International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia.

Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Münster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% ± 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% ± 7.2% and 50% ± 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% ± 5.3% on ALL-type primary treatment compared with 0% ± 0% and 28% ± 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL-type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with ≥5% blasts after remission induction. The results provide a basis for a prospective trial.

Juvenile xanthogranuloma with clonal proliferation in the bone marrow.

The triple association between juvenile xanthogranuloma (JXG), juvenile myelomonocytic leukemia and neurofibromatosis was described in literature in about 20 cases. In this paper, the case of an 11-month-old infant boy with a disseminated JXG with unusual cytogenetic representation in the bone marrow was reported. Neurofibromatosis and juvenile myelomonocytic leukemia were excluded, just the same as other leukemias. Bone marrow and peripheral blood cytogenetic analysis revealed a karyotype with many rearrangements 46,XY,-6,der(12)t(6;12)(p21;p13),del(7)(p13p22),+9 once described in the literature as a B-acute lymphoblastic leukemia case. On the contrary, in our patient immunologic testing demonstrated a high activity of T lymphocytes, however, inflammation was excluded. To the best of our knowledge this is the first described case of systemic JXG with determined karyotype representing unusual chromosomal aberrations.

Prognostic impact of combined fludarabine, treosulfan and mitoxantrone resistance profile in childhood acute myeloid leukemia.

BACKGROUND: The role of cellular drug resistance in childhood acute myeloid leukemia (AML) has not yet been established. The aim of the study was the analysis of the clinical value of ex vivo drug resistance in pediatric AML. PATIENTS AND METHODS: A cohort of 90 children with de novo AML were assayed for drug resistance profile by the 3-4,5-dimethylthiazol-2-yl-2,5-difenyl tetrazolium bromide (MTT) assay and prognostic model of in vitro drug sensitivity was analyzed. RESULTS: Children who relapsed during follow-up showed higher in vitro resistance of leukemic blasts to most of the drugs tested, except for cytarabine, cladribine, vincristine, mercaptopurine and thioguanine. A combined in vitro drug resistance profile to fludarabine, treosulfan and mitoxantrone (FTM score) was defined and it had an independent prognostic significance for disease free survival in pediatric AML. CONCLUSION: The combined fludarabine, treosulfan and mitoxantrone resistance profile to possibly may be used for better stratification of children with AML or indicate the necessity for additional therapy.

Predictive value of multidrug resistance proteins and cellular drug resistance in childhood relapsed acute lymphoblastic leukemia.

PURPOSE: Cellular resistance in childhood acute leukemias might be related to profile and function of multidrug resistance proteins and apoptosis regulating proteins. The aims of the study were: (1) analysis of expression of MRP1, PGP1, LRP, BCL-2 and p53 proteins; (2) correlation with ex vivo drug resistance, and (3) analysis of their prognostic impact on clinical outcome in childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemia. METHODS: Total number of 787 children diagnosed for initial ALL (n = 527), relapsed ALL (n = 104), initial AML (n = 133) and relapsed AML (n = 23) were included into the study. Mean follow-up period was 3.5 years. Drug resistance for up to 30 anticancer agents was performed by the MTT assay. Expression of all proteins was tested by flow cytometry. RESULTS: Both initial AML and relapsed ALL samples showed higher drug resistance than initial ALL samples. No significant differences were found in drug resistance between initial and relapsed AML samples. The presence of multidrug resistance and apoptosis proteins had no impact on pDFS in iALL and iAML, however strong trend towards adverse prognostic impact of MRP1, PGP and LRP on pDFS in rALL was observed. The same trend was observed for each of analyzed co-expressions of tested multidrug resistance proteins. CONCLUSIONS: The phenomenon of cellular drug resistance in childhood acute leukemias is multifactorial and plays an important role in response to therapy. Expression of MRP1, PGP and LRP proteins, as well as their co-expression play possible role in childhood relapsed ALL.

Chronic Disseminated Candidiasis Complicated by Immune Reconstitution Inflammatory Syndrome in Child with Acute Lymphoblastic Leukemia.

Hepatosplenic candidiasis also known as chronic disseminated candidiasis is a rare manifestation of invasive fungal infection typically observed in patients with acute leukemia in prolonged, deep neutropenia. Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory disorder triggered by rapid resolution of neutropenia. Diagnosis and treatment of IRIS are still challenging due to a variety of clinical symptoms, lack of certain diagnostic criteria, and no standards of treatment. The diagnosis of IRIS is even more difficult in patients with hematological malignancies complicated by "probable" invasive fungal infection, when fungal pathogen is still uncertain. We report a case of probable hepatic candidiasis in 4-year-old boy with acute lymphoblastic leukemia. Despite proper antifungal therapy, there was no clinical and radiological improvement, so diagnosis of Candida-related IRIS was made and corticosteroid therapy was added to antifungal treatment achieving prompt resolution of infection symptoms.

Individualized tumor response testing profile has a prognostic value in childhood acute leukemias: multicenter non-interventional long-term follow-up study.

