Mixed phenotype acute leukemia: Biological profile, clinical characteristic and treatment outcomes: Report of the population-based study.

OBJECTIVES: The aim of this population-based, retrospective study was to analyze biological and clinical features and treatment results in children diagnosed with MPAL in all Polish pediatric oncology centers between 2007 and 2018. METHODS: Among 2893 children and adolescents diagnosed and treated for acute leukemia, 39 (1.35%) patients fulfilled the WHO criteria of MPAL. The T/myeloid phenotype was most prevalent. RESULTS: Cytogenetics findings were seen in 2 (5.1%), while chromosomal abnormalities were found in 14 (35.9%) patients. Thirty-two patients achieved CR-1, including 23 (92.0%) treated with ALL-directed chemotherapy and 9 (64.3%) treated with AML-type induction regimens. Within these patients, 4 (12.5%) died due to treatment-related complications and 11 (34.4%) relapsed. Nineteen (63.3%) patients underwent allo-HSCT in CR-1 and 14 (73.7%) of them have been in CR-1. In total, 17 (43.6%) patients remain in CR-1 for 1-12 years, including 14 (58.3%) with T/myeloid MPAL. The 5-year pOS and pEFS were 51.8% and 44.2%, respectively. The overall survival for ALL-directed therapy was significantly better than the one for AML-type chemotherapy (P = .001). It was also better for patients who underwent HSCT in CR-1 (P = .001). CONCLUSIONS: The prognosis of MPAL is unsatisfactory, but initial treatment with ALL-directed chemotherapy consolidated with allo-HSCT improves the outcomes in MPAL.

The influence of different intensity of treatment on hormonal markers of gonadal function in acute lymphoblastic leukemia survivors.

Anti-cancer treatment in children can deteriorate gonadal function and affect future fertility. We analyzed the hormonal markers of gonadal function in adolescent leukemia survivors, treated in childhood with different levels of aggressiveness. We analyzed hormone levels in 69 adolescents and young adults, leukemia survivors stratified into standard (SR), intermediate (IR), and high (HR) risk groups, and in 80 healthy controls (38 men) at a similar age. We assessed follicular stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B in the whole group, testosterone in males, and E2 and anti-Müllerian hormone (AMH) in females. Males classified into HR group presented, in comparison to control, higher levels of FSH, LH, lower inhibin B, and normal testosterone, whereas in SR and IR group, the hormonal values were comparable to the control. In females, in all risk groups, the levels of FSH, LH, E2, and inhibin B were comparable with the control, but the mean AMH levels were slightly lowered. We did not observe the effect of prophylactic cranial irradiation (12 or 18 Gy) or the time of treatment (before vs. during puberty) on hormone levels. In females, a positive correlation was found between the time interval after the end of treatment and AMH levels. Male leukemia survivors having undergone more intensive chemotherapy show the symptoms of disturbed spermatogenesis and need to be followed-up in the future. Women, irrespective of the risk group, can develop the signs of preterm ovarian insufficiency. They should be informed about the impact of the treatment on gonadal function.

Correction to: Health status of Polish children and adolescents after cancer treatment.

The first and family names of the authors were interchanged. The correct author names are now correctly presented in this article.

Health status of Polish children and adolescents after cancer treatment.

