[Recurrences of acute promyelocytic leukemia in children: experience with arsenic trioxide therapy and autologous hematopoietic cell transplantation].

AIM: To analyze the specific features of recurrences of acute promyelocytic leukemia (APL) in children after standard therapy with daunorubicin, cytosine arabinoside (Ara-C), all-trans retinoic acid (ATRA) and to develop further programmed treatment policy. SUBJECTS AND METHODS: The study included 9 patients with recurrent APL. The recurrences developed significantly more frequently in a very high-risk group (patients with minimal residual disease being preserved after the intensive therapy phase). Induction used arsenic trioxide (ATO) and/or standard chemotherapy + ATRA; ATO monotherapy was in consolidation. CD34+ cells were mobilized until molecular remission was achieved with high-dose Ara-C and granulocyte colony-stimulating factor. Pretransplantation conditioning involved melfalan as a basic drug in combination with high-dose AraC (5 pts), treosulfan (1 pt) or bisulfan (1 pt). Six patients received gemtusumab ozogamicin, 3-9 mg/m2, at different stages of therapy. RESULTS: Before therapy one patient died; 8 patients achieved the second molecular remission; CD34+ cell mobilization and sampling were effective in 7 cases. Five patients were in long-term molecular remission after autologous hemopoietic stem cell transplantation (autoHSCT). Follow-up was 23-40 months. One patient is being prepared for transplantation. Following autoHSCT, another patient with a developed repeat recurrence died from complications due to related partially compatible transplantation. Visceral, including cardiological, toxicity of therapy was insignificant. In the APL-2003 protocol, overall and event-free survival rates were 93 +/- 3 and 76 +/- 6%, respectively. CONCLUSION; The application of ATO and autoHSCT in recurrent APL makes it possible to achieve and preserve the second molecular remission in case of insignificant extrahematological toxicity. Russian clinics should have access to ATO.

[Long-term results of combined treatment of acute promyelocytic leukemia in children and adolescents with gene therapy].

AIM: To analyse the results of treatment of children and adolescents with acute promyelocytic leukemia (APL) including polychemotherapy and ATRA (protocols APL 93, 98 and 2003). MATERIAL AND METHODS: The course of the disease, modification of the treatment protocols with reduction of anthracyclines and ATRA doses, results of molecular monitoring of PML/RARalpha transcript have been analysed for 107 APL patients. RESULTS: For prognosis of the disease important are initial characteristics of the patient and the time of the tumor regress assessed by molecular methods--establishment of molecular remission and molecular recurrence. CONCLUSIONS: In APL it is necessary to conduct molecular monitoring especially in patients at high risk and with poor prognosis in a decrease of treatment intensity for toxicity relief. Detection of molecular recurrence is indication for treatment. To raise efficacy of APL recurrence therapy it is necessary to design a special updated protocol.

Fludarabine, low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplantation from HLA-compatible related donors.

Allogeneic hematopoietic stem cell transplantation (SCT) from unaffected donors remains the only modality for the correction of hematological abnormalities in Fanconi anemia (FA) patients. We performed four HLA-matched related donor SCT using a novel irradiation and cyclophosphamide-free conditioning regimen. The protocol included fludarabine 150 mg/m(2), busulfan 4 mg/kg, and antithymocyte globulin 90 mg/kg. Graft-versus-host disease (GVHD) prophylaxis was cyclosporin A, MTX, and daclizumab. The engraftment and occurrence of full stable donor hemopoiesis was rapid in all cases with minimal short-term toxic complications. There were no infections or febrile episodes during the inpatient phase. Three patients developed acute GVHD grade I-II involving gut and skin and one patient progressed to extensive chronic GVHD. The preparative conditioning regimen is safe and associated with low organ toxicity and effective immunosupression for the stable engraftment in FA patients undergoing SCT with matched related donors.

Large proportion of Epstein-Barr virus-associated small noncleaved cell lymphomas among children with non-Hodgkin's lymphoma at a single institution in Moscow, Russia.

To evaluate clinical and biologic features of children with non-Hodgkin's lymphoma (NHL) treated in Moscow, Russia, we studied 53 cases treated in the Republican Children's Hospital from 1990 to 1994. Histologic examination disclosed a predominance of the small noncleaved cell subtype (32 cases, 60%); a smaller percentage of the lymphoblastic and large-cell subtypes (14 cases, 26% and 7 cases, 13%, respectively) were identified. The frequencies of primary sites of involvement in descending order included 60% in abdomen, 19% in mediastinum, 15% in head/neck, and 4% in peripheral nodes. The majority of children presented with advanced stage disease (St. Jude stage III/IV/B-ALL, 92.5%). Of interest, 8 of 15 (53%) small noncleaved cell NHL cases examined contained Epstein-Barr virus (EBV). The high frequency of EBV association in this study suggests that this virus may play a more global role in NHL pathogenesis than previously recognized.

Intermediate-dose busulfan and cyclophosphamide as a conditioning regimen for bone marrow transplantation in a case of Fanconi anemia in myelodysplastic transformation.

