bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular genetic testing patterns for patients with newly diagnosed acute myeloid leukemia (AML) enrolled in the CONNECT MDS/AML disease registry.
Authors: Pollyea Daniel Aaron , George Tracy , Foucar Kathryn M , Erba Harry Paul , Thompson Michael A. , Abedi Mehrdad , Roboz Gail J. , Landau Danny , Pagel John M. , Seiter Karen , Cogle Christopher R. , Nifenecker Melissa , Swern Arlene S. , Kiselev Pavel , Sugrue Mary M. ,   On Behalf of the CONNECT MDS/AML Disease Registry Scientific Steering Committee
Published: September 2018

7022 Background: Recurrent mutations in AML-associated genes have prognostic value and may help guide treatment decisions. Molecular genetic testing patterns for AML in clinical practice are largely unknown. Previously the CONNECT MDS/AML Disease Registry (George et al. ASH 2016. Abstract 3548) showed suboptimal adherence to WHO 2008 recommendations for AML in a cohort of newly diagnosed (ND) AML patients (pts) in clinical practice. Here we report a detailed analysis of patterns of molecular genetic testing in pts with ND AML in community and academic settings. Methods: The CONNECT MDS/AML Disease Registry (NCT01688011) is a US prospective, observational cohort study of pts with ND AML (≥55 years) or MDS. Enrollment is ongoing. All clinical decisions are made by study clinicians. The current analysis evaluated the percentage of pts with AML with molecular genetic testing recommended by NCCN guidelines ( NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, DNMT3A, and KIT). Chi-square tests evaluated effects of several variables on likelihood of molecular genetic testing. Results: Between 12 Dec 2013, and 8 Dec 2016 (data cutoff), 259 AML pts were enrolled at 86 sites. Molecular genetic testing was reported in 67% (173/259) of pts. Likelihood of testing varied, respectively, for academic vs community sites (76% [70/92] vs 62% [103/167], P= .018), normal vs abnormal karyotype (77% [79/103] vs 59% [79/133], P= .006), age < 65 vs ≥65 (83% [65/78] vs 60% [108/181], P= .0003), and Medicare vs other insurance (61% [83/137] vs 74% [90/122], P= .025). In pts with molecular genetic testing (n = 173), the mutations tested varied substantially. All of the NCCN-recommended molecular genetic tests were reported in 9% (15/173) of pts, including 8% (6/79) of those with normal karyotype. Of the 7 NCCN-recommended tests, NPM1 (77%) and FLT3-ITD (76%) were most often reported and DNM T3A least often (16%). Conclusions: Early data from the CONNECT MDS/AML Disease Registry reveal that despite molecular testing reported in 67% of ND AML pts, a majority do not receive guideline-recommended testing. This prospective registry is uniquely positioned to capture changes in testing patterns as guidelines are established.
Outcomes in AML patients age ≥70: A very large single institution experience.
