Chronic leukemia

CML/CLL
MODERATOR :
DR. EFREM HAILE, MD, CONSULTANT INTERNIST,
HEMATOLOGIST, AAU-CHS
DR.GEBEYAW ,CONSULTANT INTERNIST,BDU-CMHS
PRESENTER : MULUGETA(IMR3)
Nove-2024
1
 Outline
 Introduction
 Epidemiology
 Pathogenesis
 Clinical manifestation
 Diagnosis
 Treatment
 Monitoring 2
 CML-Introduction
 CML is a clonal HSC neoplasm, a type of myeloproliferative
disorder
 Driven by the BCR/ABL1 chimeric gene, formed by a t(9;22)
translocation, also known as the Philadelphia chromosome
 It follows a biphasic or triphasic course:
 Pre-TKI Era: Median survival 3-7 yrs; 10 yr survival <30%.
 Introduction of TKIs since 2000 has revolutionized treatment,
with a 10-year survival rate >85%.
 SCT:2nd /3rd -line therapy after TKI failure.
3
 Epidemiology
 Accounts for 15% of all cases of adult leukemia.
 Has an annual incidence of 1 to 2 cases per 100,000 with a slight
male predominance
 The median age at diagnosis is 55-65 years.
 Only 3% of patients are younger than 20 years.
 Incidence increases slowly with age, steeper increase after the age
of 40-50 years.

4
 Etiology
 High doses of ionizing radiation can increase the occurrence of CML
 Populations at risk:
• Japanese atomic bomb survivors : median latent period of 11 years.
• Patients with ankylosing spondylitis treated with spine irradiation: , latent
period ~4 years.
• Women with uterine cervical Ca:latent period ~9 years.
 CML accounted for 20-30% of leukemia cases in these groups
 Chemical Leukemogens: Benzene & alkylating agents not linked to CML
 CML does not generally arise as a secondary malignancy
 No familial associations in CML
5
 Pathophysiology
 Philadelphia Chrom(Ph):t(9;22) translocation occurs in >90% of CML cases
• It results from a balanced reciprocal translocation between the long arms of
chromosomes 9 and 22.
 DNA sequences from the cellular oncogene ABL1 are translocated next to the
major BCR gene on chromosome 22, generating a hybrid oncogene, BCR-ABL1.
• This fusion gene codes for a novel oncoprotein of molecular weight 210 kDa,
referred to as p210BCR-ABL1
 BCR-ABL1 fusion gene forms, leading to a constitutively active tyrosine kinase
(p210 BCR-ABL1).
 It drives excessive cell proliferation and reduces apoptosis, giving CML cells a
growth advantage

6
 ……Pathophysiology
 When the breakpoint in BCR is more centromeric mBCR,
• This fusion gene codes for a novel oncoprotein of molecular weight 190
kDa, referred to as p190 BCR-ABL1 ,predicts worse outcome.
 A third rare breakpoint in BCR occurs telomeric to the major BCR
region and is called micro-BCR (μ-BCR).
• produces a larger p230 oncoprotein, which is associated with a more
indolent CML course.
 P190 has the highest intrinsic kinase activity, followed by p210 and p230 .

7
 Phases of CML
 Based on the number of immature WBC/blasts in blood or BM
• Chronic phase
• Accelerated phase
• Blast phase
 Progression from chronic to accelerated /blast phase is driven by
multiple factors, but the exact mechanisms are not fully understood.

