bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of alterations of pathways regulating autophagy in acute myeloid leukemia.
Authors: Marconi Giovanni , Fontana Maria Chiara , Papayannidis Cristina , Padella Antonella , Lo Monaco Silvia , Abbenante Maria Chiara , Sartor Chiara , Bertamini Luca , Nanni Jacopo , Ghelli Luserna di Rorà Andrea , Robustelli Valentina , Tenti Elena , Tenti Elena , Fonzi Eugenio , Simonetti Giorgia , Ottaviani Emanuela , Baldazzi Carmen , Testoni Nicoletta , Martinelli Giovanni 
Published: September 2018

7038 Background: Nowadays, science is debating if autophagy in cancer can lead to therapy resistance or it can favor apoptosis. Autophagy pathways are involved pro-apoptotic mechanism, or they can improve stresses survival eliminating damaged mitochondria and proteins. Levels and activity of pro-apoptotic and anti-apoptotic proteins (eg. bcl-2 and p53), high levels of cAMP, and a pink/park complex could play as fulcrum on this lever. Our study aims to define the role of autophagy in AML. Methods: We analyzed 148 consecutive non M3 AML with Affymetrix SNP array. We screened all patients for TP53, FLT3, NMP1 mutations. Patients was treated with intensive induction chemotherapy regimens. Survival data were collected prospectively, with a median follow-up of 18 months. Results: Autophagy alteration (gene group 1: ULK1 CHR11; ULK1 CHR17; BECN1; ATG14; AMBRA1; UVRAG; ATG9A; ATG9B; PIK3C3; PIK3R4) was related to lower Complete Remission rate (CR%) after induction in univariate (p < .001) and multivariable regression model with age, karyotype, secondary AML, TP53 mutation (p = .014); autophagy alteration shown to confer worst Overal Survival (OS) (p < .001) and was significantly associated with complex karyotype and TP53 mutation (p < .001). We detected significant differences in term of survival independently both in gain and loss in group 1 genes (p < .001). Alterations in genes in cAMP pathway (group 2: SESN1; PRKAA1 CHR 3; PRKAB1: PRKAA1 CHR 1: PRKAG1 CHR11; PRKAG1 CHR 7; PRKAG3; PRKAB1) and in genes that could be related to a switch from a physiological role of autophagy to a resiliency mechanism (group 3: CCND1; BCL2; PINK1; PARK2; TP53; MDM1; MDM4) showed to confer worst OS (p < .001 in both groups); Alteration in group 2 and group 3 were related to lower CR% after induction (p < .001 in both groups). Whole Exome Sequencing on 56 patients in our set did not found any significant mutation in genes we analyzed with the exception of TP53. Conclusions: Alterations in autophagy regulator genes are associated with poor prognosis and therapy resistance. A loss in autophagy could block apoptosis, a gain could confer cell resiliency. Acknowledgements: ELN, AIL, AIRC, Progetto Regione-Università 2010-12,FP7 NGS-PTL, HARMONY
Timing of initiation of defibrotide (DF) post-diagnosis of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) after hematopoietic stem cell transplantation (HSCT): Final data from an expanded-access protocol.
