Hematopoietic stem cell transplantation does not increase the risk of infection-related complications for pediatric patients with Hodgkin and non-Hodgkin lymphomas: A multicenter nationwide study.

BACKGROUND: Hodgkin (HL) and non-Hodgkin lymphoma (NHL) represent a spectrum of lymphoid malignancies that are often curable with currently applied treatment regimens; however, 15%-30% of lymphoma patients still suffer from relapsed or refractory (rel/ref) disease. Although hematopoietic stem cell transplantation (HSCT) improves outcomes of second-line therapy for lymphoma in childhood, the complication rates in this group of patients, especially infectious complications (IC), remain unclear. OBJECTIVE: The aim of this population-based cohort study was a retrospective analysis of incidence, epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in primary or rel/ref lymphoma patients, both HL and NHL. PATIENTS AND METHODS: We subdivided lymphoma patients into three groups: patients with primary conventional chemotherapy/radiotherapy regimens (group A), patients with rel/ref lymphoma treated with second-line chemotherapy (group B), and rel/ref lymphoma patients who underwent HSCT (group C). The medical records of the patients were biannually reported by each pediatric oncology center, and the data were analyzed centrally. RESULTS: Within 637 patients with primary lymphoma, at least one IC was diagnosed in 255 (40.0%), among 52 patients with rel/ref lymphoma 24 (46.2%) ICs were observed, and in transplanted group, 28 (57.1%) out of 49 children were diagnosed with IC (P = .151). The distribution of etiology of IC differed between the patient groups (A, B, C), with a predominance of BI in group A (85.6% vs 72.0% and 47.9%, respectively), VI in group C (9% and 16.0% vs 46.6%, respectively), and IFD in group B (5.4% vs 12.0% vs 5.5%, respectively). Overall, 500 (68.0%) episodes of bacterial IC were diagnosed in the entire group. Apart from HL patients treated with chemotherapy, in all the other subgroups of patients Gram-positives were predominant. The rate of multidrug-resistant bacteria was high, especially for Gram-negatives (41.1% in group A, 62.5% in group B, and 84.6% in group C). The infection-related mortality was comparable for each group. CONCLUSIONS: The incidence of IC was comparable during first- and second-line chemotherapy and after HSCT, but their profile was different for primary or re/ref lymphoma and depended on the type of therapy.

Incidence, course, and outcome of Clostridium difficile infection in children with hematological malignancies or undergoing hematopoietic stem cell transplantation.

Clostridium difficile infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation (HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age < 5 years and diagnosis other than acute leukemia were the positive prognostic factors influencing clinical CDI course.

Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial.

A newly developed recombinant factor IX (BAX326(1) ) was investigated for prophylactic use in paediatric patients aged <12 years with severe (FIX level <1%) or moderately severe (FIX level 1-2%) haemophilia B. The aim of this prospective clinical trial was to assess the safety, haemostatic efficacy and pharmacokinetic profile of BAX326 in previously treated paediatric patients. BAX326 was administered as prophylaxis twice a week for a period of 6 months, and on demand for treatment of bleeds. Safety was assessed by the occurrence of related AEs, thrombotic events and immunologic assessments. Efficacy was evaluated by annualized bleeding rate (ABR), and by treatment response rating (excellent, good, fair, none). PK was assessed over 72 h. None of the 23 treated paediatric subjects had treatment-related SAEs or AEs. There were no thrombotic events, inhibitory or specific binding antibodies against FIX, rFurin or CHO protein. Twenty-six bleeds (19 non-joint vs. 7 joint bleeds) occurred (mean ABR 2.7 ± 3.14, median 2.0), of which 23 were injury-related. Twenty subjects (87%) did not experience any bleeds of spontaneous aetiology. Haemostatic efficacy of BAX326 was excellent or good for >96% of bleeds (100% of minor, 88.9% of moderate and 100% of major bleeds); the majority (88.5%) resolved after 1-2 infusions. Longer T1/2 and lower IR were observed in younger children (<6 years) compared to those aged 6 to 12 years. BAX326 administered as prophylactic treatment as well as for controlling bleeds is efficacious and safe in paediatric patients aged <12 years with haemophilia B.

First-line immunosuppressive treatment in children with aplastic anemia: rabbit antithymocyte globulin.

