Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP.

This retrospective study evaluated 35 children (median age 5.2 years; range 0.4-18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II-IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3-41.1) vs 58.8% (31-78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1-32.8), relapse incidence was 15.9% (5.6-30.9), progression-free survival (PFS) was 66.1% (47-79.7), GvHD-free relapse-free survival was 50% (30.6-66.7), and overall survival (OS) was 71.1% (51.4-84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3-96.1) vs 50.8% (26.3-71), p = 0.03, and 90.9% (50.8-98.7) vs 54% (28.1-74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3-53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.

Hematopoietic stem cell transplantation for pediatric patients with non-anaplastic peripheral T-cell lymphoma. An EBMT pediatric diseases working party study.

Peripheral T-cell lymphomas (PTCL) other than anaplastic large-cell lymphoma are rare in children, and the role of hematopoietic stem cell transplantation (HSCT) has not been clarified yet. In a retrospective analysis of registry-data of the European Society for Blood and Marrow Transplantation we analyzed 55 patients aged < 18 years who received allogeneic (N = 46) or autologous (N = 9) HSCT for PTCL. Median age at HSCT was 13.9 years; 33 patients (60%) were in first remission, and 6 (19%) in progression at HSCT. Conditioning was myeloablative in 87% of the allogeneic HSCTs and in 27 (58.7%) based on total body irradiation. After allogeneic HSCT the 5-year overall- and progression-free survival was 58.9% (95% CI 42.7-71.9) and 52.6% (95% CI 36.8-66.1), respectively. 5-year relapse incidence was 27.6% (95% CI 15.1-41.6), the non-relapse mortality rate was 19.8% (95% CI 9.7-32.6). Five of the six patients with progression at HSCT died. Seven of nine patients after autologous HSCT were alive and disease-free at last follow-up. Our data suggest a role of allogeneic HSCT in consolidation-treatment of patients with high-risk disease, who reach at least partial remission after primary- or relapse-therapy, whereas patients with therapy-refractory or progressive disease prior to transplantation do not profit from HSCT.

Cytogenetic abnormalities predict survival after allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia: a PDWP/EBMT study.

Poor-risk (PR) cytogenetic/molecular abnormalities generally direct pediatric patients with acute myeloid leukemia (AML) to allogeneic hematopoietic stem cell transplant (HSCT). We assessed the predictive value of cytogenetic risk classification at diagnosis with respect to post-HSCT outcomes in pediatric patients. Patients younger than 18 years at the time of their first allogeneic HSCT for AML in CR1 between 2005 and 2022 who were reported to the European Society for Blood and Marrow Transplantation registry were subgrouped into four categories. Of the 845 pediatric patients included in this study, 36% had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 16% had other PR cytogenetic abnormalities. In a multivariable model, 11q23 (hazard ratio [HR] = 0.66, P = 0.03) and other PR cytogenetic abnormalities (HR = 0.55, P = 0.02) were associated with significantly better overall survival when compared with monosomy 7/del7q or monosomy 5/del5q. Patients with other PR cytogenetic abnormalities had a lower risk of disease relapse after HSCT (HR = 0.49, P = 0.01) and, hence, better leukemia-free survival (HR = 0.55, P = 0.01). Therefore, we conclude that PR cytogenetic abnormalities at diagnosis predict overall survival after HSCT for AML in pediatric patients.

Matched unrelated donor transplantation versus haploidentical transplantation with post-transplant cyclophosphamide in children with acute myeloid leukemia: a PDWP-EBMT study.

In children with acute myeloid leukemia (AML) who lack an HLA identical sibling, the donor can be replaced with an HLA matched unrelated donor (MUD) or a haploidentical donor (haplo). We compared outcomes of patients <18 years with AML in first and second complete remission (CR1 and CR2) undergoing a hematopoietic stem cell transplantation (HCT) either with a MUD with anti-thymocyte globuline (ATG) (n=420) or a haplo HCT with PT-CY (n=96) after a myeloablative conditioning regimen (MAC) between 2011 and 2021, reported to EBMT. A matched pair analysis was performed to adjust for differences among groups. The final analysis was performed on 253 MUD and 95 haplo-HCTs. In the matched cohort, median age at HCT was 11.2 and 10 years and median year of HCT was 2017 and 2018, in MUD and haplo- HCT recipients, respectively. The risk of grade III-IV aGvHD was significantly higher in the haplo group (HR=2.33, 95%CI1.18-4.58, p=0.03). No significant differences were found in 2 years overall survival (OS; 78.4%vs71.5%; HR 1.39, 0.84-2.31, p=0.19), leukemia-free-survival (LFS; 72.7%vs69.5%; HR1.22, 0.76-1.95, p=0.41), CI of relapse (RI; 19.3%vs19.5%; HR=1.14, 0.62-2.08, p=0.68) non-relapse-mortality (NRM; 8%vs11%; HR=1.39, 0.66-2.93, p=0.39) and graft versus host free-relapse free survival (GRFS; 60.7%vs54.5%, HR=1.38, 0.95-2.02, p=0.09) after MUD and haplo-HCT respectively. Our study suggests that haplo-HCT with PT-CY is a suitable option to transplant children with AML lacking a matched related donor.

Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study.

Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.

Safe transfer of pediatric patients from hematopoietic stem cell transplant unit into the pediatric intensive care unit: views of nurses and physicians.

Sufficient communication between hematopoietic stem cell transplantation (HSCT) and pediatric intensive care unit (PICU) teams is pivotal for a successful advanced support in the PICU for HSCT-related complications. We evaluated perceived communication and barriers between both teams with the aim of providing recommendations for improvement. In this cross-sectional survey, a self-designed online questionnaire was distributed among ESPNIC and EBMT members. Data were analyzed using descriptive statistics. Over half of HSCT respondents employed a transfer indication protocol and patient assessment tool, but less structured checklist prior to patient transfer. Nearly all PICU respondents perceived this checklist as improvement for communication. Most HSCT and PICU physicians have daily rounds upon patient transfer while this is mostly missing between nursing teams. Half of both HSCT and PICU nurses indicated that HSCT training for PICU nurses could improve communication and patient transfer. Most respondents indicated that structured meetings between HSCT and PICU nurses could improve communication. Overall there is good communication between HSCT and PICU units, although barriers were noted between members of both teams. Based on our findings, we recommend use of a structured and specific checklist by HSCT teams, HSCT training for PICU personnel, and structured meetings between HSCT and PICU nurses.

Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.

Specialized Pediatric Palliative Care Services in Pediatric Hematopoietic Stem Cell Transplant Centers.

Hematopoietic stem cell transplantation (HSCT) is widely used in pediatric patients as a successful curative therapy for life-threatening conditions. The treatment is intensive, with risks of serious complications and lethal outcomes. This study aimed to provide insight into current data on the place and cause of death of transplanted children, the available specialized pediatric palliative care services (SPPCS), and what services HSCT professionals feel the SPPCS team should provide. First, a retrospective database analysis on the place and cause of death of transplanted pediatric HSCT patients was performed. Second, a survey was performed addressing the availability of and views on SPPCS among HSCT professionals. Database analysis included 233 patients of whom the majority died in-hospital: 38% in the pediatric intensive care unit, 20% in HSCT units, 17% in other hospitals, and 14% at home or in a hospice (11% unknown). For the survey, 98 HSCT professionals from 54 centers participated. Nearly all professionals indicated that HSCT patients should have access to SPPCS, especially for pain management, but less than half routinely referred to this service at an early stage. We, therefore, advise HSCT teams to integrate advance care planning for pediatric HSCT patients actively, ideally from diagnosis, to ensure timely SPPCS involvement and maximize end-of-life preparation.

Outcomes of Unmanipulated Haploidentical Transplantation Using Post-Transplant Cyclophosphamide (PT-Cy) in Pediatric Patients With Acute Lymphoblastic Leukemia.

HLA-haploidentical transplantation (haplo-HCT) using post-transplantation-cyclophosphamide (PT-Cy) is a feasible procedure in children with malignancies. However, large studies on Haplo-HCT with PT-Cy for childhood acute lymphoblastic leukemia (ALL) are lacking. We analyzed haplo-HCT outcomes in 180 children with ALL. Median age was 9 years, and median follow-up was 2.7 years. Disease status was CR1 for 24%, CR2 for 45%, CR+3 for 12%, and active disease for 19%. All patients received PT-Cy day +3 and +4. Bone marrow (BM) was the stem cell source in 115 patients (64%). Cumulative incidence of 42-day engraftment was 88.9%. Cumulative incidence of day-100 acute graft-versus-host disease (GVHD) grade II-IV was 28%, and 2-year chronic GVHD was 21.9%. At 2 years, cumulative incidence of nonrelapse mortality (NRM) was 19.6%. Cumulative incidence was 41.9% for relapse and 25% for patients in CR1. Estimated 2-year leukemia free survival was 65%, 44%, and 18.8% for patients transplanted in CR1, CR2, CR3+ and 3% at 1 year for active disease. In multivariable analysis for patients in CR1 and CR2, disease status (CR2 [hazard ratio {HR} = 2.19; P = .04]), age at HCT older than 13 (HR = 2.07; P = .03) and use of peripheral blood stem cell (PBSC) (HR = 1.98; P = .04) were independent factors associated with decreased overall survival. Use of PBSC was also associated with higher NRM (HR = 3.13; P = .04). Haplo-HCT with PT-Cy is an option for children with ALL, namely those transplanted in CR1 and CR2. Age and disease status remain the most important factors for outcomes. BM cells as a graft source is associated with improved survival.

