Background
Naïve T‐cell‐depleted grafts have been employed as an ex vivo T‐cell depletion (TCD) platform to prevent graft‐versus‐host disease (GvHD) and improve immune reconstitution by providing ...rapid donor memory T‐cell reconstitution after allogenic hematopoietic stem cell transplantation (allo‐HSCT). CD45RA− memory T cells confer protection against viruses such as cytomegalovirus, Epstein–Barr virus, and adenovirus; however, reports have shown an unexpectedly high incidence of human herpesvirus (HHV)‐6B encephalitis among pediatric allo‐HSCT patients.
Methods
We report the first 18 consecutive allo‐HSCT, 16 haplo‐HSCT, and two human leukocyte antigen‐matched related donors implanted with naïve TCD grafts. All donors were administered three cell products: first, a CD34+ stem cell product; second, a CD45RA+ TCD graft, followed by an adoptive natural killer (NK) cell infusion within 10 days after HSCT. The study's primary endpoint was the incidence of HHV‐6B encephalitis.
Results
Engraftment was achieved in 94.5% of cases; 2‐year overall survival, event‐free survival, and GvHD/relapse‐free survival were 87.2% (95% CI 78.6–95.8), 67.3% (95% CI 53.1–81.5), and 64% (95% CI 50.5–78.1), respectively. HHV‐6B reactivation occurred in 7 of the haplo‐HSCT patients, six of who received a cell infusion with an NK/CD4 ratio <2. None of the patients developed encephalitis.
Conclusions
In this clinical study, we show that early adoptive NK cell infusion after a 45RA+ TCD allo‐HSCT graft is safe and can prevent HHV‐6B encephalitis. We recommend infusing adoptive NK cells after allo‐HSCT using CD45RA+ TCD grafts.
Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the ...GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of "operational cure" was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.
Severe aplastic anemia and congenital amegakaryocytic thrombocytopenia are rare bone marrow failure syndromes. Treatment for aplastic anemia consists of hematopoietic stem cell transplantation (HSCT) ...from a matched sibling donor or immunosuppressant drugs if there is no donor available. Congenital amegakaryocytic thrombocytopenia is a rare autosomal recessive disease that causes bone marrow failure and has limited treatment options, except for transfusion support and HSCT. In the absence of a suitable matched sibling donor, matched-unrelated, haploidentical, or mismatched donors may be considered. A 2-step partial T-cell-depletion strategy can remove CD45RA+ naïve T cells responsible for graft-versus-host disease (GvHD) while preserving memory T cells. Five patients underwent transplantation using this strategy with rapid neutrophil and platelet recovery. Acute and chronic GvHD ≥ grade 2 appeared in two and one patient, respectively. No severe infections were observed before day + 100. A high (60%) incidence of transplant-associated microangiopathy was observed. Three patients (60%) remain alive, with a median follow-up of 881 (range 323–1248) days. CD45RA-depleted HSCT is a novel approach for patients lacking a suitable matched donor; however, further improvements are needed.
Purpose
Use of adoptive immunotherapy with virus-specific T cells (VST) in patients with inborn errors of immunity prior to hematopoietic stem cell transplantation (HSCT) has been reported in few ...patients. We report our experience, reviewing all the cases previously reported.
Methods
We report four children with inborn errors of immunity who received VST infusion in a pre-HSCT setting in two reference centers in Spain and review all inborn errors of immunity cases previously reported.
Results
Taking into account our four cases, nine children have been reported to receive VST prior to HSCT to date: 3 severe combined immunodeficiency, 2 CTPS1 deficiency, 1 dyskeratosis congenital, 1 ORAI1 deficiency, 1 Rothmund-Thomson syndrome, and 1 combined immunodeficiency without confirmed genetic defect. In four patients, immunotherapy resulted in clinical improvement, allowing to proceed to HSCT. In these cases, the infusion was started closely to viral diagnosis mean time 28 days (IQR; 17–52 days), and the VST was followed shortly thereafter by HSCT mean time 28 days (IQR; 10–99 days). Viremia was controlled after HSCT in two cases (performed 7 and 36 days after the infusion). Multiple infusions were required in many cases. Five out of nine patients died before receiving HSCT. These patients presented with a prolonged and uncontrolled infection before VST administration mean time from viral diagnosis to VST infusion was 176 days (IQR; 54–1687).
