bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementing cost transparency in oncology: A qualitative study of barriers, facilitators, and patient preferences.
Authors: Aakhus Erin , Rosenstein Abigail , Joffe Steven , Bradbury Angela R.
Published: September 2018

6597

Background: As cancer drug prices rise and insurance plans shift toward greater cost sharing, studies link patients’ high out-of-pocket (OOP) costs to non-adherence and early discontinuation of treatment. Meanwhile, few oncologists routinely discuss OOP costs with their patients. Using qualitative methods, we explored barriers and facilitators of cost transparency (i.e., disclosure of financial risks of cancer treatment). Methods: We performed semi-structured interviews with cancer patients (n = 22) and providers (n = 19) at an academic medical center and three affiliated community practices between August, 2015 and May, 2016. Two analysts coded the transcribed interview data using textual thematic methods, and hypotheses were generated employing grounded theory method. Results: We grouped themes that emerged into three major domains: 1) barriers, 2) facilitators, and 3) patient preferences. Patients and providers both expressed a strong aversion to making tradeoffs between financial and physical health outcomes. While patients feared being “profiled” based on their ability to pay, providers feared that cost transparency might threaten the doctor-patient relationship by exposing personal or institutional financial conflicts of interest. Pragmatic barriers included time constraints and difficulty in providing accurate cost estimates. Important facilitators were strong doctor-patient relationships and availability of support staff with financial expertise. We detected substantial heterogeneity in patient preferences. While some patients wanted to discuss costs with their provider, others feared “distracting” providers from their primary roles as health advocates. Conclusions: With implementation of OOP cost transparency, oncology practices will need to consider patient/provider aversion to financial/health tradeoffs, patients’ sensitivity to socioeconomic “profiling,” provider- and practice-level financial incentives, time constraints, accuracy of cost estimates, and variability in patient preferences. Meanwhile, strong provider-patient relationships and availability of support staff will facilitate OOP cost transparency.
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.
Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: Interim results of an on open-label, phase II study.
Authors: Nastoupil Loretta J. , Westin Jason R. , Fowler Nathan Hale , Fanale Michelle A. , Samaniego Felipe , Oki Yasuhiro , Obi Chizobam , Cao JingJing , Cheng Xiaoyun , Ma Man Chun John , Wang Zhiqiang , Chu Fuliang , Feng Lei , Zhou Shouhao , Davis Richard Eric , Neelapu Sattva Swarup
Published: September 2018

7519

Background: Follicular lymphoma (FL) tumors are infiltrated with antitumor T cells, however, their function is impaired by immune checkpoints such as PD-1/PD-ligand pathway. Blocking PD-1 enhances the function of antitumor T cells in FL. In addition, blocking PD-1 on NK cells has been shown to enhance the ADCC effect of NK cells. We reasoned that the combination of pembrolizumab (P), an anti-PD-1 antibody (ab), and rituximab (R), an anti-CD20 ab that induces ADCC, is likely to be synergistic through activation of both the innate and adaptive immune systems and result in enhanced clinical activity in FL. Methods: We evaluated P and R in an open-label, non-randomized, single institution, phase II trial (N=30). Key inclusion criteria included adult (age ≥ 18 years), FL grade 1-3a, ECOG 0-1, in relapse after ≥1 prior therapy (tx) and R sensitive disease, defined as a complete (CR) or partial response lasting at least 6 months (mos) after most recent R-containing therapy. Pts received R (375 mg/m2 IV) on days 1, 8, 15, and 22 of cycle 1 and P (200mg IV) q 3 weeks for up to 16 cycles starting on day 2 of cycle 1. Primary endpoint was overall response rate (ORR). Results: 27 pts have initiated therapy, median age 65 (range 42-79), 52% male, 76% had intermediate or high risk FLIPI, 56% met GELF criteria. Median prior tx =1 (range 1-4). Adverse events (AE) regardless of causality were mild, most grade 1-2. Grade 3 AE’s included nausea (N=2), infusion reaction (N=2), aseptic meningitis (N=1), pneumonia (N=1). Immune-related AEs included grade 2 diarrhea (N=2), grade 2 pneumonitis (N=1), grade 2 skin rash (N=1). At the pre-planned interim analysis (N=15), ORR was 80%, CR rate was 60%. With a median follow up of 7 mos (range 0.5-17), median DOR, PFS, and OS has not been reached. PD-L1 expression was tested in 8 baseline tumor samples using PD-L1 22C3 IHC pharmDx and was detected in histiocytes in all 8 tumors, present in only 1-8% of tumor cells in 5 tumors. Additional biomarker analyses are ongoing. Conclusions: The combination of P and R is well tolerated in relapsed FL and is associated with high overall and CR rate. These interim results warrant further investigation of this combination in FL. Clinical trial information: NCT02446457.
Ongoing phase 1/2 study of INCB050465 for relapsed/refractory (R/R) B-cell malignancies (CITADEL-101).
Authors: Ramchandren Rod , Phillips Tycel Jovelle , Wertheim Michael , Gutierrez Martin , Edenfield William Jeffery , Akard Luke Paul , Caimi Paolo Fabrizio , Call Justin , Persky Daniel Oscar , DeMarini Douglas James , Zhou Li , Yeleswaram Swamy , Forero-Torres Andres
Published: September 2018

