky lymphadenopathy Has role in consolidation therapy for elimination of minimal residual disease.
- 57. Monoclonal Antibodies Anti-viral prophylaxis and prophylactic antibiotics for Pneumocystis carnii are recommended for pts receiving Alemtuzumab and for 2 – 4 months after treatment Rituximab – (monoclonal antibody specific for CD 20) used extensively in combination with chemotherapy. Fludarabine combined with Rituximab – shown higher clinical remission rates than fludarabine alone . FCR – ( Fludarabine, Cyclophosphamide, Rituximab ) – shown clinical response rates of 76% in trials. CFAR – ( Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab ) still under trials
- 58. Monoclonal Antibodies LENALIDOMIDE : An immunomodulatory drug currently approved for use in Multiple Myeloma and MDS with deletion of Chr 5q . Studies have shown response rates of 47 – 38 % with complete response rates of 9 % and elimination MRD have been reported.
- 59. Bone Marrow Transplantation Allogenic bone marrow transplantation is the only known curative therapy. Addition of ALEMTUZUMAB to pts receiving hematopoetic stem cell transplantation aids in elimination of MRD ( Minimal Residual Disease )
- 60. Radiotherapy For many decades, irradiation of spleen was primary treatment of CLL. Useful in pts with bulky lymph nodes compressing nerves / other organs & massive / painful splenomegaly. IRRADIATION of mediastinum, extracorporeal irradiation of blood and total body irradiation – may reduce the peripheral blood lymphocyte counts and size of lymph node, spleen and liver. Total body irradiation plus cyclophosphamide & prednisolone had higher response to those treated with TBI alone.
- 61. Supportive therapy Hypogammaglobulinemia : IV Immunoglobulins Prednisolone - useful against autoimmune manifestations of disease. Rituximab alone / in combination : effective in eliminating the B cell clone inducing autoimmune disorders, particularly autoimmune thrombocytopenia Leukapheresis : removal of leukemic cells reduces tumor load and leukostasis. Long term antibiotics
- 65. CML-Principles of Treatment Control & prolong chronic phase (non-curative) - Tyrosine kinase inhibitors-Imatinib - Alpha-Interferon - Oral chemotherapy (Hydroxyurea) Eradicate malignant Clone (curative) - Allogeneic BM/stem cell transplantation - Alpha Interferon - Imatinib? 2nd line TKIs
- 66. TREATMENT OF CML Tyrosine kinase inhibitor (TKI) Imatinib (Glivec) is the first line treatment In resistent cases 2nd line TKIs (Nilotinib, Dasatinib, Bosutinib) very useful Allogenic bone marrow trasnsplantation can be curative in pts resisrant to TKIs but has significant complications & mortality Accelerated and blast phase Treat like AML or ALL followed by BMT
- 67. Bone marrow or PBSC transplantation in leukemias 1. 2. Types of transplant Autologous transplant Allogeneic Transplant Purpose of transplant Autologous -To deliver a high dose of chemo to kill any residual cancer (lymphoma, multiple myeloma) Allogeneic -To eradicate residual leukemia cells -Graft vs leukemia effect
- 68. THANK YOU