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1.
Longitudinal Clinical Data Improves Survival Prediction after Hematopoietic Cell Transplantation Using Machine Learning
Zhou, Y., Smith, J., Keerthi, D., Li, C., Sun, Y., Mothi, S. S., Shyr, D., Spitzer, B., Harris, A. C., Chatterjee, A., et al
Blood advances. 2023
Abstract
Serial prognostic evaluation of patients after allogeneic hematopoietic cell transplantation (alloHCT) might help identify patients at high risk of developing potentially lethal organ dysfunction. Current prediction algorithms are based on models that do not incorporate changes to the patients' clinical condition that occur after alloHCT in the model development, which limits their predictive ability. We developed and validated a robust risk-prediction algorithm to predict short-term and long-term survival after alloHCT in pediatric patients that includes baseline biological variables, as well as changes in the patients' clinical status after alloHCT. The model was developed using clinical data from children and young adults treated at a single academic quaternary-care referral center. The model was created using a randomly split training dataset (70% of the cohort), internally validated (remaining 30% of the cohort from the same center), and then externally validated on patient data from another tertiary-care referral center. Repeated clinical measurements performed from 30 days before alloHCT to 30 days afterwards were extracted from the electronic medical record and incorporated into the model to predict survival at 100 days, 1-year, and 2-years after alloHCT. Of the 738 patients who underwent their first alloHCT at our institution between 2000 and 2020, 517 (70%) were randomly included in the training dataset and 221 (30%) constituted the validation dataset. When compared with models constructed from baseline variables alone, the naïve-Bayes machine learning models incorporating longitudinal data were significantly better at predicting whether patients would be alive or deceased at the given timepoints. This proof-of-concept study demonstrates that unlike traditional prognostic tools that use fixed variables for risk assessment, incorporating dynamic variability using clinical and laboratory data improves the prediction of mortality in patients undergoing alloHCT.
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2.
Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience
Blomain, E. S., Jiang, A., Donaldson, S. S., Agarwal, R., Bertaina, A., Shyr, D., Eisenberg, M. L., Hoppe, R. T., Hiniker, S. M., Oh, J.
Advances in radiation oncology. 2023;8(1):101071
Abstract
PURPOSE Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center. METHODS AND MATERIALS We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset. RESULTS Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively (P = .31). On multivariable analysis, boost was not associated with improved relapse-free survival or overall survival. More patients in the boost subset (35 of 51, 69%) had abnormal serum gonadal blood work compared with the nonboost subset (18 of 42, 43%) (P = .03). CONCLUSIONS Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.
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3.
Impact of treosulfan exposure on early and long-term clinical outcome in pediatric allogeneic HSCT recipients: a prospective multicenter study
van der Stoep, Myec, Bertaina, A., Moes, Djar, Algeri, M., Bredius, R. G. M., Smiers, F. J. W., Berghuis, D., Buddingh, E. P., Mohseny, A. B., Guchelaar, H. J., et al
Transplantation and cellular therapy. 2021
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Abstract
BACKGROUND Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationship between systemic treosulfan exposure, early and long term clinical outcome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant diseases is as yet unresolved. OBJECTIVE In this study we assessed the association between treosulfan exposure and early, and in particular, long term clinical outcomes. STUDY DESIGN We conducted a multicenter, prospective observational study and included 110 pediatric patients with non-malignant diseases transplanted between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected and treosulfan area under the curve (AUC(0-8)) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationship between treosulfan exposure, OS and EFS. The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days is evaluated using a multivariable logistic regression analysis. RESULTS In the overall cohort, overall survival (OS) and event-free survival (EFS) at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children under the age of 2 years. The occurrence of grade II-IV aGvHD, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio (OR) 3.97, 95% confidence interval (CI) 1.26-13.68, p=0.02) and all grade mucositis (OR 4.43, 95%CI 1.43-15.50, p=0.02), but not = grade 2 mucositis (OR 1.51, 95%CI 0.52-4.58, p=0.46) was related to high treosulfan exposure (>1750 mg*h/L). CONCLUSION Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with non-malignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring (TDM), thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether de-escalation of treosulfan doses is possible in order to minimize early and long term toxicity without compromising efficacy.
PICO Summary
Population
Children with non-malignant diseases who received allogeneic HSCT at two centres in the Netherlands and Italy (n=110)
Intervention
Treosulfan conditioning
Comparison
None
Outcome
In the overall cohort, overall survival (OS) and event-free survival (EFS) at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children under the age of 2 years. The occurrence of grade II-IV aGvHD, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio (OR) 3.97, 95% confidence interval (CI) 1.26-13.68, p=0.02) and all grade mucositis (OR 4.43, 95%CI 1.43-15.50, p=0.02), but not = grade 2 mucositis (OR 1.51, 95%CI 0.52-4.58, p=0.46) was related to high treosulfan exposure (>1750 mg*h/L).
