Impact of allogeneic stem cell transplantation on thyroid function.

PURPOSE: Primary hypothyroidism is a main endocrine complication after allogeneic stem cells transplantation (allo-SCT) in children, but in adults data on post-SCT hypothyroidism are limited. The aims of this observational, cross-sectional study were to assess the prevalence of hypothyroidism in adult allo-SCT recipients according to time from transplantation, and to identify risk factors. METHODS: One hundred and eighty-six patients (M 104; F 82; median age 53.4 years) who underwent allo-SCT between January 2010 and December 2017 were enrolled and divided into three groups, according to time from allo-SCT (1-3 years; 3-5 years; > 5 years). Pre-transplant TSH and fT4 levels were available for all patients. After transplantation, TSH, fT4 and anti-thyroperoxidase antibodies (TPO-Ab) were evaluated. RESULTS: After a follow-up of 3.7 years, 34 (18.3%) patients developed hypothyroidism, with higher prevalence in females (p < 0.001) and in patients who received matched unrelated donor grafts (p < 0.05). No difference in prevalence was found at different time points. Patients who developed hypothyroidism showed higher rate of TPO-Ab positivity (p < 0.05) and higher pre-transplant TSH levels (median 2.34 µU/ml) compared to those with preserved thyroid function (median 1.53 µU/ml; p < 0.001). Multivariable analysis identified higher pre-transplant TSH levels as a positive predictor of hypothyroidism (p < 0.005). The ROC curve analysis identified a pre-SCT TSH cutoff of 1.84 µU/ml, which can predict hypothyroidism with sensitivity 74.1% and specificity 67.2%. CONCLUSIONS: About one out of four patients developed hypothyroidism after allo-SCT, with a greater incidence in females. Pre-transplant TSH levels seem to predict the onset of post-SCT hypothyroidism.

Treatment of symptomatic oral mucositis with sodium hyaluronate and synthetic amino acid precursors of collagen in patients undergoing haematopoietic stem cell transplantation.

The purpose of the study is to evaluate the clinical effects of Mucosamin® (a spray preparation containing sodium hyaluronate combined with a pool of amino acids of precursor collagen, including L-Proline, L-Leucine, L-Lysine and glycine) on wound healing and pain management of oral mucositis after hematopoietic stem cell transplantation. The importance of professional dental hygiene by dental hygienist in reducing the severity of oral mucositis as unique therapy or in addition to therapy with Mucosamin® was also evaluated. One hundred thirty-seven patients undergoing hematopoietic stem cell transplantation were recruited in a case-control study and divided into 4 groups: Group A: professional oral hygiene + Mucosamin®; Group B: professional oral hygiene + standard treatment with chlorhexidine 0.20%;; Group C: only Mucosamin®; Group D: only standard treatment with chlorhexidine 0.20%. The following evaluations were made: WHO mucositis scale, OMAS mucositis scale, VAS, periodontal recording, days of mucositis. Comparing the groups at the onset of OM on WHO scale, it was observed that Group A grade 1 occurrence was more statistically significant than Group B (p= 0.03*); comparison between Group A and D showed a statistically significant difference in favour of Group A (p= 0.0002*). Also OMAS scale showed a statistically significant difference between groups who assumed Mucosamin, who developed lower OM grade (p = 0.001*). There was a statistically significant difference between group A compared with group B over the overall duration of OM (p = 0.02*), as well as between group A and group D (p=0.03*). According to the present study the combination of a careful debridement, correct oral hygiene during hospitalization and the use of Mucosamin® exponentially reduces the severity and duration of mucositis and consequently the discomfort of the patient. Moreover, it can be stated that the use of Mucosamin® also results in a reduction in the extent of chemotherapy lesions. Hyaluronic acid and amino acid-based sprays can be a valuable therapeutic aid in the treatment of mucositis.

Extracellular vesicles as potential biomarkers of acute graft-vs-host disease.

Acute graft-vs-host disease (GVHD) is a serious complication after allografting. We carried out an exploratory study to investigate a potential correlation of surface antigens on extracellular vesicles (EVs) and acute GVHD. EVs were extracted from serum samples from 41 multiple myeloma patients who underwent allografting. EVs were characterized by flow cytometry using a panel of 13 antibodies against specific membrane proteins that were reported to be predictive of acute GVHD. We observed a correlation between three potential biomarkers expressed on EV surface and acute GVHD onset by both logistic regression analysis and Cox proportional hazard model. In our study, CD146 (MCAM-1) was correlated with an increased risk-by almost 60%-of developing GVHD, whereas CD31 and CD140-α (PECAM-1 and PDGFR-α) with a decreased risk-by almost 40 and 60%, respectively. These biomarkers also showed a significant change in signal level from baseline to the onset of acute GVHD. Our novel study encourages future investigations into the potential correlation between EVs and acute GVHD. Larger prospective multicenter studies are currently in progress.

