bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics, pharmacodynamics, safety, and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.
Authors: Elassaiss-Schaap Jeroen , van Zandvoort Peter , Lo Jeannette , Nair Nitya , Walling Jackie , Hari Parameswaran , Bensinger William
Published: March 2020

8022

Background: APRIL (“a proliferation-inducing ligand”) levels are elevated in the serum of patients diagnosed with multiple myeloma (MM) and is correlated to promotion of malignancy, chemo- and immune-resistance. BION-1301 (BION) is a recombinant, humanized monoclonal antibody against APRIL. We report on the initial pharmacokinetic/ pharmacodynamic (PK-PD) profile, safety, and tolerability of BION in adults with relapsed or refractory MM. Methods: Adults with MM and disease progression after ≥3 systemic therapies were recruited for the study. BION was administered every 14 days through intravenous infusion. This ongoing Phase 1/2, open-label, multicenter study is evaluating 6 cohorts with increasing BION dose levels of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Serum was analyzed for BION, anti-drug antibodies (ADA), and free APRIL (fAPRIL) at baseline and upon treatment, and evaluated by PK-PD modeling. Results: As of 7Dec2018 reporting through the first 4 cohorts, 15 patients were enrolled in the study (N = 3-4 per cohort). BION has been well-tolerated to date. While exposure increased dose-proportionally from 50 to 1350 mg, half-life and clearance did not significantly differ between 50 and 1350 mg. APRIL serum levels decreased with increasing BION doses. To date no DLT was observed. Non-neutralizing ADA were detected in 1 of the 15 patients. BION transiently reduced fAPRIL levels starting at a dose of 50 mg. A prolonged reduction was seen at higher doses, and at 450 mg, reduction was maintained in 2 patients on treatment for 6 cycles (5.5 months). The area under the normalized fAPRIL curve (Days 1-15) decreased 5-fold from 50 to 1350 mg. Data fit well in an exploratory PK-PD model, with kinetic binding of BION and fAPRIL according to in vitro parameters, and peripheral compartments for both entities. While at 450 mg, 95% target engagement (TG) was achieved around peak exposure levels, at 1350 mg this 95% TG was maintained throughout the dosing interval of 3 doses. Conclusions: BION dose-dependently inhibits serum levels of fAPRIL between 50 to 1350 mg dose levels. Exposure was approximately dose-linear over the dose range evaluated, with a low incidence of ADA. Promising TG was obtained at prolonged dosing of 450 mg Q2W. A favorable safety profile supports continued dose escalation and more frequent dosing regimens based on PK-PD modeling. The study is ongoing with subjects exposed to higher and/or more frequent doses anticipated to result in accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.
Effect of iFISH defined 1q21 amplification/gain in multiple myeloma patients treated on total therapy protocols.
Authors: Zangari Maurizio , Mohan Meera , Weinhold Niels , Rasche Leo , Sawyer Jeffrey , Van Rhee Frits , Thanendrarajan Sharmilan , Schinke Carolina D. , Davies Faith , Tian Erming
Published: March 2020

8023

Background: The amplification of the proximal 1q21 region has been reported by interphase FISH (iFISH) in about 40% of newly diagnosed patients, and in 70% of MM patients at relapse. We hereby report the prognostic value of 1q21 amplification/gain by iFISH at enrollment in subjects treated on total therapy (TT) 4, 5 and 6 protocols. Methods: TT4 protocol enrolled newly diagnosed patients with LR disease as defined GEP 70 model ≤ 0.66. TT5 was designed for newly diagnosed patients with HR MM.TT6 enrolled previously treated patients with both HR and LR disease. iFISH was performed on bone marrow samples obtained at the time of study enrollment. FISH probes were generated from specific BAC DNA clone for CKS1B gene locus (1q21) gene locus. MM cells were identified post hybridization using isotype specific antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) to stain Ig-Kappa or Ig-Lambda light chain in cytoplasm (cIg) of MM cells. The iFISH signals in 100 of MM cells were recorded. A 20% cutoff point was used for detection of significant abnormalities i.e. gain of 1q21 (≥ 3 copies). Results: 607 patients were included in this analysis. With a median age of 61 years, 39% had high risk and 88% low risk disease. 1q21 abnormalities were present in 55% of patients at enrollment. 591 patients (97%) received at least one HDT ASCT. The analysis included 382 TT4 patients with a median PFS of 7.2 years and OS not yet reached. 75 patients enrolled on TT5 protocol experienced median PFS of 2.2 years and median OS of 5.6 years.150 TT6 enrolled patients experienced median PFS of 4.1 years and median OS of 7.5 years. Statistically significant difference in PFS (p < 0.0001) and OS (p < 0.0001) was observed between 1q21 defined groups (figure 1). No differences in survival were observed based on the 1q21 copy number > 3. Conclusions: This retrospective analysis clearly showed that 1q21 amplification/gain detected by interphase iFISH in different stages of disease can identify patients with significant shorter progressive free and overall survival even if exposed to total therapy regimens. Clinical trial information: NCT00734877, NCT00869232.
Correlation of minimal residual disease negativity (MRD-) with prognosis in high-risk myeloma (HRM).
Authors: Kunacheewa Chutima , Patel Krina K. , Lee Hans Chulhee , Thomas Sheeba K. , Amini Behrang , Srour Samer , Bashir Qaiser , Qazilbash Muzaffar H. , Weber Donna M. , Neelapu Sattva Swarup , Orlowski Robert Z. , Feng Lei , Lin Pei , Manasanch Elisabet Esteve
Published: March 2020