We report an 11-year old female with myelodysplastic (refractory anemia with excess of blasts) presentation of Fanconi anemia. After failure of initial chemotherapy with low doses of 6-mercaptopurine and prednisolone she underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched sibling. Busulfan 8 mg/kg and cyclophosphamide 40 mg/kg were used as conditioning. The post-transplant course was uneventful with fast trilineage engraftment and mild cutaneous acute GVHD. She is alive 17 months after BMT with full hematological reconstitution without evidence of MDS.

[Results of treatment of acute leukemia in children using intensive therapy programs]. / Rezul'taty lecheniia ostrykh leikozov u detei s ispol'zovaniem programm intensivnoi terapii.

The authors report the results of the treatment according to the programs BFM-ALL-90 and BFM-AML-83 and 87. A total of 110 children with acute lymphoblastic leukemia (ALL) and 35 with acute myeloblastic leukemia (AML) were treated with remission rate 94.5% and 74.5%, respectively. Under programmed treatment of ALL the recurrences occurred in 12.2% against 46% of the cases in nonprogrammed treatment. 2-year survival made up 75% and 47.3%, respectively. Among AML cases there were frequently prognostically unfavorable ones and patients with neuroleukemia this dictating the necessity of the treatment intensification and irradiation of the skull in AML. Improvement of adjuvant therapy is a must in advance of acute leukemia treatment.

[Comparative effectiveness of treatment of non-Hodgkin's lymphoma in children using protocols BFM NHL-90 and non-programmed courses based on the ACOP regimen]. / Sravnitel'naia éffektivnost' lecheniia nekhodzhkinskikh limfom u detei po protokolam BFM NHL-90 i nonprogrammnym kursam na osnove rezhima ATsOP.

170 NHL children aged 1-14 [mean age 6] have been treated for the last 5 years. The diagnostic examination included the disease history, physical examination, bone marrow cytology, tumor histology (all patients), immunophenotyping (17 cases), x-ray and sonography of the chest and abdomen. According to the International NHL staging system, 35% of the patients had NHL stage II, 65% stage III or IV. The study entered 71 patients who underwent additional lactate dehydrogenase test, CT-scanning. 44 of them received nonprogrammed therapy on the basis of ACOP (group I), 27 patients were treated according to BFM-NHL-90 for B-, non-B- and large-cell anaplastic lymphomas (group II). The efficiency of the methods did not differ for patients at stage IIR. At the II NR stage complete remission (CR) was up to 41% in the group I and 60% in the group II. 50% of the children from group I and 20% from the group II were resistant to treatment. All the group I patients developed relapses, none got relapses in the group II. CR was observed in 64% and 78% of patients from group I and II, respectively, who had NHL stage III and IV. Relapses occurred in 41% and 14%, respectively. CCR was in 22% in the group I and in 67% of the group II patients. Effectiveness of B-NHL treatment according to BFM protocols was higher than in other types of NHL as to the number of relapses and frequency of CCR: the latter was 76% compared to 50% of non-B-NHL.(ABSTRACT TRUNCATED AT 250 WORDS)

Release of active oxygen radicals by leukocytes of Fanconi anemia patients.

The release of oxygen radicals by blood and bone marrow leukocytes of patients with Fanconi anemia (FA) has been studied. It was found that the nonstimulated FA leukocytes and those stimulated by concanavalin A, SiO2, latex, and opsonized zymosan produced enhanced levels of luminol- and lucigenin-dependent chemiluminescence (CL) in comparison with normal leukocytes. At the same time, the ratio of the intensity of lucigenin-dependent CL to that of luminol-dependent CL was significantly smaller for FA leukocytes than for normal leukocytes. From these findings and from the effects of antioxidative enzymes and free radical scavengers on CL, it was concluded that FA leukocytes release enhanced amounts of oxygen radicals and that these free radicals contain enhanced amounts of hydroxyl or hydroxyl-like radicals more active than superoxide ion. It was proposed that elevated reactivity of the oxygen radicals released by FA leukocytes may be a major factor in the development of Fanconi anemia; this proposal is supported by the first positive results of treatment of FA patients with rutin (a nontoxic natural free radical scavenger and chelator).

[Antioxidant enzyme activity of the erythrocytes in anemia in children]. / Aktivnost' nekotorykh antioksidantnykh fermentov éritrotsitov pri anemiiakh u detei.

Theoretical prerequisites have been submitted for possible alteration in the activity of erythrocytic antioxidant enzymes in children with anemia. The results are presented of the investigation of children with varying anemias for activity of erythrocytic superoxide dismutase and catalase.

[The role of free oxygen radicals in the pathogenesis of Fanconi's anemia]. / Rol' svobodnykh radikalov kisloroda v patogeneze anemii Fankoni.

The authors describe the results of a study into antioxidants (superoxide dismutase and catalase) and production of the active forms of oxygen (superoxide anion radical, hydrogen peroxide, hydroxyl radical, and singlet oxygen) by blood and bone marrow leukocytes from patients with Fanconi's anemia. The generation of the active forms of oxygen was induced by silica particles while the formation of radical products was recorded by means of luminol-dependent chemiluminescence. Unbalanced excessive production of oxygen radicals such as hydroxyl radicals combined with a decrease in the activity of antioxidant defence enzymes was discovered. It is believed that it is this circumstance that causes the derangement of the membranous structures and multiple breakdowns in the hereditary apparatus. It is suggested that antiradical preparations may be applied to correcting therapy of patients with Fanconi's anemia.