Authors: Grupp Stephan A. , Richardson Paul G. , Smith Angela R. , Triplett Brandon , Kernan Nancy A. , Antin Joseph Harry , Lehmann Leslie , Giralt Sergio , Liang Wei , Hume Robin , Tappe William , Soiffer Robert 
Published: September 2018

7047 Background: VOD/SOS is an unpredictable, potentially life-threatening complication of HSCT. VOD/SOS with multi-organ dysfunction (MOD) may be associated with > 80% mortality. DF is approved to treat hepatic VOD/SOS with renal/pulmonary dysfunction post-HSCT in the US and to treat severe hepatic VOD/SOS post-HSCT in the European Union. Methods: In an expanded-access study, VOD/SOS patients (pts) with or without renal/pulmonary MOD after HSCT or chemotherapy received DF 25 mg/kg/d (6.25 mg/kg q6h) for a recommended ≥21 days. For these exploratory analyses, D ay +100 survival rates in HSCT pts were examined post hoc by time from diagnosis to start of DF for (1) all pts before/after days 1, 2, 3, 4, 7, and 14, using Fisher’s exact test and (2) pts starting DF on a particular day: 0, 1, 2, 3, 4, 5, 6, 7, 8–14, and ≥15, by Cochran-Armitage test for trend across days. Causes of treatment delay were not assessed. Results: In the final dataset, timing of initiation was available for 1000 HSCT pts (512 with MOD) who received ≥1 dose of DF. In 31.0% of pts, DF was started the day of diagnosis; in 92.9%, by Day 7. In the analysis of initiation before/after days 1, 2, 3, 4, 7, and 14 post-diagnosis, earlier initiation was associated with significantly higher Day +100 survival rates for all days ( P≤.001), except Day 14 (2.6% of pts started DF after Day 14). The trend test for particular initiation days also showed a significant trend over time for higher Day +100 survival with earlier DF initiation post-diagnosis ( P< .001). Adverse events (AEs) and serious AEs occurred in 70.8% and 53.4% of pts. Other than VOD/SOS and MOD, the most common AE was hypotension (11.7%) and most common serious AE was respiratory failure (7.3%). Conclusions: In this exploratory analysis of final study data, earlier DF initiation post-VOD/SOS diagnosis improved Day +100 survival, confirmed by the Cochran-Armitage test ( P< .001). No specific day provides a clinically meaningful cutoff for better Day +100 survival, suggesting that later intervention retains value if treatment must be delayed. Support: Jazz Pharmaceuticals. Clinical trial information: NCT00628498.
Relationship of bone marrow blast (BMBL) response to overall survival (OS) in a multicenter study of rigosertib (Rigo) in patients (pts) with myelodysplastic syndrome (MDS) with excess blasts progressing on or after treatment with a hypomethylating agent (HMA).
Authors: Al-Kali Aref , Hiwase Devendra , Baer Maria R. , Greenberg Peter , Shortt Jake , Collins Robert , Steensma David P. , Verma Amit , Roboz Gail J. , Shammo Jamile M. , Ottmann Oliver G. , Seymour John Francis , Szer Jeffrey , Meyer Wolfgang , Zbyszewski Patrick Simon , Petrone Michael E. , Fruchtman Steven M. , Garcia-Manero Guillermo , Silverman Lewis R. 
Published: September 2018

7056 Background: No therapies are approved for MDS after HMA failure. 04-24 was a single-arm study to evaluate best BMBL response as a potential surrogate for OS in higher-risk (HR) MDS pts who progressed on or after an HMA. Rigo is a Ras-mimetic that inhibits the RAS-RAF-MEK pathway, which is frequently activated in HR MDS (Athuluri-Divakar Cell 2016; Gil-Bazo Cancer Biol Ther 2016). Methods: Eligible MDS pts had 5-30% BMBL confirmed within 6 wks pre-study and progression per International Working Group (IWG) 2006 criteria on or after HMAs within 2 yrs. Rigo 1800 mg/24 hrs was continuously infused over 72 hrs q 2 wks × 8 cycles, then q 4 wks until progression or unacceptable toxicity. Primary endpoint was relationship of best BMBL IWG response to OS by Kaplan Meier method. Results: 64 pts were treated (median 5 cycles, range 1-32+), with 61% male, median age 73 (range 47-87), median prior HMA duration 10.8 mos (range 1.2-70.2). Revised International Prognostic Scoring System scores were low 2%, intermediate 11%, high 27%, very high 53%, and unknown 8%. ≥Grade 3 adverse events in ≥10% of pts were anemia 19%, thrombocytopenia 19%, and febrile neutropenia 16%. At the analysis time 40 pts (63%) had died. Best BMBL IWG response was marrow complete response (mCR) 14 pts (22%), stable disease (SD) 30 (47%), progressive disease (PD) 15 (23%), and failure (early death/withdrawal) 5 (8%); 2 mCR pts had transplant. Median OS was 7.0 mos (95% confidence interval 4.8-10.8). Landmark median OS (from day of best BMBL response) was mCR not reached; SD 6.3 mos; PD 3.3 mos. Median OS of mCR+SD was 8.5 mos, with log-rank p = 0.011 (mCR+SD OS to PD OS). Conclusions: BMBL response is a predictor of survival for MDS pts receiving Rigo after HMA failure, confirming findings in earlier Phase 1/2 studies (Silverman ASCO 2015 Abstr 7017). Based on earlier results identifying an MDS subset benefitting from Rigo (Garcia-Manero Lancet Oncol 2016; ASCO 2016 Abstr 165681), a randomized Phase 3 trial of Rigo vs physician’s choice (INSPIRE) is ongoing to determine if Rigo improves survival after HMA failure within 9 cycles. Clinical trial information: NCTO 1928537.
