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
Treatment for autoimmune complications of CLL
Glucocorticoids and immunosuppressive therapies
Before proceeding with definitive therapy for the underlying disease.
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
Patients with CLL rarely exhibit evidence of leukostasis resulting from profound leukocytosis
Treatment for hypogammaglobulinemia and recurrent life-threatening infections
Periodic IV immunoglobulin infusions
Hypogammaglobulinemia should not be used as a reason to treat the disease.
Used as the prominent alkylating agent for the treatment of CLL until 2000
Chlorambucil
TRUE OR FALSE
Chlorambucil as monotherapy in CLL is virtually never used.
TRUE
Chlorambucil as monotherapy in CLL is virtually never used.
Regimen for older patients who are unable to take novel targeted therapies because of their cost, comorbidities, or contraindications
Chlorambucil + CD20 antibody obinutuzumab
Inferior to ibrutinib plus obinutuzumab, acalabrutinib plus obinutuzumab, and venetoclax plus obinutuzumab, and is therefore not a preferred regimen
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
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.
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
Fludariabine + chemotherapy is used for lymphodepletion given to patients with CLL before chimeric antigen receptor T cells or allogeneic hematopoietic stem cell transplant
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
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
CD20 Targeting Antibodies
Rituximab
Ofatumumab
Obinutuzumab
The most common toxicity of Rituximab
Infusion reactions
Predominantly observed with the first dose
The infusion reactions can be minimized with:
Prophylactic acetaminophen, antihistamine, and glucocorticoid, and by slowing the infusion rate.
Important and potentially severe toxicity of Rituximab
Tumor lysis syndrome
Prophylactic hydration, allopurinol, and electrolyte monitoring during and after the first infusion.
A fully human, type 1, IgG1, CD20-targeting, monoclonal antibody that binds more effectively to a different epitope of CD20 than rituximab.
Ofatumumab
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.
A fully humanized, type II, IgG1 antibody with additional structural modifications that explain its enhanced activity.
Obinutuzumab
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
Antibody of choice when chemoimmunotherapy is used with chlorambucil
Obinutuzumab
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.
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
With Ibrutinib, side effects generally decreased with time, with the notable exception of__________________, which became more frequent over the course of observation
Hypertension
Toxicity with ibrutinib consisted of bruising/hemorrhage, atrial fibrillation, rash, gastrointestinal symptoms (diarrhea, nausea), infections, and cytopenias
The bleeding diathesis observed with ibrutinib is possibly caused by _______
Collagen-mediated platelet aggregation defect
Potentially exacerbated by anticoagulation therapy—particularly warfarin
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
A study that compared ibrutinib with chlorambucil in previously untreated patients, aged 65 years or older, with CLL
Resonate 2 study
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.
Virtually all patients with CLL are sensitive to ibrutinib and failure to respond should prompt reexamination of the histology.
The _______ variant (and rare others) occurs in more than 80% of patients who develop ibrutinib-resistance.
C481S variant
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
Most common adverse effect of Acalabrutinib
Diarrhea (52%) and headache (51%)
Others:
Grade 3 or greater neutropenia (14%), pneumonia (11%), and hypertension (7%)
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
Adverse effects of Idelalisib
Pneumonia (20%), neutropenic fever (11%), and diarrhea (6%)
Serious toxicities observed with idelalisib included transaminase elevations, diarrhea with colitis, and pneumonitis
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
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
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).
An oral, potent BH3-mimetic that targets BCL-2 with selectivity
Venetoclax
Ramp-up dosing schedule from 20 mg to 400 mg over a five-week period
Most common treatment-emergent grade 3 or 4 adverse events with use of Venetoclax
Neutropenia (51%), thrombocytopenia (29%), and anemia (29%)
An outstanding salvage therapy for ibrutinib refractory CLL
Venetoclax
TRUE OR FALSE
Autologous transplantation has a role in the management of CLL
FALSE
Autologous transplantation has no role in the management of CLL
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.
Indications for splenectomy
- Refractory autoimmune hemolytic anemia and thrombocytopenia
- Symptomatic splenomegaly
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.
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
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
Patients with a remission but with persistent cytopenias related to drug toxicity are classified as having
CR with incomplete marrow recovery
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
Recommended as initial therapy in younger, fitter patients with IGHV-mutated disease with intact TP53
Immunochemotherapy (FCR)
However, higher rates of “deep” CRs can be achieved with combinations such as venetoclax and ibrutinib
Recommended for patients with IGHV-unmutated disease or patients not suitable for FCR
BTK inhibitor (ibrutinib or acalabrutinib), with or without a CD20 antibody
Recommended for patients for whom BTK inhibitors are inappropriate or patients who desire time-limited therapy
Venetoclax plus obinutuzumab
Given the short follow-up that exists with venetoclax trials currently, this is not a first choice.
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
Treatment of choice in both younger and older patients who had not previously received BTK Inhibitor
Ibrutinib
One of the most common cancers seen in patients with CLL
Skin cancer
This includes basal cell carcinoma, squamous cell carcinoma, cutaneous melanoma, and Merkel cell carcinoma.
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.
Hypogammaglobulinemia is universally present in patients with CLL and progressively worsens with advancing stage of the disease.
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
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.
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
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
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
It is best to first treat the autoimmune complication and then the CLL if symptoms persist.
Treatment options for immune complications of CLL that have disease relapse after discontinuation of steroids
IVIG or rituximab
Cyclosporine
Thrombopoietin agonists (immune thrombocytopenia)
Defined as a transformation of CLL into an aggressive, high-grade, large B-cell non-Hodgkin lymphoma
The syndrome is characterized by rapid development of B symptoms and rapidly progressive lymphadenopathy
Richter transformation
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
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.
Prognosis of Richter transformation is related to
The clonality of the malignant clone
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.
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
Patients can also experience transformation to prolymphocytic leukemia (PLL), characterized by the presence of ______________prolymphocytes in the marrow
more than 55%
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
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
Patients are predisposed to a higher frequency of infections and also secondary malignancies
