Real pandemic world results of pharmacokinetic-tailored personalized prophylaxis of bleeds in Polish children and adolescents with severe hemophilia A.

Introduction: In 2020, the new nationwide protocol of prophylaxis in Polish plasma-derived FVIII (pdFVIII) previously treated patients (PTPs) with severe hemophilia A (sHA) was introduced, resulting in the necessity of switching from pdFVIII to recombinant FVIII (octocog-alpha; rFVIII). The study aimed to: (1) assess the safety of switching from pdFVIII to rFVIII, (2) assess the safety and efficacy of pharmacokinetically based (PK-based) personalized prophylaxis in severe hemophilia A. Patients and methods: 151 children and adolescents receiving prophylaxis with a standard dose (40 U/kg 3 x weekly) of pdFVIII were included in this study. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were analyzed for all patients before enrollment. Using myPKFiT application, pharmacokinetic (PK) analysis followed by the selection of the optimal model of prophylaxis was performed in all patients. Two possible models of prophylaxis (standard-dose rFVIII versus PK-based rFVIII) were discussed, with parents leaving the choice to their decision. Parents reported all episodes of bleeds. Screening for inhibitor was performed every 3 months. ABR and AJBR were prospectively analyzed again after a minimum follow-up time of 26 weeks. Results: 141/151 (93.4%) patients completed the study. 34 patients decided to continue standard prophylaxis with rFVIII (Group I), whereas 107 were switched to PK-based prophylaxis (Group II). The risk of inhibitor development could be assessed in 137/151 (90.7%) patients. Only 2/137 (1.47%) patients (both on PK-based prophylaxis) developed low-titer inhibitor with its spontaneous elimination. The retrospective analysis of bleeds during the last 12 months of standard pdFVIII prophylaxis revealed that patients who decided to continue standard prophylaxis had historically lower ABR and AJBR than those who started PK-based personalized prophylaxis. After a minimum of 26 weeks, ABR and AJBR improved significantly in both groups. There was no significant difference in ABR and AJBR between Group I and Group II during the follow-up period. However, the rate of reduction of ABR and AJBR was higher in patients on PK-based personalized prophylaxis. Conclusion: (1) Switching from pdFVIII to rFVIII (octocog-alpha) in PTPs with sHA is safe, (2) PK-based personalized prophylaxis may decrease ABR and AJBR in children and adolescents with sHA.

Characteristics and treatment results of refractory and relapsed acute myeloid leukaemia in paediatric patients treated in Polish Paediatric Leukaemia/Lymphoma Study Group institutions according to the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 and a review of novel treatment possibilities in paediatric acute myeloid leukaemia.

Introduction: This study aimed to present the clinical features and results of treatment of patients diagnosed with refractory or relapsed acute myeloid leukaemia (AML) in Polish Paediatric Leukaemia/Lymphoma Study Group (PPL/LSG) institutions, treated in accordance with the Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012, as their first-line therapy. Material and methods: The outcome data of 10 patients with refractory AML (median age 9.5 years) and 30 with relapsed AML (median age 12 years) were analysed retrospectively. Re-induction was usually based on idarubicin, fludarabine, and cytarabine along with allogeneic haematopoietic stem cell transplant (allo-HSCT) in 5 patients with refractory AML and 7 relapsed AML children. Results: 37.5% (3/8) of refractory AML patients achieved second complete remission second complete remission (CRII). One of ten patients (1/10; 10%) was alive and stayed in complete remission for 34 months after the allo-HSCT. The probability of 3-year event-free survival (pEFS) in this group was 0.125 ±0.11. In the group of relapsed AML patients, the CRII was achieved in 9 patients (34%), and the probability of survival was: pEFS = 0.24 ±0.08; probability overall survival (pOS) = 0.34 ±0.09, with significantly better results achieved in patients who underwent allo-HSCT (pOS = 0.54 ±0.14 vs. 0.08 ±0.08, p < 0.0001). Conclusions: The prognosis of refractory AML and the first AML recurrence in children who were first-line treated in PPL/LSG centres according to Protocol Acute Myeloid Leukaemia Berlin-Frankfurt-Munster 2012 is poor. Failures of re-induction treatment particularly result from difficulties in achieving remission. Allogeneic HSCT improves prognosis in children with refractory and first recurrent AML, under the condition it is performed in complete remission. Novel therapeutic approaches are needed to increase the remission rate and improve the outcomes.

