ALBERT

Description: The Internet is changing the way that people learn about health and illness. At present do not exist data of the use of Internet by patients of lymphoma and her caregivers in Spain. OBJECTIVE: To investigate the distribution and patterns of Internet use by patients with lymphoma and her caregivers. PATIENTS AND METHODS: 585 subjects (258 patients, 264 relatives and 63 health professionals), 228 male and 357 female, they have responded a questionnaire on diverse aspects of the use of Internet. RESULTS: Two hundred fifty (42,7%) subjects use Internet, although only 27% make to obtain data on lymphoma. With respect to the group of patients 31% recognize to use Internet, but only the 23,3% do it by questions related to their disease. The main reasons for Internet use are to obtain information about treatments (74.7%) or second opinion medical (9.3%). The 77,6% have been using Internet for more than 3 years; the 47,2% have university studies and the 58,4% have between 33–50 years. Mainly the information search is made in Spanish language and through the Google finder. They consider that Information on lymphoma is acceptable (44.9%) or of enough quality (43.7%), trustworthy (50.6%) or of enough reliability (33.5%) and useful (45.6%) or quite useful (37.3%). COMMENTARIES: This study contributes data on the use of Internet by patients with lymphoma and her caregivers in Spain. Oncologists should be familiar with this important resource to help patients access appropriate material.

Description: Introduction:Renal impairment (RI) is a common complication of multiple myeloma (MM). Almost 20% of patients (pts) present with RI at diagnosis, while approximately 40%-50% of pts will develop RI during the course of their disease. However, there is little information on the renal response of pts with relapsed refractory MM (RRMM) receiving treatment with new drugs in clinical practice. Aims: This is an observational, prospective, multicenter study conducted in pts with RRMM and RI (defined as an estimated glomerular filtration rate [eGFR] 〈 50 mL/min) to evaluate renal response to the administered therapy in pts with moderate (creatinine clearance [CrCl] 30-50 mL/min) or severe (CrCl 〈 30 mL/min) RI. Secondary objectives include MM response rate, overall survival, safety, and health resource utilization. We present results from an interim analysis 4 mos after completion of the inclusion period (cutoff: June 13, 2016). Methods:Renal and MM responses were evaluated according to International Myeloma Working Group criteria. Both eGFR by the Cockroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas were compared to analyze renal response. Results:Overall, 312 pts (mean ± SD age 75 ± 9 yrs, 50% male, 57% in first relapse) were included in the study; 217 (70%) had moderate and 95 (30%) had severe RI, respectively. Anti-myeloma therapies administered were lenalidomide (LEN; 35% of pts), bortezomib (BORT; 21%), different chemotherapy regimens (CT; 22%), and other non-CT treatments (22%). Median follow-up was 7 mos (range, 0-39 mos). To date, 123 pts (39%) have discontinued treatment, 12% due to adverse events (AEs), and 37% have died. The main causes of death were disease progression (8.3%) and infections (6.4%). The mean baseline eGFR according to CG and MDRD formulas was 38.7/41.7 (± 8.5/11.8) mL/min in the moderate RI subgroup and 20.3/20.1 (± 8.0/10.1) mL/min in the severe RI group, with a strong correlation (coefficient 0.91) between the CG and MDRD eGFR. Overall, 13.5% (95% CI, 9.7%-17.2%) of patients had a renal response (5.8% renal complete response [renalCR], 0.3% renal partial response [renalPR], and 7.4% renal minor response [renalMR]) according to the CG formula while responses measured by the MDRD formula, were 17.3% (9.9% renalCR, 0.3% renalPR, and 7.1% renalMR). Median time to best renal response was 1.8 mos (range, 0.5-8.9 mos). After adjusting for demographic and clinical characteristics, there were no significant differences in GFR improvement between pts receiving LEN- and BORT-based treatments (P = 0.706). Arterial hypertension and female sex were statistically significantly associated with poor renal response. The overall MM efficacy response rate (≥ PR) was 33.4%, achieved after a median of 3.4 mos (range, 0.07-37.8 mos). For pts receiving BORT and LEN, respectively, the overall response rates were 43.5% and 44.8%, whereas only 23% of pts receiving CT achieved at least PR. Progression-free survival was 13.3 mos with LEN-based, 6.8 mos with BORT-based, and 7.5 mos with CT-based therapies (P = 0.006). Conclusions: Preliminary results of this study in pts with RRMM and RI show that LEN- and BORT-based therapies are the regimens most commonly used in clinical practice in these pts. Overall, these therapies can improve RI in approximately 13% of cases, with no differences seen in renal function improvement between LEN- and BORT-based treatments. Disclosures De La Rubia: Amgen, Bristol Myers, Celgene, Janssen: Consultancy. Morales:Celgene: Consultancy. García-Muñoz:Celgene, Roche: Consultancy. Duran:Celgene: Employment.

