ALBERT

Description: In March–April 2020, the Corona Virus Disease 19 (COVID-19) pandemic suddenly hit Italian healthcare facilities and in some of them many staff members became infected. In this work 595 health care workers from a public company were tested for Severe acute respiratory syndrome coronavirus 2 (82 positive) and asked to complete a questionnaire on early COVID-19 symptoms. Respiratory symptoms were present in 56.1% of cases. Anosmia and dysgeusia in COVID-19 cases were found to have an odds ratio (OR) = 100.7 (95% Confidence Interval [CI] = 26.5–382.6) and an OR = 51.8 (95%CI 16.6–161.9), respectively. About one in three of the cases (29.3%) never manifested symptoms. Anxiety was reported by 16.6% of COVID-19 cases and depression by 20.3%, with a significant increase in the estimated risk (OR = 4.3; 95%CI = 2.4–7.4 for anxiety, OR = 3.5; 95%CI = 2.0–6.0 for depression). In cases, sleep was a significant moderating factor in the relationship between occupational stress, or organizational justice, and anxiety. The early diagnosis of COVID-19 in health care workers, must consider, in addition to respiratory disorders and fever, anosmia, dysgeusia, exhaustion, myalgias and enteric disorders. The frequency of anxiety and depression disorders in the population examined was not higher than that commonly recorded in the same company during periodic checks in the years preceding the epidemic. In COVID-19 cases there was a significant risk of anxiety, especially in those who had low sleep quality. Mental health support and improvement interventions must mainly concern workers with positive tests and should also tend to improve sleep quality.

Description: The failure of peripheral blood stem cell (PBSC) mobilization and harvest is a critical issue for multiple myeloma (MM) patients undergoing high-dose chemotherapy. Plerixafor (PLX) is an effective mobilizing agent; however, its use for every MM patient undergoing high-dose chemotherapy has led to a notable increase in costs. We designed a highly specific and sensitive algorithm for identifying patients likely to fail PBSC mobilization after chemotherapy and G-CSF (Blood Transfusion 2013.11:94). The use of this algorithm thereby allows selective administration of PLX to patients predicted to fail mobilization after chemotherapy and G-CSF (on-demand PLX) and may reduce failure rate of PBSC mobilization while limiting cost. We performed a multicenter phase II prospective study of on-demand PLX used according to our algorithm for patients with lymphoma or MM, who were mobilized by cyclophosphamide and G-CSF. The study was powered to demonstrate a reduction in mobilization failure from 14% to 7% for the entire population of treated patients. Here, we report the final results for MM patients. The inclusion criteria for MM patients were as follows: diagnosis of symptomatic MM, age 18-70 yr, achievement of any response after first-line treatment administered for 4-8 months, first mobilization attempt, cardiac and pulmonary function adequate for high-dose chemotherapy. Mobilization schedule was cyclophosphamide (CTX, 4 g/m2) and G-CSF (5-10 mcg/Kg), PLX (240 mcg/Kg) was administered only to patients selected by the algorithm. Estimation of costs was performed according to a previously reported study (BJH 2014, 164, 113). There were 111 patients with MM who underwent treatment. Successful CD34+ cell mobilization (〉20×109 cells/mL in PB) was achieved for 97.2% (108/111) of patients, and failure of mobilization occurred in the remaining 3 (2.8%); minimal apheretic harvest success (〉2.0×106 CD34+ cells/Kg) was achieved for 97.2% (108/111); and optimal harvest success (=/〉4.0×106 CD34+ cells/Kg) was achieved for 84.6% (94/111). On-demand PLX was needed for 8.2% of patients (9/111). After autologous hematopoietic transplantation, neutrophil (N) engraftment (N〉0.5x109 cells/L) was reached at day +11.8 (range day +8 to +24). We compared these prospective results with the mobilization results obtained retrospectively in a control group of 183 MM patients who received the same mobilization schedule without PLX. After the two groups were adjusted for unbalanced factors, multivariable logistic regression analysis revealed that on-demand PLX treatment according to the algorithm led to significant increases in the probabilities of achieving a successful minimal apheretic harvest (p=0.006; hazard ratio [HR] 5.624, 95% confidence interval [CI] 1.168-19.548) and optimal harvest (p=0.02; HR 2.121, 95% CI 1.118-4.025). The mean cost increase for the first mobilization in the PLX-on-demand prospective study, in respect to control group, was 615 €/patient. The incremental cost-effectiveness ratio (ICER) was calculated as: (cost1-cost2)/(result1-result2). ICER was 47 €/1% increase in probability of a minimal apheretic harvest while it was 68 €/1% increase in probability of an optimal apheretic harvest. In conclusion, the final analysis of our study found that on-demand PLX for MM patients, which was added to the mobilization schedule of CTX (4 g/m2) + G-CSF (5-10 mcg/Kg), allowed a successful harvest from the first mobilization treatment in 〉 97% of patients, with 85% of patients achieving a harvest sufficient for two rounds of high-dose chemotherapy. These results indicate that on-demand PLX added to mobilization chemotherapy is a significant improvement over the same type of mobilization chemotherapy without PLX. The limited use of PLX in this study allowed for a favorable incremental cost-effectiveness ratio of this expensive agent. On-demand PLX used according to a validated algorithm in addition to CTX plus G-CSF may be considered a new standard for PBSC mobilization and harvest in patients with MM. Table 1.Failure of CD34+ Mobilization in PB Failure of Minimal Harvest Failure of Optimal Harvest Cost per PatientICER (Minimal Harvest)ICER (Optimal Harvest)PLX on Demand (n 111)2.8%2.8%15.4%3,969 €47 €/ 1% increase in probability of a Minimal Harvest68 €/ 1% increase in probability of an Optimal HarvestControl Cohort (n 183)7.6%15.8%24.4%3,354 €P (adjusted for comparisons)NS0.0060.02 Disclosures Milone: Sanofi: Consultancy. Martino:Sanofi: Consultancy. Olivieri:Sanofi: Consultancy.