7530

Background: INCB050465 is a selective PI3Kδ inhibitor with no preclinical hepatotoxicity at clinically relevant doses. We report emerging safety and efficacy data from a phase 1/2 study of INCB050465 in patients (pts) with r/r B-cell malignancies (NCT02018861). Methods: The protocol was initiated with a single patient cohort, treated with INCB050465 5 mg QD PO. Subsequent cohorts used a 3+3 design and evaluated doses of 10–45 mg QD. Based on PK/PD, the 20 and 30 mg QD cohorts were expanded. Responses were assessed Q9W by the Lugano Classification or International Working Group on Chronic Lymphocytic Lymphoma (CLL) criteria. Results: As of the data cutoff (Nov 1, 2016), 52 pts were treated (median age, 65 y [range, 30–88]; baseline tumors: diffuse large B-cell lymphoma [DLBCL], n=14; follicular lymphoma [FL], n=10; Hodgkin lymphoma [HL], n=9; marginal zone lymphoma [MZL], n=8; CLL, n=6; mantle cell lymphoma [MCL], n=5; 62% had >3 prior systemic regimens). Median duration of therapy was 3.3 mo (range, 0.6–13.4); no DLTs were identified. 67% of pts discontinued therapy (disease progression, 31%; AEs, 25%); 33% had dose interruption; 4% had reduction. Most common nonhematologic AEs (all grade [Gr]; Gr ≥3): nausea (38%; 0%), diarrhea (31%; 6%), vomiting (25%; 0%); Gr ≥3 hematologic AEs: neutropenia (21%), lymphopenia (17%), thrombocytopenia (10%), anemia (4%). 40% of pts had serious AEs, most frequently colitis, diarrhea, hypotension (all n=3). 1 pt had Gr 3 pneumonitis; none had Pneumocystis jirovecii pneumonia (PJP) or Gr ≥2 elevated transaminase. Objective responses (ORs) occurred at all doses (Table), except 5 mg QD; 90% were observed at first assessment. Conclusions: INCB050465 demonstrated manageable toxicities with no clinically meaningful transaminitis/PJP. OR rates were generally high, with 90% observed at first assessment. Different dosing regimens/schedules, long-term safety, and disease-specific cohorts are being evaluated. Clinical trial information: NCT02018861. [Table: see text]
Phase II study of single-agent copanlisib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
Authors: Lenz Georg , Hawkes Eliza , Verhoef Gregor , Haioun Corinne , Thye Lim Soon , Heo Dae Seog , Ardeshna Kirit , Chong Geoffrey , Christensen Jacob Haaber , Shi Vivian , Lippert Susanne , Hiemeyer Florian , Piraino Paolo , Pena Carol Elaine , Buvaylo Viktoriya , Childs Barrett H. , Gorbatchevsky Igor , Salles Gilles A.
Published: September 2018

