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1.
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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Allogeneic transplantation in high-risk chronic lymphocytic leukemia: a single-center, intent-to-treat analysis.
Hoffmann, A, Dietrich, S, Hain, S, Rieger, M, Hegenbart, U, Sellner, L, Ho, AD, Müller-Tidow, C, Dreger, P
Haematologica. 2019;(7):e304-e306
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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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Abstract
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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Quality of life during and following sequential treatment of previously untreated patients with multiple myeloma: findings of the Medical Research Council Myeloma IX randomised study.
Royle, KL, Gregory, WM, Cairns, DA, Bell, SE, Cook, G, Owen, RG, Drayson, MT, Davies, FE, Jackson, GH, Morgan, GJ, et al
British journal of haematology. 2018;(6):816-829
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Abstract
In the Medical Research Council (MRC) Myeloma IX trial (ISRCTN684564111) patients were randomised to sodium clodronate or zoledronic acid and induction treatment: cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or cyclophosphamide, thalidomide and dexamethasone (CTD) followed by autologous stem cell transplant (ASCT) in the intensive pathway; attenuated CTD or melphalan and prednisolone (MP) in the non-intensive pathway. Subsequent randomisation allocated patients to either thalidomide or observation. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QoL) questionnaires, QLQ-C30 and QLQ-MY24, were administered at baseline, 3, 6 and 12 months and annually thereafter, enabling the effect of sequential treatment on patient-reported health-related QoL (HR-QoL) to be investigated. The protocol specified four subscales of interest: Pain, Fatigue, Global Health Status/Quality of Life and Physical Functioning at 3, 6 and 12 months that were compared using linear models. The intensive pathway showed significant differences in favour of CTD for Fatigue at 3 months and Physical Functioning at 12 months. The non-intensive pathway and maintenance phase reported significant differences at 3 months; Pain (improved with attenuated CTD) and Global Health status/Quality of Life (improved with observation). The improved outcomes in MRC Myeloma IX were accompanied by some beneficial and few detrimental effects on HR-QoL.
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Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma.
Shah, N, Li, L, McCarty, J, Kaur, I, Yvon, E, Shaim, H, Muftuoglu, M, Liu, E, Orlowski, RZ, Cooper, L, et al
British journal of haematology. 2017;(3):457-466
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Abstract
Multiple myeloma (MM) is a disease with known immune dysregulation. Natural killer (NK) cells have shown preclinical activity in MM. We conducted a first-in-human study of umbilical cord blood-derived (CB) NK cells for MM patients undergoing high dose chemotherapy and autologous haematopoietic stem cell transplantation (auto-HCT). Patients received lenalidomide (10 mg) on days -8 to -2, melphalan 200 mg/m2 on day -7, CB-NK cells on day -5 and auto-HCT on day 0. Twelve patients were enrolled, three on each of four CB-NK cell dose levels: 5 × 106 , 1 × 107 , 5 × 107 and 1 × 108 CB-NK cells/kg. Ten patients had either high-risk chromosomal changes or a history of relapsed/progressed disease. There were no infusional toxicities and no graft-versus-host disease. One patient failed to engraft due to poor autologous graft quality and was rescued with a back-up autologous graft. Overall, 10 patients achieved at least a very good partial response as their best response, including eight with near complete response or better. With a median follow-up of 21 months, four patients have progressed or relapsed, two of whom have died. CB-NK cells were detected in vivo in six patients, with an activated phenotype (NKG2D+ /NKp30+ ). These data warrant further development of this novel cellular therapy.
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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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Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers.
Anandasabapathy, N, Breton, G, Hurley, A, Caskey, M, Trumpfheller, C, Sarma, P, Pring, J, Pack, M, Buckley, N, Matei, I, et al
Bone marrow transplantation. 2015;(7):924-30
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Abstract
Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 μg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.
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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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Pretransplantation fluorine-18-deoxyglucose--positron emission tomography scan lacks prognostic value in chemosensitive B cell non-hodgkin lymphoma patients undergoing nonmyeloablative allogeneic stem cell transplantation.
Sauter, CS, Lechner, L, Scordo, M, Zheng, J, Devlin, SM, Fleming, SE, Castro-Malaspina, H, Moskowitz, CH
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2014;(6):881-4
Abstract
Whether chemosensitivity, as determined by positron emission tomography using fluorine-18-deoxyglucose (FDG-PET), is a requirement for successful allogeneic hematopoietic stem cell transplantation (allo-SCT) has yet to be established. We analyzed 88 patients with B cell non-Hodgkin lymphoma (B-NHL) for event-free (EFS) and overall survival (OS) according to computed tomography (CT) and FDG-PET criteria before uniform nonmyeloablative (NMA) allo-SCT. Patients who were chemosensitive, according to CT criteria, experienced significantly greater EFS (P < .001) and OS (P < .03) compared with those who were chemorefractory at the time of allo-SCT. Of 58 patients within this cohort who were chemosensitive by CT criteria, there was no difference in EFS (P = .85) or OS (P = .96) between FDG-PET-positive (Deauville 4 to 5, n = 24) and FDG-PET-negative (Deauville 1 to 3, n = 34) patients. There was no difference in survival according to age < or ≥ 60 years, prior autologous-stem cell transplantation, allograft characteristics, or histology. FDG-PET adds no prognostic value in chemosensitive B-NHL before NMA-allo-SCT.
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Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia.
Yanada, M, Tsuzuki, M, Fujita, H, Fujimaki, K, Fujisawa, S, Sunami, K, Taniwaki, M, Ohwada, A, Tsuboi, K, Maeda, A, et al
Blood. 2013;(16):3095-102
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The optimal treatments for relapsed acute promyelocytic leukemia (APL) remain equivocal. We conducted a phase 2 study to evaluate the efficacy and feasibility of a sequential treatment consisting of induction and consolidation with arsenic trioxide (ATO), peripheral blood stem cell (PBSC) harvest after high-dose cytarabine chemotherapy, and autologous hematopoietic cell transplantation (HCT). Between 2005 and 2009, 35 patients (26 with hematologic and 9 with molecular relapse) were enrolled. Induction therapy resulted in complete remission in 81% of those with hematologic relapse, and most patients became negative for PML-RARα after the first ATO consolidation course, but 4 remained positive. Administration of the second ATO consolidation course further decreased the transcript levels in 3 patients. In total, 25 patients proceeded to PBSC harvest, all of whom successfully achieved the target CD34+ cell doses, and 23 underwent autologous HCT with PML-RARα-negative PBSC graft. Posttransplant relapse occurred in 3 patients, and there was no transplant-related mortality. With a median follow-up of 4.9 years, the 5-year event-free and overall survival rates were 65% and 77%, respectively. These findings demonstrate the outstanding efficacy and feasibility of the sequential treatment featuring ATO and autologous HCT for relapsed APL. This study was registered at http://www.umin.ac.jp/ctr/ as #C000000302.