ACUTE LYMPHOBLASTIC LEUKEMIA WITH COEXPRESSION OF CD56 AND CD57: Case Reports

The authors present the clinical profile of a 6-year-old girl with an unusual immunophenotype of acute lymphoblastic leukemia (ALL). At the initial presentation, massive hepatosplenomegaly developed. The leukemic cells were myeloperoxidase-negative and morphologically lymphoblastic. These cells were positive for B-precursor-cell (CD10, CD19) antigens and natural killer cells (CD56, CD57). Rearrangements of both immunoglobulin heavy chain alleles and monoallelic rearrangement of T-cell receptors (TCRs)-β and -δ genes, but not that of TCR-γ gene, were detected, suggesting that these cells being of B-precursor origin. The patient received chemotherapy for extremely high-risk ALL with a good response. To the authors' knowledge, this is the first pediatric case describing coexpression of CD56 and CD57 on B-lineage ALL.     

ACUTE LYMPHOBLASTIC LEUKEMIA AND KLINEFELTER SYNDROME IN CHILDREN: Two Cases and Review of the Literature

The occurrence of mediastinal germ cell tumor and breast cancer have been repeatedly reported in men with Klinefelter syndrome (KS) but this association is debated controversially for patients with hematologic malignancies. The authors describe 2 tall adolescents in whom diagnostic workup for acute lymphoblastic leukemia (ALL) revealed 47, XXY and 47, XXY/48, XXXY karyotype, respectively. Among 4195 registered male patients in the ALL-BFM study group since 1983, no further patients with ALL and KS were identified. Given the lack of epidemiological data, this retrospective analysis illustrates the association of previously described cases of hematologic malignancies with KS. In contrast to other chromosomal aberrations, the incidence of ALL does not seem to be increased in pediatric patients with KS.     

ACUTE LYMPHOBLASTIC LEUKEMIA IN SWEDISH CHILDREN 1973–1978

ABSTRACT. Gustafsson, G., Kreuger, A. and Dohlwitz, A. (Departments of Paediatrics, University Hospital, Uppsala, and County Hospital, Nykoping, Sweden). Acute lymphoblastic leukemia in Swedish children 1973–1978. Acta Paediatr Scand, 70:609,.–Three hundred and sixty-seven children with acute lymphoblastic leukemia have been diagnosed in Sweden 1973–1978, 345 of whom were treated according to the national uniform regimens of the Swedish Child Leukemia Group (SCLG). The patients were classified into an SR (standard risk) and an IR (increased risk) group. Remission was obtained in 354 patients (96%). With 12–84 months observation time the total survival was 54% and the diseasefree survival 44 %. A more intensive cytostatic regimen in the induction period increased considerably the diseasefree survival for the SR and to some extent also for the IR patients. Relapses were significantly more common in the IR group in spite of a more intensive cytostatic regimen. The most decisive IR criteria were B-LPK and age at diagnosis. Prognosis was significantly worse for boys in all groups. After 3 years in CCR treatment was discontinued in 95 out of 246 children (38%) of whom 19 later relapsed (20%)     

CARDIAC INVOLVEMENT IN AN ADOLESCENT WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Cardiac complications of the pediatric patients with acute leukemia are common. Most of the cardiac complications may be due to chemotherapeutics such as antracyclins, besides anemia, infections, or direct leukemic infiltrations of the heart. It is reported that leukemic infiltration is frequent in the postmortem examination of the myocardium and pericardium. However, at the antemortem examination, pericardial involvement is rare and there is no myocardial involvement reported at the time of diagnosis in patients with acute leukemia in the English literature. Here, the authors report an adolescent with acute lymphoblastic leukemia who had myocardial infiltration at the time of diagnosis.     

MEASLES,MUMPS, AND RUBELLA ANTIBODY STATUS AND RESPONSE TO IMMUNIZATION IN CHILDREN AFTER THERAPY FOR ACUTE LYMPHOBLASTIC LEUKEMIA