8024

Background: MRD is a standard measurement for response assessment in MM. Despite new treatments, HRM patients continue to have poor prognosis. We evaluated the impact of MRD- in high vs standard (SRM) risk patients. Methods: We retrospectively evaluated all consecutive MM/plasma cell leukemia patients who had routine MRD testing by 1-tube 8-color advanced flow cytometry with 2,000,000 events and sensitivity level 10-5 at our center from 2015-2018 after initial therapy. Kaplan-Meier and log-rank test were used to assess survival estimates and differences between study groups. Results: 136 patients with MRD testing after initial therapy/autologous transplant (ASCT) were identified. Patient and disease characteristics are included in Table. At a median follow-up of 14 months (1-36), PFS and OS were significantly worse in HRM vs SRM. During the study period, 50% of HRM had progressed (relapse and/or death) vs 20% in SRM (p=0.0006). No patients with SRM died, but 4 (14%) in the HRM group did (p=0.0007). Regardless of MRD status, HRM patients had statistically significant worse PFS than SRM; at median f/u 10% SRM MRD-; 20% SRM MRD+; 40%HRM MRD-; 45% HRM MRD+ had either relapsed or died (p=0.0041). MRD status did not impact OS in either group (p=0.0914), however longer follow up is needed to assess survival. Conclusions: Genetic abnormalities (FISH/GEP) remain a powerful prognostic indicator for myeloma regardless of MRD status. For newly diagnosed myeloma patients treated with novel triple initial therapy and frontline ASCT, achieving MRD negative status didn’t mitigate the poor prognosis outcomes of HRM. [Table: see text]
Safety and efficacy of once-weekly carfilzomib (K) dosing in frail patients (pts): A subgroup analysis from the phase 3 A.R.R.O.W. study.
Authors: Mateos Maria-Victoria , Ludwig Heinz , Kumar Shaji , Rosenbaum Cara Ann , Huang Mei , Goldrick Amanda , Blaedel Julie , Dimopoulos Meletios A.
Published: March 2020

8027

Background: A.R.R.O.W. demonstrated superior progression-free survival (PFS) with once-weekly K (70 mg/m2)-dexamethasone (Kd70) vs twice-weekly K (27 mg/m2)-dexamethasone (Kd27) in relapsed and refractory multiple myeloma (RRMM) pts, regardless of age. Weekly Kd70 is US-approved for relapsed or refractory MM (1–3 prior therapy lines). For a comprehensive fitness measure, frailty scales were developed incorporating age, comorbidities, and functional status. (Palumbo Blood 2015; Facon Blood 2015). Here we assessed post hoc pt outcomes by frailty status. Methods: PFS and safety were assessed by treatment arm and a frailty algorithm incorporating age, medical history–derived Charlson Comorbidity Index, and ECOG performance status; pts with frailty scores of 0, 1, or ≥2 were classified as fit, intermediate (int), or frail, respectively. PFS was assessed with the Kaplan-Meier method. Safety was assessed in pts who received ≥1 treatment dose. Results: Pt distribution by frailty status was generally balanced between arms (Table). Once-weekly Kd70 vs twice-weekly Kd27 resulted in median PFS for fit, int, and frail pts of 15.7 vs 5.7 (mos; HR 0.53 [95% CI, 0.33–0.86]), 11.1 vs 7.7 mos (HR 0.81 [95% CI, 0.55–1.19]), and 10.3 vs 6.6 mos (HR 0.76 [95% CI, 0.49–1.16]), respectively. Rates of grade ≥3 treatment-emergent adverse events (TEAEs) of interest were similar between treatment arms across frailty subgroups (Table). In the once-weekly Kd70 subgroups, there was no grade ≥3 peripheral neuropathy (PN); grade ≥3 cardiac failure rates were ≤4%. Conclusions: Once-weekly Kd70 resulted in PFS benefits vs twice-weekly Kd27 with a favorable benefit/risk profile regardless of frailty score as defined. These results support weekly Kd70 as a treatment option for both fit and frail RRMM pts. Clinical trial information: NCT02412878. [Table: see text]
Implications and outcomes of MRD-negative multiple myeloma patients with immunofixation positivity.
Authors: Tschautscher Marcella , Jevremovic Dragan , Buadi Francis , Lacy Martha , Gertz Morie A. , Dispenzieri Angela , Kapoor Prashant , Dingli David , Hayman Suzanne R. , Lust John Anthony , Russell Stephen J. , Leung Nelson , Go Ronald S. , Lin Yi , Gonsalves Wilson I. , Kourelis Taxiarchis , Warsame Rahma M. , Kyle Robert A. , Rajkumar S. Vincent , Kumar Shaji
Published: March 2020

8034

Background: Minimal residual disease (MRD) assessment in multiple myeloma (MM) has improved our ability to assess disease activity, resulting in more advanced prognostication. While MRD assessment remains confined to the bone marrow (BM) plasma cell population, serum studies including immunofixation (IFE) are required to complete response evaluation. The significance of those who are MRDneg yet have detectable monoclonal protein through IFE remains unclear. Methods: We retrospectively studied 256 MM patients who had MRD assessment via the Euroflow multiparametric flow cytometry on the BM with concomitant serum IFE testing. Patients who were MRDneg were included in the study. Outcomes included probability of disease progression (PD) at 1 year. The Cox-proportional hazards model was used to compare probability of PD among different groups. Time to progression (TTP) was calculated as the difference from date of MFC analysis to PD in months. Results: Among the entire cohort, 178 (70%) patients were MRDneg and median follow-up from MRD assessment was 6.3 months. Among these patients, 74 (42%) had a positive IFE at the time of MRD analysis. Within the MRDneg/IFEpos group, 31 (42%) patients remained IFEpos after a median follow up of 5.5 mo from initial MRD/IFE testing while 34 patients eventually became IFEneg after a median of 2.8 mo with no subsequent IFE available in 9 patients. The 1 year probability of PD in the MRDneg/IFEneg group was 20% compared to 41% in the MRDneg/IFEpos group (P < 0.01, Wilcoxon test). When comparing subsequent IFE status in those who were MRDneg/IFEpos, those who remained IFEpos had a trend towards shorter TTP compared to patients who later became IFEneg. Conclusions: Persistent monoclonal protein in the face of MRD negativity predicts for a shorter TTP. This likely reflects persistent disease that was not sampled on the BM aspirate in many of these patients compared to those who eventually become IFEneg with a trend towards longer TTP owing to the prolonged half-life and therefore clearance of M protein. This supports the current strategy of assessing for MRD at the time of suspected complete response to reduce the chance of positive MRD tests and thus avoidance of multiple BM exams.
Plasma cell-free DNA chromosomal instability score as early predictor to monitor tumor burden in response to therapeutic in multiple myeloma patients.
Authors: Du Juan , Jia Yanchun , Qiang Wanting , Lu Jing , Li Lu , Jiang Hua , Ziliang Qian , Fu Weijun
Published: March 2020

