91 Chronic Lymphocytic Leukemia Flashcards
The diagnosis of CLL requires the presence of at least ________ circulating monoclonal B cells/L with clonality demonstrated by flow cytometry
5 × 109
The American Cancer Society estimates a median age of diagnosis of CLL to be
70 years
More common in men
Americans of European descent > Americans of African descent»_space; Americans of Asian descent
The InterLymph study identified multiple factors that were associated with the presence of CLL:
(1) having a family history of a first-degree relative with hematologic malignancy including a lymphoma, leukemia, or myeloma;
(2) having a history of working or living on a farm;
(3) being a hairdresser;
(4) having a history of hepatitis C infection
Factors that were found to decrease the likelihood of the disease
(1) a history of allergies
(2) having had blood transfusions
(3) having exaggerated sun exposure, and
(4) being a smoker
The only type of common adult leukemia not related to radiation
CLL
The most common cytogenetic abnormality in patients with CLL
del 13q14
2nd most common cytogenetic abnormality in patients with CLL
trisomy 12
50%
3rd most common cytogenetic abnormality in patients with CLL
del 11q22.3
15-20%
Mutation that tend to have more aggressive disease, with bulky lymphadenopathy and poorer outcomes
del 11q22.3
10-15%
Mutation that do not respond to cytotoxic therapy and have a higher risk of Richter transformation to more aggressive lymphomas over the course of their disease; they also have a high frequency of genomic instability with complex karyotypes
del 17p13.1
tumor protein p53 (TP53) gene
BTK inhibitor
Ibrutinib
PI3K isoform delta inhibitors
Idelalisib and duvelisib
The median age at diagnosis
70 years
Flow cytometry for immunophenotyping the B cells in CLL
- positive for CD19
- dim CD20
- dim surface immunoglobulin
negative for CD10, CD79b, and FMC7
Isolated lymph node involvement by cells of comparable morphology and immunophenotype, without blood elevation, are classified as
Small lymphocytic lymphoma (SLL)
Marker uniformly expressed on CLL and SLL and, less commonly, on most other B-cell malignancies
CD200
Patients can also have large prolymphocytes with prominent nucleoli in the blood, but these lymphocytes must be less than _______of the total lymphocyte population to still be considered CLL
55%
TRUE OR FALSE
A marrow aspirate and biopsy are required to establish a diagnosis for the vast majority of patients with CLL at initial presentation
FALSE
A marrow aspirate and biopsy are not required to establish a diagnosis for the vast majority of patients with CLL at initial presentation
A marrow aspirate and biopsy are recommended in patients with anemia and thrombocytopenia to evaluate the presence of autoimmune hemolytic anemia and/or immune thrombocytopenia.
TRUE OR FALSE
Lymph node biopsy is not typically required for further establishment of the diagnosis of CLL.
TRUE
Lymph node biopsy is not typically required for further establishment of the diagnosis of CLL.
Lymph nodes typically show architectural effacement by diffuse infiltration by cells of a similar morphology as observed in the blood.
The minimum FISH panel should include assessment for
del 17p13, del 11q23, trisomy 12, and del 13q14, and for t(11;14) to exclude mantle cell lymphoma
Patients with atypical presentations, especially those with absent or low CD23 expression should have a negative FISH study for t(11;14) to exclude mantle cell lymphoma.
Conventional stimulated karyotype analysis is helpful in identifying the global structural abnormalities in chromosomes, especially of ________________ that cannot be routinely detected on FISH analysis, and also identifying chromosome complexity.
Chromosomes 14, 3, and 6
Patients with CLL acquire additional cytogenetic abnormalities/ “clonal evolution” ; this is predominantly observed in patients with
Unmutated IGHV
It is therefore recommended that the stimulated karyotyping and FISH studies are repeated before the initiation of a new line of treatment.
Gene associated with potential familial predisposition
POT1
Gene associated with development of Richter syndrome
NOTCH1, XPO1
The only recommended gene for assessment by the National Comprehensive Cancer Network (NCCN) and iwCLL guidelines
TP53 mutation
TP53 mutation and/or deletion represents the strongest predictor of poor outcome relative to treatment-free survival, response duration, and OS for new targeted therapies, and development of Richter transformation.