8
 …….con
 Key Mechanisms Driving Progression:
1. BCR-ABL1 TK Overexpression and Constitutive activation
• Promotes uncontrolled cell proliferation & survival, contributing to disease
progression.
2. Differentiation Arrest
• Block in myeloid differentiation leads to an accumulation of immature,
undifferentiated cells, shifting the disease towards more aggressive phases.
3. Genetic Instability & Cytogenetic Abnormalities
• The leukemic clone in CML acquires chromosomal abnormalities (e.g.,
trisomies, Ph duplication), in over 80% of patients as the disease progresses
4. Inactivation of Tumor Suppressor Genes

9
 CLINICAL PRESENTATION
 Onset: generally insidious
 In the U.S, 50-60% of cases are diagnosed through routine blood
tests with minimal symptoms (e.g, fatigue)
 In areas with limited healthcare access, patients may present with
higher disease burden (splenomegaly, anemia, weight loss, fatigue).
 Less Common Symptoms: Thrombotic or hyper viscosity-related
events (priapism, CV issues, visual disturbances, stroke).

10
 …….. CLINICAL
 Features related to granulocyte or platelet dysfunction
 Splenomegaly (20-70%), hepatomegaly (5-10%), LAP(5-10%), extra
medullary disease (skin lesions).
 Progression of CML is associated with worsening symptoms.
 Less than 10-15% of newly diagnosed patients present with
accelerated disease or de novo blastic phase

11
 Laboratory evaluation
 Leukocytosis: Common, ranging from 10–500 × 10⁹/L.
 Basophils and Eosinophils: Frequently increased
 Thrombocytosis: Common; thrombocytopenia is rare and typically
suggests a worse prognosis or disease acceleration.
 Anemia: Present in 1/3rd of patients
 Cyclic Oscillations: Observed in 10-20% of untreated patients,
characterized by fluctuations in cell counts
 Biochemical Abnormalities: Low LAP. Hyperuricemia , Elevated LDH
 PB: Shows left-shifted hematopoiesis with predominance of neutrophils
and various stages of myeloid cells (bands, myelocytes, metamyelocytes,
promyelocytes, and blasts, usually ≤5%). 12
Peripheral smear

13
 Marrow Findings:
• Establish diagnosis, assess marrow blasts,confirm Ph chromosome,
and check for ACAs
• Hyper cellular: 75-90% hematopoietic tissue, with reduced fat
• Granulocytic-to-erythroid ratio 10:1 to 30:1 Vs Normal 2:1 to 4:1
• Erythropoiesis: Decreased; megakaryocytes may be normal or
increased.
• Blasts: Typically ≤5%; >5% suggest disease transformation to
accelerated phase (≥15% blasts).
• Increased collagen and micro vessel density in about half of
patients(Fibrosis)
14
 Cytogenetic and molecular test
 Critical in diagnosis, management and monitoring of CML
 Detect genetic abnormalities associated with CML
 Especially the Ph-chromosome and BCR-ABL1 fusion gene
 Done by
• Conventional cytogenetic analysis (karyotyping)
• Fluorescence in situ hybridization (FISH) analysis
• Reverse transcription polymerase chain Rxn (RT-PCR)

15
 Cytogenetics
• Detects large-scale chromosomal abnormalities via microscope
• Visualizes structural changes (Philadelphia chromosome)
• Sensitivity: Detects ~5% Philadelphia-positive cells
• May miss complex rearrangements and provide false negatives
 FISH
• Direct detection of the chromosomal position of the BCR and ABL1 genes
• Identify complex chromosomal rearrangement that masks t(9;22)
translocation
• Mostly cannot distinguish among different chromosome 22 breakpoints
• Estimates abnormal cell proportion, not exact levels

16
 RT-PCR
• Precisely quantifies specific DNA sequences.
• It is diagnostic test of choice for ph-positive leukemia
• Can detect all variant translocations of ph-chromosome.
• Capable of detection of one Ph +Ve cell in 105-106 normal cells
• Highly sensitive & precise measurement of genetic
abnormalities.
• Used to monitor treatment response & detect MRD after allo-
SCT

17
 DIAGNOSIS
 Identifying the typical findings in the blood and bone marrow
 Confirmed by the demonstration of the Philadelphia
chromosome

