A prospective study of incidence, clinical and quality of life consequences of oral mucositis post palifermin prophylaxis in patients undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation.

Autologous hematopoietic cell transplantation (AHCT) has presented a revolutionary advance in the management of hematologic malignancies with low toxicity. However, oral mucositis (OM) remains a distressing toxic effect of AHCT and one of the major side effects of the conditioning. This prospective, observational study aimed to evaluate the severity of oral cavity pain and quality of life (QOL) and explore incidence, duration, and potential risk factors of moderate/severe OM. Thirty-nine patients receiving prophylactic palifermin post-AHCT were enrolled. QOL and severity of pain were assessed using validated questionnaires (Functional Assessment of Cancer Therapy-General (FACT-G) and mouth and throat soreness (MTS), respectively). The incidence of moderate/severe OM was 28.2 % with a median duration of 5 days and was associated with younger age and female gender. Severity of pain related to OM was generally low or moderate with only 25 % of patients reporting a score >6 on the MTS scale of 0-10 on day +7. Health-related QOL was worse on day +7 in the transplant unit compared to day 1, while on discharge day, all scores recovered and the total FACT-G score was not different from that on day 1. In our population, the incidence and duration of OM and the severity of pain related to OM appeared to be lower compared to that reported in previous studies. The impact of OM on QOL assessments seemed to be reversible with optimal supportive care despite the major transient disabilities mainly attributable to OM.

High alloreactivity of low-dose prophylactic donor lymphocyte infusion in patients with acute leukemia undergoing allogeneic hematopoietic cell transplantation with an alemtuzumab-containing conditioning regimen.

The value of prophylactic donor lymphocyte infusion (pDLI) is unclear and differs among diseases and transplantation protocols. Experience with this approach in patients with acute leukemia undergoing hematopoietic cell transplantation (HCT) with an alemtuzumab-incorporating conditioning protocol is lacking. We conducted a single-center prospective study to investigate the applicability and efficacy of prophylactic donor lymphocyte infusion (pDLI) in patients with leukemia undergoing HCT with a low-dose alemtuzumab-containing conditioning regimen. Inclusion criteria were high-risk acute myelogenous leukemia, acute lymphoblastic leukemia, or increasing mixed chimerism. All patients included were tapered off of immunotherapy. Exclusion criteria were a history of ≥ grade II or active graft-versus-host disease (GVHD). Of the 56 consecutive patients who underwent HCT with an alemtuzumab-containing regimen, 15 patients (8 with acute myelogenous leukemia and 7 with acute lymphoblastic leukemia) met the study inclusion criteria and received prophylactic DLI (total of 45 infusions) from 7 sibling donors and 8 unrelated donors. The first infusion was given at a median of 162 days posttransplantation. The median number of DLIs was 3, and the median cumulative CD3(+) cell dose was 2 × 10(6)cells/kg. Six of the 8 patients (75%) who received pDLI while in mixed chimerism converted to stable, complete donor chimerism. Some 47% of DLI recipients developed GVHD (4 acute GVHD and 3 with chronic GVHD) after a median cumulative dose of 2 × 10(6) CD3(+) cells/kg. After a median follow-up of 575 days, 11 (73%) pDLI recipients were alive. All 4 deaths were due to GVHD-related causes. None of the patients who received pDLIs relapsed. Patients with leukemia who received low-dose pDLI after conditioning with alemtuzumab are at low risk for relapse; however, this approach is associated with a relatively high incidence of severe GVHD.

Study protocol: Phase I/II trial of induced HLA-G+ regulatory T cells in patients undergoing allogeneic hematopoietic cell transplantation from an HLA-matched sibling donor.

Regulatory T-cell (Treg) immunotherapy has emerged as a promising and highly effective strategy to combat graft-versus-host disease (GvHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Both naturally occurring Treg and induced Treg populations have been successfully evaluated in trials illustrating the feasibility, safety, and efficacy required for clinical translation. Using a non-mobilized leukapheresis, we have developed a good manufacturing practice (GMP)-compatible induced Treg product, termed iG-Tregs, that is enriched in cells expressing the potent immunosuppressive human leucocyte antigen-G molecule (HLA-G+). To assess the safety and the maximum tolerable dose (MTD) of iG-Tregs, we conduct a phase I-II, two-center, interventional, dose escalation (3 + 3 design), open-label study in adult patients undergoing allo-HCT from an HLA-matched sibling donor, which serves also as the donor for iG-Treg manufacturing. Herein, we present the clinical protocol with a detailed description of the study rationale and design as well as thoroughly explain every step from patient screening, product manufacturing, infusion, and participant follow-up to data collection, management, and analysis (registered EUDRACT-2021-006367-26).

