Indolent monoclonal proliferation of mature CD5+ B lymphocytes — most common adult leukemia in Western countries.
Also known as: CLL, chronic lymphocytic leukemia, small lymphocytic lymphoma, SLL
Overview
Mature B-cell neoplasm characterized by clonal proliferation and accumulation of small CD5+ CD19+ CD23+ B lymphocytes in peripheral blood, bone marrow, and lymphoid tissues. CLL and small lymphocytic lymphoma (SLL) are the same disease distinguished by site (CLL has ≥5,000 monoclonal B cells/μL in peripheral blood; SLL is tissue-predominant).
Epidemiology
Most common adult leukemia in the United States and Europe (rare in Asia). Median age at diagnosis ~70 years. Male predominance (~2:1). Annual US incidence ~5 per 100,000. Often asymptomatic and discovered on routine CBC.
🔒 Free preview limit reached
Keep reading — start your free trial
You've read your 2 free diagnosis previews. Create your free account to unlock the full Chronic Lymphocytic Leukemia (CLL) outline — plus all 514 diagnoses, 3,500+ board-style questions, flashcards, and an AI tutor. Your 7-day free trial includes everything, and there's no credit card required.
Family history (~8x increased risk in first-degree relatives — strongest familial predisposition of any hematologic malignancy)
Monoclonal B-cell lymphocytosis (MBL) — precursor state with <5,000/μL clonal cells; ~1-2% annual progression risk to CLL
No clear environmental cause; Agent Orange exposure (recognized by VA)
Pathophysiology
Clonal CD5+ B cells accumulate due to defective apoptosis (BCL-2 overexpression) and chronic B-cell receptor (BCR) signaling. Antigen drive and microenvironmental signals (BTK, PI3K, NF-κB pathways) sustain the clone. The malignant cells are functionally incompetent, producing hypogammaglobulinemia and immune dysfunction. Common cytogenetic abnormalities (FISH panel): del(13q) (favorable, most common), trisomy 12 (intermediate), del(11q) (ATM, adverse), del(17p) (TP53, very adverse).
Clinical presentation
Symptoms
Often asymptomatic — discovered on incidental lymphocytosis (60-70% of cases)
TP53 sequencing for mutations (treatment selection)
IGHV mutational status — mutated (favorable) vs unmutated (unfavorable)
Direct antiglobulin test (DAT) for autoimmune hemolysis screen
Quantitative immunoglobulins — hypogammaglobulinemia common
Beta-2 microglobulin (prognostic)
Bone marrow biopsy not required for diagnosis; reserved for unexplained cytopenia evaluation
Rai or Binet staging based on lymphocytosis, lymphadenopathy, organomegaly, anemia, thrombocytopenia
Imaging
CT chest/abdomen/pelvis at diagnosis for baseline lymphadenopathy assessment and before therapy
PET/CT if Richter transformation suspected (sudden enlargement of one node or B symptoms)
Diagnostic algorithm
Rai Stage
Findings
Median Survival (untreated, pre-targeted era)
0 (Low risk)
Lymphocytosis only
>10 years
I (Intermediate)
Lymphocytosis + lymphadenopathy
~8 years
II (Intermediate)
Lymphocytosis + hepatomegaly or splenomegaly (± LAD)
~6 years
III (High)
Lymphocytosis + anemia (Hb <11)
~2-4 years
IV (High)
Lymphocytosis + thrombocytopenia (Plt <100K)
~2-4 years
Rai staging for CLL — modern targeted therapy markedly improves survival across all stages.
