91 Chronic Lymphocytic Leukemia Flashcards
1
Q
The diagnosis of CLL requires the presence of at least ________ circulating monoclonal B cells/L with clonality demonstrated by flow cytometry
A
5 × 109
2
Q
The American Cancer Society estimates a median age of diagnosis of CLL to be
A
70 years
More common in men
Americans of European descent > Americans of African descent»_space; Americans of Asian descent
3
Q
The InterLymph study identified multiple factors that were associated with the presence of CLL:
A
(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
4
Q
Factors that were found to decrease the likelihood of the disease
A
(1) a history of allergies
(2) having had blood transfusions
(3) having exaggerated sun exposure, and
(4) being a smoker
5
Q
The only type of common adult leukemia not related to radiation
A
CLL
6
Q
The most common cytogenetic abnormality in patients with CLL
A
del 13q14
7
Q
2nd most common cytogenetic abnormality in patients with CLL
A
trisomy 12
50%
8
Q
3rd most common cytogenetic abnormality in patients with CLL
A
del 11q22.3
15-20%
9
Q
Mutation that tend to have more aggressive disease, with bulky lymphadenopathy and poorer outcomes
A
del 11q22.3
10-15%
10
Q
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
A
del 17p13.1
tumor protein p53 (TP53) gene
11
Q
BTK inhibitor
A
Ibrutinib
12
Q
PI3K isoform delta inhibitors
A
Idelalisib and duvelisib
13
Q
The median age at diagnosis
A
70 years
14
Q
Flow cytometry for immunophenotyping the B cells in CLL
A
- positive for CD19
- dim CD20
- dim surface immunoglobulin
negative for CD10, CD79b, and FMC7
15
Q
Isolated lymph node involvement by cells of comparable morphology and immunophenotype, without blood elevation, are classified as
A
Small lymphocytic lymphoma (SLL)
16
Q
Marker uniformly expressed on CLL and SLL and, less commonly, on most other B-cell malignancies
A
CD200
17
Q
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
A
55%
18
Q
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
A
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.
19
Q
TRUE OR FALSE
Lymph node biopsy is not typically required for further establishment of the diagnosis of CLL.
A
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.
20
Q
The minimum FISH panel should include assessment for
A
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.
21
Q
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.
A
Chromosomes 14, 3, and 6
22
Q
Patients with CLL acquire additional cytogenetic abnormalities/ “clonal evolution” ; this is predominantly observed in patients with
A
Unmutated IGHV
It is therefore recommended that the stimulated karyotyping and FISH studies are repeated before the initiation of a new line of treatment.
23
Q
Gene associated with potential familial predisposition
A
POT1
24
Q
Gene associated with development of Richter syndrome
A
NOTCH1, XPO1
25
The only recommended gene for assessment by the National Comprehensive Cancer Network (NCCN) and iwCLL guidelines
TP53 mutation
## Footnote
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.
26
The assessment of IGHV somatic mutation is made by
Polymerase chain reaction–based assay
## Footnote
Patients with **less than 2% homology** in their nucleotide sequence compared with consensus germline sequence are considered to have **unmutated** IGHV.
27
# 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
28
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
## Footnote
Confer an aggressive phenotype similar to leukemic cells from patients with unmutated IGHV
29
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)
## Footnote
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.*
30
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
## Footnote
CD38 is found to be strongly associated with other unfavorable prognostic factors but is not an independent prognostic factor
31
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
## Footnote
Aggressive disease course and inferior survival
32
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
33
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%
34
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
35
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
36
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
## Footnote
*Nodal areas counted as one each of the following: axillary, cervical, inguinal lymph nodes (whether unilateral or bilateral), spleen, and liver.
37
# 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.
## Footnote
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
38
Treatment of patients with CLL is initiated at
Time of symptomatic progressive disease
39
Treatment for autoimmune complications of CLL
Glucocorticoids and immunosuppressive therapies
## Footnote
Before proceeding with definitive therapy for the underlying disease.
40
# TRUE OR FALSE
An elevated white cell count should be used as a criterium for initiating treatment
FALSE
An elevated white cell count should virtually never be used as the sole criterium for initiating treatment
## Footnote
Patients with CLL rarely exhibit evidence of leukostasis resulting from profound leukocytosis
41
Treatment for hypogammaglobulinemia and recurrent life-threatening infections
Periodic IV immunoglobulin infusions
## Footnote
Hypogammaglobulinemia should not be used as a reason to treat the disease.
42
Used as the prominent alkylating agent for the treatment of CLL until 2000
Chlorambucil
43
# TRUE OR FALSE
Chlorambucil as monotherapy in CLL is virtually never used.
TRUE
Chlorambucil as monotherapy in CLL is virtually never used.
