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Chronic Leukemia (CLL & CML)

Indolent or chronic leukemias: CLL is mature B-cell leukemia of older adults; CML is BCR-ABL myeloproliferation treated with tyrosine kinase inhibitors

Review date
reviewed 2026-05-04
Reading time
9 min read
Author
Dr Kola Tytler MBBS CertHE MBA MSt MRCGP
Hematology & Oncologycommonlong-term-condition
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Condition details
Hematology & Oncology
common
9 min read
reviewed 2026-05-04
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About This Page

This is a clinician-written, evidence-based summary aligned to the USMLE Step 2 CK Content Outline. It is intended for medical students preparing for USMLE Step 2 CK. Management reflects current ACC/AHA, USPSTF, and APA guidelines. Always cross-reference with UpToDate, institutional protocols, and clinical judgment.

Key points

  • CLL is the most common adult leukemia in Western countries and often presents incidentally with lymphocytosis
  • CLL smear shows smudge cells; flow cytometry shows clonal B cells coexpressing CD5 and CD23
  • CML is caused by BCR-ABL t(9;22) Philadelphia chromosome and often has leukocytosis with left shift and basophilia
  • First-line CML treatment is a BCR-ABL tyrosine kinase inhibitor
  • Asymptomatic early CLL is observed, not treated immediately

Overview

Chronic leukemias mature enough to produce functional or partially functional cells and often follow a more indolent course than acute leukemias. CLL is a mature clonal B-cell malignancy that overlaps biologically with small lymphocytic lymphoma. CML is a myeloproliferative neoplasm driven by constitutive BCR-ABL tyrosine kinase activity.

Epidemiology

CLL usually affects older adults and is more common in men. Many patients are diagnosed on routine CBC. CML can occur at any adult age but is most common in middle-aged to older adults. BCR-ABL testing transformed CML prognosis because targeted TKIs produce durable remissions in most patients.

Clinical Features

Symptoms
CLL: often asymptomatic lymphocytosis
Painless lymphadenopathy, fatigue, night sweats, weight loss
Recurrent infections from hypogammaglobulinemia in CLL
CML: early satiety or left upper quadrant fullness from splenomegaly
Rapidly worsening fever, bone pain, cytopenias, or blasts suggesting transformation/blast crisis
Signs
CLL: lymphadenopathy and splenomegaly
CML: marked splenomegaly may be present
Pallor, bruising, or infections if marrow failure develops
Autoimmune hemolytic anemia signs in CLL: jaundice, splenomegaly

Investigations

First-line
CBC with differential and smearCLL: absolute lymphocytosis with smudge cells. CML: leukocytosis with left shift, basophilia, eosinophilia
Flow cytometryCLL: clonal B cells expressing CD5, CD23; distinguishes from mantle cell lymphoma
BCR-ABL testingPCR or FISH confirms CML and guides monitoring
Second-line
FISH/cytogenetics in CLLdel(17p)/TP53 mutation, del(11q), trisomy 12, del(13q) affect risk and treatment selection
Bone marrow biopsyUsed when diagnosis uncertain, cytopenias unexplained, or before selected treatments
Immunoglobulin levelsEvaluate recurrent infections in CLL
Specialist
Quantitative BCR-ABL PCR monitoringTracks molecular response to CML therapy
Mutation testingABL kinase mutation testing if CML resistance; TP53/IGHV testing in CLL treatment planning

Management

NCCN Guidelines for CLL/SLL and CML
1
CLL management
  • Observe asymptomatic early-stage CLL; early treatment does not improve survival
  • Treat when symptomatic: bulky/progressive nodes or spleen, B symptoms, progressive marrow failure, autoimmune cytopenias refractory to steroids, or rapid lymphocyte doubling
  • Modern first-line options include BTK inhibitors or venetoclax-obinutuzumab depending on genetics and comorbidities
2
CML management
  • Start BCR-ABL tyrosine kinase inhibitor for chronic-phase CML
  • Monitor quantitative BCR-ABL transcript levels at defined intervals
  • Assess adherence and drug interactions before labeling TKI failure
  • Switch TKI based on resistance mutation, intolerance, or inadequate molecular response
3
Transformation and emergencies
  • CML accelerated/blast phase requires urgent hematology care and often AML/ALL-like therapy plus TKI
  • Allogeneic transplant is considered for advanced-phase or TKI-resistant disease in selected patients

Complications

  • CLL infections: Hypogammaglobulinemia, pneumonia, shingles, and opportunistic infections with therapy
  • Autoimmune cytopenias: Warm autoimmune hemolytic anemia or ITP in CLL
  • Richter transformation: CLL transforms to aggressive diffuse large B-cell lymphoma
  • CML blast crisis: Transformation to acute leukemia
USMLE Step 2 CK Exam Tips
  • 1Smudge cells in older adult with lymphocytosis = CLL
  • 2CLL is observed if asymptomatic; do not treat just because lymphocyte count is high
  • 3CML = t(9;22) BCR-ABL Philadelphia chromosome
  • 4CML smear: left shift with basophilia
  • 5Imatinib and related TKIs treat CML
  • 6CLL can cause autoimmune hemolytic anemia
  • 7Richter transformation = CLL to aggressive lymphoma with rapidly enlarging nodes and B symptoms

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Verified Sources & References

NCCN Clinical Practice Guidelines in Oncology
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