Hematopoietic Stem Cells: Acute Leukemias — Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia

Definition and Approach

Acute leukemias are hematologic malignancies in which clonal myeloid or lymphoid precursor cells, arrested at an immature stage, proliferate without restraint and with abnormally delayed differentiation, infiltrating bone marrow, blood, and sometimes other tissues. The classic diagnostic threshold is blasts exceeding 20% of the bone marrow or blood — a cutoff that no longer applies uniformly in the current classification (see the classification update below). In adults, acute myeloid leukemia (AML) is substantially more common than acute lymphoblastic leukemia (ALL); the reverse is true in children.

Acute leukemia is a medical urgency — days matter between suspicion and treatment. A practical approach has four elements: (1) secure the diagnosis quickly with marrow examination, flow cytometry, cytogenetics, and molecular studies, because the subtype dictates everything; (2) assign genetic risk early, since post-remission strategy (chemotherapy versus allogeneic transplantation) follows directly from it; (3) assess the patient's fitness and comorbidities honestly, because treatment intensity determines both the chance of cure and the risk of treatment-related death; and (4) open goals-of-care conversations at the outset, especially in older patients in whom cure is unlikely.

AML: Epidemiology and Pathogenesis

AML is the most common acute leukemia in older adults, with a median age at diagnosis of 69 years. Roughly 20,000 new cases are diagnosed annually in the United States — about 1% of all cancers and about one-third of new acute leukemias — yet AML causes nearly two-thirds of leukemia deaths, and only about one-third of patients survive five years. The age divide is stark: AML is curable in 35% to 40% of adults aged 60 or younger, but cure rates fall to just 5% to 15% in adults older than 60, in whom comorbidities such as cardiopulmonary disease often preclude intensive chemotherapy or transplantation.

Most cases are idiopathic, but several etiologic routes are recognized. Therapy-associated AML is the leading identifiable cause: after alkylating agents, leukemia typically emerges 4–6 years later, often with multilineage dysplasia, chromosome 5 or 7 abnormalities, TP53 mutation, and a poor prognosis; after topoisomerase II inhibitors it appears sooner (1–3 years) and often shows monocytic features with 11q23 (KMT2A) rearrangements. Ionizing radiation, benzene, and antecedent marrow-failure states can also precede AML. Inherited predisposition is uncommon but increasingly recognized — germline pathogenic variants in CEBPA, DDX41, TP53, RUNX1, ANKRD26, ETV6, and GATA2, and in bone marrow failure and telomere biology syndromes (Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita); a family history of AML or chronic cytopenias should prompt consideration of genetic counseling. Down syndrome confers increased AML risk in young children, classically with megakaryocytic differentiation.

At the molecular level, AML is understood as a disease of stepwise somatic mutation. Many older adults harbor clonal hematopoiesis of indeterminate potential (CHIP) — clonally expanded blood cells carrying potentially premalignant mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1. CHIP confers roughly a 10-fold increase in the risk of hematologic malignancy, but additional mutational "hits" are needed before leukemia develops; CHIP also carries an excess cardiovascular risk, plausibly from inflammatory effects of clonal myeloid cells on the vascular endothelium. Mutations in IDH1 or IDH2 illustrate how a single lesion can hijack cell biology: the mutant enzyme produces the oncometabolite 2-hydroxyglutarate, which disrupts epigenetic regulation and blocks differentiation — exactly the vulnerability exploited by IDH inhibitors.

AML: Classification and Risk Stratification

Cytogenetic and molecular classification is increasingly important: the genetic lesions of the leukemic clone drive clinical presentation, prognosis, and therapy selection. Historically the diagnosis required ≥20% blasts plus morphologic categorization; the current systems instead define most AML subtypes by their characteristic genetic abnormalities.

A growing number of molecular markers guide prognosis and therapy. Mutated NPM1 — found in about half of patients with AML and in the majority of cytogenetically normal cases — is associated with a favorable outcome. In contrast, FLT3 internal tandem duplications (FLT3-ITD), found in approximately one-third of patients with cytogenetically normal AML, confer an unfavorable outcome and merit consideration of allogeneic transplantation in first remission; the duplication drives proliferative and anti-apoptotic signaling in myeloid precursors. Additional prognostically important lesions include in-frame bZIP mutations of CEBPA (favorable) and TP53 mutation or a complex karyotype (adverse, with virtually no chance of cure without transplantation).

