Leukemia in children. Haemolytic Uraemic Syndrome (HUS).

1. Leukemia in children. Haemolytic Uraemic Syndrome (HUS). Sakharova Inna. Ye., MD, Univ. assistant

3. Acute lymphoblastic leukaemia (ALL)is a malignant transformation of a clone of cells from the bone marrow where early lymphoid precursors proliferate and replace the normal cells of the bone marrow.

4. Risk factors for the development of childhood leukemia • Heredity(presence of inherited genetic syndromes, for example Down syndrome or ataxia telangiectasia, presence of cytogenetic abnormalities) • Environmental factors(ionizing radiation and electromagnetic fields, parental use of alcohol and tobacco)

5. The conclusion of the USA National Radiological Protection Board is: Laboratory experiments have provided no good evidence that extremely low frequency electromagnetic fields are capable of producing cancer, nor do human epidemiological studies suggest that they cause cancer in general. There is, however, some epidemiological evidence that prolonged exposure to higher levels of power frequency magnetic fields is associated with a small risk of leukaemia in children. In practice, such levels of exposure are seldom encountered by the general public in the UK. In the absence of clear evidence of a carcinogenic effect in adults, or of a plausible explanation from experiments on animals or isolated cells, the epidemiological evidence is currently not strong enough to justify a firm conclusion that such fields cause leukaemia in children.

6. According to the French-American-British (FAB) classification, leukemic lymphoblasts in ALL subdivide into three categories: • L1lymphoblasts are small cells with homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and scanty cytoplasm. This subtype is the most common in children with ALL. • L2lymphoblasts are large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and nucleolus often large. They are much less common than L1 cells and are sometimes mistaken for myeloblasts.

7. L3lymphoblasts are large and homogeneous cells and cytoplasmic vacuolisation that often overlies the nucleus as the most prominent feature. This is just 1 to 2% of cases.

8. Immunological classification (on the basis of immunophenotype): • Non-T, non-B cell ALL accounts for 80 % of all cases; • Malignancy of B cell precursors; • B-cell ALL; • T-cell ALL.

9. Shown here is bone marrow aspirate from a child with B-precursor acute lymphoblastic leukemia. Note that the marrow is replaced primarily with small, immature lymphoblasts that show open chromatin, scant cytoplasm, and a high nuclear-cytoplasmic ratio.

10. Shown here is bone marrow aspirate from a child with T-cell acute lymphoblastic leukemia. The marrow is replaced with lymphoblasts of varying size. No myeloid or erythroid precursors are seen. Megakaryocytes also are absent.

11. Shown here is bone marrow aspirate from a child with B-cell acute lymphoblastic leukemia. The lymphoblasts are large and have basophilic cytoplasm with prominent vacuoles.

12. The first symptoms of acute leukemia are: · Tiredness, irritability ·Intermittent fever ·Failure to thrive (poor growth) ·Bleeding from gums/nose ·Easy bruising ·Bone pain ·Headache ·Nausea/vomiting with CNS involvement

13. The signs of acute leukemia during examination are: • Skin pallor, tachycardia and a flow murmur may be obvious because of anemia presence. • Signs of infection can be non-specific like fever or pneumonia may be present. • Thrombocytopenia often causes petechiae on the lower limbs. Disseminated intravascular coagulation (DIC) may aggravate the situation and cause larger ecchymoses. Petechiae are small dots, purpura is larger and ecchymoses are larger bruises.

14. Hepatomegaly may be found. • Lymphomatous features: massive splenomegaly, anterior mediastinal mass, massive lymphadenopathy. • Leukaemia cutis is an uncommon condition due to infiltration of the skin. • Superior vena cava syndrome is caused by mediastinal adenopathy compressing the superior vena cava. A prominent venous pattern develops over the upper chest from collateral vein enlargement. The face may appear plethoric and the periorbital area may be edematous.

15. Involvement of sanctuary sites: 1) CNS involvement manifests as diffuse meningeal infiltration with signs of increased intracranial pressure; 2) testes, one or both of which may be involved, with infiltration producing enlargement that is out of proportion to the child’s sexual development

16. Diagnostics of ALL: • General blood count:normochromic anaemia with a low reticulocyte index, thrombocytopenia, neutropenia, different WBC count (leucopenia or hyperleucocytosis), presence of lymphoblasts; • Bone marrow aspiration and biopsy(sternal puncture) are the definitive diagnostic tests to confirm the diagnosis: more than 25 % of lymphoblasts prove the diagnosis of ALL;

17. Bone marrow samples should undergocytogenetics and flow cytometry for identification of the type of leukemia; • DIC may occur and this produces an elevated prothrombin time, reduced fibrinogen level and the presence of fibrin degradation products incoagulogram; • Lactic dehydrogenase levels (LDL) are usually raised and rapid cell turnover may raise uric acid inbiochemical blood test;

18. Lumbar puncturewith cytospin morphologic analysis: This is performed before systemic chemotherapy is administered to assess the presence of CNS involvement and to administer intrathecal chemotherapy. • Liver and renal function(ultrasonography)must be checked before initiating chemotherapy; • CXRmay show pneumonia or an enlarged mediastinal mass;

19. Multiple gated acquisition (MUGA)scan is required because many chemotherapeutic agents used in treatment are cardiotoxic,ECGis also necessary; • Molecular techniques, including reverse-transcriptase polymerase chain reaction (RT-PCR), Southern blot analysis, and fluorescence in situ hybridization (FISH).