44
Regimen for older patients who are unable to take novel targeted therapies because of their cost, comorbidities, or contraindications
Chlorambucil + CD20 antibody obinutuzumab
## Footnote
Inferior to ibrutinib plus obinutuzumab, acalabrutinib plus obinutuzumab, and venetoclax plus obinutuzumab, and is therefore not a preferred regimen
45
Alkylating agent with superior efficacy compared with chlorambucil
Has features common with alkylating agents and purine analogues, but its activity is primarily derived from the alkylating agent moiety
Bendamustine
46
# TRUE OR FALSE
Bendamustine plus rituximab is used in the treatment of CLL because of multiple phase 3 studies showing it to be superior to fludarabine, rituximab, and cyclophosphamide; ibrutinib, acalabrutinib, or venetoclax plus rituximab.
FALSE
Bendamustine plus rituximab is **used in the treatment of lymphoma but is rarely used in CLL** because of multiple phase 3 studies showing it to be **inferior** to fludarabine, rituximab, and cyclophosphamide; ibrutinib, acalabrutinib, or venetoclax plus rituximab.
47
Used for the treatment of patients with **IGHV-mutated CLL** who desire time-limited therapy and also have the potential of cure.
Fludarabine, cyclophosphamide, and rituximab
## Footnote
Fludariabine + chemotherapy is used for lymphodepletion given to patients with CLL **before chimeric antigen receptor T cells** or **allogeneic hematopoietic stem cell transplant**
48
A **CD52**-targeting, humanized, monoclonal antibody that mediates its efficacy through direct cytotoxicity, complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)
Alemtuzumab
## Footnote
Extremely effective in **clearing the blood and marrow of disease** and is also active in patients with **del 17p disease**
**Limited efficacy in patients with bulky lymphadenopathy**, especially in patients with lymph nodes that are greater than 5 cm in diameter
Only rarely used in patients with **CLL who have nonbulky nodal relapsed disease**
No longer actively marketed for CLL
49
CD20 Targeting Antibodies
Rituximab
Ofatumumab
Obinutuzumab
50
The most common toxicity of Rituximab
Infusion reactions
## Footnote
Predominantly observed with the first dose
51
The infusion reactions can be minimized with:
Prophylactic acetaminophen, antihistamine, and glucocorticoid, and by slowing the infusion rate.
52
Important and potentially severe toxicity of Rituximab
Tumor lysis syndrome
## Footnote
Prophylactic hydration, allopurinol, and electrolyte monitoring during and after the first infusion.
53
A fully human, **type 1, IgG1, CD20-targeting**, monoclonal antibody that binds more effectively to a different epitope of CD20 than rituximab.
Ofatumumab
## Footnote
Monotherapy, both as maintenance in patients who had received at least two lines of therapy and in patients with CLL refractory to fludarabine and alemtuzumab
In combination with chemotherapy, it is approved as initial therapy with chlorambucil and as second or greater-line therapy with fludarabine and cyclophosphamide.
54
A fully humanized, **type II, IgG1** antibody with additional structural modifications that explain its enhanced activity.
Obinutuzumab
## Footnote
A **better CD20 antibody in combination with chemotherapy** and set a new (but now surpassed) standard of care in this large subset of **older and unfit adults with CLL**
55
Antibody of choice when chemoimmunotherapy is **used with chlorambucil**
Obinutuzumab
56
# TRUE OR FALSE
Unlike rituximab or ofatumumab, where infusion events occur 1 to 2 hours into therapy, those with obinutuzumab typically occur within the first 5 to 10 minutes of starting therapy.
TRUE
Unlike rituximab or ofatumumab, where infusion events occur **1 to 2 hours** into therapy, those with obinutuzumab typically occur within the first **5 to 10 minutes** of starting therapy.
57
An **irreversible inhibitor of BTK** and covalently binds to Cys-481 near the ATP binding domain of the BTK molecule, and abrogates enzyme activity and BCR-mediated survival signals.
Has the ability to irreversibly target IL-2–inducible T-cell kinase in T cells and other Tec family kinases
Ibrutinib
58
With Ibrutinib, side effects generally decreased with time, with the notable exception of__________________, which became more frequent over the course of observation
Hypertension
## Footnote
Toxicity with ibrutinib consisted of **bruising/hemorrhage, atrial fibrillation, rash, gastrointestinal symptoms (diarrhea, nausea), infections, and cytopenias**
59
The **bleeding diathesis** observed with ibrutinib is possibly caused by _______
Collagen-mediated platelet aggregation defect
## Footnote
Potentially exacerbated by anticoagulation therapy—particularly warfarin
60
Approved in 2014 for the treatment of all patients with **relapsed CLL** and for the treatment of all patients with **del 17p CLL**
Used in **untreated** patients as **monotherapy** or **together with obinutuzumab or rituximab**
Ibrutinib
61
A study that compared **ibrutinib with chlorambucil** in previously untreated patients, aged 65 years or older, with CLL
Resonate 2 study
62
# TRUE OR FALSE
Treatment with ibrutinib does not result in CR in most patients.
