bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of the EORTC QLQ-C30 Summary Score in patients with hematological malignancies.
Authors: Cottone Francesco , Efficace Fabio , Sommer Kathrin , Caocci Giovanni , Fazi Paola , Vignetti Marco , Giesinger Johannes M. 
Published: March 2020

e18551 Background: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) is a widely used questionnaire, which assesses 15 patients’ self-reported health domains, including physical and emotional functioning and key cancer symptoms. As this poses analytical challenges such as multiple testing, a single QLQ-C30 summary score (SS) was recently validated in solid tumors. In this work, we investigated its validity in patients with hematological malignancies. Methods: According to the published scoring algorithm, the SS is the mean of 13 QLQ-C30 scale scores, a higher SS rating reflecting a better health status. We performed univariate linear regression analysis to investigate the ability of the SS to discriminate between patients groups differing on known characteristics, i.e. ECOG performance status (0-1 vs. 2-3), comorbidity (yes vs. no), red blood cells transfusion dependency (TD, yes vs. no, MDS patients only), age (≤ 60 vs. > 60 years) and sex. We used linear mixed models to assess responsiveness of the SS to change, comparing baseline versus post-induction scores. For all analyses, we compared the SS performances to those of each original QLQ-C30 scale by Cohen's effect size (ES). Results: Analyses were based on pooled data from 2,134 patients diagnosed with myelodysplastic syndromes (MDS, n = 1,031), chronic myeloid leukemia (n = 382), acute myeloid (AML, n = 477) and promyelocytic leukemia (n = 244). Overall, 56.4% patients were male and the mean age was 51.5 years. Comparing groups by ECOG and comorbidity, SS outperformed 12 of the QLQ-C30 scales for ECOG (ES = 0.66) and 11 scales for comorbidity (ES = 0.17). With patients grouped by age (ES = 0.17) and sex (ES = 0.25), SS outperformed 13 and 12 scales respectively. For TD the SS (ES = 0.21) showed better discrimination than eight QLQ-C30 scales. When comparing baseline versus post-induction scores (AML patients), SS was more sensitive to change (ES = 0.41) than 10 of QLQ-C30 scales. Conclusions: Our findings provide support for the validity of the EORTC QLQ-C30 summary score as an endpoint in patients with hematological malignancies, when previous knowledge does not allow for domain-specific hypotheses.
Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: A systematic review and meta-analysis.
Authors: Molica Stefano , Giannarelli Diana , Montserrat Emili 
Published: March 2020

e19003 Background: Chronic lymphocytic leukemia (CLL) patients with undetectable minimal residual disease (U-MRD) (i.e., < 10-4) after upfront chemotherapy (CT) or chemo-immunotherapy (CIT) have better outcomes than those with detectable MRD (D-MRD). To validate the importance of achieving U-MRD and to assess the magnitude of improvement in progression free survival (PFS) and overall survival (OS) we conducted a systematic review and meta-analysis. Methods: The screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The search strategy yielded 365 records, including 22 articles assessed for eligibility. Results: Eleven studies comprising 2457 CLL patients treated upfront with CT or CIT were considered suitable for inclusion in the quantitative meta-analysis. Four studies (n = 924) analyzed the impact of U-MRD on both PFS and OS while 8 studies (n = 1984) provided data only on PFS and 6 (n = 1074) exclusively on OS. U-MRD status was associated with significantly longer PFS overall (P < .001) and in patients who achieved complete remission (CR) according to the International Workshop on CLL (IWCLL) guidelines (P = 0.01). Tests of heterogeneity revealed significant differences across studies evaluating PFS in both patients with U-MRD (Q = 49.27; P = 0.00; I2= 80%) and D-MRD (Q = 199.15; P = 0.00; I2= 95%). OS was also longer in patients with U-MRD overall (P < .001). Test of heterogeneity revealed no significant differences across studies evaluating OS in patients with U-MRD (Q = 9.16; P = 0.06; I2= 56%). Of note, U-MRD did not predict for a longer OS in patients who achieved IWCLL CR. (P = 0.82). This contrasts with data from single series and needs prospective assessment. Conclusions: This study validates the importance of achieving U-MRD in newly diagnosed patients with CLL treated with CT or CIT and provides quantitative evidence of the improvement regarding PFS and OS. MRD status should be incorporated as endpoint into prospective clinical trials and in the evaluation of new agents for CLL therapy as already accepted by the European Medicines Agency (EMA). The clinical significance of MRD in patients treated with BCR or BCL2 inhibitors is largely unknown and warrants study.
CAP-100: First-in-class antibody for CCR7+ hematological malignancies.
Authors: Cuesta Carlos , Munoz-Callega Cecilia , Loscertales Javier , Terron Fernando , Mol Wim 
Published: March 2020

