Leukemias

• Definition: Leukemias are clonal malignancies of hematopoietic stem or progenitor cells that proliferate in the marrow and spill into blood. Acute forms are blast-predominant with arrested differentiation; chronic forms retain partial maturation, so the blood fills with more mature-appearing cells.
• Why it matters: Untreated acute leukemia is fatal within weeks — death comes from marrow failure (infection, hemorrhage) rather than tumor bulk. Recognizing blasts, coagulopathy, or hyperleukocytosis on a first CBC is a same-day intervention.

Epidemiology worth recalling

• ALL: peak incidence in early childhood (roughly ages 2–5), the most common pediatric malignancy; a second smaller rise occurs in older adults, where prognosis is much worse.
• AML: the most common acute leukemia of adults, with median age at diagnosis in the late 60s; incidence climbs steeply with age.
• CML: a myeloproliferative neoplasm of middle-aged and older adults, defined by BCR::ABL1; a minority of adult leukemia overall but disproportionately tested.
• CLL: the most common leukemia in adults in the United States and Western Europe, a disease of the elderly, frequently found incidentally on a routine CBC; it is rare in East Asian populations.
• Classification: The WHO (5th edition) and ICC systems now classify acute leukemias primarily by defining genetic lesion rather than morphology alone; NCCN guidelines organize U.S. treatment along these genetic subgroups, which is why molecular testing is obtained at diagnosis and not after induction.

Non-modifiable — germline and constitutional

• Down syndrome (trisomy 21): markedly increased risk of both ALL and acute megakaryoblastic leukemia; neonates may show transient abnormal myelopoiesis with GATA1 mutation that can later evolve to AML.
• Inherited marrow failure and instability syndromes: Fanconi anemia, Bloom syndrome, ataxia-telangiectasia, Li-Fraumeni (germline TP53) — defective DNA repair or checkpoint control permits accumulation of leukemogenic lesions.
• Germline predisposition genes: RUNX1, CEBPA, DDX41, GATA2 — suspect when a young adult with AML/MDS has affected relatives; WHO now recognizes these as distinct entities.
• Neurofibromatosis type 1: NF1 loss removes RAS-GAP activity → juvenile myelomonocytic leukemia.
• Family history: strongest for CLL, where first-degree relatives carry a substantially increased risk.

Acquired clonal states

• Antecedent MDS or MPN: AML arising from a pre-existing clone ("secondary AML") carries adverse genetics and poor response.
• Clonal hematopoiesis of indeterminate potential (CHIP): age-related DNMT3A/TET2/ASXL1 mutations increase later myeloid neoplasm risk.

Modifiable / exposure-related — the stem's usual planted clue

• Ionizing radiation: atomic bomb and therapeutic radiation survivors; latency of years.
• Benzene and petroleum solvents: occupational (refinery, rubber, painting) — classic AML exposure.
• Cigarette smoking: a genuine, modifiable AML risk factor.
• Prior chemotherapy (therapy-related myeloid neoplasm):
• Alkylating agents/radiation: longer latency, often preceded by MDS, with del(5q) or −7.
• Topoisomerase II inhibitors (etoposide, anthracyclines): shorter latency, balanced KMT2A (11q23) translocations, monocytic morphology.
• HTLV-1 infection: adult T-cell leukemia/lymphoma, endemic to Japan and the Caribbean.

• Initiating lesion: A somatic translocation, mutation, or aneuploidy in a hematopoietic stem/progenitor cell creates either a fusion oncoprotein or a mutated transcription factor. Two cooperating classes of hit are typically required: a class I lesion conferring proliferative/survival signaling (*FLT3*-ITD, KRAS/NRAS, BCR::ABL1) and a class II lesion blocking differentiation (RUNX1::RUNX1T1, PML::RARA, CEBPA).
• Differentiation arrest: In PML::RARA APL, the fusion recruits corepressors to retinoic acid response elements, freezing maturation at the promyelocyte stage — physiologic retinoid concentrations cannot displace it, but pharmacologic ATRA can, which is why the lesion is directly druggable.
• Constitutive kinase signaling: In CML, t(9;22) juxtaposes BCR with ABL1, and BCR-mediated oligomerization forces the ABL1 kinase into a permanently active conformation → autonomous JAK/STAT, RAS-MAPK, and PI3K signaling with preserved granulocytic maturation. Hence the left-shifted leukocytosis with basophilia rather than a pure blast picture.
• Failure of apoptosis: CLL cells overexpress BCL-2, so the clone accumulates as long-lived, immunoincompetent B cells rather than proliferating rapidly — the basis for venetoclax sensitivity and for the profound hypogammaglobulinemia.

