bubble_chart Overview

Acute leukemia is the malignant transformation of one or more hematopoietic stem cells and progenitor cells, which lose their normal abilities to proliferate, differentiate, and mature. These cells uncontrollably and continuously proliferate, gradually replacing the bone marrow and infiltrating throughout the body's tissues and organs via the bloodstream.

bubble_chart Clinical Manifestations

The onset is abrupt, with approximately 66% of patients developing symptoms within one month. The condition progresses rapidly and severely. Anemia is a common and early symptom, presenting as severe and progressive anemia, accompanied by pale skin, dizziness, lack of strength, edema, and shortness of breath after activity. Fever is the initial symptom in 50–84% of cases, with varying patterns. There are two scenarios: ① Leukemia-related Bingben systemic fever; caused by increased leukocyte turnover and heightened nucleoprotein metabolism, resulting in low-grade fever, generally not exceeding 38.0°C, and unresponsive to antibiotics. ② Infection: Due to the lack of mature cells and reduced immunity in leukemia patients, various infections often occur, with temperatures potentially reaching 39–41°C, which is a major cause of death. Common infections include upper respiratory tract infections, pharyngitis, tonsillitis, stomatitis, pain, pneumonia, urinary tract infections, and sepsis, with stomatitis being the most frequent. Bleeding often occurs due to thrombocytopenia and infiltration of abnormal immature cells into blood vessels. In adults, early bleeding symptoms account for 38.6% of acute leukemia cases; in the middle to advanced stage, bleeding occurs in about 50–80% of cases, with approximately 10–15% of patients dying from hemorrhage. Fever can exacerbate or trigger bleeding.

Bleeding may occur throughout the body, most commonly in the skin, gums, oral cavity, and nasal membrane, followed by the gastrointestinal tract, urinary tract, uterus, and respiratory tract. In patients with promyelocytic leukemia, bleeding can occur intracranially, in the subarachnoid space, or beneath the dura mater, often with severe consequences. Retinal hemorrhage is often a precursor to intracranial bleeding. Symptoms of abnormal immature leukocyte infiltration include: ① Hepatosplenomegaly, most common, especially in ALL (acute lymphocytic leukemia). ② Lymphadenopathy, occurring in 45.5% of cases, often localized to the neck, armpits, and groin. Generalized lymphadenopathy is most prevalent in ALL, reaching 80% at initial diagnosis. Mediastinal lymphadenopathy is more common in pediatric ALL. ③ Skeletal manifestations: More common in ALL, patients often experience tenderness and pain at the lower end of the sternum, soreness or dull pain in limb joints, and in severe cases, joint swelling. Some patients may develop osteoporosis, osteolytic destruction, or even pathological fractures. AML (acute myeloid leukemia) patients may exhibit orbital infiltration leading to exophthalmos, diplopia, or even blindness, known as chloroma. ④ Neurological manifestations: Approximately 2% of acute leukemia patients present with meningeal leukemia at initial diagnosis. Without prophylactic treatment for central nervous system leukemia, 70% of ALL cases, 20–40% of pediatric cases, and 5% of adult ANLL (acute non-lymphocytic leukemia) cases may develop meningeal leukemia. Leukocyte infiltration into the subarachnoid space can cause hydrocephalus and symptoms of intracranial hypertension. If the subarachnoid space or cerebral blood vessel walls are infiltrated, focal or diffuse cerebral hemorrhage may occur. ⑤ Others: Infiltration of the skin, membranes, testes, lungs, digestive tract, heart, and other areas may lead to corresponding signs.

bubble_chart Auxiliary Examination

Hemoglobin and platelet counts are decreased. The total white blood cell count varies, generally ranging from 20.0 to 50.0×10⁹/L, with a few cases exceeding 100×10⁹ or falling below 10.0×10⁹/L. In over half of the patients, a large number (sometimes up to 90%) of abnormal primitive leukocytes are observed in the peripheral blood smear. Hematocytochemical staining methods can determine the type of acute leukemia. Approximately 45% of cases exhibit chromosomal abnormalities, including haploidy, hyperdiploidy, and various marker chromosomes. The bone marrow is hyperplastic, markedly hyperplastic, or extremely hyperplastic, predominantly composed of leukemic cells. In the bone marrow, a primitive cell count >6% is suspicious, exceeding 30% is more definitive for diagnosis, and primitive cells + early (immature) cells ≥50% confirm the diagnosis. In the entire bone marrow, the erythroid and megakaryocytic series are significantly reduced. When blood and bone marrow findings are insufficient to confirm acute leukemia, lymph node puncture smear and specific skin lesion imprint examinations can be performed to identify corresponding leukemic cell combinations, aiding in diagnosis. Blood generation and transformation tests include: ① Terminal deoxynucleotidyl transferase (TDT): Activity is elevated in ALL but absent in ANLL. ② Alkaline phosphatase (AKP): Markedly elevated in ALL but significantly reduced in AML. ② Lactate dehydrogenase (LDH): Significantly increased in ALL. Additionally, serum uric acid concentration is elevated, and urinary uric acid excretion is increased, especially during treatment with cytotoxic drugs.

bubble_chart Diagnosis

I. Medical History and Symptoms

(1) History Inquiry: Note: ① Onset conditions. ② Exposure to radiation or chemical substances such as benzene and its derivatives. ③ Use of alkylating agents like chlorambucil, melphalan, or nitrogen mustard. ④ Presence of diseases such as Bloom syndrome, Fanconi anemia, or Down syndrome.

(2) Clinical Symptoms: General anemia symptoms, epistaxis, gum bleeding or gastrointestinal bleeding, fever, bone pain, arthralgia. Central nervous system involvement may manifest as headache, nausea, vomiting, spasm, incontinence, or even unconsciousness.

II. Physical Examination Findings

Anemic appearance, petechiae or ecchymosis on the skin, gum bleeding or hyperplasia, lymphadenopathy, tenderness in the middle and lower sternum, mild hepatosplenomegaly (grade II).

III. Auxiliary Examinations

Blood Test: Progressive decrease in hemoglobin and platelets; white blood cell count may increase or decrease, with the presence of blasts or immature cells in the differential count.

Bone Marrow Examination: Hypercellular to markedly hypercellular, possibly accompanied by myelofibrosis or bone marrow necrosis. Based on the proliferating cell lineage, it is classified into acute non-lymphocytic leukemia (ANLL) and acute lymphocytic leukemia (ALL). The bone marrow characteristics are as follows:

(1) ANLL: ① M1 (Acute Myeloblastic Leukemia, Undifferentiated): Myeloblasts ≥90% (non-erythroid cells), with few promyelocytes; myelocytes and later stages are absent or rare. Auer rods may be observed. Erythroid and megakaryocytic lineages are suppressed.

② M2 (Acute Myeloblastic Leukemia, Partially Differentiated): Myeloid hyperplasia with Auer rods; erythroid and megakaryocytic lineages are suppressed. Further subdivided by granulocyte differentiation: M2a: Myeloblasts 30–90% (non-erythroid cells), monocytes <20%，早幼粒細胞以下階段> <10%. M2b: Marked increase in myeloblasts and promyelocytes, but abnormal neutrophilic myelocytes predominate (>30%), with prominent nucleoli and nuclear-cytoplasmic asynchrony.

③ M3 (Acute Promyelocytic Leukemia with Increased Granules): Hyperplasia of abnormal promyelocytes with increased granules (>30% of non-erythroid cells); Auer rods are common. Erythroid and megakaryocytic lineages are suppressed. Subtypes: M3a (Coarse Granular Type): Large, dense, or fused azurophilic granules. M3b (Fine Granular Type): Dense and fine azurophilic granules.

④ M4 (Acute Myelomonocytic Leukemia): Myeloid and monocytic hyperplasia; erythroid and megakaryocytic lineages are suppressed. Subtypes: M4a: Predominantly myeloblasts and promyelocytes, monocytes ≥20% (non-erythroid cells). M4b: Predominantly monoblasts and promonocytes, myeloblasts and promyelocytes >20% (non-erythroid cells). M4c: Blasts with both myeloid and monocytic features (>30% of non-erythroid cells). M4Eo: Additionally, large round eosinophilic granules and dark basophilic granules (5–30% of non-erythroid cells).

