Chronic lymphocytic leukemia

1. Chronic Lymphocytic Leukemia

2. Definition
• Clonal B cell malignancy.
• Progressive accumulation of long lived
mature lymphocytes.
• Increase in anti-apoptotic protein bcl-2.
• Intermediate stage between pre-B and
mature B-cell.

3. Cancer statastics 2000; CA J Clin 2000;
50:7-33
Epidemiology
• Most common leukemia of Western world.
• Less frequent in Asia and Latin America.
• Male to female ratio is 2:1.
• Median age at diagnosis is 65-70 years.
• In US population incidence is similar in
different races.

4. Etiology & Risk factors
• High familial risk with two-fold to seven-
fold higher risk.
• No documented association with
environmental factors.
• No established viral etiology.

5. Blood 1996; 87: 4990
Diagnostic Criteria
• Defined by NCI & IWCLL.
• Persistent lymphocytosis.
• Absolute count more than 5000.
• Mature appearing B-cells with <10% of
prolymhocytes

6. Flow Cytometry
• CD 19 and/or CD 20 are always co
expressed with CD 5.
• Weak expression of surface
immunoglobulins (sIgM & sIgD).
• CD 21, CD 23, CD 24 may be expressed.

7. Bone Marrow
• Not required for diagnosis.
• Recommended to estimate the extent for
prognostic implications.
• Diffuse infiltration has poor prognosis.

8. J Mol Med 1999; 77:266
Cytogenetics
• Deletions in chromosome 13 at q 14
• Chromosome 11 at q22 or q23.
• Trisomy-12.
• Less common are deletions in chromosome
17 & 6.

9. Clinical Features
• Disease of elderly with wide spectrum of
clinical features.
• 20% are asymptomatic.
• Classic B symptoms.
• Variable physical findings with normal to
diffuse LAD , hepato/splenomegaly.

10. Other Labs
• Hypogammaglobulinemia seen >50%.
• 5-10% have small monoclonal peak.
• Positive Coombs’ test in 30% .
• Autoimmune hemolytic anemia &
thrombocytopenia in <10%

11. The Rai Staging System
Stage 0 Lymphocytosis only (> 15,000/mm3
)
Stage 1 Lymphocytosis and lymphadenopathy
Stage 2 Lymphocytosis and splenomegaly with
or without lymphadenopathy
Stage 3 Lymphocytosis and anemia (Hgb <11 g/dL)
with or without lymphadenopathy or
hepatosplenomegaly
Stage 4 Lymphocytosis and thrombocytopenia (Plt <
100,000/UL) with or without anemia,
lymphadenopathy or hepatosplenomegaly

12. Modified Rai Staging g.
• Low-risk: stage 0, MS > 13 years.
• Intermediate-risk: stage I & II with MS
about 8 years.
• High-risk: stages III & IV with MS about
3 years

13. The Binet Staging System
Stage A No anemia, no thrombocytopenia,
<3 involved nodal areas
Stage B No anemia, no thrombocytopenia,
>=3 involved nodal areas
Stage C Anemia (Hgb < 10 g/dL) and/or
thrombocytopenia (Plt < 100,000/uL)

14. Blood 94: 1848-1854, 1999
Other Prognostic Features
• Bone marrow pattern of lymphoid infiltration.
• Lymphocyte doubling time.
• Serum beta-2-microglobulin.
• Mutational status of Ig V and CD 38
expression have recently been identified.

15. Blood 1996; 88 (suppl 1): 141a
Treatment
• Nucleoside analogs like Fludarabine is the
drug of choice.
• More effective in higher CR & longer PFS
compared to alkyalating agents.
• No survival advantage.
• Fludarabine in various combinations with
Cyclophosphane & Rituximab are widely
used.

16. Blood 1999; 94 (suppl 1); 705a
Monoclonal antibodies
• Alemtuzumab (anti-CD 52) is recently
approved for refractory CLL.
• Results in profound lympocytopenia, both
B and T cells are destroyed.
• Rituximab&Obinutuzumab (anti CD 20) is
widely used both as single agent and in
combination.

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

18. CLL WITH DELETION
17P/P53 MUTATION
• 1. First Line:
Ibrutinib
±Rituximab ± Alemtuzumab
±HDMP + Rituximab
• 2. Second Line:
- Ibrutinib ± Venetoclax (anti-bcl 20)
- Ibrutinib ± Idealisib (phosphoinositide 3-kinase inhibitor)
- Idealisib + Rituximab
- HDMP + Rituximab
- Rituximab ± Alemtuzumab
- Rituximab ± Lenalidomide

19. RELAPSE/
REFRACTORY THERAPY

20. J Clin Oncol 16:2817-2724
Bone marrow transplantation
• Allogenic BMT is a viable option in
younger patients.
• Durable response rates seen in advanced,
refractory disease.
• Autologous BMT using purged marrow
have been investigated in elderly.

21. Transformation
• Large- cell lymphoma/ Richter’s
– Aggressive presentation
– Extranodal involment
– Sharp rise in LDH
– CHOP is standard treatment.
• Prolymphoctic leukemia.
– > 55% increase in prolymphocytes
– Progression of splenomegaly & cytopenias
– Refractoriness to treatment.