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study.
Authors: Rummel Mathias J. , Maschmeyer Georg , Ganser Arnold , Heider Andrea , von Gruenhagen Ulrich , Losem Christoph , Heil Gerhard , Welslau Manfred , Balser Christina , Kaiser Ulrich , Weidmann Eckhart , Dürk Heinz Albert , Ballo Harald , Stauch Martina , Blau Wolfgang , Burchardt Alexander , Barth Juergen , Kauff Frank , Brugger Wolfram 
Published: September 2018

7501 Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or mantle cell lymphoma and was first published in The Lancet in 2013. The final analysis demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group compared to the CHOP-R group, with a median PFS of 69.5 vs. 31.2 months, respectively. In the current analysis, we present updated results for overall survival (OS), time-to-next-treatment (TTNT), and secondary malignancies (sNPL) with a median follow-up of 113 months for patients with indolent lymphomas (excluding MCL). Methods: 447 pts with indolent lymphomas were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: Patient characteristics were well balanced between arms; median age was 64 years. The difference in OS between the two treatment arms was not statistically significant, with 60 deaths in the B-R group vs 68 deaths with CHOP-R (HR 0.82, 95% CI 0.58 – 1.15, p = 0.249). The estimated 10-year survival rates were 71% for B-R and 66% for CHOP-R. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.52, 95% CI 0.38 – 0.69, p < 0.001). Median TTNT was not yet reached in the B-R group (95% CI 124.9 – n.y.r) vs. 56 months in the CHOP-R group (95% CI 39.1 – 82.0). Patients treated initially with B-R needed fewer second-line treatments due to disease progression compared to CHOP-R treated pts: 73 pts (34%) in the B-R group received salvage treatment compared with 106 pts (52%) in the CHOP-R group. For B-R pts, CHOP-R was used as second-line therapy 26 times (36%), whereas B-R was used for pts initially treated with CHOP-R 49 times (46%). 36 pts with sNPL were observed in the B-R group compared with 39 in the CHOP-R group, with 7 hematological malignancies in both groups to date. Conclusions: In pts with previously untreated indolent lymphomas, B-R demonstrates a PFS and TTNT benefit over CHOP-R. Clinical trial information: NCT00991211.
Combination ibrutinib (Ibr) and venetoclax (Ven) for the treatment of mantle cell lymphoma (MCL): Primary endpoint assessment of the phase 2 AIM study.