Description: Introduction: Rituximab plus CHOP every 3 weeks is associated with a increase in the survival of elderly patients. Dose intensification and dose compression with G-CSF support may provide an advantage compared with standard-dose CHOP. Purpose: To evaluate the efficacy and safety of Rituximab plus CHOP with increased dose of cyclophosphamide and shortened intervals between chemotherapy courses in newly-diagnosed patients with diffuse large-B-cell lymphoma. Therapeutic scheme: Rituximab 375 mg/m2 (d1), cyclophosphamide 1.500 mg/m2 (d1), vincristine 1.4 mg/m2 maximum 2 mg (d1), adriamycin 50 mg/m2 (d1) and prednisone were given. G-CSF (5–10 μg/kg) was added on days 3 to 11 in each course. Six to 8 courses were applied at 14-day intervals. Results: Between january 2002 and may 2005 twenty eight patients, from seven institutions, were included in this study and received 187 courses. Their median age was 48 years (19 to 59 years). The four last patients have not yet finished their treatment and were not evaluable for response. All patients exhibited alopecia and acceptable myelosupression. Thirteen episodes of fever were reported. Among 24 evaluable patients ORR was 83.3% (70.8% CR and 12.5% PR). With a median follow-up of 11 months (range 4–42) the OS and EFS at 30 months is 83% and 75%, respectively. Conclusions: The administration of Rituximab plus CHOP every 14 days with enhanced dose of cyclophosphamide is safe. The toxicity is mainly hematological, but can be surmounted with the use of G-CSF and EPO. Recruitment of more patients and longer follow-up are required to confirm these results.

Description: Unlike Jak1, Jak2, and Tyk2, Jak3 is the only member of the Jak family of secondary messengers that signals exclusively by binding the common gamma chain of interleukin receptors IL2, IL4, IL7, IL9, IL15, and IL21. Jak3-null mice display defective T and NK cell development, which results in a mild SCID phenotype. Still, functional Jak3 expression outside the hematopoietic system remains unreported. Our data show that Jak3 is expressed in endothelial cells across hematopoietic and non-hematopoietic organs, with heightened expression in the bone marrow and spleen. Increased arterial zonation in the bone marrow of Jak3-null mice further suggests that Jak3 is a marker of sinusoidal endothelium, which is confirmed by fluorescent microscopy staining and single-cell RNA-sequencing. We also show that the Jak3-null niche is deleterious for the maintenance of long-term repopulating hematopoietic stem and progenitor cells (LT-HSCs) and that Jak3-overexpressing endothelial cells have increased potential to expand LT-HSCs in vitro. In addition, we identify the soluble factors downstream of Jak3 that provide endothelial cells with this functional advantage and show their localization to the bone marrow sinusoids in vivo. Our work serves to identify a novel function for a non-promiscuous tyrosine kinase in the bone marrow vascular niche and further characterize the hematopoietic stem cell niche of sinusoidal endothelium. Disclosures No relevant conflicts of interest to declare.