e19008 Background: CCR7 is highly expressed in many hematological malignancies including CLL, several B-cell non-Hodgkin lymphomas (NHL), and various T-cell neoplasias with nodal involvement. Upon engagement by its ligands (CCL19 and CCL21), CCR7 controls trafficking of cells to locations where these chemokines are expressed, such as the lymph node (LN) and central nervous system. In these protective microenvironments CCR7 ligands contribute to tumor cell survival and proliferation. Indeed, both high CCR7 surface expression levels and high migratory responses to CCR7 ligands correlate with LN involvement, adverse prognostic factors, and shorter patient survival. Thus, strategies targeting CCR7 could provide a novel therapeutic approach for CCR7+ hematological malignancies. Methods: We have generated CAP-100, the first humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds to human CCR7 and neutralizes ligand-mediated signaling from both CCL19 and CCL21, and evaluated the antibody in various in-vitro and in-vivo preclinical models. Results: CAP-100 effectively inhibited in vitro migration of primary patient samples of CLL, B-cell NHLs and T-cell neoplasias such as T-PLL or T-ALL. Furthermore, in in vivo pre-clinical studies, CAP-100 was shown to inhibit entry of CCR7-expressing cells to LNs. CAP-100 also abrogated survival elicited by CCR7 in CLL, and showed potent cell killing activity against CLL or CCR7+ T-lymphomas cells. This Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) clearly outperformed anti-CD20 or anti-CD52 standard-of-care antibodies in B-NHL and T-lymphomas respectively. In all cases, ADCC and migration inhibition were both independent of prognostic markers for high risk disease. Finally, when given as monotherapy in disseminated B-NHL and CLL xenograft tumors in SCID mice, CAP-100 exhibited tumor growth inhibition and extended survival significantly. Conclusions: Our results demonstrate that CAP-100, the first-in-class anti-CCR7 mAb, is a potent antagonist with biological activity in several CCR7+ hematological malignancies, including relapsed/refractory disease. Moreover, these results highlight the relevance of the CCR7-CCL19/CCL21 pathway as a therapeutic target in these diseases. CAP-100’s unique propensity to block migration of tumor cells to the LN, in combination with its potent cell killing activity provides the biological rationale for use of CAP-100, either as monotherapy or in combination with novel agents. Clinical trials in CLL and CCR7-expressing NHL will be initiated soon.
Long-term time trends in incidence, survival and mortality of Hodgkin lymphoma in the United States: A surveillance, epidemiology, and end results (SEER) database study 1975-2015.
Authors: Asif Samia , Raza Shahzad 
Published: March 2020

