bluuebunny/crossref_metadata_2025_split huggingface dataset:
Off-the-shelf virus specific T-cells for therapy of adenovirus disease in immunosuppressed patients.
Authors: Rafei Hind , Imahashi Nobuhiko , Basar Rafet , Banerjee Pinaki Prosad , Daher May , Ganesh Christina , Hosing Chitra , Kaur Indreshpal , Kebriaei Partow , Khouri Issa F. , Mehta Rohtesh , Nieto Yago , Olson Amanda Leigh , Qazilbash Muzaffar H. , Spencer Bryan P , Srour Samer , Shpall Elizabeth J. , Champlin Richard E. , Marin David , Rezvani Katayoun 
Published: March 2020

7008 Background: Adenovirus infection can cause significant morbidity and mortality in immunosuppressed patients. Cidofovir is commonly used, but its nephrotoxicity is concerning and efficacy limited. Another approach is to restore the anti-adenovirus immunity. Indeed, virus specific T-cells have been shown to be safe and effective in stem cell transplant recipients. Methods: Immunosuppressed pts with either adenovirus viremia or adenovirus-related end organ damage were enrolled. Most closely HLA-matched adenovirus cytotoxic T lymphocytes (CTLs) were generated by expanding donor derived T-cells with a peptide library derived from the hexon protein of adenovirus serotype 3 in the presence of IL-2 20 IU/ml, IL7 10 ng/ml, IL4 10 ng/ml. After receiving 2x105 /kg T cells, pts were monitored for response and adverse events. Results: Eight pts received adenovirus CTLs with one infusion. The Table summarizes their characteristics and responses. Seven pts had complete resolution of their symptoms (CR) and adenovirus becoming undetectable (ND). Those pts are alive to date. The remaining patient initially responded but then lost the response when started on high dose prednisolone for treatment of GVHD to which she eventually succumbed. Best response was achieved after a median time of 13 days [10-36]. No cytokine release syndrome occurred and we did not observe any side effect attributable to the CTLs. Conclusions: The use of off-the-shelf adenovirus CTLs is a feasible, safe, and effective approach to treat severe adenovirus infections in immunosuppressed pts. Clinical trial information: NCT03425526. [Table: see text]
Treatment-free remission (TFR) following frontline (1L) nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 192-week data from the ENESTfreedom study.
Authors: Giles Francis J. , Masszi Tamas , Gómez Casares María Teresa , Hellmann Andrzej , Stentoft Jesper , Conneally Eibhlin , García Gutierrez Valentin , Gattermann Norbert , Le Coutre Phillipp D. , Martino Bruno , Saussele Susanne , Radich Jerald P. , Ross David M. , Saglio Giuseppe , Sondhi Manu , Acharyya Suddhasatta , Aimone Paola , Hochhaus Andreas 
Published: March 2020

7013 Background: In ENESTfreedom (NCT01784068), which evaluated TFR following 1L NIL in CML-CP pts, 51.6% remained in TFR 48 wks after stopping treatment (primary endpoint) and durability of TFR was demonstrated at 144 wks. Data from longer follow-up (192 wks) evaluating maintenance of TFR are reported. Methods: Pts with MR4.5 ( BCR-ABL1IS ≤0.0032%) and ≥2y of 1L NIL entered a 1y consolidation; pts with sustained deep molecular response (MR) were eligible for TFR. NIL was resumed after loss of major MR (MMR; BCR-ABL1IS ≤0.1%). At the latest data cut-off (Sep 17 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 190 pts entering TFR, 87 were ongoing, 91 had resumed NIL, and 12 had permanently discontinued. The TFR rate at 192 wks was 44.2% (84/190, 95% CI: 37.0–51.6%). Of 89 pts with successful TFR at 144 wks, 5 were not assessable for TFR at 192 wks as 2 had discontinued by 192 wks due to pt/physician decision, and 3 with MR4.5 previously did not have 192 wk PCR data. Of 91 pts who resumed NIL, 90 (98.9%) regained MMR and 84 (92.3%) regained MR4.5. 75/90 and 73/84 pts, respectively, had stable MMR and MR4.5 at 48 wks later. There were no cases of disease progression or new deaths. 10 deaths were reported in the 144-wk analysis, none due to CML. The 192-wk treatment-free survival rate was 48.7% (95% CI 41.4–55.6%). Of 89 pts remaining in TFR for > 144 wks (including 87 pts for > 192 wks), all-grade AE rates during consolidation and each subsequent 48 wk period of TFR were 84.3%, 77.5%, 70.8%, 48.3%, and 52.8%, respectively. All-grade musculoskeletal pain AE rates were 15.7%, 40.4%, 9.0%, 3.4% and 3.4%, respectively; cardiovascular event rates were low across these periods. Among pts who resumed NIL, most common AEs were nasopharyngitis (18.7%) and pruritus, fatigue, and increased lipase (14.3% each); the majority of AEs were grade 1/2. Conclusions: Results continue to support the long-term durability and safety of TFR at 192 wks after stopping 1L NIL; overall AE rates declined during the TFR phase and musculoskeletal pain AEs were transient. Pts should continue to be regularly monitored during TFR. Clinical trial information: NCT01784068.
Allogeneic hematopoietic stem cell transplantation contributes to eradication of minimal residual disease in adult Philadelphia chromosome-positive acute lymphoblastic leukemia patients treated with dasatinib.
Authors: Chang Jeremy , Akhtari Mojtaba 
Published: March 2020

