CLL Flashcards
CLL diagnosis requires presence of monoclonal B lymphocytes _______ x 109/L in peripheral blood
≥5 x 109/L
Clonality of B cells should be confirmed by
Flow cytometry
Presence of lymphadenopathy and/or splenomegaly with monoclonal B lymphocytes ≤5 x 109/L in peripheral blood
SLL
TRUE OR FALSE
Biopsy is generally not required.
TRUE
Biopsy is generally not required.
If diagnosis is not established by flow cytometry, then proceed with lymph node biopsy.
Diagnostics that are informative for prognostication and/or therapy determination
- FISH to detect: +12; del(11q); del(13q); del(17p)
- TP53 sequencing
- CpG-stimulated metaphase karyotype for complex karyotype (CK)
- Molecular analysis to detect: Immunoglobulin heavy chain variable region gene (IGHV) mutation status
- Beta-2-microglobulin
Features of Monoclonal B-cell lymphocytosis (MBL)
- Absolute monoclonal B-lymphocyte count <5 x 109/L
- All palpable lymph nodes <1.5 cm
- No anemia
- No thrombocytopenia
- No palpable organomegaly
- No constitutional symptoms
Persists more than 3 months
Categories of MBL
- Low-count MBL (<0.5 x 109/L) that rarely progresses to CLL
- High-count MBL (0.5 – 4.9 x 109/L) that can progress to CLL requiring therapy at a rate of 1% to 2% per year.
Observation is recommended for all individuals with MBL
Typical immunophenotype of CLL:
CD5+, CD23+, CD43+/-, CD10-, CD19+, CD20 dim, sIg dim+, and cyclin D1-
Some cases may be sIg bright+ or CD23- or dim
Some MCL may be CD23+
Marker that may distinguish CLL from mantle cell lymphoma (MCL)
CD200
CLL: CD200+
May be helpful in suspected cases of MCL that are cyclin D1-negative
LEF1 and SOX11
When are CT scans warranted
Evaluation of symptoms of bulky disease or for the assessment of risk for TLS prior to initiating venetoclax
Treatment for SLL/Localized (Lugano Stage I)
Locoregional involved-site radiation therapy (ISRT) (if indicated)
Indications for treatment:
- 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, symptomatic, or bulky disease (spleen >6 cm below costal margin, lymph nodes >10 cm)
- Progressive thrombocytopenia
- Progressive anemia
- Steroid-refractory autoimmune cytopenias
Absolute lymphocyte count (ALC) alone is not an indication for treatment in the absence of leukostasis, which is rarely seen in CLL.
Select patients with mild, stable cytopenia _______________ may continue to be observed.
- ANC <1000/μL
- Hgb <11 g/dL or
- Platelet <100,000/μL)
Other causes of anemia/ thrombocytopenia (eg, autoimmune disorders, vitamin/iron deficiency) should be excluded.
TRUE OR FALSE
IGHV mutation status changes over time and analysis should be repeated if previously done prior to initiation of treatment.
FALSE
IGHV mutation status does not change over time and analysis does not need to be repeated if previously done prior to initiation of treatment.
Unfavorable Prognostic Variables:
- del(17p)
- del(11q)
- Mutated TP53
- IGHV ≤2% mutation
- Complex Karyotype
Intermediate: +12, Normal
Favorable: del(13q) (as a sole abnormality), TP53 Wild-type; IGHV >2%
TRUE OR FALSE
Immune-mediated cytopenias are not the basis for these stage definitions.
TRUE
Immune-mediated cytopenias are not the basis for these stage definitions.