[Long-term observations of children with acute lymphoblastic leukemia and high leukocytosis treated according to modified "New York" protocols (1987-2003)]. / Wieloletnie obserwacje dziec z ostra bialaczka limfoblastyczna i wysoka liczba krwinek bialych leczonych wedlug zmodyfikowanych protokolow "Nowy Jork" (1987-2003).

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Due to new therapeutic schedules and cooperation between oncological centers it is curable in more than 80% of affected children. For the optimalization of the therapy there is necessary to assess the risk criteria that have influence on the treatment results in the certain groups of patients. Hyperleukocytosis and the age (less than 1 year and more than 10 years) are known as unfavorable risk factors. The study was designed to assess the long-term treatment results in children with ALL and the initial leukocytosis over 50 000/mm3 with the use of the modified "New York" protocols. We present the treatment results of 340 children with ALL treated in nine centers of Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) according to three consecutive versions of modified "New York" protocol (group I, II, and III) between 1987 and 2003. Within the analyzed groups the first complete remission (I CR) was achieved in 91%, 95% and 96% of the patients, respectively. Relapses occurred in 37%, 21.5% and 26% of the patients and 3.7%, 1.8% and 5.7% of children died in the I CR due to complications, in the I, II and III therapeutic group, respectively. Obtained 5-and 10-year event-free survival (EFS) were 56% and 53.5% for the group I and 73% and 73% for the group II. Five-year EFS for the group III was 67%. The implementation of the New York protocol in 1987 and New York I in 1997 has improved the treatment results in children with ALL and initial leukocytosis over 50 000/mm3. Protocol New York II did not further improve the treatment results. Among analyzed parameters (age, gender, the initial leukocytosis, the blast cells immunophenotype) only age had the statistical significance. The implementation of modified "New York" protocols has improved the treatment results in children with ALL and initial leukocytosis over 50 000/mm3 compared to previous results.

Lymphoepithelioma-like thymic carcinoma in a 16-year-old boy with nephrotic syndrome--a case report.

Nephrotic syndrome can occur as a consequence of, among others, malignancy. In this report we describe a 16-year-old boy with secondary nephrotic syndrome associated with lymphoepithelioma-like thymic carcinoma, an extremely rare subtype ofthymic carcinoma with poor prognosis.

Laparoscopic splenectomy in children: experience in a single institution.

PURPOSE: To assess the safety and effectiveness of laparoscopic splenectomy in children. MATERIALS AND METHODS: Hospital records of 63 patients who underwent laparoscopic splenectomy between 1998 and 2005 were reviewed retrospectively. In 16 patients concomitant cholecystectomy was performed. All procedures were performed by the same surgeon. The indications for splenectomy were hereditary spherocytosis (n = 35), idiopathic thrombocytopenic purpura (n = 22), autoimmune hemolytic anemia (n = 3), and other diseases (n = 3). Details of operative technique were reviewed and their implications on intraoperative complications are analyzed. The postoperative course and long-term results were assessed. RESULTS: There were 35 girls and 28 boys, whose average age was 11.3 years (range, 3.9-19.5 years). There were 7 conversions, mainly at the beginning of the series. A mild degree of intraoperative bleeding was observed in 23 (36.5%) cases. In two cases (3%) severe bleeding led to conversion. Postoperatively, 1 patient required blood transfusion and 1 patient had signs of mild general infection that was treated conservatively. There was no mortality in this series. The mean operation time was 134 minutes for splenectomy and 174 minutes for splenectomy and cholecystectomy. Operative time did not significantly diminish at the end of the 7-year study period. CONCLUSION: Laparoscopic splenectomy in children performed by an experienced team proved to be safe and effective with minimal side effects and should be recommended as a procedure of choice in children who require splenectomy.