18
 ….DIAGNOSIS
 AP-CML
 Number of myoblast increases, and new chromosomal changes or
mutations may occur alongside the Ph chromosome
 Diagnostic criteria include:
• BM/PB Blasts: 10-19%
• Basophils: ≥ 20%.
• Thrombocytopenia <100K/microL
• ACA- Second Ph chromosome,Trisomy 8 ,Isochromosome
17q,Trisomy 19,Abnormalities of 3q26.2
 BP-CML
 Distinguished from AP based on either EM infiltrate or ≥ 20% blast. 19
…DIAGNOSIS

20
 Prognostic Factors
 Unfavorable prognostic factors:
• Accelerated or blast phase CML
• Age ≥ 60 years
• Enlarged spleen
• Platelet > 1,000,000/< 100,000 at diagnosis
• High number of blasts in the blood
• Increased numbers of basophils
 3 prognostic scoring systems are used to assess risk profile of pts at
diagnosis

21
Risk score

22
Pretreatment evaluation Hyperuricemia & Hyper
 CML disease phase leukocytosis
 Prognostic score  Allopurinol : and adequate
 Comorbidities hydration before and during therapy.
 Rasburicase :a recombinant urate
Goals of treatment oxidase, is effective in hours
 Hydroxyurea :
 Achieve remission cure ? • WBC >300 × 109/L
 Maintaining long term control • Symptomatic splenomegally
 Avoid progression to advanced • Systemic symptoms due
phases hyperviscosity syndrome

23
 TREATMENT
 Available treatment options include:
• Tyrosine kinase inhibitors (TKIs)
• Palliative therapy with cytotoxic agents
• Allogeneic hematopoietic cell transplantation (HCT)

24
 TARGETED TREATMENT (TKIs)
 Oral targeted therapies block the BCR::ABL1 protein, stopping CML
cell growth and causing their death.
 First-line TKIs for CP-CML: Imatinib, Dasatinib, Nilotinib, Bosutinib
 Asciminib and Ponatinib are for patients with resistance to 2+ TKIs
or the T315I mutation

25
26
 Selecting Frontline TKI Therapy
1.Aims of Therapy
• Survival: Imatinib and second-generation TKIs are equivalent.
• 2G TKIs may achieve DMR faster, beneficial for younger patients aiming for TFR.
2. Patient Factors
• Age: Younger patients may benefit from 2G TKIs for faster DMR; older patients focus on survival.
• Comorbidities:
• Imatinib: Mild side effects (fatigue, edema, weight gain).
• Dasatinib: Risks of pleural effusion, PAH, bleeding (avoid in heart/lung issues)
• Nilotinib: Hyperglycemia, CV issues, QT prolongation (avoid in diabetes/heart disease)
• Bosutinib: GI and liver issues (avoid in bowel or renal diseases)
3. Affordability-Imatinib is affordable for LR/IR , while 2G TKIs are more expensive, suited for HR or TFR
goals
4. Risk Profile-LR/IR : Imatinib is effective. High Risk: 2G TKIs may offer better early responses

27
 STEM CELL TRANSPLANT
 Option for certain patients, Involves infusion of donor stem cells to
replace diseased BM, Can be curative
 Serious complications, such as graft-vs-host disease and life-
threatening side effects
 Not ideal for older patients or those with other health issues
 TKIs now control CML for long periods with fewer side effects
 Choosing b/n SCT&TKIs depends on response to TKIs and patient
health

28
 …… STEM CELL TRANSPLANT
 Considered for patients with:
• Resistance to 2+ TKIs
• Intolerance to all TKIs
• CML in AP/BP
 Phase of CML at time of transplant is the most important
determinant of long-term survival
• Chronic Phase: 80% disease-free at 5 years
• Accelerated Phase: 40-50% disease-free at 5 years
• Blast Phase: 10-20% disease-free at 5 years.
29
 OTHER TREATMENTS
 Prior to TKIs: Interferon was 1St-line for patients not eligible for SCT
• Today Reserved for patients intolerant to TKIs or those who are pregnant
 Chemotherapy
• Hydroxyurea: Reduces CML burden, temporary or in combination with TKIs.
• Busulfan: Used in SCT regimens; rarely for cCML due to side effects.
• Other Agents: Cytarabine, 6-mercaptopurine, for disease control.
 Other Options
• Splenectomy: Rarely used for splenomegaly.
• Leukapheresis: For extreme leukocytosis.
• High-dose cytarabine/Hydroxyurea: Tumor lysis management.

