Understanding Leukemias: Types, Diagnosis, and Treatment Options

1. The Leukemias • Sherron R. Helms, M.D. • March 24, 2005

2. Leukemias • Proliferation of abnormal clone of hematopoietic cells • Poor response to normal regulatory signals • Diminished capacity for differentiation • Ability to expand at expense of normal cells • Ability to suppress growth of normal cells

3. Leukemias- Etiology • Generally unknown • Host susceptibility- DNA repair mechanisms, Down syndrome • Chromosomal damage- physical (XRT) or chemical (alkylating agents, benzene) • Viral- EBV in Burkitt, HTLV-I in T cell ALL

4. Leukemias- Diagnosis • Generally requires bone marrow biopsy and aspirates with flow cytometry and cytogenetics • CLL can be reliably diagnosed by flow cytometry on peripheral blood • There must be > 20% blasts in marrow for diagnosis of acute leukemia

5. Leukemias- Classification • Acute vs Chronic • Based on natural history of the untreated disease • Myeloid vs Lymphoid • Based on the primary cell line involved

6. Leukemias • Lymphoid • CLL • ALL • Myeloid • CML • AML

7. Chronic Lymphocytic Leukemia

8. CLL • Relatively indolent clonal lymphoid disease • Primarily B cell • Includes Hairy Cell Leukemia • Most common leukemia in adults • Median age at diagnosis: 62 y • Etiology unknown • Morphology: Normal B cells

9. CLL- Molecular Biology • Normal appearance, abnormal function • CD 5 expression • Defective apoptosis • Overexpression of bcl-2 gene

10. CLL- Clinical Presentation • Asymptomatic • Lymphocytosis noted on routine CBC • Lymphadenopathy and/or splenomegaly in ~50% at diagnosis • Staph, Strep, Herpes infections common • Autoimmune hemolytic anemia in 10% • ITP in 2%

11. CLL- Immune dysfunction • CLL B cells produce reduced levels of immunoglobulin in response to antigenic stimuli • Quantitative and qualitative abnormalities in B, T, NK cells • Impaired complement activation

12. CLL- Staging • LOW RISK • Lymphocytosis only • Average survival >10 yrs • INTERMEDIATE RISK • + Adenopathy and/or splenomegaly • Average survival 7 yrs • HIGH RISK • + Anemia and/or thrombocytopenia • Average survival 1.5 yrs

13. CLL- Clinical course • Generally, indolent with gradual increase in lymphocytosis, adenopathy, splenomegaly. May be years before Rx required • Richter syndrome- ~5% transform to aggressive large cell lymphoma/leukemia • Develop fever, weight loss, worsening anemia & thrombocytopenia, rising lymphocyte count • Short survival, poor response to therapy

14. CLL- Treatment • No survival advantage to therapy at time of diagnosis in low risk patients • Indications for therapy: • B symptoms • AIHA, ITP (steroids) • Massive hepatosplenomegaly • Bulky adenopathy • Recurrent infections

15. CLL- Treatment Options-I • Chlorambucil- Oral alkylator, ~50% RR, rare complete response • Fludarabine- IV purine analog, 70% RR, 30% CR, prolonged T cell suppression • IVIG: Only in pts with repeated bacterial infections

16. CLL- Treatment Options-II • Monoclonal Antibodies • Rituximab- antiCD20; when combined with chemo, 95% RR, 68% CR • Alemtuzumab- antiCD52- effective in clearing blood and marrow; less effective on nodes. Prolonged, severe T cell suppression • Bone Marrow Transplantation- autologous and allogeneic under study for healthy pts under 70yo

17. Hairy Cell Leukemia • Male predominance • Cytopenias, splenomegaly • Therapy: Cladribine- nucleoside analog • Single course of therapy • 90% response rate • Responses very durable • Resistant disease- BL-22: MoAb antiCD22 + pseudomonas exotoxin induces apoptosis- 75% RR in clinical trials

21. Acute lymphocytic leukemia

22. Acute lymphoblastic leukemia • Malignant disease of early B and T cells • Aberrant differentiation and proliferation • Cells accumulate in marrow and suppress normal hematopoiesis • In addition to marrow and peripheral blood, involves nodes, liver, spleen, CNS, and skin