e19014 Background: We examined epidemiological trends and patient characteristics such as age, gender, race, incidence and survival in Hodgkin Lymphoma (HL) using the updated largest population-based cancer registry in the US. Methods: Patients diagnosed with HL between 1975-2015 were identified in SEER registries. We incorporated SEER 9 registries to calculate incidence, race, disease characteristics and relative survival. Age-standard incidence rates (AI) were calculated using SEER 18 data and overall survival (OS) trends compared among different groups. Results: Rates for HL cases have been falling on average 1.8% per year and mortality rates (MR) have been falling on average 2.8% per year from 2006-2015. Males had higher incidence rates than females (3/100000 vs.2.3/100000). Bimodal distribution with prominent peaks at ages 20-24 and 75-79 years were noted among all groups except black (B) men. AI for women are higher at age of 20-24 years, but for men, higher at the later peak of 75-79 years. The AI for B men was highest at 50-54 years. The 10-year OS is 83.1% (Cl 82.3-83.9) in women with no significant difference between B, non-Hispanic white (NHW) or Asian Pacific Islander (API). In men, 10-year OS was 79.3% (Cl 78.4-80.1); lowest for B compared to NHW and API (72.6% vs. 80.0% vs.78.6). B patients had higher proportion of cases diagnosed with stage III/IV HL than NHW and API (48%. vs.40.6% and 39.9%, p < 0.001). Males and patients > 50 years were more frequently diagnosed with stage III/IV HL. The 10-year OS was only 40.8% for patients > 65 years (CI 38.2-43.5) in contrast to 86.8% for patients < 65 year (CI 86.3-87.4, p < 0.001). Interestingly, first year MR was 33.1% (CI 34.7-31.7) for patients > 65 years compared to 4.1% (CI 3.9-4.3) to those < 65 year. Conclusions: Epidemiological trends show improved OS in HL among all groups. B men, patients with advanced age and stage III/IV have poor outcomes. First year MR are exceptionally high in patients > 65years among all groups. Since B men have poor survival than B women, we postulate underlying disease biology may be a potential factor for worse outcome in this group.
Ability of routine blood tests (RBTs) in asymptomatic patients (pts) with indolent non-Hodgkin lymphoma (iNHL) to detect relapse or clinically significant disease progression.
Authors: Piercey Oliver , Loh Zoe , Chan Joanna , Chong Geoffrey , Grigg Andrew , Cheema Steven , Cushion Tania , Gill Gurjot , Whybird Matthew , Hawkes Eliza Anne 
Published: March 2020

e19027 Background: Pts with iNHL undergo active surveillance to detect disease relapse or progression. International guidelines recommend regular RBTs for surveillance but evidence for this practice is lacking. Methods: We conducted a retrospective analysis of pts aged ≥16 yrs from 2008-17 undergoing routine surveillance at 2 Australian centres for grade 1-3a follicular lymphoma (FL) or marginal zone lymphoma (MZL), to assess the utility of full blood count, lactate dehydrogenase & beta-2-microglobulin to detect progression events; (i.e relapse or progression) or to change management. Abnormal results were defined as acute deviations from local laboratory normal ranges not explained by a concurrent medical condition. Eligible pts were either treatment-naive or had achieved a response to lymphoma-directed therapy, had ≥6 mths follow up and an absence of progression events within 3 mths of prior therapy. Demographic data were collected as well as treatment, follow up appointment (appt) details including presence of signs/symptoms, RBT results, survival status & further therapy. The study was ethically approved. Results: 180 eligible pts (FL:142, MZL:38) underwent 1757 follow up appts (median follow up 38 months). RBTs were done at 83% of appts. 74 progression events occurred in a total of 62 pts; 48/74 (65%) had immediate therapy. 2/74 (3%) were detected by RBTs alone, (both treatment naïve pts); 88% by signs/symptoms & 9% by routine imaging. 20/243 (8%) of abnormal RBTs in asymptomatic pts led to a change in subsequent management (10 had imaging; 8 earlier appts; 2 repeat RBTs alone). The sensitivity & positive predictive value of abnormal RBTs to detect progression events were 39% & 9% respectively. In asymptomatic patients, the number of RBTs required to change management and to detect a progression event were 64 and 644 respectively. Conclusions: RBTs rarely detect clinically significant disease progression or relapse and seldom solely lead to a change in management in asymptomatic pts with iNHL. Clinical signs/symptoms are far more likely to detect progression or relapse. Guidelines should reflect the benefit & risk of RBTs in the clinical setting.
Dominant-negative PD1-armored CART cells induce remission in refractory diffuse large B-cell lymphoma (DLBCL) patients.
Authors: Chen Tong , Yuan Yan , Huang Liansheng , Pu Chengfei , Ding Tianling , Xiao Xibin , Cao Zhiyuan , Wu Ting , Ding Luying , Sun He , Wu Zhao , Xiao Lei , Zhang Xiaohong 
Published: March 2020