Conclusions
In patients with inborn errors of immunity, the efficacy of VST for treating disseminated viral infections in pre-transplant settings seems to have a limited efficacy. However, this therapy could be used in a pre-emptive setting before severe viral disease occurs or closely to HSCT.
SF3B1
is a highly mutated gene in myelodysplastic syndrome (MDS) patients, related to a specific subtype and parameters of good prognosis in MDS without excess blasts. More than 40% of MDS patients ...carry at least two myeloid-related gene mutations but little is known about the impact of concurrent mutations on the outcome of MDS patients. In applying next-generation sequencing (NGS) with a 117 myeloid gene custom panel, we analyzed the co-occurrence of
SF3B1
with other mutations to reveal their clinical, biological, and prognostic implications in very low/low- and intermediate-risk MDS patients. Mutations in addition to those of
SF3B1
were present in 80.4% of patients (median of 2 additional mutations/patient, range 0–5). The most frequently mutated genes were as follows:
TET2
(39.2%),
DNMT3A
(25.5%),
SRSF2
(10.8%),
CDH23
(5.9%), and
ASXL1
,
CUX1
, and
KMT2D
(4.9% each). The presence of at least two mutations concomitant with that of
SF3B1
had an adverse impact on survival compared with those with the
SF3B1
mutation and fewer than two additional mutations (median of 54 vs. 87 months, respectively:
p
= 0.007). The co-occurrence of
SF3B1
mutations with specific genes is also linked to a dismal prognosis:
SRSF2
mutations were associated with shorter overall survival (OS) than
SRSF2
wt (median, 27 vs. 75 months, respectively;
p
= 0.001), concomitant
IDH2
mutations (median OS, 11 mut vs. 75 wt months;
p
= 0.001),
BCOR
mutations (median OS, 11 mut vs. 71 wt months;
p
= 0.036), and
NUP98
and
STAG2
mutations (median OS, 27 and 11 vs. 71 months, respectively;
p
= 0.008 and
p
= 0.002). Mutations in CHIP genes (
TET2
,
DNMT3A
) did not significantly affect the clinical features or outcome. Our results suggest that a more comprehensive NGS study in low-risk MDS
SF3B1
mut
patients is essential for a better prognostic evaluation.
Hematopoietic stem cell transplantation is a procedure necessitating the administration of high-dose chemoradiotherapy. This therapy may induce aggressive disruptions that can lead to special ...nutritional and metabolic conditions. These patients are at an increased risk for malnutrition in the phase before transplantation and afterward. Artificial nutrition, total parenteral nutrition in particular, is provided to patients undergoing hematopoietic stem cell transplantation to help minimize adverse nutritional consequences.
To investigate the impact of immunophenotypic response (IR) versus complete response (CR) and CR plus normal serum free light chain (sFLC) ratio (stringent CR) in elderly patients with multiple ...myeloma (MM) treated with novel agents.
From a total of 260 elderly patients newly diagnosed with MM included in the GEM05>65y trial, 102 patients achieving at least a partial response with ≥ 70% reduction in M-component after the six planned induction cycles were simultaneously analyzed by immunofixation, sFLC, and multiparameter flow cytometry (MFC) immunophenotyping; this population is the focus of this study.
Forty-three percent of patients achieved CR, 30% achieved stringent CR, and 30% achieved IR. Patients in stringent CR showed no significant survival advantage compared with those in CR, whereas patients in IR showed significantly increased progression-free survival (PFS) and time to progression (TTP) compared with those in stringent CR or CR; this was confirmed by multivariate analysis (hazard ratio, 4.1; P = .01 for PFS). Discrepancies between the three techniques were relatively common. Notably, in all seven patients achieving IR but remaining immunofixation positive, the M-component disappeared in follow-up analysis. In contrast, MFC-positive patients who were immunofixation negative (n = 20) showed a tendency toward early reappearance of the M-component (median, 3 months). Similarly, in five of 11 stringent CR but MFC-positive patients, symptomatic disease progression was recorded at a median of 13 months after induction.
Achieving an IR translates into superior PFS and TTP compared with conventional CR or stringent CR. These techniques provide complementary information and thus, an effort should be made to refine response criteria in MM.
