Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed—from diagnosis to LT—with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016–2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population

Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed-from diagnosis to LT-with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016-2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population.Peer reviewe

Variability of Care and Access to Transplantation for Children with Biliary Atresia Who Need a Liver Replacement

Background & Aims: Biliary atresia (BA) is the commonest single etiology indication for liver replacement in children. As timely access to liver transplantation (LT) remains challenging for small BA children (with prolonged waiting time being associated with clinical deterioration leading to both preventable pre- and post-transplant morbidity and mortality), the care pathway of BA children in need of LT was analyzed—from diagnosis to LT—with particular attention to referral patterns, timing of referral, waiting list dynamics and need for medical assistance before LT. Methods: International multicentric retrospective study. Intent-to-transplant study analyzing BA children who had indication for LT early in life (aged < 3 years at the time of assessment), over the last 5 years (2016–2020). Clinical and laboratory data of 219 BA children were collected from 8 transplant centers (6 in Europe and 2 in USA). Results: 39 patients underwent primary transplants. Children who underwent Kasai in a specialist -but not transplant- center were older at time of referral and at transplant. At assessment for LT, the vast majority of children already were experiencing complication of cirrhosis, and the majority of children needed medical assistance (nutritional support, hospitalization, transfusion of albumin or blood) while waiting for transplantation. Severe worsening of the clinical condition led to the need for requesting a priority status (i.e., Peld Score exception or similar) for timely graft allocation for 76 children, overall (35%). Conclusions: As LT currently results in BA patient survival exceeding 95% in many expert LT centers, the paradigm for BA management optimization and survival have currently shifted to the pre-LT management. The creation of networks dedicated to the timely referral to a pediatric transplant center and possibly centralization of care should be considered, in combination with implementing all different graft type surgeries in specialist centers (including split and living donor LTs) to achieve timely LT in this vulnerable population

Stem cell transplantation for relapsed or refractory pediatric solid tumors

Refractory or recurrent pediatric solid tumors continue to have a poor prognosis despite all the progress made in recent decades. Autologous and allogeneic (haploidentical) stem cell transplantation in combination with intensive chemotherapy are potentially curative therapeutic approaches. These therapeutic options have been retrospectively investigated in the presented studies using nephroblastoma and neuroblastoma as examples. It could be shown that both procedures can be performed with low toxicity and without transplantation-related mortality and thereby raising the chances of long-term survival significantly compared to other therapy options. In particular, haploidentical stem cell transplantation offers the possibility of a "salvage therapy" for patients with severe, refractory, or recurrent disease, even when all other therapy options (including autologous stem cell transplantation) have been exhausted. The low rate of side effects combined with a long-term survival rate of approximately 25% offer these patients with otherwise unfavorable prognosis a last chance for a tumor-free life. Additionally, the results of the studies provide a good starting point for modern therapeutic concepts such as immune or cell therapies. Due to the rarity of these tumors, systematic studies with large numbers of patients are not possible to conduct. Especially for haploidentical stem cell transplantation in neuroblastomas, the literature often comprises only individual case reports or very small cohorts. At the time of its publication, the presented study comprises the largest systematically evaluated cohort on this topic. Hopefully, both studies thus contributed to improving the prognosis of these difficult to treat patient groups. The results of these studies suggest that these therapeutic concepts are very likely to be transferable to other solid tumors in terms of feasibility, toxicity, and transplantation-related mortality and thus offer a promising alternative to palliative treatment for all children with refractory or recurrent solid tumors

Vorteilhaftes Langzeitüberleben von Kindern mit rezidivierten Nephroblastomen nach Hochdosis-Chemotherapie und autologem Stammzellrescue

