Defibrotide for Prophylaxis of Hepatic Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplantation: Subanalysis Data from an Open-Label, Phase III, Randomized Trial

Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of conditioning for hematopoietic stem cell transplantation (HSCT) and is associated with patient and transplant-related risk factors, such as prior therapies, underlying diagnoses, and conditioning regimen. Unpredictable in its occurrence and severity, VOD/SOS is clinically characterized by painful hepatomegaly, hyperbilirubinemia, ascites, and weight gain. Overall estimated prevalence is 14% post-HSCT, while rates in some high-risk populations (eg, osteopetrosis or prior gemtuzumab ozogamicin) are >60% (Wadleigh M et al. Blood . 2003;102:1578-82; Corbacioglu S et al. Bone Marrow Transplant . 2006;38:547-53). Evidence suggests that defibrotide stabilizes endothelial cells, with direct and endothelial-cell mediated restoration of the thrombo-fibrinolytic balance. Defibrotide is approved in the European Union for the treatment of severe hepatic VOD/SOS in patients receiving HSCT, and is available in the United States through an expanded-access study. In a previously reported randomized clinical trial, defibrotide prophylaxis for VOD/SOS in high-risk pediatric patients undergoing HSCT reduced the overall incidence of VOD/SOS by day +30 post-HSCT. Here we report novel subgroup analyses of VOD/SOS incidence from this trial in patients with specific VOD/SOS risk factors at baseline. Methods This was a phase 3, multicenter, open-label, randomized, controlled trial in patients aged 5% weight gain. Patients were randomized to standard care with or without defibrotide prophylaxis dosed at 25 mg/kg/day in 4 divided infusions of 6.25 mg/kg. Osteopetrosis was a stratification variable. Defibrotide began the same day as HSCT conditioning and continued for 30 days post-HSCT, or ≥14 days for patients discharged from hospital before day +30 post-HSCT. Control patients who developed VOD/SOS received defibrotide treatment. The primary endpoint was incidence of VOD/SOS at day +30 post-HSCT. Results The intent-to-treat population included 356 patients: 180 randomized to defibrotide prophylaxis and 176 in the control group. Mean (SD) age was 6.6 (5.3) years, and 40.7% of patients were female. Demographic and clinical characteristics, including VOD/SOS risk factors (Table), were well-matched in the defibrotide and control groups. The most common risk factors among all patients were conditioning with busulfan and melphalan (58%), preexisting liver disease (27%), and second myeloablative transplantation (13%). VOD/SOS occurred by day +30 post-HSCT in 22 (12%) patients in the defibrotide prophylaxis group vs 35 (20%) patients in the control group. For the stratification variable, osteopetrosis, rates of VOD/SOS were 14% in the defibrotide prophylaxis arm and 67% in the control arm (Table). Differences in rates of VOD/SOS were lowest for adrenoleukodystrophy (no cases) and prior abdominal irradiation (11% vs 13%, respectively) (Table). Conclusions Across risk-factor subgroups, the rate of VOD/SOS was lower in patients receiving defibrotide compared with controls (except adrenoleukodystrophy: no VOD/SOS in either group). In particular, rates of VOD/SOS by day +30 were reduced by ≥50% in the defibrotide arm vs the control arm among patients with osteopetrosis, hemophagocytic lymphohistiocytosis, second myeloablative transplantation, and prior gemtuzumab treatment. Although the total numbers of patients with these risk factors were small, these between-group differences are of clinical interest and should be further explored. | Risk Factor | Defibrotide (n=180) | Control (n=176) | | ------------------------------------ | ----------------------------------------------- | --------------- | ----------------------------------------------- | | Total n | VOD/SOS incidence (n=22; 12.2%) n (%*) | Total n | VOD/SOS incidence (n=35; 20.0%) n (%*) | | Adrenoleukodystrophy | 1 | 0 (0) | 1 | 0 (0) | | Osteopetrosis | 7 | 1 (14) | 6 | 4 (67) | | Prior abdominal irradiation | 9 | 1 (11) | 8 | 1 (13) | | Hemophagocytic lymphohistiocytosis | 10 | 0 (0) | 15 | 6 (40) | | Prior gemtuzumab | 11 | 2 (18) | 5 | 2 (40) | | Allogeneic HSCT for leukemia | 17 | 2 (12) | 11 | 2 (18) | | Second myeloablative transplantation | 25 | 2 (8) | 23 | 4 (17) | | Pre-existing liver disease | 41 | 6 (15) | 54 | 12 (22) | | Busulfan/melphalan conditioning | 106 | 15 (14) | 99 | 17 (17) | * *Percent of patients with VOD/SOS. Table. Support: Jazz Pharmaceuticals Disclosures Corbacioglu: Gentium S.p.A.: Consultancy, Honoraria. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Bader: Amgen: Consultancy; Medac: Other: Institutional grants; Neovii: Other: Institutional grants; Riemser: Other: Institutional grants; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy

Yoga in school sports improves functioning of autonomic nervous system in young adults: A non-randomized controlled pilot study