30
 Response and Monitoring

 Follow-up bone marrow studies at 3, 6, and 12 months are not necessary.

Alternatively FISH and PCR on peripheral blood.
 Optimal Response: If BCR::ABL1 (IS) are <1%, marrow examinations can be
31
omitted.
32
Early Treatment Response Milestones and Follow-up

Recommendation

33
 MONITORING……….
 Most pts achieve CcyR 12 months of imatinib therapy .
 Failure to achieve a CcyR by 12 months or occurrence of later
cytogenetic or hematologic relapse is RX failure.
 Salvage therapy with other TKIs may re-establish good outcome
 Cytogenetic relapse on imatinib is an indication of treatment failure
and need to change TKI therapy
 5-year survival is ~80–90%, which is better than allogeneic SCT

34
 Discontinuation of TKIs&Treatment-Free Remissions
 TFR is when a patient discontinues TKI and maintains a MMR with
BCR::ABL1 levels <0.1%, without needing to restart treatment
 Considered a main goal of treatment for CML patients

Patients should be informed about TFR, potential molecular recurrence, frequent monitoring,
reliable qPCR testing, and the possibility of restarting treatment, along with the risk of TKI
withdrawal syndrome
40-60% of pts relapse within 12 months after stopping TKI therapy, but restarting treatment
35
quickly leads to undetectable disease
 Management of CML in A/B vs Chronic Phase
 At Higher risk of resistance or intolerance to first-line TKIs
 Aggressive Treatment-Use of 2nd-line TKIs, chemo, or SCT
 Frequent Monitoring for disease progression and treatment
adjustments
 Poorer response to TKIs, with higher risk of resistance and relapse.
 Less favorable Prognosis, with increased risk of progression to
acute leukemia and reduced survival

36
 TREATMENT OF ACCELERATED PHASES
 Leukemia cells can acquire new genetic mutations that reduce
treatment effectiveness
 BCR-ABL1 gene mutation analysis is essential before starting Rx
 If No Prior TKI Therapy: Start with approved 2/3G TKIs:
 If CML Progresses During TKI Therapy: Increase TKI dose or switch
to another TKI.

37
 Primary Goal is to Achieve remission by eliminating all cells
containing the BCR-ABL1 gene.
 If Not Achievable- return the disease to the chronic phase for
more manageable treatment options.
 Omacetaxine mepesuccinate: For resistance or intolerance to 2+
TKIs.
 Allogeneic stem cell transplant: For eligible patients.
 Major Hematologic Response (Single TKI): 30-50%

38
 TREATMENT OF BLAST PHASE
 Similar to AL , with higher BCC and more severe symptoms.
 Key Tests Before Starting Treatment:
• Flow Cytometry:Essential for guiding treatment decisions.
• Determines whether blast cells are myeloid or lymphoid.
• BCR::ABL1 Kinase Domain Mutation Analysis:
• Checks for mutations in the BCR::ABL1 gene.
• Mutations can impact resistance to TKIs, influencing drug
choice (e.g., ponatinib, asciminib for T315I mutation).