Background: High-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) is a treatment option for pediatric patients with relapsed nephroblastoma. We present long term results of 9 patients treated between 1993 and 2013 at our center. Procedure: Reinduction therapy was carried out according to GPOH and SIOP recommendations. The conditioning regimen consisted of carboplatin (1 200 mg/m²), etoposide (800 mg/m² or 40 mg/kg) and melphalan (180 mg/m²). Purging of the grafts with immunomagnetic CD34 positive selection was performed in 5 patients. Results: 8 of 9 Patients (90%) are alive without evidence of disease after a median follow-up of 8.5 years. Leukocyte engraftment occurred after a median of 10 days (range 8-12). Median numbers of 667/µl CD3+, 329/µl CD4+, 369/µl CD8+T cells and 949/µl B cells were reached after 180 days. No negative impact of CD34 selection was observed. No transplantation-related death occurred. Acute toxicity comprised mucositis III°-IV° in all and veno-occlusive disease in one patient. Long term effects probably related to treatment occurred in 3/7 evaluable patients and comprised hearing impairment, reduced renal phosphate reabsorption, mild creatinine elevation and hypothyroidism (n=1, each). Conclusion: Thus, in our experience HDC with ASCR is an effective treatment of recurrent or refractory nephroblastoma with acceptable side effects. However, a randomized trial proving its efficiency with a high level of evidence is needed.Hintergrund: Hochdosischemotherapie mit autologem Stammzellrescue ist eine Therapieoption für paediatrische Patienten mit rezidivierten Nephroblastomen. Wir präsentieren Langzeitergebnisse von 9 Patienten, die in den Jahren 1993–2013 in unserem Zentrum auf diese Weise therapiert wurden. Methods: Reinduktionstherapie wurde nach Empfehlung der SIOPH-GPOH durchgeführt. Das Konditionierungsregime bestand aus Carboplatin (1 200 mg/m²), Etoposid (800 mg/m² oder 40 mg/kg) und Melphalan (180 mg/m²). Immunomagnetische CD-34 positive Selektion wurde bei 5 Patienten durchgeführt. Results: 8 von 9 Patienten sind nach einem medianen Follow-Up von 8,5 Jahren ohne Nachweis der Erkrankung am Leben. Der Leukozyten-Take wurde im Median nach 10 Tagen erreicht (Range 8–12). Nach 180 Tagen wurden hinsichtlich der Immunrekonstitution im Median 667/μl CD3 + Zellen, 329/μl CD4 + Zellen, 369/μl CD8 + Zellen und 949/μl B-Zellen erreicht. Es wurde kein negativer Einfluss auf die Immunrekonstitution durch CD34-Selektion beobachtet. Kein Patient starb an den Nebenwirkungen der Transplantation. Die akuten Nebenwirkungen beinhalten Mukositis °III– °IV bei allen Patienten und veno-occlussive disease (VOD) bei einem Patienten. Langzeitfolgen, die eventuell mit der Therapie in Zusammenhang stehen traten in 3/7 evaluierbaren Patienten auf und beinhalten Hörstörungen, leichte Kreatininerhöhung, Störung der Phosphatrückresorption und Hypothyreodismus (jeweils 1 ×). Schlussfolgerung: Nach unserer Erfahrung ist Hochdosischemotherapie mit autologem Stammzellrescue eine effektive Therapieoption für rezidivierte und refraktäre Nephroblastome mit tolerablen Nebenwirkungen. Jedoch ist eine große randomisierte Studie notwendig um die Effizienz mit hoher Evidenz beweisen zu können

Haploidentical Stem Cell Transplantation for Refractory/Relapsed Neuroblastoma

Pediatric patients with refractory or relapsed metastatic neuroblastoma (NBL) have a poor prognosis despite autologous stem cell transplantation (SCT). Allogeneic SCT from a haploidentical donor has a remarkable alloreactive effect in patients with leukemia; thus, we evaluated this approach in children with very high-risk NBL. We analyzed data from 2 prospective phase I/II trials. A total of 26 patients with refractory (n = 5), metastatic relapsed (n = 20), or locally relapsed MYCN-positive (n = 1) NBL received a median of 17 × 106/kg T/B cell-depleted CD34+ stem cells with 68 × 103/kg residual T cells and 107 × 106/kg natural killer cells. The conditioning regimen comprised melphalan, fludarabine, thiotepa, OKT3, and a short course of mycophenolate mofetil post-transplantation. Engraftment occurred in 96% of the patients. Event-free survival and overall survival at 5 years were 19% and 23%, respectively. No transplantation-related mortality was observed, and the single death was due to progression/subsequent relapse. The median duration of follow-up was 8.1 years. Patients in complete remission before SCT had a significantly better prognosis than those with residual tumor load (P < .01). All patients with progressive disease before SCT relapsed within 1 year. Grade II and grade III acute graft-versus-host disease (GVHD) occurred in 31% and 12% of the patients, respectively. Chronic limited and extensive GVHD occurred in 28% and 10%, respectively. Our data indicate that haploidentical SCT is a feasible treatment option that can induce long-term remission in some patients with NBL with tolerable side effects, and may enable the development of further post-transplantation therapeutic strategies based on the donor-derived immune system