SLL STAGING SYSTEM
Lugano Modification of Ann Arbor Staging System
(for primary nodal lymphomas)
Limited
Stage I: One node or a group of adjacent nodes
Stage IE: Single extranodal lesions without nodal involvement
Stage II: Two or more nodal groups on the same side of the diaphragm
Stage IIE: Stage I or II by nodal extent with limited contiguous extranodal involvement
Advanced
Stage III: Nodes on both sides of the diaphragm; Nodes above the diaphragm with spleen involvement
Stage IV: Additional non-contiguous extralymphatic involvement
Rai System
- 0: Lymphocytosis, lymphocytes in blood >5 x 109/L clonal B cells and/or >40% lymphocytes in the bone marrow
- I: Stage 0 with enlarged node(s)
- II: Stage 0–I with splenomegaly, hepatomegaly, or both
- III: Stage 0–II with hemoglobin <11.0 g/dL or hematocrit <33%
- IV: Stage 0–III with platelets <100,000/mm3
Binet System
- A: Hemoglobin ≥10 g/dL and, Platelets ≥100,000/mm3 and, <3 enlarged areas
- B: Hemoglobin ≥10 g/dL and Platelets ≥100,000/mm3 and ≥3 enlarged areas
- C: Hemoglobin <10 g/dL and/or Platelets <100,000/mm3 and any number of enlarged areas
Laboratory hallmarks of TLS:
- High potassium
- High uric acid
- High phosphorous
- Low calcium
- High LDH
Consider TLS prophylaxis for patients with the following risk factors:
- Patients receiving treatment with venetoclax, CIT, lenalidomide, and obinutuzumab
- Progressive disease after small-molecule inhibitor therapy
- Bulky lymph nodes
- Spontaneous TLS
- Elevated white blood cell (WBC) count
- Pre-existing elevated uric acid
- Renal disease or renal involvement by tumor
Centerpiece of treatment includes:
- Rigorous hydration
- Management of hyperuricemia
- Frequent monitoring of electrolytes and aggressive correction (essential)
First-line and at retreatment for hyperuricemia
Low-Risk Disease:
Allopurinol or febuxostat beginning 2–3 days prior to CIT and continued for 10–14 days
Intermediate-Risk Disease (Stage I/II and LDH <2X ULN):
Allopurinol or febuxostat
OR
Rasburicase if renal dysfunction and uric acid, potassium, and/or phosphate >ULN
High-Risk Disease (Stage III/IV and/or LDH ≥2 X ULN):
Rasburicase
Treatment for Autoimmune Cytopenias
- Corticosteroids
- Rituximab
- IVIG
- Cyclosporin A
- Splenectomy
- Eltrombopag, or romiplostim (ITP), or
- BTKi-based therapy for steroid-refractory or recurrent AIHA
Patients with CLL/SLL have a higher risk of developing secondary cancers, including:
Melanoma and non-melanoma skin cancers
Annual dermatologic skin screening is recommended.
Recommended for prevention of thromboembolic events in patients receiving lenalidomide:
Aspirin 81 mg PO daily if platelets above 50 x 1012/L
Reaction seen on those taking Lenalidomide
Painful lymph node enlargement or lymph node enlargement with evidence of local inflammation, occurring with treatment initiation; may also be associated with spleen enlargement, low-grade fever, and/or rash
Tumor Flare Reactions
Treatment for Tumor Flare Reactions
- Steroids (eg, prednisone 25–50 mg PO daily for 5–10 days)
- Antihistamines for rash and pruritus
Prophylaxis:
* Consider in patients with bulky lymph nodes (>5 cm)
* Steroids (eg, prednisone 20 mg PO daily for 5–7 days followed by rapid taper over 5–7 days)
BTKi interruption before surgery
Minor surgical procedure:
Major surgical procedure:
Minor surgical procedure: 3 days before
Major surgical procedure: 7 days before
Preferred Regimens for CLL/SLL Without del(17p)/TP53 Mutation
- Acalabrutinib ± obinutuzumab (category1)
- Venetoclax + obinutuzumab (category 1)
- Zanubrutinib (category 1)
OTHER
* Ibrutinib (category 1)
* Ibrutinib + obinutuzumab (category 2B)
* Ibrutinib + rituximab (category 2B)
* Ibrutinib + venetoclax (category 2B)
Based on the results of the phase III randomized studies (ELEVATE-TN, SEQUOIA, and CLL14)
Ibrutinib under “other recommended regimens” is based on the toxicity profile.
Considered regimen for IGHV-mutated CLL in patients aged < 65 y without significant comorbidities
Without del(17p)/TP53 Mutation
FCR (fludarabine, cyclophosphamide, rituximab)
Considered regimens when BTKi and venetoclax are not available or contraindicated or rapid disease debulking needed
Without del(17p)/TP53 Mutation
- Bendamustine + anti-CD20 mAb
- Obinutuzumab ± chlorambucil
- High-dose methylprednisolone (HDMP) + anti-CD20 mAb (category 2B; category 3 for patients <65 y without significant comorbidities)
A non-covalent (reversible) BTKi used for resistance or intolerance to prior covalent BTKi therapy
Pirtobrutinib
Covalent BTK Inhibitors: Acalabrutinib, ibrutinib, and zanubrutinib
Chimeric antigen receptor (CAR) T-cell therapy for R/R CLL after prior BTKi and Venetoclax-based regimens
Lisocabtagene maraleucel (CD19-directed)
Preferred Regimens for CLL/SLL With del(17p)/TP53 Mutation
- Acalabrutinib ± obinutuzumab
- Venetoclax + obinutuzumab
- Zanubrutinib
CIT is not recommended since del(17p)/TP53 mutation is associated with low response rates.
Ibrutinib under “other recommended regimens” is based on the toxicity profile.
