Diagnosis, Staging, guideline of CLL therapy

1. • Introduction
• Diagnosis
• Staging
• Indications of therapy
• Proposed therapeutic regimens
• Discussion
• Take home message

2. Introduction
• Chronic Lymphocytic Lymphoma is a disease of the elderly
• Median age at diagnosis of 72 years
• Almost 70% patients are older than 65 years at the time of diagnosis;
• Younger than 45 years of age <2%
• Between 45 and 54 years 9.1%,
• Between 55 and 64 years 19.3%,
• Between 65 and 74 years 26.5%,
• Between 75 and 84 years 30.0%,
• More than 85 years of age 13.2%
According to European Registry, ESMO, 2022

3. • The incidence shows demographic variation
• Reported as the most common leukemia in the USA (>30%)
• While least common reported leukemia in India(<5%)
• According to SEER data, in India
• 9.1% of patients are younger than 45 years
• Younger age of presentation at a median age of 61 years
Chronic Lymphocytic Leukemia - Cancer Stat Facts [Internet]. SEER. [cited 2022 May 29]. Available
from: https://seer.cancer.gov/statfacts/html/clyl.html

4. • Males are affected twice than female
• More common in white than black Americans
• Median age at death from CLL of 79 years.
• Strong familial risk factor (5%) +
• Younger age of diagnosis (58 years)
• Similar survival
+Lynn R. Goldin, Susan L. Slager; Familial CLL: Genes and Environment. Hematology Am Soc Hematol Educ Program 2007; 2007

5. Presentation
• Up to 80% of patients are asymptomatic at the time of diagnosis
• Discovered incidentally after CBC due to another reason
• Wide range of signs and symptoms
• Repeated infections- pneumonia, herpes simplex and zoster
• Early satiety and/or abdominal discomfort- splenomegaly (30-54%)
• Mucocutaneous bleeding and/or petechiae- thrombocytopenia.
• Tiredness and fatigue- anemia, AIHA (10%)
• B- symptoms (5-10%)
• Lymph node swelling
Jacque N, Leblond V. [Chronic lymphocytic leukemia]. Presse Med. 2019 Jul-Aug. 48 (7-8 Pt 1):807-815

6. B symptoms
• Unintentional weight loss of 10% or more over the previous 6
months
• Fevers greater than 38°C for more than 2 weeks without evidence
of infection,
• Night sweats more than 4 weeks without any evidence of infection
• Extreme fatigue (ECOG status 2 or greater).
Michael Hall et all, iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of
CLL. Blood 2018; 131 (25): 2745–2760

7. Diagnosis of CLL
Clonal expansion of abnormal B lymphocytes in PB
• At least 5 X 109 B lymphocytes/L (5000/microL)
• Lymphoid cells ≤55% atypical/immature
• Low density of surface Ig (IgM or IgD) with Kappa or Lambda light
chains
• B- cell surface antigènes (CD19, CD20dim, CD23)
• CD5 surface antigen
• Dim expression of CD20 and surface immunoglobulin is highly
characteristic of CLL

8. Prognostic and therapeutic determination:
• FISH to detect: +12; del(11q); del(13q); del(17p)
• TP53 sequencing
• CpG-stimulated metaphase karyotype for complex karyotype (CK)
• IGHV mutation status
• if NA, then by CD38, CD49d, ZAP-70
NCCN Guidelines Version 2.2023

9. IGHV mutation
• percentage of sequence variability between the V region in a clonal CLL
population compared to the homologous germline V region
• How it is done?
• Amplify IGHV transcript by PCR
• sequencing the gene through Sanger sequencing
• comparing the transcript to known germline sequence.
• Interpretation
• Mutated IGVH is classified as ≥2% mutated when compared to germline
• Surrogate markers
• CD38 and ZAP-70 expression by IPT
Tobin, G., Rosenquist, R. Prognostic usage of VH gene mutation status and its surrogate markers and the role of antigen selection in chronic lymphocytic
leukemia. Med Oncol 22, 217–228 (2005)

10. Useful additional workups
• Quantitative immunoglobulins
• Reticulocyte count, haptoglobin, and DCT
• Chest/abdominal/pelvic CT with contrast
• Beta-2-microglobulin
• Uric acid, LDH
• Unilateral bone marrow aspirate + biopsy to rule out immune mediated or disease
related cytopenia
• Hepatitis B and C testing if treatment is planned

11. Rai Staging (1975)
STAGE CLINICAL FEATURES MEDIAN SURVIVAL IN
YEARS
0 (low) Lymphocytosis in blood and
marrow only
>10
I & II (intermediate) Lymphadenopathy, splenomegaly
+/- Hepatomegaly
7
III & IV (high) Anemia, thrombocytopenia 0.75-4
Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia

12. Binet Group (1981)
GROUP CLINICAL FEATURES MEDIAN SURVIVALL
IN YERAS
A Fewer than 3 areas of lymphadenopathy; no
anemia or thrombocytopenia
12
B More than 3 involved node areas; no anemia or
thrombocytopenia
7
C Hemoglobin <100 g/L, platelets <1,00,000/ML 2-4
Binet JL et all. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206.

13. CLL IPI (2016)
ADVERSE FACTORS GRADE
AGE >65 Years age 1
CLINICAL STAGE Rai I-IV/ Binet B-C 1
BETA 2 MICROGLOBULIN >3.5 mg/L 2
IGHV MUTATION STATUS Unmutated (>98% homology with germline) 2
DEL 17p OR TP53 MUTATION Present 4
RISK SCORE 5 YEAR OVERALL SURVIVAL
LOW 0-1 93%
INTERMEDIATE 2-3 79%
HIGH 4-6 63%
VERY HIGH 7-10 23%
An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): A meta-analysis of individual patient data. The Lancet Oncology. 2016;17(6):779–90.

14. PROGNOSTIC INFORMATION FOR CLL
Method of Detection Prognostic Variable Risk Category
Interphase cytogenetics (FISH)
del(17p) Unfavorable
del(11q) Unfavorable
+12 Intermediate
Normal Intermediate
del(13q) (as a sole abnormality) Favorable
DNA sequencing
TP53 Wild-type: Favorable
Mutated: Unfavorable
IGHV >2% mutation: Favorable
≤2% mutation: Unfavorable
CpG-stimulated metaphase
karyotype
≥3 unrelated clonal chromosome abnormalities
in more than one cell on karyotype Unfavorable
NCCN Guidelines Version 2.2023

15. Indications of therapy in Rai Low (O) and Intermediate Risk (I-II)
• Significant disease-related symptoms:
• Fatigue (severe)
• Drenching night sweats
• Unintentional weight loss (≥10% in previous 6 months)
• Fever without infection
• Threatened end-organ function
• Progressive bulky disease (spleen >6 cm below costal margin, lymph nodes >10 cm)
• Progressive anemia
• Progressive thrombocytopenia
• Steroid-refractory autoimmune cytopenia
NCCN Guidelines Version 2.2023

16. • CLL with Rai high (III-IV) risk with cytopenia- indicated for immediate
therapy
v/s iwCLL guideline 2018
• Progressive lymphocytosis
• increase of ≥50% over a 2-month period, or
• lymphocyte doubling time (LDT) <6 months.
• Absolute lymphocyte count alone is not an indication for treatment in
the absence of leukostasis, rare in CLL
• NCCN Guidelines Version 2.2023

17. NCCN Guidelines for treatment of CLL
Version 2.2023

18. For therapeutic purpose CLL patients are categorised into two groups
CLL withoutdel17p/ TP53
mutation
CLL with del17p/ TP53
mutation
• BTK inhibitor (BTKi) ± anti-
CD20 monoclonal antibody
• Venetoclax + anti-CD20 mAb

19. CLL without TP53/del17p on BTKi ± anti-CD20 mAb
Intolerance Response Progression
while on therapy
Venetoclax ±
anti CD 20 mAb
Continue same BTK
till progression
Venetoclax ±
anti CD 20 mAb
as 2nd line of
therapy

20. 1st line therapy regimens
• Preferred regimen
• Alcabrutinib ± Obinutuzumab
• Venitoclax + Obinutuzumab
• Zanbrutinib
• Other recommended regimens
• Ibrutinib
• Ibrutinib + Obinutuzumab
• Ibrutinib + rituximab
• Ibrutinib + venetoclax
Cont..

21. • Bendamustine + anti-CD20 mAb
• Chlorambucil + obinutuzumabl
• Obinutuzumab
• High-dose methylprednisolone (HDMP) + rituximab or
obinutuzumab for patients without significant comorbidities
• Useful in certain circumstances
• IGHV-mutated patients age <65 years
• FCR (fludarabine, cyclophosphamide, rituximab)

22. CLL/SLL WITH DEL(17p)/TP53 MUTATION ON CIT OR IMMUNOTHERAPY
Response after
completion of therapy
Refractory or Progressive
disease
Observe until relapse
with indication of
therapy
Consider treatment with 2nd line agents
Venetoclax ± anti CD 20 mAb
Or
BTKi

23. 1st line therapy regimens with del17p
• Preferred regimens
• Acalabrutinib± obinutuzumab
• Venetoclax + obinutuzumab
• Zanubrutinib
• Other recommended regimens
• Alemtuzumabr ± rituximab
• HDMP + rituximab
• Ibrutinib
• Obinutuzumab
• Ibrutinib + venetoclax
*CIT is not recommended due to low response rates

24. ESMO Guideline for Frontline therapy
2021

25. SYMPTOMATIC EARLY STAGE OR ADVANCED STAGE CLL
IGHV Unmuted
No TP53 mutation
or del 17q
IGHV Mutated
No TP53 mutation
or del 17q
TP53 mutation or
del 17q
Unfit patients
Fit patients
Ibrutinib
CIT, FCR
Ibrutinib
CIT, FCR
• Venitoclax + Obinutuzumab
• Ibrutinib
• Acalabrutinib
• CIT- chlorambucil plus
obinutuzumab
Unfit patients
Fit patients
Ibrutinib
FCR/BR
• Venitoclax + Obinutuzumab
• Ibrutinib
• Acalabrutinib
• CIT- chlorambucil plus
Obinutuzumab
• Ibrutinib
• Acalabrutinib
• Venitoclax +
Obinutuzumab
• Idelalisib +
Rituximab

27. THANK YOU