Beata Wójcik

Megachemotherapy followed by autologous stem cell transplantation in children with Ewing's sarcoma.

Abstract:  Twenty‐one children with high‐risk Ewings tumor received high‐dose chemotherapy with a PBSCT. Aim of the study was evaluation of efficiency and safety of this procedure. All but three patients have meta‐static disease at presentation. There were 11 females and the median age at diagnosis was 12 yr (range 4.5–18 yr). Megachemotherapy consisted of melphalan 140 mg/m2/busulfan 16 mg/kg in 12 patients, melphalan 140 mg2/treosulfan 10.0 g/m2 in two patients and melphalan with other drugs in seven patients. Eight of 11 patients transplanted in CR survived with a median follow‐up 24 month (range 14–60) and probability of 2‐year OS is 0.68 and DFS is 0.63. There was no severe regimen‐related toxicity in this group. Children transplanted without remission died: Two of them due to transplant related causes and eight had progression of disease in a median time 7 month after PBSCT. Megachemotherapy with PBSCT is a safe procedure in children with Ewings sarcoma in remission. Autologos transplantation in children with metastatic Ewings sarcoma seems to improve their outcome. Patients with Ewings sarcoma, resistant to conventional therapy and with recurrent disease did not benefit from megachemotherapy. New approaches such as anti‐tumor vaccination or using of imatinib are reasonable to introduce in patients with relapsed or resistant to therapy Ewings tumor.

Cytomegalovirus (CMV) infections in children undergoing hematopoetic stem cell transplantation.

Cytomegalovirus (CMV) is one of the major causes of morbidity and mortality after hematopoetic stem cell transplantations (HSCT). The purpose of the study was to analyze risk factors of CMV disease in children undergoing HSCT. A total of 110 children who undergone hematopoetic stem cells transplantation were analyzed. In 16 patients (14.5%) CMV antigenemia in white blood cells was diagnosed. Most patients with CMV infection had undergone alloHSCT; one patient had undergone autologous transplantation. Second CMV reactivation in 4 of 16 patients was observed. Acute GvHD occurred in 11/15 patients. Early onset of CMV infection in 13/16 patients and late onset in 3/16 patients were diagnosed. CMV serological status of the donor and recipient before transplantation in children with CMV antigenemia was analyzed. The risk factors of CMV infection in analyzed group of children were type of transplant, recipient seropositivity before transplantation, and presence and intensity of GvHD. In most cases reactivation of CMV infection was diagnosed. CMV infection can also occur in the late post-transplantation period. CMV reactivation can occur in patients after autologous HSCT.

Outcome of refractory and relapsed acute myeloid leukemia in children treated during 2005–2011 – experience of the Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG)

Aim of the study Recent studies showed relatively better outcome for children with refractory (refAML) and relapsed acute myeloid leukemia (relAML). Treatment of these patients has not been unified within Polish Pediatric Leukemia/Lymphoma Study Group (PPLLSG) so far. The goal of this study is to analyze the results of this therapy performed between 2005–2011. Material and methods The outcome data of 16 patients with refAML and 62 with relAML were analyzed retrospectively. Reinduction was usually based on idarubicine, fludarabine and cytarabine with allogenic hematopoietic stem cell transplant (alloHSCT) in 5 refAML and 30 relAML children. Results Seventy seven percent relAML patients entered second complete remission (CR2). Five-year OS and disease-free survival (DFS) were estimated at 16% and 30%. The outcome for patients after alloHSCT in CR2 (63%) was better than that of those not transplanted (36%) with 5-year OS of 34% vs. 2-year of 7% and 5-year DFS of 40% vs. 12.5%. Second complete remission achievement and alloHSCT were the most significant predictors of better prognosis (p = 0.000 and p = 0.024). The outcome of refAML children was significantly worse than relAML with first remission (CR1) rate of 33%, OS and DFS of 25% at 3 years and 53% at 2 years, respectively. All survivors of refAML were treated with alloHSCT after CR1. Conclusions The uniform reinduction regimen of the documented efficacy and subsequent alloHSCT in remission is needed to improve the outcome for ref/relAML children treated within PPLLSG. The focus should be on the future risk-directed both front and second line AML therapy.

HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.

Rituximab as immunotherapy following autologous stem cell transplantation (ASCT) in a 17-year-old boy with diffuse large B cell lymphoma - a case report

Summary Rituximab is a human-mouse chimeric monoclonal antibody with specifity for the CD20 antigen expressed on B-lineage cells. We are reporting a 17-year old boy diagnosed with diffuse large B cell lymphoma, CD20(+). He was treated by standard chemotherapy and megachemotherapy with ASCT. The boy relapsed in the mediastinum and lungs one year after the treatment was completed. He underwent secondary treatment: surgical procedure, chemotherapy and immunotherapy with rituximab, second ASCT and again immunotherapy in the post-transplantation period. No severe complications during the treatment with rituximab were observed except for leukopenia and central venous catheter infection. The CT scans performed one year after the therapy was completed showed regression of changes previously observed.

89. Rituximab jako immunoterapia po autologicznym przeszczepie komórek macierzystych u 17-letniego chłopca ze wznową chłoniaka olbrzymiokomórkowego – opis przypadku

Rituximab (Mabthera) jest ludzko-mysim przeciwcialem monoklonalnym skierowanym wybiorczo przeciwko antygenowi blonowemu CD20 limfocytow B. Potwierdzona jest jego skutecznośc w leczeniu agresywnych chloniakow nieziarniczych u doroslych razem z konwencjonalną chemioterapią oraz w polączeniu z megachemioterapią i autoHSCT, rowniez jako terapia podtrzymująca remisje. Przedstawiamy przypadek 17-letniego chlopca ze wznową chloniaka olbrzymiokomorkwego środpiersia rozpoznaną rok po zakonczeniu leczenia konwencjonalną chemioterapią i megachemioterapią z auto PBSCT. Wznowe chloniaka stwierdzono w środpiersiu i plucach. Po usunieciu operacyjnym guza środpiersia i mnogich przerzutow w plucach przeprowadzono chemioterapie (IVAC) z immunoterapią (Rituximab), planując kolejną megachemioterapie z autoPBSCT. W badaniu KT klp przed przeszczepem stwierdzono cześciową regresje zmian plucno-oplucnowych, bez patologicznego powiekszenia wezlow chlonnych. Po przeprowadzeniu megachemioterapii i auto PBSCT zdecydowano sie na immunoterapie Mabthera (4 cykle co 4 tygodnie, dawka jednorazowa 375 mg/m 2 ). Przebieg immunoterapii bez powiklan, nie obserwowano objawow zespolu uwalniania cytokin. Z odchylen w badaniach laboratoryjnych stwierdzaliśmy leukopenie, dwukrotnie bedącą przyczyną wydluzenia odstepu miedzy kolejnymi dawkami leku. Aktualnie chlopiec miesiąc po zakonczeniu immunoterapii, w remisji choroby zasadniczej, w kontrolnym badaniu KT klp stwierdzono zmniejszenie ilości zmian wloknistych plucno-oplucnowych.

Pediatric hematopoietic stem cell transplantation in Poland – development and current status

