frontline therapy in multiple myeloma fast start for a long game

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JAK-2 inhibitors and allogeneic transplant in myelofibrosis

7The activation of the JAK1/JAK2 pathway plays a crucial role in the pathogenesis of myelofibrosis. Treatment with the JAK2 inhibitor ruxolitinib demonstrated to reduce splenomegaly and symptoms in patients affected by myelofibrosis, leading to a significant improvement of overall survival in comparison with the supportive therapies. Taking in account this recent therapeutic progress, it is necessary to redefine the role of the allogeneic hematopoietic stem cell transplantation, which has been considered the only curative option for fit myelofibrosis patients up to now. In the era of JAK2 inhibitors, allogeneic transplant is still indicated in patients with intermediate-2 and high-risk myelofibrosis or red blood cell transfusion dependent patients or patients with unfavourable karyotype. There is no direct evidence to recommend which conditioning regimen should be preferentially adopted. Graft failure, relapse and transplant related mortality are still current issues of the allogeneic stem cell transplantation, particularly from unrelated donors. Ruxolitinib can be efficaciously included in the platform of allogeneic transplant. In fact, ruxolitinib treatment for 3-4 months before transplant has demonstrated to reduce spleen and improve performance status in about 30-50% of patients, without impairing the outcome of the subsequent transplant. Ruxolitinib has to stopped the day before conditioning to avoid rebound phenomenon. There are no sufficient data to recommend ruxolitinib administration after transplant with the aim of eradicating minimal residual disease and preventing relapse.openopenPatriarca, F; Sperotto, A; De Marchi, R; Perali, G; Cigana, C; Lazzarotto, D; Fanin, RPatriarca, Francesca; Sperotto, A; De Marchi, R; Perali, G; Cigana, C; Lazzarotto, D; Fanin, Renat

Nickel-Titanium peripheral stents: can fracture mechanics shed light on their fatigue failure?

The major concern about Nickel-Titanium (Ni-Ti) stents, which are the gold standard in the treatment of occlusive peripheral disease, is fatigue and the consequent fracture in vivo. Indeed, their failure might be responsible for severe drawbacks, among which is the re-occlusion of the treated artery. Although many phenomenological approaches have been proposed to study this topic, the current literature lacks extensive knowledge on the Ni-Ti local damage mechanisms produced by the cyclic loads that promote crack nucleation and lead to the failure of thin struts, such as those of stents. Moreover, due to the super-elastic property of the alloy, the standard approach for interpreting the fracture of metals might be not accurate for this case. This work aims at increasing awareness of fatigue failure in superelastic Ni-Ti thin struts, such as those of stents. To do so, multi-wire specimens, sharing the same dimensions and thermo-mechanical treatment of the stent struts, were fatigue tested under different strain levels and the number of cycles to failure was recorded for each sample. Numerical simulations corroborated the experimental results to gain information on the local stress and strain fields during the fatigue cycles. A fracture mechanics-based fatigue model adopting the cyclic J-integral was here proposed, giving promising results for the interpretation of such failures

Investigating the role of organizational stress in nurses' psychosomatic complaints: Evidence from a study in northeastern Italy

Nursing is a profession known for its indispensable role in healthcare, yet it comes with multifaceted challenges, including high levels of organizational stress. This study aims to investigate the associations between exposure to organizational stressors, measured by the Health and Safety Executive Management Standards Indicator Tool, and psychosomatic complaints among nurses in a medium-sized city hospital in northeastern Italy. A total of 215 nurses participated in the study, completing self-report questionnaires assessing organizational stressors and the prevalence of psychosomatic complaints over the last six months. Results revealed significant associations between various organizational stressors and psychosomatic complaints, with the Relationships factor emerging as a significant predictor of palpitations, irritability, anxiety, physical and mental tiredness, and headache. Additionally, Demands and Managers' support were identified as significant predictors of specific psychosomatic complaints. Strengths of the study include the use of a well-established measurement tool and a comprehensive assessment of psychosomatic complaints. However, limitations such as the cross-sectional design and self-report measures need consideration. These findings underscore the critical role of addressing organizational stressors, particularly those related to interpersonal relationships, in promoting nurse well-being and optimizing patient care delivery. By prioritizing supportive work environments and implementing targeted interventions, healthcare organizations can foster a culture of well-being among nurses, ultimately enhancing the quality and safety of healthcare delivery