ABO incompatibile graft management in pediatric transplantation.

Up to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor's RBCs have antigens missing on the recipient's cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.

Pediatric acute graft-versus-host disease prophylaxis and treatment: surveyed real-life approach reveals dissimilarities compared to published recommendations.

Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.

Correction: Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

Gonadal Function after Busulfan Compared with Treosulfan in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplant.

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

Transplant center practices for psychosocial assessment and management of pediatric hematopoietic stem cell donors.

Understanding the potential emotional and psychological risks of pediatric sibling HSC donation is an area of research that remains in its infancy. A cross-sectional survey was distributed electronically to directors at all CIBMTR and EBMT centers to describe current transplant center practices for obtaining assent, preparation for the physical/emotional experiences of donation, and monitoring the post-donation well-being of pediatric donors (<18 years of age). Respondents were 45/91 (49%) and 66/144 (46%) of CIBMTR and EBMT centers, respectively. Although 78% of centers reported having a mechanism in place to ensure donor free assent, centers also reported only limited assessment of psychosocial suitability to manage the emotional risks of donation. More than half of centers reported no psychosocial follow-up assessment post-donation. Few centers have policies in place to address donor psychological needs. Future investigations should include medical and psychosocial outcomes following full integration of comprehensive psychosocial screening and surveillance of pediatric donors.

Solid organ transplantation after hematopoietic stem cell transplantation in childhood: A multicentric retrospective survey.

We report data obtained from a retrospective multicenter pediatric survey on behalf of the European Society for Blood and Marrow Transplantation (EBMT). Information on solid organ transplantation (SOT) performed in pediatric recipients of either autologous or allogeneic hematopoietic stem cell transplantation (HSCT) between 1984 and 2016 was collected in 20 pediatric EBMT Centers (25.6%). Overall, we evaluated data on 44 SOTs following HSCT including 20 liver (LTx), 12 lung (LuTx), 6 heart (HTx), and 6 kidney (KTx) transplantations. The indication for SOT was organ failure related to intractable graft-vs-host disease in 16 children (36.3%), acute or chronic HSCT-related toxicity in 18 (40.9%), and organ dysfunction related to the underlying disease in 10 (22.8%). The median follow-up was 10.9 years (95% confidence interval: 1.7-29.5). The overall survival rate at 1 and 5 years after SOT was 85.7% and 80.4%, respectively: it was 74% and 63.2% after LTx, 83.2% after HTx, and 100% equally after LuTx and KTx. This multicenter survey confirms that SOT represents a promising option in children with severe organ failure occurring after HSCT. Additional studies are needed to further establish the effectiveness of SOT after HSCT and to better understand the mechanism underlying this encouraging success.

Second Hematopoietic Stem Cell Transplantation for Post-Transplantation Relapsed Acute Leukemia in Children: A Retrospective EBMT-PDWP Study.

Outcome data were collected from the European Society for Blood and Marrow Transplantation registry on 373 children from 120 centers with relapsed leukemia (214 with acute lymphoblastic leukemia [ALL] and 159 with acute myelogenous leukemia [AML]) who underwent second allogeneic hematopoietic stem cell transplantation (HSCT) between 2004 and 2013. Overall survival (OS) was 38% at 2 years and 29% at 5 years, and leukemia-free survival (LFS) was 30% at 2 years and 25% at 5 years. Median follow-up after second HSCT was 36.4 months in the ALL group and 50.2 months in the AML group. In the ALL group, OS was 43% at 2 years and 33% at 5 years, and LFS was 34% at 2 years and 31% at 5 years. In the AML group, OS was 32% at 2 years and 24% at 5 years, and LFS was 24% at 2 years and 17% at 5 years. The 2-year nonrelapse mortality (NRM) rate was 22% in the ALL group and 18% in the AML group. Favorable prognostic factors (P < .05) for OS and LFS included >12 months between transplantations and chronic graft-versus-host disease after the first HSCT (in both groups), complete response before the second HSCT (ALL group only), and age >12 years (AML group only). Findings were more consistent over time in the ALL group, with no significant differences between 2-year and 5-year rates of relapse, NRM, and LFS. Children with relapsed acute leukemias have a substantial likelihood of long-term survival following second HSCT. Given the many novel targeted and immunomodulation therapies currently under development, it is important to identify specific patient subpopulations that may benefit from a second HSCT compared with those better suited to new approaches.