This document provides an overview of Chronic Lymphocytic Leukemia (CLL) presented by Dr. Subhash Thakur. It discusses the incidence, clinical features, diagnosis, staging, management and treatment of CLL at different stages. It also covers complications, response evaluation, and long-term implications. CLL most commonly presents with recurring infections in elderly adults. Physical exams may reveal enlarged lymph nodes and splenomegaly. Peripheral blood flow cytometry is most helpful for diagnosis. Watchful waiting is the recommended strategy for asymptomatic early-stage CLL patients.

1. Chronic Lymphocytic
Leukemia (CLL)
Dr. Subhash Thakur
Clinical Oncologist
MD (PGIMER, Chandigarh)
MBBS 3rd 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:
1. Peripheral blood > 5000 monoclonal B
Lymphocytes/MicroL. Clonity needs to be confirmed by
flow cytometry.
2. 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.
3. Larger atypical Lymphocytes or prolymphocytes may be
seen but must exceed 55%

11. 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.

12. Other Lymphoma to be separated from
CLL are
1. Leukemic marginal zone lymphoma
2. Lymphoplasmacytic Lymphoma
3. 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 * 109 /L
- Diagnosis of SLL: confirmed by Histo-pathological evaluation of a LN biopsy
- Expression of CD20 is dim in CLLmphoma 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.

13. 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

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

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

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

17. Binet Staging System

18. Rai Staging

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

20. a) 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

21. 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

22. 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

23. 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

24. • 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

25. • 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

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

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

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

31. 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

32. 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

33. 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

34. CLL HL
• Chemotherapy: convention Chemotherapy of HL

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

36. Revision with MCQs

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

38. 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

39. 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

40. 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

41. The round nuclei with block-type chromatin or
soccer ball chromatin are seen in cells of
a. CLL
b. AML
c. ALL
d. CML

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

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

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

45. CLL Stands for
a. Chronic Leucocytic Leukemia
b. Chronic Lymphocytic Leukemia
c. None of These
d. Chronic Leukemic Lymphoma

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

47. 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

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

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

50. Thank You