In the last 40 years, considerable progress was made in the treatment of childhood cancer. Nearly 80% of children achieve long-term clinical remission or are permanently cured. This improvement is however not without sacrifice. This is the first Polish study analyzing the general health status and epidemiology of organ late effects in the cohort of Polish childhood and adolescent cancer survivors monitored by doctors and registered in the on-line national database for late effects (N = 1761). This tool collects information on previous therapy and current health status (medical history, physical examination, laboratory tests) of cancer survivors. The survivors are invited to take part in the follow-up examination 5 years after the end of treatment. In the study group, 207 survivors (11.75%) had no complaints; whereas in 1554 cases (88.25%), one or more symptoms/complaints suggesting organ dysfunction were reported. In the whole group, the circulatory problems were most common (31.7%); more than 20% of survivors presented complaints or abnormal function of the urinary tract and had skin, dental, skeletal/muscular problems, or difficulty with chewing. Obesity or short stature alone (21.4%) and a variety of endocrine problems (short stature, obesity, thyroid dysfunction, and gonads toxicity) were present in 323 patients (118 females 15.0% and 205 males 21.0%). Gonadal dysfunction, as the only problem, occurred in 75 girls (9.6%) and 131 boys (13.4%). In our cohort, severe or life-threatening health conditions (3 and 4 grade according to toxicity criteria) were present in low percentage, i.e., 0.2% in the circulatory system, 0.3% in the respiratory tract and, 0.7% in kidney insufficiency. CONCLUSION: Our findings indicate that many childhood cancer survivors demonstrate numerous complaints, even a short time after treatment, suggesting the importance of regular follow-up examinations in subsequent years. What is Known: • Contemporary studies indicate that a significant number of childhood cancer survivors present different long-term side effects which influence their quality of life. What is New: • This is the first nationwide study performed in the largest cohort of Polish childhood cancer survivors concerning general health status and frequency of organ dysfunction.

Reed-Sternberg cells in classical Hodgkin lymphoma in children seem to be predominantly oestrogen receptor α negative and oestrogen receptor ß positive.

Oestrogen receptor α (ERα) is responsible for activation of gene transcription, while oestrogen receptor ß (ERß) serves as a negative regulator of ERα function. Since ER status is a prognostic and predictive factor in some cancers, we analysed the immunohistochemical expression of ERα and ERß in Reed-Sternberg (RS) cells in paraffin-embedded lymph node specimens from 27 children with classical Hodgkin lymphoma (HL) in relation to histological type, clinical stage, age, and gender. Percentage of RS cells with positive nuclear reaction for the presence of ERα and/or ERß was assessed. ERα positive RS cells were present in 11% (3/27) of lymph nodes (range 1-8%, mean 0.4%) whereas ERß positive RS cells were detected in 96% (26/27) of lymph nodes (range 1-97.5%, mean 61.8%). The highest percentage of ERß positive RS cells was observed in patients with the most advanced (IVB) disease as compared to patients with lower stages (90.3% vs. 56.9% respectively, p = 0.004). To the best of our knowledge this is the first report on the expression of ERß in RS cells in children. We conclude that RS cells in classical HL in children seem to be mainly ERß positive and ERα negative.

Activation of NF-ĸB in leukemic cells in response to initial prednisone therapy in children with acute lymphoblastic leukaemia: relation to other prognostic factors.

Nuclear factor ĸB (NF-ĸB) is a transcription regulator of proliferation and cell death. Increased activation of NF-ĸB may be responsible for treatment failure in children with acute lymphoblastic leukaemia (ALL). This study aimed to assess changes in NF-ĸB activation in peripheral blood mononuclear cells prior to and after 6 and 12 h of prednisone administration in relation to age, initial WBC count at diagnosis and early treatment response in childhood ALL. The study comprised 55 children with de novo ALL. Cells were stained with mouse anti-NF-ĸB (p65) antibody followed by goat anti-mouse antibody conjugated with FITC and measured by laser scanning cytometer. The nuclear/cytoplasmic (N/C) ratio of NF-ĸB reflecting activation of NF-ĸB was decreased 12 h after treatment in the standard risk group patients, whereas it remained statistically unchanged in the non-standard risk group patients. Changes in the N/C ratio of NF-ĸB were not associated with age and early treatment response; however, in children with an initial WBC count higher than 20 000/µl at diagnosis, this ratio was increased after 6 and 12 h from prednisone administration. The association of higher activation of NF-ĸB with an elevated initial WBC count suggests that activation of NF-ĸB may be responsible for treatment failure in children with ALL.

Simultaneous assessment of p53 and MDM2 expression in leukemic cells in response to initial prednisone therapy in children with acute lymphoblastic leukemia.