Seventy-seven patients with acute lymphoblastic leukemia (ALL) who were in complete remission and whose therapies had been stopped for at least 6 months before enrollment in this study were retrospectively analyzed regarding their antibody status for measles, mumps, and rubella, with the aim to demonstrate the seropositivity rate after treatment in the authors’ group. Each patient's serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA) method to determine the antibody titers before and after immunization. Measles serology was available in 77 children; 45 (58%) were seronegative. Initial ages of measle-seronegative patients were statistically lower than those of seropositive cases (median 3.29 versus 4.91 years, respectively). Mumps serology was available in 76 children; 36 (47%) were seronegative. Mumps-seropositive cases tended to have more frequent previous history of infection than seronegative cases (55.0% versus 28.6%, respectively, P = .05). Rubella serology was available in 76 children, and 20 (26.3%) were seronegative. It was determined that initial ages of rubella-seronegative patients were statistically lower than those of seropositive cases (median 3.03 versus 4.32 years, respectively). The authors concluded based on the results of their study that at a median of 3.31 years after completion of chemotherapy for ALL, the majority of cases had antibody levels lower than protective values for measles (58.4%); however, these values were 47.3% for mumps and 26.3% for rubella. Seroconversion rates after measles (55%) and mumps vaccination (57.1%) were still low. However, in the available cases, relatively adequate response to rubella vaccination (92.3%) was observed.     

UROLITHIASIS IN AN ACUTE LYMPHOBLASTIC LEUKEMIA CHILD DURING INDUCTION CHEMOTHERAPY

An 11-year-old acute lymphoblastic leukemia patient suddenly developed severe abdominal flank pain and hematuria caused by renal stone during induction chemotherapy. The patient was treated with forced hydration, and the pain was relieved after the renal stone passed through. The renal stone was composed of calcium phosphate. The patient is currently in continuous complete remission, has had no recurrence of the urolithiasis, and is on consolidation chemotherapy. Although urolithiasis is extremely rare in childhood acute lymphoblastic leukemia, it should be considered in patients who complain of abdominal flank pain or back pain during chemotherapy.     

ASSOCIATION BETWEEN DEFB1 GENE HAPLOTYPE AND HERPES VIRUSES SEROPREVALENCE IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Recent studies investigated the role of an unusual immune response to infective agents in the etiology of acute lymphoblastic leukemia (ALL) in children. Human β-defensin-1 (hBD-1) is an anti-microbial peptide of the innate immune system, which exerts a killing role against pathogens. In the present study, three polymorphisms have been genotyped, namely, -52G/A, -44C/G and -20G/A, of DEFB1 gene, coding for hBD-1, in 40 ALL patients and 40 healthy children, and tested for an association between genetic variants of the protein and seroprevalence of antibodies for herpes viruses. The seroprevalence of cytomegalovirus (CMV), herpes simplex viruses (HSV) and Epstein-Barr virus (EBV) IgG antibodies in leukemic children was higher than that in controls (CMV: 61.5 vs. 27.3%, p = .008; HSV: 50 vs. 24.2%, p = .04; EBV: 61.3 vs. 46.2%, p = ns, respectively). Carriers of the GCA haplotype were found to have a significantly higher rate of immunization against CMV and HSV in ALL children compared to controls (CMV: 68 vs. 29%, p = .006; HSV: 56 vs. 26%, p = .04, respectively). No such observation was made when we analyzed the immunization against Epstein-Barr virus (EBV) by GCA haplotype in case and controls (58 vs. 40%, p = ns). These findings suggest that leukemic patients carrying untranslated variants of hBD-1 display a higher susceptibility to herpes viruses infections than controls.     

TEN CASES OF SO-CALLED LONG SURVIVAL IN CHlLDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Abstract. Armata, J. Cyklis, R. and Wyszkowski, J. (Institute of Paediatrics, Medical Academy in Cracow, Cracow, Poland). Ten cases of so-called long survival in children with acute lymphoblastic leukemia. Acta Paediatr Scand 63: 369, 1974.–Ten cases of acute lymphoblastic leukemia are presented, in children all of whom survived more than 4 years. WBC and blast cell counts were registrered at low levels at the onset of the disease and at subsequent bone marrow relapses. Extramedullary leukemia occurred after 2 years (average) in bone marrow remission, which did not predict early bone marrow relapse. From 1962 to 1970 three treatment regimens for acute leukemia were compared; the best results depended on the intensity of treatment during the first remission.     