Identification of a novel HLA-G+ regulatory population in blood: expansion after allogeneic transplantation and de novo HLA-G expression at graft-versus-host disease sites.

BACKGROUND: The human leukocyte antigen-G (HLA-G) has been considered to be an important tolerogeneic molecule playing an essential role in maternal-fetal tolerance, which constitutes the perfect example of successful physiological immunotolerance of semi-allografts. In this context, we investigated the putative role of this molecule in the allogeneic hematopoietic cell transplantation setting. DESIGN AND METHODS: The percentage of HLA-G(+) cells in peripheral blood of healthy donors and allo-transplanted patients was evaluated by flow cytometry. Their immunoregulatory and tolerogeneic properties were investigated in in vitro immunostimulatory and immunosuppression assays. Immunohistochemical analysis for HLA-G expression was performed in skin biopsies from allo-transplanted patients and correlated with the occurrence of graft-versus-host disease. RESULTS: We identified a CD14(+)HLA-G(pos) population with an HLA-DR(low) phenotype and decreased in vitro immunostimulatory capacity circulating in peripheral blood of healthy individuals. Naturally occurring CD14(+)HLA-G(pos) cells suppressed T-cell responses and exerted an immunotolerogenic action on T cells by rendering them hyporesponsive and immunosuppressive in vitro. After allogeneic hematopoietic cell transplantation, HLA-G(pos) cells increase in blood. Interestingly, besides an increase in CD14(+)HLA-G(pos) cells, there was also a pronounced expansion of CD3(+)HLA-G(pos) cells. Of note, CD3(+)HLA-G(pos) and CD14(+)HLA-G(pos) cells from transplanted patients were suppressive in in vitro lymphoproliferation assays. Furthermore, we found an upregulation of HLA-G expression in skin specimens from transplanted patients that correlated with graft-versus-host disease. Inflammatory cells infiltrating the dermis of transplanted patients were also HLA-G(pos). CONCLUSIONS: We report the presence of naturally occurring HLA-G(pos) monocytic cells with in vitro suppressive properties. HLA-G expressing regulatory blood cells were found in increased numbers after allogeneic transplantation. Epithelial cells in skin affected by graft-versus-host disease revealed elevated HLA-G expression.

Tongue graft-versus-host disease: remission with ruxolitinib.

Graft-versus-host disease (GvHD) is a potentially life-threatening and commonly encountered event of allogeneic haematopoietic stem cell transplantation. Here, we present a young adult male with primary refractory Hodgkin's lymphoma who received a transplant and developed cutaneous GvHD after donor lymphocyte infusion, which was managed with cyclosporine and steroids. However, while the patient was under immunosuppressive treatment, diffuse confluent whitish patches on the patient's tongue were observed. A biopsy of the tongue lesions revealed lichenoid, hyperkeratotic tissue changes and intraepithelial T-cell infiltration consistent with chronic GvHD. He was treated with mycophenolate mofetil for 6 months with minimal improvement. Janus-associated kinase inhibitor (ruxolitinib) treatment was commenced, with complete resolution of the tongue lesions and treatment discontinuation 5 months later. Currently, 5 years after allogeneic transplantation, he is in remission and does not need immunosuppressive therapy.

Pretransplant Genetic Susceptibility: Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pretransplant genetic susceptibility is evident in adult TA-TMA and further investigated the association of TMA-associated variants with clinical outcomes. We studied 40 patients with TA-TMA, donors of 18 patients and 40 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pretransplant peripheral blood was sequenced for TMA-associated genes. Donors presented significantly lower frequency of rare variants and variants in exonic/splicing/untranslated region (UTR) regions, compared with TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13, CD46, CFH, and CFI. The majority of TA-TMA patients (31/40) presented with pathogenic or likely pathogenic variants. Patients refractory to conventional treatment (62%) and patients that succumbed to transplant-related mortality (65%) were significantly enriched for variants in exonic/splicing/UTR regions. In conclusion, increased incidence of pathogenic, rare and variants in exonic/splicing/UTR regions of TA-TMA patients suggests genetic susceptibility not evident in controls or donors. Notably, variants in exonic/splicing/UTR regions were associated with poor response and survival. Therefore, pretransplant genomic screening may be useful to intensify monitoring and early intervention in patients at high risk for TA-TMA.