⑤ M5 (Acute Monocytic Leukemia): Monocytic hyperplasia with fine Auer rods; erythroid, myeloid, and megakaryocytic lineages are suppressed. Subtypes: M5a (Undifferentiated): Monoblasts ≥80% (non-erythroid cells). M5b (Partially Differentiated): Blasts and immature cells >30%, monoblasts <80% (non-erythroid cells).

⑥M6 type (erythroleukemia): Erythroid series >50%, with morphological abnormalities, non-erythroid myeloblasts (or blasts + immature monocytes >30% (non-erythroid cells); if myeloblasts or monoblasts in peripheral blood >5%, then myeloblasts or blasts + immature monocytes in bone marrow non-erythroid cells >20%. Megakaryocytes are reduced.

⑦M7 type (acute megakaryoblastic leukemia): Megakaryoblasts >30%. Erythroid and granulocytic lineages show relative suppression.

⑵ALL: ① L1 type: Marked proliferation of primitive and immature lymphocytes with increased proportion, predominantly small lymphocytes; nuclei are round, occasionally indented or folded, chromatin is coarse and structurally uniform, nucleoli are few and indistinct; cytoplasm is scanty, mildly or grade II basophilic.

②L2 type: Marked proliferation of primitive and immature lymphocytes with increased proportion, lymphocytes vary in size, predominantly large cells; nuclear shape is irregular, indentations and folds are easily seen, chromatin is looser and structurally non-uniform, nucleoli are more distinct, one or multiple; cytoplasm is more abundant, mildly or grade II basophilic.

③L3 type: Marked proliferation of primitive and immature lymphocytes with increased proportion, but cell size is relatively uniform, predominantly large cells; nuclear shape is more regular, chromatin appears uniformly fine and punctate, nucleoli are one or multiple, more prominent, vesicular; cytoplasm is abundant, deep blue, vacuoles are often prominent, appearing honeycomb-like.

Cytochemical staining:

⑴Peroxidase and Sudan black staining: heat stranguria cells are negative (positive <3%）；急粒細胞呈強陽性；急單細胞呈陽性或弱陽性。

⑵Glycogen staining: heat stranguria cells are positive (coarse granules or clumps, often localized to one side of the cytoplasm); acute myeloid and monocytic cells are weakly positive (diffuse fine granular); erythroleukemia: erythroblasts are strongly positive.

⑶Non-specific esterase staining: Acute monocytic cells are strongly positive, significantly inhibited by sodium fluoride (>50%); acute myeloid cells are positive or weakly positive, sodium fluoride grade I inhibition ( <50%）；急淋細胞一般呈陰性。

⑷Neutrophil alkaline phosphatase staining: heat stranguria leukemia shows increased or normal scores; acute myeloid leukemia is markedly decreased; acute monocytic leukemia may be increased or decreased.

Immunological, cytogenetic, and gene typing should be performed if conditions permit.

IV. Differential Diagnosis

Should be differentiated from aplastic anemia, myelodysplastic syndrome, pestilence mononucleosis, idiopathic thrombocytopenic purpura, and leukemoid reactions.

bubble_chart Treatment Measures

1. Treatment Principles: The general treatment principle is to eliminate leukemia cell populations and control the excessive proliferation of leukemia cells, thereby alleviating various clinical manifestations caused by leukemia cell infiltration.

2. Supportive Treatment

(1) Rest: Patients with high fever, severe anemia, or significant bleeding should rest in bed. Consume high-calorie, high-protein foods and maintain water and electrolyte balance.