Considered regimens when BTKi and venetoclax are not available or contraindicated or rapid disease debulking needed
With del(17p)/TP53 Mutation
- HDMP + anti-CD20 mAb
- Obinutuzumab
CIT is not recommended since del(17p)/TP53 mutation is associated with low response rates.
TRUE OR FALSE
A baseline cardiovascular risk assessment should be considered prior to initiation of covalent BTKi.
TRUE
A baseline cardiovascular risk assessment should be considered prior to initiation of covalent BTKi.
TLS Risk with Venetoclax
Low: All lymph nodes <5 cm AND Absolute lymphocyte count (ALC) <25 x 109/L
Medium: Any lymph node 5 cm to <10 cm OR ALC ≥25 x 109/L
High: Any lymph node ≥10 cm OR ALC ≥25 x 109/L AND any lymph node ≥5 cm
For patients with CrCl <80 mL/min and medium tumor burden, consider management as high risk for TLS.
Prophylaxis for TLS with Venetoclax Use
- Low: Oral hydration (1.5–2 L); Allopurinol
- Medium: Oral hydration (1.5–2 L) and consider additional intravenous hydration; Allopurinol
- High: * Oral hydration (1.5–2 L) and intravenous hydration (150–200 mL/h as tolerated); Allopurinol or febuxostat; Consider rasburicase if baseline uric acid is elevated
Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax.
For patients at risk of TLS, monitor blood chemistries at 6–8 hours and at 24 hours at each subsequent ramp-up dose.
TRUE OR FALSE
“Accelerated CLL,” “CLL with expanded proliferation centers,” and CLL/PL (defined on HT-1) are not considered Richter transformation, but are associated with more aggressive disease and poorer outcome.
TRUE
“Accelerated CLL,” “CLL with expanded proliferation centers,” and CLL/PL (defined on HT-1) are not considered Richter transformation, but are associated with more aggressive disease and poorer outcome.
Suggested CIT regimens for RT to DLBCL
- Dose-adjusted EPOCH-R
- HyperCVAD
- OFAR (oxaliplatin, fludarabine, cytarabine, rituximab)
- RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
- Venetoclax + RCHOP (category 2B)
Generally managed with treatment regimens recommended for DLBCL
However, these regimens typically result in poor responses and optimal first-line therapy is not established
__________ gene usage is associated with poor outcomes regardless of the IGHV mutation status
VH3-21
Most common cytogenetic abnormalities
- Del(13q) (55%)
- del(11q) (18%)
- trisomy 12 (16%)
- del(17p) (7%)
- del(6q) (7%)
Del(13q) as a sole abnormality was associated with favorable prognosis and the longest median survival (133 months) after chemoimmunotherapy.
Prognostic tool that is based on the cytogenetic abnormalities detected by FISH, IGHV mutation status, and CD38 expression.
Integrated CLL Scoring System (ICSS)
Prognostic tool based on TP53 and IGHV mutation status, serum beta-2 microglobulin concentration, clinical stage, and age
International Prognostic Index for CLL (CLL-IPI)
Prognostic tool that predicts the likelihood of disease progression to need treatment in patients with early-stage CLL and stratifies patients with early-stage CLL into three risk groups with significantly different TTFT
International Prognostic Score for Early-Stage CLL (IPS-E)
TRUE OR FALSE
Venetoclax-based combination regimens offer a fixed-duration treatment with a treatment-free remission period.
TRUE
Venetoclax-based combination regimens offer a fixed-duration treatment with a treatment-free remission period.
Fixed-duration treatment with venetoclax-based combination regimens also results in higher rates of uMRD, which is an independent predictor of improved survival.
Clinical trials of CLL
- ELEVATE-TN trial: acalabrutinib ± obinutuzumab
- CLL14 study: Venetoclax + Obinutuzumab
- SEQUOIA: Zanubrutinib
- RESONATE-2: Ibrutinib
- iLLUMINATE: Ibrutinib + obinutuzumab
- E1912 and FLAIR: Ibrutinib + rituximab
- CAPTIVATE, CLARITY: Ibrutinib + venetoclax
- BRUIN: Pirtobrutinib
- MURANO: VenR
- TRANSCEND CLL 004: Lisocabtagene maraleucel
RESPONSE DEFINITIONS AFTER TREATMENT FOR CLL/SLL
CR
- LN: None ≥1.5 cm in longest dimension
- Spleen size <13 cm; liver size normal
- Constitutional symptoms: none
- Circulating lymphocyte count: Normal
- Platelet count: ≥100,000/μL
- Hemoglobin: ≥11 g/dL (untransfused and without erythropoietin)
- Marrow: Normocellular, no CLL cells, no B-lymphoid nodules
- Neutrophils without growth factors: ≥1500/μL
Features associated with TTO in patients with CLL
- High WBC count
- mutated IGHV
- Positive DAT
- ZAP70 positivity
