Leukemia in children. Leukemia in children. Haemolytic Uraemic Haemolytic Uraemic

Syndrome (HUS).Syndrome (HUS).

Sakharova Inna. Ye., MD, Sakharova Inna. Ye., MD,

Univ. assistantUniv. assistant

A c u tely m p h o b la s t ic le u k e m ia

(A L L )

A c u ten o n ly m p h o c y t ic le u k e m ia

(A N L L ) o r a c u te m y e lo b la s t ic le u k e m ia (A M L )

C h r o n ic m y e lo c y t ic le u k e m ia

(C M L )

L e u k em ia

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.

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)

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.

According to the French-American-British According to the French-American-British (FAB) classification, leukemic (FAB) classification, leukemic lymphoblasts in ALL subdivide into lymphoblasts in ALL subdivide into three three categories:categories:

L1L1 lymphoblasts are small cells with lymphoblasts are small cells with homogeneous chromatin, regular nuclear homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and shape, small or absent nucleolus, and scanty cytoplasm. This subtype is the scanty cytoplasm. This subtype is the most common in children with ALL. most common in children with ALL.

L2L2 lymphoblasts are large and lymphoblasts are large and heterogeneous cells, heterogeneous heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and chromatin, irregular nuclear shape, and nucleolus often large. They are much less nucleolus often large. They are much less common than L1 cells and are sometimes common than L1 cells and are sometimes mistaken for myeloblasts.mistaken for myeloblasts.

L3L3 lymphoblasts 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.

Immunological classification (on the basis of immunophenotype):

• Non-T, non-B cell ALL accounts for Non-T, non-B cell ALL accounts for 80 % of all cases;80 % of all cases;

• Malignancy of B cell precursors;Malignancy of B cell precursors;• B-cell ALL;B-cell ALL;• T-cell ALL.T-cell ALL.

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

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

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

The first symptoms of acute leukemia are:

· · Tiredness, irritability Tiredness, irritability ··    Intermittent feverIntermittent fever·· Failure to thrive (poor growth)Failure to thrive (poor growth)··    Bleeding from gums/nose Bleeding from gums/nose ··    Easy bruising Easy bruising ··    Bone pain Bone pain ··    Headache Headache ··    Nausea/vomiting with CNS Nausea/vomiting with CNS

involvement involvement

The signs of acute leukemia during

examination are: Skin pallor, tachycardia and a flow murmur Skin pallor, tachycardia and a flow murmur

may be obvious because of anemia presence. may be obvious because of anemia presence. Signs of infection can be non-specific like fever Signs of infection can be non-specific like fever

or pneumonia may be present.or pneumonia may be present. Thrombocytopenia often causes petechiae on Thrombocytopenia often causes petechiae on

the lower limbs. Disseminated intravascular the lower limbs. Disseminated intravascular coagulation (DIC) may aggravate the situation coagulation (DIC) may aggravate the situation and cause larger ecchymoses. Petechiae are and cause larger ecchymoses. Petechiae are small dots, purpura is larger and ecchymoses small dots, purpura is larger and ecchymoses are larger bruises.are larger bruises.

Hepatomegaly may be found.Hepatomegaly may be found. Lymphomatous features: massive Lymphomatous features: massive

splenomegaly, anterior mediastinal mass, splenomegaly, anterior mediastinal mass, massive lymphadenopathy.massive lymphadenopathy.

Leukaemia cutis is an uncommon condition Leukaemia cutis is an uncommon condition due to infiltration of the skin. due to infiltration of the skin.

Superior vena cava syndrome is caused by Superior vena cava syndrome is caused by mediastinal adenopathy compressing the mediastinal adenopathy compressing the superior vena cava. A prominent venous superior vena cava. A prominent venous pattern develops over the upper chest from pattern develops over the upper chest from collateral vein enlargement. The face may collateral vein enlargement. The face may appear plethoric and the periorbital area appear plethoric and the periorbital area may be edematous.may be edematous.

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

Diagnostics of ALL:Diagnostics of ALL:

General blood countGeneral blood count:: normochromic normochromic anaemia with a low reticulocyte index, anaemia with a low reticulocyte index, thrombocytopenia, neutropenia, different thrombocytopenia, neutropenia, different WBC count (leucopenia or WBC count (leucopenia or hyperleucocytosis), presence of hyperleucocytosis), presence of lymphoblasts;lymphoblasts;

Bone marrow aspiration and biopsyBone marrow aspiration and biopsy (sternal puncture) are the definitive (sternal puncture) are the definitive diagnostic tests to confirm the diagnosis: diagnostic tests to confirm the diagnosis: more than 25 % of lymphoblasts prove more than 25 % of lymphoblasts prove the diagnosis of ALL;the diagnosis of ALL;

Bone marrow samples should undergoBone marrow samples should undergo cytogeneticscytogenetics and and flow cytometryflow cytometry for for identification of the type of leukemia;identification of the type of leukemia;

DIC may occur and this produces an DIC may occur and this produces an elevated prothrombin time, reduced elevated prothrombin time, reduced fibrinogen level and the presence of fibrinogen level and the presence of fibrin degradation products infibrin degradation products in coagulogramcoagulogram;;

Lactic dehydrogenase levels (LDL) are Lactic dehydrogenase levels (LDL) are usually raised and rapid cell turnover usually raised and rapid cell turnover may raise uric acid inmay raise uric acid in biochemical biochemical

blood testblood test;;

Lumbar punctureLumbar puncture with cytospin with cytospin morphologic analysis: This is morphologic analysis: This is performed before systemic performed before systemic chemotherapy is administered to chemotherapy is administered to assess the presence of CNS assess the presence of CNS involvement and to administer involvement and to administer intrathecal chemotherapy.intrathecal chemotherapy.