7536

Background: Relapsed/refractory (r/r) DLBCL patients (pts) are characterized by poor prognosis. Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor, with modest single-agent activity in unselected DLBCL pts. Here we report the treatment effect of copanlisib in r/r DLBCL pts with regards to cell of origin (COO) and molecular biomarker profiles (NCT02391116). Methods: Patients with r/r DLBCL and ≥1 prior lines of therapy were eligible. Copanlisib (60 mg IV infusion) was administered on days 1, 8 and 15 of a 28-day cycle. Tumor samples were evaluated for COO, CD79B mutations and > 400 genes by next generation sequencing (NGS). The primary endpoint was objective tumor response rate (ORR; per Lugano Classification, 2014) by COO and CD79B status. Results: The full-analysis (FAS) and per-protocol sets (PPS; ≥3 doses, post-baseline scans and NGS/COO data) included 67 and 40 pts, respectively. Pts were 58% male, median age 69 (range 25-93), ECOG status 0/1/2 22%/57%/21%, and heavily pretreated (median prior lines = 3, range 1-13). In the PPS, COO (and mutant CD79B status) analysis identified 22 GCB DLBCL (2 mutant), 16 ABC DLBCL (6 mutant), and 2 unclassifiable. The ORR in the PPS was 25% (10 of 40), with 5 complete responses (CR) and 5 partial responses (PR); stable disease in 12 pts. The ORR was 13.6% with 1 CR in GCB pts and 37.5% with 4 CRs (25%) in ABC pts. Response to copanlisib was 25% in pts with (2/8) and without (8/32) CD79B mutations. Five of 10 ABC DLBCL-wtCD79B pts and one GCB DLBCL-mCD79B responded (ongoing > 17 cycles). NGS analysis in 54 pts detected 348 mutations; BCL2 (54% of pts), TP53 (41%), BCL6 (30%), MYC (22%), CD79B (19%)/A (6%), MYD88 (19%), TNFAIP3 (17%), CARD11 (13%), and NFKBIA (9%). Response to copanlisib was not significantly different based on BCL2, BCL6, MYC, and MYD88 mutations. With a median of 6 cycles (range 1-29), the most common AEs (% all grade/gr3+4) were diarrhea (36/2), nausea (31/2), fatigue (31/3), fever (21/2) and transient hypertension (40/33) and hyperglycemia (34/31). There were 14 gr5 AEs (none drug-related). Conclusions: Copanlisib treatment of r/r DLBCL pts resulted in encouraging responses, especially in the ABC subtype, with a manageable toxicity. Clinical trial information: NCT02391116.
Early disease progression in patients (pts) with newly diagnosed localized nasal extranodal NK/T-cell lymphoma, nasal type (ENKL) treated with radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC).
Authors: Yamaguchi Motoko , Suzuki Ritsuro , Oguchi Masahiko , Asano Naoko , Miyazaki Kana , Terui Yasuhito , Kubota Nobuko , Maeda Takeshi , Kobayashi Yukio , Amaki Jun , Soejima Toshinori , Saito Bungo , Shimoda Emiko , Fukuhara Noriko , Tsukamoto Norifumi , Shimada Kazuyuki , Choi Ilseung , Utsumi Takahiko , Ejima Yasuo , Katayama Naoyuki ,   NKEA Project
Published: September 2018

