CLL

1. The Chronic Lymphocytic Leukemia
(CLL)
Dr. Ayush Garg

2. • B-CLL is a neoplastic disease characterized by
proliferation and accumulation of small, mature, long-
living lymphocytes in blood, marrow and lymphoid
tissues (lymph nodes, spleen)
• IWCLL 2008 criteria- an absolute malignant b
lymphocyte count >5000
THE B-CLL - DEFINITION

3. • Most common adult leukemia in Europe and North
America (in USA incidence of about 3/100.000
population)
• predominantly, CLL is a disease of elderly
• 40% of leukemias in patients over 60 years old
• men affect twice as often as women; 2:1 ratio of male to
female
• CLL morbidity rapidly increases with age (especially
between 50 and 60 years of age)
B-CLL EPIDEMIOLOGY
≥ 65 years
72%years
20–54 years
3%
55–64 25%

4. • The cause of CLL is unknown
• There is increased incidence in farmers,
rubber manufacturing workers and tire repair
workers
• Genetics factors have been postulated to play a
role in high incidence of CLL in some families (10%)
B-CLL ETIOLOGY &
PATHOGENESIS

5. • Often none! - 40% of patients are asymptomatic and
the diagnosis is typically accidental
• Unspecific: night sweats, fever, weakness (many patients
have fatigue, reduced exercises tolerance or malaise, weight
loss)
• Recurrent infections (bacterial, viral – herpes zoster, fungal) –
they are the most common cause of death
• Bleeding and symptoms of anemia and thrombocytopenia
• Lymphadenopathy (lymph node enlargement)
– At diagnosis - nontender in 80% of patients
– Later - may become very large
• Splenomegaly - mild to moderate in 50% of patients
• Hepatomegaly
• Some organs infiltration (lungs, pleura, skin and soft tissue)
B-CLL CLINICAL SYMPTOMS

6. CLL – Initial Symptoms
• Approximately 40% are asymptomatic at diagnosis –
discovered by a CBC
• In symptomatic cases the most common complaint is
fatigue
• Well’s syndrome – increase sensitivity to insects bites
• B symptoms – fever, sweats, weight loss
• Less often the initial complaint are enlarged nodes or
the development of an infection (bacterial)

7. B-CLL clinical symptoms
Cervical
limfadenopathy in
patient with B-CLL

8. B-CLL CLINICAL SYMPTOMS
The CLL
patient can
have
splenomegaly

9. • Is always the transformation of CLL into an aggressive
lymphoma – diffuse large cell lymphoma (DLCL) or hodgkin‘s
lymphoma
• Usually evolves after a long indolent course -
• Can occur as 1st manifestation of CLL: primary richter‘s - but
still CLL
• Has a poor prognosis
RICHTER’S SYNDROME

10. DIAGNOSIS

11. B-CLL LABORATORY FEATURES
• Bone Marrow smear (cytological examination)
– extensive replacement of marrow element by mature
lymphocytes (more than 30%)

12. – CD5+/CD19+/CD23+/ dim CD20+
– 90% of the patient have a very weak expression of
surface immunoglobulin (kappa or lambda light chain,
IgM, IgD)
– sometimes also CD38+,
– Dim expression of CD20, CD25, CD11c;
– lack expression of CD 10, CD 103, CD79a, FMC7
IMMUNOPHENOTYPING

13. • Conventional metaphase cyto difficult d/t very low
proliferation activity of leukemic cells
• Cytogenetic examinations - clonal chromosomal
abnormalities are detected in approximately 30- 50% of
CLL patients
– deletion 13 (13q14.3)
– trisomy 12
– structural abnormalities of chromosomes 11 (11q-), 14,
17
B-CLL LABORATORY FEATURES

14. FISH
• FISH positive in 80% of cases
• m/c del13 q (55%), f/b del 11q (18%), trisomy
12(16%), del17p(7%), del 6q(7%)
• Good- 13q
• Neutral- normal, 12+
• Bad- 17p, 11q
• Addition of an alkylating agent to fludarabine may
help to overcome adverse prognostic sign of 11q

15. STAGING

16. RAI’S CLINICAL STAGING SYSTEM
Stage Clinical Features at Diagnosis Median
Survival
(years)
0
Low risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
>12,5
I
Intermediate
risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and enlarged lymph nodes
8
II
Intermediate
risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and enlarged spleen and/or liver
6
III
High risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and anemia (Hb < 11g/dl)
1,5-2
IV
High risk
Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and thrombocytopenia(< 100 000 /ul)
1,5-2

17. BINET’S CLINICAL STAGING SYSTEM
Stage Clinical Features at Diagnosis Median
Survival
(month)
> 120
month
60 month
24 month
A. Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and less than 3 areas of palpable lymphoid-tissue enlargement
Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and Thrombocytopenia
B. Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
and 3 and more areas of palpable lymphoid-tissue enlargement
Without anemia (Hb >= 6,21 mmol/l, 10 g/dl) and Thrombocytopenia
C. Blood lymphocytosis>5G/l,
Bone marrow lymphocytosis>30%
with anemia (Hgb <10g/dL) or thrombocytopenia (Plt
<100.000/uL)