Background Yoga in school is a beneficial tool to promote the good health and well-being of students by changing the way they react to stress. The positive effects of yoga—taught in schools—on children, youth and young adults have been demonstrated in former studies using mostly subjective psychometric data. Aim The present trial aims to evaluate the potential effects of yoga on autonomic regulation in young adults by analyzing heart rate variability (HRV). Methods This study is a non-randomized, explorative, two-arm-pilot study with an active control group. Fourteen healthy young adults took part in a 10-week yoga program (90 min once a week) in school and were compared to a control group of 11 students who participated in conventional school sports (90 min once a week over 10 weeks). 24-hour electrocardiograms (ECGs) were recorded at baseline and following the 10-week intervention. From 20-minute of nocturnal sleep phases, HRV parameters were calculated from linear (time and frequency domain) and nonlinear dynamics (such as symbolic dynamics and Poincaré plot analysis). Analyses of variance (ANOVA) followed by t-tests as post-hoc tests estimating both statistical significance and effect size were used to compare pre-post-intervention for the two groups. Results The statistical analysis of the interaction effects did not reveal a significant group and time interaction for the individual nocturnal HRV indices. Almost all indices revealed medium and large effects regarding the time main effects. The changes in the HRV indices following the intervention were more dramatic for the yoga group than for the control group which is reflected in predominantly higher significances and stronger effect sizes in the yoga group. Conclusion In this explorative pilot trial, an increase of HRV (more parasympathetic dominance and overall higher HRV) after ten weeks of yoga in school in comparison to regular school sports was demonstrated, showing an improved self-regulation of the autonomic nervous system

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

In hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis, high transplant-related mortality after busulfan-based myeloablative regimens has been observed. Conditioning regimens with reduced toxicity based on melphalan or treosulfan are promising alternatives. We retrospectively analyzed hematopoietic stem cell transplantations in 19 hemophagocytic lymphohistiocytosis patients after conditioning with fludarabine, treosulfan, alemtuzumab, with or without thiotepa. Overall and disease-free survivals were 100% (follow up 7-31 months). Two patients required second transplant (1 after haploidentical transplantation). In 6 patients, overall donor chimerism dropped below 75% and prompted donor lymphocyte infusions. Administration of donor lymphocytes or second transplantation were significantly more frequent after transplantation from a human leukocyte antigen mismatched (9/10) versus matched (10/10) donor (P=0.018). The toxicity profile was favorable, with one veno-occlusive disease, one grade 3 graft-versus-host disease after donor lymphocyte infusion, and 2 severe viral infections (1 influenza, 1 Epstein Barr virus). In conclusion, the treosulfan-based regimen in hemophagocytic lymphohistiocytosis is effective with low toxicity and gives excellent overall and disease-free survival rates. In the future, the incidence of mixed chimerism, particularly after human leukocyte antigen mismatched donor transplants, needs to be addressed

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

In hematopoietic stem cell transplantation for hemophagocytic lymphohistiocytosis, high transplant-related mortality after busulfan-based myeloablative regimens has been observed. Conditioning regimens with reduced toxicity based on melphalan or treosulfan are promising alternatives. We retrospectively analyzed hematopoietic stem cell transplantations in 19 hemophagocytic lymphohistiocytosis patients after conditioning with fludarabine, treosulfan, alemtuzumab, with or without thiotepa. Overall and disease-free survivals were 100% (follow up 7-31 months). Two patients required second transplant (1 after haploidentical transplantation). In 6 patients, overall donor chimerism dropped below 75% and prompted donor lymphocyte infusions. Administration of donor lymphocytes or second transplantation were significantly more frequent after transplantation from a human leukocyte antigen mismatched (9/10) versus matched (10/10) donor (P=0.018). The toxicity profile was favorable, with one veno-occlusive disease, one grade 3 graft-versus-host disease after donor lymphocyte infusion, and 2 severe viral infections (1 influenza, 1 Epstein Barr virus). In conclusion, the treosulfan-based regimen in hemophagocytic lymphohistiocytosis is effective with low toxicity and gives excellent overall and disease-free survival rates. In the future, the incidence of mixed chimerism, particularly after human leukocyte antigen mismatched donor transplants, needs to be addressed

Evaluating STAT5 Phosphorylation as a Mean to Assess T Cell Proliferation

Here we present a simple and sensitive flow cytometric—based assay to assess T cell proliferation. Given the critical role STAT5A phosphorylation in T cell proliferation, we decided to evaluate phosphorylation of STAT5A as an indicator of T cell proliferation. We determined pSTAT5A in T cell treated with either CD3/CD28 or PHA. After stimulation, T cells from adult healthy donors displayed a strong long-lasting phosphorylation of STAT5A, reaching a peak value after 24 h. The median fluorescence intensity (MFI) of pSTAT5A increased from 112 ± 17 to 512 ± 278 (CD3/CD28) (24 h) and to 413 ± 123 (PHA) (24 h), the IL-2 receptor-α (CD25) expression was greatly enhanced and after 72 h T cell proliferation amounted to 52.3 ± 10.3% (CD3/CD28) and to 48.4 ± 9.7% (PHA). Treatment with specific JAK3 and STAT5 inhibitors resulted in a complete blockage of phosphorylation of STAT5A, CD25 expression, and suppression of T cell proliferation. Compared with currently available methods, STAT5A phosphorylation is well-suited to predict T cell proliferation. Moreover, the method presented here is not very time consuming (several hours) and delivers functional information from which conclusions about T cell proliferation can be drawn

