Pediatric Hematopoietic Stem Cell Transplantation in Lithuania - 20 Years of Progress through Collaboration.

Abstract

Hematopoietic stem cell transplantation (HSCT) is a complex procedure that is curative for several fatal pediatric malignancies and non-malignant diseases. Despite its complexity, potential toxicity, and high costs HSCT has become a standard procedure worldwide for several decades. Pediatric HSCT programs encounter several specific challenges. The rarity and heterogeneity of primary diseases, result in an almost 10-fold inferior number of pediatric HSCT as compared to adults. In con-trast to the adult programs, where autologous HSCT is more common, allogeneic HSCT (that is more complex) prevails in pediatric setting which is underpinned by a higher number of inborn disorders transplanted in early childhood. In Here we summarize conference proceedings presented at the scientific event “Pediatric hematopoietic stem cell transplantation in Lithuania – 20 years of progress through collaboration”. The meeting held on September 22-23, 2022, in Vilnius and aimed at commemorating 20 years of the launch of the pediatric transplant program in Lithuania. The event pursued sharing the experience in the field of pediatric HSCT in the Baltic countries. Given a very in all three Baltic countries, and face an additional challenge in maintaining sufficient transplant volume and gaining experience. Several distinguished speakers from USA, Spain, UK and shared their expertise in the field and emphasized the crucial role of national and international collaboration to achieve progress in the management of this very rare and complex procedure that offers for otherwise fatal pediatric conditions. Background: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. High-risk NB still has a poor prognosis and requires complex aggressive therapy. For a decade, immunotherapy with dinutuximab – anti GD2 chimeric monoclonal antibody – was integrated into treatment protocols as a routine part of the treatment. However, drug administration is related to potentially severe adverse effects. Thus, its administration is recommended in experienced centers. We aim to describe the first Lithuanian experience with dinutuximab. Methods: We performed a retrospective analysis of patients with high-risk NB treated with dinutuximab at our institution in 2020-2022. Toxicity and treatment outcomes were evaluated. The data were retrieved from electronic and paper records. Results: in 2020-2022, four patients were treated with dinutuximab. Totally, 20 cycles were de-livered, 5 cycles in each patient. One patient received dinutuximab as the first-line treatment. In 3 children dinutuximab was administered as second-line therapy with a median of 18 months (range 9-21) after relapse. For the majority of patients, the treatment tolerance was acceptable. The main adverse events were fever (n = 4), vision impairment (n = 1) and capillary leak syndrome (n = 1). The adverse events were 1-2 degrees, so all patients completed the treatment. At the time of analysis, two patients remain in complete remission, one patient achieved stable disease and one patient died because of disease progression. Five-year overall survival was 66.7% Conclusions: Immunotherapy is currently the standard for first-line maintenance treatment of high-risk neuroblastoma. Dinutuximab administration is associated with a risk of severe adverse events, so the treatment should be performed in an experienced pediatric oncology center. T-precursor remission and negative MRD were achieved. neutropenia and systemic candidemia ( Candida tropicalis beginning of Consolidation 1 phase, the developed into pustules, which ruptured occasionally. chronic inflammation with PAS/Groccot positive fungi. showed pancytopenia, later developed to neutrophilosis. Regardless of sufficient leuko- and neutropoiesis, a disseminated IFI with multiple infiltrates in liver, spleen and were detected. The treated with different combinations of five antifungal agents. Multiple blood cultures were repeated, no fungi growth was identified. There is a of an Background. Allogeneic hematopoietic stem cell transplantation (aHSCT) is the only curative treatment for childhood high-risk, primary refractory, or relapsed acute myeloid leukemia (AML). In Lithuania AML-BFM protocol was used to treat pediatric AML in 2002-2013. Since 2014 the first-line treatment switched to the NOPHO-DBH AML protocol. The risk stratification, indications for aHSCT differed between the protocols. periods: Background. Bloodstream infection is one of the most important causes of morbidity and mortality among patients with acute leukemia. The risk of infection is increased due to indwelling venous catheters, long-term hospitalization, multidrug-resistant microorganisms, and other predisposing factors. Nevertheless, native valve infective endocarditis (IE) is a rare complication. Aim. To report a first complicated case of IE due to S. aureus in a patient with acute leukemia. Case presentation. A 