Authors: Lancet Jeffrey E. , Kim Jongphil , Al Ali Najla , Sehovic Marina , Reljic Tea , Djulbegovic Benjamin , Extermann Martine 
Published: September 2018

7031 Background: AML in older adults is associated with poor outcomes. The Moffitt Cancer Center AML Database was used to evaluate a very large cohort of patients (pts) age ≥ 70 with untreated AML to identify key prognostic variables affecting outcome. Methods: Overall survival (OS): Kaplan-Meier method and was compared across groups using the log-rank test. Association between OS and predictors: Cox regression model. Impact of participation of initial clinical trial on OS: Propensity score with stratified log-rank test. A predictive model for 12 month OS was developed using multiple logistic regression with backward elimination method. Results: Nine hundred eighty (980) pts were identified. M/F(%): 66/34. Median age at diagnosis: 75.7 years (range 70 – 95.7 years). De novo/secondary (%): 43/57. Fifty two % of pts had prior hematologic disease (AHD). Baseline karyotype at AML diagnosis: adverse in 31% and non-adverse in 58%. Baseline ECOG PS: 0-1 in 79%; ≥2 in 19%. Median OS was 7.1 months (95% CI 6.4 – 7.9) for the entire cohort. In the univariable model, factors associated with inferior survival included: secondary AML (sAML) status, poor-risk karyotype, ECOG ≥2, non HMA therapy (including clinical trials), Charlson Comorbidity Index ≥3, older age, increased WBC, decreased platelets (plts), and decreased hemoglobin (hgb). Independent negative predictors for OS in the multivariate model included sAML, poor-risk karyotype, ECOG ≥2, non-HMA initial therapy, older age, increased WBC, decreased plts, and decreased hgb. Propensity score matching revealed no significant difference in OS amongst pts receiving initial treatment on a clinical trial (median 7.8 months, 95% CI 6.4 – 10.4) vs not (median 7.0 months, 95% CI 6 –7.9). A model to predict OS at 12 month was developed in a subset of 446 pts. Independent predictive variables included karyotype, ECOG PS, AML type (de novo vs sAML), age, and WBC, with AUC of 0.78, indicating strong discriminatory capacity. Conclusions: In this largest reported cohort of AML pts age ≥ 70, prognostic modeling identifies differences in longer-term survival with conventional therapies, discriminating the highest risk subsets. Decision modeling to further assist choice of optimal therapies for these pts is in progress.
Better survival with fludarabine and timed sequential busulfan regimen in older patients with AML/MDS.
Authors: Popat Uday R. , Saliba Rima , Oran Betul , Ahmed Sairah , Alousi Amin Majid , Bashir Qaiser , Ciurea Stefan O. , Hosing Chitra , Kebriaei Partow , Khouri Issa F. , Marin David , Nieto Yago , Olson Amanda Leigh , Qazilbash Muzaffar H. , Rezvani Katayoun , Valdez Ben , Jones Roy B. , Shpall Elizabeth J. , Andersson Borje , Champlin Richard E. 
Published: September 2018

7046 Background: We previously reported 6% 100 day NRM with a MA fludarabine (Flu) and busulfan (Bu) in older patients with a median age of 60 years. MA dose of Bu in this timed sequential (TS) regimen was administered over a longer period of time. To assess its impact on survival, we compared the outcomes of older patients treated with the TS Bu (TS cohort) or the RIC Flu/Bu regimen, which is used as standard (ST) for older patients at our center (ST cohort). Methods: Patients in the TS cohort received IV Bu 80 mg/m2/d on day -13 and -12 and Flu 40 mg/m2/d followed by IV Bu on day -6 to -3, dose adjusted to achieve a total Bu course AUC of 20,000 μmol-min based on PK studies. Patients in the ST cohort received Flu 40 mg/m2day followed by IV Bu daily for 4 days (day -6 to -3) dosed to achieve AUC of 16,000 μmol-min. Patients with AML or MDS were eligible for the study if they had adequate organ function, had matched related or unrelated donor and were treated between Jan 2012 and Sept 2016. Results: 162 patients, 50 with MDS and 112 with AML, were included in this study. Patient characteristics including age, sex, disease status, cytogenetic risk group, donor type, graft source CMV status and comorbidity were well balanced and without any significant difference in the two cohorts. Median age was 66 and 65 years in ST and TS cohorts, respectively. Overall survival (OS) and progression free survival (PFS) were significantly better in the TS cohort (see Table). This was due to a reduction in the disease progression without any increase in the non-relapse mortality (NRM). After adjusting for other covariates, the multivariate analysis for PFS confirmed longer PFS with TS Bu regimen (HR: 0.36; P=0.003). The benefit was mainly seen in patients with a comorbidity score ≤ 3. Conclusions: The myeloablative timed sequential Bu regimen improves survival and appears promising in older patients with AML/MDS. Clinical trial information: NCT01572662. [Table: see text]
Tyrosine kinase inhibitor (TKI) therapy discontinuation in patients with CML in chronic phase: A US clinical practice perspective.
Authors: Ritchie Ellen K. , Wolff Johannes E. , Latremouille-Viau Dominick , Guerin Annie , Pivneva Irina , Briggs Owanate , Joseph George J. , Atallah Ehab L. 
Published: September 2018

7052 Background: This study assessed TKI discontinuation practice in the US before the publication of new practice guidelines in November 2016 including recommendations on TKI discontinuation for patients (pts) with CML in chronic phase (CML-CP). Methods: From 10/12/2016 to 11/9/2016, 300 US oncologists/hematologists completed a survey on the reasons for TKI discontinuation in pts with CML-CP, their perspective on adequate response pts should achieve before considering TKI discontinuation (minimum response to TKI, response duration, and TKI therapy duration), and post-discontinuation CML monitoring. Results: One third of participating physicians reported having attempted TKI discontinuation (102 of 300); 66 did so outside of a clinical trial. Physicians who reported TKI discontinuation were more likely to practice in academic centers; were more experienced clinicians ( > 10 years in practice); and followed a larger number of CML pts vs those who did not. Among the 66 physicians, the majority would consider TKI discontinuation for medical reasons (76% adverse events, 47% pregnancy planning), with fewer for economic reasons (35%); 12% reported they would consider it for all of their pts who achieve an adequate response. There was no consensus on the minimum response achieved (56% consider a decrease in BCR-ABL of ≥4.5 log, 21% 3 log, and 11% 1 log), the minimum response duration (29% 3 yrs, 24% 2 yrs, and 20% 1 yr), and the minimum TKI therapy duration (44% 3yrs, 20% 2 yrs, 19% 1 yr) before TKI discontinuation. There was no consensus on the frequency of CML monitoring post-discontinuation with < 10% of physicians considering monthly molecular monitoring in the first year. Conclusions: TKI discontinuation in pts with CML-CP responding to TKI was attempted outside of clinical trials without clear guidelines. Conditions under which TKI therapy was discontinued differed from new recommended practice guidelines, which may have resulted in discontinuation where deep response may not be achieved and disease not adequately monitored. The recommended practice guidelines need to be communicated to physicians as TKI discontinuation is likely to be conducted in a broader population.
Axl blockade in vitro and in patients with high-risk MDS by the small molecule inhibitor BGB324.
Authors: Loges Sonja , Ben Batalla Isabel , Heuser Michael , Berenbrok Nikolas , Schroeder Thomas , Geyh Stefanie , Micklem David , Chromik Jörg , Kebenko Maxim , Fiedler Walter M. , Yule Murray , Cortes Jorge E. , Gjertsen Bjorn T. 
Published: September 2018

7059 Background: The interplay with bone marrow stroma plays an important role in the pathobiology of MDS. Gas6 is secreted by mesenchymal bone marrow stroma cells and promotes survival and therapy resistance of AML cells expressing the Axl receptor. We hypothesized that inhibiting Axl by the small molecule inhibitor BGB324 might hold therapeutic potential in MDS. Methods: We investigated the inhibitory effect of BGB324 on primary bone marrow mononucleated cells (BMMNC) and mesenchymal stroma cells (MSC) from MDS patients in comparison to healthy donors. In the ongoing first-in-patient Phase 1a/b trial BGBC003 A standard 3 + 3 dose escalation study was performed to identify the maximum tolerated dose of BGB324 in patients with previously treated high risk MDS or AML. BGB324 was administered as an oral loading dose on days one and two followed by a reduced daily maintenance. Three dose levels were explored 400/100mg, 600/200mg and 900/300mg. Results: We found that BGB324 inhibited BMMNC from low- and high-risk MDS patients with an IC50 of 2.1 µM and 3.8 µM, respectively (n = 5). In comparison, BMNNC from healthy donors were resistant to BGB324 (IC50 9.4 µM, p < 0.05, n = 10). Axl expression was present in MSC isolated from the BM of MDS patients and BGB324 inhibited the proliferation of MSC from low- and high-risk MDS patients (IC50 2.5 µM and 2.7 µM, respectively; n = 7/5).To date, 3 patients with MDS were treated with 400 mg loading dose and 100 mg maintenance dose of BGB324. Therapy has been well-tolerated and the MTD has not yet been reached. The majority of adverse events reported have been Grade 1 and 2. The most common related adverse events are diarrhea and fatigue. One patient with MDS was treated for 80 weeks and experienced a PR. Evidence of target inhibition was demonstrated by almost complete inhibition of Axl phosphorylation accompanied by reduction in phosphoErk and phosphoAkt signalling at day 21 of treatment. Conclusions: BGB324 is well-tolerated and might represent a promising novel treatment approach in MDS. Safety and efficacy of BGB324 will be explored further in clinical trials. Clinical trial information: NCT02488408.
Phase I/II trial of glasdegib in patients with primary or secondary myelofibrosis.
Authors: Gerds Aaron Thomas , Tauchi Tetsuzo , Ritchie Ellen K. , Deininger Michael W.N. , Jamieson Catriona HM , Mesa Ruben A. , Heaney Mark L. , Komatsu Norio , Minami Hironobu , Su Yun , Shaik Mohammed Naveed , Zhang Xiaoxi , DiRienzo Christine , Zeremski Mirjana , Woolfson Adrian , Chan Geoffrey , Talpaz Moshe 
Published: September 2018

7061 Background: Glasdegib is a small molecule inhibitor of the Sonic Hedgehog pathway, and data from the single arm, lead-in cohort of a phase 1b/2 trial in myelofibrosis (MF) are shown. Methods: Patients (age ≥18 yrs) with primary/secondary MF previously-treated with ≥1 Janus Kinase inhibitor (JAKi) were enrolled and received glasdegib 100 mg QD orally in 28 day cycles. AEs and laboratory abnormalities were assessed. Key efficacy endpoints were proportion of patients with spleen volume reduction (SVR) ≥35% and ≥50% reduction in total symptom score (TSS) measured by the MPN Symptom Assessment Diary (MPN-SAD) at Week 24. Results: 21 patients were enrolled between Oct '14-Oct '15 in this ongoing study. Mean age was 69.3 yrs (range 58-83). Median duration of treatment was 85 days (22-343). 52% were refractory patients with inadequate response to prior JAKi. Baseline symptoms were mostly mild (1-4), except fatigue (>4). No patients achieved SVR ≥35%, 5 patients had some SVR (maximum 2.3-21.4% reduction from baseline), and no progressive disease prior to Day 71. At week 24, 1 patient had ≥50% reduction in TSS, but 3/21 and 4/21, respectively showed 30% and 20% TSS reduction. Of 14 patients with severe baseline symptoms (1 with ≥5, or ≥2 with ≥3), 1, 1, and 2 achieved 50%, 30%, and 20% TSS reduction, respectively at week 24. TSS, spleen-related, and constitutional symptom scores showed a trend of reduction over 24 weeks with spleen-related symptoms, inactivity, and fatigue showing greatest improvement (52%, 58%, and 36%, respectively). Dysgeusia (N=13), muscle spasms (N=12), alopecia (N=8), decreased appetite (N=7), fatigue (N=7), lipase increase (N=5), and weight decrease (N=5) occurred in ≥20% patients. None, except 1 episode of fatigue, were considered serious AEs. Glasdegib steady state PK was consistent with previous single agent data. Conclusions: Glasdegib has an acceptable toxicity profile in patients with primary/secondary MF previously treated with JAKi. Symptom responder definition for refractory patients may not be the same as for JAKi naïve patients. Patient reported symptom improvement may be a more sensitive indicator of treatment benefit vs SVR. Further study of glasdegib may be warranted. Clinical Trial Information: NCT02226172.
Allogeneic hematopoietic cell transplantation for myelofibrosis (MF) in high risk patients.
Authors: Narayana Swapna , Chhabra Saurabh , Narra Ravi Kishore , Szabo Aniko , Hamadani Mehdi , Pasquini Marcelo C. , Shah Nirav , Hari Parameswaran 
Published: September 2018

7062 Background: Although allogeneic transplantation(alloHCT) is the only curative treatment modality for MF, given the median age of MF, most patients are not candidates for alloHCT due to concerns for treatment-related mortality(TRM), age and comorbidities. Methods: We reviewed the outcomes of 24 recipients of matched related/unrelated donor alloHCT for MF at the Medical College of Wisconsin. All patients with JAK2 mutation(62%) and/or constitutional symptoms recieved Roxulitinib atleast 4 months prior to alloHCT with discontinuation of Ruxolitinib 48 hrs prior to the start of conditioning. Majority(91%) received conditioning with Fludarabine and Busulfan(Flu/Bu4, Flu/Bu3,Flu/Bu4). Only 2 patients received TBI based regimen; Flu/TBI(2-4Gy). Those with splenomegaly > 22cm received pre-transplant splenic radiation(n = 11;49%). Survival outcomes were analyzed using Kaplan-Meier curves and compared between groups using log-rank test. Results: Median age was 57 years(range,40-67) with 29% > 60 years. A 46% had primary ET or PV that evolved to MF and 17% had MDS cytogenetics. Majority(74%) patients MF-3 grade. More than 80% recieved Ruxolitinib and 25% were treated with hypomethylating/cytotoxic chemotherapy. HCT-CI score was≥3 in 62%. Four patients had cirrhosis and portal hypertension(PHTN), and another 3 had PHTN without Cirrhosis.At median follow up of 36months, 3-year overall survival(OS) and relapse-free survival were(RFS) 70%. Marrow fibrosis improved post HCT with only 15% grade 3. One patient relapsed and died from AML 15 months post-HCT. TRM was 25% at 3 years; causes of death were sepsis(n = 3), alveolar hemorrhage(n = 1) and myocardial infarction(n = 1). Variables such as type of donor, DIPSS scoring, MF grade and age of the patient were not significantly associated with OS/RFS on univariate analysis. Conclusions: Despite advanced age and 62% with HCT CI≥3, we report excellent survival outcomes compared to other prior data. Careful patient selection, use of Ruxolitinib pre-HCT, splenic irradiation pre-HCT and Flu/Bu based conditioning regimen all contributed to the remarkable results in this series.
Radiotherapy to bulky disease PET-negative after immunochemotherapy in elderly DLBCL patients: Results of a planned interim analysis of the first 187 patients with bulky disease treated in the OPTIMAL>60 study of the DSHNHL.
Authors: Pfreundschuh Michael , Christofyllakis Konstantinos , Altmann Bettina , Ziepert Marita , Haenel Mathias , Viardot Andreas , Neubauer Andreas , Held Gerhard , Truemper Lorenz , Schmidt Christian , Kanz Lothar , Hallek Michael J. , Schmitz Norbert , Heintges Tobias , Koelbel Christian , Schneider Guenther , Ruebe Christian , Hellwig Dirk , Poeschel Viola , Murawski Niels 
Published: September 2018

7506 Background: RT to bulky sites improves outcome of elderly DLBCL patients [Lancet Oncol 2008; 9: 105-116; J Clin Oncol 2014; 32:112-1118]. Whether RT can be spared in PET-negative pts. after R-CHOP was prospectively addressed in OPTIMAL >60. Methods: 61 to 80 y-old pts. were randomized in a 2x2 factorial design to 6xCHOP-14 or 6xCHLIP-14 (liposomal instead of conventional vincristine) plus 8 x rituximab 375 mg/m2(R) q 2 wks. or 12xR (days -4,-1,1,4,14,28,42,56,91,126,175, 238). Pts. with bulk (>=7.5 cm) PET-positive after 6 cycles chemotherapy were assigned to RT (39.6 Gy), while PET-negative bulks were observed. Results: 187/505 (37%) had bulky disease and were compared to 117/306 (38%) RICOVER-60 pts. (38%) who had received 6xCHOP-14+8R. OPTIMAL>60 pts. were older (70 vs. 68 years) and had more IPI=3 (33% vs. 29%) and IPI=4,5 (34% vs. 23%) compared to RICOVER-60. PET was performed in 166/187 OPTIMAL>60 bulk pts. (reasons for no PET: early death: 5; excessive toxicity: 3; protocol violation: 1, non-compliance: 4, change of diagnosis: 6, others: 2). 