(2) Prevention and Treatment of Infections: Severe infections are a major cause of death, making infection prevention and treatment crucial. "Sterile" wards or zones should be established in hospital areas to isolate patients with low neutrophil counts or those undergoing chemotherapy. Pay attention to oral, nasopharyngeal, and perianal skin hygiene to prevent mucosal ulcers, erosions, and bleeding. Prompt symptomatic treatment should be administered if these occur. Food and utensils should be sterilized. Non-absorbable oral antibiotics, such as gentamicin and colistin, and antifungals, such as nystatin and vancomycin, should be used to kill or reduce intestinal bacteria and fungi. For patients with existing infections, bacterial cultures and drug sensitivity tests should be conducted before treatment to select effective antibiotics. Generally, fungal infections can be treated with nystatin, clotrimazole, or miconazole; viral infections may be treated with Ara-c or ribavirin. For infections caused by granulocytopenia, leukocyte or plasma transfusions may be administered for symptomatic relief.

(3) Correction of Anemia: Patients with significant anemia may receive red blood cell or fresh whole blood transfusions as needed. Autoimmune anemia can be treated with adrenal corticosteroids, testosterone propionate, or anabolic steroids.

(4) Control of Bleeding: Chemotherapy for leukemia to achieve remission is the most effective way to correct bleeding. However, before chemotherapy-induced remission, thrombocytopenia-related bleeding may occur, which can be prevented with oral adrenobazone. Severe bleeding may be treated with adrenal corticosteroids, whole blood transfusions, or platelet transfusions. Acute leukemia (especially early-stage) is prone to DIC. Once diagnosed, heparin should be administered promptly. When DIC is complicated by fibrinolysis, antifibrinolytic drugs (such as aminocaproic acid or tranexamic acid) should be given alongside heparin therapy. Fresh blood or plasma transfusions may be necessary in severe cases.

(5) Prevention and Treatment of Hyperuricemia: In patients with very high white blood cell counts undergoing chemotherapy, massive leukocyte destruction and breakdown can increase uric acid levels, sometimes leading to urinary tract obstruction by uric acid stones. Therefore, special attention should be paid to urine output, and urinalysis and uric acid concentration measurements should be performed. In addition to encouraging fluid intake, patients should be given allopurinol at 10 mg/kg/day, divided into three oral doses for 5–6 days. When uric acid levels exceed 59 µmol/L, aggressive fluid therapy and urine alkalinization are required.

3. Chemotherapy: Chemotherapy is the primary method for treating acute leukemia and can be divided into two phases: remission induction and maintenance therapy. Additional stages may include intensification therapy, consolidation therapy, and central nervous system (CNS) prophylaxis. Remission induction involves high-dose, multi-drug combination chemotherapy aimed at rapidly and extensively killing leukemia cells, controlling the disease, and achieving complete remission (CR), laying the foundation for subsequent treatments. Complete remission refers to the complete disappearance of leukemia symptoms and signs, with blood and bone marrow morphology largely returning to normal. In untreated acute leukemia, the estimated number of leukemia cells in the body is around 5×10^10 to 10^13. Even when remission criteria are met after treatment, a significant number of leukemia cells may persist, estimated to be below 10^8 to 10^9, and some leukemia cell infiltration may still exist in hidden extramedullary sites. Maintenance therapy involves a series of lower-dose, milder treatment regimens administered over an extended period. Its purpose is to consolidate the complete remission achieved through induction and enable patients to maintain this "disease-free" state long-term, ultimately leading to a cure. Consolidation therapy follows maintenance therapy. Before maintenance therapy begins, the remission induction regimen may be repeated if the patient's condition permits. Intensification therapy involves repeating the original remission induction regimen during the course of maintenance therapy. CNS prophylaxis should be initiated immediately after remission is achieved during induction therapy to prevent or reduce the occurrence of CNS leukemia. A comprehensive treatment plan should adhere to the principles outlined above.

(1) Treatment of Acute Lymphoblastic Leukemia

①Remission Induction Therapy: The commonly used chemotherapy regimen for ALL is the VP regimen. Based on the VP regimen, many effective multi-drug combination regimens have been developed by incorporating drugs such as DRN (daunorubicin), ADM (adriamycin), Ara-c, L-ASP (L-asparaginase), and 6-MP. The complete remission (CR) rate for initial treatment in children can reach 90–95%, while in adults, it can reach 80–90%. Multi-drug combination regimens are mainly used for the treatment of refractory and relapsed cases. Common regimens are listed in the table below.