8036

Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by chromosomal instabilities (CIN). Here we investigate the potential of cell-free DNA CIN as non-invasive biomarker to predict early response for MM treatments. Methods: In this prospective study, we recruited 11 relapsed/refractory (RRMM) and 19 newly diagnosed (NDMM) patients at Changzheng Hospital. Plasma samples were collected after finished two cycles or one month (RRMM) of therapy, with matched ones before the current regimen. cfDNA was extracted, followed by CIN analyses by using a customized bioinformatics workflow, ultrasensitive chromosomal aneuploidy detector (UCAD). Criteria for response and progression were according to the IMWG (Durie BG et al. 2006). Results: 7 (23%) patients (5 RRMM and 2 NDMM) showed high cfDNA CIN regard as strong positive after two cycles of treatment. Plasma cfDNA CIN profiling found complex clonal evolution compared two cycles to baseline. Multiple genomic regions, including chr7, 17p (TP53), 12q and 3p, were involved in clonal evolution. The degree of cfDNA CIN correlated with myeloma stage and overall survival. Remarkably, of the 5 heavily treated RRMM patients and 1 primary refractory newly diagnosed patient, 3 died within 60 days after the last time of cfDNA detection. Nine patients (30%) of patients showed positive cfDNA CIN after two cycles of treatment, which response rate was 11% (n=1) with SD, 33% (n=3) with MR, and 56% with PR, respectively. Fourteen patients with 5 RRMM and 9 NDMM were detected marginal or negative cfDNA CIN after two cycle’s treatment. The overall response rate in 14 patients was 100%, including 14.3% with a complete response, 14.3% with a very good partial response (VGPR), 57.1% with a PR, and 14.3% with a MR. Of these patients, 3 RRMM who received with more than six lines of therapy, showed positive cfDNA CIN. Subsequently, these three heavily treated RRMM patients have chance to enroll the chimeric antigen receptor T-Cell immunotherapy (CAR-T) therapy (enrolled NCT03093168). Surprisedly, all of them benefit from the CAR-T therapy to improve responses dramatically, meanwhile, the dynamics of total cfDNA concentration correlated with tumor burden to negative. Conclusions: We provide evidence that cfDNA level correlates with tumor burden and response rate in MM. For heavily pre-treated advanced RRMM patients with cfDNA CIN positive were benefit from the CAR-T therapy. Therefore, serial plasma cfDNA analysis is a robust and sensitive tool for monitoring response to therapy.
Efficacy and safety of daratumumab, lenalidomide, and dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): Updated subgroup analysis of POLLUX based on cytogenetic risk.
Authors: Kaufman Jonathan L. , Dimopoulos Meletios A. , Leiba Merav , Morton James , Ho P. Joy , Kim Kihyun , Moreau Philippe , Sutherland Heather J , Iida Shinsuke , Kim Jin Seok , Prince H. Miles , Rocafiguera Albert Oriol , Bahlis Nizar J. , Chari Ajai , Avet-Loiseau Herve , Chiu Christopher , Soong David , Ukropec Jon , Qi Ming , San Miguel Jesus
Published: March 2020

8038

Background: High-risk cytogenetic abnormalities confer poor outcomes in MM patients (pts). In POLLUX, D-Rd demonstrated significant clinical benefit, including prolonged progression-free survival (PFS) vs lenalidomide and dexamethasone (Rd), and tolerability in RRMM pts. We present a subgroup analysis of POLLUX, based on cytogenetic risk. Methods: Pts had ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of fluorescence in situ hybridization/karyotype testing and next-generation sequencing (NGS). High-risk pts had t(4;14), t(14;16), or del17p abnormalities; standard (std)-risk pts did not meet high-risk criteria. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0. Results: In POLLUX (D-Rd, n = 286; Rd, n = 283), 17.1% of pts in the D-Rd group and 20.1% of pts in the Rd group had high-risk abnormalities. After 44.3 months (mo) of median follow up, D-Rd prolonged PFS vs Rd in pts with high- (median 26.8 vs 8.8 mo; HR, 0.54 [95% CI, 0.32-0.91]; P = 0.0175) or std-risk (median not reached [NR] vs 19.9 mo; HR, 0.41 [95% CI, 0.31-0.55]; P <0.0001). Responses with D-Rd were deep, including higher rates of MRD negativity and sustained MRD negativity vs Rd (Table). D-Rd prolonged PFS in first relapse pts (high risk: median 46.0 vs 7.3 mo; HR, 0.26 [95% CI, 0.11-0.59]; P = 0.0005; std risk: median NR vs 20.6 mo; HR, 0.43 [95% CI, 0.28-0.66]; P <0.0001) and prolonged PFS2 vs Rd in high- (median 38.3 vs 22.1 mo; HR, 0.53 [95% CI, 0.30-0.93]; P = 0.0249) or std-risk (median NR vs 33.8 mo; HR, 0.53 [95% CI, 0.39-0.72]; P <0.0001) pts. Additional data will be presented. Conclusions: D-Rd demonstrates significant efficacy in high-risk RRMM. Among high-risk pts, MRD negativity was only achieved with D-Rd. Clinical trial information: NCT02076009. [Table: see text]
Weekly 20/56 mg/m² carfilzomib, lenalidomide, and dexamethasone until progression in early relapsed refractory multiple myeloma.
Authors: Gruchet Cecile , Richez Valentine , Guidez Stephanie , Fouquet Guillemette , Azais Isabelle , Durand Geraldine , Javaugue Vincent , Plasse Florent , Machet Antoine , Moya Niels , Gardeney Helene , Bobin Arthur , Levy Anthony , Sabirou Florence , Bonnin Anthony , Dieval Celine , Primault Sylvain , Bridoux Frank , Avet-Loiseau Herve , Leleu Xavier
Published: March 2020