39
 Treatment Options for Blast Phase CML:
• TKI (± chemo):Preferred drugs: 2G TKIs or ponatinib.
• TKI alone is generally inadequate to revert BP-CML to CP-CML.
Only 31% achieve hematologic response, even with
ponatinib
• Allogeneic SCT :Best chance of long-term remission.
• Most successful if disease is returned to chronic phase
before transplant.
 Best Outcomes: Achieved with a combination of TKI, intensive
chemotherapy, and allo-HSCT
 Long-term survival with allo-HSCT: 15-40% (AP)&10-20% (BP)
40
 Prognosis and Course
 Before the imatinib era, the annual mortality in CML was 10% in the
first 2 years and 15–20% thereafter
 With imatinib it has decreased to 2% in the first 12 years of
observation
 The median survival time was 3–7 years (with hydroxyurea-busulfan
and interferon α)
 Without a curative option like SCT ,CML inevitably progresses to
accelerated or blastic phases, leading to death

41
 ….Prognosis and Course
 Life expectancy of CP-CML pts now approaches that of the general
population.
 In the first 2yrs of TKI therapy transformations are rare (1–2%)
 2G TKIs have reduced the incidence of transformation in the first 2–
3yrs from 6-8% to 2–4% .
 Disease transformation to advanced phase is rare on continued TKI
therapy~ <1% annually in years 4–8 of follow-up.
 Among patients in CcyR survival is similar independent of whether
they achieve a MMR

42
 Atypical CML
 BCR-ABL1-negative MPN characterized by both dysplasia and proliferation
 Not a form of classic CML, though it shares some clinical features
 Associated with cytogenetic abnormalities like trisomy 8 and
isochromosome 17q
 Genetically distinct from classic CML and behaves more aggressively
 TKIs are ineffective; chemotherapy, hypomethylating agents, and SCT are
options
 Affects elderly patients (60-70 years), with a male predominance.
 median survival 10-28 months and a high rate of leukemic transformation
(>15-20% at 5 years)
43
44
45
 References
 Harrison 21st edition
 Williams Hematology, 10th Edition-McGraw Hill
(2021)
 CML 2024 update on diagnosis, therapy, and
monitoring
 Revised LLS-2023
 Up-to-date -2024

46
Thank
you
47
Chronic Lymphocytic
Leukemia

48
 INTRODUCTION

 CLL/SLL is a mature B cell neoplasm characterized by

a progressive accumulation of monoclonal B
lymphocytes.
 The malignant cells seen in CLL and SLL have identical
pathologic and immunophenotypic features.
 The term CLL is used when the disease manifests
primarily in the blood, whereas the term SLL is used
when involvement is primarily nodal
49
 CLL is a heterogeneous disease in terms of natural history,
• Some are asymptomatic and never requiring therapy
• Whereas others present with symptomatic disease, require
multiple lines of therapy, and eventually die of their disease .

50
 EPIDEMIOLOGY
 Commonest type of leukemia in Western,25-35% of all leukemias
 The M:F ratio is 2:1; however equal at the age ≥80
 Incidence rates among males and females in the US~ 6.75 and
3.65 per 100,000/year, respectively.
 The prevalence of CLL has increased over the past decades.
 Globally, there are 191,000 CLL/SLL cases and 61,000 deaths
annually.
 The disease is most common in Caucasians
51
 Risk Factors of CLL
 There are few known risk factors for CLL.
 Include exposure to Agent Orange, benzene, and working in rubber
manufacturing.
 Genetic factors likely play a role in the development of CLL, as
some families have more than one affected family member with
the disease
 The disease generally affects older people

52
 Pathogenesis
 The cell of origin in CLL has not definitively been established.
 The morphology, immunophenotype, and gene expression
pattern of CLL cells are that of a mature B cell
 It has been presumed that the initiating cell is a mature
lymphocyte, perhaps memory B cells with activated BCR
signaling pathway and genetic abnormalities .

53
 ……Pathogenesis
 Defective immune surveillance can cause clonal proliferation of long-lived,
immunologically incompetent CD5+ B lymphocytes
 Involves several steps, with only a minority of cases progressing at each step.
 Steps:
• Establishment of Monoclonal B-cell Lymphocytosis (MBL)
• Progression from MBL to Asymptomatic CLL/SLL
• Progression to Symptomatic CLL/SLL
• Evolution to More Aggressive Disease
 Some patients may develop autoimmune anemia and thrombocytopenia.