Ineffective apoptosis is one of main causes of a treatment failure in childhood acute lymphoblastic leukemia (ALL). p53 plays a crucial role in triggering apoptosis of ALL in response to prednisone treatment. MDM2 is the endogenous inhibitor of apoptosis that downregulates the functional activity of p53 protein. This study is aimed to evaluate changes in MDM2 and p53 expression in peripheral blood mononuclear cells collected from children with ALL prior to and after 6 and 12 h of prednisone administration in relation to early treatment response. The study comprised 35 children with newly diagnosed ALL, subdivided into good (n = 24) and poor (n = 11) early treatment responders. MDM2 - associated APC fluorescence and p53 - associated FITC fluorescence were measured by the laser scanning cytometer. In the group of poor responders, p53 and MDM2 fluorescence were significantly higher than in the group of good responders. In the group of good early treatment responders, a statistically significant rise of p53 fluorescence measured in the nucleus and in the cytoplasm 12 h after prednisone administration as well as increase in MDM2 fluorescence measured in the cytoplasm 6 and 12 h after prednisone administration were seen. These data suggest that pretreatment overexpression of MDM2 protein may contribute to poor early treatment response.

[Genotyping and minimal residual disease study in children with acute myeloid leukemia: preliminary results]. / Genotypowanie i oznaczania choroby resztkowej u dzieci z ostra bialaczka mieloblastycznq: wstepne wyniki.

The aim of the paper is to present the initial results of molecular examination which was started in 2006 for children with acute myeloid leukemia. Better knowledge of biology of this disease, can result in establishing of new risk factors what allows more precise patient stratification to different therapeutic groups. Study was obtained patients until to 18 years of age treated according to AML-BFM 2004 INTERIM protocol in 14 centers of the Polish Pediatric Leukemia/Lymphoma Study Group. Mononuclear cells were collected from bone marrow on time points established according to the AML-BFM 2004 INTERIM protocol. Collected cells were isolated on Ficoll gradient, and RNA and DNA were isolated using TRIZOL reagent. To synthesize cDNA an amount of 1 mg of total RNA was used. To perform quantitative RT-PCR and RQ-PCR reactions 4 fusion gene transcripts (AML1-ETO, CBFb-MYH11, PML-RARA /subtype bcrl and bcr3/) were used according to the protocol established by Europe Against Cancer Program. An expression of WT1 gene was tested additionally. An analysis of ABL control gene was used to normalize of achieved results. Determination of duplication of FLT3 gene in DNA sample was performed with starters complementary to JM region. Genotyping was performed in 75 patients with acute myeloid leukemia so far. AML1-ETO fusion gene transcript was found in 14 patients (19%). PML-RARA (subtype bcr3) and CBFB-MYH11 gene transcripts were detected in 3 (4%) and 3 (4%) patients, respectively. Duplication of FLT3 gene was found in 4 (5.3%) cases. Between 67 tested children over expression of WT1 was present in 51 patients (76%). Analysis of MRD level in subsequent time points showed systematic decrease of number of fusion gene transcript copies and gene WT1 expression. To establish the rate of molecular marker presence in AML in children and the influence of the presence of MRD on the treatment results as well, the study has to be conducted on a larger group of patients with longer follow-up.

[Treatment failure in children with acute myelocytic leukemia: over 25-year experience of Polish Pediatric Leukemia/Lymphoma Study Group with four consecutive unified treatment protocols for childhood acute myelocytic leukemia]. / Niepowodzenia leczenia w ostrej bialaczce szpikowej u dzieci: ponad 25-letnie doswiadczenia Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

Four consecutive intensive unified regimens (BFM-AML-83, PGP-AML 94, PGP-AML 98 AML-BFM 2004 Interim) for acute myelocytic leukemia (AML) have been conducted by the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) since 1983. The last one, introduced four years ago is still active, and only preliminary result may be presented. There were 726 children with AML diagnosed (226, 102, 247 and 151 in the I, II , III and IV periods, respectively), and 603 of them were eligible for evaluation (208, 83, 195 and 117, respectively). Complete remission rates were: 71.4%, 67.5%, 81.4% and 87% in consecutive periods, respectively. Five-year overall survival (OS) and event-free survival (EFS) rates were: 33% and 32% for PGP-AML 83 regimen, 38% and 36% for PGP-AML 94 regimen, and 53% and 46% for PGP-AML 98 regimen, respectively. For AML-BFM Interim 2004 the 3-year OS and EFS were 57% and 57%, respectively. Despite continuous improvement of the treatment results, the number of failures have remained too high, but the pattern have changed in the following way: Early deaths (from diagnosis to 15 day of treatment) decreased only in the fourth period to 3%. "Aplasia deaths" (between day 15 and 42) decreased gradually from 16% in the first period to 1.5% and 2.2% in the third and in the fourth period, respectively. Deaths in remission decreased from 10% in first and second period to 3.5% at present. Number of non responders increased between first and second period from 6% to 18%, later decreased to 8.2% at present. These trends e.g. decrease of early death and treatment related mortality reflect both the better efficacy of antileukemic treatment and the improvement of supportive care.

