Chronic Lymphocytic Leukemia (CLL)

This presentation is about chronic lymphocytic leukemia (CLL), its epidemiology and incidence, staging, molecular characteristics, clinical features and management.

1. Chronic Lymphocytic Leukemia (CLL) Dr. Subhash Thakur Clinical Oncologist MD (PGIMER, Chandigarh) MBBS 3 rd Year Lecture @ CMC, Bharatpur , Nepal 25/04/2021

2. Content Introduction to Leukemia Classification CLL Incidence and Epidemiology Clinical Features Diagnosis and Molecular Biology Staging and Risk Assessment Management Management of early disease Stage Management of Advanced disease Stage Management of Relapse and refractory Disease Role of Hematopoietic Stem Cell Transplant Treatment of CLL complications Response Evaluation Follow up and Long Term Complication

3. Introduction to Leukaemia Malignant Haematological Disorder Proliferation of abnormal White Cells that infiltrate bone marrow, peripheral blood and organs

4. Classification

5. An elderly man with very high WBC, say 69000 ???? Next: DLC >90% Neutrophils or >90% Lymphocytes >90% Neutrophils LAP test: Low: CML, if High: Reactive or Leukemoid >90% Lymphocytes: CLL

6. Chronic Lymphocytic Leukaemia (CLL)

7. Incidence and Epidemiology Most Common Leukemia in the western World Incidence: 4.2:100000/year Incidence increases to >30:100000/year at an age of >80 years.

8. Incidence and Epidemiology Cont … Median age at diagnosis: 72 years 10% patients are younger than 55 years Inherited genetic susceptibility, 6 to 9 fold increased risk for family members of CLL patients

9. Diagnosis and Molecular Biology Diagnosis of CLL is established by following criteria: Peripheral blood > 5000 monoclonal B Lymphocytes / MicroL . Clonity needs to be confirmed by flow cytometry. Leukemic Cells in blood smear are characterized by small, mature-appearing lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli, having partially aggregated chromatin. Larger atypical Lymphocytes or prolymphocytes may be seen but must exceed 55%

10. Immunohistocytochemistry (IHC) CD5 antigen and B Cell surface antigens: CD19, 20 and CD23 Surface Immunoglobulin CD20 and CD79b are characteristically low compared with those found on normal B-Cells.

11. Other Lymphoma to be separated from CLL are Leukemic marginal zone lymphoma Lymphoplasmacytic Lymphoma Mantle Cell Lymphoma (CD 5+, CD19+, FMC – 7+, CD 23-) WHO Classification: SLL (Small Lymphocytic Lymphoma) and CLL are considered to be a single entity. SLL: Lymphadenopathy +/- Splenomegaly, B Lymphocytes in peripheral blood < 5 * 10 9 /L Diagnosis of SLL: confirmed by Histo -pathological evaluation of a LN biopsy Expression of CD20 is dim in CLL mphoma whereas it is bright in mantle cell lymphoma Another feature that can help in differentiating the two conditions is that mantle cell lymphoma expresses CD5 and CD19, but not CD23 antigen —something that is expressed in CLL. In addition, mantle cell lymphoma usually expresses FMC-7 .

12. Monoclonal B-Lymphocytosis Absence of Clinical Symptoms , Lymphadenopathy, organomegaly , cytopenia and presence of <5000 monoclonal B-Lymphocytes/ microL 5% of subjects with normal blood count Progression to CLL: 1-2% of MBL/year

13. Clinical Features Does not usually Cause Symptoms When symptoms develop, they may include: getting infections often anaemia  bleeding and bruising more easily than normal

14. a high temperature night sweats unintentional weight loss swollen glands  in your neck, armpits or groin swelling and discomfort in your abdomen

15. Staging and Risk Assessment Commonly used Staging System: Europe: Binet Staging System US: Rai System

16. Binet Staging System

17. Rai Staging

18. Management Management of early disease Stage Binet Stage A and B without active disease: Rai 0, I and II without active disease Management of Advanced disease Stage Management of Relapse and refractory Disease

19. Binet Stage A and B without active disease: Rai 0, I and II without active disease Watch and Wait Strategy Blood Counts and Clinical Examination: every 3-12 months

20. B. Treatment of advanced disease stage b). Binet Stage A and B with active disease or Binet Stage C, Rai (0-II) with active disease or Rai (III-IV) Treatment should only be initiated in patients with symptomatic, active disease

21. Active Disease Significant B-Symptoms Cytopaenias not caused by autoimmune phenomenon Symptoms /complications from Lymphadenopathy, splenomegaly or hepatomegaly Lymphocytes doubling time < 6 months Autoimmune anaemia and/or thrombocytopenia poorly responsive to conventional therapy