INFECTIONS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA: An Analysis of 222 Febrile Neutropenic Episodes

A retrospective analysis was performed on febrile neutropenic episodes in patients with acute lymphoblastic leukemia (ALL) from 1992 to 2002. There were 222 febrile neutropenic episodes in 266 ALL patients with documented ANC < 500/mm³. Of the 222 episodes, 98 (44%) had documented focus of infection; the rest were fever without focus. There were 274 different sites of infection in the 98 episodes of documented focus of infection; pulmonary infections were the commonest site of infection (27.3%) followed by HEENT (22.9%). Of 69 bacterial isolates, gram-negative bacteria (n = 46, 67%) were twice as common as gram-positive bacteria (n = 23, 33%). Most common site of isolation for gram-negative bacteria was blood (50%) followed by urine (32.6%). Blood (78.3%) was predominant site of isolation of gram-positive bacteria followed by HEENT (8.7%). Escherichia coli (45.7%) was the commonest gram-negative isolate, while Staphylococcus aureus (39%) was the commonest gram-positive bacterial isolate. There were a total of 22 fungal isolates, the majority from urine (n = 12) and HEENT (n = 9). Of the 22 fungal isolates, 19 were detected in induction phase of chemotherapy. A total of 95/222 (42.8%) febrile neutropenic episodes improved with first-line antibiotic therapy, while modification was required in 127 episodes (57.2%). Antifungal therapy was used in 86 episodes (38.7%). There were a total of 13 deaths, 6 each during induction and intensification/consolidation phases, while 1 died during maintenance phase. Of the 13 deaths, 10 had pneumonia, 8 had bacteremia, and 7 had fungal infection. The current study stresses the importance of frequent reviewing of type, frequency, severity, and outcome of infection complications over the years to detect changing epidemiological patterns. The majority of fungal infections were detected during induction chemotherapy, which highlights the need to consider this type of infection in the evaluation of patients.     

CEREBROSPINAL FLUID OXIDATIVE STRESS DURING CHEMOTHERAPY OF ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN

In this study the authors addressed the question whether neurotoxicity due to the chemotherapy of acute lymphoblastic leukemia (ALL) is associated with cerebrospinal fluid (CSF) oxidative stress. Examination of 38 ALL patients revealed significant increases in 8-isoprostane concentration and important decreases in total antioxidative capacity of CSF during therapy. The mean 8-isoprostane level at diagnosis was 9.05 ± 1.62 pg/mL, and no correlations with initial leukocytosis, organomegaly, and lactate dehydrogenase levels were noted. 8-Isoprostane concentrations were increased on the 59th day of treatment (mean level: 24.85 ± 7.59 pg/mL [P < .01]) and remained elevated at 4 points of the consolidation phase (17.28 ± 2.16 pg/mL [P < .05]; 22.72 ± 6.04 pg/mL [P < .05]; 24.92 ± 6.31 pg/mL [P < .01]; 32.32 ± 7.94 pg/mL [P < .01]) as compared to their level at diagnosis. The mean total antioxidative capacity at diagnosis was 203.08 ± 6.17 μmol/L and was remarkably decreased on the 59th day of treatment (189.76 ± 1.9 μmol/L [P < .05]) and at one point of the consolidation phase (188.29 ± 3.46 μmol/L [P < .05]) as compared to the level at diagnosis. This study indicates that neurotoxicity of standard ALL treatment may be related to oxidative stress.     

CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PRESENTING WITH SEVERE OSTEOLYSIS: A Model to Study Leukemia-Bone Interactions and Potential Targeted Therapeutics

Interference with the molecular mechanisms that generate tumor supportive niches in the bone microenvironment is a rational approach to inhibit the growth of hematological malignancies. However, the advancement of knowledge in this area has been slowed down by the lack of in vitro models to facilitate the screening of potential candidate agents. The rare cases of acute lymphoblastic leukemia (ALL) in children presenting with extensive bone involvement may represent an exaggerated form of some aspects of the normal tumor-bone interactions. Thus, these cases can provide insight into processes that are otherwise challenging to uncover. The authors describe the case of a 6-year-old child who presented with severe osteopenia that resolved at the time of leukemic remission. Compared to control sera, serum taken at disease presentation contained increased levels of a group of osteolytic cytokines and was effective in activating preosteoclast cells in culture. Based on these findings, the authors describe an experimental model to identify agents that would interfere with leukemia mediated osteolytic process.     