Authors: Tam Constantine Si Lun , Roberts Andrew Warwick , Anderson Mary Ann , Dawson Sarah-Jane , Hicks Rodney J , Burbury Kate , Turner Gillian , Di Iulio Juliana , Bressel Mathias , Westerman David A. , Agarwal Rishu , Pott Christiane , Dreyling Martin H. , Dawson Mark A , Seymour John Francis 
Published: September 2018

7520 Background: Both ibr and ven have activity in relapsed/refractory (R/R) MCL, but complete remissions (CR) are attained in <25% with either. We sought to determine the activity of the combination in an investigator-initiated, phase 2 study. Methods: Enrolment of 24 patients (pts) with R/R (n=23) or frontline (n=1) MCL completed in 09/16. Pts received 4 weeks of ibr (560mg/d), followed by introduction of ven (weekly ramp-up to target 400mg/d). The primary endpoint was CR rate at week 16, as assessed by PET/CT, BMAT, flow & molecular MRD, and endoscopy (if baseline gut involvement). Response was calculated separately with and without knowledge of the PET result by IWG criteria (Cheson JCO 2007), in order to compare with published studies (ibr, 9% CR at wk16; ven, best CR rate 21%). Results: Median age of pts was 68 (range, 47-81) years. For the R/R pts (n=23), median lines of prior therapy was 2 (1-6), 48% were refractory to last treatment, and 30% had failed previous autologous SCT. As of data cutoff on Jan 11 2017, 18 pts remain on therapy, and 6 stopped treatment due to progressive disease (4), adverse event (1) or unrelated death (1). At week 16, ORR was 71% (63% CR) and 80% of complete responders were flow-cytometry negative in the marrow (sensitivity 10-3 to 10-4). Using CT without PET, the comparison responses were CR 42%, CRu 17%, PR 17% (ORR 78%). After a median follow-up of 8.3 (range 1.4-17.7) months, the 8-month estimates of PFS and OS months are 74% and 81%. Adverse events ≥20%, irrespective of attribution, were fatigue (71%), diarrhea (67%), nausea (50%), URTI (38%), gastro-esophageal reflux (33%), neutropenia (33%), cough (25%) and bruising (21%); with the exception of neutropenia (25% grade 3-4), these were predominantly grade 1-2 in severity. Tumour lysis syndrome occurred in 2 pts with high tumour burden, leading to revision of the protocol ven starting dose from 50mg, to 20mg/d. Conclusions: The combination of ibr and ven was tolerable and achieved CR rate of 63% at week 16 in pts with MCL. The efficacy results compare favorably with historical results, and warrant further phase III investigation. Clinical trial information: NCT02471391.
Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for previously untreated patients with chronic lymphocytic leukemia (CLL) with mutated IGHV and non-del (17p).
Authors: Jain Nitin , Thompson Philip A. , Burger Jan Andreas , Borthakur Gautam , Bose Prithviraj , Estrov Zeev , Ferrajoli Alessandra , Gandhi Varsha , Plunkett William , Lopez Wanda , Kantarjian Hagop M. , O'Brien Susan Mary , Keating Michael J. , Wierda William G. 
Published: September 2018

7522 Background: Pts with mutated IGHV ( IGHV-M) have favorable long-term outcomes after FCR. Methods: We designed an investigator-initiated phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). The intent was to limit FC to 3 courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through addition of ibrutinib and obinutuzumab. Key eligibility included age ≥18, IGHV-M, no del17p. Pts received 3 courses of iFCG. G-CSF was not mandated. Primary endpoint: CR/CRi with bone marrow (BM) MRD-neg (4-color flow-cytometry) after 3 courses of iFCG. Pts meeting primary endpoint received ibrutinib with obinutuzumab (iG) for C3-6, then ibrutinib C7-12. Pts not achieving primary endpoint received iG (C4-12). All pts who are MRD neg at 1 year will stop all therapy, including ibrutinib. Pts MRD+ at 1 year may continue ibrutinib. Historic C3 BM MRD-neg with FCR in IGHV-M 26% (Strati, Blood 2014). Target BM MRD-neg after iFCG x3 is 45%. Sample size 45. Results: 23 pts started treatment. Median age 59 yrs (25-71). Prognostic markers [del13q (n=17), negative (n=3); trisomy 12 (n=3)]. 18 pts completed 3 courses of iFCG and had initial response assessment (the remaining 5 pts too early). All 18 pts had a response; 14/18 (78%) achieved MRD-neg in BM at 3 month with 7/18 achieving CR/CRi (all MRD neg). No pt has progressed, and all but one continue to receive treatment. Of the 23 pts, 11 pts had G3-4 neutropenia and 5 pts had G3-4 thrombocytopenia. 4 pt had neutropenic fever. 1 pt who achieved MRD-neg CR developed pulmonary MAC infection, and declined further therapy. 1 pt had atrial fibrillation. G3 ALT developed in 3 pts. FC was dose reduced in 10 pts; ibrutinib dose-reduced in 2 pts. Conclusions: iFCG achieves high rate of MRD-neg remission after 3 courses. Pt enrollment continues, and updated results will be presented at the ASCO meeting. Clinical trial information: NCT02629809. [Table: see text]
Significance of MYC rearrangement and chemotherapy type on survival outcomes of patients with central nervous system lymphoma.
