Abstract

The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide (BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE?±?9.0) in the BuCy group, 59.2 % (SE?±?8.1) after BuCyMel, and 66.7 % (SE?±?7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p?=?0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p?=?0.06). Younger age was a predictor for relapse (p?=?0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p?

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.

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%.

Abstract

PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients = 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

Abstract

PURPOSE Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory. METHOD This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018. RESULTS The indications of HCT were severe combined immunodeficiency (SCID, n?=?158, 27%) and non-SCID PID (n?=?438, 73%). The median age at HCT was 2.3 years (range, 0.04 to 18.3 years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3 years (0.08 to 14.7 years). The CIN of post-HCT AD was 3% (2-5%) at 1 year post-HCT, 7% (5-11%) at 5 years post-HCT, and 11% (7-17%) at 8 years post-HCT. The median onset of post-HCT AD was 2.2 years (0.12 to 9.6 years). Autoimmune thyroid disorder (n?=?19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n?=?7, 22%) and rheumatological manifestations (n?=?5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p?=?0.01) and T cell-depleted graft (p? CONCLUSION Post-HCT AD occurred in 11% at 8 years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.

Abstract

Allogeneic HSCT represents the only potentially curative treatment for very high risk (VHR) ALL. Two consecutive international prospective studies, ALL-SCT-(I)BFM 2003 and 2007 were conducted in 1150 pediatric patients. 569 presented with VHR disease leading to any kind of HSCT. All patients >2 year old were transplanted after TBI-based MAC. The median follow-up was 5 years. 463 patients were transplanted from matched donor (MD) and 106 from mismatched donor (MMD). 214 were in CR1. Stem cell source was unmanipulated BM for 330 patients, unmanipulated PBSC for 135, ex vivo T-cell depleted PBSC for 62 and cord-blood for 26. There were more advanced disease, more ex vivo T-cell depletion, and more chemotherapy based conditioning regimen for patients transplanted from MMD as compared to those transplanted from MSD or MD. Median follow up (reversed Kaplan Meier estimator) was 4.99 years, median follow up of survivals was 4.88, range (0.01-11.72) years. The 4-year CI of extensive cGvHD was 13?±?2% and 17?±?4% (p?=?NS) for the patients transplanted from MD and MMD, respectively. 4-year EFS was statistically better for patients transplanted from MD (60?±?2% vs. 42?±?5%, p?

Abstract

INTRODUCTION Gonadal impairment is an important late effect having 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 post-pubertal children. MATERIAL AND METHODS This is a retrospective, multicenter study including children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemo-radiotherapy before the transplant. RESULTS We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range 5-18); 89 patients were males and 48 were females. Eighty-nine patients were pre-pubertal at transplant, while 48 were post-pubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of females treated with Treo in pre-pubertal stage reached spontaneous puberty compared to those treated with Bu (p=0.02). Spontaneous menarche was more frequent after Treo than after Bu (p< 0.001). Post-pubertal males and females treated with Treo had significantly lower luteinizing hormone (LH) levels (p=0.03 and p=0.04, respectively) compared to the Bu group. CONCLUSIONS 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.

Abstract

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

Abstract

BACKGROUND Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentations of lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data for non-transplanted patients beyond previous patient reports or meta-reviews are scarce. OBJECTIVE This international, retrospective study was conducted to elucidate the longitudinal clinical course of transplanted and non-transplanted LRBA-deficient patients. METHODS We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity (IDDA) score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS Twenty-four of 76 LRBA-deficient patients from 29 centers (10 years median follow-up, range: 1-52) underwent HSCT from 2005 to 2019. Overall survival after HSCT (median follow-up 20 months) was 70.8% (17/24 patients); all deaths were due to non-specific, early, transplant-related mortality. Currently, 82.7% (43/52) of non-transplanted patients (aged 3-69 years) are alive. Of 17 HSCT survivors, seven are in complete and five in good partial remission without treatment (12/17, 70.6%). Only five of 43 non-transplanted patients (11.6%) are without immunosuppression. IDDA scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P=0.005) or in patients who received abatacept or sirolimus as compared to other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSIONS The life-long disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.