Treatment
First-line
Indications for treatment (iwCLL criteria) — DO NOT TREAT asymptomatic early-stage disease (Binet A or Rai 0-II without symptoms) — observation is standard; treatment indicated for symptomatic/progressive disease, threatening lymphadenopathy or organomegaly, rapid lymphocyte doubling time (<6 months), B symptoms, autoimmune cytopenias unresponsive to steroids, marrow failure (Hb <10, plt <100)
BTK inhibitors — ibrutinib, acalabrutinib, zanubrutinib — first-line for most CLL patients including del(17p)/TP53 mutated disease; second-generation BTKis (acala, zanu) have improved cardiac safety (less afib, hypertension)
Venetoclax (BCL-2 inhibitor) + obinutuzumab (anti-CD20) — fixed-duration 12-month regimen, deep responses including MRD negativity (CLL14 trial)
Chemoimmunotherapy (FCR fludarabine + cyclophosphamide + rituximab; BR bendamustine + rituximab) — historical first-line; now reserved for selected younger fit IGHV-mutated patients without del(17p)/TP53
PI3K inhibitors — idelalisib, duvelisib — less commonly used due to toxicity (colitis, pneumonitis, hepatotoxicity, infection); reserved for multiply relapsed
Pirtobrutinib — non-covalent BTK inhibitor for BTK C481-mutated resistance
Supportive care: IVIG for recurrent infection with hypogammaglobulinemia, vaccinations (avoid live vaccines), PJP prophylaxis with chemoimmunotherapy or PI3Ki
Manage autoimmune cytopenias: prednisone first, rituximab second
Complications
Recurrent bacterial infections (encapsulated organisms — pneumococcus, H. flu); opportunistic infections (PJP, fungal) in heavily treated
Autoimmune cytopenias (warm AIHA, ITP, pure red cell aplasia)
Hypogammaglobulinemia — major contributor to morbidity and mortality
Richter transformation (~5-10%) — aggressive diffuse large B-cell lymphoma; sudden node enlargement, B symptoms, elevated LDH; poor prognosis
Second malignancies (skin cancer especially, increased rates)
Tumor lysis syndrome with venetoclax (dose ramp-up over 5 weeks)
BTK inhibitor toxicities: atrial fibrillation, hypertension, bleeding, diarrhea, infections; acalabrutinib and zanubrutinib have improved profile vs ibrutinib
Smudge cells (basket cells) on peripheral smear in an older adult with absolute lymphocytosis are nearly diagnostic of CLL.
CLL is the only major leukemia where observation ('watch and wait') is the standard of care for early-stage asymptomatic disease — early treatment does not improve survival.
del(17p) / TP53 mutation: very adverse prognosis with chemoimmunotherapy; standard care is BTK inhibitor or venetoclax-based therapy (NOT chemoimmunotherapy).
IGHV mutational status is a major prognostic factor — mutated favorable, unmutated unfavorable.
Hypogammaglobulinemia → recurrent encapsulated organism infections; vaccinate against pneumococcus, influenza, meningococcus, and consider IVIG for severe recurrent infection.
Richter transformation — sudden development of aggressive lymphoma (DLBCL most commonly) in CLL; clue is rapid node growth and B symptoms; biopsy diagnostic; PET shows high SUV.
Venetoclax requires tumor lysis prophylaxis with stepwise dose escalation over 5 weeks plus hydration, allopurinol/rasburicase, and frequent labs.
Ibrutinib causes atrial fibrillation and bleeding (especially with anticoagulants); newer BTKis (acalabrutinib, zanubrutinib) have lower rates.
References
iwCLL 2018 — iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL (Hallek et al., Blood 2018)
CLL14 — Venetoclax-Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukemia (Fischer et al., NEJM 2019)
RESONATE — Ibrutinib versus Ofatumumab in Previously Treated CLL (Byrd et al., NEJM 2014)
MURANO — Venetoclax-Rituximab in Relapsed or Refractory CLL (Seymour et al., NEJM 2018)
ELEVATE-TN — Acalabrutinib with or without obinutuzumab versus obinutuzumab + chlorambucil in treatment-naive CLL (Sharman et al., Lancet 2020)
Practice Hematology questions on FirstPassPA
Turn this outline into retention. 3,500+ board-style questions with an AI tutor that explains every answer — free to start, no card required.
Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants.