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Randomized Study of enterade® to Reduce Diarrhea in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation.
De Filipp, Z, Glotzbecker, B, Luque, L, Kim, HT, Mitchell, KM, Cheuvront, SN, Soiffer, RJ
Asian Pacific journal of cancer prevention : APJCP. 2021;(1):301-304
Abstract
High-dose chemotherapy frequently causes injury to the gastrointestinal mucosa, resulting in diarrhea. The purpose of the current study was to assess the tolerability and efficacy of enterade® in reducing ≥ grade 2 diarrhea (G2D) in association with high-dose melphalan followed by autologous stem cell transplantation (ASCT). We conducted a prospective, double blinded, multi-center trial in which 114 subjects were randomized to receive enterade® or placebo twice daily during the transplant hospitalization. Gastrointestinal toxicities (nausea, vomiting, oral mucositis and dysphagia) resulted in poor study compliance in both arms. Among subjects who were able to complete planned therapy (13%), the incidence of G2D was lower for those receiving enterade® as compared to placebo (16% vs 86%, p <0.03). Twice daily oral administration of enterade® and placebo following high-dose chemotherapy and ASCT was not feasible due to significant gastrointestinal toxicities. Future explorations of enterade® should be conducted in populations capable of reasonable oral intake.
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High serum neurofilament light chain normalizes after hematopoietic stem cell transplantation for MS.
Thebault, S, R Tessier, D, Lee, H, Bowman, M, Bar-Or, A, Arnold, DL, L Atkins, H, Tabard-Cossa, V, Freedman, MS
Neurology(R) neuroimmunology & neuroinflammation. 2019;(5):e598
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Abstract
OBJECTIVE To evaluate neurofilament light chain (NfL) levels in serum and CSF of patients with aggressive MS pre- and post-treatment with immunoablation followed by autologous hematopoietic stem cell transplantation (IAHSCT) and examine associations with clinical and MRI outcomes. METHODS Paired serum and CSF in addition to MRI and clinical measures were collected on 23 patients with MS at baseline and 1 and 3 years post-IAHSCT. An additional 33 sera and CSF pairs were taken from noninflammatory neurologic controls. NfL levels were quantitated using the Simoa platform (Quanterix). RESULTS Baseline MS NfL levels were significantly elevated relative to controls in serum (p = 0.001) and CSF (p = 0.001). Following IAHSCT, high pretreatment NfL levels significantly reduced in serum (p = 0.0023) and CSF (p = 0.0068) and were not significantly different from controls. Serum and CSF NfL levels highly correlated (r = 0.81, p < 0.0001). Baseline NfL levels were associated with worse pretreatment disease measures (Expanded Disability Status Scale [EDSS], relapses, MRI lesions, and MR spectroscopy (MRS) N-acetylaspartate/creatine). Elevated baseline NfL levels were associated with persistently worse indices of disease burden post-IAHSCT (sustained EDSS progression, cognition, quality of life, T1 and T2 lesion volumes, MRS, and brain atrophy). CONCLUSION These data substantiate that serum and CSF NfL levels reflect disease severity and treatment response in patients with MS and may therefore be a useful biomarker. Baseline serum levels associated with markers of pretreatment disease severity and post-treatment outcomes. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that for patients with aggressive MS, serum NfL levels are associated with disease severity.
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Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms.
Carrillo-Cruz, E, García-Lozano, JR, Márquez-Malaver, FJ, Sánchez-Guijo, FM, Montero Cuadrado, I, Ferra I Coll, C, Valcárcel, D, López-Godino, O, Cuesta, M, Parody, R, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;(15):4616-4623
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PURPOSE The biologically active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (vit D), has immunoregulatory properties via binding vitamin D receptor (VDR). In a prospective trial, we previously reported a reduction in the incidence of chronic GvHD (cGvHD) among patients who received vit D after allogeneic stem cell transplantation (allo-HSCT; Clinical Trials.gov: NCT02600988). Here we analyze the role of patients and donors' VDR SNPs on the immunomodulatory effect of vit D. PATIENTS AND METHODS Patients undergoing allo-HSCT were included in a prospective phase I/II clinical trial (Alovita) in three consecutive cohorts: control (without vit D), low-dose (1,000 IU/day), and high-dose (5,000 IU/day) groups. Vit D was given from day -5 until +100 after transplant. Genotyping of four SNPs of the VDR gene, FokI, BsmI, ApaI, and TaqI, were performed using TaqMan SNP genotyping assays. RESULTS We observed a decrease in the incidence of overall cGvHD at 1 year after allo-HSCT depending on the use or not of vit D among patients with FokI CT genotype (22.5% vs 80%, P = 0.0004) and among those patients without BsmI/ApaI/TaqI ATC haplotype (22.2% vs 68.8%, P = 0.0005). In a multivariate analysis, FokI CT genotype significantly influenced the risk of cGvHD in patients treated with vit D as compared with the control group (HR 0.143, P interaction < 0.001). CONCLUSIONS Our results show that the immunomodulatory effect of vit D depends on the VDR SNPs, and patients carrying the FokI CT genotype display the highest benefit from receiving vit D after allo-HSCT.