7546

Background: Approximately 25% of all pts with localized nasal ENKL experience disease progression during the first two years (yrs) after diagnosis under new treatments including concurrent chemoradiotherapy. The clinical features of those pts are largely unknown. Methods: The database of our study (NKEA project; UMIN000015491) was used for the present analysis. Data from pts with newly diagnosed localized (stage IE and contiguous IIE) nasal ENKL diagnosed between 2000 and 2013 at 31 institutes in Japan and treated with RT-DeVIC were retrospectively analyzed. Progression of disease within 2 yrs (POD24) (Casulo, JCO 2015) was applied as the definition of early progression. Results: Of 162 pts, 38 were in the POD24 group (23%) and 124 were in the reference group. Treatment yrs and doses of RT and DeVIC were not associated with the incidence of POD24. With a median follow-up of 5.8 yrs, the overall survival (OS) of the POD24 group was inferior to that of the reference group ( P < 0.00001; 2-yr OS, 26% vs. 100%; 5-yr OS, 23% vs. 89%). The POD24 group showed the following features more frequently than the reference group: serum soluble interleukin-2 receptor (sIL-2R) level > upper limit of normal (ULN) (25/33, 76%; P = 0.000012), C-reactive protein (CRP) > ULN (28/37, 76%; P = 0.013), and detectable Epstein-Barr virus (EBV)-DNA in peripheral blood (15/17, 88%; P = 0.033). The positive predictive value and negative predictive value of elevated sIL-2R for POD24 were 42% and 90%, respectively; those of elevated CRP were 31% and 87%, respectively; and those of detectable EBV-DNA were 39% and 90%, respectively. Of the 9 pts who were negative for all three factors, none experienced POD24. A multivariate analysis in the POD24 group identified elevated sIL-2R as an independent predictive factor for worse OS (HR 3.16; 95% CI, 1.07 - 9.32). Conclusions: Pretreatment sIL-2R, CRP, and EBV-DNA were associated with POD24 among pts with localized nasal ENKL treated with RT-DeVIC. The strong association of elevated sIL-2R with early progression and short OS in the POD24 group provides a rationale for targeting strategies.
Circulating tumor DNA assessment in patients with diffuse large B-cell lymphoma following CAR-T therapy.
Authors: Dahiya Saurabh , Le Ryan , Hossain Nasheed Mohammad , Abramian Matthew , Muffly Lori S. , Miklos David Bernard
Published: September 2018

7552

Background: Circulating tumor DNA(CTD) have been used for disease monitoring in Diffuse Large B Cell Lymphoma(DLBCL) (Kurtz ASCO 2016). Role of CTD assessment in DLBCL patients treated with CAR-T therapy has not been studied. We prospectively analyzed CTD of dynamics measured by next generation sequencing(NGS) of BCR using ClonoSeq MRD(Adaptive Biotechnologies), before and after CAR-T therapy to determine feasibility and clinical utility. Methods: At Stanford, 7 patients were enrolled on ZUMA-1 clinical trial NCT02348216, treating chemo-refractory DLBCL patients with anti-CD19, CAR-T. Complete radiologic data and CTD analysis was collected for six subjects. Tumor-DNA was extracted from archival paraffin-embeded tissue & analyzed using the NGS-based assay. PCR amplification of IGH-VDJ, IGH-DJ & IGK regions using universal consensus primers was performed followed by NGS to determine the tumor clonotype(s). Blood collected at day 0,7,14,28,60 & 90 days in relation to CAR-T infusion was used to detect CTD by ClonoSeq quantification of clonotypes. Results: Clonotypes were successfully determined for all 6 subjects, and 30 blood samples for 6 patients were prospectively analyzed. All patients had measurable disease burden pre-CAR-T infusion. CTD dynamics correlated with PET-CT outcomes in 100% of the patients. Increasing CTD temporally preceded progressive disease(PD) before PETCT recognition in 4 of 5 patients and was always increasing when PETCT showed PD. Preceding CTD quantification correlated with disease volume increase. One patient achieved durable KTE-19 complete response(CR) and detectable CTD became undetectable on day 14(and on subsequent samples) following CAR-T infusion, corresponding to 1 & 3 month PETCT CR. Additionally, the burden of disease measured by lymphoma molecules per ml allowed volumetric response assessment in all the patients who experienced massive reduction in tumor volume, but by traditional response definition had partial response. Conclusions: ClonoSeq CTD provides precise total tumor quantification of DLBCL in the CAR-T cell setting. This technology may overcome fundamental limitations of DLBCL imaging(cost, radiation exposure & limited repetition).
Interim metabolic tumor volume to predict response in diffuse large B-cell lymphoma.
Authors: Islam Prioty , Goldstein Jordan , Sethi Ila , Lee Daniel , Flowers Christopher
Published: September 2018