20. Patients can be divided into 3 groups on the basis of risk (The Children’s Cancer Group): • Good prognosis(have 80 % or greater chance of cure): age between 2 and 10 years, WBC  10 G/L, absence of L3 cells, absence of lymphomatous features, platelet count greater 100 G/L. • Poor prognosis (have less than 50 % chance of cure): age less than 1 year old or greater than 10 years old, WBC  50 G/L, presence of chromosomes translocations, B cell ALL with L3 cells, blasts with T-cell phenotype. • intermediate prognosis(have 50 % or greater chance of cure).

21. Good prognosis for those who have brisk initial response to therapy • The Children’s Cancer Group found an improved prognosis in patients with less than 5 % blasts in the bone marrow after seven days of chemotherapy. • The Berlin-Frankfurt-Münster group found a similar prognosis in patients who had less than 1000 blasts/ml in the peripheral blood after seven days of prednisone.

22. With the exception of B-cell ALL, the treatment of childhood ALL may be considered in three categories: • Induction of remission • Consolidation of remission • Maintenance of remission and all stages involve treatment with cytotoxic agents and steroids varying in intensity. In some books 4. The treatment of subclinical CNS leukemia is divided into special category also.

23. Induction is by quadruple therapy with vincristine, prednisolone, anthracycline, and cyclophosphamide or L-asparaginase or a 5-drug regimen of vincristine, prednisolone, anthracycline, cyclophosphamide, and L-asparaginase.Intrathecal metotrexate is used in proper days also. It is given over the course of 4 to 6 weeks. This type of therapy induces complete remission in more than 95% of patients.

24. The main sign of remission is less than 5 % of blasts in bone marrow; additionally it should be less than 50 % of lymphocytesin peripheral blood.

25. This is usually followed byconsolidation therapyoften in the form of dexamethasone, vincristine, and doxorubicin, followed by cyclophosphamide, anthracycline, and 6-thioguanine beginning at week 20. In this phase of therapy, the drugs are used at higher doses than during induction. Consolidation therapy, first used successfully in the treatment of patients with high-risk disease, also appears to improve the long-term survival of patients with standard-risk disease.

26. Maintenance therapy often consists of periodic “reinduction” pulses of prednisone and vincristin as well as: 1) Daily oral 6-merkaptopurine and weekly oral methotrexate for low-risk patients 2) More intensive multiagent therapy for intermediate- and poor-risk patients.

27. Relapses still occur in 30-40 % of patients. If relapse occurs in the CNS or testes, many children can still be cured with irradiation and additional chemotherapy. If relapse occurs in the marrow within 18 months of diagnosis, the chance of cure with either chemotherapy or stem cell transplantation is less than 10 %.

28. Bone marrow transplantation is used rather more in children than in adults. If a first-degree relative with a HLA match is not available it is possible to use autologous (own) bone marrow rather than allogeneic (donor) marrow. However, the results of autologous are inferior to sibling donors and a study gave 3 years survival after remission and bone marrow transplant of 26% with autologous bonemarrow compared with 68% with donor marrow.

29. Primary features of tumor lysis syndrome include hyperuricemia (due to metabolism of purines), hyperphosphatemia, hypocalcemia, and hyperkalemia.

30. Haemolytic Uraemic Syndrome (HUS)a triad of microangiopathic haemolytic anaemia (Coombs’ test negative), thrombocytopenia and acute renal failure.

31. HUS has been associated with E. coli with somatic (O) antigen 157 and flagella (H) antigen 7. It produces a toxin called shigaand hence this group is called Shiga-toxin-producing Escherichia coli (STEC). An alternative name is vero toxin-producing Escherichia coli (VTEC).

32. HUS clinical features • profuse diarrhoea that turns bloody 1 to 3 days later and rarely on the first day • fever, abdominal pain and vomiting

33. HUS diagnostic criteria include • packed cell volume of less than 30% • evidence of erythrocyte destruction on peripheral blood smear • platelet count less than 150 x 109/L • serum creatinine above the upper limit for age • haemoglobinuria

34. Therapy of HUS • Antibiotics confer no benefit, even if given early • Massive intravenous infusions with potassium adding (under urine volume control)