The iron chelator deferasirox is widely used in patients with iron overload. Patients with low-grade myelodysplastic syndromes (MDS) get transfusion dependency and need to be treated with deferasirox ...to avoid iron overload. Moreover, in some patients an increase in both erythroid and platelets have been observed after deferasirox therapy. However, the mechanisms involved in these clinical findings are poorly understood. The aim of this work was to analyze, in patients treated with deferasirox, the changes in the gene-expression profile after receiving the treatment. A total of 15 patients with the diagnosis of low-grade MDS were studied. Microarrays were carried out in RNA from peripheral blood before and after 14 weeks of deferasirox therapy. Changes in 1457 genes and 54 miRNAs were observed: deferasirox induced the downregulation of genes related to the Nf kB pathway leading of an overall inactivation of this pathway. In addition, the iron chelator also downregulated gamma interferon. Altogether these changes could be related to the improvement of erythroid response observed in these patients after therapy. Moreover, the inhibition of NFE2L2/NRF2, which was predicted in silico, could be playing a critical role in the reduction of reactive oxygen species (ROS). Of note, miR-125b, overexpressed after deferasirox treatment, could be involved in the reduced inflammation and increased hematopoiesis observed in the patients after treatment. In summary this study shows, for the first time, the mechanisms that could be governing deferasirox impact in vivo.
Natural killer group 2D (NKG2D) is a natural killer (NK) cell-activating receptor that recognizes different stress-induced ligands that are overexpressed in a variety of childhood and adult tumors. ...NKG2D chimeric antigen receptor (CAR) T cells have shown potent anticancer effects against different cancer types. A second-generation NKG2D CAR was generated by fusing full-length human NKG2D to 4-1BB costimulatory molecule and CD3ζ signaling domain. Patient-derived CAR T cells show limitations including inability to manufacture CAR T cells from the patients' own T cells, disease progression, and death prior to return of engineered cells. The use of allogeneic T cells for CAR therapy could be an attractive alternative, although undesirable graft vs. host reactions may occur. To avoid such adverse effects, we used CD45RA
memory T cells, a T-cell subset with less alloreactivity, as effector cells to express NKG2D CAR. In this study, we developed a protocol to obtain large-scale NKG2D CAR memory T cells for clinical use by using CliniMACS Prodigy, an automated closed system compliant with Good Manufacturing Practice (GMP) guidelines. CD45RA
fraction was depleted from healthy donors' non-mobilized apheresis using CliniMACS CD45RA Reagent and CliniMACS Plus device. A total of 10
CD45RA
cells were cultured in TexMACS media supplemented with 100 IU/mL IL-2 and activated at day 0 with T Cell TransAct. Then, we used NKG2D-CD8TM-4-1BB-CD3ζ lentiviral vector for cell transduction (MOI = 2). NKG2D CAR T cells expanded between 10 and 13 days. Final cell products were analyzed to comply with the specifications derived from the quality and complementary controls carried out in accordance with the instructions of the Spanish Regulatory Agency of Medicines and Medical Devices (AEMPS) for the manufacture of investigational advanced therapy medicinal products (ATMPs). We performed four validations. The manufacturing protocol here described achieved large numbers of viable NKG2D CAR memory T cells with elevated levels of NKG2D CAR expression and highly cytotoxic against Jurkat and 531MII tumor target cells. CAR T cell final products met release criteria, except for one showing
overexpression and another with viral copy number higher than five. Manufacturing of clinical-grade NKG2D CAR memory T cells using CliniMACS Prodigy is feasible and reproducible, widening clinical application of CAR T cell therapies.
To increase productivity, new types of beans that present different characteristics, such as higher grain yieldare necessary. The cultivar RS Centenário is the result of a selection carried out in ...2007 using the “Iraí” cultivar, in a plot of genetic seed production. In the 2008 crop season, the seeds of the selected plants originated a segregant population. In 2009, the mass selection was carried out again. After two advancing generations, the phenotypic uniformity of the population was reached and the seeds were harvested in bulk. After several tests, the “SM 0112” lineage was denominated cultivar “RS Centenário” and the results of the assessed at a value for cultivation and use (VCU) trials were used to register the new cultivar. “RS Centenário” was registered as a new cultivar to be commercially grown in the Rio Grande do Sul state (RS), in southern Brazil. “RS Centenário” is a common bean (Phaseolus vulgaris L.) cultivar with a brindle seed coat, average weight of 1,000 seeds of 343 g, erect plants, indeterminate growth habit II/III, cycle of 88 days, high added value and average yield of 1,685 kg ha-1.
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