The assessment of IGHV somatic mutation is made by
Polymerase chain reaction–based assay
Patients with less than 2% homology in their nucleotide sequence compared with consensus germline sequence are considered to have unmutated IGHV.
Mutated or unmuntated IGHV
Have a significantly prolonged treatment-free interval, longer remission durations, and OS
These patients also have a very low incidence of clonal evolution or transformation to an aggressive histology
Mutated IGHV
The IGHV mutation status does not vary over time and serves as a reliable marker for predicting longterm disease outcomes.
**The only currently known exception to the “mutation rule” **
IGHV 3–21
Confer an aggressive phenotype similar to leukemic cells from patients with unmutated IGHV
An intracellular tyrosine kinase that is typically associated with T-cell development and Tcell receptor signaling and represents the most commonly referred to surrogate for IGHV
Zeta-chain–associated protein kinase of 70 kDa (ZAP-70)
Cytoplasmic assessment of ZAP-70 in CLL B cells by flow cytometry correlates strongly with IGHV mutational status and clinical outcomes, with an expression of 20% or more predictive of poor outcomes.
The NCCN guidelines do not recommend the routine use of ZAP-70 as a prognostic marker outside of clinical trials.
A 45-kDa transmembrane glycoprotein that can be detected on the surface of CLL B cells by flow cytometry; a level of expression greater than 30% correlates strongly with progression-free survival (PFS)
CD38
CD38 is found to be strongly associated with other unfavorable prognostic factors but is not an independent prognostic factor
A surface subunit of the integrin heterodimer that is involved in promoting survival of the CLL cells through growth signals derived from the microenvironment
CD49d
Aggressive disease course and inferior survival
The iwCLL states that less than _______ months doubling time is an indicator for treatment, but this particular indicator is controversial among CLL experts.
6 months
Unfavoable Prognostic Factors
- LDH elevated
- Lymphocyte doubling time ≤12 months
- Thymidine kinase activity elevated
- β2-microglobulin elevated
- Soluble CD23 levels elevated
- CD38 expression >30%
- Cytigenetics: 11q– 17p–
- IGHV mutational status: Unmutated (≥98%)
- CD49d expression >30%
- TP53 mutation: Mutated
- Stimulated Karyotype: Complex
- Zap-70 Expression Present in >20%
Factors included in CLL international prognostic index
- TP53 status or del[17p] (no abnormalities vs del[17p] or TP53 mutation or both)
- IGHV mutational status (mutated vs unmutated)
- serum β2-microglobulin (≤3.5 mg/L vs >3.5 mg/L)
- Clinical stage (Binet A or Rai 0 vs Binet B-C or Rai I-IV)
- Age (≤65 years vs >65 years)
2Clinical-3labs AS-BIT
Modified Rai Clinical Staging System
- 0 - Lymphocytosis >5 × 109/L only
- 1- Lymphocytosis + lymph node (LN) enlargement
- 2- Lymphocytosis + spleen/liver (S/L) enlargement ± LN
- 3- Lymphocytosis + anemia (with hemoglobin <110 g/L) ± LN or S/L
- 4- Lymphocytosis + thrombocytopenia (< 100 × 109/L) ± LN or S/L
Binet Clinical Staging System
- A- Lymphocytosis >5 × 109/L only with <3 enlarged nodal areas; no anemia, no thrombocytopenia
- B- Lymphocytosis >5 × 109/L + ≥3 enlarged nodal areas; no anemia, no thrombocytopenia
- C- Lymphocytosis >5 × 109/L + anemia (hemoglobin <100 g/L) or thrombocytopenia (<100 × 109/L) regardless of the number of enlarged nodal areas
*Nodal areas counted as one each of the following: axillary, cervical, inguinal lymph nodes (whether unilateral or bilateral), spleen, and liver.
TRUE OR FALSE
Computed tomography (CT) scans are generally not required for the routine initial evaluation of patients with CLL because conventional staging systems rely on physical examination findings.
TRUE
Computed tomography (CT) scans are generally not required for the routine initial evaluation of patients with CLL because conventional staging systems rely on physical examination findings.
Similarly, a positron emission tomography (PET) scan has no role in the routine management of patients with CLL outside of trying to exclude an alternative diagnosis.
CLL lymph nodes are fluorodeoxyglucose non-avid
Treatment of patients with CLL is initiated at
Time of symptomatic progressive disease