A total number of 817 children with acute lymphoblastic leukemia (ALL) and 181 with acute myeloblastic leukemia (AML) were assessed for individualized tumor response testing (ITRT) profile as a prognostic factor in long-term follow-up. For each patient, ITRT, initial response to therapy and long-term outcome were assessed. In initial ALL, an impact on long-term response was shown in ITRT for 13 drugs, while in initial AML only for cytarabine. For patients with ALL, a combined five-drug ITRT profile for prednisolone, l-asparaginase, vincristine, cytarabine and daunorubicin or doxorubicin had predictive value for probability of disease-free survival (pDFS) in univariate analysis, whereas in multivariate analysis, bone marrow response by day 33 was the only prognostic factor. For patients with AML, no factor had prognostic value for pDFS in univariate analysis, while ITRT to cytarabine almost reached significance. In conclusion, ITRT can possibly be regarded as a risk factor in childhood acute leukemias.

Differential ex vivo activity of bortezomib in newly diagnosed paediatric acute lymphoblastic and myeloblastic leukaemia.

The proteasome inhibitor, bortezomib, is known to be effective in the therapy of various neoplasms. The objective of this study was the analysis of the ex vivo activity of bortezomib in paediatric acute lymphoblastic leukaemia (ALL), in comparison to paediatric acute myeloid leukaemia (AML). A total of 159 patients entered the study, including 106 ALL (including 86 precursor-B-cell ALL, and 20 T-cell ALL) and 53 AML children. The ex vivo sensitivity to bortezomib and 16 other drugs was studied by MTT assay. Paediatric AML samples were more resistant than paediatric ALL samples to most of the tested drugs, except for cytarabine and thioguanine. With respect to immunophenotype, ex vivo drug resistance in T-cell ALL (T-ALL) was higher for most of the drugs. No differences in drug resistance between T-ALL and common/pre-B-cell-ALL were found for daunorubicin, mitoxantrone and 6-thioguanine. Bortezomib was the only compound which was more active in T-ALL than in common/pre-B-ALL paediatric samples. In conclusion, bortezomib had good ex vivo activity in paediatric T-ALL samples.

Infant acute bilineal leukemia.

Most cases of acute leukemia can be assigned to the myeloid, B or T lineage. There are rare cases of acute leukemia, which cannot be clearly classified, because either blasts express antigens of more than one lineage (acute biphenotypic leukemias) or distinct blast populations of two lineages co-exist (acute bilineal leukemias, aBLL). We present a 10-month-old infant with de novo aBLL, characterized by blasts of monocytic and B-cell precursor lineages. All leukemic cells harbored identical complex MLL gene rearrangement. Despite poor initial response, both to acute lymphoblastic leukemia (ALL) induction treatment and acute myeloid leukemia induction blocks, the child reached complete clinical remission with minimal residual disease negative status and was transplanted. Unfortunately, 16 months from HSCT the patient experienced BM relapse with all blasts characterized by pro-B-ALL immunophenotype. This case report illustrates that aBLL is a very aggressive type of acute leukemia that should be individually treated and monitored, particularly in children less than 1 year of age.

[Lineage switch - conversion of acute lymphoblastic leukaemia to acute myeloid leukaemia in 4 years old girl]. / "Lineage Switch"- konwersja ostrej bialaczki limfoblastycznej w ostra bialaczke szpikowa u 4-letniej dziewczynki.

We report a case of a 4-year-old girl with diagnosed proB acute lymphoblastic leukaemia with co-expression CD33 antigen, treated according to Acute Lymphoblastic Leukaemia Intercontinental - Berlin Frankfurt Münster 2002 (ALL-IC BFM 2002) protocol for standard risk group. Haematological remission was obtained on day 33 of induction treatment (on time). During induction and consolidation therapy there were no early serious adverse effects. The late isolated bone marrow relapse of acute myeloid leukaemia, type 7 was noted in our patient. We recognized this case as a lineage switch acute lymphoblastic leukaemia to acute myeloid leukaemia. In spite of Ida Flag regimen and following Acute Myeloid Leukaemia - Berlin Frankfurt Münster 2004 (AML-BFM 2004) protocol were administered, the clinical and haematological remission was not achieved and the patient died because of disease progression (circulatory and respiratory insufficiency).

[Analysis of prognostic factors in children with B-cell non-Hodgkin lymphoma (B-NHL)]. / Analiza czynników prognostycznych u dzieci z nieziarniczym chloniakiem b-komórkowym.