e19028 Background: The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to relapse/refractory B cell malignancy. However, tumor microenvironment influences and affects CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated Programmed cell death protein 1 (PD1) during T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy. Methods: We generated CAR T cells including an anti-CD19 second generation (2G) CAR molecule and a dominant negative PD1 molecule (Figure A). Compared with conventional CART cells, these “armored” CART cells show the enhanced capability of tumor killing after multiple-round tumor challenging and more “memory-like” phenotypes (Figure B). These results suggest dominant negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment. Results: We report clinical trials of three refractory diffuse large B cell lymphomas (DLBCLs) patients that were successfully treated using the armored CAR T cells described above. All of these three patients failed to achieve response after multiple rounds of chemotherapy and radiotherapy. However, after infused with autologous CART cells at 5.23×10^6/kg and 1.97×10^6/kg, respectively, they showed significant tumor mass decrease and SUV max declines in PET/CT results and ongoing responses (e.g., from 34.48 to 3.89 at day 27, from 25.02 to 2.38 at day 31, respectively, see Figure C). Conclusions: These three clinical trials revealed the significant anti-bulky lymphoma response with respect to these armored CAR T cells and limited and tolerated cytokine release syndrome and central nervous system toxicity. Also, dominant negative PD1 molecules may augment CAR T cells persistence in patients after activation by lymphoma cells, thus enhancing the efficacy of CAR T cells in the treatment of hematomas. Finally, the techniques described herein are a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to recruit more patients for the clinical trials. Clinical trial information: ChiCTR1900021295.
Time to first treatment is an independent prognostic factor for multiple myeloma (MM).
Authors: Goyal Gaurav , Tella Sri Harsha , Kommalapati Anuhya , Durani Urshila , Paludo Jonas , Go Ronald S. 
Published: March 2020

e19523 Background: Previous studies have shown a disparity in outcomes of MM between clinical trials and real-world practice. This could be partly due to clinical trial exclusion of patients who need urgent treatment due to high burden of disease or significant illness. In this study, we aim to analyze the impact of time to initiation of systemic therapy for MM on overall survival (OS). Methods: We included MM patients reported to National Cancer Data Base (2004-2014). We excluded 2,860 patients with suspected smoldering MM due to initial treatment beyond 120 days. Relative risk of delayed time to systemic therapy was assessed by logistic regression model. Kaplan-Meier method and Cox multivariate analysis were used to evaluate the association between time to therapy and OS. Results: A total of 53, 519 MM patients were included. Median time to systemic therapy in our cohort was 18 days (range 0-120). Of the entire cohort, 24% patients received systemic therapy for MM < 7 days from diagnosis, and 32% received it after 30 days. Factors associated with time to systemic therapy > 30 days were Black race (OR 1.12, CI 1.07-1.16), female sex (OR 1.10, CI 1.06-1.14), lower Charlson comorbidity score (OR 1.36, CI 1.28-1.45), and academic facility (OR 1.18, CI 1.13-1.24). The median OS for patients who initiated therapy > 30 days after diagnosis was longer than those who received it within 7 days (37 vs. 29 month, p < 0.001). Similarly, on multivariate analysis, patients who received treatment > 30 days after diagnosis were found to have a lower mortality as compared to those who initiated treatment < 7 days (HR 0.81, CI 0.79-0.83; Table). Conclusions: In our study, time to initiation of systemic therapy was an independent prognostic factor in MM. This could be related to the high-risk nature of disease of patients treated within a short duration of diagnosis. These findings have implications for future clinical trial design, which should allow for a pragmatic approach toward enrollment of these high-risk patients to improve external validity. [Table: see text]
Appendicular skeleton MRI in multiple myeloma: Utility and clinical implications.
Authors: Faraji Navid , Smith Daniel Arnold , Laukamp Kai , Parikh Keval , Kosmas Christos , Ramaiya Nikhil H. 
Published: March 2020

e19527 Background: Skeletal MRI plays an integral role in diagnosing Multiple Myeloma and, in many cases, dictates need for treatment. While axial skeleton MRI is performed with established clinical utility, appendicular MRI is performed sparingly with utility not fully ascertained. We aim to assess the utility of appendicular MRI while establishing clinical factors which may predict outcomes. Methods: 107 appendicular skeleton MRIs were included for retrospective analysis over 15 years. No statistically significant age or gender related variability was noted. Variables including patient age, diagnosis, disease stage/activity, indication, transplant status, MRI result, treatment course, and survival were analyzed via Likelihood Ratio Chi-Square test or logistic regression. Results: Patient age, disease stage, presence of active marrow disease, history of relapse, and presence of axial or appendicular osseous disease were found to have a statistically significant correlation with MRI result. Disease stage and presence of active hematologic disease correlated with post MRI management alterations. Additionally, presence of active hematologic disease at time of MRI demonstrated a correlation with post MRI management strategy. Furthermore, MRI result was a predictor of downstream development of additional skeletal lesions. Interestingly, MRI result was not a predictor of survival. Conclusions: Several parameters may be used to determine a clinical pre-test probability of appendicular disease at the time of MRI. In addition, these clinical parameters and MRI results correlate with trends in subsequent patient treatment strategies. [Table: see text]
Role of extra corporeal methods for light chain removal on renal recovery in multiple myeloma: A systematic review.
Authors: Hassan Hamza , Rafae Abdul , Iftikhar Nimra , furqan fateeha , Iftikhar Ahmad , Mushtaq Adeela , Ashraf Afia , Majeed Ammara , Kashinath Sanjana , Razzaq Faryal , Anwer Faiz 
Published: March 2020