80/166 (48%) bulks remained PET-positive after 6 cycles of chemotherapy and 62/80 (78%) were irradiated (reasons for no RT: progression: 8; medical reasons: 9; negative biopsy: 1), reducing RT from 67/117 (57%) in RICOVER-60 by 42% to 62/187 (33%) in OPTIMAL>60. Despite the unfavorable demographics, outcome of the 187 bulk pts. in OPTIMAL>60 was non-inferior to RICOVER-60, not even in the least intensive of the 4 OPTIMAL>60 treatment arms consisting of 47 pts. who received 6xCHOP-14+8R as in RICOVER-60. 2-year PFS and OS in OPTIMAL>60 was 79% and 88%, respectively, compared to 75% and 78% of the 117 RICOVER-60 pts. In a multivariable analysis adjusting for the IPI risk factors, the hazard ratio of the OPTIMAL>60 compared to the RICOVER-60 bulk pts. was 0.7 (95% CI: 03.; 1.5; p=0.345) for PFS and 0.5 (95% CI: 02.; 1.3; p=0.154) for OS. Conclusions: RT can be spared in bulky disease PET-negative after chemotherapy. This strategy results in a 42% reduction of RT without compromising the outcome of these patients. Supported by Amgen, Roche, Spectrum. Clinical trial information: NCT01478542.
CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001).
Authors: Abramson Jeremy S. , Palomba Maria Lia , Gordon Leo I. , Lunning Matthew Alexander , Arnason Jon E. , Forero-Torres Andres , Wang Michael , Albertson Tina M. , Allen Tara , Sutherland Claire , Xie Benhuai , Garcia Jacob , Siddiqi Tanya 
Published: September 2018

7513 Background: JCAR017 is a second-generation, CD19-directed, 4-1BB CAR T cell product comprising CD8 and CD4 CAR T cells in a 1:1 ratio. A multicenter phase 1 trial of JCAR017 in R/R B-cell NHL (NCT02631044) is underway. Methods: Patients with R/R DLBCL, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. There was no minimum ALC requirement for apheresis; no test expansion was required. Treatment includes lymphodepletion with fludarabine and cyclophosphamide, followed by JCAR017. Multiple dose levels (DLs)/administration schedules of JCAR017 are being evaluated. Study objectives include safety, PK, and antitumor response. Results: As of November 23, 2016, 28 patients have been treated and are evaluable for safety and efficacy. Nineteen were male, 9 female; 25 DLBCL, 2 MCL, and 1 FL grade 3B. Median age was 63 years (range 37-79), median number of prior therapies was 4 (range 1-8), 23 (82%) were refractory to their last chemotherapy, and 16 (57%) had prior transplant. No severe cytokine release syndrome (sCRS) was observed; 10 patients had grade 1-2 CRS (1 received tocilizumab). Five patients developed neurotoxicity, including 4 grade 3-4; all events resolved in the 4 patients who had adequate follow up. Median onset of CRS and neurotoxicity were 5 and 11 days, respectively. Four deaths after disease progression occurred, none related to JCAR017. In 20 patients treated at DL1 (5×107 cells), the RR was 80% with 60% achieving CR. One patient with secondary CNS involvement achieved CR without neurotoxicity. JCAR017 was detected at 3 and 6 months in responding patients, including some who relapsed; higher mean peak levels were detected in patients with durable response at 3 months. Data on patients treated at DL2 (1×108 cells), alternative dose schedules, tumor biopsy, and additional biomarkers will be presented. Conclusions: Treatment with JCAR017 results in high CR rate in patients with heavily pretreated R/R DLBCL. Relapses can occur despite persistence of JCAR017, suggesting tumor immune evasion mechanisms may contribute to relapse. Observed toxicities are manageable and occurred at rates lower than those reported for other CD19-directed CAR T cell products. Clinical trial information: NCT02631044.