Table Remission Induction Regimens for Acute Lymphoblastic Leukemia

Note: VP and DVP regimens are suitable for pediatric cases.

②Maintenance therapy: After achieving CR with the above regimens, continue with the original regimen to consolidate efficacy. For VP and VDP regimens, continue for another 2～3 weeks; for POMP regimen, administer two more courses. During the remission stage, use 6-MP 100mg/d orally for 7 consecutive days, followed by CTX 400mg IV; after a 7-day interval, administer MTX 15mg IV or orally on days 1, 5, 9; repeat the above treatment sequence after a 3-day interval.

③Treatment of relapse: Continue with VP regimen or Ara-C 5～10mg IV daily for 4 doses, or DRN 1mg/kg·d IV for 4 days.

(2)Treatment of acute non-lymphocytic leukemia

①Remission induction: Treatment regimens are shown in Table 30-3.

Note: In the VPP regimen, DRN can be replaced with ADM, dose 20mg, intravenous injection, days 1 and 2

②Maintenance therapy: Generally, MTX 15mg intramuscular injection or oral administration, 6-MP 100mg/d, CTX 200mg/m²oral administration, once weekly, long-term maintenance. Consolidation and intensification with the original induction regimen should be added at 1/2, 1, 2, 4, 7, and 16 months after the start of maintenance therapy. After 16 months, repeat every 6 months for at least 2～4 years.

(3) Pediatric ALL treatment regimen

①Remission induction: (VP regimen and variations) 1)VCR 2.0mg/m²/week, for 4 weeks. 2)PDN 60mg/m²/day. 3)Alternatively, add ADM 20mg/m², days 14 and 15.

②Prevention and treatment of central nervous system leukemia: MTX 12mg/m² (large dose: 30mg/m²) intrathecal injection, once every 2 weeks
, for 3 consecutive weeks; in addition, 24Gy (2400rad) cranial irradiation is added.

③ Stage of remission Maintenance therapy:

Protocol 1──⑥ 6-MP 75mg/m², continuous oral administration. ⑥ VCR 2.0mg/m² on day 1 every 4 weeks per cycle. ① PDN 120mg/m²/day for 5 consecutive days.

Protocol 2──＠ MTX 50mg/m² IV, every 2 weeks alternated with the following drugs. ⑥ VCR 2.0mg/m² on day 1. ② PDN 120mg/m²/day for 5 consecutive days, alternated with MTX every 2 weeks. ① 6-MP 100mg/m²/day × 5 days. ^{Protocol 3──⑧ MTX 75～225mg/m}2 ^{IV, every 2 weeks alternated with the following drugs. ⑥ VCR 2.0mg/m}2 ^{on day 1, alternated with MTX every 2 weeks. ② PDN 120mg/m}2^{/day for 5 consecutive days. ① 6-MP 125～175mg/m}2

/day × 5 days.

(4) Chemotherapy for pediatric ANLL

The VAPA protocol is a multi-drug intensified sequential comprehensive treatment program, lasting 14 months, excluding CNS prophylactic treatment. It has significantly improved the treatment outcomes for pediatric ANLL, especially in achieving long-term remission. The structure and administration of the VAPA protocol are as follows: ^{Treatment Phase I──ADM 45mg/m}2^{/day, IV, day 1; Ara-C 200mg/m}2

/day, IV, days 1～5. The above regimen is repeated every 3～4 weeks as one cycle, for a total of 4 cycles. ^{Treatment Phase II──ADM 30mg/m}2^{/day, IV, day 1; Ara-C 150mg/m}2

/day, IV, days 1～5; The above regimen is repeated every 4 weeks as one cycle, for a total of 4 cycles. ^{Treatment Phase III──VCR 1.5mg/m}2^{/day, IV, day 1; Me-PDN 800mg/m}2

/day, IV, days 1～5; ^{6-MP 500mg/m}2^{/day, IV, days 1～5; MTX 7.5mg/m}2

/day, IV, days 1～5; The above regimen is repeated every 3 weeks as one cycle, for a total of 4 cycles. ^{Treatment Phase IV──Ara-C 200mg/m}2

/day, IV, days 1～5, repeated every 3～4 weeks as one cycle, for a total of 4 cycles.

