Leukemia: A High-Yield USMLE Review

Leukemia is cancer of the blood-forming cells. It is classified along two axes: cell type (lymphoid vs. myeloid) and acuity (acute, driven by blasts and rapidly progressive, vs. chronic, composed of more mature cells and indolent). This creates four major categories — ALL, AML, CLL, and CML — each with distinct hallmarks that are heavily tested.

Presentation

• Acute leukemias (ALL, AML) present with bone marrow failure: anemia (fatigue, pallor), thrombocytopenia (bleeding, petechiae), and neutropenia (infections)
• Leukemic infiltration causes hepatosplenomegaly, lymphadenopathy (more common in ALL), CNS involvement (more common in ALL), bone pain, gingival hypertrophy (AML, especially monocytic M4/M5 subtypes), and leukemia cutis
• AML with acute promyelocytic leukemia (APL, M3) presents with DIC and life-threatening bleeding; leukostasis from very high WBC causes stroke-like symptoms and respiratory distress
• CLL is often asymptomatic and found incidentally on CBC, with painless generalized lymphadenopathy, splenomegaly, recurrent infections from hypogammaglobulinemia, and autoimmune complications (warm AIHA, ITP)
• CML classically presents with fatigue, weight loss, night sweats, massive splenomegaly, early satiety, and left upper quadrant discomfort

Diagnosis

• CBC and peripheral smear: acute leukemias show ≥20% blasts; AML reveals Auer rods (pathognomonic, pink needle-like cytoplasmic inclusions) and is myeloperoxidase positive; CLL shows marked lymphocytosis with fragile 'smudge cells'; CML shows very elevated WBC with full myeloid maturation, basophilia, and eosinophilia
• Flow cytometry: in CLL, CD5+ (aberrant), CD19+, CD20 dim, CD23+ with weak monoclonal surface immunoglobulin (usually IgM); ALL shows lymphoid markers and TdT positivity, AML shows myeloid markers
• Cytogenetics/FISH and RT-PCR: t(9;22)/BCR-ABL1 confirms CML (RT-PCR also used for monitoring); in CLL, FISH assesses del(17p) and del(11q) for prognosis and IGHV mutation status is checked; low LAP distinguishes CML from a leukemoid reaction
• Bone marrow biopsy confirms diagnosis and quantifies blast percentage

Management

• AML: induction with '7+3' (cytarabine × 7 days plus an anthracycline × 3 days), followed by consolidation with high-dose cytarabine or stem cell transplant, plus mutation-directed targeted agents (FLT3 or IDH inhibitors)
• APL (M3) is a medical emergency: start all-trans retinoic acid (ATRA) immediately on clinical suspicion (do not wait for cytogenetics) with arsenic trioxide; ATRA forces differentiation of arrested promyelocytes, and this is one of the most curable adult leukemias — watch for differentiation syndrome, treated with dexamethasone
• CLL: watch-and-wait in early stage, treating only when symptomatic (B symptoms, cytopenias, massive adenopathy/splenomegaly, rapid lymphocyte doubling); first-line is a BTK inhibitor (ibrutinib, acalabrutinib) or venetoclax-based regimen; check immunoglobulins and consider IVIG for infection prevention
• CML: tyrosine kinase inhibitors targeting BCR-ABL1 (imatinib was the first), which transformed CML into a chronic, manageable disease

High-yield

• Auer rods = AML (myeloperoxidase positive); ≥20% blasts defines acute leukemia
• Smudge cells + CD5+ B cells + hypogammaglobulinemia = CLL, the most common leukemia in adults in Western countries
• Philadelphia chromosome t(9;22)/BCR-ABL1 with low LAP and basophilia = CML, treated with TKIs
• APL (M3): t(15;17) PML-RARA, DIC with bleeding, faggot cells — start ATRA immediately, >90% cure
• CD5 is normally a T-cell marker; its aberrant expression on B cells is characteristic of CLL (and mantle cell lymphoma)
• Richter transformation: CLL transforming into aggressive large cell lymphoma (DLBCL) in 5–10%, with poor prognosis
• TPMT genotyping before thiopurine (6-MP, azathioprine) therapy in leukemia prevents profound, prolonged pancytopenia

Pitfalls

• Do not delay ATRA in suspected APL waiting for cytogenetic confirmation — DIC can be rapidly fatal; ATRA addresses the underlying disease while platelet transfusion is only supportive
• Recurrent infections in CLL are due to hypogammaglobulinemia (non-functional B cells), not neutropenia — the patient has many B cells that simply do not work
• Distinguish reactive lymphocytosis (large, atypical lymphocytes from viral infection, pertussis, or stress) from CLL, where lymphocytes are small and mature-appearing
• In CLL with warm AIHA, a pan-reactive autoantibody makes all crossmatches appear incompatible; give the 'least incompatible' units after excluding alloantibodies rather than canceling needed transfusion
• Basophilia should prompt consideration of CML and other myeloproliferative neoplasms rather than being overlooked