Haploidentical hematopoietic stem cell transplantation as individual treatment option in pediatric patients with very high-risk sarcomas

Background Prognosis of children with primary disseminated or metastatic relapsed sarcomas remains dismal despite intensification of conventional therapies including high-dose chemotherapy. Since haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of hematological malignancies by mediating a graft versus leukemia effect, we evaluated this approach in pediatric sarcomas as well. Methods Patients with bone Ewing sarcoma or soft tissue sarcoma who received haplo-HSCT as part of clinical trials using CD3+ or TCRα/β+ and CD19+ depletion respectively were evaluated regarding feasibility of treatment and survival. Results We identified 15 patients with primary disseminated disease and 14 with metastatic relapse who were transplanted from a haploidentical donor to improve prognosis. Three-year event-free survival (EFS) was 18,1% and predominantly determined by disease relapse. Survival depended on response to pre-transplant therapy (3y-EFS of patients in complete or very good partial response: 36,4%). However, no patient with metastatic relapse could be rescued. Conclusion Haplo-HSCT for consolidation after conventional therapy seems to be of interest for some, but not for the majority of patients with high-risk pediatric sarcomas. Evaluation of its future use as basis for subsequent humoral or cellular immunotherapies is necessary

Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis

Minimal residual disease prior to allogeneic hematopoietic cell transplantation has been associated with increased risk of relapse and death in patients with acute myeloid leukemia, but detection methodologies and results vary widely. We performed a systematic review and meta-analysis evaluating the prognostic role of minimal residual disease detected by polymerase chain reaction or multiparametric flow cytometry before transplant. We identified 19 articles published between January 2005 and June 2016 and extracted hazard ratios for leukemia-free survival, overall survival, and cumulative incidences of relapse and non-relapse mortality. Pre-transplant minimal residual disease was associated with worse leukemia-free survival (HR=2.76 [1.90-4.00]), overall survival (HR=2.36 [1.73-3.22]), and cumulative incidence of relapse (HR=3.65 [2.53-5.27]), but not non-relapse mortality (HR=1.12 [0.81-1.55]). These associations held regardless of detection method, conditioning intensity, and patient age. Adverse cytogenetics was not an independent risk factor for death or relapse. There was more heterogeneity among studies using flow cytometry-based than WT1 polymerase chain reaction-based detection (I(2)=75.1% vs. <0.1% for leukemia-free survival, 67.8% vs. <0.1% for overall survival, and 22.1% vs. <0.1% for cumulative incidence of relapse). These results demonstrate a strong relationship between pre-transplant minimal residual disease and post-transplant relapse and survival. Outcome heterogeneity among studies using flow-based methods may underscore site-specific methodological differences or differences in test performance and interpretation

Integrative medicine during the intensive phase of chemotherapy in pediatric oncology in Germany: a randomized controlled trial with 5-year follow up

Background: Integrative medicine is used frequently alongside chemotherapy treatment in pediatric oncology, but little is known about the influence on toxicity. This German, multi-center, open-label, randomized controlled trial assessed the effects of complementary treatments on toxicity related to intensive-phase chemotherapy treatment in children aged 1-18 with the primary outcome of the toxicity sum score. Secondary outcomes were chemotherapy-related toxicity, overall and event-free survival after 5 years in study patients. Methods: Intervention and control were given standard chemotherapy according to malignancy & tumor type. The intervention arm was provided with anthroposophic supportive treatment (AST); given as anthroposophic base medication (AMP), as a base medication for all patients and additional on-demand treatment tailored to the intervention malignancy groups. The control was given no AMP. The toxicity sum score (TSS) was assessed using NCI-CTC scales. Results: Data of 288 patients could be analyzed. Analysis did not reveal any statistically significant differences between the AST and the control group for the primary endpoint or the toxicity measures (secondary endpoints). Furthermore, groups did not differ significantly in the five-year overall and event-free survival follow up. Discussion: In this trial findings showed that AST was able to be safely administered in a clinical setting, although no beneficial effects of AST between group toxicity scores, overall or event-free survival were shown

Treosulfan–fludarabine–thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies

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Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies. Results: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m(2)/day with weekly dose escalations of 50 mg/m(2) until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m(2)/day was determined (maximum, 580 mg/m(2)/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher C-max. Five patients achieved prolonged disease control (> 12 months) and showed a higher C-max (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion: An SDR of 130 mg/m(2)/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker