Treatment of steroid resistant acute graft versus host disease with an anti-CD26 monoclonal antibody-Begelomab
Bone marrow transplantation. 2020
We have treated 69 patients with steroid refractory acute graft versus host disease (SR-aGvHD), with an anti-CD26 monoclonal antibody (Begelomab): 28 patients in two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19), and 41 patients on a compassionate use study. The median age of patients was 42 and 44 years; the severity of GvHD was as follows: grade II in 8 patients, grade III in 33, and grade IV in 28 patients. There were no adverse events directly attributable to the antibody. Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. In conclusion, Begelomab induces over 60% responses in SR-aGvHD, including patients with severe gut and liver GvHD, having failed one or more lines of treatment.
Patients with steroid refractory acute graft versus host disease (n=69)
Begelomab, an anti-CD26 monoclonal antibody in prospective study (n=28)
Begelomab, an anti-CD26 monoclonal antibody in compassionate use (n=41)
Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. There were no adverse events directly attributable to the antibody
Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Bone marrow transplantation. 2020
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.
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)
Bone marrow transplantation. 2020
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.
Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children
British journal of haematology. 2020
Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0.0001). Achievement of a subsequent remission impacted survival (P = <0.0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0.046) and donor choice (matched family vs. matched unrelated donor, P = 0.029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%.
Veno-occlusive Disease in HSCT Patients: Consensus-based Recommendations for Risk Assessment, Diagnosis, and Management by the GITMO Group
Variation in clinical practice affects veno-occlusive disease (VOD) management, mainly in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT). Disputes about diagnostic criteria, treatment and prophylaxis, due to the lack of high-quality data, are at the base of this variability. With the aim of limiting inconsistency in clinical care, thus improving both patient outcomes and data collection reliability, the Italian Society of Stem cell transplant (GITMO) launched a collaborative effort to formulate recommendations based on integration of available evidence and expert's consensus. A systematic method, according to US National Institute of Health (NIH) guidelines and Italian National System for Guidelines, was used. Twenty-nine recommendations were approved with a strong (20) or weak (9) level of agreement, while 26 were rejected. In particular, the Panel pointed out the need to achieve an early diagnosis, encouraging the adoption of EBMT criteria and the prompt use of ultrasonography. Moreover, our experts strongly recommended in favour of prophylactic use of ursodeoxicolic acid (UDCA). As soon as a VOD diagnosis is established, treatment with defibrotide should be started for at least 21d. A number of areas of uncertainty, particularly concerning risk stratification and use of diagnostic tools such as elastography has been identified and discussed.
Phenotypic and Functional Characterization of NK Cells in aßT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia
NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after aßT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and ?dT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR(+)NKG2A(-)CD57(+) NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed.
Population pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation
British journal of clinical pharmacology. 2019
AIMS: Treosulfan is an alkylating agent increasingly used prior to hematopoietic stem cell transplantation (HSCT). The aim of this study was to develop a population pharmacokinetic model of treosulfan in pediatric HSCT recipients and to explore the effect of potential covariates on treosulfan pharmacokinetics (PK). Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. METHODS In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m(2) treosulfan, administered over 3 consecutive days, were enrolled. A population pharmacokinetic model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. RESULTS A two-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*hr/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. CONCLUSIONS This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure.
SINUSOIDAL OBSTRUCTION SYNDROME / VENO-OCCLUSIVE DISEASE AFTER AUTOLOGOUS OR ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN: a retrospective study of the AIEOP-HSCT (Italian Hematology-Oncology Association-Hematopoietic Stem Cell transplantation) Group
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
INTRODUCTION Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy applying the new EBMT criteria, and to analyze the risk factors underlying this complication. MATERIALS AND METHODS We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP-affiliated centers between January, 2000 and April, 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. RESULTS Among 5,072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range 1-104 days). Sixty-nine patients (67%) were treated with Defibrotide (DF) for a median time of 16 days (range 4-104). In multivariable analysis, age <2 years, use of busulfan during the conditioning regimen, female gender and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival (OS) at 1 year was worse in patients with SOS/VOD (p=0.0033), and this difference disappeared 5 years after HSCT. Non-relapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (p<0.001). CONCLUSION Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Non-relapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood.
Unrelated donor vs HLA-haploidentical alpha/beta T-cell and B-cell depleted HSCT in children with acute leukemia
Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating acute leukemia (AL) children in need of an allograft. Recently, HLA-haploidentical HSCT after alphabeta T-cell/B-cell depletion (alphabetahaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 macthed UD (MUD), 118 mismatched (MMUD) and 98 alphabetahaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and alphabetahaplo-HSCT group. In MUD vs MMUD-HSCT recipients, the cumulative incidence (CI) of grade II-IV and grade III-IV acute GvHD was 35% vs 44% and 6% vs 18%, as compared to 16% and 0% in alphabetahaplo-HSCT recipients (P<0.001). Children treated with alphabetahaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GvHD (p<0.01). Eight (6%) MUD, 32 (28%) MMUD and 9 (9%) alphabetahaplo-HSCT patients died from transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55% and 62% respectively. In the three groups, chronic GvHD-free/relapse-free (GRFS) probability of survival was 61%, 34% and 58%, respectively (P<0.001). When compared to patients given MMUD-HSCT, alphabetahaplo-HSCT recipients had a lower CI of NRM and a better GFRS (P<0.001). These data indicate that alphabetahaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.
Solid organ transplantation after haematopoietic stem cell transplantation in childhood: a multicentric retrospective survey
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018
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 were 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-versus-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% CI: 1.7-29.5). The overall survival (OS) 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 occurred 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. This article is protected by copyright. All rights reserved.