Chronic Leukemias

1. Chronic Leukemias

2. Chronic Leukemias • CLL • CML • CMML

3. Normal CBC with lymphocyte

4. Chronic Leukemias • CLL • CML • CMML

5. Chronic Leukemias • CLL- Chronic Lymphocytic • CML • CMML

6. Chronic Leukemias • CLL • incidence 4:100,000 • Male to Female 2:1 age <65 • Mean age 72 • Less than 3% in age <45 • Risk factors(FH, agricultural agents, viral-HTLV-1,2)

7. Peripheral Smear CLL

8. What are the Types of CLL? B-Cell CLL is more common, occurring in about 95% of all diagnosed cases T-Cell CLL is less common and progresses more rapidly

9. Chronic Leukemias • CLL • CML – Chronic Myelogenous • CMML

10. Chronic Leukemias • CML • incidence 1.7:100,000 • Male to Female 1.3:1 • Mean age 53 (20-70) • up to 50% <45 • Risk factors(noFH, radiation, no agricultural agents, no viral etiology) -bcr/abl fusion translocation t(9;22)

11. Peripheral smear CML

12. Chronic Leukemias • CLL • CML • CMML- Chronic Myelomonocytic Leukemia (CMMoL)

13. Chronic Leukemias • CMML • incidence MDS 4:100,000 (0.4:100,000) • Male to Female equal but rare Juvenile • Juvenile CMML transplant (AML) • Risk factors(FH, previous chemotherapy,) • Monosomy 7, t(5;12)

14. Normal CBC with lymphocyte

15. What is the Function of Lymphocytes? Found in the blood, bone marrow, spleen, and in lymph (clear fluid that flows through small vessels and collects in lymph nodes)

16. CLL and Diagnosis • Signs • Symptoms • Lab Findings

17. CLL and Diagnosis • Signs- often none as asymptomatic • Symptoms • Constitutional B Symptoms • Fevers • Chills • Wt loss • Night sweats

18. CLL and Diagnosis • Symptoms -recurrent infections sinusitis pneumonia viral infections

19. CLL and Diagnosis Symptoms • Bulky sensation • Early satiety (splenomegaly) • Lymph node swelling, lymphedema • Back pain (retroperitoneal adenopathy) • Urinary Retention

20. CLL and Diagnosis • Signs- often none as asymptomatic • Symptoms • Fatigue and Malaise (anemia related) • Bruising (thrombocytopenia)

21. CLL and Diagnosis • Signs • Symptoms • Laboratory Observations

22. CLL and Diagnosis • Signs • Symptoms • Lab Findings • Lymphocytosis >9000 (60-90%WBC) • Flow cytometry showing B cells markers (CD19, 20, 23) and CD5, monoclonal • Bone Marrow involved by 30%

23. Bone Marrow CLL

24. CLL and Diagnosis • More Lab Findings • B2 microglobulin elevated • IgG, IgA, IgM decreased (hypogammaglobulinemia) • LDH elevated • Anemia with or without hemolysis

25. CLL and Diagnosis • Cytogenetic/Molecular Lab Findings • good prognosis • intermediate prognosis • poor prognosis

26. CLL and Diagnosis Cytogenetic/Molecular Lab Findings (Survival and Response to therapy) good prognosis - trisomy 8 intermediate prognosis • 13 q del • Trisomy 12 (10-12 yrs) POOR PROGNOSIS • 17p del ( 20-80mo) • 11q del

27. CLL and Molecular detailsp53 gene is located on p17p53 responsible for DNA repairp53 induces apoptosis in damaged cellsp53 mutation or deletion of this protein is associated with resistance to chemotherapy

28. Wake up • Clinical diagnosis • Review Slide and do a good EXAM

29. Staging System • Rai System • 0 Low, lymphocytosis in blood and marrow only (MS greater than 10 yrs) NO ADENOPATHY • I Intermediate, lymphocytosis and adenopathy • II Intermediate lymphocytosis and organomegaly(MS 6 yrs) • III High with any above AND cytopenias (MS 2 yrs) • Binet System

30. Staging System • Rai System • Binet System • A Hb > 10gm/dl and normal plts, <3 areas • B Hb > 10gm/dl and normal plts, >3 areas • C Cytopenias independent of organs