INTRODUCTION: The aim of this study was to analyze prognostic factors in patients with diagnosed B-cell non-Hodgkin lymphoma (B-NHL). PATIENTS AND METHODS: The retrospective analysis of 44 children with B-NHL, newly diagnosed and treated at the Clinical Department of Paediatric Oncology, Haematology and Transplantology in Poznan. RESULTS: Complete remission was achieved in 39 and partial remission in 2 children. Three children died due to progression of the disease. Relapses was observed in 13 children (male to female ratio 12:1). Median age at diagnosis of both relapsed and non-relapsed children was 8 years. Relapses were observed from 8 to 46 months (median: 26 months). There was no relapse in stage I, whilst in stage II - 1 relapse occurred, in stage III - 5 relapses, and in stage IV - 7 relapses. The mean time of achieving complete remission was 67 days in patients demonstrating relapse and 59 days in non-relapsed patients. In patients with relapse the mean initial serum lactate dehydrogenase (LDH) level was significantly lower than in non-relapsed group. Among relapsed patients, 12 (92%) were EBV-seropositive at diagnosis, whereas only 13 (42%) in the group of non-relapsed patients. In the subgroup of children with primary bone marrow involvement the mean absolute count of lymphoblasts in peripheral blood measured at diagnosis was 38.5 G/L in relapsed children and 5.2 G/L in non-relapsed children. CONCLUSIONS: 1. In the studied group EBV-seropositivity and initial lower serum LDH level are suggested to be risk factors of relapse of the lymphoma. Nevertheless, further investigations based on larger group of patients are needed. 2. In children with bone marrow involvement initial absolute lymphoblast count in peripheral blood significantly increases the risk of relapse. 3. In the studied group there was no significant impact of age and time period of remission on the risk of relapse.

[Ovarian malignant tumours. Efficacy of germ cell and sex cord tumour treatment protocol in Poland]. / Nowotwory zlosliwe zlokalizowane w obrebie jajników. Ocena skutecznosci programu leczenia zlosliwych guzów germinalnych i guzów sznurów plciowych u dzieci w Polsce.

UNLABELLED: Approximately 1% of all malignant tumours among children are localized in the ovary. The majority belongs to germ cell tumours and occurs in the peripubertal period. AIM of the study was the evaluation of the efficacy of malignant ovarian germ cell tumour treatment programme in children. MATERIAL AND METHODS: Since 1998, 40 girls with malignant ovarian tumours were enrolled in the multicentre trial. Mixed germ cell tumours with yolk sac elements and dysgerminoma occurred the most often. Alfa-fetoprotein (AFP) was increased in almost one half of patients. Tumour exceeded the ovary margin in more than half the patients and 25% were qualified as high risk group. 38 children completed the treatment. All but one patient with neuroblastoma received TGM protocol (Tumeurs Germinates Malignes). A VBP regimen (vinblastine, bleomycin, cisplatin) was applied in 19 girls, VIP regimen (etoposide, ifosfamide, cisplatin) in 16, two received no chemotherapy. Due to delayed remission after first-line chemotherapy it was prolonged with ABK (adriamycine, bleomycine, carboplatin) in 3 patients, 1 megachemotherapy regimen with autologous bone marrow transplantation was realized, one patient received a 1.5 year long oral chemotherapy. All the children underwent surgery, 34 primary (56% complete), 12 secondary (75% complete). 8 children were operated twice. RESULTS: Among 34 children with germ cell tumours and 3 with sex cord tumours who completed the treatment all are alive in the first remission. 1 child with neuroblastoma localised in the ovary died due to recurrence. A median follow-up period was 42 months. CONCLUSIONS: The TGM protocol appears to be highly efficient in treatment of germ cell tumours even in advanced stages.

[Testicular malignant tumours. Efficacy of germ cell and sex cord tumours treatment protocol in Poland]. / Zlosliwe nowotwory jader. Ocena skutecznosci programu leczenia zlosliwych guzów germinalnych i guzów sznurów plciowych u dzieci w Polsce.

UNLABELLED: Approximately 2% of of all malignant tumours in boys are localised in the testis. Among them 80% are germ cell tumours with the malignant elements of yolk sac tumour. AIM of the study was evaluation of the efficacy of malignant testicular tumour treatment programme in children. MATERIAL AND METHODS: Since 1998 31 boys aged 1 month to 18 years (median 14 years) with malignant testicular tumours were enrolled in the multicentre trial. Patomorphologically clear yolk sac tumour (33%) and mixed germ cell tumour (42%) with the majority of yolk sac tumour component or carcinoma embryonale, occurred most often. Alfa-feto-protein was increased in 63% and choriogonadotropin in 26 patients. 61% patients had local clinical stage and the tumour was localized in the testis. In 39% patients tumour exceeded the testis margin. 4 patients were excluded from analysis as 3 are actually treated and 1 died on the second day of admittance to hospital. All patients received TGM 95 regimen (Tumeurs Germinales Malignes). Surgery (orchidectomy) was applied in 27 boys, 26 were primary (81% complete), 3 secondary (100% complete). 33% received no chemotherapy after surgery, in 41% VBP protocol (vinblastine, bleomycin, cisplatin) was given and in 26%o VIP protocol (ethoposide, ifosphamide, cisplatin). Two patients received also ABK (adriamycine, bleomycin, carboplatin). RESULTS: Among 26 children with germ cell tumours, 25 (96%) are alive, 23 (88%) are in first remission after completion of treatment. One child died due to central nervous system metastases. 2 children had local recurrence treated with chemotherapy or surgery with good result. Median follow-up is 45 months. CONCLUSIONS: TGM regimen is highly efficient in the treatment of malignant testicular tumours. Problems occur in cases of disseminated disease.