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4.
TCRaß/CD19 depleted HSCT from an HLA-haploidentical relative to treat children with different non-malignant disorders
Merli, P., Pagliara, D., Galaverna, F., Li Pira, G., Andreani, M., Leone, G., Amodio, D., Pinto, R. M., Bertaina, A., Bertaina, V., et al
Blood advances. 2021
Abstract
Several non-malignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders or metabolic diseases, lacking a fully-matched donor or requiring urgent transplantation, underwent TCRaß/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study (#NCT01810120). Median age at transplant was 3.5 years (range 0.3-16.1); median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (e.g., aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade I-II acute GvHD was 14.4% (no patient developed grade III-IV acute GVHD). Only one patient at risk developed mild chronic GvHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRaß/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment for children with NMDs. Prompt donor availability, low incidence of GvHD and TRM make this strategy an attractive option in NMDs patients.
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Outcomes of pediatric patients with therapy-related myeloid neoplasms
Sharma, A., Huang, S., Li, Y., Brooke, R. J., Ahmed, I., Allewelt, H. B., Amrolia, P., Bertaina, A., Bhatt, N. S., Bierings, M. B., et al
Bone marrow transplantation. 2021
Abstract
Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.
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6.
A study assessing the feasibility of randomization of pediatric and young adult patients between matched unrelated donor bone marrow transplantation and immune-suppressive therapy for newly diagnosed severe aplastic anemia: A joint pilot trial of the North American Pediatric Aplastic Anemia Consortium and the Pediatric Transplantation and Cellular Therapy Consortium
Pulsipher, M. A., Lehmann, L. E., Bertuch, A. A., Sasa, G., Olson, T., Nakano, T., Gilio, A., Burroughs, L. M., Lipton, J. M., Huang, J. N., et al
Pediatric Blood & Cancer. 2020;67(10):e28444
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Abstract
BACKGROUND Recent data show survival after matched unrelated donor (MUD) bone marrow transplantation (BMT) is similar to matched sibling procedures for young patients with severe aplastic anemia (SAA). Donor delays, risk of transplant-related mortality (TRM), and concern about chronic graft versus host disease raise questions about whether MUD BMT or immune suppression therapy (IST) should be preferred initial therapy for young patients lacking matched sibling donors. PROCEDURE We performed a pilot trial to assess the feasibility of randomizing patients under age 26 with newly diagnosed SAA to receive IST versus MUD BMT. Primary aims assessed the acceptability of randomization and timing of BMT. Secondary aims measured toxicities, response, and survival. RESULTS Sixty-seven patients with possible SAA were screened at nine centers. Of 57 with confirmed SAA, 23 underwent randomization and received therapy with a median follow-up of 18 months. Of 12 randomized to BMT, 10 started BMT as initial therapy at a median of 36 days after randomization. One BMT recipient experienced secondary graft failure, requiring a second procedure. Six of 11 randomized to IST responded, whereas five with refractory disease underwent successful salvage BMT. One patient achieving complete response relapsed after discontinuation of immune suppression and died of infection after salvage BMT. CONCLUSIONS This feasibility study showed that a high percentage of patients underwent randomization and received up-front MUD BMT. Our study lays the groundwork for a larger randomized trial that will define best initial therapy for young patients with SAA who have an available MUD.
Clinical Commentary
What is known?
NIHMS1699978
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
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7.
Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Willasch, A. M., Peters, C., Sedlacek, P., Dalle, J. H., Kitra-Roussou, V., Yesilipek, A., Wachowiak, J., Lankester, A., Prete, A., Hamidieh, A. A., et al
Bone marrow transplantation. 2020
Abstract
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.
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8.
Outcome of children relapsing after first allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia: a retrospective I-BFM analysis of 333 children
Uden, T., Bertaina, A., Abrahamsson, J., Ansari, M., Balduzzi, A., Bourquin, J. P., Gerhardt, C., Bierings, M., Hasle, H., Lankester, A., et al
British journal of haematology. 2020
Abstract
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%.
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9.
Phenotypic and Functional Characterization of NK Cells in aßT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia
Meazza, R., Falco, M., Loiacono, F., Canevali, P., Della Chiesa, M., Bertaina, A., Pagliara, D., Merli, P., Indio, V., Galaverna, F., et al
Cancers. 2020;12(8)
Abstract
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.
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10.
Population pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation
van der Stoep, Myec, Zwaveling, J., Bertaina, A., Locatelli, F., Guchelaar, H. J., Lankester, A. C., Moes, Djar
British journal of clinical pharmacology. 2019
Abstract
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.