Authors: Grover Natalie Sophia , Deal Allison Mary , Mathews Stephanie , Freeman Ashley , Dittus Christopher , Park Steven I. 
Published: September 2018

7548 Background: Central nervous system lymphoma (CNSL) has a poor prognosis and an optimal treatment regimen has not been established. Due to the rarity of this disease and frequently poor performance status at diagnosis, there have been few prospective therapeutic clinical trials in this patient population. We therefore performed a retrospective analysis of prognostic factors and treatment outcomes of patients with CNSL treated at a single institution. Methods: Pathology records were used to identify patients diagnosed with CNSL from 1/1/2005 to 9/1/2016 at the University of North Carolina Cancer Hospital. Information about demographics, disease characteristics, treatment, and outcomes was gathered from the electronic medical record. Overall (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method. Results: We identified 100 patients with CNSL. 49% had primary CNSL (PCNSL). 78% of cases were diffuse large B cell lymphoma. Out of 51 patients evaluated for MYC translocation by FISH, 13 were positive (3 PCNSL and 10 secondary CNSL). Out of 74 patients treated with chemotherapy, 51% received methotrexate (MTX), procarbazine, and vincristine (MPV), with or without rituximab, 28% were treated with other high dose MTX based regimens, with or without rituximab, and 20% received a non-MTX based regimen. There was no significant difference in OS between PCNSL and secondary CNSL (13.7 vs 7.9 months, p = 0.97). Patients with MYC translocation had a worse OS compared to those without MYC translocation (5.1 vs 29.5 months, p = 0.004). Patients treated with MPV had a longer PFS compared to those treated with other high dose MTX based regimens or those who were treated with a non-MTX based regimen (19.1 vs 10.9 vs 3.9 months, p = 0.05), but difference in OS did not reach statistical significance (29.5 vs 22.4 vs 10.6 months, p = 0.12). Conclusions: In this single institution analysis of CNSL, MYC translocation was associated with worse survival. MPV was associated with improved PFS compared to other chemotherapy regimens. Further prospective studies are needed comparing MPV to other MTX-based regimens in CNSL.
Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients (pts) with newly diagnosed multiple myeloma (MMY1001): An open-label, phase 1b study.
Authors: Jakubowiak Andrzej J. , Chari Ajai , Lonial Sagar , Weiss Brendan M. , Comenzo Raymond L. , Wu Kaida , Khokhar Nushmia Z. , Wang Jianping , Doshi Parul , Usmani Saad Zafar 
Published: September 2018

8000 Background: DARA in combination with established standard of care regimens prolongs PFS, deepens responses, and demonstrates a favorable safety profile in relapsed or refractory multiple myeloma (MM). The tolerability and efficacy of DARA-KRd in newly diagnosed MM pts was examined. Methods: Newly diagnosed pts regardless of transplantation eligibility were enrolled. Pts received DARA 16 mg/kg QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. All pts received the 1st dose of DARA split over 2 days. Carfilzomib (K) was administered on Days 1, 8 and 15 of each 28-day cycle (20 mg/m2 on C1D1, 36 or 70 mg/m2 subsequently based on tolerability of first dose) for ≤13 cycles or elective discontinuation for ASCT. Lenalidomide 25 mg was given on Days 1-21 and dexamethasone 20-40 mg per week. The primary endpoint was tolerability. Results: Twenty-two pts (median [range] age, 60 [34-74] y) were enrolled and received a median of 8 (1-10) treatment cycles. Nineteen pts escalated K dose to 70 mg/m2 by C1D15. Median (range) duration of follow-up was 7.4 (4.0-9.3) months. Six (27%) pts discontinued treatment (1 AE [pulmonary embolism]; 1 PD; 4 other [ASCT]). Serious AEs occurred in 46% of pts, and 14% were possibly related to DARA; 18 (82%) experienced a grade 3/4 TEAE. The most common grade 3/4 TEAEs (>10%) were lymphopenia (50%) and neutropenia (23%); 1 (5%) cardiac grade 3 TEAE was observed (congestive heart failure) which resolved; pt quickly resumed study treatment with reduced K dose. No grade 5 TEAE was reported. All DARA-associated infusion reactions (27% of pts) were grade ≤2. Treatment with DARA-KRd yielded an ORR (≥partial response) of 100% (5% complete response, 86% ≥very good partial response) in 21 response-evaluable pts. The 6-month PFS rate was 100%. Conclusions: The addition of DARA to KRd was well tolerated; the overall safety profile was consistent with that previously reported for KRd, with no additional toxicity observed with the addition of DARA. Deep and durable responses were observed. These data support further investigation of DARA-KRd as a frontline treatment regimen. Updated data will be presented based on longer follow up. Clinical trial information: NCT01998971.