DOUBLE INVASIVE FUNGAL INFECTION AND TYPHLITIS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Invasive fungal infection is one of the major causes of morbidity and mortality in immunocompromised patients. The occurrence of two invasive fungal infections in one patient at the same time is quite rare. Here the authors report on two adolescent patients with acute lymphoblastic leukemia who developed combined invasive pulmonary aspergillosis and hepatosplenic candidiasis during chemotherapy. They were treated with liposomal amphotericin B, but one of them died due to massive pulmonary hemorrhage during recovery from neutropenia.     

THE IMPORTANCE OF NUCLEOLAR ORGANIZER REGIONS IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA

The silver-staining of the nucleolar organizer regions (AgNORs) was performed in patients with acute lymphoblastic leukemia (ALL) to verify the role of cell proliferation in predicting complete remission and survival. Bone-marrow aspiration smears of 20 pediatric cases with ALL were stained with argyrophilic method during the diagnosis, remission, and 3rd, 6th, 9th, and 12th months after remission. The mean NORs count (NORsc) and the mean of (nucleolar organizer regions surface/total nuclear surface × 100) value (NORss/TNs) for each case were calculated. At diagnosis, the NORsc and NORss/TNs value for the whole series were 3.30 ± 0.86 and 4.77 ± 1.15, respectively. In complete remission, NORsc and NORss/TNs values were 1.23 ± 0.20 and 3.45 ± 0.87, respectively and the differences were statistically highly significant (p <. 001). The most important parameters of prognostic factors that effect diagnosis NORss/TNs and NORsc values were found to be FAB morphology and leukocyte count according to the multivariant analysis test. AgNORs analysis is a suitable method to assess cell proliferation in bone marrow aspirate and can predict complete remission, remission duration, and survival in pediatric ALL patients.     

ISOLATED RELAPSE OF ACUTE LYMPHOBLASTIC LEUKEMIA IN THE BREAST OF A YOUNG FEMALE

A 20-year-old female developed a relapse of B-precursor acute lymphoblastic leukemia (ALL) as a mass in her left breast after 6 years of maintained continuous complete remission. No leukemic lesions were identified in other sites such as the bone marrow or cerebrospinal fluid. The relapsed leukemic cells in the breast revealed the same immunophenotypes (CD10⁺, CD19⁺, CD20⁺, HLA-DR⁺, CD34⁺) as those of the onset ALL cells in the bone marrow. A literature survey found 10 other cases of ALL relapse in the breast without bone marrow involvement, mostly consisting of adolescent girls. Including the present report, a total of 11 cases were analyzed; the onset ages of ALL were a median of 16.5 (range 5–50) years old and the ages of relapse in the breast a median of 20 (range 12–51) years old. Data suggest that, although rare, the breast could become one of the extramedullary relapse sites of ALL developed in adolescent girls.     

EVALUATION OF RENAL FUNCTION IN TURKISH CHILDREN RECEIVING BFM-95 THERAPY FOR ACUTE LYMPHOBLASTIC LEUKEMIA

This study examined renal function in 42 children with acute lymphoblastic leukemia (ALL) treated according to BFM-95 protocol. Fifteen (group 1) were investigated longitudinally at 3 time points: before (T1), 4 weeks after (T2), and 2–6 months after (T3) consolidation therapy with high-dose methotrexate (HDMTX). The frequency of abnormalities in glomerular and tubular tests were nil at T1 and ranged from 13 to 40% at T2 and 7 to 33% at T3 in group 1. Twenty percent of the patients (n = 10) in group 2, who were examined at a single time point 7–36 months after consolidation, had glomerular and tubular abnormalities. There was only mild tubular abnormality in 5.8% of patients (n = 17) in group 3, who were examined at a single time point a mean of 56.1 ± 12.5 months after completion chemotherapy. These data show that consolidation therapy with HDMTX is frequently associated with acute renal toxicity in children with ALL but does not leave clinically significant late sequelae.     

THROMBOTIC EFFECTS OF ASPARAGINASE IN TWO ACUTE LYMPHOBLASTIC LEUKEMIA PROTOCOLS (NOPHO ALL-1992 VERSUS NOPHO ALL-2000): A Single-Institution Study

Asparaginase is essential in the treatment of lymphoproliferative malignancies, but it is associated with several side effects. The objective of this study was to compare asparaginase-induced alterations of the coagulation inhibitors and the impact on central line-associated thrombosis in children treated according to 2 different asparaginase regimens. The study enrolled 30 children treated for acute lymphoblastic leukemia, and they were divided into 2 groups with respect to asparaginase preparation and protocol (NOPHO ALL-1992 versus NOPHO ALL-2000). The coagulation inhibitors antithrombin, protein C, and proteins S were measured prior to and during asparaginase therapy, and incidence of central line-associated thromboses was compared to evaluate the protocols' thrombogenicity. Thirteen children received Erwinia asparaginase and 17 children received E. coli asparaginase. Independent of protocol, the coagulation inhibitors were significantly reduced during asparaginase therapy (p < .001), and central line-associated thromboses were frequent. Four children developed thrombosis in the course of asparaginase therapy, and there was a correlation between asparaginase-induced fall of antithrombin and occurrence of new thromboses (p = .01).     