7024 Background: Philadelphia Chromosome-Positive (Ph+) disease is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). Recent studies have shown that the eradication of minimal residual disease (MRD) in this population leads to improved survival outcomes. While hematopoietic stem cell transplantation (HSCT) has demonstrated clinical benefits in Ph+ ALL patients treated with the tyrosine kinase inhibitor (TKI) imatinib, its role is less clear with the use of more potent, newer-generation TKIs such as dasatinib. Methods: This was a retrospective study analyzing the impact of allogeneic HSCT on MRD status in Ph+ ALL patients treated with dasatinib. Patients were divided into 2 groups: those treated with chemotherapy plus dasatinib followed by allogeneic HSCT and those who received chemotherapy plus dasatinib alone. All patients underwent bone marrow biopsy with MRD analysis following induction therapy and subsequent re-evaluation of MRD status at day 100 post-transplant in the HSCT group and after further cycles of chemotherapy plus dasatinib in the non-transplant group. MRD-negative disease was defined as the absence of a BCR-ABL1 transcript by real-time quantitative polymerase chain reaction (qRT-PCR) with a sensitivity of 0.01%. Results: A total of 51 adult Ph+ ALL patients with MRD-positive disease following induction therapy were included. Twenty-seven patients (53%) were male and the median age at time of diagnosis was 42 years (range 23-68). There were 29 patients in the transplant group and 22 patients in the non-transplant group. When analyzing rates of MRD eradication, 18 (62%) patients in the transplant group were found to have MRD-negative disease at day 100 post-transplant compared to 7 (32%) patients in the non-transplant group who only received further cycles of chemotherapy plus dasatinib (risk ratio 0.56, 95% confidence interval 0.32-0.96, p = 0.048). Conclusions: In the era of newer-generation TKIs, allogeneic HSCT continues to have notable benefits in Ph+ ALL such as a significantly higher rate of MRD eradication as demonstrated in this study.
Mechanism of biologic therapy for pre B-cell acute lymphoblastic leukemia with CRLF2 overexpression.
Authors: Watson WayAnne , Stoian Cornelia , Coats Jacqueline S. , AlKashgari Hossam , Vidales Veriah , Baez Ineavely , Personius Juliette , Choi Hannah , Becerra Benjamin , Chavan Rishikesh , Kamal Muhammad Omair , Farzin Gohar Shadi , Payne Kimberly J 
Published: March 2020