Description: Background: Over the last two decades several phenotypic, molecular, and chromosomal markers have been identified that are significantly associated with the prognosis of CLL patients. Therefore, clinicians managing CLL patients would benefit from a simplified prognostic index. Methods: We analyzed prospectively collected data from 337 Binet A CLL patients enrolled in Italian the O-CLL1-GISL protocol with the aim of developing scores capable of predicting treatment free survival (TFS). Factors independently associated with TFS were included in the prognostic indexes. To account for differences in the magnitude of the association between the individual independent factors and TFS, we assigned a weighted risk score to each factor based on ranges of their corresponding hazard ratios (HRs) (i.e., 1 point for HR 1.1-1.9; 2 points for HR 2.0-2.9, etc.). The total risk score was then calculated by the sum of the ratings of each factor on individual basis. Risk groups were identified combining risk categories with a non-statistically different TFS. Results: We developed two scores based on weighted multivariable models: the first included clinical and laboratory parameters [clinical score (c-score)], while the second was based on biological markers [biological score (b-score)] (Table 1). The c-score allowed to predict the TFS of patients through the combination of Rai stage, b2-microglobulin and absolute lymphocyte count (ALC), while the b-score predicted TFS by IGHV mutational status and CD38 expression. The c-score showed a C-statistic of 0.72, while the b-score was 0.67, although cases stratified according to the b-score showed a more specific mRNA/microRNA profile. When the two scores were forced in a multivariate analysis, both showed an independent predictive value on TFS with a similar HR, demonstrating their complementarity. Thus, we attempted to integrate the two scores performing a further multivariate analysis in which all parameters, significantly associated with TFS at univariate analysis, were tested (Table 1). ALC, Rai stage, b2-microglobulin together with IGHV mutational status, resulted independently associated with TFS. We constructed a weighted score [comprehensive score (co-score)], including all the above 4 variables, which allowed the identification of 3 different risk groups with significantly different TFS (Figure 1). The C-statistic of the g-score was 0.75, showing a better concordance than the other two scores. Moreover, its validity was externally validated in a series of 297 newly diagnosed Binet A CLL patients from the Mayo Clinic, USA. Conclusions: Using this multistep process and external validation, we developed a score with high discriminatory power and predictive significance on the individual patient level. Table 1. Univariate and multivariate Cox proportional Hazards Models Variable Univariate analysis Multivariate analysis Clinical model Biological model Comprehensive model HR (95% CI) P HR (95% CI) P score HR (95% CI) P score HR (95% CI) P score Age (years) 60 1.12 (0.73-1.74) 0.59 - - - - - - - - - Sex Male/Female 0.93 (0.6-1.44) 0.93 - - - - - - - - - Rai stage 0/I-II 2.30 (1.47-3.50)