Description: Background: There is a significant variation in disease incidence and outcomes among Multiple Myeloma (MM) patients (pts) from different ethnic backgrounds. Currently, there is a paucity of data regarding the influence of demographics and ethnicity on behavioral patterns of pts, their attitudes, beliefs, and knowledge about MM and its treatment, which could in turn affect outcomes. We conducted a questionnaire-based study to examine behavioral patterns of MM pts, especially focusing on ethnic minorities and how this may impact patient awareness and symptom complex related to the disease and its treatment. Methods: Apaper-basedquestionnaire consisting of 61 questions encompassing four broad categories was provided to participating pts at the University of Southern California Medical Centers. These included demographics, disease/treatment related quality of life (QoL), satisfaction regarding treatment, and satisfaction regarding treating physician/healthcare staff. Information on clinical characteristics and MM-related treatment was collected through an IRB-approved protocol. Pts were stratified by age, gender, and ethnicity (Hispanics vs. Non-Hispanics). Any missing patient responses were withdrawn from the final analysis of that question. Categorical and continuous variables were compared among groups using Chi-square and Kruskal-Wallis tests, respectively. All statistical analysis utilized SAS software (v9.3) with a two-sided significance level of 0.05. Results: A total of 89 pts (males: 40, females: 49) from March 2012 to October 2013 responded to the questionnaire of the 100 pts that were consented (81%). Median age was 59 (range: 23-81) years and 43 (48%) pts were Hispanic while 46 (52%) were Non-Hispanic. Baseline clinical characteristics are shown in Table 1A. As compared to Non-Hispanics, Hispanic pts were less likely to have completed college (70% vs. 30%, p

Description: Background A lack of objective data exists on differences in treatment practices and outcomes for MM between countries. The EMMOS study aimed to document and describe current treatment regimens and disease progression patterns of MM pts at different stages of the disease in real-world medical practice. Methods Adult pts initiating any new MM therapy, irrespective of treatment line at study entry or therapy type received, were eligible for inclusion in the EMMOS registry. A multi-staged pt/site recruitment model was applied to minimize selection bias; enrollment was stratified by country, region, and practice type. Pts' medical/disease features, treatment history, and remission status were recorded at baseline. Prospective data on treatment, efficacy, and safety were collected electronically every 3 mos until 2 yrs after the last pt enrolled. Responses were investigator-assessed (no predefined criteria). Here we report data from the final analysis of EMMOS. Pts were grouped according to receipt of high-dose chemotherapy/stem cell transplantation in any treatment line (SCT pts, non-SCT pts). Within a given line, pts may have received induction, SCT, consolidation, and/or maintenance therapy; if multiple drug combinations were used within a line, the line grouping was based on the combination received in cycle 1. Results 2358 pts were enrolled between Oct 2010-Oct 2012 in 22 countries in Europe and Africa; the last pt completed follow-up in Oct 2014. Of these, 775 pts had undergone SCT in any treatment line. Baseline characteristics in the prospective phase by starting line are shown in the Table. As expected, there was a higher proportion of younger pts (≤65 yrs) in the SCT vs non-SCT group across all treatment lines, and in both groups a higher proportion of pts in 4th + vs earlier lines with ISS stage III disease. While cytogenetics were evaluated in a small number of pts overall (670/2358 [28%]), these assessments were performed significantly more frequently in SCT vs non-SCT pts (p

Description: Autophagy maintains hematopoietic stem cell integrity and prevents malignant transformation. In addition to bulk degradation, selective autophagy serves as an intracellular quality control mechanism and requires autophagy receptors, such as p62 (SQSTM1), to specifically bridge the ubiquitinated cargos into autophagosomes. Here, we investigated the function of p62 in acute myeloid leukemia (AML) in vitro and in murine in vivo models of AML. Loss of p62 impaired expansion and colony-forming ability of leukemia cells and prolonged latency of leukemia development in mice. High p62 expression was associated with poor prognosis in human AML. Using quantitative mass spectrometry, we identified enrichment of mitochondrial proteins upon immunoprecipitation of p62. Loss of p62 significantly delayed removal of dysfunctional mitochondria, increased mitochondrial superoxide levels, and impaired mitochondrial respiration. Moreover, we demonstrated that the autophagy-dependent function of p62 is essential for cell growth and effective mitochondrial degradation by mitophagy. Our results highlight the prominent role of selective autophagy in leukemia progression, and specifically, the importance of mitophagy to maintain mitochondrial integrity.