7035 Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, of which pre B-cell ALL with CRLF2 overexpression is a high risk subtype. CRLF2 B-ALL is associated with poor outcome, increased rate of relapse, and health disparities in Hispanic children. Together with IL-7 receptor alpha (IL-7Rα), CRLF2 makes up a receptor complex that is activated by the cytokine, thymic stromal lymphopoetin (TSLP). Activation of the receptor complex leads to JAK2/STAT5 and PI3/AKT/mTOR signals that promote leukemia cell survival and proliferation. To study the role of TSLP in CRLF2 B-ALL, we developed a patient-derived xenograft (PDX) model of CRLF2 B-ALL that allows us to alter circulating levels of human TSLP (hTSLP). We generated PDX from CRLF2 B-ALL cells harvested from patient samples and compared leukemia burden in mice with varying levels of hTSLP. In PDX models with hTSLP levels at or below physiological levels in pediatric cancer patients, CRLF2 B-ALL cells grew robustly. However, in PDX with elevated levels of hTSLP, leukemia cells were essentially eliminated. Our objective is to elaborate on the mechanism of high dose hTSLP’s antileukemic effect. Methods: We performed TSLP dose response studies and used flow cytometry to evaluate the effect of TSLP on SOCS protein expression, CRLF2 signaling shutdown, and loss of TSLP receptor components. Results: CRLF2 B-ALL cells cultured with hTSLP showed a dose-dependent loss in the ability to induce STAT5 and S6 phosphorylation following hTSLP stimulation. This loss was correlated with the loss of IL-7Rα, and maintained for 24-48 hours following a pulse of high-dose, but not low-dose, hTSLP. The loss of signaling and surface IL-7Rα could be prolonged if high-dose hTSLP levels were maintained. Flow cytometry analysis showed that high-dose hTSLP upregulated SOCS1 and SOCS3 proteins in CRLF2 B-ALL cells. Whole genome microarray showed that SOCS1, SOCS2, SOCS3 and CISH mRNA were upregulated in primary CRLF2 B-ALL cells cultured with high dose hTSLP. Conclusions: These data support the hypothesis that TSLP exerts its anti-leukemia effects through shutdown of CRLF2-mediated signals and that these effects are at least partially mediated by the loss of the IL-7Rα component, and potentially through SOCS family proteins. These studies elucidate the mechanism of the human TSLP cytokine as a potential biologic therapy to treat CRLF2 B-ALL. Supported in part by 1R01CA209829 (KJP), 1R43CA224723 (KJP), ASH HONORS Award 2018-2019 (WBW), and Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship 2018-2019 (WBW).
First-in class selective AXL inhibitor bemcentinib (BGB324) in combination with LDAC or decitabine exerts anti-leukaemic activity in AML patients unfit for intensive chemotherapy: Phase II open-label study.
Authors: Loges Sonja , Heuser Michael , Chromik Jörg , Vigil Carlos Enrique , Paschka Peter , RE Francesca , Di Renzo Nicola , Lemoli Roberto , Mattei Daniele , Ben Batalla Isabel , Hellesøy Monica , Micklem David , Holt Robert J , Lorens Katherine , Lorens James B. , Shoaib Muhammad , Aly Hassan , Fiedler Walter M. , Cortes Jorge E. , Gjertsen Bjorn T. 
Published: March 2020

7043 Background: The RTK AXL represents a therapeutic target promoting AML cell proliferation and survival by pleiotropic mechanisms and is a negative regulator of anti-tumour immunity. Bemcentinib is a first-in-class, highly selective, oral AXL inhibitor that has previously shown encouraging anti-leukaemic activity as a monotherapy in r/r AML and hr-MDS. Methods: A monotherapy dose-escalation and expansion part of this trial is complete. In this second, phase II part of the study, 11 and 15 AML pts unfit for intensive chemotherapy received bemcentinib at RP2D (200 mg po/d) in combination with low-dose cytarabine (LDAC) and decitabine, respectively. Median age was 77 yr (range: 50-83), median screen myeloblast count 39% (3-95%) and 2/19 (11%) of pts evaluable for FLT3 were FLT3+. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at screen and following treatment. Results: The most common TRAEs (≥ 15% of pts) were ECG QT prolongation (35%) and diarrhoea (15%). Among these, 3 were Grade 3, and none 4 or 5. All TRAEs were manageable and/or reversible. As of Feb ‘19, 9 pts (2 de novo, 1 secondary, 6 r/r) in the bemcentinib + LDAC group were evaluable for response and 4 (44%; 2 de novo + 2 relapsed) achieved rapid CRi at C2D1. Responses were durable (range: 7 – 11 cycles) in 3 of the 4 responders. A further 2 pts (22%, 1 secondary + 1 relapsed) achieved durable SD (5 and 6 cycles). mPFS among the 5 pts with durable CRi or SD was 5 months (range: 3.5-7.7). Further, at the time of writing, 11 pts (8 de novo, 3 r/r) in the bemcentinib + decitabine group were evaluable for response of which 4 (36%, all de novo) achieved CRi after ≥ 4 cycles. One additional de novo pt achieved durable SD lasting for 5 cycles. Conclusions: Bemcentinib in combination with LDAC exerted early durable responses in patients with both de novo and relapsed AML whilst the combination of bemcentinib + decitabine exerted comparably fewer and later responses in de novo AML. Soluble biomarker correlations will be presented at the meeting. Both combinations were generally well-tolerated and further exploration is warranted. Clinical trial information: NCT02488408.
Late infectious complications in hematopoietic cell transplantation survivors.
Authors: Chow Eric Jessen , Cushing-Haugen Kara , Boeckh Michael , Carpenter Paul , Flowers Mary , Lee Stephanie , Leisenring Wendy M. , Mueller Beth , Hill Joshua A. , Foord Aimee 
Published: March 2020