Description: INTRODUCTION: Aim of our study was to determine the role of acute-GVHD in influencing early marrow function and whether assessment of “GVHD-associated marrow impairment” may predict transplant outcome. METHODS: We have prospectively studied 62 patients who received T-replete allogeneic stem cell transplantation because of various malignancies. At day +18/+19, we determined in bone marrow: CD34+ cells, frequency of clonogenic cell (CFU-GM and BFU-E) and, in 20 patients, also CD34+ cells showing apoptosis (AnnexinV/7-AAD). Results were related to acute-GVHD and to clinical outcome in terms of Treatment Related Mortality (TRM), Relapse Rate (RR) and Overall Survival (OS). To distinguish the effect of a-GVHD from that determined by corticosteroid, patients were divided in three groups according to time of presentation of a-GVHD: “Early a-GVHD, “No a-GVHD” and “Impending a-GVHD”. The latter group consisted of patients presenting a-GVHD after engraftment. RESULTS: In univariate analysis “Febrile neutropenia” and” Acute GVHD” were important factors for a reduction of frequency of marrow clonogenic cells assessed on day +18/+19. However, in multivariate analysis only “Acute GVHD” was able to influence frequency of marrow CFU-GM and BFU-E at day +18/+19. Patients not developing “a-GVHD” until day +90, had on day+18 a median growth of CFU-GM of 202/10e5 plated cells while patients suffering “early GVHD” had a marrow CFU-GM growth significantly reduced: 82/10e5 plated cells, (p= 0.0009). Median CFU-GM was found significantly reduced also in patients defined as “impending GVHD” (onset of a-GVHD at day +20-/+90) (p=0.01). Apoptotic CD34+ cells in marrow cells at day +18/+19 were inversely correlated to frequency of marrow BFU-E (r= -0.5, p=0.04). Taking into account competing risks, Cumulative Incidence of TRM at 2 y in the group of patients having a frequency of marrow CFU-GM over median was 5% while it was 30% in the group having CFU-GM below the median (log-rank: p=0.004). Cumulative incidence of Relapse was not significantly different in these two groups (31% versus 34%). OS was significantly better in group having CFU-GM over median: 62% versus 35% (logrank: p=0.02). Frequency of CFU-GM over median at day +18/+19 was a factor important for a reduced risk of death (HR=0.358; p=0.004) also after adjusting, using multivariate Cox analysis, for Disease Status (Early versus Advanced). CONCLUSIONS: acute-GVHD impairs early and significantly marrow function, marrow-GVHD is a sensitive biomarker for prediction of TRM and OS. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Elotuzumab (Elo), an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), received marketing approval in Italy for relapsed or refractory multiple myeloma (RRMM), in combination with lenalidomide (R) and dexamethasone (d) (EloRd) in April 2017. Here we report preliminary data of an Italian real-life experience on EloRd as salvage therapy for RRMM patients treated outside of controlled clinical trials. The primary objectives of this study were to assess the toxicity profile and the efficacy of EloRd administered as salvage therapy in a real-world setting. Methods Retrospective data collection received approval from local ethic committee. The cohort included 180 RRMM patients from 28 Italian centers who received at least one cycle of EloRd as salvage treatment between April 2017 and June 2018. Patients were treated with EloRD according to marketing approval as follows: Elo 10 mg/kg i.v. on days 1, 8, 15, and 22 during the first two cycles and then on days 1 and 15 of each following cycle, R 25 mg on days 1 to 21 of each cycle and d at a dose of 40 mg during the week without Elo, and 36 mg on the day of Elo administration. Responsive patients had to reach at least a partial remission (PR). Results Baseline characteristics are shown in Table 1. Median age of the 180 patients was 72 years (range 48-89 years); 53.9% were males (Table 1). The median number of previous therapy regimens was 1 (range 1-7); 69 patients (38.3%) received a previous autologous stem cell transplantation (ASCT). One hundred and ten patients (61.1%) showed a symptomatic relapse, 36 (20%) a biochemical relapse, and 34 cases (18.9%) were refractory to the last therapy, including bortezomib in 12.8% of patients. Forty-four patients (24.4%) had creatinine clearance ≤60 mL/min. Among the 138 cases evaluable for International Scoring System (ISS), 54 (39.1%) had stage I, 56 (40.6%) stage II, and 28 (20.3%) stage III. At last data collection (June 2018), 164 cases were evaluable for response. The median number of courses administered so far was 5 (range 1-18). The overall response rate (ORR) was 78%, with 9 complete remissions (CRs) (5.5%) and 49 very good partial remissions (VGPRs) (35.4%). A significant higher ORR was observed in patients who had received only 1 previous line of therapy than those who had received 〉1 line (64% vs 37.5%; p=0.004). Age (