From clone to clinical findings

• Marrow crowding and cytokine-mediated suppression of normal hematopoiesis → anemia (fatigue, pallor), thrombocytopenia (petechiae, mucosal bleeding), and neutropenia despite a high total WBC — the functional neutropenia that explains fever.
• Marrow expansion under the periosteum → bone/joint pain, the classic limping child in ALL.
• Extramedullary infiltration: lymphoid clones home to lymph nodes, spleen, liver, CNS, and testis; monocytic myeloid clones migrate to skin and gingiva (leukemia cutis, gum hypertrophy).
• Hyperleukocytosis raises blood viscosity and blast-endothelial adhesion → leukostasis.
• APL promyelocyte granules release tissue factor and annexin A2–driven fibrinolysis → DIC with hemorrhage.
• High cell turnover releases nucleic acids, potassium, and phosphate → tumor lysis physiology.

Shared marrow-failure syndrome (all leukemias)

• Fatigue, pallor, dyspnea on exertion: anemia from displaced erythropoiesis.
• Fever, mucositis, perirectal or pulmonary infection: functional neutropenia — fever in this setting is neutropenic fever until proven otherwise.
• Petechiae, ecchymoses, epistaxis, gingival oozing, menorrhagia: thrombocytopenia; wet purpura signals higher bleeding risk.

Presentation by subtype and the demographic the stem names

• ALL — a preschool child with weeks of fever, bone pain or refusal to bear weight, bruising, and hepatosplenomegaly with lymphadenopathy. T-ALL: an adolescent or young adult male with a mediastinal mass causing cough, dyspnea, or SVC syndrome. Sanctuary-site disease produces cranial nerve palsies, headache/vomiting from meningeal infiltration, or painless testicular enlargement.
• AML — an adult in the seventh decade with rapid-onset fatigue and bleeding. Monocytic subtypes give gingival hyperplasia and leukemia cutis (violaceous nodules/plaques); a soft tissue mass of blasts is a myeloid sarcoma (chloroma). Hyperleukocytosis presents as dyspnea, hypoxemia with a clear-ish chest film, confusion, or visual change — leukostasis.
• CML — a middle-aged adult, often asymptomatic, with early satiety, left upper quadrant fullness, or weight loss and drenching sweats; massive splenomegaly is the physical hallmark. Marked basophilia is a clue on the differential.
• CLL — an elderly patient with an incidental lymphocytosis; symmetric, rubbery, painless cervical/axillary lymphadenopathy, splenomegaly, and recurrent sinopulmonary infections from hypogammaglobulinemia. Sudden B symptoms with one rapidly enlarging node and rising LDH suggests Richter transformation.

Red-flag presentations demanding immediate action

• Spontaneous bruising plus a promyelocytic blast picture → suspected APL with DIC.
• Fever with an absolute neutrophil count below the neutropenic threshold → empiric antipseudomonal beta-lactam within an hour, per IDSA febrile neutropenia guidance.
• Priapism or stroke-like symptoms with a very high WBC → leukostasis.

Step 1 — initial studies

• CBC with differential and peripheral smear: cytopenias with or without leukocytosis; look for blasts, Auer rods (AML), smudge cells (CLL), or a full myeloid left shift with basophilia and eosinophilia (CML).
• Chemistries, LDH, uric acid, phosphate, potassium, calcium, creatinine: establishes baseline tumor lysis risk.
• PT, aPTT, fibrinogen, D-dimer: mandatory when acute leukemia is suspected — hypofibrinogenemia with a prolonged PT points to APL.

Step 2 — establishing lineage and clonality

• Flow cytometry immunophenotyping is the workhorse. Myeloid: CD13, CD33, CD117, MPO. B-ALL: CD19, CD10, TdT. T-ALL: cytoplasmic CD3, TdT. CLL: a CD5+/CD19+/CD23+ B cell with dim surface immunoglobulin and dim CD20.
• CLL can be diagnosed on peripheral blood alone when clonal B lymphocytes reach at least 5 × 10⁹/L, per iwCLL criteria; fewer clonal cells without adenopathy or cytopenia is monoclonal B-cell lymphocytosis, and nodal disease without blood involvement is SLL. Marrow biopsy is not required.

Step 3 — bone marrow aspirate and biopsy for acute leukemia

• ≥20% blasts establishes acute leukemia. Under WHO 5th edition, several AML-defining genetic abnormalities — including PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11 — permit the diagnosis below that threshold.
• Send karyotype, FISH, and multigene NGS (*FLT3*-ITD/TKD, NPM1, IDH1/2, TP53, KMT2A) — results directly select targeted agents, so ELN 2022 risk stratification and NCCN treatment assignment both depend on them.
• APL cannot wait: begin ATRA on morphologic suspicion while rapid FISH/PCR for PML::RARA is pending.
• Lumbar puncture for CNS staging in ALL (and symptomatic AML), with intrathecal chemotherapy given at the same procedure.