Description: Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of a serum monoclonal protein 3.0 g/dl, who never had a skeletal survey in our system, had a light chain myeloma, plasmacytoma, chronic lymphocytic lymphoma(CLL), amyloidosis or protein evaluation done for diagnosis other than MGUS. We had 620 such patients. We collected data regarding their age, sex, ethnicity, date of diagnosis, type and level of the M-protein, hemoglobin level, serum calcium and creatinine at baseline, result of the MBS, date of progression to multiple myeloma (MM) if any and the date of last follow up if they did not progress to MM. Positive MBS is defined as x ray findings consistent with myelomatous changes with bone marrow aspiration confirming diagnosis of MM. Results: Of 620 patients, 36 had a positive MBS and applying non parametric Mann Whitney test and a chi-squared test, positive results seemed to correlate with higher level of M-protein, IgG subtype, lower hemoglobin and higher creatinine. Male sex and older age were other risk factors. Using the LOES curve to graph the risk of a positive skeletal event with the level of M-protein, risk was noted to increase significantly with M-protein in the range of 1.8– 3.0 (odds ratio 8.84 compared with 1.31 if level was less than 1.8), which was highly statistically significant as shown in figure 1. Further for 97/620 who progressed to multiple myeloma, the risk of progression was significantly higher for males, younger age at diagnosis of MGUS, lower hemoglobin, higher level of M-protein, IgG subtype and a positive skeletal event. Discussion: Our study is a retrospective chart review with its own limitations. However to our knowledge this is the first study to define the level of M-protein in patients with MGUS above which obtaining a MBS may be of value. Our study identifies 1.8 as a cut off value of M-protein below which doing routine MBS without symptoms of bone pains or other laboratory features suggesting progression to multiple myeloma might be unnecessary. Other risk factors for a positive event and progression to MM like lower hemoglobin, higher creatinine, older age, male sex and IgG subtype in our study are in keeping with what has been described in the literature. Conclusion: Based on our study, obtaining baseline MBS in all patients with suspected MGUS was not beneficial. Hence, we would not recommend obtaining MBS in patients with M-protein

Description: Patients with β-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P 〈 .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P 〈 .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P 〈 .001) and 371 ng/mL (n = 147; P 〈 .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with β-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.

Description: A variable degree of immune impairment is present in lymphomas, either as a cause or a consequence of the disease. There is preliminary evidence that this immune status is related to disease control and survival. Our objective was to analyze the relationship of the immune status with the main clinical prognostic variables in DLCL. Seventeen patients with DLCL de novo were prospectively included in the study, receiving an homogenous induction treatment based on CHOP-R regimen. Median age was 60 (29–74); ECOG PS 〉 1 in 65%; Ann-Arbor stage 〉 II in 53%; B-symptoms in 47%; more than one extranodal site in 47%; bulky mass present in 59%; high LDH in 65%; high beta-2-microglobulin in 56%. Levels of B, T and NK subpopulations were assessed at diagnosis by flow cytometry, including general populations as well as cytotoxicity, costimulation and adhesion phenomena. This was compared with main clinical prognostic variables included in the adjusted-IPI (a-IPI) and MD. Anderson Tumor Score (TS) by U of Mann-Whitney non parametric test or Kaplan Meier survival analysis. Worst a-IPI patients (2–3 scores) (59%) showed significant lower levels of total lymphocytes as well as of the following populations: General T lymphoid markers (CD2 and CD3); expression of adhesion molecules (CD3+CD11a+, CD4+CD11a+ and CD8+CD11a+); expression of costimulatory molecules (CD4+CD28+ and CD8+CD28+); cytotoxicity in CD56+ cells (CD56+ Perforin+). Worst TS patients (3–4 scores) (59%) showed significant lower levels of the following populations: Activated or regulatory lymphoid subsets (CD3+CD25+); expression of costimulatory molecules (CD4+CD152+ and CD8+CD152+); cytotoxicity in CD56+ cells (CD56+ Perforin+). With a median follow-up of 16 months we observed a better overall survival and progression-free survival data in patients with levels above median of CD56+ and expression of perforin by T and NK cells. We conclude that worst prognostic groups of a-IPI and TS in DLCL are associated with a worst immune status, based on T and NK immune phenomena analysis. Perforin expression by NK and T CD56+ cells was associated with outcome in DLCL.