18. PROGNOSTICATION

19. MAJOR PHENOMENA UNDERLYING
CLL CLINICAL BEHAVIOR
• CLL has a highly varied clinical course.
• Phase 1: Diagnosis to need of first therapy (TTFT).
• Short TTFT independently associates with expression of ZAP70,
IgVH-UM status, INSR expression/del11q, TP53 mutations/del17p and
elevated genomic complexity.
• Phase 2: Time from first therapy to death (Survival).
• Short survival is determined by TP53 mutations/del17p, del11q status
and most comprehensively SNP array-based elevated genomic
complexity.
• Most CLL markers are unstable longitudinally necessitating outcome
analysis from the dates of marker measurements.

20. Prognostic factor Good prognosis Bad prognosis
A
0
B, C
I, II, III, IV
Clinical stage according to
Binet & Rai
Bone marrow infiltration in
-bone marrow biopsy
-cytological examination
Leucocytosis
Prolymphocytes in
peripheral blood
Leukemia cell doubling time
Non-Difussed
infiltration
<=80% lymphocytes
<= 50 x 109/l
<= 10%
> 12 months
Difussed
infiltration
> 80% lymphocytes
> 50 x 109/l
>10%
<= 12 months
NEW PROGNOSTIC INDICATORS IN B-CLL

21. • Clinical Stage
• Bone Marrow Histology (Diffuse Replacement Carries
Worst Prognosis)
• Leukemia Cell Doubling Time (Less Than 1
Year - Worse Prognosis)
• Percentage Of Prolymphocyte
• High Cell-surface Expression Of CD38
• ZAP-70 Expression
• Serum Level Of: B2-microglobulin; Thymidine Kinaze,
LDH, Scd23
• Igvh Mutational Status
• Genetic Features - FISH Cytogenetic
– Low-risk: Normal Kariotype; Isolated Del(13q)
– High-risk: Del(17p0, Del(11q), Trisomy 12
NEW PROGNOSTIC INDICATORS
IN B-CLL - SUMMARY

22. TREATMENT

23. • We have to remember:
– B-CLL – indolent lymphoma, but incurable
– Elderly patients – risk of additional diseases
– Course of the disease can be very long, indolent for many years,
patient can die because of another reason which is not connected
to B-CLL.
• Decision about treatment depends on clinical stage, prognostic factors
and patient’s condition
CLL – TREATMENT

24. CLL THERAPY 1960-2014 MANY THINGS HAVE
CHANGED…
• From chlorambucil (<10% CR) to chemoimmunotherapy
(60%-70% CR)
• Chemoimmunotherapy new gold-standard for CLL
therapy
• MRD- negativity CRs correlates with better outcome
• Improved PFS and OS

25. • Leukemia cell doubling time <6 months
• Grade 2 or greater fatigue
• Night Sweats
• B symptoms for >2weeks
• Lymph nodes of >10 cm
• Symptomatic liver or splenic enlargement (> 10 cm)
• Anemia hb <10 gm%
• Thrombocytopenia <1 lac platelets
• Wbc count >3 lac on 2 occasions 2 weeks apart
• Severe paraneoplastic process related to CLL
INDICATIONS OF TREATMENT

28. CLL WITHOUT DELETION 17P/P53 MUTATION
• 1. Frail patient with significant morbidity-
Obinutuzumab + Chlorambucil
Ibrutinib
Rituximab + Chlorambucil
• 2. Age ≥ 65 or younger patients with significant comorbidities-
Same as above
Rituximab ± Bendamustine 70mg/m2
• 3. Age < 65 without significant comorbidities-
FCR Regime
FR Regime
Rest same as above

29. CLL WITH DELETION 17P/P53 MUTATION
• 1. First Line-Ibrutinib
Rituximab ± Alemtuzumab
HDMP + Rituximab
• 2. Second Line-Ibrutinib
Venetoclax
Idealisib
Idealisib + Rituximab
HDMP + Rituximab
Rituximab ± Alemtuzumab
Rituximab ± Lenalidomide

30. RELAPSE/
REFRACTORY THERAPY

31. RSESPONSE

32. SUPPORTIVE CARE
Antiviral Prophylaxis: Acyclovir or Cotrimoxazole
Tumor Lysis Syndrome: Allopurinol
Antiummne Cytopenia: Corticosteroids
iv Immunoglobulins
Cyclosprin A
Splenectomy
Blood Transfusion
Thrombocytopenia: Anticoagulants
Aspirin / Warfarin
Tumor Flare Reaction: Steroids + Antihistamine
Vaccination: Annual Influenza Vaccine
Pneumococcal Vaccine every 5 years