Myeloproliferative neoplasm defined by the Philadelphia chromosome (BCR-ABL1) — transformed by targeted TKI therapy into a chronic, manageable disease.
Also known as: CML, chronic myeloid leukemia, chronic myelogenous leukemia, Philadelphia chromosome
Overview
Clonal myeloproliferative neoplasm of hematopoietic stem cell origin, defined by the Philadelphia chromosome — t(9;22)(q34;q11) reciprocal translocation creating the BCR-ABL1 fusion gene encoding a constitutively active tyrosine kinase. Progresses through chronic phase → accelerated phase → blast crisis if untreated.
Epidemiology
Annual incidence ~1-2 per 100,000. Median age at diagnosis ~65 years. Accounts for ~15% of adult leukemias. With TKI therapy, life expectancy approaches that of the general population.
🔒 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 Myeloid Leukemia (CML) 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.
No clear familial or environmental factors otherwise
Rare association with prior chemotherapy
Not associated with chronic infection or autoimmune disease
Pathophysiology
Acquired t(9;22) translocation fuses BCR (chromosome 22) and ABL1 (chromosome 9) to form the BCR-ABL1 oncoprotein, a constitutively active tyrosine kinase that drives proliferation, blocks apoptosis, and confers genomic instability. The result is expansion of myeloid lineage with preserved differentiation in chronic phase (leukocytosis with full spectrum of mature and immature granulocytes), progressing to accelerated phase (genomic instability, secondary mutations) and blast crisis (acute leukemia phenotype, either myeloid 70% or lymphoid 30%).
Clinical presentation
Symptoms
Often asymptomatic — diagnosed on incidental leukocytosis (~40-50% of cases)
Fatigue, malaise, weight loss, low-grade fever, night sweats (constitutional symptoms)
Early satiety, abdominal fullness from splenomegaly
Bone pain (marrow expansion), splenic infarct pain
Hyperviscosity symptoms with very high WBC (>200K): visual changes, priapism, stroke, TIA
Blast crisis: bleeding, infection, organ infiltration
Signs / physical exam
Splenomegaly (massive in advanced disease; one of the largest causes of palpable spleen)
Hepatomegaly (less prominent)
Pallor (anemia in advanced disease)
Lymphadenopathy uncommon in chronic phase (suggests progression)
Sternal tenderness
Classic findings
Middle-aged adult with marked leukocytosis (often 100-500K), left-shifted granulocytosis with all stages of myeloid maturation, basophilia, and splenomegaly.
Differential diagnosis
Leukemoid reaction — Reactive granulocytosis from infection/inflammation; LAP (leukocyte alkaline phosphatase) HIGH (LOW in CML); no Philadelphia chromosome; identifiable trigger
Other myeloproliferative neoplasms (PV, ET, MF) — JAK2 V617F (or CALR, MPL) mutation; no BCR-ABL1; distinct hematologic patterns
Chronic neutrophilic leukemia — Rare; CSF3R mutation; no BCR-ABL1
Atypical CML BCR-ABL1 negative — Granulocytic proliferation with dysplasia; CSF3R or SETBP1 mutations
Acute leukemia (CML blast crisis) — >20% blasts; lymphoid or myeloid blast crisis; antecedent CML history
Diagnostic workup
Diagnostic criteria
BCR-ABL1 fusion (by cytogenetics t(9;22), FISH, or PCR) in a patient with myeloproliferative features. Phase determined by blast count and clinical criteria.
BCR-ABL1 tyrosine kinase inhibitors for CML — selection tailored to mutation status and comorbidities.
Treatment
First-line
Tyrosine kinase inhibitor (TKI) — imatinib, dasatinib, nilotinib, bosutinib (first-line options); ponatinib for T315I mutation or failure of multiple TKIs
Imatinib (Gleevec) — first-generation, well-tolerated, long-term safety data; standard initial therapy in many settings
Second-generation TKIs (dasatinib, nilotinib, bosutinib) achieve faster and deeper molecular responses; preferred for higher-risk disease
Monitoring: quantitative BCR-ABL1 IS% every 3 months; goals — major molecular response (MMR, BCR-ABL1 ≤0.1%) by 12 months; early molecular response (≤10%) by 3 months
Treatment-free remission (TFR) — TKI discontinuation possible in selected patients with deep, durable molecular response (≥MR4.5 for ≥2 years on therapy); ~40-50% maintain response off therapy
Hydroxyurea as bridging therapy for cytoreduction with very high WBC
Allopurinol for tumor lysis prevention with high WBC
Allogeneic HSCT — reserved for TKI-resistant disease or advanced phase (now rarely needed in chronic phase)
Second-line / adjunct
TKI resistance/intolerance: switch to alternative TKI; check BCR-ABL1 kinase domain mutations to guide selection (T315I → ponatinib or asciminib)
Asciminib (STAMP inhibitor) — novel allosteric BCR-ABL1 inhibitor approved for previously treated CML and T315I mutation
Accelerated phase: increase TKI dose or switch; consider HSCT
Blast crisis: combine TKI with chemotherapy appropriate to lineage (AML or ALL induction); allogeneic HSCT if remission achieved
Pregnancy: TKIs teratogenic; counsel contraception; interferon-alpha or imatinib interruption in selected cases
Manage TKI side effects: dasatinib pleural effusion, nilotinib hyperglycemia and arteriosclerosis, ponatinib vascular events, imatinib edema/weight gain
Cardiovascular events with second/third-generation TKIs
Treatment-free remission failure with molecular relapse
PANCE pearls
Leukocytosis 100K-500K with basophilia + splenomegaly + Philadelphia chromosome = CML.
LAP score is LOW in CML, HIGH in leukemoid reaction — useful when imaging or cytogenetics not immediately available.
Imatinib (Gleevec) was the first molecularly targeted cancer therapy and transformed CML from a fatal disease (median survival ~3-5 years pre-imatinib) to a chronic condition with near-normal life expectancy.
Monitor BCR-ABL1 IS% every 3 months — goal is major molecular response (MMR, ≤0.1%) by 12 months.
T315I mutation confers resistance to all standard TKIs (imatinib, dasatinib, nilotinib, bosutinib) — requires ponatinib or asciminib.
Dasatinib causes pleural effusion in ~30% — switch TKI if symptomatic or refractory.
Treatment-free remission (TKI discontinuation) is possible after sustained deep molecular response — ~40-50% maintain remission off therapy.
Allogeneic HSCT, once curative gold standard, is now reserved for TKI-resistant or advanced-phase disease.
References
ELN 2020 — European LeukemiaNet 2020 recommendations for treating CML (Hochhaus et al., Leukemia 2020)
IRIS Trial — Long-term outcomes of imatinib treatment for CML (Hochhaus et al., NEJM 2017)
DASISION — Dasatinib versus Imatinib in Newly Diagnosed Chronic-Phase CML (Kantarjian et al., NEJM 2010)
ENESTnd — Nilotinib versus Imatinib for Newly Diagnosed CML (Saglio et al., NEJM 2010)
STOP-IM/EURO-SKI — Discontinuation of TKIs in CML in deep molecular response (Saussele et al., Lancet Oncol 2018)
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.