Disease-specific confirmatory tests

• CML: quantitative RT-PCR for BCR::ABL1 on the International Scale, the same assay used for response monitoring; FISH or karyotype for the Philadelphia chromosome.
• CLL staging: Rai or Binet, with FISH for del(17p), TP53 sequencing, and IGHV mutation status driving therapy choice.
• Post-induction measurable residual disease (MRD) by flow or molecular assay is the strongest prognostic variable in ALL and increasingly in AML.

Immediate stabilization (before definitive therapy)

• Tumor lysis prophylaxis: aggressive IV isotonic fluids plus a xanthine oxidase inhibitor (allopurinol) for standard risk, or rasburicase (recombinant urate oxidase) for high tumor burden/high uric acid. Urinary alkalinization is no longer recommended. Rasburicase is contraindicated in G6PD deficiency.
• Febrile neutropenia: empiric antipseudomonal beta-lactam (cefepime or piperacillin-tazobactam) within one hour of fever, per IDSA.
• Hyperleukocytosis with leukostasis: cytoreduction with hydroxyurea and prompt induction; leukapheresis may be used as a temporizing measure. Avoid red cell transfusion until the count falls — it raises viscosity.
• Suspected APL: start ATRA immediately, transfuse platelets and cryoprecipitate/fibrinogen liberally, and correct coagulopathy — early hemorrhagic death is the leading cause of APL mortality (NCCN).

First-line by subtype (per NCCN)

• AML, fit patients: intensive cytarabine-plus-anthracycline induction, with a FLT3 inhibitor (midostaurin) added for *FLT3*-mutated disease and gemtuzumab ozogamicin for core-binding factor AML; consolidation with high-dose cytarabine or allogeneic HSCT by ELN risk group.
• AML, unfit/older patients: a hypomethylating agent (azacitidine or decitabine) plus the BCL-2 inhibitor venetoclax — now the standard non-intensive regimen.
• APL: ATRA plus arsenic trioxide, chemotherapy-sparing and curative in most patients.
• ALL: multi-agent induction–consolidation–maintenance over years, with CNS-directed intrathecal therapy in every patient; add a TKI (imatinib or dasatinib) for Philadelphia-positive ALL. Pediatric-inspired regimens are preferred for adolescents and young adults.
• CML: a BCR-ABL tyrosine kinase inhibitor — imatinib or a second-generation agent — with molecular monitoring against milestone transcript levels; switch for resistance, and use ponatinib for the T315I gatekeeper mutation, which all earlier TKIs miss.
• CLL: treat only for iwCLL-defined active disease. Modern first line is targeted: a covalent BTK inhibitor (acalabrutinib) or time-limited venetoclax plus obinutuzumab.

Escalation and salvage

• Allogeneic HSCT is the definitive curative option for adverse-risk AML, relapsed ALL, and TKI-refractory CML.
• Immunotherapy for relapsed B-ALL: blinatumomab (CD19 BiTE), inotuzumab ozogamicin, and CD19-directed CAR T-cell therapy.

Contraindicated / avoid

• Live vaccines during therapy; vincristine given intrathecally is uniformly fatal; **chemoimmunotherapy in CLL with *del(17p)*/TP53 aberration** — use targeted agents instead.

Disease-related — emergencies first

• Tumor lysis syndrome (emergency): massive cell lysis releases potassium, phosphate, and purines → hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia from calcium-phosphate precipitation; signals are rising creatinine, arrhythmia, tetany, and seizures. Graded by Cairo-Bishop criteria.
• Disseminated intravascular coagulation (emergency): promyelocyte granule tissue factor in APL; low fibrinogen, prolonged PT, rising D-dimer, and intracranial or pulmonary hemorrhage.
• Neutropenic fever/sepsis (emergency): absent phagocyte defense; may present as fever alone with no localizing sign.
• Leukostasis (emergency): hypoxemia, altered mental status, or retinal hemorrhages with a very high blast count.
• CNS involvement: cranial neuropathies or meningismus, especially untreated ALL.
• Autoimmune cytopenias and hypogammaglobulinemia in CLL: warm AIHA and ITP (Evans syndrome); encapsulated-organism infection risk.
• Richter transformation: abrupt B symptoms, one dominant enlarging node, sharply rising LDH.
• Blast crisis in CML: loss of TKI response with rising blasts.