Predictive value of pretransplantation molecular minimal residual disease assessment by WT1 gene expression in FLT3-positive acute myeloid leukemia

The FMS-like tyrosine kinase 3 (FLT3) mutation in acute myeloid leukemia (AML) is a negative prognostic factor and, in these cases, allogeneic stem cell transplantation (allo-SCT) can represent an important therapeutic option, especially if performed in complete remission (CR). However, it is increasingly clear that not all cytological CRs (cCRs) are the same and that minimal residual disease (MRD) before allo-SCT could have an impact on AML outcome. Unfortunately, FLT3, due its instability of expression, is still not considered a good molecular MRD marker. We analyzed the outcome of allo-SCT in a population of FLT3-positive AML patients according to molecular MRD at the pretransplantation workup, assessed by the quantitative expression evaluation of the panleukemic marker Wilms\u2019 tumor (WT1) gene. Sixty-two consecutive AML FLT3-positive patients received allo-SCT between 2005 and 2016 in our center. The median age at transplantation was 55 years. The quantitative analysis of the WT1 gene expression (bone marrow samples) was available in 54 out of 62 (87%) cases, both at diagnosis (100% overexpressing WT1 with a mean of 9747 \ub1 8064 copies) and before allo-SCT (33 WT1-negative and 21 WT1-positive cases at the pretransplantation workup). Of these cases, 33/54 (61%) were both in cCR and molecular remission (WT1-negative) at the time of transplantation, 13/54 (24%) were in cCR but not in molecular remission (WT1-positive), and 8/54 (15%) showed a cytological evidence of disease (relapsed or refractory). Both post-allo-SCT overall survival (OS) and disease-free survival (DFS) were significantly better in patients who were WT1-negative (WT1 250 copies), with a median OS and DFS not reached in the WT1-negative group and 10.2 and 5.5 months, respectively, in the WT1-positive group (OS log\u2013rank p = 0.0005; hazard ratio [HR] = 3.7, 95% confidence interval [95% CI] = 1.5\u20139; DFS log\u2013rank p = 0.0001; HR = 4.38, 95% CI = 1.9\u201310). Patients with cCR who were WT1-positive had the same negative outcome as those with a cytological evidence of disease. The relapse rate after allo-SCT was 9% (3/33) in pre-allo-SCT WT1-negative cases and 54% (7/13) in WT1-positive cases (p = 0.002). At multivariate analysis, WT1 negativity before allo-SCT and grade <2 acute graft versus host disease were the only independent prognostic factors for improved OS and DFS. These data show that pre-allo-SCT molecular MRD evaluation through WT1 expression is a powerful predictor of posttransplantation outcomes (OS, DFS, relapse rate). Patients with both cCR and a WT1-negative marker before allo-SCT have a very good outcome with very low relapse rate; conversely, patients with positive molecular MRD and refractory/relapsed patients have a negative outcome. The WT1 MRD stratification in FLT3-positive AML is a valuable tool with which to identify patients who are at high risk of relapse and that could be considered from post-allo-SCT prophylaxis with FLT3 inhibitors or other strategies (donor lymphocyte infusion, tapering of immunosuppression, azacitidine). \ua9 2017 ISEH - International Society for Experimental Hematolog

Minimal residual disease after transplantation or lenalidomide-based consolidation in myeloma patients: a prospective analysis

We analyzed 50 patients who achieved at least a very good partial response in the RV-MM-EMN-441 study. Patients received consolidation with autologous stem-cell transplantation (ASCT) or cyclophosphamide-lenalidomide-dexamethasone (CRD), followed by Lenalidomide-based maintenance. We assessed minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. By MFC analysis, 19/50 patients achieved complete response (CR) after consolidation, and 7 additional patients during maintenance. A molecular marker was identified in 25/50 patients, 4/25 achieved molecular-CR after consolidation, and 3 additional patients during maintenance. A lower MRD value by MFC was found in ASCT patients compared with CRD patients (p = 0.0134). Tumor burden reduction was different in patients with high-risk vs standard-risk cytogenetics (3.4 vs 5.2, ln-MFC; 3 vs 6 ln-PCR, respectively) and in patients who relapsed vs those who did not (4 vs 5, ln-MFC; 4.4 vs 7.8 ln-PCR). MRD progression anticipated clinical relapse by a median of 9 months while biochemical relapse by a median of 4 months. MRD allows the identification of a low-risk group, independently of response, and a better characterization of the activity of treatments