54
 Clinical presentation
 Most cases are asymptomatic, diagnosed through lymphocytosis
during routine exams
 Symptoms like fatigue, weight loss, and exercise intolerance are
nonspecific
 B symptoms are rarely present initially,present in later stages of
the disease
 Suggests transformation to large cell lymphoma.
 Increased infection risk, mainly RTI from encapsulated bacteria,
followed by skin and UTI
55
 …….Clinical presentation
 As the disease advances, neutropenia, T-cell deficiency, and
hypogammaglobulinemia heighten
 Resulting in infections from Gram-negative bacteria, fungi, and
viruses (HZ, HSV)
 Most patients have LAP, Splenomegaly (40%) and hepatomegaly
(10%) at diagnosis
 Feelings of fullness, Early satiety

56
 Laboratory
 CBC  Diagnostic CT
• WBC- 10- 500,000 • Chest,Abdomen ,Pelvis
• Anemia, TCP  Pregnancy test
 Coomb’s
test,LDH,Haptoglobin,Reticulocy
te count
 RFT,LFT
 PICT,HBsAg,HCV-ab
 CXR
57
58
 Immunophenotype
Flow cytometry : is a key component to the diagnosis of CLL .
 Most cases can be identified using a panel of antibodies specific for CD5,
CD19, CD20, CD23, and kappa and lambda immunoglobulin light chain.
 There are three major sets of characteristic immunophenotypic findings :
• Expression of the B cell-associated antigens CD19, CD20, and CD23.
• Expression of CD5, an antigen expressed on T cells and subsets of mature B cells.
• Expression of low levels of surface membrane immunoglobulin.
 The presence of CD23,CD200 and CD5+ are useful to differentiate CLL
from mantle cell lymphoma.
 CLL cells lack CD79b

59
FISH:
 Can be performed with peripheral blood lymphocytes and identifies
cytogenetic lesions in 80% of cases.
 Chromosome changes to be testing for:
• Del(13q): Missing parts of chro-13, Favorable outcome.
• Del(17p): Missing parts of chro-17, linked to TP53 gene mutation,
high-risk CLL, poor response to treatment.
• Del(11q): Missing parts of chro-11, associated with higher-risk
disease.
 Molecular analysis to detect/ IGHV mutation /ZAP-70 and CD38 .
60
 B2-microglobulin-small protein found in most cell ,released by B-cell
into blood ,high level=CLL is growing
 BM examination-not needed routinely unless there is an indication
 LN biopsy-only when SLL/transformation to DLBL suspected (Ritcher’s
transformation)

61
 Diagnosis
 Using the 2018 iwCLL guidelines, when both of the following
criteria are met:
 Peripheral Clonal B lymphocytes >5000/µL for at least 3 months.
 The following Typical Immunophenotypic Pattern for CLL
• CD19+, CD5+, CD20+ (low), CD23+, kappa or lambda (light
chain restriction)
 MBL:<5000/µL B lymphocytes, with no cytopenias /organomegaly
• Can progress to CLL at 1-2% per year.

62
 …Diagnosis
 The classification of patients with clonal B lymphocytes and ALC
<5000/µL depends on the number & type of manifestations
• Patients with cytopenias due to BM infiltration with typical CLL
cells are diagnosed with CLL regardless of the ALC or the
presence of LAP
• Patients with nodal, splenic, or other extra medullary
involvement, without cytopenias due to BM infiltration, are
diagnosed with SLL.
 BMA:Not required for initial diagnosis, Useful to determine if
cytopenias are due to leukemic infiltration
63
STAGING SYSTEMS of CLL