Description: Novel therapies targeting BTK (ibrutinib), PI3Kδ (idelalisib) and BCL2 (venetoclax) are active in poor-risk chronic lymphocytic leukemia (CLL) and are widely administered to patients with relapsed/refractory (R/R)-CLL. Given the activity of ibrutinib in high-risk CLL patients, including those with del17p/TP53 mutation or germline IGHV genes, we assumed that this drug could diminish the prognostic utility of the CLL-IPI, because the outcome of patients with high- and very high-risk CLL-IPI scores may improve. Recently, Soumerai et al (Lancet Hematology, 2019) proposed a new risk score for overall survival (OS) based on four accessible markers, called BALL (β2-microglobulin, anemia, LDH, last therapy), in the setting of R/R-CLL patients receiving chemo-immunotherapy or targeted therapies in clinical trials. This model segregates CLL patients into three groups with significantly different OS. This multicenter, observational retrospective study aimed at validating the proposed BALL score for R/R-CLL real-world patients treated with ibrutinib. The primary objectives were to determine whether: i) the BALL score is of prognostic value for ibrutinib R/R-CLL patients, ii) the BALL score is predictive of progression-free survival (PFS); and iii) the CLL-IPI retains its prognostic power also in R/R patients treated with ibrutinib. This study, from an institutional Italian multicenter working group on CLL ('Campus CLL'), included CLL patients collected from 18 Italian centers and 1 Israeli center, who received ibrutinib 420 mg/day outside of clinical trials as salvage therapy with available data for the calculation of the BALL and CLL-IPI scores at the time of the start of treatment. OS was estimated for all subgroups according to both scores. Additionally, risk-specific PFS was assessed. Kaplan-Meier curve, log-rank test and Cox regression analyses were performed. The prognostic accuracy of the predictive model was assessed by the Harrell's C-index. Overall, 541 CLL patients were included in this analysis. The majority of patients were Binet stages B and C (87.2%). The median age was 70.4 years (range 37 - 88) and 353 cases (65.2%) were male. The median number of previous therapies was 2 (range 1-9). The baseline patients' features are listed in Table 1. After a median follow-up of 1.8 years (range 1 month to 5.8 years), 101 patients had died and 206 experienced an event (death or progression). According to the BALL score, 372 patients (68.8%) were classified as low-risk, 132 (24.4%) as intermediate-risk and 37 (6.8%) as high-risk. Stratification of patients according to the BALL score predicted significant differences in terms of OS. Thus, low-risk patients had a 2-year OS probability of 89.2% (HR=1), intermediate-risk of 79.9% (HR=2.8, 95%CI 1.8-4.4, P

Description: The assessment of the vitamin K status and its effects on clinical outcomes in kidney transplantation (KT) patients has sparked interest, but it is still largely unfulfilled. In part, this is due to difficulties in laboratory measurements of vitamin K, especially K2 vitamers. Vitamin K status is currently best assessed by measuring undercarboxylated vitamin-K-dependent proteins. The relative contribution of vitamin K1 and K2 to the health status of the general population and CKD (chronic kidney disease) patients, including KT patients, is also poorly studied. Through a complete and first review of the existing literature, we summarize the current knowledge of vitamin K pathophysiology and its potential role in preventing KT complications and improving organ survival. A specific focus is placed on cardiovascular complications, bone fractures, and the relationship between vitamin K and cancer. Vitamin K deficiency could determine adverse outcomes, and KT patients should be better studied for vitamin K assessment and modalities of effective therapeutic approaches.

Description: BACKGROUND: Peripheral blood (PB) hematopoietic progenitor cells (HPC) mobilized with G-CSF are the first-choice source for allogeneic stem cell transplantation. We carried out a prospective study on healthy donors (HDs), to identify donor characteristics that could influence the effectiveness of mobilization. STUDY DESIGN AND METHODS: PB-HPC allogeneic donations from sibling HDs were analyzed. We tested somatic variables (sex, age, weight, height, volemia) and blood counts (WBC, platelets, hemoglobin, CD34+ cell count). Two different determinations of CD34+ cells were done in each HD: baseline (before G-CSF administration) and in PB on the morning of the fifth day (after G-CSF administration). HDs received G-CSF subcutaneously at a dose of 10 µg/kg per day. RESULTS: 128 consecutive HDs (66 males) with a median age of 43 years were enrolled. The mean value of CD34+ on day 5 was 90.8 cells/µL, 84.2 cells/µL in females and 97.2 cells/µL in males. The median values of CD34+ on day 5 were 75.5 cells/µL for the overall sample, 74 cells/µL in females and 80 cells/µL in males. On univariate correlation analysis, donor weight r=0.19, P