23. A.L.L. • 20% of adult leukemia • Most common malignant disease in childhood • Symptoms: fatigue, fevers, bone pain, infection, bleeding, adenopathy • CNS involvement in 5-10% • Blasts in peripheral blood in 90% • Leukostasis uncommon even with WBC 100,000

24. A.L.L. Treatment • Induction, consolidation, maintenance • Use multiple chemotherapy agents to prevent resistance (vincristine, prednisone, daunorubicin, asparaginase) • Use prophylactic Rx of CNS (intrathecal methotrexate and AraC) • Postremission chemo to eliminate minimal residual disease • Adults: 65-90% remission; 20-30% cure • Allogeneic transplants in high risk pts

27. Acute Myelogenous Leukemia

28. A.M.L. • Most common acute leukemia in adults • Median age at diagnosis: 60 yrs • The most common type of leukemia induced by alkylating agents (nitrogen mustard [7y]) or epipodophyllins (VP16, 1-2 y)

29. AML • Auer rods: accumulation of lysosomal granules in cytoplasm, seen in ~10% • Diagnosis by flow cytometry, cytogenetics on marrow • FAB classification has 8 subtypes (M0- M7); WHO classification has 19

30. AML- Clinical Features • Presenting symptoms: fatigue, bruising, infection • Acute promyelocytic subtype presents with bleeding, sometimes frank DIC • Acute myelomonocytic subtype often has gum and/or skin involvement • Leukostasis (pulm and CNS) common when blast count >50,000

31. A.M.L.- Therapy • Remission induction with cytarabine and daunorubicin • all-trans retinoic acid (ATRA) is added in acute promyelocytic leukemia (APL) • Postremission: consolidation chemo using high dose cytarabine for 2 cycles • 40% cure rate in young and middle aged adults • Maintenance therapy only in APL (ATRA) • Allogeneic transplant in high risk pts <70y who have match and are in CR

32. AML in Elderly • Poorer outcome, ~10% long term survivors • Less able to withstand intensive chemotherapy and complication of prolonged marrow suppression • Less marrow regenerative capacity • More often have poor-prognosis subtypes of leukemia • More often have MDS evolving into AML, multiple mutations and drug resistant

33. Acute Promyelocytic Leukemia (APL) • M3 subtype of AML • Promyelocytes contain granules with procoagulant and fibrinolytic activity • t(15;17) juxtaposes the RARa gene on 17 with the PML gene on 15 • The resulting PML/RARa represses transcription of the RAR needed for differentiation/apoptosis • High doses of ATRA cause release of the corepressor

34. A.P.L. • Retinoic acid + standard chemotherapy with daunorubicin and cytosine arabinoside (AraC) • 95% remission rate, 70% cure rate • Arsenic trioxide active in relapsed disease (causes histone acetylation, differentiation, & apoptosis)

38. Chronic Myelogenous Leukemia

39. Chronic Myelogenous Leukemia • A myeloproliferative disorder (CML, P. Vera, E.T.) • Clonal disorder of pluripotential stem cell • Median age 45-55 yrs • Philadelphia chromosome [t(9;22)] in 95%

40. CML • Expansion of myeloid cells at various stages of maturation • Three clinical phases: chronic, accelerated, and blast crisis • Patients proceed through these phases over ~4yrs if untreated • Symptoms: fatigue, night sweats, sx related to splenomegaly • High WBC, increased basophils, high platelet count

41. Ph Chromosome • BCR-ABL –protein product of the translocation • Transfection of BCR-ABL in mice causes CML • Inhibition of BCR-ABL in patients reverses CML • Acquired disorder • Cause of mutation unknown- radiation in some

42. Ph Chromosome- BCR-ABL • Tyrosine kinase activity • Leads to increased transcription of genes that control cell proliferation • Inhibits expression of cell adhesion molecules • Suppresses apoptosis

43. CML- Treatment • The BCR-ABL proteins must be phosphorylated to have tyrosine kinase activity • Imatinib (Gleevec) blocks phosphorylation • Oral agent, well tolerated • 87% RR, 76% complete cytogenetic response • Allogeneic stem cell transplant cures 75% of pts under age 70