64
64
Prognostic Markers in CLL

65
65
 Management -CLL
Indications
 Asymptomatic Early-Stage Disease (Rai 0, Binet A):
• Monitor without therapy unless progression
• Early treatment does not improve survival
 Intermediate- and High-Risk Disease (Rai I-IV, Binet B or C)
• Treatment usually required
• But some patients (especially Rai intermediate or Binet B) can be monitored
until evidence of symptoms appear
 Symptomatic / active disease with iwCLL criteria

Monitoring-CBC and Clinical examination

Q3 mnths for the first 12 months, then every 6-12 months 66
 iwCLL criteria for Active disease-At least 1
1. Progressive marrow failure:Hb <10 g/dL or (plts <100 K).
2. Massive or symptomatic splenomegaly >6 cm
3. Massive or progressive LAP (nodes >10 cm).
4. Progressive lymphocytosis: ≥50% increase over 2 months or lymphocyte
doubling time <6 months.
5. Autoimmune complications: Anemia or thrombocytopenia unresponsive to
steroids.
6. Extra nodal involvement: Skin, kidney, lung, spine.
7. Disease-related symptoms:
• Weight loss ≥10% in 6 months.
• Fatigue (ECOG 2+).
• Persistent fevers (>38°C) or night sweats >1 month. 67
 Autoimmune Complications-Managed with GCs and
immunosuppressive before definitive CLL treatment.
 Leukostasis -Rare ; elevated WBC is not a sole indication for Rx
 Hypogammaglobulinemia -Not a reason to initiate therapy.
• IV Ig for recurrent infections

68
 Initial management
Principles of treatment Goals to control disease, not cure
 Active observation  Slow CLL cell growth
 Supportive care  Achieve long remission periods
 Standard drug therapies  Improve survival
• Chemo Vs. targeted  Manage symptoms and
 Stem cell transplantation complications

Treatment options depend on age, fitness, and health

69
 Some Drugs for the Treatment of CLL
 Targeted Therapies: Attack specific cancer cell substances with minimal
harm to healthy cells, milder side effects
• Ex: Ibrutinib, Idelalisib, Venetoclax.
 Monoclonal Ab: Use lab-made ab to kill CLL cells, milder side effects
• Ex: Rituximab, Obinutuzumab ,Alemtuzumab)
 Chemotherapy: Designed to kill cancer cells.
• Ex: Cladribine, Fludarabine, Cyclophosphamide
 Chemoimmunotherapy : Combine chemo with targeted therapies
• FCR (Fludarabine, Cyclophosphamide, Rituximab).

70
71
72
 Response definition

 Timing of Response Assessment

• Chemoimmunotherapy: Assess at least 2 months after therapy
completion.
• For maintenance therapies, assess at least 2 months after achieving
maximum response
• No therapy interruption needed for response assessment
 Response Parameters
• Group A: Assess lymphoid tumor load and constitutional symptoms.
• Group B: Assess hematopoietic system (e.g., bone marrow, blood counts).
• Response should be sustained for at least 2 months before assessment.
73
 Clinically beneficial response- CR and PR
 All other outcomes (SD, NR, PD , or death) are considered
treatment failures
 Relapse is disease progression in a patient who had CR or [R for
over 6 months.

74
 Relapse treatment
 Currently, the mainstays of treatment for relapsed CLL are
the same classes as initial therapy.
 The sequence of either BTK inhibitor and then BCL2 inhibitor
or the reverse are both acceptable.
 PI3K inhibitors also have activity in relapsed CLL following
both BTK and BCL2 inhibitors is likely minimal.

75
 Disease Complication
 Infection
 Autoimmune Complications
 Secondary Malignancies
 Richter Transformation

76
 References
 Harrison 21st edition
 CML 2024 update on diagnosis, therapy, and
monitoring
 iWcll guidelines for diagnosis, indications for treatment,
response assessment, and supportive management of
CLL 2018
 Up-to-date -2024
 NCCN CLL Guideline 2024

77
Thank
you
78