Leukemia: Types, Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Leukemia is a malignancy of the hematopoietic system characterized by clonal proliferation of abnormal white blood cells that infiltrate the bone marrow, peripheral blood, and other organs. Approximately 61,000 new US cases are diagnosed annually (2023 estimates), making leukemia the 10th most common cancer by incidence. The four major categories are determined by the cell of origin (myeloid vs. lymphoid) and disease tempo (acute vs. chronic): Acute Myeloid Leukemia (AML, approximately 20,000 US cases/year), Acute Lymphoblastic Leukemia (ALL, approximately 6,000 US cases/year), Chronic Myeloid Leukemia (CML, approximately 9,000 US cases/year), and Chronic Lymphocytic Leukemia (CLL, approximately 21,000 US cases/year, the most common adult leukemia). Each subtype has a distinct molecular pathogenesis, clinical presentation, and treatment strategy. AML and ALL are rapidly progressive and require urgent initiation of treatment. CML and CLL are often indolent and may not require immediate treatment. Key therapeutic advances include imatinib for CML, venetoclax for AML and CLL, ibrutinib for CLL, and CAR-T cell therapy for relapsed ALL.

Leukemia arises from acquired somatic mutations in hematopoietic stem or progenitor cells. Ionizing radiation is an established cause of AML and ALL (demonstrated in atomic bomb survivors at Hiroshima and Nagasaki and in patients receiving prior radiotherapy). Benzene exposure — historically from rubber manufacturing and now from gasoline, paints, and solvents — causes AML. Prior chemotherapy with alkylating agents (cyclophosphamide, melphalan) or topoisomerase II inhibitors (doxorubicin, etoposide) causes therapy-related AML, typically arising 5-10 years or 2-3 years post-exposure, respectively. Down syndrome (trisomy 21) confers 15-20-fold elevated risk of AML and ALL. Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms can progress to AML (blast-phase transformation). HTLV-1 retrovirus causes adult T-cell leukemia/lymphoma in endemic regions (Japan, Caribbean, West Africa). Tobacco smoking increases AML risk. CLL has familial clustering suggesting genetic susceptibility without identified dominant hereditary mutations.

Acute leukemias (AML, ALL) present abruptly over days to weeks with symptoms reflecting bone marrow failure: anemia (pallor, fatigue, dyspnea), thrombocytopenia (petechiae, purpura, spontaneous bruising, gingival bleeding, epistaxis), and neutropenia (fever from bacterial infection). Hyperleukocytosis — extreme elevation of blast count greater than 100,000/microL — causes leukostasis syndrome: pulmonary infiltrates, confusion, and stroke from blast aggregation in small vessels. Tissue infiltration causes hepatosplenomegaly, lymphadenopathy, bone pain (ALL, particularly in children), and, in ALL, central nervous system involvement (headache, cranial nerve palsies, meningismus). CML presents with insidious fatigue, night sweats, left upper quadrant fullness from massive splenomegaly, and is frequently detected incidentally on a routine blood count showing marked leukocytosis with the full spectrum of myeloid precursors. CLL may be asymptomatic for years; symptomatic disease causes lymphadenopathy, splenomegaly, cytopenias, and susceptibility to infections including encapsulated bacteria and herpes zoster.

Diagnosis requires bone marrow aspirate and biopsy with morphology, flow cytometry, cytogenetics (conventional karyotype), and molecular testing. AML: WHO 2022 classification requires greater than or equal to 20% blasts in blood or marrow (or less than 20% with AML-defining genetic abnormalities: PML-RARA, RUNX1-RUNX1T1, CBFbeta-MYH11, BCR-ABL1 [AML-like], or CEBPA biallelic mutation). European LeukemiaNet (ELN) 2022 risk stratification classifies AML into favorable (NPM1 without FLT3-ITD, biallelic CEBPA, inv(16), t(8;21)), intermediate (NPM1 with FLT3-ITD high, others), and adverse (TP53 mutation, RUNX1, ASXL1, complex karyotype, monosomal karyotype) for transplant and treatment decisions. ALL: WHO classification by immunophenotype (B-ALL, T-ALL), cytogenetics (Philadelphia chromosome BCR-ABL1, ETV6-RUNX1 favorable, KMT2A-rearranged, iAMP21), and gene expression (Ph-like ALL). CML: BCR-ABL1 PCR (quantitative, IS%) is the diagnostic standard and treatment monitoring tool; chronic phase, accelerated phase, and blast phase define disease progression. Rai/Binet staging for CLL using lymphocyte count, lymphadenopathy, hepatosplenomegaly, anemia, and thrombocytopenia thresholds guides treatment initiation.

AML: Induction chemotherapy with cytarabine 200 mg/m2 continuous infusion (7 days) plus daunorubicin or idarubicin (3 days, '7+3') achieves complete remission in 60-80% of younger fit patients. Gemtuzumab ozogamicin (anti-CD33 antibody-drug conjugate) is added for CD33-positive, favorable-risk AML. FLT3-mutated AML receives midostaurin plus '7+3' (RATIFY trial: improved OS). IDH1-mutated AML: ivosidenib; IDH2: enasidenib. Older/unfit patients: venetoclax plus azacitidine (VIALE-A trial: significantly improved CR rate 37% vs 18% vs azacitidine alone). Allogeneic stem cell transplant (allo-SCT) in first remission for intermediate/adverse-risk AML. ALL: BFM or GRAALL-based intensive induction (vincristine, corticosteroids, L-asparaginase, daunorubicin plus central nervous system prophylaxis); Ph-positive ALL receives ponatinib or dasatinib plus chemotherapy as first-line. CAR-T cell therapy (tisagenlecleucel, FDA-approved to age 25) for relapsed/refractory B-ALL: approximately 80% CR rate. Blinatumomab (CD19/CD3 bispecific T-cell engager) for MRD-positive or relapsed B-ALL. CML: Imatinib 400 mg/day (first-line, all phases), dasatinib, nilotinib, or bosutinib (second-line); asciminib (STAMP inhibitor, BCR-ABL1 T315I mutation) for resistant CML. CLL: Ibrutinib (BTK inhibitor) or venetoclax (BCL-2 inhibitor) plus obinutuzumab are first-line options; all produce superior PFS to traditional chemoimmunotherapy.

AML: 5-year overall survival approximately 30% overall; favorable-risk AML (CBF-AML, NPM1-mutated, biallelic CEBPA) achieves 5-year OS greater than 50%; adverse-risk approximately 10-20%. AML in adults over 70 has 5-year OS of approximately 5-15% with conventional chemotherapy. ALL: Children 5-year OS greater than 90%; adults approximately 40-50% due to higher frequency of adverse cytogenetics and inferior chemotherapy tolerance. CML: 10-year OS exceeds 80% with imatinib; treatment-free remission (TFR) achievable in approximately 40-50% of patients with deep molecular response. CLL: median OS greater than 10 years for all stages; Rai stage 0-II median OS greater than 15 years; Rai III-IV approximately 5-8 years; TP53-deleted/mutated CLL has poorer prognosis but responds to ibrutinib and venetoclax.

Minimizing exposure to known leukemogenic agents reduces risk: benzene exposure requires proper industrial controls and personal protective equipment in at-risk occupations (rubber manufacturing, petroleum refining, shoe manufacturing). Tobacco cessation reduces AML risk. Occupational ionizing radiation exposure should be kept within regulatory limits using ALARA (as low as reasonably achievable) principles. Patients who received prior chemotherapy (alkylating agents, topoisomerase II inhibitors) or radiation therapy require annual complete blood count monitoring for therapy-related AML (t-AML), particularly during the first 10 years after treatment. MDS patients with high-risk features (International Prognostic Scoring System, IPSS-R: Very High or High) require prompt consideration of allogeneic SCT before AML transformation. Children with Down syndrome require heightened vigilance for transient myeloproliferative disorder (TMD) and subsequent AML, with specialized pediatric hematology follow-up. No population-based screening for leukemia is currently recommended.

Seek urgent medical evaluation for unexplained persistent fatigue, pallor, or shortness of breath combined with any of the following: spontaneous bruising or pinpoint red spots (petechiae) under the skin without trauma, bleeding from the gums or nose that does not stop normally, or fever without clear infectious source. These may indicate bone marrow failure from acute leukemia, requiring same-day blood count evaluation. Bone pain — particularly in children with localized limb pain at night — combined with fatigue, fever, or lymph node swelling should prompt urgent evaluation. Any individual found to have markedly elevated or markedly depressed white cell count on a routine blood test should be referred urgently to hematology for evaluation including peripheral blood smear and further workup. In known CML or CLL patients on observation or treatment: new onset of night sweats, unexplained weight loss greater than 10% of body weight, rapidly enlarging lymph nodes, fever, or worsening fatigue should prompt contact with the hematology team without waiting for the next scheduled appointment, as these may indicate disease transformation or progression.