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Autologous hematopoietic cell transplantation for multiple myeloma patients with renal insufficiency: a center for international blood and marrow transplant research analysis.
Mahindra, A, Hari, P, Fraser, R, Fei, M, Huang, J, Berdeja, J, Callander, N, Costa, L, Diaz, MA, Freytes, C, et al
Bone marrow transplantation. 2017;(12):1616-1622
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Abstract
Autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) patients with renal insufficiency (RI) is controversial. Patients who underwent AHCT for MM between 2008 and 2013 were identified (N=1492) and grouped as normal/mild (⩾60 mL/min), N=1240, moderate (30-59), N=185 and severe RI (<30), N=67 based on Modification of Diet in Renal Disease. Multivariate analyses of non-relapse mortality (NRM), relapse, PFS and overall survival (OS) were performed. Of the 67 patients with severe RI, 35 were on dialysis prior to AHCT. Patients received melphalan 200 mg/m2 (Mel 200) in 92% (normal/mild), 75% (moderate) and 33% (severe) RI; remainder received 140 mg/m2 (Mel 140). Thirty four of 35 patients with severe RI achieved post-AHCT dialysis independence. The 5-year PFS for normal, moderate and severe RI was 35 (95% CI, 31-38)%, 40 (31-49)% and 27 (15-40)%, respectively, (P=0.42); 5-year OS for normal, moderate and severe RI was 68 (65-71)%, 68 (60-76)% and 60 (46-74)%, respectively, (P=0.69). With moderate RI, 5-year PFS for high-dose melphalan 140 mg/m2 was 18 (6-35)% and for Mel 200 was 46 (36-57)% (P=0.009). With severe RI, 5-year PFS Mel 140 was 25 (11-41) % and for Mel 200 was 32 (11-58)% (P=0.37). We conclude that AHCT is safe and effective in patients with MM with RI.
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Vitamin D Deficiency and Survival in Children after Hematopoietic Stem Cell Transplant.
Wallace, G, Jodele, S, Howell, J, Myers, KC, Teusink, A, Zhao, X, Setchell, K, Holtzapfel, C, Lane, A, Taggart, C, et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2015;(9):1627-31
Abstract
Vitamin D has endocrine function as a key regulator of calcium absorption and bone homeostasis and also has intracrine function as an immunomodulator. Vitamin D deficiency before hematopoietic stem cell transplantation (HSCT) has been variably associated with higher risks of graft-versus-host disease (GVHD) and mortality. Children are at particular risk of growth impairment and bony abnormalities in the face of prolonged deficiency. There are few longitudinal studies of vitamin D deficient children receiving HSCT, and the prevalence and consequences of vitamin D deficiency 100 days after transplant has been poorly studied. Serum samples from 134 consecutive HSCT patients prospectively enrolled into an HSCT sample repository were tested for 25-hydroxy (25 OH) vitamin D levels before starting HSCT (baseline) and at 100 days after transplantation. Ninety-four of 134 patients (70%) had a vitamin D level < 30 ng/mL before HSCT, despite supplemental therapy in 16% of subjects. Post-transplant samples were available in 129 patients who survived to day 100 post-transplant. Vitamin D deficiency persisted in 66 of 87 patients (76%) who were already deficient before HSCT. Moreover, 24 patients with normal vitamin D levels before HSCT were vitamin D deficient by day 100. Overall, 68% of patients were vitamin D deficient (<30 ng/mL) at day 100, and one third of these cases had severe vitamin D deficiency (<20 ng/mL). Low vitamin D levels before HSCT were not associated with subsequent acute or chronic GVHD, contrary to some prior reports. However, severe vitamin D deficiency (<20 ng/mL) at 100 days post-HSCT was associated with decreased overall survival after transplantation (P = .044, 1-year rate of overall survival: 70% versus 84.1%). We conclude that all pediatric transplant recipients should be screened for vitamin D deficiency before HSCT and at day 100 post-transplant and that aggressive supplementation is needed to maintain sufficient levels.
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Phase 2 trial of high-dose rituximab with high-dose cytarabine mobilization therapy and high-dose thiotepa, busulfan, and cyclophosphamide autologous stem cell transplantation in patients with central nervous system involvement by non-Hodgkin lymphoma.
Chen, YB, Batchelor, T, Li, S, Hochberg, E, Brezina, M, Jones, S, Del Rio, C, Curtis, M, Ballen, KK, Barnes, J, et al
Cancer. 2015;(2):226-33
Abstract
BACKGROUND High-dose thiotepa, busulfan, and cyclophosphamide (TBC) with autologous stem cell transplantation (ASCT) has been used in patients with central nervous system (CNS) involvement by non-Hodgkin lymphoma (NHL). Despite limited penetration into the CNS, rituximab is active in primary CNS NHL. Therefore, high-dose rituximab was combined with TBC for ASCT in patients with CNS NHL. METHODS A single-arm phase 2 trial using high-dose rituximab with cytarabine for stem cell mobilization followed by high-dose rituximab combined with thiotepa, busulfan, and cyclophosphamide (R-TBC) for ASCT was conducted. Doses of rituximab at 1000 mg/m(2) were given on days 1 and 8 of mobilization and on days -9 and -2 of TBC. The primary endpoint was efficacy. RESULTS Thirty patients were enrolled. Eighteen patients had primary CNS NHL (12 with complete remission (CR)/first partial remission (PR1) and 6 with CR/PR2), and 12 patients had secondary CNS lymphoma (5 with CR/PR1 and 7 with CR/PR2 or beyond). All patients were in partial or complete remission. Twenty-nine patients proceeded to R-TBC ASCT. Two patients developed significant neurotoxicity. The 100-day nonrelapse mortality rate was 0%, and 1 patient died because of nonrelapse causes 5 months after ASCT. For all patients, at a median follow-up of 24 months (range, 12-40 months), the estimated 2-year progression-free survival rate was 81% (95% confidence interval, 59%-92%), and the 2-year overall survival rate was 93% (95% confidence interval, 76%-98%). There were no relapses or deaths among the 18 patients with primary CNS lymphoma. CONCLUSIONS For patients with CNS involvement by B-cell NHL and especially for patients with primary CNS NHL, R-TBC ASCT shows encouraging activity and merits further study.
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Are orange lollies effective in preventing nausea and vomiting related to dimethyl sulfoxide? A multicenter randomized trial.
Gonella, S, Berchialla, P, Bruno, B, Di Giulio, P
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2014;(9):2417-24
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PURPOSE Nausea and vomiting (NV) related to DMSO affect patients undergoing auto-SCT despite antiemetic measures. Orange flavoring may reduce gastrointestinal symptoms. METHODS A multicenter, randomized, three-arm, open-label trial in four Italian large bone marrow transplant centers was conducted to assess the effectiveness of orange aroma in preventing NV related to DMSO. Patients were randomized to orange ice lollies, non-citrus ice lollies, and routine treatment (deep breaths) during reinfusion. Data on NV were collected up to 5 days after infusion; 69/98 patients were randomized: 23 to orange, 21 to non-citrus ice lollies, and 25 to routine treatment. RESULTS Although 48 h after transplantation no differences were observed in controlled nausea (Numerical Rating Scale (NRS) 0-100, ≤25) or vomiting, significantly fewer patients had no episodes of vomiting, no antiemetic rescue therapy, and no nausea (NRS <5) in the deep breath vs lollies groups (P = 0.017). The intensity of nausea over time differed significantly between ice lollies vs routine care (P = 0.001) groups, but not between the orange and non-citrus groups (P = 0.428). CONCLUSION The vasoconstrictive action of ice may prevent NV related to DMSO in the acute phase and reduce the need for rescue antiemetic therapy. Ice lollies offer a simple, noninvasive, and economic means for relieving nausea and vomiting related to this preservative.