'Real-life' report on the management of chronic GvHD in the Gruppo Italiano Trapianto Midollo Osseo (GITMO).

Several guidelines have been published about management of chronic GvHD (cGvHD), but the clinical practice still remains demanding. The Gruppo Italiano Trapianto di Midollo Osseo (GITMO) has planned a prospective observational study on cGvHD, supported by a dedicated software, including the updated recommendations. In view of this study, two surveys have been conducted, focusing the management of cGvHD and ancillary therapy in cGvHD, to address the current 'real life' situation. The two surveys were sent to all 57 GITMO centers, performing allografting in Italy; the response rate was 57% and 66% of the interviewed centers, respectively. The first survey showed a great disparity especially regarding steroid-refractory cGvHD, although extracorporeal photo-apheresis resulted as the most indicated treatment in this setting. Another challenging issue was the strategy for tapering steroid: our survey showed a great variance, and this disagreement could be a real bias in evaluating outcomes in prospective studies. As for the second survey, the results suggest that the ancillary treatments are not standardized in many centers. All responding centers reported a strong need to standardize management of cGvHD and to participate in prospective trials. Before starting observational and/or interventional studies, a detailed knowledge of current practice should be encouraged.

Circulating endothelial cell count: a reliable marker of endothelial damage in patients undergoing hematopoietic stem cell transplantation.

The physio-pathologic interrelationships between endothelium and GvHD have been better elucidated and have led to definition of the entity 'endothelial GvHD' as an essential early phase prior to the clinical presentation of acute GvHD. Using the CellSearch system, we analyzed circulating endothelial cells (CEC) in 90 allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients at the following time-points: T1 (pre-conditioning), T2 (pre-transplant), T3 (engraftment), T4 (onset of GvHD) and T5 (1 week after steroid treatment). Although CEC changes in allo-HSCT represent a dynamic phenomenon influenced by many variables (that is, conditioning, immunosuppressive treatments, engraftment syndrome and infections), we showed that CEC peaks were constantly seen at onset of acute GvHD and invariably returned to pre-transplant values after treatment response. Since we showed that CEC changes during allo-HSCT has rapid kinetics that may be easily missed if blood samples are drawn at pre-fixed time-points, we rather suggest an 'on demand' evaluation of CEC counts right at onset of GvHD clinical symptoms to possibly help differentiate GvHD from other non-endothelial complications. We confirm that CEC changes are a suitable biomarker to monitor endothelial damage in patients undergoing allo-transplantation and hold the potential to become a useful tool to support GvHD diagnosis (ClinicalTrials.gov NCT02064972).

Use of sodium hyaluronate and synthetic amino acid precursors of collagen for the symptomatic treatment of mucositis in patients undergoing haematopoietic stem cell transplants.

Oral mucositis (OM) may occur in up to 100% of patients undergoing condition regimen to hematopoietic stem cell transplant (HSCT). From the patient’s perspective, OM is one of the most debilitating side effects of transplantation. It is commonly thought that oral hygiene can modify the incidence and severity of oral mucositis, therefore professional oral health care (POHC) is recommended prior to conditioning regimen for HSCT. A new strategy for the treatment of OM is sodium hyaluronate (SH) combined with amino acid precursors of collagen (Aas) (Mucosamin®). SH is a mucoaderent polymer acting as a mechanical barrier and pain reliever. Furthermore, it allows prolonged contact of the product with the mucous membrane. In this study, a total of 68 adult patients due to undergo HSCT for allogenic and autologous transplant were enrolled at the Stem Cell Transplant Unit. The patients were divided into two groups. One group was treated with POHC before HSCT and applications of Mucosamin® during the recovery after transplantation. The second group served as controls, with the usual treatment of Clorexidine 0.20% adopted by the department. After HSCT the same clinician, an expert in oral medicine trained for the clinical trial, evaluated symptoms of the patients’ mucositis of both groups every day. The treated patients developed less severe OM, therefore Mucosamin® seems to have a protective role against the more severe phases of mucositis. The maximum OM pain, measured with the VAS scale, was higher in patients who did not use Mucosamin®. In the treated group OM resolved sooner than in the control group.

Clinical impact of immunophenotypic remission after allogeneic hematopoietic cell transplantation in multiple myeloma.