8041

Background: Triplet-based Carfilzomib (K), Lenalidomide and Dexamethasone combination (KRd) has led to approval in early RRMM based on ASPIRE International phase 3 study. However, K was used on a twice a week basis at 27mg/m2 and limited to 18 months exposure. We have reported already that KRd on a weekly basis at 56 mg/m2 was active similar to ASPIRE KRd and safe. We report herein the long-term exposure data on KRd weekly given until progression. We aimed to evaluate the efficacy of KRd given on a prolong duration beyond 18months, and to validate the safety profile of continuous exposure to K. Methods: 28 patients were prospectively recruited. Carfilzomib 20/56mg/m2 was administered on days 1,8,15, Lenalidomide 25mg/day was given 21/28 days and Dexamethasone was administered weekly on 28 days cycles until progression. Results: With a median follow-up at start of KRd of 30 months, 50% of patients relapsed and 39% died. 24/28 patients received 1 prior line of treatment. 8/28 patients are still on treatment with duration > 24 month and 6/28 with duration > 30 months. The median number of cycles was 15. ORR and CBR was 85.7% and 89.3%, whom 46% ≥ CR ; with a median DOR of 13 months and 43% having more than 18 months. 6 patients had negative MRD at 10-6 and normalized PET CT. Median of OS is not reached, and the 30 month-expected OS from the start of KRd was 56%. The median PFS and EFS was at 29 months, and the 30 month-expected PFS and EFS was 45%. PFS and EFS being superimposable speaks to that there was no safety concern related to prolonged exposure to K. Only 4 patients stopped KRd for safety issues. Hematologic and non-hematologic adverse events ≥ grade 3 were reported in 16/28 and 10/28 patients. Adverse events ≥ grade 3 seen in ≥10% of patients were neutropenia, thrombocytopenia, vomiting and pyrexia. Of note, 5 patients (18%) were ≥ 65 years old and showed similar data compared to the cohort. Conclusions: KRd weekly is effective and safe to early in RRMM patients, provides improved safety profile to patients allowing treating patients until progression. Further studies are warranted to confirm this data on a larger early RRMM population and validate the concept of long duration of treatment using Carfilzomib combination.
A phase I trial of ruxolitinib, lenalidomide, and methylprednisolone for patients with relapsed/refractory multiple myeloma (MM).
Authors: Berenson James R. , To Jennifer , Spektor Tanya M. , Martinez Daisy , Sanchez Armando Jose , Ghermezi Matthew , Turner Carley , Swift Regina A. , Eades Benjamin M , Schwartz Gary , Eshaghian Shahrooz , Stampleman Laura , Moss Robert A. , Nassir Youram , Patel Ravindranath , Bessudo Alberto , Lim Stephen , Vescio Robert A.
Published: March 2020

8048

Background: Preclinical studies from our laboratory have demonstrated that ruxolitinib (RUX) in combination with lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 is responsible for LEN resistance in MM cells, and RUX blocks its expression in MM cells. Thus, RUX may restore sensitivity to LEN. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and methylprednisolone (MP) for relapsed/refractory (RR) MM patients (pts) who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods: A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 pts. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, pts received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results: As of September 1, 2018, 36 pts were enrolled, and 32 were evaluable for efficacy. The median age was 66 years (range, 46-81), and 21 (58%) were male. Pts received a median of 6 prior treatments including LEN and steroids to which they were all refractory and a proteasome inhibitor. No DLTs occurred, and DL+3 was expanded. Among evaluable pts, the CBR and ORR were 47% and 41%, respectively (1 CR, 2 VGPR, 10 PR and 2 MR), and 14 and 3 pts showed SD and PD. All 15 responding pts were refractory to LEN. G3 AEs included anemia (17%), neutropenia (14%), sepsis (14%), lymphocytopenia (11%), thrombocytopenia (11%), and pneumonia (11%). Most common SAEs included sepsis (14%) and pneumonia (11%). Conclusions: This Ph 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RR MM pts. These promising results are leading to expansion of the current clinical trial to 78 pts, and represents a novel therapeutic approach for treating MM. Clinical trial information: NCT03110822.
Prognosis of young patients with monoclonal gammopathy of undetermined significance.
Authors: Pang Li , Kumar Shaji , Lakshman Arjun , Kyle Robert A. , Rajkumar S. Vincent
Published: March 2020