Liver and renal functionLiver and renal function (ultrasonography)(ultrasonography) must be checked must be checked before initiating chemotherapy; before initiating chemotherapy;

CXRCXR may show pneumonia or an may show pneumonia or an enlarged mediastinal mass; enlarged mediastinal mass;

Multiple gated acquisition (MUGA)Multiple gated acquisition (MUGA) scan is required because many scan is required because many chemotherapeutic agents used in chemotherapeutic agents used in treatment are cardiotoxic,treatment are cardiotoxic, ECGECG is is also necessary;also necessary;

Molecular techniquesMolecular techniques, , including including reverse-transcriptase polymerase reverse-transcriptase polymerase chain reaction (RT-PCR), Southern chain reaction (RT-PCR), Southern blot analysis, and fluorescence in blot analysis, and fluorescence in situ hybridization (FISH).situ hybridization (FISH).

Patients can be divided into 3 Patients can be divided into 3 groups on the basis of risk (The groups on the basis of risk (The Children’s Cancer Group):Children’s Cancer Group):

Good prognosisGood prognosis (have 80 % or greater (have 80 % or greater chance of cure): age between 2 and 10 chance of cure): age between 2 and 10 years, WBC years, WBC 10 G/L, absence of L3 cells, 10 G/L, absence of L3 cells, absence of lymphomatous features, platelet absence of lymphomatous features, platelet count greater 100 G/L.count greater 100 G/L.

Poor prognosisPoor prognosis (have less than 50 % chance (have less than 50 % chance of cure): age less than 1 year old or greater of cure): age less than 1 year old or greater than 10 years old, WBC than 10 years old, WBC 50 G/L, presence of 50 G/L, presence of chromosomes translocations, B cell ALL with chromosomes translocations, B cell ALL with L3 cells, blasts with T-cell phenotype.L3 cells, blasts with T-cell phenotype.

intermediate prognosisintermediate prognosis (have 50 % or greater (have 50 % or greater chance of cure).chance of cure).

Good prognosis for those who Good prognosis for those who have brisk initial response to have brisk initial response to

therapytherapy

The Children’s Cancer Group found an The Children’s Cancer Group found an improved prognosis in patients with less improved prognosis in patients with less than than 5 % blasts in the bone marrow 5 % blasts in the bone marrow after seven days of chemotherapy. after seven days of chemotherapy.

The Berlin-Frankfurt-Münster group The Berlin-Frankfurt-Münster group found a similar prognosis in patients found a similar prognosis in patients who had who had less than 1000 blasts/ml in the less than 1000 blasts/ml in the peripheral blood after seven days of peripheral blood after seven days of prednisone.prednisone.

With the exception of B-cell ALL, the With the exception of B-cell ALL, the treatment of childhood ALL may be treatment of childhood ALL may be considered in three categories:considered in three categories:

1.1. Induction of remissionInduction of remission

2.2. Consolidation of remissionConsolidation of remission

3.3. Maintenance of remissionMaintenance of remission

and all stages involve treatment with and all stages involve treatment with cytotoxic agents and steroids varying in cytotoxic agents and steroids varying in intensity. In some books intensity. In some books

4. The treatment of subclinical CNS leukemia 4. The treatment of subclinical CNS leukemia

is divided into special category also. is divided into special category also.

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

The main sign of remission is less than 5 % of blasts in bone marrow; additionally it should be less than

50 % of lymphocytes in peripheral blood.

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

Maintenance therapyMaintenance therapy often consists of often consists of periodic “reinduction” pulses of periodic “reinduction” pulses of prednisoneprednisone and and vincristinvincristin as well as: as well as:

1) Daily oral 1) Daily oral 6-merkaptopurine6-merkaptopurine and weekly and weekly oral oral methotrexatemethotrexate for low-risk patients for low-risk patients

2) More intensive multiagent therapy for 2) More intensive multiagent therapy for intermediate- and poor-risk patients.intermediate- and poor-risk patients.

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

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

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

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

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

HUS clinical featuresHUS clinical features

profuse diarrhoea that turns bloody profuse diarrhoea that turns bloody 1 to 3 days later and rarely on the 1 to 3 days later and rarely on the first dayfirst day

fever, abdominal pain and vomitingfever, abdominal pain and vomiting

HUS diagnostic criteria includeHUS diagnostic criteria include

• packed cell volume of less than 30%packed cell volume of less than 30% • evidence of erythrocyte destruction on evidence of erythrocyte destruction on

peripheral blood smearperipheral blood smear • platelet count less than 150 x 10platelet count less than 150 x 1099/L/L • serum creatinine above the upper limit serum creatinine above the upper limit

for agefor age • haemoglobinuriahaemoglobinuria

Therapy of HUSTherapy of HUS

Antibiotics confer no benefit, even if Antibiotics confer no benefit, even if given earlygiven early

Massive intravenous infusionsMassive intravenous infusions

with potassium adding (under with potassium adding (under urine urine volume control)volume control)