[Acute lymphoblastic leukemia in children with initial leucocytosis above 50,000/mm3: summary of treatment results of Polish Pediatric Leukemia/Lymphoma Study Group]. / Ostra bialaczka limfoblastyczna u dzieci ze wstepna leukocytoza powyzej 50,000/mm3: podsumowanie wyników leczenia Polskiej Pediatrycznej Grupy ds. Leczenia Bialaczek i Chloniaków.

Initial leucocytosis, presence of t(9;22) and t(4;11) translocations and poor response to therapy with steroids or induction chemotherapy are still included to poor risk factors group. From 1981 to 1986, children with acute lymphoblastic leukemia (ALL) and initial WBC above 50,000/mm3, achieved significantly worse treatment results than children with lower WBC: over 6-year disease-free survival were respectively 33% and 60%. In attempt to improve treatment results in children with hyperleucocytosis, modified American protocols called: New York (1987), New York I (1997), and New York II (1999) were introduced consecutively in the centers of Polish Pediatric Leukemia/ Lymphoma Study Group. Actually treatment results obtained with those protocols in three groups of patients: group I: 214 children (1987-1996), group II: 58 children (1997-1999), and group III: 77 children (1999-2001) are presented. The observation was completed in March 31, 2004. In evaluated groups the first complete remissions (CR) were achieved in 91%, 95%, and 96% of patients, respectively. Relapses occurred in 72 patients of group I (37%), in 12 patients of group II (21%), and in 13 patients of group III (18%). The 5-year overall survivals were: 62%, 79%, and 78% (p=0.05) respectively; 5 year event-free survivals (EFS) were: 52%, 74%, and 69% (p=0.01) respectively. A significant improvement in treatment results in second compared with first group was achieved. Treatment results obtained with New York II are comparable with results obtained with New York I. The analysis of treatment results achieved shows the improvement of the prognosis in children with ALL and initial WBC above 50 000/mm3 in comparison with patients treated before 1987. There is strong necessity of unification of risk group qualification criteria in childhood ALL in term of comparable estimation treatment results achieved in different centers all over the world.

Experiences with recombinant activated factor VII in the treatment of severe refractory thrombocytopenia.

Approximately 5% of chronic immune thrombocytopenic purpura (ITP) manifests itself as symptomatic, severe thrombocytopenia requiring splenectomy. The surgical procedure increases the risk of serious hemorrhage, especially in patients refractory to platelet transfusions. Recombinant factor VIIa (rFVIIa) has been found to enhance thrombin generation on activated platelets and may be a promising agent in preventing life-threatening bleedings. The administration of rFVIIa in two patients with severe refractory ITP, who underwent splenectomy, is presented. Combined therapy with agents of different mechanisms of action could be useful in cases with the highest probability of bleeding.

[Efficacy of idarubicin in the treatment of childhood acute non-lymphoblastic leukemia: report of Polish Pediatric Leukemia/Lymphoma Study Group]. / Zastosowanie idarubicyny w leczeniu ostrej bialaczki nielimfoblastycznej u dzieci--Raport Polskiej Grupy Pediatrycznej ds Bialaczek i Chloniaków.

UNLABELLED: Results of treatment of childhood ANLL remained unsatisfactory for a long time, and introduction of a new drug seemed justified as the EFS achieved in this disease between 1993-97 was 42%. In 1998 a new protocol containing idarubicine in dose 12 mg/m2 (each dose regardless of treatment phase) was introduced. Between 1998 and 2001, 137 children with ANLL were referred to nine participating centers of PPLLSG. Thirty nine were uneligible, so 98 were evaluated. Among them 56 were qualified to standard risk group (SRG) and 35 to high risk group (HRG). In 7 children the risk group was not established due to early death. Remission rate was 79% in the whole group and 98% and 63% in SRG and HRG, respectively. The actuarial 3-year overall survival (OS), 3-year event-free survival (EFS) and 3-year event-free interval (EFI) are respectively: In the whole group 61%, 54% and 67%; in SRG 81%, 70% and 71%; in HRG 40%, 40%, and 53%. CONCLUSIONS: Due to introduction if idarubicine significant improvement of the results was achieved in SRG (better OS, EFS and EFI). Better new treatment methods are required in HRG.