7557

Background: DLBCL is a heterogeneous disease with varied clinical outcomes following treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). [18F] fluorodeoxyglucose (FDG) – positron emission tomography (PET)/computed tomography (CT) imaging is ubiquitously used in monitoring of DLBCL. PET-derived metrics for analysis of tumor FDG uptake include: tumor maximum standardized uptake value (SUV); metabolically active tumor volume (MTV); and total lesion glycolysis (TLG), calculated from the intensity of FDG uptake in tumor volume. We evaluated the predictive value of interim SUV, MTV and TLG for patients (pts) with DLBCL treated with R-CHOP. Methods: Pts with DLBCL treated at Emory University 2005-2016 were eligible. Cases were included if there was a diagnosis of DLBCL confirmed by record review, available information on date of diagnosis, date of last contact or date of death. Analyses were restricted to patients who received R-CHOP and had PET/CT scans available at baseline, Cycle 2 or 4 and end of treatment. Maximum SUV, MTV, and TLG were calculated using MIM software for tumor with an SUV threshold of > 4. Logistic regression analysis was used to calculate the predictive value of interim PET/CT metrics on end of treatment response. Results: Pre-treatment PET/CT scans for 42 patients were identified, along with 28 interim and 31 post-treatment scans. The mean pre-treatment MTV was 303ml (range 4 – 1,327) and mean TLG was 3188 (range 28 – 16,176). MTV and TLG were undetectable in 79% of interim scans and 74% of the post-treatment scans. A Deauville score of 3 or less was observed in 71% of the interim PET/CT scans and 56% of the post-treatment scans. A positive interim MTV was correlated with a positive post-treatment MTV and post-treatment Deauville score at 0.58 and 0.66, respectively, and a positive interim MTV result was a significant predictor of a positive post-treatment MTV result (p = 0.02). Conclusions: PET-derived metrics of assessing interim tumor response to therapy offer significant predictive value for end of treatment response, and can guide a response-adapted treatment approach for DLBCL pts that builds on the R-CHOP backbone.
Lenalidomide, doxorubicin hydrochloride and dexamethasone versus bortezomib, lenalidomide, and dexamethasone prior to scheduled stem cell transplant in newly diagnosed myeloma.
Authors: Knop Stefan , Langer Christian , Engelhardt Monika Martha , Wangemann Johanne , Muegge Lars Olof , Bassermann Florian , Schaefer-Eckart Kerstin , Blau Igor W. , Wolleschak Denise , Reichle Albrecht , Metzler Ivana von , Metzner Bernd , Röllig Christoph , Hertenstein Bernd , Pfreundschuh Michael , Brümmendorf Tim H. , Gramatzki Martin , Ritgen Matthias , Held Swantje , Einsele Hermann ,   Deutsche Studiengruppe Multiples Myelom
Published: September 2018