[The influence of acute limphoblastic leukaemia and its treatment on the patient's mental functioning--a literature review]. / Wplyw zachorowania na bialaczke w wieku dzieciecym i jej leczenia na funkcjonowanie psychiczne pacjentów--przeglad pismiennictwa.

The aim of the literature review was the problem of psychiatric complications of intensive chemo- and radiotherapy, which were used in childhood. These days most children who suffer from acute leukaemia are successfully treated. Most studies indicate cognitive dysfunctions, anxiety and mood disorders. These days a new scheme of chemo- and radiotherapy should be introduced, which should consider the mental state of the patients.

Development of treatment and clinical results in childhood acute myeloid leukemia in Poland.

BACKGROUND: Since 1983 four consecutive unified regimens: acute myeloid leukemia-Polish pediatric leukemia/lymphoma study group (AML-PPLLSG) 83, AML-PPLLSG 94, AML-PPLLSG 98 and AML-BFM 2004 Interim, for AML have been conducted by the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG). In this paper, we review four successive studies on the basis of acute myeloid leukemia-Berlin-Frankfurt-Munster (AML-BFM) protocol, in which a stepwise improvement of treatment outcome was observed. Treatment results of the last protocol AML-BFM 2004 Interim are presented in detail. METHODS: Three hundred and three patients with de novo AML were treated according to the AML-BFM 2004 Interim at 15 Polish centers from January 1, 2005 to June 30, 2011. A confrontation with previous treatment periods was based upon historical, already published data. RESULTS: In four consecutive periods, 723 children were eligible for evaluation (208, 83, 195, and 237, respectively). Complete remission rates in consecutive periods were: 71, 68, 81 and 87 %, respectively. The 5-year overall survival rates, event-free survival rates, and relapse-free survival rates were 33, 32, and 45%, respectively for AML-PPLLSG 83 regimen; 38, 36, and 53 % respectively for AML-PPLLSG 94 regimen; 53, 46, and 65 % respectively for AML-PPLLSG 98 regimen, and 63, 52, and 64 % for AML-BFM Interim 2004, respectively. Incidence of early deaths and that due to complications (mainly infections) in the first remission decreased over time from 22 to 4.6 % and from 10 to 5.9 %, respectively. CONCLUSIONS: Despite continuous improvement in the treatment outcome, the number of failures still remains too high. Further progress seemed to be possible due to continued cooperation of oncology centers within large international study groups.

[Venous sinus thrombosis which occurred during treatment of a 15-years old girl with t cell non-Hodgkin lymphoma - case report]. / Zakrzepica zatok zylnych mózgu w przebiegu leczenia 15-letniej pacjentki z nieziarniczym chloniakiem zlosliwym t-komórkowym-opis przypadku.

Venous thrombosis (VT) is a rare condition in childhood, being usually associated with congenital predisposition or acquired risk factors. The incidence of VT among children with cancer is between 1 and 36%. The highest incidence is among children with acute lymphoblastic leukaemia, followed by those with lymphoma and solid tumours. Malignancy and/or chemotherapy complications are considered as triggering factors. We report a case of a 15-year-old girl with non-Hodgkin lymphoma who developed generalized seizures during chemotherapy. Head computed tomography revealed right transverse and sagittal sinus thrombosis. Anticoagulation treatment using heparin as well as thrombolytic treatment with recombinant human tissue plasminogen activator (rhtPA) were introduced. The immediate application of rhtPA resulted in recanalisation of initially involved vessels which led to recovery with no neurological deficits. The reported case of severe venous thrombosis suggests that systemic treatment with rhtPA is effective and safe in children with cerebral venous sinus thrombosis.