8049

Background: Monoclonal gammopathy of undetermined significance (MGUS) is rare in young patients (pts; age <40 years at diagnosis), with a prevalence of < 0.3%, representing approximately 2% of all patients with MGUS. We hypothesized that MGUS detected in pts <40 years of age may be associated with a higher risk of progression. Methods: We identified 249 pts with MGUS <40 yrs old, evaluated at Mayo Clinic, Rochester from 1997 to 2016. The endpoint was time to progression assessed by Kaplan-Meier method. Results: 119 were male, 130 were female. Most (n= 179, 72%) were diagnosed between the ages of 30-39. The type of MGUS was IgG 69%, IgA 10%, IgM 15%, and other 5%. 135 pts (54%) had concurrent immune-related conditions, including autoimmune, inflammatory, and infectious disorders at the time of diagnosis of MGUS. Pts without immune-related conditions tend to have higher M protein compared to pts with immune-related conditions (mean, 0.36 gm/dl VS 0.20 gm/dl, p =0.057). During follow up, the M protein resolved in 36 patients. The M protein was more likely to resolve in pts with immune-related conditions compared with pts without immune-related conditions (RR 1.91, 95% CI 1.02-3.59). Progression was seen in 16 pts: 9 smoldering multiple myeloma (SMM), 4 multiple myeloma (MM), 1 macroglobulinemia, 2 non-Hodgkin’s lymphoma. The rate of progression to SMM, MM, or related disorder at 5 and 10 years was 6.0% and 13.8%, respectively. The size of M protein was a significant risk factor for progression (HR 4.23, 95% CI 2.17-7.91) The risk of progression at 5 and 10 years for pts with immune-related conditions concurrently present when MGUS was first diagnosed was 1.5% and 10.1% respectively; corresponding rate in pts without immune-related conditions at the time of diagnosis was higher at 12.3% and 18.9%, respectively (p =0.016), (HR 2.36, 95% CI 0.85-6.52). Similar results were seen when patients in whom the M protein resolved were excluded. Conclusions: Young patients with MGUS may have a higher risk of progression, 1.4% per year; approximately 50% are diagnosed in the setting of immune-related disorders. When occurring in the setting of immune related disorders, the M protein is smaller, more likely to resolve, and may have a lower risk of progression than in pts in whom MGUS is detected without concurrent immune-related disorder.
Phase I trial of a novel DNA vaccine in patients (pts) with smoldering Waldenstrom macroglobulinemia (sWM).
Authors: Thomas Sheeba K. , Cha Soungchul , Parshottam Sapna R , Rao Sheetal S , Olsem Jasper B. , Crumpton Brandon N. , Feng Lei , Lee Hans Chulhee , Manasanch Elisabet Esteve , Weber Donna M. , Patel Krina K. , Orlowski Robert Z. , Neelapu Sattva Swarup , Kwak Larry W.
Published: March 2020

8050

Background: Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given pt’s B-cell lymphoma are unique to that tumor, and thus are a tumor-specific marker. This study aims to use an idiotype DNA vaccine to lengthen the smoldering phase of WM without inducing cross-resistance to available therapies. Administered vaccine used recombinant plasmid DNA encoding a fusion protein, consisting of autologous lymphoma scFv (pt-specific idiotype) and human CCL20 (macrophage inflammatory protein-3 alpha - MIP-3α) chemokine. Targeted delivery of this fusion protein to APCs, and subsequent processing and presentation, is hypothesized to break tolerance and generate an immune response against the idiotype, promoting eradication of antigen-expressing B-cell lymphoma cells. Methods: Pts with sWM received 3 i.d. vaccinations of pt-specific DNA vaccine at 4-week (wk) intervals (wks 0, 4 and 8). Two dose levels (500µg; 2500µg) were evaluated in a 3+3 design. Primary objective: to evaluate the vaccine’s safety and identify it’s MTD. Secondary objectives: 1) to assess immunogenicity of the vaccine 2) to determine time to symptomatic WM. Results: Between 1/2016 - 1/2019, 9 pts (7 men) were treated (500 µg: n = 3; 2500µg: n = 6). Median age at enrollment was 67 yrs (range 56-78); median time from diagnosis to 1st vaccination was 26.5 mos (8.8-120.9). MYD88 L265P + (6 pts). CXCR4 WHIM + (1 pt). With median follow up of 26.5 months (range: 8-36.4), all pts remain alive. Seven have stable disease; 2 progressed to symptomatic WM (8 mos. (1pt) and 26 mos. (1pt) from 1st vaccination). All pts completed planned therapy. No DLTs or Grade 4 AEs occurred. Ten mos. after the 3rd vaccination, 1 pt had a grade 3 pleural effusion and leukopenia with an increase in rheumatoid factor (23.1 IU/mL [normal range 0.0-15.9]) and ANA titer of 1:80; all resolved within 2 mos. Grade 1-2 AEs ( > 3pts): leukopenia (6), nausea (5), anemia (4), increased creatinine (4), fatigue (4). Conclusions: Idiotype (scFv-CCL20) DNA vaccine therapy appears to be safe in pts with sWM. Results of immunogenicity assays are underway, and will inform whether tumor specific immune responses are induced. Additional follow up is required to determine time to symptomatic WM. Clinical trial information: NCT01209871.
Initial reporting of NRG-LU001 (NCT02186847), randomized phase II trial of concurrent chemoradiotherapy (CRT) +/- metformin in locally advanced Non-Small Cell Lung Cancer (NSCLC).
Authors: Tsakiridis Theodoros , Hu Chen , Skinner Heath Devin , Santana-Davila Rafael , Lu Bo , Erasmus Jeremy J. , Doemer Anthony , Videtic Gregory M.M. , Coster James , Yang Xuezhong , Lee Richard , Werner-Wasik Maria , Schaner Philip E. , McCormack Steven Eric , Esparaz Benjamin , McGarry Ronald , Bazan Jose G. , Struve Timothy , Bradley Jeffrey D.
Published: March 2020

8502

Background: Metformin, a diabetes agent that inhibits mitochondria complex I, enhances radiotherapy and chemotherapy responses in pre-clinical models of NSCLC. NRG-LU001 examined whether metformin can improve outcomes of curative CRT in locally advanced (LA)-NSCLC. Methods: The primary endpoint of this trial was 1-year progression free survival (PFS). Unresected, non-diabetic, stage IIIA/B NSCLC patients were randomized (1:1) to either carboplatin-paclitaxel chemotherapy concurrent with chest RT (60Gy), followed by consolidation carboplatin-paclitaxel chemotherapy (Control Arm) or the same and oral metformin (2000mg daily) during cytotoxic therapy (Experimental Arm). PFS and overall survival (OS) were estimated with the Kaplan-Meier method; time to local-regional progression (TTLRP), time to distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded with CTCAE v.4.0. Results: Between Aug.2014 and Dec.2016, 170 patients were accrued. Analysis was planned at 102 PFS events (Feb. 2019). There was no significant difference in rates or grade of toxicity between the two arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Metformin arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP or TTDM. Conclusions: NRG-LU001 center reported outcomes show that oral daily metformin was well-tolerated in combination with CRT treatment for LA-NSCLC. However, metformin did not improve PFS and OS and did not alter the rates of local-regional failure or distant metastasis. Acknowledgements: TT and HS are Co-Principal Investigators. This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). Clinical trial information: NCT02186847.
Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial.
Authors: Paz-Ares Luis G. , Trigo Perez Jose Manuel , Besse Benjamin , Moreno Victor , Lopez Rafael , Sala Maria Angeles , Ponce Aix Santiago , Fernandez Cristian Marcelo , Siguero Mariano , Kahatt Carmen Maria , Zeaiter Ali Hassan , Zaman Khalil , Boni Valentina , Arrondeau Jennifer , Martinez Aguillo Maite , Delord Jean-Pierre , Awada Ahmad , Kristeleit Rebecca Sophie , Olmedo Garcia Maria Eugenia , Subbiah Vivek
Published: March 2020