e19530 Background: Renal impairment (RI) in Multiple Myeloma (MM) adversely affects the prognosis. Removing circulating free light chains via hemodialysis (HD) or plasma exchange (PLEX) along with chemotherapy can improve renal outcomes in MM. Methods: Per PRISMA guidelines a systematic search yielded 7311 articles since 2009 on 4 databases. After screening, 16 studies were included. Results: Main modalities were high cut off (HCO) HD, high flux (HF) HD, conventional HD and PLEX. N = 541 patients underwent HD/PLEX. 375/541 (69.3%) patients received HCO HD. In 2 RCTs, there was no significant difference in renal recovery (55.8% vs 51.6%; 41% vs 33%). The overall survival (OS) between the 2 groups was lower in the HCO group vs conventional HD (55.8% vs 76.6%) at 2 years while there was no significant difference in second study. Conclusions: HCO has failed to show promising efficacy with 2 RCTs failing to show statistical OS difference. There is paucity of data and further trials are needed. [Table: see text]
Impact of autologous stem cell transplant in myeloma patients on renal function and overall survival.
Authors: Abudayyeh Ala , Abdelrahim Maen , Lin Heather Y. , Saliba Rima , Martinez Charles , Delgado Ruby , Page Valda D , Sanders Paul W , Qazilbash Muzaffar H. 
Published: March 2020

e19535 Background: Renal impairment has been negatively associated with progression free survival and overall survival in patients diagnosed with multiple myeloma (MM). Autologous stem cell transplant (ASCT) has become a standard of care for treatment in MM. Most previous studies have assessed the safety of ASCT and the improvement in renal function in patients with MM. However, a critical question about renal function over time, and its impact on survival after ASCT has rarely been addressed. In our study we sought to understand how renal function was impacted over time, the predictors of renal function, and overall survival after ASCT. Methods: We performed a retrospective review of all MM patients who underwent ASCT at MDACC from January1, 2008 through December 31, 2013. A total of 885 none dialysis patients who received Melphalan alone as the conditioning regimen were identified. We collected demographic information, ISS stage, and disease status at time of transplant and at last follow up. Creatinine, GFR (calculated using CKD Epi equation), calcium, and LDH were also collected at day 0, 100, 180, & 365. Given the longitudinal nature of the data, linear mixed effect models were used to study the change of GFR over time. A joint model approach for longitudinal and survival data was used to assess association between overall survival and GFR with patient’s age at transplant, ISS, disease status, disease risk category and response to treatment prior to transplant included in the linear mixed effect models and hazard models. As sensitivity analyses, landmark analyses were conducted with day 0, 100, 180, and 365 days post-transplant as landmark time points. Results: Patients’ GFR at post-transplant time points were significantly higher (p ≤ 0.025) compared to the day of ASCT. A higher ISS stage at diagnosis was significantly associated with a lower GFR (p < .0001) at all stages of chronic kidney disease. Specifically, compared to the patients with ISS stage I, those with ISS stage II or higher had lower GFR across all time points (p ≤ .0003). GFR value was not significantly associated with OS in any of the analyses described above. In contrast, disease status, ISS stage, response to induction prior to SCT were all associated with shorter OS. Conclusions: The study demonstrates in a large cohort and in a longitudinal manner that MM patients who underwent ASCT did not have further decline in GFR over time. In addition, GFR was strongly associated with ISS stage. As far as OS, MM-related factors significantly impacted the survival while GFR did not.