31. Staging System • Rai System • Binet System • Newer adapted Mutated vs. UnMutated immunoglobulin heavy chain variable gene (IgVH) mutation, SHM (somatic hypermutated)—means the gene is less than 98% homologous to germline and this is a GOOD prognostic marker

32. Staging System • Rai System • Binet System • Newer adapted Mutated vs. UnMutated IgVH • ZAP-70, CD38 (?poor prognos, observed unmutated)

33. Hemolysis (AIHA- spherocytes)

34. Who to treat? • Progressive symptoms • Bone Marrow involvement with cytopenias • Painful splenomegaly • Progressive Bulky Adenopathy • Autoimmune Hemolytic anemia or thrombocytopenia • DO NOT TREAT THE WBC NUMBER

35. Treatment • Chlorambucil • Corticosteroids • CHOP • R-CHOP, R-CVP • R, Fludarabine • R,F,C • Campath (CD52 humanized Monoclonal Antibody to both T and B lymphocytes • Radiation • Splenectomy

36. Treatment • Bendamustine- newly approved alkylating agent 100 mg/m2 on days 1 and 2 of a 28-day treatment cycle (for up to 6 cycles) • IVIG • Investigational transplant (allo) • Transfusion

37. How is CLL Treated? Treatment depends on the patient’s stage, risk status and overall health Watch and wait option: many people may not require treatment right away Chemotherapy Monoclonal antibodies Radiation therapy More than one treatment may be used

38. CLL Treatment: Chemotherapy Use of drugs to kill cancer cells Chemotherapy may be given orally, intravenously (IV) or subcutaneously (under the skin) Typical medications include fludarabine (Fludara), pentostatin (Nipent), cladribine (Leustatin), chlorambucil (Leukeran), cyclophosphamide (Cytoxan or Neosar), prednisone A combination of medications is often used

39. CLL Treatment: Monoclonal Antibodies • Targeted therapy • CD20, CD52 • Rituximab (Rituxan); can be used for B-cell CLL • Alemtuzumab (Campath), a monoclonal antibody approved for use by the U.S. Food and Drug Administration (FDA) for treatment of advanced CLL after other treatments fail. It is used in both B-cell and T-cell CLL

40. CLL Treatment: Radiation Therapy Different methods of delivery External beam: outside the body Usually given to shrink an enlarged spleen or swollen lymph nodes and eliminate symptoms associated with such growths Side effects can include fatigue, mild skin reactions, nausea, diarrhea, or constipation

41. Supportive Treatment for CLL Used to control or treat symptoms (either from CLL or its treatment) White blood cell or red blood cell growth factors (increase the bone marrow production of normal white or red blood cells) Blood transfusions Antibiotics to treat infection Immunoglobulin infusion for people with recurrent infections Splenectomy (surgery used to remove an enlarged spleen)

42. Current Research: Stem Cell Transplantation Being studied as an effective treatment for CLL A patient’s bone marrow is treated with high doses of chemotherapy and/or radiation therapy to decrease the leukemia cells and prevent immune cells from attacking the donated stem cells Allogeneic (ALLO) transplantation: stem cells are from a tissue matched donor

43. Current Research: Stem Cell Transplantation, continued Mini-transplant: dose of chemotherapy given is less than in a standard transplantation Graft-versus-host disease: a serious complication in which the donor’s immune cells attack the patient’s healthy cells Other side effects may include liver abnormalities, diarrhea, infection, rash, and organ damage

44. Survival vs Response to Rx • Overall Survival • Median Survival • Progression Free Survival • Time to Relapse • Overall Response Rate (Clinical/ Cytogenetic) • Complete Response • Partial Response • Durable Response

45. Survival Curves (no RX) 10 yrs 6 yrs 3 yrs 2 yrs

46. Survival Data

47. Board Question • 51y/o male with male found to have asymptomatic anemia on routine CBC for preop hernia repair. WBC 18K with 60% mature lymphocytes. The following smear is shown below: What is the next appropriate step • 1) perform bone marrow biopsy • 2) administer IVIG • 3) type and cross for transfusion • 4) proceed with hernia repair

48. CBC

49. CBC

50. Board Question • 51y/o male with male found to have asymptomatic anemia on routine CBC for preop hernia repair. WBC 18K with 60% mature lymphocytes. The following smear is shown below: What is the least favorable prognostic marker • 1) high LDH • 2) T cell phenotype • 3) HIV positive for 10years • 4) Immunoglobulin hypermutation • 5) finding del 17p