8506

Background: Lurbinectedin (L) is a novel anticancer drug that inhibits activated transcription and induces DNA double-strand breaks, leading to apoptosis. Methods: A multicenter phase 2 basket trial assessed the efficacy and safety of L in several cancer types, including small cell lung cancer (SCLC). Primary endpoint was confirmed overall response rate (ORR) by RECIST v.1.1. In the SCLC cohort, a target ORR ≥30% was set. One-hundred and five patients (pts) with ECOG PS 0-2 who had received one prior chemotherapy line were treated with L 3.2 mg/m2 as a 1-hour i.v. infusion on Day 1 q3wk. Results: Median age was 60 years (range, 40-83), 60% were male, ECOG PS 0/1/2 (32%/62%/6%), liver metastasis 41%, history of CNS involvement 3.8%, prior platinum 100%, median chemotherapy-free interval (CTFI): 3.5 (0-16.1) months; prior immunotherapy (IO): 7.6%. Pts received a median of 4 cycles (range, 1-24). Conclusions: L monotherapy is active in second-line SCLC in both resistant and sensitive disease. The acceptable and manageable safety profile is also associated to a convenient treatment administration (Day 1 q3wk). L as second-line treatment in SCLC emerges as a new promising drug for this unmet clinical need. Clinical trial information: NCT02454972. [Table: see text]
Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): A phase II multicenter exploratory study—Final data of patients who underwent surgical assessment.
Authors: Provencio Mariano , Nadal Ernest , Insa Amelia , Garcia-Campelo Rosario , Casal Rubio Joaquín , Domine Manuel , Majem Margarita , Rodriguez-Abreu Delvys , Martinez Marti Alex , Cobo Manuel , Lopez-Vivanco Guillermo , del Barco Elvira , Bernabé Reyes , Vinolas Nuria , Barneto Isidoro , Viteri Santiago , Martín-Martorell Paloma , Jove Maria , Franco Fabio , Massuti Bartomeu
Published: March 2020

8509

Background: Patients with stage IIIA (N2 or T4N0) are potentially curable but median overall survival is only around 15 months and complete pathologic response with conventional chemotherapy (CT) is no more than 9%. Methods: A Phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC adult patients with CT plus IO as a neoadjuvant treatment: three cycles of Nivolumab (NV) 360mg IV Q3W + paclitaxel 200mg/m2 + carboplatin AUC 6 IV Q3W followed by adjuvant NV treatment for 1 year. After complete neoadjuvant therapy, tumor assessment is performed prior to surgery. Surgery is performed in the 3rd or 4th week after day 21 of the third cycle of neoadjuvant treatment. The study aims to recruit 46 pts. The primary endpoint is Progression-Free Survival (PFS) at 24 months. Efficacy is explored using objective pathologic response criteria. We present final data on all patients included in this study that underwent surgical assessment. Results: At the time of submission, 46 pts had been included and 41 had undergone surgery. CT-IO was well-tolerated and surgery was not delayed in any patient. None of the pts withdrew from the study preoperatively due to progression or toxicity. 41 surgeries had been performed and all tumors were deemed resectable, with R0 resection in all cases. 34 pts (83%) achieved major pathologic response (MPR) (CI 95% 71-95%), and 24 (71%) of them had a complete pathologic response (CPR) (CI 95% 54-87%). Downstaging was seen in 90% (CI 95% 81-100%) of cases. By RECIST, 29 pts (71%) (CI 95% 56-85%) had partial response and 3 (7%) (CI 95% 0-16%) complete response. Conclusions: This is the first multicentric study to CT-IO in the neoadjuvant setting in stage IIIA. Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yields a high complete pathologic response rate that has never been seen previously and unsuspected by RECIST criteria. Preliminary correlative analyses in blood samples are included in a separate abstract. EudraCT Number: 2016-003732-20. Clinical trial information: NCT 03081689.
Prospective phase I multi-institutional trial of PD-1 blockade with pembrolizumab during concurrent chemoradiation for locally advanced, unresectable non-small cell lung cancer.
Authors: Jabbour Salma K. , Berman Abigail T. , Decker Roy H. , Lin Yong , Feigenberg Steven J. , Gettinger Scott N. , Aggarwal Charu , Langer Corey J. , Simone Charles B. , Bradley Jeffrey D. , Aisner Joseph , Malhotra Jyoti
Published: March 2020