Immunosuppressive therapy is the treatment of choice in children with acquired severe aplastic anemia (AA) and no HLA-matched family donor. The paper presents results of a multicenter study of 63 children with AA treated with rabbit antithymocyte globulin (r-ATG) and cyclosporine A as the first line treatment in the years 1996-2012. Therapeutic effects were evaluated at Days 112, 180, and 360. At Day 112, remission was achieved in 28 out of the 63 patients (44.4 %), complete remission in 10 patients (15.9 %), and partial remission in 18 (28.5 %). At Day 180, 31 patients (49.2 %) were in remission including 15 cases in complete (23.8 %), and 16 cases in partial remission (25.4 %). One year after therapy onset, 34 patients (64.9 %) were in remission including 24 patients (38.0 %) in complete and 10 (15.9 %) in partial remission. Relapse occurred in 4 patients, from 8 months up to 2 years and 2 months after remission. One child, 5 years after remission, was diagnosed with paroxysmal nocturnal hemoglobinuria. The estimated 10-year overall survival rate and 10-year event-free survival rate were 67 % and 57 %, respectively.

Safe switching from a pdFIX (Immunine®) to a rFIX (Bax326).

The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma-derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine® to a recently developed rFIX Bax326 product. Patients (aged <65 years) who completed a pretreatment study which prospectively documented the exposure to Immunine® and monitored FIX inhibitors while receiving prophylactic treatment were transitioned into pivotal (patients aged 12-65 years) and paediatric (patients aged <12 years) clinical studies investigating prophylaxis and treatment of bleeding episodes with Bax326. None of the 44 patients developed inhibitory or specific binding anti-FIX antibodies during the course of the studies. A total of 38 unrelated adverse events (AEs) were occurred in 20/44 (45.5%) subjects during the Immunine® study. Following a switch to Bax326, 51 AEs were reported in 25/44 (56.8%) subjects. The incidence of AEs related to Bax326 treatment (two episodes of dysgeusia in one patient) was low (2.3%); there were no serious adverse reactions. The comparison between Immunine® and Bax326 demonstrated analogous haemostatic characteristics and annualized bleeding rates. Overall, there is direct evidence indicating a safe and clinically effective transition from a pdFIX (Immunine®) to a newly developed rFIX (Bax326(1) ) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.

Allelic loss of selected tumor suppressor genes in acute lymphoblastic leukemia in children.

Defect in function of tumor suppressor genes may lead to initiation/progression of leukemias. RB1, CDKN2A and TP53 gene alterations are found in acute lymphoblastic leukemia (ALL) in children. Data showing a contribution of these alterations to the pathomechanism of leukemias are contradictory and their impact on a disease course still remains undefined. The main aim of the study was to identify and the characterize of RB1, CDKN2A and TP53 allele loss in ALL children patients at diagnosis. 46 children with de novo ALL were examined. Fluorescent in situ hybridization was performed on bone marrow smear preparations. We demonstrated that at least one of three investigated deletions occurred statistically more frequently in T-lineage leukemia patients (p = 0.044); this was the most frequent in respect to RB1 gene (p = 0.054). Additionally, at least one of the examined deletions was observed statistically more frequently in patients with WBC above 20 000/µl (p = 0.043), this was the most frequent for CDKN2A gene (p = 0.066). Presented results seem to give an evidence that deletions of RB1 and CDKN2A genes may contribute to the development of hyperleukocytic type of T-lineage ALL in children, nevertheless this observation needs further investigations.

Pediatric pulmonary Hodgkin lymphoma: analysis of 10 years data from a single center.

Several reports indicate that lungs are the extralymphatic site most commonly affected in patients with Hodgkin lymphoma; however, the data in children are rather limited. This retrospective study aimed to assess the frequency, clinical picture, and the impact on prognosis in children with pulmonary Hodgkin lymphoma, who were diagnosed and treated in a single center during a 10-year period. Pulmonary lesions related to HL: nodules and parenchymal infiltrates with cavitations were found in 3 of 32 (9.4%) patients; in 2 cases these were found as the concomitant manifestation whereas in 1 case as the solitary form (Primary Pulmonary Hodgkin Lymphoma). B-DOPA and MVPP chemotherapy combined with mediastinal and pulmonary irradiation resulted in sustained remissions in all 3 patients, lasting 3, 7, and 64 months, respectively. Lung involvement occurs in up to 10% of children with Hodgkin lymphoma. Primary pulmonary Hodgkin lymphoma is a rare and atypical form of Hodgkin lymphoma; thus is associated with delayed diagnosis which does not seem to affect prognosis. It should be suspected in a child with non-resolving pneumonia and pulmonary parenchymal infiltrates with cavitations.

Idiopathic pulmonary hemosiderosis in a 9-year-old girl.

Diffuse alveolar hemorrhage (DAH) is a rare and life-threatening condition characterized by hemoptysis, dyspnoea, alveolar infiltrates on chest radiograph and various degrees of anemia. It may occur either as a primary disease of the lungs or a secondary condition due to cardiac, systemic vascular, collagen or renal diseases. Idiopathic pulmonary hemosiderosis (IPH) is a separate form of DAH of unknown origin, associated in some cases with celiac disease. The estimated incidence of IPH in children is 0.24-1.23 cases per million, with a mortality rate as high as 50%. Only about 500 cases of this disease have been described in medical literature. We present a case of a 9-year-old girl diagnosed with IPH, which was confirmed by the presence of many hemosiderin-laden macrophages in bronchoalveolar lavage obtained by bronchofiberoscopy. Therapy with glucocorticoids was initiated with a partial and transient response. Azathioprine and a gluten-free diet were subsequently introduced. However, the girl still suffers from recurrent episodes of hemoptysis, dyspnea and anemia.