[Advances in the treatment of children with high risk acute lymphoblastic leukemia (ALL) treated with modified "NEW YORK" protocols between 1987 and 2002]. / Postepy w leczeniu dzieci z ostra bialaczka limfoblastyczna (ALL) wysokiego ryzyka wg modyfikowanych programów "NOWY JORK" w latach 1987-2002.

From 1981 to 1986, in children with ALL and initial WBC > or = 50,000/mm3, over 6-year disease-free survival was significantly lower (33%) than in children with WBC < 50,000/mm3 (60%). In attempt to improve this unsatisfactory results, three modified American protocols named: "New York", "New York I", and "New York II", "New York I", and "New York II" were introduced consecutively in the centers of Polish Pediatric Leukemia Lymphoma Study Group (respectively, in 1987, 1997, and 1999). The treatment results achieved in three consecutive therapeutic groups of children with ALL and initial WBC > or = 50,000/mm3: group I--213 children (1987-1996), group II--58 children (1997-1999), and group III--52 children (1999-2001) are presented. The observation was completed in December 31, 2002. In three evaluated groups the first complete remissions (CRs) were achieved in 90.6%. 94.8%. and 94.2% of patients, respectively. Relapses occurred in 71 patients of group I (37%), in 9 patients of group II (16%), and in 6 patients of group III (12%). The complications of treatment caused death in 7 children of group I, in 1 child of group II, and in 2 children of group III. Eighty-one (38%), 11 (18.9%), and 9 (17.3%) patients, respectively, died due to progression of disease. The event-free survival (EFS) in three evaluated groups did not depend on age of children and WBC. The rates of 2-, 5-, and 10-year event-free survival (EFS) in group I were: 69.9%, 55.3%, and 53.6%, respectively and the rates of 2- and 5-year EFS in group II were: 80.7% and 72.7%, respectively. The rate of 2-year EFS in group III was 71.6%. The analysis of achieved treatment results in three evaluated groups shows the gradual improvement of the prognosis in children with ALL and initial WBC > or = 50,000/mm3 treated with the use of modified protocols "New York" and "New York I" in comparison with patients treated before 1987. Longer observation is needed for evaluation of efficacy and complications of "New York II" protocol.

Immunologic effects of intermediate-dose IL-2 i.v. after autologous hematopoietic cell transplantation in pediatric solid tumors.

Adoptive immunotherapy with interleukin-2 (IL-2) may control minimal residual disease (MRD) and prevent relapse after autologous hematopoietic cell transplantation (AHCT). The objective of this study was to determine the immunologic effects of intermediate doses of intravenous (i.v.) IL-2 after AHCT in children with poor-prognosis solid tumors. Eleven patients received a median five cycles consisting of escalating doses of IL-2 i.v. for 5 days after a median time interval of 94 days post-AHCT. The phenotype of lymphocyte subsets was investigated before and after each cycle, and parallel determination of natural killer (NK) cell activity was performed. Immunotherapy induced a significant increase in total lymphocyte count (TLC), T, NK, and, to some extent, B cells. Among NK cells, CD56+ bright cells expanded more than CD56+ dim cells. High expansion of CD56+ cells with CD94 inhibitory receptor was observed, whereas no difference was recorded in the number of CD3+ CD56+ and CD8+ CD57+ cells. NK activity stabilized after the first cycle of IL-2 and remained elevated during the study period. Cycles of IL-2 immunotherapy induced repeated significant expansion of T cells and NK cells, mostly of the immature CD56+ bright phenotype. Despite enhanced NK activity, relapses occurred frequently, which might have been due to increased CD94 activation and a poor response from the cytotoxic NK T cells and CD8+ CD57+ T cells.