CLL Flashcards
Typical clinical course with CLL
While most patients will have an initial CR or PR, ALL will relapse eventually.
Preferred first line options for CLL
1) venetoclax + obinutuzumab
2) acalabrutinib + obinutuzumab
CLL drug classes
- Bruton’s tyrosine kinase [BTK] inhibitors
- PI3-kinase inhibitors
- BCL2 inhibitors
- novel antibodies and other investigational therapies (eg, chimeric antigen receptor T cells)
clinical significance of IgVH mutational status
= mutated immunoglobulin heavy chain variable
- UNmutated = shorter survival overall and a higher risk of relapse following conventional treatment, including chemoimmunotherapy and hematopoietic cell transplantation
13q deletion clinical significance
very good prognosis because the median time for survival (that is, 50 percent survival) is almost
17q deletion clinical significance
1) poor prognosis (median survival historically only 3 years from the time of diagnosis)
2) predicts lack of benefit from standard chemoimmunotherapy
3) Favorable response to ibrutinib
11q deletion clinical significance
poor prognosis
most common adult leukemia
CLL
median age at diagnosis
72
CLL RF’s
Male, older age, caucasian
Variables involved in CLL staging
- lymphocytosis
- presence of hepatomegaly and splenomegaly
- presence of cytopenias
- **no imaging
What typically leads to CLL diagnosis?
- incidental lymphocytosis
- asymptomatic lymphadenopathy
presentation
- fatigue and malaise, early satiety, abdominal discomfort (splenomegaly), B symptoms (fevers, night sweats, weight loss), recurrent infections
Diagnostic criteria + what is required for diagnosis
1) Peripheral blood B-lymphocyte count >5K
2) Flow cytometry confirmation of circulating B lymphocyte clonality (CD5+ + CD23+)
3) Percentage of prolymphocytes <55% of lymphocytes
* BMB not needed. Just flow cytometry.
typical cell surface markers
CD5, CD19, CD23
average time to initiation of therapy
4-5 years
CLL workup
FISH
Flow cytometry
Immunohistochemistry
NO BMB needed
Poor prognosticator on FISH testing
Deletion 17p (OS 2-3 years) Deletion 11q (OS 6-7 years)
Favorable prognosticator on FISH testing
Deletion 13q
Factors that influence treatment strategy
Age
Functional status and comorbidities
Cytogenetics
management of AIHA in CLL
IF indication for CLL exists independent of anemia –> treat CLL
IF no indication for CLL treatment: steroids + folic acid, followed by SLOW taper
common side effects of ibrutinib
Diarrhea + peripheral lymphocytosis (may look like CLL progression but is not) + rash + Afib + antiplatelet effect (increased bleeding risk)
Contraindication to ibrutinib
patient on anticoagulation
purine analogs
pentostatin and cladribine
prophylaxis when using alemtuzumab
- acyclovir for HSV ppx
- PCP prophylaxis with bactrim
prophylaxis when using purine analogs
- acyclovir for HSV ppx
- PCP prophylaxis with bactrim
what is richter’s transformation + clinical importance
Extraordinarily rare transformation of CLL or hairy cell leukemia into a fast-growing DLBCL. Very bad prognosis.
treatment of richter’s transformation
Same treatment as for DLBCL
treatment regimen depends on…
presence of 17p deletion (but preferred first line regimens are the same with and without)
Labs
absolute lymphocytosis (threshold = 5K but can be up to 100K) + hemolytic anemia + hypogammaglobulinemia (25%) + mild cytopenias (neutropenia, anemia, thrombocytopenia) + elevated LDH
Major branch point in management
Presence of 17p mutation
Indications for starting treatment
1) Evidence of progressive marrow failure (worsening anemia and/or thrombocytopenia)
2) Massive (ie, ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly
3) Massive (ie, ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
4) Progressive lymphocytosis with an increase of >50 percent over a two-month period or lymphocyte doubling time (LDT) of <6 months.
constitutional symptoms (Significant fatigue (ie, Eastern Cooperative Oncology Group performance status [ECOG PS] ≤2, inability to perform usual activities), Night sweats for ≥1 month without evidence of infection, Unintentional weight loss ≥10 percent within the previous six months, Fevers for ≥2 weeks without other evidence of infection
Clinical staging system for CLL
Rai
CLL labs
absolute lymphocytosis (threshold = 5K but can be up to 100K) + hemolytic anemia + hypogammaglobulinemia (25%) + mild cytopenias (neutropenia, anemia, thrombocytopenia) + elevated LDH
CLL diagnosis
Peripheral blood B-lymphocyte count >5K
+ Characteristic immunophenotype = Flow cytometry with CD5+ + CD23+
Also – Percentage of prolymphocytes <55% of lymphocytes
*BMB not needed.
Important cytogenetic markers in CLL
11,13,17
CLL vs. B cell SLL
The term CLL is used when the disease manifests primarily in the blood, whereas the term SLL is used when involvement is primarily nodal.
Disease warranting treatment in CLL is referred to as
“active disease”
CLL clinical course
extremely heterogeneous disease with certain subsets of patients having survival rates without treatment that are similar to the normal population
Criteria for defining massive splenomegaly
Greater than 6 cm below the left costal margin
Adverse prognostic features
- low ZAP-70
- CD38
- P53 mutant
- unmutated IGHV
Major branch point in selection of initial systemic therapy
Presence of 17p deletion, TP53 mutational status
Term for premalignant phase
MBL (monoclonal b lymphocytosis)
Cutoff levels for cytopenias that are typically used to initiate treatment and caveat
- Hgb <10
- plt count <100k
- assuming declining, some people have stable platelet counts below 100k and don’t need treatment
clinical significance of ZAP-70 + interpretation
- Surrogate for IGHV mutation status but it will change overtime, unlike IGHV
- Low is good (correlates to mutated IGHv)
predictive vs. prognostic
prognostic = independent of treatment predictive = response with treatment
prognosis of patients who transform to DLBCL (Richter’s)
Absolutely dismal (worse than FL transformation)
Clinical significance of TP53 mutation
TP53 mutations are both predictive of worse clinical outcomes with chemoimmunotherapy as compared to targeted therapies (eg, BTK or BCL2 inhibitors)
Preferred BTK inhibitor and why
- acalabrutinib
- less cardiotoxicity
highest risk cytogenetic finding
17p deletion (tp53)
11q significance in CLL
intermediate, can be overcome by newer therapies
