Acute leukemias

Acute leukemia Malignant disorder in which haemopoietic blast cells constitute >20% of bone marrow cells. These primitive cells usually also accumulate in the blood, infiltrate other tissues and cause bone marrow failure.

Classification Acute lymphoblastic leukaemia (ALL) Acute myeloid (myeloblastic) leukaemia (AML) Rare cases are undifferentiated or mixed. Subclassification of ALL or AML depends on morphological, immunological, cytochemical and cytogenetic criteria.

FAB-classification In 1976, a group of 7 French, American and British hematologists proposed a system of nomenclature, the French-American-British (FAB) cooperative classification system, which is based on the morphology and cytochemical staining of blasts.

M0 Myeloblastic (minimally differentiated by morphology + cytochemistry, myeloid immunophenotype) M1 Myeloblastic (without maturation). Little differentiation, >90% blasts M2 Myeloblastic (with maturation), 20–90% blasts M3 Promyelocytic: intensely granular, variant form is microgranular M4 Myelomonoblastic (biphasic M1 and M5) M5 Monoblastic M6 Erythroblastic, >50% of mononuclear cells are erythroid M7 Megakaryoblastic L1 Acute lymphoblastic (principally pediatric). Small cells. L2 Lymphoblastic (principally adult). Larger cells, lower nuclear/cytoplasmic ratio L3 Burkitt-type.Vacuolated, basophilic blast cells

Incidence ALL is the most common malignancy in childhood (peak age 4 years) but also occurs in adults. AML occurs at all ages but is rarer than ALL in childhood, being most common in the elderly.

Clinical features • Short (<3-month) history of symptoms due to bone marrow failure (e.g. of anaemia, abnormal bruising/bleeding or infection). Disseminated intravascular coagulation (DIC) with bleeding is particularly common in acute promyelocytic leukaemia (AML M3). Increased cellular catabolism may cause sweating, fever and general malaise. Lymphadenopathy and hepatosplenomegaly are frequent, especially in ALL. Tissue infiltration, e.g. of meninges, testes (more common in ALL), skin, bones, gums with hypertrophy (AML M5 or M4).

Laboratory features Anaemia, thrombocytopenia and often neutropenia. Leucocytosis caused by blast cells in the blood usually occurs. Leucopenia is less frequent. The bone marrow shows infiltration by blast cells (>20% and often 80–90% of marrow cells). Coagulation may be abnormal and DIC can occur, especially with AML M3. Serum uric acid, lactate dehydrogenase (LDH) may be raised.

Morphological analysis usually reveals cytoplasmic granules or Auer rods (condensations of granules) in AML. Cytochemical stains are helpful—AML blasts have granules positive by Sudan black, myeloperoxidase and chloroacetate esterase, while monoblasts are positive for non-specific and butyrate esterase. B-lineage lymphoblasts show blocks of positive material with periodic acid–Schiff (PAS) stain, and in T-lineage ALL with acid phosphatase.

Immunophenotype analysis Involves the use of antibodies to identify cell antigens (many termed clusters of differentiation or CD) which correlate with lineage and maturity. Other antigens, e.g. TdT, and cytoplasmic immunoglobulin may be also be detected.

Cytogenetic and DNA microarray analysis gives diagnostic and prognostic information

Neuroleucemia Asimptomatic; PNS infiltration; Intratumor; Headache, vomiting, weakness, nistagm.

Diff. DS Aplasia; MDS; IT; hypersplenism; agranulocytosis; Viruses (hep. В, С, HIV, EB); Leucemoid reactions (sepsis); Myeloproliferation (CML, PMF), LPD with leucemisation (CLL, Bercit lymfoma leucemisation).

Diagnosis Sternal punction. Hematologist’s consultation as fast as possible. Symptomatic treatment before chemotherapy

Treatment Remission-induction - highdose intensive combination chemotherapy to reduce or eradicate leukaemic cells from the bone marrow and re-establish normal haemopoiesis. Further therapy is postinduction chemotherapy: this may be intensive (‘intensification’ or ‘consolidation’ chemotherapy) or less intensive (maintenance chemotherapy). Each course of intensive treatment typically requires 4–6 weeks in hospital.

Acute myeloid leukaemia Remission induction regimes usually comprise an anthracycline (e.g. daunorubicin), cytosine arabinoside and in some protocols etoposide. All trans retinoic acid (ATRA) is given concurrently in acute promyelocytic leukaemia (AML M3) to induce differentiation. More than 80% of patients under the age of 60 years achieve remission, defined as a normal full blood count and <5% blasts in bone marrow, with one course, and >85% patients with two courses. Older patients and those with preceding MDS or AML secondary to another disease (e.g. myeloproliferative disorder, MPD) have lower remission rates. Three further courses are given as post-induction therapy, and other agents used include mitoxantrone, M-AMSA, idarubicin and high dose ara-c. Tumour lysis syndrome may occur

Acute lymphoblastic leukaemia Remission induction regimes comprise vincristine, prednisolone and L-asparaginase often with daunorubicin, cyclophosphamide. Post-remission therapy is with two or three ‘intensification’ blocks with additional drugs. Patients then receive maintenance chemotherapy for a further 2–3 years with daily mercaptopurine, weekly methotrexate and monthly vincristine and dexamethasone. Central nervous system involvement is common in ALL in children and adults, and normal practice is to give multiple intrathecal injections and courses of high-dose systemic chemotherapy with methotrexate or ara-C, or cranial radiotherapy to prevent or treat this complication.

Symptomatic treatment Cytopenias: Hemarragic symptom infections Anemia Antibacterial therapy. hyperleucocytosis– predphase, heparin

Clinicohematological remission – normalisation of perif Clinicohematological remission – normalisation of perif. blood, blasts in bone marrow < 5% (control^ every month during induction and consolidation, later – 1 time per 3 months). Cytogenetic remission – absence of cytogenetic abnormalities Molecular remission– absence of molecular abnorm.

AL relapse more 15% blasts in the bone marrow: Early – < 12 months after remission Late – > 12 months.

Prognosis AML (М0 – М5) - 25 – 30 % - 5-year surv. AML (М6-М7) – poor prognosis М3 - 80-95% - 5-year surv

ALL- 40% - 50% - 5-year surv ALL (adults) – 30% ALL (children) – up to 90%

Transplantation ALL, OML relapse, AML with poor prognosis