22. Front Line Treatment Physically fit patients (physically active, no major health problem, normal renal function) without TP53 del/mutation FCR Fludarabine Cyclophosphamide Rituximab Fit but elderly patients FCR: a/w higher rate of severe infection BR Bendamustine Rituximab

23. BR produces fewer complete remission than FCR Patients with comorbidities, Older and without TP53 mutation/deletion : Chlorambucil + anti CD20 antibody (Rituximab, Ofatumumab or obiztuzumab ) Standard of care, is a/w increased progression free survival

24. Patients with TP53 del/mutation Poor prognosis even after FCR therapy Novel inhibitors : Ibrutinib , Idealasib and Rituximab in front line and relapse setting Fit patients responding to Inhibitor treatment: Allogenic Stem Cell Transplant may be discussed Maintenance therapy: generally not recommended

25. Relapse/Refractory Disease As for 1 st line treatment, treatment at relapse should only be started in symptomatic patients. Relapse after 24-36 months: 1 st line treatment may be repeated if TP53 del/mutation was excluded Relapse after 24-36 months or if disease does not respond to any 1 st line therapy Therapeutic regimen should be changed

26. Treatment Options BCL 2 antagonists alone or in combination Brenton’s TKI: Ibrutinib PI3K Inhibitor idealisib in combination with Rituximab

27. Role of Hematopoietic SCT Not useful in CLL AlloSCT : remission with kinase inhibitors or BCL2 antagonist and/or del 17p or TP53 mutation

28. Treatment of CLL Complications Infections: Corticosteroids use should be minimal Antibiotic and antiviral prophylaxis in patients with recurrent infection and/or high risk of developing infections. Pneumococcal and seasonal influenza vaccine Autoimmune Anaemia Steroids: not responding to steroids: Rituximab

29. Response Evaluation A Careful physical examination and blood count Bone marrow biopsy to define CR Chest X-ray and USG abdomen or CT for response evaluation if abnormal before therapy

30. Follow up and Long term Implications CLL: Incurable disease: Life long observation and follow up is required Asymptomatic Patients: Blood count and palpation of LN, Liver and Spleen every 3-12 months Transformation to DLBCL or HL: 2-15% Of CLL patients Diagnosis: Biopsy for confirmation

31. CLL HL Chemotherapy: convention Chemotherapy of HL

32. CLL DLBCL Richter’s Transformation Very Poor prognosis Treatment: R-CHOP or R+CVAD

33. Revision with MCQs

34. In patients with CLL, which of the following is the most common presenting symptom? Recurring infections Abdominal discomfort Enlarged Lymph nodes Fatigue

35. In addition to lymphadenopathy, physical examination of a patient with CLL may reveal which of the following? Low White Blood Cell Count Splenomegaly Arrhythmia Fever

36. Which of the following tests is the most helpful for diagnosing CLL? Peripheral Blood Flow Cytometry Bone marrow Biopsy Ultrasonography of Liver Ultrasonography of Spleen

37. What is an indication of CLL rather than mantle cell lymphoma? Expression of CD20 is dim Expression of CD20 is bright Expression of FMC 7 is dim Expression of FMC 7 is bright

38.  The round nuclei with block-type chromatin or soccer ball chromatin are seen in cells of CLL AML ALL CML

39.  “Fried egg” or “honeycomb” appearance in bone marrow biopsy is characteristically seen in Hairy Cell Leukemia Mycosis Fungoides Burkitt Lymphoma Hodgkins Lymphoma

40. Majority of chronic Lymphocytic leukemia arise from B Cell T Cell NK Cell Null Cell

41.  Transformation of CLL to diffuse large B cell lymphoma is known as Richter Syndrome Prolymphocytic transformation Lymphoma Spill over Aggressive transformation

42. CLL Stands for Chronic Leucocytic Leukemia Chronic Lymphocytic Leukemia None of These Chronic Leukemic Lymphoma

43. Which Is the most common age group affected by CLL? Elder Young Adolescent Infants

44. Absence of Clinical symptoms, Lymphadenopathy, organomegaly, cytopenia and Lymphocytes count < 5000/microliter is representative of A. CLL B. SLL C. Monoclonal B- Lymphocytosis D. Hairy Cell Leukemia

45. Which of the following Staging system is not used in CLL A. Binet B. Rai C. Md anderson

46. Which strategy should be used for asymptomatic CLL patients? FCR BR Wait and Watch R- CHOP

47. Thank You