Increased risk of infections and infection-related mortality in children undergoing haematopoietic stem cell transplantation compared to conventional anticancer therapy: a multicentre nationwide study.

This nationwide multicentre study analysed the epidemiology of bacterial, viral and fungal infections in paediatric haematopoietic stem cell transplantation (HSCT) and paediatric haematology and oncology (PHO) patients over a period of 24 consecutive months, including incidence, hazard risk and outcome of infections as well as occurrence of multidrug-resistant bacteria. During this period, 308 HSCTs were performed and 1768 children were newly diagnosed for malignancy. Compared to PHO, the risk in HSCT patients was significantly higher for all infections (hazard ratio (HR) 2.7), bacterial (HR 1.4), fungal (HR 3.5) and viral (HR 15.7) infections. The risk was higher in allo- than auto-HSCT for bacterial (HR 1.4), fungal (HR 3.2) and viral (HR 17.7) infections. The incidence of resistant bacteria was higher in HSCT than in PHO patients for both G-negative (72.5% vs. 59.2%) and G-positive (41.4% vs. 20.5%) strains. Cumulative incidence of bacterial, fungal and viral infections in HSCT patients was 33.9, 22.8 and 38.3%, respectively. Cumulative incidence of viral infections in allo-HSCT was 28.0% for cytomegalovirus, 18.5% for BK virus, 15.5% for Epstein-Barr virus, 9.5% for adenovirus, 2.6% for varicella zoster virus, 0.9% for influenza, 0.9% for human herpesvirus 6 and 0.3% for hepatitis B virus. Survival rates from infections were lower in HSCT than in PHO patients in bacterial (96.0 vs. 98.2%), fungal (75.5 vs. 94.6%) and most viral infections. In conclusion, the risk of any infections and the occurrence of resistant bacterial strains in allo-HSCT patients were higher than in auto-HSCT and PHO patients, while the outcome of infections was better in the PHO setting.

DNA aneuploidia in cells of acute leukemia non B non T type in children.

In 31 children with acute lymphoblastic leukemia of non B and non T type the cellular DNA amount using cytophotometric method was estimated. Parallely the computer microscopic image analysis was performed. These investigations were made using Morphoquant of C. Zeiss, Jena, GDR. The cells were studied before the introduction of therapy, after obtaining the first phase remission, during remission and at the relapse. DNA-diploidal type in 13 cases, aneuploidio-poliploidal in 8 cases and hipoploidal type in 13 cases. The survival time of investigated children was the largest in the case with diploidal and hyperploidal types of leukemic cells. The children with DNA-aneuploidopoliploidal type cells had the shortest survival time. Besides the estimation of the cellular DNA amount the defining of the percentage of the cells being in S phase seems to be very important. In differentiating between the normal and leukemic lymphocytes, containing the same amount of DNA as non neoplastic lymphocytes, it may be advisable to analyse the morphological picture, particularly of such parameters as chromatin compactness degree and the presence of nucleoli.

[Survival of patients and DNA-ploidy of cells in non-Hodgkin's lymphoma of low-grade malignancy]. / Przezycie chorych a DNA-ploidia w komórkach chloniaków nieziarniczych o niskiej zlosliwosci.

DNA-ploidy in lymphoma cells obtained from lymph nodes of 107 patients with non-Hodgkin's lymphomas of low grade malignancy was studied prior to the treatment introduction. The survival of patients was within the range of 24-126 months (median 63 months). There were 70 hyperdiploidic and 37 diploidic patients. The statistical tendency to prolonged survival was seen among patients with lymphocytic lymphoma (CLL) as compared to other histological types of the disease. There were no statistical differences in the probability of survival (p-P) between diploidic and hyperdiploidic patients either in the whole studied group or in particular histologic types of lymphoma.

[Hyperglycemia as a side effect of using L-asparaginase in children with acute lymphoblastic leukemia (ALL]. / Hiperglikemia jako powiklanie stosowania L-asparaginazy u dzieci z ostra bialaczka limfoblastyczna (OBL).

Two cases of hyperglycemia complicating therapy of childhood ALL with the use of L-asparaginase are described. Both patients required insulin administration. The relationship between L-aspa therapy and clinical manifestation of hyperglycemia seems to indicate that this could be the side effects of the drug.