Muscle reaction function of individuals with intellectual disabilities may be improved through therapeutic use of a horse.

Reaction time and muscle activation deficits might limit the individual's autonomy in activities of daily living and in participating in recreational activities. The aim of the present study was to assess the effects of a 14-week hippotherapy exercise program on movement reaction time and muscle activation in adolescents with intellectual disability (ID). Nineteen adolescents with moderate ID were assigned either to an experimental group (n=10) or a control group (n=9). The experimental group attended a hippotherapy exercise program, consisting of two 30-min sessions per week for 14 weeks. Reaction time, time of maximum muscle activity and electromyographic activity (EMG) of rectus femoris and biceps femoris when standing up from a chair under three conditions: in response to audio, visual and audio with closed eyes stimuli were measured. Analysis of variance designs showed that hippotherapy intervention program resulted in significant improvements in reaction time and a reduction in time to maximum muscle activity of the intervention group comparing to the control group in all 3 three conditions that were examined (p<0.05). The present findings suggest that the muscle reaction function of individuals with ID can be improved through hippotherapy training. Hippotherapy probably creates a changing environment with a variety of stimuli that enhance deep proprioception as well as other sensory inputs. In conclusion, this study provides evidence that hippotherapy can improve functional task performance by enhancing reaction time.

A long road of T-cells to cure cancer: from adoptive immunotherapy with unspecific cellular products to donor lymphocyte infusions and transfer of engineered tumor-specific T-cells.

The notion that immunocompetent cells, contained within adult bone marrow or peripheral blood, are capable of mediating an antitumor effect was first validated experimentally in 1957. T-cell immunotherapy for malignant disease is now routinely used in the context of allogeneic bone marrow transplantation. After 50 years of investigations into the use of T-cells for cancer therapy, adoptive cellular immunotherapy for cancer has progressed from the delivery of unspecific cellular products to the transfer of engineered tumor-specific T-cells. Adoptive cellular immunotherapy for cancer has now reached a stage of increasing feasibility and efficacy.

Effect of a hippotherapy intervention program on static balance and strength in adolescents with intellectual disabilities.

The aim of this study was to assess the effects of a hippotherapy program on static balance and strength in adolescents with intellectual disability (ID). Nineteen adolescents with moderate ID were assigned either an experimental group (n=10) or a control group (n=9). The experimental group attended a 10-week hippotherapy program. To assess static balance, three tasks of increasing difficulty (Double-Leg Stance with opened or closed eyes, and One-Leg Stance with opened eyes) were performed while standing on an EPS pressure platform (Loran Engineering S.r.I., Bologna, Italy). The strength measurements consisted of three maximal isometric half-squats from the seating position (knee joint at 90°). The hippotherapy intervention program resulted in significant improvements in strength parameters, and on the more complex balance task (i.e. standing on one leg). In conclusion, this study provides evidence that hippotherapy can be used as an effective intervention for improving balance and strength in individuals with ID, and could thus influence functional activities and quality of life.

Hematopoietic stem cell transplantation from alternative donors for high-risk acute leukemia: the haploidentical option.

Much progress has been made in the clinical, biological and technical aspects of the T-cell-depleted full-haplotype mismatched transplants for acute leukemia. Our experience demonstrates that infusing a megadose of extensively T-cell-depleted hematopoietic peripheral blood stem cells after an immuno-myeloablative conditioning regimen in acute leukemia patients ensures sustained engraftment with minimal graft-vs-host disease (GvHD) without the need of any post-transplant immunosuppressive treatment. Since our first successful pilot study, our efforts have concentrated on developing new conditioning regimens, optimizing the graft processing and improving the post-transplant immunological recovery. The results we have so far achieved in more than 200 high-risk acute leukemia patients show that haploidentical transplantation is now a clinical reality. Because virtually all patients in need of a hematopoietic stem cell transplant have a full-haplotype mismatched donor, who is immediately available, a T-cell depleted mismatched transplant should be offered, not as a last resort, but as a viable option to high risk acute leukemia patients who do not have, or cannot find, a matched donor.