Treatment-related

• Differentiation syndrome (emergency): with ATRA or arsenic — cytokine release causing fever, dyspnea, pulmonary infiltrates, weight gain, hypotension; treat promptly with dexamethasone.
• Anthracycline cardiotoxicity: cumulative dose-dependent dilated cardiomyopathy; falling LVEF on surveillance echo.
• Asparaginase: hepatotoxicity, pancreatitis, and thrombosis (including cerebral sinus thrombosis) from depleted antithrombin.
• Vincristine: dose-limiting peripheral neuropathy, loss of ankle reflexes, constipation/ileus.
• Methotrexate: mucositis, myelosuppression, nephrotoxicity — rescue with leucovorin.
• Cyclophosphamide: hemorrhagic cystitis from acrolein — prevent with mesna and hydration.
• Arsenic trioxide: QT prolongation → torsades; monitor electrolytes and ECG.
• TKI class effects: imatinib periorbital edema and cytopenias; dasatinib pleural effusion; nilotinib QT prolongation and vaso-occlusive events; ponatinib arterial thrombosis.
• Venetoclax: rapid apoptosis causes TLS — hence the mandated stepwise ramp-up.
• BTK inhibitors: atrial fibrillation, bleeding, hypertension (more with ibrutinib than acalabrutinib).
• Allogeneic HSCT: acute and chronic GVHD (rash, cholestatic LFTs, diarrhea), sinusoidal obstruction syndrome, and CMV reactivation.
• Late effects: therapy-related myeloid neoplasm and secondary solid tumors after alkylators, topoisomerase II inhibitors, or radiation.

• Blasts plus hypofibrinogenemia = APL until proven otherwise, and the single best next step is to start ATRA before genetic confirmation returns. Waiting for FISH costs lives; early death in APL is hemorrhagic, not chemoresistant disease.
• **The T315I gatekeeper mutation is the classic imatinib-resistance answer, and ponatinib** is the TKI that retains activity against it. Second-generation agents (dasatinib, nilotinib) do not overcome T315I.
• Rasburicase is contraindicated in G6PD deficiency — urate oxidase generates hydrogen peroxide, precipitating hemolysis and methemoglobinemia. Also remember that urinary alkalinization has been abandoned because it promotes calcium-phosphate deposition.
• A very high WBC with a normal or low ANC is still neutropenia. Do not be reassured by the total count; febrile patients need an antipseudomonal beta-lactam within an hour (IDSA).
• TdT positivity separates lymphoblasts (ALL) from myeloblasts; MPO and Auer rods mark AML. Smudge cells with a CD5+/CD19+/CD23+ phenotype are CLL — CD5 on a B cell is otherwise the mantle cell clue, and mantle cell is cyclin D1+/CD23−.
• Distinguish a leukemoid reaction from CML: both show neutrophilic leukocytosis with a left shift, but CML has basophilia and BCR::ABL1, while a leukemoid reaction has toxic granulation, Döhle bodies, and a high leukocyte alkaline phosphatase. The definitive test is molecular, not the LAP score.
• Every ALL patient gets CNS-directed intrathecal therapy because systemic chemotherapy does not cross the blood–brain barrier; the CNS and testis are sanctuary sites and common relapse locations.
• Common distractor: assuming t(9;22) means CML. Philadelphia-positive ALL is a distinct, historically adverse-risk entity treated with chemotherapy plus a TKI — and its outcomes have improved markedly with that combination.

• Acute leukemias present rapidly (weeks); chronic leukemias develop slowly (months-years)
• ALL most common childhood cancer; AML most common adult acute leukemia
• Diagnosis requires >20% blasts in bone marrow (formerly >30%)
• Philadelphia chromosome t(9;22) = CML and some ALL (BCR-ABL fusion)
• Tumor lysis syndrome risk: hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia

• ALL: t(12;21) (ETV6-RUNX1) = best prognosis; t(9;22) = worst prognosis; CNS prophylaxis required
• AML: t(15;17) = APL (APML) with DIC/hemorrhage → treat with ATRA + arsenic trioxide; t(8;21), inv(16) = better prognosis
• CML: Imatinib (Gleevec, TKI) is first-line; Philadelphia chromosome (BCR-ABL); progresses to blast crisis in 3-5 years if untreated
• CLL: Often CD5+ B-cell; Richter transformation to DLBCL is poor prognostic sign
• Auer rods = AML; Smudge cells = CLL; Lymphoblasts = ALL

• Confusing Philadelphia+ ALL with CML: Both have t(9;22), but ALL presents acutely in children; CML is chronic in adults. Prognosis differs markedly.
• Missing DIC/coagulopathy in AML/APL: Especially APL (APML)—check PT/PTT/fibrinogen at diagnosis; bleeding risk is high before treatment.
• Forgetting CNS prophylaxis in ALL: CNS involvement occurs in ~5% at diagnosis and ~50% if untreated; intrathecal chemotherapy is standard.

Quick mnemonic: ALL = child; AML = adult; CML = chronic (Philadelphia+); CLL = Cluster of lymphocytes (elderly)