4. Prevention and treatment of central nervous system (CNS) leukemia ^{Both CNS leukemia and meningeal leukemia are treatable, with MTX as the first-choice drug for intrathecal injection. However, the prognosis is often poor, emphasizing the importance of CNS prophylactic treatment. Generally, MTX 0.25～0.5mg/kg/dose or 42mg/m}2

/dose (maximum 20.0mg) is administered intrathecally until symptoms resolve. Subsequently, the same drug and dose are given intrathecally every 6～8 weeks to prevent relapse. Radiotherapy, such as 60Co cranial irradiation or spinal irradiation, may also be used.

5. Radiotherapy {|156|} (1) Splenic irradiation: For cases with splenomegaly, pain, or inoperability. The dose is 1000～2000cGy/3～10 fractions over 3 to 12 days.

(2) Hard membrane external infiltration compressing the spinal cord: The irradiation field extends beyond the lesion area by 2 vertebral bodies both above and below. The irradiation dose is 300–400 cGy per session. After 3 sessions, it is changed to 200 cGy per session for a total of 15 sessions.

(3) Central Nervous System Irradiation: Primarily used for patients with elevated white blood cell counts, T-cell type, thrombocytopenia, and significant lymph node and spleen enlargement. ① Prophylactic irradiation: Begins after symptom relief through chemotherapy, with whole-brain irradiation using bilateral opposing fields, at a dose of 1800–2200 cGy. ② Therapeutic irradiation: Combined with chemotherapy, whole-brain irradiation at 1800 cGy. ③ Recurrence treatment: Central nervous system irradiation, with cranial doses of 2000–2500 cGy and spinal cord doses of 1000–1250 cGy.

(4) Total Marrow Ablation: 800 cGy per session, administered over 3 days.

Additionally, localized irradiation can be used for extramedullary lesions, excluding palliative treatment. Radiotherapy should be combined with high-dose adrenal corticosteroids and may also include intrathecal injections of MTX + Ara-C + hydrocortisone.

6. Immunotherapy: Although prolonged consolidation and intensification therapy are administered, a certain number of leukemia cells remain in the body, which chemotherapy cannot completely eliminate. The body's immune system may help eradicate these residual leukemia cells. In recent years, immunotherapy has gradually been applied clinically, with commonly used agents including BCG, TF, and IFN.

7. Bone Marrow Transplantation: More effective for ANLL. ① Syngeneic bone marrow transplantation, with donors being identical twins. ② Allogeneic bone marrow transplantation, with donors being the patient's siblings. ③ Autologous bone marrow transplantation, which does not require donor selection and is easier to promote.

bubble_chart Prognosis

The average survival time for untreated individuals is only about 3 months. However, with modern chemotherapy, the disease can be alleviated, survival time significantly prolonged, and even long-term survival or cure achieved. Factors determining treatment efficacy, in addition to the direct impact of treatment methods, include certain intrinsic factors of leukemia and the patient. High-risk factors associated with poor prognosis include: ① Age under 1 year or over 9 years in children and adults, with particularly poor outcomes in those over 60; ② Worse prognosis for boys compared to girls; ③ Pre- or post-treatment cell counts above 50–100×10⁹/L; ④ FAB classification of L₂, L₃, L₄, L₅, L₆, or L₇; ⑤ Immunophenotyping of lymphocytic leukemia as T-cell or B-cell; ⑥ Presence of chromosomal abnormalities, especially breaks and translocations, except for t(8;21); ⑦ Pre-treatment platelet count <20–50×10⁴/L; ⑧ Slow reduction of leukemia cells post-treatment, prolonged time to remission, or short remission duration; ⑨ Significant hepatosplenomegaly or presence of CNS leukemia.