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A multi-center, randomized, controlled trial of parenteral nutrition titrated to resting energy expenditure in children undergoing hematopoietic stem cell transplantation ("PNTREE"): rationale and design.
Bechard, LJ, Feldman, HA, Gordon, C, Gura, K, Sonis, A, Leung, K, Venick, R, Guinan, EC, Duggan, C
Contemporary clinical trials. 2010;(2):157-64
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BACKGROUND Children undergoing hematopoietic stem cell transplantation (HSCT) frequently require prolonged courses of parenteral nutrition (PN) as a consequence of gastrointestinal dysfunction related to preparative chemotherapy and radiation. PN has been associated with shorter engraftment time and decreased mortality during HSCT, however, it is also linked with complications, including infections, liver disease, and metabolic disturbances. Some of these complications may be a result of providing PN in excess of nutrient requirements. We previously described significant reductions in resting energy expenditure (REE), as measured by indirect calorimetry, over the course of HSCT. We also documented a decline in mid-arm muscle area, suggesting depletion of muscle mass, while triceps skinfold, a marker of fat stores, was unchanged. These results suggested the need for further study of energy expenditure, body composition and nutritional intake in this group of high risk patients. DESIGN AND HYPOTHESIS We hypothesize that changes in body composition affect REE during HSCT, and that standard nutritional support may lead to overfeeding. We are performing a randomized controlled trial of parenteral nutrition among children undergoing allogeneic HSCT. Subjects are randomized to receive PN designed to provide 100% of measured REE, or standard PN, i.e., 140% of estimated energy expenditure. The primary outcome variable is change in percent body fat. Secondary outcomes include glycemic control and frequency of infections, changes in REE and body composition. CONCLUSION This study will provide unique and comprehensive nutritional data and its results will guide nutritional therapy for children undergoing HSCT and possibly other catabolic patients.
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Economic impact of palifermin on the costs of hospitalization for autologous hematopoietic stem-cell transplant: analysis of phase 3 trial results.
Elting, LS, Shih, YC, Stiff, PJ, Bensinger, W, Cantor, SB, Cooksley, C, Spielberger, R, Emmanoulides, C
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2007;(7):806-13
Abstract
A double-blind, randomized trial showed that, compared with placebo, palifermin (recombinant human keratinocyte growth factor) reduced the frequency and duration of oral mucositis in patients with hematologic malignancies undergoing high-dose chemotherapy and total-body irradiation with autologous stem-cell support. This previously published study also showed a significant reduction in the incidence of adverse subsequent outcomes. The objective of this study was to estimate the impact of palifermin prophylaxis on hospital costs of transplantation in the trial. This was a retrospective, economic analysis of estimated costs for a previously published clinical trial. Costs were not collected during the trial. Therefore, we estimated the direct medical costs of hospitalization using hospital charges from similar patients' hospitalization charges selected from the National Inpatient Sample, a population-based, nationally representative sample of hospital claims. Costs were estimated from charges using Medicare's state-specific cost-to-charge ratios. These cost estimates were applied to the outcome data (incidence of febrile neutropenia, bacteremia/fungemia, or pneumonia, and use of total parenteral nutrition) from the clinical trial. Patients were those with hematologic malignancies who received high-dose chemotherapy and total-body irradiation with autologous stem cell transplant. We compared the estimated total hospital costs (in 2005 United States dollars) incurred by patients who received palifermin in the clinical trial with those incurred by patients who received placebo. Costs were analyzed from the provider's perspective. The mean cost of a hospital day in this population varied between $2,834, when no adverse outcomes occurred, and $4,663, when all 4 outcomes occurred. Reductions in adverse outcomes and their associated hospital stay offset the acquisition price of palifermin. A nonsignificant mean savings of $3,595 per patient (95% confidence interval: $2,090-$5,103) was observed. In sensitivity analyses, this observation was robust to all plausible values of per diem hospital costs and hypothetic per diem outpatient costs. In addition to its previously demonstrated clinical benefit, palifermin prophylaxis offers a favorable economic profile among patients with hematologic malignancies who receive total body irradiation and autologous stem cell support.