AML: Clinical Presentation and Diagnosis

AML typically manifests with the consequences of marrow replacement: anemia (fatigue and dyspnea, whose severity varies with age and comorbidities), thrombocytopenia, and functional neutropenia due to infiltration by abnormal myeloblasts. Petechiae, epistaxis, and other mucosal hemorrhages become common once the platelet count dips below 20,000/μL (20 × 10⁹/L). Although the leukocyte count is often elevated, the absolute neutrophil count tends to be low, which increases infection risk. Myeloblasts are usually visible on the peripheral smear but may be absent despite unequivocal marrow involvement — a reassuring differential does not exclude the disease.

Fatigue is the most frequent first symptom, and fever is the presenting complaint in about 10%. The median presenting leukocyte count is roughly 15,000/μL, but about one-fifth of patients have hyperleukocytosis (>100,000/μL), which risks leukostasis — pulmonary compromise and early CNS bleeding — and is an emergency. Extramedullary blast tumors (myeloid sarcomas), classically associated with t(8;21), can involve skin, lymph nodes, gut, soft tissue, or testis and may precede marrow disease. Gingival hypertrophy, skin infiltration, and meningeal involvement are hallmarks of monocytic subtypes and KMT2A-rearranged AML.

A classic dermatologic association is Sweet syndrome (acute febrile neutrophilic dermatosis): fever, neutrophilia, and tender, sharply demarcated "juicy" edematous red-purple plaques and nodules with a dense dermal infiltrate on histology (MKSAP Figure 6). Sweet syndrome occurs in patients with hematologic abnormalities, particularly MDS and MDS evolving into AML.

The diagnostic workup should be swift and complete: bone marrow aspirate and biopsy with morphology, multiparameter flow cytometry, cytogenetics, and molecular studies; baseline assessment of cardiac, pulmonary, hepatic, and renal function; early HLA typing for potential transplant candidates; and tumor lysis prophylaxis with hydration and allopurinol (reserving rasburicase for severe hyperuricemia or kidney injury). Cryopreservation of leukemic cells enables future molecular testing as new diagnostics and therapeutics emerge.

Acute Promyelocytic Leukemia: A Distinct Subtype and an Emergency

Acute promyelocytic leukemia (APL), defined by t(15;17)(q22;q12) or the PML::RARA fusion, deserves separate emphasis. The fusion protein blocks differentiation at the promyelocyte stage, and the resulting immature leukocytes carry distinctive abnormal primary granules that trigger coagulopathy (MKSAP Figure 5). Disseminated intravascular coagulation — causing both hemorrhage and, counterintuitively, thrombosis — is the signature of APL presentation and the main driver of early death.

APL was an early prototype of targeted therapy in hematologic malignancy because treatment reverses the underlying differentiation block. ATRA induces maturation of the leukemic promyelocytes; combined with arsenic trioxide (ATO), ATRA-ATO is the standard regimen for low-risk APL (leukocyte count ≤10,000/μL), superior to ATRA plus anthracycline chemotherapy. Complete remission rates in low-risk disease approach 100%, and roughly 85% of all APL patients achieve long-term survival. High-risk APL (leukocyte count >10,000/μL) behaves differently: patients need immediate cytoreduction with chemotherapy because differentiating cells can drive a rapidly rising leukocyte count and life-threatening differentiation syndrome.

After therapy, serial PCR for the PML::RARA transcript is the standard monitoring tool: disappearance of the signal predicts durable disease-free survival, while persistence or re-emergence reliably precedes overt relapse, allowing reinduction to begin early.

AML Treatment (Non-APL): Induction and Consolidation

Induction aims to ablate the marrow and eliminate blasts. The standard "7+3" regimen delivers continuous-infusion cytarabine (100–200 mg/m²/day for 7 days) with an anthracycline — daunorubicin 60–90 mg/m² or idarubicin 12 mg/m² — on days 1–3. The expected result is a period of marrow aplasia lasting three to four weeks, during which the patient is supported with transfusions (erythrocytes and platelets; platelets typically maintained above 10,000/μL, with higher thresholds for fever, active bleeding, or DIC) and prompt empiric broad-spectrum, antipseudomonal antibiotics for neutropenic fever, adding antifungal coverage if fever persists. A complete response is achieved in 60% to 85% of patients younger than 60. The anti-CD33 immunoconjugate gemtuzumab ozogamicin may be added to induction, especially in core-binding factor AML, and liposomal cytarabine-daunorubicin (CPX-351) is an option for fit patients with myelodysplasia-related AML.

Because virtually all patients who achieve a complete remission will eventually relapse without further therapy, consolidation is mandatory. For low-risk disease, consolidation consists of additional cycles of chemotherapy — two to four cycles of intermediate-dose cytarabine (1–1.5 g/m² every 12 hours on days 1–3), which is as effective as higher doses without the added toxicity. For intermediate- and adverse-risk disease, allogeneic hematopoietic stem cell transplantation in first remission is the most effective relapse prevention: its power lies in the graft-versus-leukemia effect of donor immune cells, traded off against graft-versus-host disease and treatment-related mortality. HLA-mismatched unrelated, haploidentical, and cord-blood donors have broadened access, so virtually any patient with a healthy parent or child has a potential donor; allogeneic transplantation is recommended up to about age 75 for patients without favorable-risk disease. For older patients who achieve remission but have no transplant option, maintenance with prolonged low-dose oral azacitidine improves survival.

Targeted agents are layered onto this backbone according to genotype. Midostaurin and gilteritinib are the FLT3 inhibitors cited as approved for first- or second-line therapy; the landscape has since expanded (see update below). Midostaurin is added to first-line chemotherapy for FLT3-mutated AML, and gilteritinib is the standard single-agent choice at relapse. Mutant IDH1 and IDH2 are targetable with ivosidenib (and olutasidenib) and enasidenib, respectively; these drugs reverse the epigenetic effects of the 2-hydroxyglutarate oncometabolite and can restore marrow function, although monotherapy is rarely curative.

Measurable residual disease (MRD) assessment — by multiparameter flow cytometry or sensitive PCR for lesions such as mutated NPM1, RUNX1::RUNX1T1, or CBFB::MYH11 — increasingly refines risk after remission. Persistent MRD predicts relapse; in NPM1-mutated AML, MRD negativity by PCR after two courses of chemotherapy predicts a favorable outcome without transplantation, while MRD positivity argues for proceeding to transplant. Even undetectable MRD does not eliminate relapse risk entirely.

Older or Unfit Patients

Historically, treatment for older or frail patients was unsatisfactory: transfusion support, lower-dose, often single-agent chemotherapy such as oral hydroxyurea or low-dose cytarabine, and hypomethylating agents (azacitidine, decitabine) sometimes combined with FLT3 or IDH inhibitors — with expected survival of only months and hospice care appropriately considered. The bar has moved: venetoclax (a BCL-2 antagonist) plus a hypomethylating agent is now the standard first-line approach for patients unfit for intensive induction (see the ELN 2022 update above), producing first-line response rates around 60%. Alternatives include IDH-inhibitor monotherapy for the frailest patients harboring IDH1/2 mutations and clinical trials for everyone; even infirm patients fare better with treatment than with supportive care alone. Cure remains unusual in this population, however — median survival with venetoclax combinations is approximately 15 months — so treatment intensity must be weighed against comorbidity and patient goals.

Relapsed/Refractory AML and Newer Agents

The duration of first remission predicts salvage success: patients relapsing after a long first remission (>12 months) often retain drug-sensitive disease, whereas early relapse is rarely cured by salvage chemotherapy alone. Eligible patients who achieve a second remission should proceed to allogeneic transplantation; relapse after transplant carries very poor outcomes, and clinical trials are the preferred route whenever available. Most new agents target recurring AML lesions — FLT3, IDH1/2, CD33 — or shared biology such as HOXA-cluster gene upregulation.

Acute Lymphoblastic Leukemia: Adult Overview

ALL is predominantly a childhood disease, with an incidence peak at ages 3–4 years; adult incidence is roughly 0.7–1.8 per 100,000 per year. Although ALL in children is often curable (about 90%), survival in adults (older than 19 years) remains inferior despite adoption of pediatric-inspired regimens. Patients present with malaise, bleeding, infections, bone pain, or a combination; a small subset (<10%) has symptomatic CNS involvement at diagnosis. Notably, the leukocyte count is normal or low in about 40% of adults, and circulating blasts can be absent in about 8% — so an automated count alone can miss the diagnosis.

In adults, 75% of ALL is of B-cell lineage. Mature B-cell ALL (Burkitt leukemia) tends to extramedullary disease, including gastrointestinal or testicular involvement. T-cell ALL (about 25% of adult cases) classically presents with a mediastinal mass — wheezing or stridor in a young patient — or skin involvement, and has higher CNS tropism. Similar to AML, ALL is classified by immunophenotype, cytogenetics, and molecular abnormalities. Ph-like ALL — a defined entity lacking BCR::ABL1 but harboring kinase-activating rearrangements (ABL1, JAK2, PDGFRB) and IKZF1 deletions — accounts for about a quarter of young adult cases.

The most important cytogenetic abnormality in adult ALL is the Philadelphia chromosome, found in 20% to 30% of adults and rising to roughly half of B-lineage cases in the elderly. Historically, Philadelphia chromosome–positive ALL had a poor prognosis; tyrosine kinase inhibitors such as imatinib and dasatinib added to chemotherapy dramatically improved remission rates, and after remission induction, patients with Philadelphia chromosome–positive ALL often receive additional intensive consolidation with allogeneic HSCT — an algorithm now being rewritten by chemotherapy-free combinations (see update below). Baseline evaluation includes lumbar puncture — with intrathecal methotrexate given at the first tap to clear any inadvertently seeded blasts — and storage of diagnostic marrow for later MRD tracking.

ALL Treatment: Phases, CNS Prophylaxis, and Immunotherapy

Regimens are complex and multi-phase: a glucocorticoid pre-phase (safe cytoreduction while the workup completes and tumor lysis is averted); induction built on vincristine, an anthracycline, corticosteroids (often dexamethasone, favored for CNS penetration), and L-asparaginase — with complete remission rates of 80% to 90%; six to eight consolidation cycles using systemic high-dose methotrexate and cytarabine to reach sanctuary sites; and a maintenance phase of daily oral mercaptopurine and weekly methotrexate lasting up to 2 years, during which medication adherence can be problematic. Adolescents and young adults do best with pediatric-inspired regimens that emphasize ALL-specific drugs over myeloablative chemotherapy (overall survival 70–80%), while elderly or frail patients benefit from lower-intensity glucocorticoid-, vincristine-, and asparaginase-based regimens that largely avoid anthracyclines and alkylators.

MRD is the single most important prognostic factor during ALL therapy. Patients in molecular complete remission after induction have disease-free survival of about 70%, compared with under 40% for MRD-positive patients; MRD-positive patients should move toward targeted therapy and, when feasible, allogeneic transplantation in first remission. MRD negativity has also become the entry point for frontline immunotherapy:

At relapse, immunotherapy is the backbone of salvage: blinatumomab (bispecific CD19/CD3 engager) converts 70–80% of MRD-positive patients to MRD negativity; inotuzumab ozogamicin (anti-CD22 immunoconjugate) achieves complete remission in roughly two-thirds of relapsed/refractory patients but carries veno-occlusive disease risk, particularly before transplantation; and CD19-directed CAR T cells induce complete remissions in 67–91% of heavily pretreated adults — MRD-negative in most responders — and are also active in CNS disease. The principal anti-CD19 toxicities are cytokine release syndrome and neurotoxicity, managed with early recognition and ICU support when needed; CD19-negative relapse from antigen downregulation remains a hurdle. Rituximab added to short intensive cycles has pushed survival in Burkitt/mature B-ALL above 80%. For T-ALL, which lacks equivalent immunotherapy targets, nelarabine added to intensive chemotherapy is the key advance, with transplantation in first remission reserved for high-risk or MRD-positive disease.

Leukemia in Pregnancy

Managing acute leukemia during pregnancy is challenging because the health of mother and fetus — and long-term infant and child well-being — must all be considered. First-trimester toxicity can be significant, although anthracycline- and cytarabine-based chemotherapy is often successfully administered during the second and third trimesters.

Survivorship and Late Effects

Adult survivors of childhood leukemia face higher risks of secondary cancer, cardiovascular disease, and the metabolic syndrome (elevated BMI and waist circumference, dyslipidemia, elevated fasting glucose, and hypertension) than age-matched controls. Primary care physicians encountering such patients should request a treatment summary from the treating facility and encourage participation in a local survivorship clinic. Screening for dyslipidemia, diabetes, and hypertension is recommended, and echocardiography to detect left ventricular dysfunction should be repeated every 3–5 years — particularly after high anthracycline exposure (such as doxorubicin exceeding 300 mg/m²) or chest radiation; female survivors have an increased risk of myocardial dysfunction during pregnancy. The high-dose glucocorticoids typical of ALL regimens raise the risk of osteopenia. The cumulative incidence of secondary cancer after radiation therapy for childhood ALL reaches 11% at 30 years (skin cancer, thyroid and parotid tumors, sarcomas, and brain tumors), and cranial radiation also increases the risk of stroke and neurocognitive deficits. Counseling should cover lifestyle risk factors, age-based screening, and early reporting of persistent symptoms.