Carfilzomib-lenalidomide-dexamethasone (KRd) vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction: Planned interim analysis of the randomized FORTE trial in newly diagnosed multiple myeloma (NDMM).
Authors: Gay Francesca Maria , Rota Scalabrini Delia , Belotti Angelo , Offidani Massimo , Petrucci Maria Teresa , Esma Fabrizio , Palmas Angelo D. , Caravita Tommaso , Grasso Mariella , Aquino Sara , Gamberi Barbara , Zambello Renato , Ledda Antonio , Montefusco Vittorio , Omedè Paola , Galli Monica , Cavo Michele , Palumbo Antonio , Musto Pellegrino , Boccadoro Mario 
Published: September 2018

8003 Background: Phase I/II studies showed the safety and efficacy of KRd and KCd in NDMM pts (Jakubowiak Blood 2012, Bringhen Blood 2014). Methods: NDMM pts ≤65 yrs were randomized (1:1:1; stratification ISS and age) to: 4 28-day KCd cycles (carfilzomib:20/36 mg/m2 IV d 1,2,8,9,15,16; cyclophosphamide 300 mg/m2 d 1,8,15; dexamethasone:20 mg d 1,2,8,9,15,16) followed by MEL200-ASCT and consolidation with 4 KCd cycles; or 4 28-day KRd cycles (carfilzomib and dexamethasone as above; lenalidomide:25 mg d 1-21) followed by MEL200-ASCT and 4 KRd cycles; or 12 KRd cycles. After the 4th induction cycle, all pts received Cyclophosphamide 2 g/m2, followed by PBSC collection. We report results of the first planned safety interim analysis on induction and mobilization and preliminary efficacy data. We pooled the 2 KRd groups since treatment was the same until mobilization. Data cut-off was October 30, 2016. Results: 281 pts were evaluated (KCd, n=94; KRd, n=187). The most frequent grade 3-4 AEs plus SAEs in both arms were hematological (mainly neutropenia) and infections (mainly pneumonia/fever); increased AST/ALT/GGT (mainly reversible) and dermatological (rash) AEs were higher in KRd; cardiac AEs were 2% (atrial fibrillation[1%]/ischemic heart disease[1%]) in KRd vs 1% (atrial fibrillation) in KCd. In KCd, 1 pt died of infection (not treatment-related) vs 3 in the KRd (2 cardiac arrest [1 not treatment-related],1 infection not treatment-related). In the KCd vs KRd arms, 99% vs 95% (P=0.44) of pts mobilized stem cells (median number of PBSC collected:9 vs 6x10^6CD34/Kg with KCd vs KRd); 10% vs 24% (P=0.01) required Plerixafor. Rate of ≥VGPR was 61% with KCd vs 74% with KRd (P=0.05). Conclusions: Safety profile was acceptable; more pts required plerixafor in KRd. Rate of VGPR was higher with KRd. Updated data on more patients will be presented at the meeting. Clinicaltrials.gov NCT02203643. [Table: see text]