8511

Background: The PACIFIC study showed that consolidative Programmed Death Ligand 1 inhibition (PD-L1i) after chemoradiation therapy (CRT) improves PFS and OS in patients with Stage IIII NSCLC (Antonia et al. NEJM 2017, 2018). Limited data, however, exist regarding the incorporation of PD-L1i concurrently during CRT. We sought to assess the safety and toxicity of PD-1i using pembrolizumab (pembro) during definitive CRT for Stage III NSCLC. Methods: In this multi-center prospective Phase I clinical trial using a 3+3 design, we evaluated the timing and dosing of pembro combined with chemotherapy (carboplatin + paclitaxel weekly) and definitive RT (60 Gy in 2 Gy/day x 30 fractions) for unresectable, locally advanced Stage III NSCLC (AJCC 7thEd). Dose Cohorts (C) evaluated were--C1: full dose (FD) pembro (200 mg IV Q3 weeks) 2-6 weeks after CRT; C2: reduced dose (RD) pembro (100 mg IV Q3 weeks) starting Day 29 of CRT; C3: FD pembro starting Day 29 of CRT; C4: RD pembro starting on Day 1 of CRT; C5: FD pembro starting on Day 1 of CRT. For each cohort, pembro was continued Q3 weeks for up to 18 cycles (as monotherapy after CRT in either RD or FD based on initial dose assignment). Dose Limiting Toxicity (DLT) was defined as Grade ≥4 pneumonitis within 21 days of cycle 1 of pembro. Results: We enrolled 23 subjects from 8/2016-11/2018; median follow up (f/u) was 11.4 mo (range, 3.1 mo- 25.2 mo). Median age was 69 yrs (range 53-85); 52% were women. No DLTs were observed in any of the cohorts (C1 to C5). Grade ≥3 immune-related adverse events (irAE) occurred in 4 patients (18%). irAE’s included: Grade 5 (bilateral), 3, 2 pneumonitis (n=1, 1, 4, respectively (6 total)); Grade 3 hyperglycemia (n=1); Grade 3 interstitial nephritis (n=1); Grade 2 thyroiditis (n=4); Grade 2 myositis (n=1); Grade 1-2 transaminitis (n=3). Median PFS for patients who received ≥2 doses (n=18) of pembro was 20.3 mo. Conclusions: Combined treatment with PD-Li and CRT for stage III NSCLC was well tolerated with promising PFS to date but showed an increased risk for irAEs, particularly pneumonitis. Based on these encouraging results, further prospective study of PD-1i and CRT for Stage III NSCLC is warranted. Clinical trial information: NCT02621398.
Phase II trial combining atezolizumab concurrently with chemoradiation therapy in locally advanced non-small cell lung cancer.
Authors: Lin Steven H. , Lin Yan , Mok Isabel , Young Jenean A. , Phan See , Sandler Alan , Papadimitrakopoulou Vassiliki , Heymach John , Tsao Anne S.
Published: March 2020

8512

Background: Consolidation durvalumab after chemoradiation (CRT) is the new standard of care in locally advanced NSCLC (LA-NSCLC). We hypothesized that adding immunotherapy concurrently with CRT (cCRT) would increase efficacy without significant additive toxicity. To test this concept, we conducted a phase II trial called DETERRED combining atezolizumab (atezo) with cCRT followed by consolidation full dose carboplatin/paclitaxel (CP) with atezo (CP-atezo) for 2 cycles and then maintenance atezo for 1 year. The primary endpoint was safety/toxicity and feasibility. Methods: This study enrolled patients (pts) between February 2016 - April 2018 and was done in two parts: In part 1 (N=10), conventionally fractionated CRT (60-66 Gy in 30-33 fractions combined with weekly low dose CP) was followed by CP-atezo then maintenance atezo. Part 2 was cCRT (N=30) with atezo followed by CP-atezo then maintenance atezo. Atezo was given at 1200 mg IV Q3 weeks. Severe adverse events (SAEs) ≥ grade 3 were defined by CTCAE v5.0. Evaluable pts received at least one dose of atezo. PD-L1 staining utilizes the DAKO 22C3 platform. Kaplan Meier were analyzed for progression free survival (PFS) and overall survival (OS), and chi-square test for PD-L1 levels on any recurrence, with significance set at <0.05. Results: In Part 1, atezo related SAEs were seen in 4 pts (40%) (2 grade 3 arthralgia, 1 grade 3 dyspnea and 1 grade 5 TE fistula). Grade 2 radiation pneumonitis (RP) was seen in 1 pt. In Part 2, seven (23%) pts had atezo related SAEs (diarrhea, nephritis, dyspnea, fatigue and heart failure). RP was seen in 3 pts, 2 grade 2 and 1 grade 3, which led to atezo discontinuation. In Part 1, with an overall median follow up (f/u) time of 22.5 months and 27.4 months for survivors, the 1-year PFS is 50%, and OS is 79%. In part 2, with a median f/u time of 11.8 months and 13.7 months for survivors, the 1-year PFS was 57%, and OS is 79%. Baseline tumor biopsy PD-L1 status was evaluable for 34 pts. There were no significant differences in cancer recurrence for PD-L1 <1% (7/16=44%) vs ≥1% (6/18=33%), or for the PD-L1 cutoff of <50% (11/26=42%) vs ≥50% (2/8=25%). Conclusions: Concurrent atezo with CRT followed by CP-atezo and maintenance atezo is safe without increased toxicities compared to CRT alone followed by CP-atezo and maintenance atezo. Updated efficacy results from DETERRED will be presented. Ultimately, the clinical benefit of immunotherapy with cCRT followed by consolidation chemo-immunotherapy will need to be compared to the PACIFIC regimen in a larger randomized trial. Clinical trial information: NCT02525757.
Refining the role of adjuvant chemotherapy in stage IB and IIA NSCLC.
Authors: Pathak Ranjan , Hoag Jessica R , Goldberg Sarah B. , Monsalve Andres F , Resio Benjamin , Boffa Daniel J.
Published: March 2020