7046 Background: Infections are a major complication of hematopoietic cell transplantation (HCT). Few studies have compared the incidence of late infections occurring ≥2y post-HCT to other cancer patients and the general population. Methods: Single center records of ≥2y HCT survivors who were Washington residents treated from 1992-2009 (n = 1,792; median age 46y; 53% allogeneic; 90% hematologic malignancies) were linked to the state’s hospital discharge and death registries. Individuals randomly selected from the state cancer registry (n = 5,455, non-HCT) and driver’s license files (n = 16,340, DOL) who survived ≥2y formed two comparison groups, matched on sex, age, year, and cancer diagnosis (non-HCT group only). Based on hospital and death registry codes, incidence rate ratios (IRR) with confidence intervals (CI) of infections by organism type and organ system were estimated using Poisson regression. Results: With 6y (range 2-20) median follow up, the incidence rate (per 1000 person-y) of all infections was 65 in HCT survivors vs. 40 in the non-HCT group (IRR 1.6, 95% CI 1.3-1.9). In contrast, the DOL group’s infection rate was 7 (HCT vs. DOL IRR 10.0, 95% CI 8.3-12.1). Specifically, bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRRs 1.7; p < 0.01). Differences in viral infection rates were more modest (IRR 1.4, p = 0.07). Infections attributed to staphylococcus, streptococcus, and non-Candida fungi including Aspergillus were twice as common in the HCT vs. non-HCT cancer survivors (IRRs 2.1-2.3; p < 0.05). IRRs for nervous system, respiratory, and musculoskeletal infections between these 2 groups were 1.9-2.8 (p < 0.05). Among potentially vaccine-preventable organisms, the IRR was 3.2 (95% CI 2.2-4.6). While the absolute incidences decreased with time, the relative risks in almost all categories were even greater when restricted to ≥5y HCT vs. non-HCT cancer survivors. Conclusions: ≥2y HCT survivors had a significantly increased incidence of infections vs. matched non-HCT cancer survivors. Providers caring for long-term HCT survivors should maintain high vigilance for infections in this population and ensure adherence to HCT antimicrobial prophylaxis and vaccination guidelines.
Role of killer cell immunoglobulin-like receptor (KIR)-ligand interactions to prevent relapse in patients (pts) receiving matched unrelated stem cell transplant (SCT) for acute myeloid leukemia (AML).
Authors: Rafei Hind , Fernández-Viña Marcelo , Carmazzi Yudith , Moore Brandt , Willis Dana , Basar Rafet , Banerjee Pinaki Prosad , Daher May , Hosing Chitra , Kebriaei Partow , Khouri Issa F. , Mehta Rohtesh , Nieto Yago , Qazilbash Muzaffar H. , Shpall Elizabeth J. , Champlin Richard E. , Marin David , Rezvani Katayoun , Cao Kai 
Published: March 2020

7049 Background: NK cells play a pivotal role in cancer immune vigilance. NK cell function is regulated by a balance between activating and inhibitory signals derived from various receptor-ligand interactions. Methods: 390 AML pts received 10/10 unrelated donor SCT. KIR genotype was performed by PCR with sequence specific primers. Hazard ratio (HR) for 2-year relapse was calculated using Fine-Gray regression and adjusted for disease risk index, remission status, pre-SCT MRD, conditioning regimen and presence of HLA-DP mismatch. KIR-ligand (K-L) match was defined as the presence a given KIR in the donor and the presence of its reported ligand in the patient (ex. 2DL1 and HLA-C2). KIRs that have no known ligands were not included in this analysis. The Table shows pt characteristics and K-L matches. Results: There was no correlation between the number of inhibitory or activating KIRs or KIR haplotype (A or B) and the probability of relapse after SCT. However, donor KIRs had a dramatic effect on relapse when they were considered together with the presence of the corresponding ligand in the pt. The 210 pts who had ≥3 inhibitory K-L matches had a significantly higher probability of relapse (HR=1.748, CI=1.147-2.667, p=0.009) than the remaining 180 pts. Similarly, the 96 pts who had at least one known activating K-L match had a lower probability of relapse (HR=0.581, CI=0.345-0.978, p=0.04). When we considered inhibitory and activating K-L matches together, we found that the 168 pts who had ≥3 inhibitory and no activating K-L matches had a significantly higher probability of relapse (HR 2.001, CI=1.376-2.908, p<0.001) than the 222 remaining pts. Conclusions: Donor-pt KIR-ligand matching should be taken into account when choosing unrelated donors for AML pts. [Table: see text]
Predictive accuracy of the low erythropoietin level for the diagnosis of polycythemia vera.
Authors: Lupak Oleksandra , Han Xiaoxia , Xie Peter , Mahmood Sharmeen , Mohammed Hadi , Donthireddy Vijayalakshmi 
Published: March 2020