The role of positron emission tomography with 18F-fluorodeoxyglucose integrated with computed tomography in the evaluation of patients with multiple myeloma undergoing allogeneic stem cell transplantation

Positron emission tomography (PET) integrated with computed tomography (PET/CT) has been reported to be useful for screening myelomatous lesions at diagnosis in patients with multiple myeloma (MM) and for monitoring response to autologous stem cell transplantation (auto-SCT). The aim of the study was to evaluate the prognostic significance of PET/CT in MM patients who received allogeneic stem cell transplantation (allo-SCT). Patients who underwent upfront auto-SCT followed by allo-SCT, either as consolidation or salvage treatment, were studied with PET/CT before and/or within 6 months after allo-SCT. The number, the maximum standard uptake value (SUV), and the location (medullary or extramedullary) of focal lesions (FLs) were recorded and investigated as predictors of progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analyses. Fifty-four patients had a PET/CT scan before allo-SCT. Of these, 22 patients (41%) had a negative PET/CT scan, 11 patients (20%) showed 1 to 3 FLs, and 21 patients (39%) had either a diffuse bone marrow involvement or more than 3 FLs. SUV was >4.2 in 21 patients (39%) and extramedullary disease (EMD) was present in 6 patients (11%). Multivariate analysis of prognostic factors before allo-SCT showed that persistence of EMD at transplantation was an independent predictor of poor PFS, whereas OS was negatively influenced by unrelated donor and SUV > 4.2. Fifty-nine patients had a PET/CT scan within 6 months after allo-SCT. Multivariate analysis of post-treatment variables showed that persistence of EMD and failure to obtain complete response or very good partial response after allo-SCT were strongly associated with shorter PFS and OS. Of the 46 patients with evaluable PET/CT scans both before and 6 months after allo-SCT, the 23 patients who maintained or reached a PET complete remission showed a significantly prolonged PFS and OS compared with the 23 patients with persistence of any PET positivity (2-year PFS: 51% versus 25%, P = .03; 2-year OS: 81% versus 47%, P = .001). This study indicates that PET/CT imaging before and after allo-SCT is significantly associated with the outcome, suggesting the utility of this technique for MM staging before allo-SCT and for response monitoring after the transplantation

Phase II Trial of Allogeneic Transplantation Plus Novel Drugs in Multiple Myeloma: Effect of Intensifying Reduced-Intensity Conditioning with Bortezomib and Adding Maintenance Treatment

The use of reduced-intensity conditioning (RIC) regimens has decreased the risk of nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). In contrast, disease relapse remains the most frequent cause of treatment failure and death. Owing to both their antimyeloma effect and immunomodulatory properties, novel drugs could improve outcomes after alloSCT. This phase II European Myeloma Network trial was designed to evaluate the combination of alloSCT with novel agents. The study was conducted to evaluate the toxicity and efficacy of RIC intensified with bortezomib (Bz) prior to alloSCT for high-risk (HR) multiple myeloma (MM) patients, as well as the efficacy of post-transplantation maintenance with Bz and lenalidomide (Len). Patients received RIC with Bz on days -9 and -2, fludarabine on days -6 to -4, and melphalan on day -3. Patients who were in complete response (CR) or near CR at day +100 post-transplantation received 6 cycles of Bz every 56 days, and the remaining received Bz, Len, and dexamethasone. Len maintenance was started on day +180 at a dose of 5 mg and continued until relapse or toxicity occurred. Of the 24 patients included, 21 were evaluable on day +100, including 12 in CR, 4 in very good partial response, 3 in partial response, and 2 with relapse or progression. The cumulative incidence (CuI) of relapse was 13.6% (95% confidence interval [CI], 3.2% to 31.3%) at 1 year and 28.5% (95% CI, 11.1% to 48.9%) at 2 years. The CuI of NRM was 21.1% (95% CI, 7.4% to 39.4%) at 2 years. With a median follow-up of 39 months (range, 1 to 67 months), the median event-free survival (EFS) was 29 months, and median overall survival (OS) was not reached. EFS and OS at 3 years were 42.5% (95% CI, 21.9% to 61.7%) and 74.01% (95% CI, 50.9% to 87.5%), respectively. The use of Bz within an RIC regimen allows for a high response rate after alloSCT. Maintenance with Bz and Len is feasible and provides remarkable results in terms of EFS and OS in HR MM patients