21-month-old boy presented with fever, sleep deprivation and appetite loss. Laboratory tests indicated: WBC, 18,2*10^9/l, NEU, 0,77*10^9/l; HGB 68 g/l; platelets, 26 *10^9/l, 56% blasts on blood smear. The diagnosis of B-precursor acute lymphoblastic leukemia (ALL) with high hyperdiploidy was based on bone marrow Results. After successful induction according to the Nopho ALLTogether protocol, the patient was stratified to the final intermediate-high risk group because of 1,3% MRD by flow cytometry. During consolidation, S. aureus caused sepsis occurred twice. After the second sepsis, the central venous line (CVL) was removed. Background. Long-term survival rates of childhood acute lymphoblastic leukemia (ALL) approach 90%, however, still a proportion of children will suffer from a relapse. Only around 50% of children with a first relapse survive long-term, and the outcome is much worse with a second or later relapse. Aim of the study. To analyze the incidence and treatment results of childhood ALL relapses in Lithuania throughout different time periods. Methods. Retrospective analysis of data of 98 children (out of 105) with relapsed T- or B-cell precursor ALL treated in Lithuania during the four time periods: 1992-1996 (N=38), 1997-2002 (N=33), 2003-2008 (N=16) and 2009-2018 (N=18) for whom the data was available. Results. Median follow-up (quartiles) for four periods was 18.2 (17.9-18.2), 15.1 (9.2-16.8), 12.6 (10.9-14.5) and 3.9 (2.0-6.1) years, respectively. Overall survival (OS) improved over periods, with 3-year OS being 30±7%, 28±8%, 44±12%, 50±12% respectively, although non-significantly. Twen-ty-four patients received allogeneic hematopoietic stem cell transplantation (HSCT) for very early (n=7), early (n=5) or late (n=12) relapse. Survival improvement was seen over the four time periods, 3-year OS being 0%, 43±19%, 50±16% and 89±11%, Background. Wilms’ tumor (WT) is the most prevalent childhood renal neoplasm. Although overall cure rate is high, relapse occurs in 15% of patients. Another concern is the emergence of treatment related secondary malignancies of which acute myeloid leukaemia represents 15-20%. It usu-ally occurs 3-10 years after initial therapy and is particularly devastating. Case. A 6 year old girl with metastatic WT (lungs, nodules size >5 mm) was treated in our hospital. The patient has a healthy monozygotic twin. Preoperative AVD chemotherapy was given by Umbrella SIOP-RTSG 2016 protocol. Following 6 weeks of preoperative chemotherapy, metastasis were absent in chest CT. Postoperative treatment after nephrectomy was given according to local stage (III) and histology (intermediate risk tumor - mixed type nephroblastoma): regimen AVD250 and flank irradiation. 7 months from nephrectomy first early lung relapse was confirmed. Histology assessment showed blastema with focal anaplasia. Complete remission achieved after BB risk group treatment by Umbrella protocol: chemotherapy ICE/CyCE, surgery, HD-LPAM with autologous PBSC rescue and pulmonary RT. Early relapse and blastema component were unexpected for us therefore primary tumor histology reassessment was done. Second lung relapse emerged 5 months after end of treatment. After nonradical excision of tumor masses histology showed diffuse anaplasia. Salvage VIT therapy was started. 8 months later a very early secondary acute monoblastic leukaemia arose (M5 according to FAB). Treatment was initiated by NOPHO-DBH 2012 Dynamics in bone marrow aspirate after 3 chemotherapy courses transplantation metastasis Background. Pediatric refractory / relapsed acute lymphoblastic leukemia (R/R-ALL) has a 5% long term survival rate when applying cytotoxic chemotherapy, hematopoietic stem cell transplantation (HSCT). Blinatumomab, a bispecific antibody linking CD19, CD3 cells, may induce beneficial effect before HSCT and has successfully been used as a frontline therapy for high risk (HR) patients [1,2]. Interfant-21 (2 remission allogenic HSCT (alloHSCT) – complete remission (CR)1. A very early (VE) extramedullary relapse (EMR) confirmed. 9-month (pre-B (11q23 MLL), CNS1) treated with Interfant-06. After VE isolated EMR and IntRe-ALL-HR Blinatumomab given (2 blocks) – CR2. Both had no Blinatumomab toxicity. 2-y.o. (pre-B , CNS1, HR), 3-y.o. (pre-B, CNS2, standard risk) with Nopho ALL-2008 with 1 st isolated early bone marrow relapse (BMR), Maintenance I and Maintenance II, respectively. 2-y.o. resistant to IntReALL Background. In pediatric population Ifosfamide (IFO) is a widely used antineoplastic drug. IFO-induced encephalopathy (IIE) develops in 10-40% of adult patients, some studies report incidence up to 10% in children. Renal, liver function, drug interactions are studied as possible risk factors. IIE mostly requires symptomatic treatment, while methylene blue (MB) prophylaxis is investigated [1-3]. Results. At tertiary centre 3 male patients were treated with IFO, 4 years old (y.o.) had retrop-eritoneal embryonic rhabdomyosarcoma, while 7 y.o., 8 y.o. had Ewing sarcomas. 7 y.o. presente