8001

Background: In younger, medically fit patients (pts) with newly diagnosed (ND) multiple myeloma (MM), autologous stem cell transplant (SCT) remains a standard of care. Prior to SCT, induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks amongst the most effective treatments. VRD + SCT proved superior over VRD alone in a randomized, controlled trial (RCT). We found encouraging efficacy and low toxicity with RAD (RD and adriamycin) + SCT and decided to compare RAD versus VRD induction in an RCT. Methods: The DSMM XIV study was set up according to a double 2x2-factorial design to enroll NDMM pts up to 65 years (yrs). Post-induction (PI) CR rate was the efficacy endpoint for the initial study phase. We hypothesized CR rate with RAD would be non-inferior to an estimated 20% CR with VRD. The study was powered to confirm non-inferiority of RAD at a 10% margin with a one-sided α level of .05. Minimal residual disease (MRD) was analyzed by eight-color flow cytometry (EuroFlow standards) on marrow samples. Results: 476 pts were randomized between 05/2012 and 06/2016, 469 of whom (median age 55 (range, 32–65) yrs) received at least one dose of study drug. 18.3% of pts had ISS stage III MM and 17.2%, elevated LDH. 11.3% of pts had del17p; 11.1% had t(4;14); and 4% had t(14;16). 232 pts were randomized to 3 four-week RAD cycles and 237 to 3 three-week VRD cycles, respectively. 89.7% of RAD versus 93.2% of VRD pts completed all induction cycles. PI CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD versus 13.0% (90% CI, 8.9-18.0) with VRD, (P = .697). 72/317 pts (22.7%) with paired baseline/PI samples achieved negative MRD at a median sensitivity level of 6.73x10-6. 47 (20.3%) RAD versus 35 (14.8%) VRD pts experienced treatment-emergent SAEs (P = .144). Treatment-related induction mortality was 0% in either arm. Conclusions: To the best of our knowledge, this is the first RCT to compare two lenalidomide-based triplets prior to SCT. The endpoint was met with comparable PI CR rates for RAD and VRD, respectively. Tolerability was encouraging in both arms. Follow-up data is needed to analyze time-dependent endpoints. Clinical trial information: NCT01685814.
Impact of denosumab (DMB) compared with zoledronic acid (ZA) on renal function in the treatment of myeloma bone disease.
Authors: Raje Noopur S. , Roodman G. David , Willenbacher Wolfgang , Shimizu Kazuyuki , Garcia-Sanz Ramon , Durie Brian G. , Zhu Li , Cheng Paul C. , Bhatta Sumita , Terpos Evangelos
Published: September 2018

8005

Background: Osteolytic bone disease and renal dysfunction are complications of multiple myeloma. ZA, used for the prevention and treatment of bone complications, can be nephrotoxic. DMB inhibits RANKL and thereby osteoclast function, and is not renally cleared. This international, phase III, randomized, double blind study evaluates the efficacy and safety of DMB compared with ZA in newly diagnosed myeloma patients (pts). Methods: Eligible pts were randomized 1:1 to DMB 120mg SC Q4W or ZA 4mg (renally adjusted) IV Q4W along with anti-myeloma therapy. Pts with baseline CrCl<30mL/min were excluded due to ZA dosing restrictions. The primary endpoint was non-inferiority of DMB to ZA with respect to time to first on-study SRE. Overall survival (OS) was a secondary endpoint; progression-free survival (PFS) was an exploratory endpoint. Renal toxicity and safety were assessed. Results: 1718 pts were randomized, 859 to each arm. Baseline renal insufficiency (CrCl ≤ 60mL/min) was reported in 26.7% of pts. DMB was non-inferior to ZA ( P = 0.01) in delaying time to first on-study SRE. Fewer AEs potentially related to renal toxicity were reported with DMB compared to ZA overall (10.0% vs 17.1%, P < 0.001) in those with baseline CrCl > 60mL/min (8.8% vs 14.2%) and particularly in those with baseline CrCl ≤ 60mL/min (12.9% vs 26.4%). 12.5% of pts on DMB experienced an increase in creatinine, compared to 20.8% of those on ZA. Median cumulative exposure (Q1, Q3) to DMB was 15.75 months (8.18, 25.79) compared to 14.78 months (7.46, 24.87) for ZA. PFS yielded a HR (95%CI) of 0.82 (0.68, 0.99); descriptive P = 0.036. OS HR (95%CI) between DMB and ZA was 0.9 ([0.70, 1.16]; P = 0.41), with fewer deaths in DMB (121 [14.1%]) than in ZA (129 [15.0%]). Conclusions: DMB achieved the primary endpoint of non-inferiority to ZA in delaying time to first on study SRE in pts with newly diagnosed MM. Pts on DMB had a significantly lower rate of renal AEs compared to ZA; more importantly this rate was 2-fold lower in pts with renal insufficiency (CrCl≤60mL/min). The bone specific benefits in combination with the renal function results and possible prolongation of PFS with DMB therapy is promising. Clinical trial information: NCT01345019.