8519

Background: The role of adjuvant chemotherapy (AC) in stage IB (pT2aN0) and IIA (pT2bN0) non-small cell lung cancer (NSCLC) is currently unclear. Existing guideline recommendations are inconsistent, ranging from all tumors >4 cm, to any patient with “high-risk features” (visceral pleural invasion (VPI), lymphovascular invasion (LVI), high grade, or sublobar resection). We used the National Cancer Data Base (NCDB) to clarify the role of AC in pT2N0 patients. Methods: The NCDB was queried for treatment-naïve, post-R0 resection, pT2N0 (AJCC 8th edition) NSCLC patients between 2010 & 2014. Patients treated with single-agent AC were excluded. Survival was calculated from 30 days after surgery to minimize immortal time bias. Multivariable Cox proportional hazards regression was used to estimate the association between AC and survival across tumor sizes (T2a: 3-4 cm and T2b: 4-5 cm to reflect guideline stratifications) and risk features. Results: Of the 10,127 patients identified, 1,856 (18%) received multi-agent AC. AC patients tended to be younger (median age 64 vs 70 yrs, p<0.001), privately insured (40% vs 24%, p<0.001), treated at a non-academic center (71% vs 66%, p<0.001), and comorbidities-free (53% vs 48%, p<0.001). In T2a patients (N=6,699), AC was not significantly associated with a mortality reduction, regardless of the presence of any high-risk features. In T2b patients (N=3,428), AC (N=931, 27%) was associated with a lower mortality (HR 0.77, 95% CI 0.65-0.9, p=0.001). However, in the absence of any high-risk features (N=1414, 41% of the 4-5 cm cohort), AC was not significantly associated with survival benefit (Table). Conclusions: The presence of high-risk features does not appear to support the guideline recommendations regarding the use of AC in stage IB patients with 3-4 cm tumors. On the other hand, the benefit of AC for 4-5 cm tumors may be limited to patients with at least one high-risk feature. [Table: see text]
Three-year overall survival update from the PACIFIC trial.
Authors: Gray Jhanelle Elaine , Villegas Augusto E. , Daniel Davey B. , Vicente David , Murakami Shuji , Hui Rina , Kurata Takayasu , Chiappori Alberto , Lee Ki Hyeong , Cho Byoung Chul , Planchard David , Paz-Ares Luis G. , Faivre-Finn Corinne , Vansteenkiste Johan F. , Spigel David R. , Wadsworth Catherine , Taboada Maria , Dennis Phillip A. , Ozguroglu Mustafa , Antonia Scott Joseph
Published: March 2020

8526

Background: In the phase 3 PACIFIC study of patients with unresectable, Stage III NSCLC without progression after chemoradiotherapy (CRT), durvalumab demonstrated significant improvements versus placebo in the primary endpoints of progression-free survival (HR, 0.52; 95% CI, 0.42–65; P < 0.0001) and overall survival (OS; HR, 0.68; 95% CI, 0.53–0.87; P = 0.00251). Safety was similar and durvalumab had no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study. Methods: Patients with WHO PS 0/1 (any tumor PD-L1 status) who received ≥2 cycles of platinum-based CRT were randomized (2:1), 1–42 days following CRT, to receive durvalumab 10 mg/kg intravenously every 2 weeks or placebo, up to 12 months, and stratified by age, sex, and smoking history. OS was analyzed using a stratified log-rank test in the ITT population. Medians and OS rates at 12, 24 and 36 months were estimated by Kaplan-Meier method. Results: In total, 713 patients were randomized of whom 709 received treatment (durvalumab, n = 473; placebo, n = 236). The last patient had completed the protocol-defined 12 months of study treatment in May 2017. As of January 31, 2019 (data cutoff), 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months (range, 0.2–51.3). Updated OS remained consistent with that previously reported (stratified HR 0.69, 95% CI, 0.55–0.86), with the median not reached (NR; 95% CI, 38.4 months–NR) with durvalumab versus 29.1 months (95% CI, 22.1–35.1) with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. After discontinuation, 43.3% and 57.8% in the durvalumab and placebo groups, respectively, received subsequent anticancer therapy (9.7% and 26.6% subsequently received immunotherapy). OS subgroup results will be presented. Conclusions: Updated OS data from PACIFIC, including 3-year survival rates, underscore the long-term clinical benefit with durvalumab following CRT and further establish the PACIFIC regimen as the standard of care in this population. Clinical trial information: NCT02125461.
Alteration in tumor immune microenvironment after chemo-radiotherapy for locally advanced non-small cell lung cancer.
Authors: Yoneda Kazue , Kuwata Taiji , Mori Masataka , Kanayama Masatoshi , Kuroda Koji , Ichiki Yoshinobu , Tanaka Fumihiro
Published: March 2020

8530

Background: The consolidation treatment with durvalumab, an anti-PD-L1 antibody, after concurrent chemo-radiotherapy (CCRT) has become a new standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). The rationale of the addition of anti-PD-L1 antibody is based on preclinical evidence suggesting that chemotherapy and radiotherapy may up-regulate PD-L1 expression on tumor cells. However, there has been reported no clinical evidence showing up-regulation of PD-L1 expression after CCRT. Methods: LA-NSCLC patients with paired sufficient histologic specimens for immune-histochemical analysis of tumoral PD-L1 expression (tumor proportion score, TPS) and stromal CD8-positive tumor-infiltrating lymphocyte density (CD8+density) before and after pre-operative treatment were eligible in this study. Twenty-three patients who underwent CCRT were reviewed in comparison with 18 patients who underwent chemotherapy. Results: PD-L1 expression was significantly enhanced after CCRT (median TPS, 48 from 1; P<0.01), but not after chemotherapy (median TPS, 7.5 from 1; P=0.62). No significant correlation between baseline TPS and TPS after CCRT (P=0.119). Stromal CD8+density was significantly increased after CCRT (median, 39 from 11; P<0.01) and after chemotherapy (median, 23 from 12; P<0.01). No significant correlation between baseline TPS and TPS after CCRT (P=0.378). Among CCRT cases, stromal CD8+density after treatment was significantly higher in cases with higher pathologic response to CCRT (median, 55 versus 27; P<0.01), and higher stromal CD8+density was a significant factor to predict a favorable survival after surgery (P=0.03 for recurrence-free survival; P=0.02 for overall survival). Conclusions: PD-L1 expression was significantly upregulated after CCRT regardless of baseline PD-L1 status, which may provide a pathologic rationale for the use of anti-PD-L1 agent after CCRT to improve the prognosis. Stromal CD8+density also increased after CCRT, which was correlated with pathologic response to CCRT and provided a significant prognostic impact.