TRUE
Treatment with ibrutinib does not result in CR in most patients.
## Footnote
Virtually all patients with CLL are sensitive to ibrutinib and failure to respond should prompt reexamination of the histology.
63
The _______ variant (and rare others) occurs in more than 80% of patients who develop ibrutinib-resistance.
C481S variant
64
A second-generation, covalent-binding BTK inhibitor that is more selective and has pharmacologic features (very short half-life) that requires dose administration twice daily.
Acalabrutinib
65
Most common adverse effect of Acalabrutinib
**Diarrhea** (52%) and **headache** (51%)
Others:
Grade 3 or greater neutropenia (14%), pneumonia (11%), and hypertension (7%)
66
An orally bioavailable, first-in-class isoform **selective PI3K-δ inhibitor** that promoted apoptosis of CLL B cells ex vivo, along with abrogating the survival signals provided by the microenvironment
Idelalisib
67
Adverse effects of Idelalisib
**Pneumonia** (20%), neutropenic fever (11%), and diarrhea (6%)
## Footnote
Serious toxicities observed with idelalisib included **transaminase elevations, diarrhea with colitis, and pneumonitis**
68
Targeted therapy for CLL that is **not associated with increasing bleeding risk** and does represent an option for patients on warfarin or with other bleeding predispositions
Idelalisib
69
A small-molecule inhibitor of **phosphoinositide 3-kinase-δ (PI3K-δ) at low doses (25 mg orally BID)** and **PI3K-δ and PI3K-γ at higher doses (75 mg orally BID)**
FDA approvedl for use in patients with **relapsed CLL who have received two prior therapies**.
Duvelisib
## Footnote
Used infrequently for the treatment of CLL and, as with idelalisib, it is mainly used in settings where **BTK inhibitors are contraindicated**.
Toxicity of this agent was very similar to that observed with idelalisib, reproducing many of the same side effects (liver function elevation, pneumonitis, diarrhea, and rash).
70
An oral, potent **BH3-mimetic** that targets **BCL-2** with selectivity
Venetoclax
## Footnote
Ramp-up dosing schedule from **20 mg to 400 mg over a five-week period**
71
Most common treatment-emergent grade 3 or 4 adverse events with use of Venetoclax
Neutropenia (51%), thrombocytopenia (29%), and anemia (29%)
72
An outstanding salvage therapy for ibrutinib refractory CLL
Venetoclax
73
# TRUE OR FALSE
Autologous transplantation has a role in the management of CLL
FALSE
Autologous transplantation has **no role** in the management of CLL
## Footnote
In contrast, allogeneic SCT offers a curative approach for patients with CLL, but its utility and timing are currently under considerable debate given the availability of multiple novel agents.
74
Indications for splenectomy
* Refractory autoimmune hemolytic anemia and thrombocytopenia
* Symptomatic splenomegaly
75
# TRUE OR FALSE
Systemic radiation or extracorporeal photopheresis has no role in the management of patients with CLL.
TRUE
Systemic radiation or extracorporeal photopheresis has **no role** in the management of patients with CLL.
## Footnote
**Involved field radiation therapy** is an extremely useful treatment modality for the management of locally symptomatic lymphadenopathy and isolated Richter transformation.
**Splenic irradiation** can be used in patients with symptomatic splenomegaly
76
Evaluation of the **marrow aspirate and biopsy** is also useful in assessing the etiology of cytopenias that can be seen frequently after chemotherapy use, although it is generally advisable to wait for **_ months** after chemotherapy to see whether spontaneous recovery occurs.
3 to 6 months
77
Patients with a remission but with persistent cytopenias related to drug toxicity are classified as having
CR with incomplete marrow recovery
78
Patients will have no evidence of disease on flow cytometry of the aspirate or on the biopsy specimen but may have nodular lymphoid aggregates
Nodular partial remission
79
Recommended as initial therapy in **younger, fitter patients with IGHV-mutated disease with intact TP53**
Immunochemotherapy (FCR)
## Footnote
However, higher rates of “deep” CRs can be achieved with combinations such as **venetoclax and ibrutinib**
80
Recommended for patients with **IGHV-unmutated disease or patients not suitable for FCR**
BTK inhibitor (ibrutinib or acalabrutinib), with or without a CD20 antibody
81
Recommended for patients for whom **BTK inhibitors are inappropriate** or patients who **desire time-limited therapy**
Venetoclax plus obinutuzumab
## Footnote
Given the short follow-up that exists with venetoclax trials currently, this is not a first choice.