[DNA index and proliferative activity of blastic cells in childhood ALL]. / Indeks DNA i aktywnosc proliferacyjna komórek bialaczkowych w OBL u dzieci.

DNA Index and the pretreatment proliferative activity of blastic cells were assessed in relation to treatment results in 58 children with acute lymphoblastic leukemia. ALL patients were treated with the use of BFM 79 protocol. After the median follow-up time of 32 months p-EFS and p-DFS were 0,425 and 0,495 respectively. There were 35 (56.45%) diploic, 21 (33.81%) hyper-diploic and 2 (3.22%) hypo-diploic patients. There was no statistical difference in p-EFS and p-DFS between diploic and hyper-diploic patients. Patients in I-st remission were characterized by significantly higher percentage of cells remaining in the S-phase of the cell cycle.

[Treatment results of acute lymphoblastic leukemia in children from centers in Bialostock and Szczecin]. / Wyniki leczenia ostrej bialaczki limfoblastycznej (OBL) u dzieci w osrodkach bialostockim i szczecinskim.

The retrospective analysis was undertaken in order to assess treatment results of childhood ALL achieved in two "independent" units: in Bialystok and Szczecin. It comprised 61 patients: 24 girls and 37 boys aged 10 - 197 months (median 64, mean 73 months), who between November 1987 and December 1992 were diagnosed as having ALL. 25 children, with risk factor greater than 0.8 were classified as intermediate risk patients. ALL 61 children were treated greater than 0.8 were classified as intermediate risk patients. ALL 61 children were treated according to BMF 86 protocol modification of the Polish Leukemia Study Group. The observation was closed in February 1993; the follow-up time was within the range of 10 - 72 months (median 32, mean 32 months). 7 patients (11.5%) did not enter remission, 4 children (6.6%) died in remission and 11 children (18.0%) relapsed. The probability of event-free survival (EFS) and disease-free survival (DFS) were 0.53 and 0.67 respectively. There was no statistical difference in p-EFS between standard and intermediate risk patients (SRG = 0.60 vs IRG = 0.53). It has been shown that p-EFS was not statistically influenced by age, sex, WBC, Hb level, paS-positive and acid-positive ALL. It has been suggested that protocol deviations were the main cause of the inferior (as compared to other domestic centers) treatment results.

CHOP treatment of childhood acute myelogenous leukemia with monocytic differentiation: a report on five cases.

Five children with M4 or M5 acute myelogenous leukemia (AML) not responding to previous treatment or in relapse were treated with a four-drug protocol consisting of cyclophosphamide, adriamycin, vincristine, prednisone, and CNS prophylaxis. There were two treatment failures; the remaining three patients have achieved complete remission, lasting 18+, 13+, and 12+ months respectively. Further follow-up is to be performed.

[Prognostic value of the reaction to steroids in the treatment of acute lymphoblastic leukemia in children]. / Znaczenie rokownicze reakcji na steroidy w leczeniu bialaczki limfoblastycznej u dzieci.

Relationship between the result of therapy in 48 cases of the acute lymphoblastic leukemia in childhood and character of response to corticosteroids, classified according to BMF group, has been assessed. Follow up period ranged from 13 to 75 months (mean 36 months, median 39 months). In was found, that the probability of survival free from any events, probability of complete remission persistence, and probability of survival after diagnosis have been statistically significantly higher in the group of patients with positive response to corticosteroids in comparison with patients non-responding to these agents. However, there was no significant difference in the number of recurrencies with the involvement of CNS. Authors share the opinion that their results confirm an opinion of Riehm et al. that the response to corticosteroids is of prognostic value in the acute lymphoblastic leukemia in childhood.

Antioxidant status of children with steroid-sensitive nephrotic syndrome.

Eighteen children with steroid-sensitive nephrotic syndrome (SSNS) were studied. The control group comprised 20 healthy children. The following indirect parameters of reactive oxygen species activity were determined in nephrotic patients during four stages of the disease (full relapse before prednisone administration, disappearance of proteinuria, prednisone cessation, unmaintained remission): plasma malondialdehyde (MDA) levels, copper/zinc superoxide dismutase (CuZn SOD) activity and glutathione peroxidase (GPX) activity in erythrocytes, reduced glutathione (GSH) and vitamin C levels in whole blood, and vitamin E level in serum. Increased MDA levels, reduced vitamin C levels, and enhanced CuZn SOD activity were found in relapse. GSH concentration was high during all four stages. Vitamin E level was also increased, parallel to the pattern of serum lipids. GPX activity remained low during the proteinuria stage and in remission. We conclude that the majority of abnormal findings can be attributed to the hyperlipidemia of NS. Low GPX activity may be a factor limiting the antioxidant capacity in NS. The present study is inconclusive regarding the role of free radicals in the proteinuria of NS.