Immunophenotypic remission (IR) is a strong prognostic factor in myeloma patients. The combination of IR and conventional CR was retrospectively evaluated in 66 patients after allografting. IR was defined as the absence of monoclonal plasma cells in BM aspirates by multiparameter flow cytometry. Conditioning was non-myeloablative in 55 patients; reduced-intensity in 10 and myeloablative in 1 patient. The allograft was given upfront in 35/66 (53%) patients. After a median follow-up of 7.1 years, 24 patients achieved both CR and IR (CR/IR group), 21 achieved IR but not CR with persistence of a urine/serum M-component (no CR/IR group) and 21 did not achieve either CR or IR (no CR/no IR group). Median OS and EFS were 'not reached' and 59 months in the CR/IR group; 64 and 16 months in the no CR/IR; and 36 and 6 months in the no CR/no IR, respectively (P<0.001). Cumulative incidence of extramedullary disease was 4.4% in the CR/IR, 38.1% in the no CR/IR and 14.3% in the no CR/no IR groups, respectively, at 4 years (P<0.001). IR was a valid tool to monitor residual disease after allografting, and allowed definition of a cohort of patients at higher incidence of extramedullary relapse.

Trichoderma species fungemia after high-dose chemotherapy and autologous stem cell transplantation: a case report.

We present a case of Trichoderma fungemia with pulmonary involvement in a multiple myeloma patient, who was severely immunocompromised and heavily treated with high-dose melphalan, and underwent autologous hematopoietic cell transplantation. This is the first report, to our knowledge, of proven Trichoderma fungemia, defined by published criteria, successfully treated with voriconazole.

Novel targeted drugs for the treatment of multiple myeloma: from bench to bedside.

Multiple myeloma remains an incurable plasma cell neoplasm. New insights into its pathogenesis have identified signaling pathways that have become potential therapeutic targets. It has clearly been established that intracellular regulatory proteins and interactions between malignant plasma cells and the bone marrow microenvironment play an important role in their survival and drug resistance. Several new agents associated with molecular targets are currently being investigated to design new treatment strategies aimed at prolonging survival and improving quality of life. This review illustrates their mechanisms of action and the possible future clinical applications.

Safety and potential efficacy of low-dose methotrexate for treatment of chronic graft-versus-host disease.

Low-dose methotrexate (MTX) is widely used in autoimmune diseases because of its anti-inflammatory activity. We report here the results of a retrospective study to review the outcomes of low-dose MTX used for treatment of refractory chronic graft-versus-host disease GVHD, with the goal of reducing the amount of prednisone needed to control the disease. In all, 14 patients with refractory chronic GVHD received MTX at a dose of 7.5 mg/m(2)/weekly for 3--0 weeks. Also, 11 patients had skin involvement, often with scleroderma or fasciitis. The median duration of chronic GVHD at the start of MTX was 38 (range 1--35) months. In this retrospective review, we found no grade 3-- toxicities, and none of the patients needed blood transfusion or growth factors. In 10 patients (71%), GVHD could be adequately controlled with prednisone at doses below 1 mg/kg every other day without the addition of other agents. Four patients decreased the amount of concomitant immunosuppressive treatment, five continued with the same regimen, four required an increase in immunosuppressive treatment, and one decided to discontinue all treatment. From this preliminary analysis, MTX appears to be a well-tolerated, inexpensive and possibly steroid-sparing agent that is worthy of further evaluation in prospective trials for treatment of chronic GVHD.

Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma.

BACKGROUND AND OBJECTIVES: The immunomodulatory drug thalidomide can inhibit angiogenesis and induce apoptosis in experimental models. It can also induce marked and durable response in advanced myeloma patients. Thalidomide has been used at doses ranging from 200 to 800 mg with significant toxicity. No data are available on the impact of low-dose thalidomide plus dexamethasone as salvage therapy for relapsed patients. DESIGN AND METHODS: To address this issue, myeloma patients were treated with 100 mg/day thalidomide continuously and dexamethasone 40 mg, days 1-4, every month. Between June 1999 and August 2000, 77 patients (median age 65 years) who had relapsed or were refractory to chemotherapy were treated with thalidomide plus dexamethasone. RESULTS: After a minimum of 3 months of treatment, 14 patients (18%) showed a myeloma protein reduction of 75%-100%, 18 patients (23%) showed a response of 50-75%, 19 patients (25%) a response of 25-50% and 26 patients (34%) a response of < 25% or disease progression. After a median follow-up of 8 months, median progression-free survival was 12 months. Thalidomide was well tolerated. Constipation (12%) and sedation (6%) were mild. Tingling or numbness were present in 17% of patients, discontinuation of treatment was required in 10% of patients. INTERPRETATION AND CONCLUSIONS: The association of low-dose thalidomide plus dexamethasone is active against advanced myeloma. A significant proportion of patients benefit from this treatment as a salvage therapy postponing the delivery of chemotherapy.