INITIAL P-GLYCOPROTEIN EXPRESSION IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA: NO EVIDENCE OF PROGNOSTIC IMPACT IN FOLLOW-UP

Treatment results in childhood acute lymphoblastic leukemia (ALL) have improved remarkably during the past 20 years, but still 25% of children cannot be permanently cured. Drug resistance is a major cause of poor outcome. One of the most investigated resistance mechanisms is the P-glycoprotein (P-gp)-mediated multiple-drug resistance (MDR). The authors prospectively analyzed P-gp using flow cytometry with monoclonal antibody JSB1 in a population-based series of 103 children with ALL treated according to intensive Nordic ALL protocols. Increased P-gp expression was detected in 55 patients (53%). With a cutoff value of 1% P-gp-positive blasts in bone marrow, no difference was found in event-free survival (EFS) or overall survival between children with low vs. increased P-gp expression. The 4-year EFS in the whole series was 77%. Patients with T-ALL had higher P-gp levels than the others, 3.6% vs. 1.0% (p = .002). P-gp expression did not correlate with the white blood cell count, age, sex, or cytogenetics. The authors conclude that the level of P-gp expression cannot be used as a tool for treatment stratification in childhood ALL.     

EXPRESSION OF PTEN AND SHP1, INVESTIGATED FROM TISSUE MICROARRAYS IN PEDIATRIC ACUTE LYMPHOBLASTIC,LEUKEMIA

PTEN and SHP1 are tumor suppressor genes involved in the regulation of cell cycle control and apoptosis. The authors investigated the protein expression of PTEN and SHP1, by immunohistochemistry in tissue microarrays from bone marrow samples in children, diagnosed with acute lymphoblastic leukaemia and nonmalignant controls. PTEN was overexpressed in diagnostic ALL samples, while SHP1 showed a low expression. Both proteins showed a significant difference in expression compared to nonmalignant controls. The roles of PTEN and SHP1 are not well investigated in pediatric leukemia and could in the future play a role as prognostic factors.     

SUCCESSFUL TREATMENT OF ASPERGILLUS BRAIN ABSCESS IN A CHILD WITH ACUTE LYMPHOBLASTIC LEUKEMIA AND LIVER FAILURE

Invasive fungal infection continues to pose a significant threat to immunocompromised patients, with cerebral aspergillosis being among the most feared ones. The authors describe an adolescent girl with acute lymphoblastic leukemia (ALL) with subsequent acute liver failure, who developed an aspergillus brain abscess. The patient was treated with combined antifungal therapy using amphotericin B local instillation, prolonged systemic amphotericin B colloidal dispersion along with vinca alkaloids-containing chemotherapy, followed by neurosurgical débridement and oral voriconazole in the setting of ongoing antileukemic maintenance chemotherapy. Her ALL remains now in complete remission 30 months from diagnosis, with no evidence of fungal infection.     

Acute lymphoblastic leukemia with coexpression of CD56 and CD57: case report

The authors present the clinical profile of a 6-year-old girl with an unusual immunophenotype of acute lymphoblastic leukemia (ALL). At the initial presentation, massive hepatosplenomegaly developed. The leukemic cells were myeloperoxidase-negative and morphologically lymphoblastic. These cells were positive for B-precursor-cell (CD10, CD19) antigens and natural killer cells (CD56, CD57). Rearrangements of both immunoglobulin heavy chain alleles and monoallelic rearrangement of T-cell receptors (TCRs)-β and -δ genes, but not that of TCR-γ gene, were detected, suggesting that these cells being of B-precursor origin. The patient received chemotherapy for extremely high-risk ALL with a good response. To the authors' knowledge, this is the first pediatric case describing coexpression of CD56 and CD57 on B-lineage ALL.