PPLLSG transplant centers Within PPLLSG three transplant centers are active, i.e. in Poznan (since 1989), in Wroclaw (since 1994) and in Lublin (since 1998). No. of transplant rooms Number of transplant rooms was growing from 1 in 1989 to 19 in 2000 (12 in Wroclaw, 4 in Lublin, 3 in Poznan). No. of patients and type (allo/auto) of HSCT per year 1989 - 1/0 (Poznan); 1990 to 1992 - 5/0 (Poznan); 1993 - 6/0 (Poznan); 1994 - 12 (1/5 in Wroclaw, 6/0 in Poznan); 1995 - 17 (1/6 in Wroclaw, 10/0 in Poznan); 1996 - 34 (9/15 in Wroclaw, 10/0 in Poznan); 1997 - 37 (5/21 in Wroclaw, 11/0 in Poznan); 1998 - 45 (8/21 in Wroclaw, 14/0 in Poznan, 0/2 in Lublin); 1999 - 66 (14/16 in Wroclaw, 1/19 in Lublin, 16/0 in Poznan); 2000 - 84 (22/21 in Wroclaw, 16/5 in Poznan, 6/14 in Lublin). Total number of patients and type of transplant: 317 [allo 172 (54,3%)/auto 145 (45,7%)]. Indications for allo-HSCT ALL 62 (36,0%), AML 31 (18,0%), CML 25 (14,5%), SAA 20 (11,6%), MDS 13 (7,6%), B-DA 6 (3,5%), NHL 5 (2,9%), SCID 5 (2,9%), FA 4 (2,3%), Ewing s. 1 (0,6%), i.e. malignant diseases 137 (79,7%) and non-malignant diseases 35 (20,3%) (congenital 15, acquired 20). Indications for auto-HSCT NHL 39 (26,9%), ALL 21 (14,5%), AML 21 (14,5%), RMS 16 (11,0%), NBL 15 (10,3%), Ewing s. 11 (7,6%), HD 9 (6,2%), CML 2 (1,4%), other solid tumors 11 (7,6%), i.e. leukemia + Iymphoma 92 (63,4%) and solid tumors 53 (36,6%). Stem cell sources for allo-HSCT BM 152 (88,4%), PBSC 17 (79,9%) - in Wroclaw since 1996, BM+PBSC 2 (1,2%), CB 1 (0,6%) - in Poznan since 2000. Stem celi sources for auto-HSCT PBSC 124 (85,5%), BM+PBSC 15 (10,3%), BM 6 (4,1%). Donor type for allo-HSCT MSD 148 (86,0%), MMRD 18 (10,5%) - in Wroclaw since 1996, MUD 6 (3,5%) - in Wroclaw since 2000. Conclusion There was significant development of HSCT within PPLLSG centers in the nineties. However, in context of 1500 new cases of cancer diagnosed and treated each year in these centers as well as in context of contemporary role of HSCT in cancer therapy in children, the number of auto- and allo-HSCT (especially from alternative donors and from alternative sources) pertormed in pediatric centers is still too low. Further increase of HSCT number is necessary to fultil therapeutical standards and to improve treatment results in Polish children with cancer.

12. Hematopoietic stem cells transplantation in children with lyphoma: multicenter results of the polish pediatric leukemia/lymphoma study group – Lublin, Poznań, Wrocław

Between 1995–2001 a total of 52 hematopoietic stem cells transplantations (HSCT) were performed in 50 children with non-Hodgkin (NHL) and Hodgkin (HD) lymphoma. Two children received double transplantations. The age of patients ranged from 2 8 12 to 8 1 12 years (median 11 9 12 years). NHL LCAL was diagnosed in 14 children, NHL-T cell in 7 children and B cell NHL – in 22 children. Hodgkin disease was diagnosed in 9 patients. In 18 children transplant was performed while in CR1 (all belonged to high risk groups), in 12 – in CR2, in 3 – in CR3. However, 13 transplanted children did not achieve complete remission (PR). HSCT was also performed in 4 relapsed children. In most cases (49) autologous stem cells were transplanted and 3 patients received allogeneic transplantation from HLA – matched siblings. As conditioning regimen the BEAM protocol was introduced in most cases (42 pts). The source of stem cells was peripheral blood – in 42 cases, bone marrow – in 5, bone marrow + peripheral blood – in 2 cases. 36 out of 50 pts are still alive with the observation time ranging from 1 month to 3 7 12 years and 33 children show CR following grafting. Fifteen patients relapsed or had progressive disease within 38 to 344 days following HSCT. 15 children died (30%) and 11 of them died due to relapse/progressive disease and 4 – due to transplant-related complications, mainly infections. No single death was noted in the group of children transplanted while in CR1. An estimated probability of survival at the 3,5 year for the whole group of transplant children with lymphoma is 0,7 and EFS – 0,65.