82
# TRUE OR FALSE
Patients whose first response lasts more than three years before relapse/progression, can be retreated with the same treatment that was used initially
TRUE
Patients whose first response lasts **more than three years** before relapse/progression, can be retreated with the same treatment that was used initially
83
Treatment of choice in both younger and older patients who had not previously received BTK Inhibitor
Ibrutinib
84
One of the most common cancers seen in patients with CLL
Skin cancer
## Footnote
This includes basal cell carcinoma, squamous cell carcinoma, cutaneous melanoma, and Merkel cell carcinoma.
85
# TRUE OR FALSE
CLL in patients with progressive disease can lead to hypogammaglobulinemia that results in a higher incidence of infections with encapsulated organisms like Streptococcus pneumoniae and Haemophilus influenzae.
TRUE
CLL in patients with progressive disease can lead to **hypogammaglobulinemia** that results in a higher incidence of infections with **encapsulated organisms** like Streptococcus pneumoniae and Haemophilus influenzae.
## Footnote
**Hypogammaglobulinemia is universally present** in patients with CLL and progressively worsens with advancing stage of the disease.
86
Can be administered for hypogammaglobulinemia- significant reduction of major infections requiring intensive supportive care and a modest reduction in the incidence of clinically significant infections.
Intravenous immunoglobulin (IVIG) at doses of 250 to 600 mg/kg administered every 4 to 6 weeks
87
# TRUE OR FALSE
The routine of use of granulocyte colony-stimulating factor for patients with CLL is recommended.
FALSE
The routine of use of granulocyte colony-stimulating factor for patients with CLL is NOT recommended.
## Footnote
Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor can be used to treat therapy-related neutropenia and for patients with febrile neutropenia to shorten the duration and severity of illness
88
# TRUE OR FALSE
Vaccination with live virus vaccines including the zoster, varicella, and measles-mumps-rubella (MMR) vaccine is contraindicated in patients with CLL
TRUE
Vaccination with **live virus vaccines** including the zoster, varicella, and measles-mumps-rubella (MMR) vaccine is **contraindicated** in patients with CLL
89
The mainstay of treatment for immune hemolytic anemia and immune thrombocytopenia.
Glucocorticoids
0.5 to 1.0 mg/kg per day for 2 to 3 weeks followed by a slow taper over several weeks
## Footnote
It is best to first treat the autoimmune complication and then the CLL if symptoms persist.
90
Treatment options for immune complications of CLL that have disease relapse after discontinuation of steroids
IVIG or rituximab
Cyclosporine
Thrombopoietin agonists (immune thrombocytopenia)
91
Defined as a transformation of CLL into an a**ggressive, high-grade, large B-cell non-Hodgkin lymphoma**
The syndrome is characterized by rapid development of **B symptoms** and rapidly progressive **lymphadenopathy**
Richter transformation
## Footnote
Patients typically have complex karyotype and involvement of TP53, ATM, RB (retinoblastoma), and MYC genes.
Transformation occurs independent of disease stage, duration of disease, type of therapy, or response to therapy
92
# TRUE OR FALSE
PET scans have generally no role in the management of patients with CLL but can be very useful in the diagnosis of transformation.
TRUE
**PET** scans have generally no role in the management of patients with CLL but can be very **useful in the diagnosis of transformation.**
93
Prognosis of Richter transformation is related to
The clonality of the malignant clone
## Footnote
Patients with **clones unrelated to the CLL tend to have a much better prognosis** than patients with clonally related disease
Patients who present with **Richter transformation before treatment for their CLL** often have a **better** outcome.
94
# TRUE OR FALSE
Patients with Hodgkin lymphoma have a similar outcome to de novo disease when matched by stage and can be treated with adriamycin, bleomycin, vinblastine, and dacarbazine–based therapy
TRUE
Patients with **Hodgkin lymphoma have a similar outcome to de novo disease** when matched by stage and can be treated with adriamycin, bleomycin, vinblastine, and dacarbazine–based therapy
95
Patients can also experience transformation to **prolymphocytic leukemia (PLL)**, characterized by the presence of ______________prolymphocytes in the marrow
more than 55%
96
PLL transformation is similar to the distinct entity of B-cell PLL, which is characterized by subacute accumulation of prolymphocytes in a predominantly **older**, **male** population with presence of what cytogenetic abnormalities:
chromosome 14q abnormalities and del 17p
97
Have **less than 5 × 109 B lymphocytes//L** in their blood, and an absence of B symptoms, lymphadenopathy, organomegaly, or cytopenias.
Monoclonal B-cell lymphocytosis
## Footnote
Patients are predisposed to a higher frequency of infections and also secondary malignancies