7060 Background: A low erythropoietin (EPO) level is a minor diagnostic criterion for Polycythemia Vera (PV) based on the updated 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms. The diagnostic value of EPO has been debated due to the increasing availability of advanced molecular testing. We hypothesized that EPO level below the normal range may not provide additional diagnostic information if JAK2 mutation status is positive. Methods: In this retrospective review we used Logistic regression to build a predictive model for the diagnosis of PV based on EPO value and JAK2V617F mutation status. 415 patient records were reviewed. 162 were used in the final statistical analysis. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the predictive accuracy. All statistical analysis was performed with R version 3.5.1. A p-value less than 0.05 was considered statistically significant. Results: EPO level below the normal range as a standalone diagnostic modality is significantly associated with PV (odds ratio (OR) 0.857; p-value < 0.001). When JAK2V617F mutation status is included in the prediction model, the association of the low erythropoietin level is not statistically significant (OR 0.962 and p-value 0.269). Positive JAK2V617F demonstrates a strong predictive value for PV (OR 670.5, p-value 0.006) either alone or in combination with other variables. Moreover, 34.2% of patients with the diagnosis of PV had EPO level within the normal range, which reflects it’s physiological variability. Conclusions: Results show that erythropoietin level below the normal range does not bring additional diagnostic value when JAK2V617F mutation status is positive. Additionally, erythropoietin level has a negative correlation with increased BMI and smoking status, making it not a reliable diagnostic marker.
Sintilimab for relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL): A multicenter, single-arm, phase 2 trial (ORIENT-4).
Authors: Tao Rong , Fan Lei , Song Yongping , Hu Yu , Zhang Wei , Wang Yafei , Xu Linxinyu , Zhou Hui , Li Jianyong 
Published: March 2020

7504 Background: ENKTL account for more than 20% of the peripheral T-cell lymphoma in Asia. Patients with r/r ENKTL have a poor prognosis after failing an L-asparaginase based regimen, and the median overall survival is less than 6 months. The overexpression of PD-L1 induced by EBV infection is a potential mechanism for ENKTL to avert immune surveillance, and recent studies of PD-1 antibodies in pts with r/r ENKTL have demonstrated potential efficacy. Sintilimab, a fully human anti-PD-1 monoclonal antibody, has a safety profile consistent with other approved PD-1 antibodies and was approved for r/r classical Hodgkin lymphoma in China in 2018. This multicenter, single-arm, phase 2 study aims to validate the efficacy and safety of sintilimab monotherapy in patients with r/r ENKTL in China. Methods: Patients with pathologically confirmed r/r ENKTL were enrolled. Sintilimab was given 200 mg IV Q3W, until PD, death, unacceptable toxicity, or withdrawal from the study. Treatment beyond PD is allowed. Tumor response evaluation was performed by both PET-CT and CT/MRI with contrast. The primary endpoint was objective response rate based on LUGANO 2014 criteria. Data cut-off date for this analysis was Feb 2, 2019. Results: From Aug 31, 2017 to Feb 7, 2018, a total of 28 patients were enrolled: 60.7% male and the median age was 37 (range: 19–65) yr. Sixty-eight percent of patients were stage IV and 89.3% were ECOG PS ≥ 1. All patients had failed an L-asparaginase based regimen, the median lines of previous therapy were 3 (range: 1–13), 78.6% patients received prior radiotherapy and 7.1% had failed HSCT. Median duration of therapy was 14.04 (range: 1.4–17.3) months and 19 patients are still receiving sintilimab. Sixty-eight percent (19/28, 95%CI: 47.6%–84.1%) of patients achieved response (CR+PR), including 4 pts who experienced PD prior to having a response. DCR was 85.7%, including 5 pts who experienced PD before SD or response. The 1-year OS rate was 82.1% and the median OS has not been reached. Most TRAEs were G1–2 (67.9%) and no patients discontinued treatment due to AEs. The most common TRAE was decreased lymphocyte count (46.4%) and 84.6% were grade 1–2. SAEs occurred in 21.4% of patients and none were related to sintilimab. No patients died from AEs. Conclusions: Sintilimab is effective and well tolerated in r/r ENKTL and could be a promising treatment option for these patients. Early disease progression observed by PET scan in this study could be pseudoprogression as it did not correlate with poor outcome, which warrants further investigation. Clinical trial information: NCT03228836.