bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)
Authors: Garcia-Manero G. , Yang A. S. , Klimek V. , Luger S. , Newsome W. M. , Berman N. , Patterson T. , Maroun C. , Li Z. , Ward R. , Martell R.
Published: March 2020

7062

Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea & anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 & 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic & clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing.

No significant financial relationships to disclose.
Phase I study of sapacitabine, an oral nucleoside analogue, in patients with advanced leukemias or myelodysplastic syndromes
Authors: Plunkett W. , Garcia-Manero G. , Faderl S. , Cortes J. , Boone P. , Hilbe C. , Green S. , Chiao J. H. , Kantarjian H.
Published: March 2020

7063

Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to induce G2 cell cycle arrest and cause irreparable single-strand DNA breaks, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg b.i.d.×7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTD of the above dosing schedule and the secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC. Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which =2/6 patients experienced a DLT during the first treatment cycle. Results: Twenty- nine patients received sapacitabine. Median age was 64 (range: 36 - 91). The majority of patients had AML (n=24) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 - 6). MTD was reached at the dose level of 375 mg b.i.d. with 2/7 patients experienced the DLT of small bowel obstruction (n=1) or neutropenic colitis (n=1). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included nausea, vomiting, diarrhea, anorexia, alopecia, and fatigue, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 7 patients (5 AML, 2 MDS) had a reduction in bone marrow blast counts to = 5% including 1 CR in refractory AML with incomplete platelet recovery and 1 CR in relapsed MDS. In addition, 2 AML patients with relapsed leukemia cutis had a significant reduction in leukemia infiltrates in skin. Conclusion: The RD of sapacitabine for the b.i.d.×7 days every 21 days schedule is 325 mg b.i.d. The DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS.

No significant financial relationships to disclose.
First-line treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and chemotherapy
Authors: Ghavamzadeh A. , Alimoghaddam K. , Ghaffari S. , Rostami S. , Jahani M. , Khodabandeh A. , Mossavi S. , Iravani M. , Eini E. , Moghadam Z. , Afshar F.
Published: March 2020

7073

Background: Standard treatment of APL is ATRA plus chemotherapy but Arsenic Trioxide (ATO) is most potent single agent against APL cells. Role of ATO in first line therapy of APL needs to clarify. Methods: Between may 2000 and September 2006,we treated 141 new cases of APL(Median age 28±12.8 y/o min=11,max=71) by 2 hours iv infusion of 0.15mg/kg ATO until complete remission. Trial approved by IRB and consent form obtained. Diagnosis was by clinical and morphologic characteristics and confirmed by cytogenetic and RT-PCR for detection of t(15,17) and presence of PML-RARa. After complete remission patients received consolidation by 28 days infusion of ATO for one or four courses.(one consolidation one month after CR and for some patients second, third and forth consolidations one month after first one and two another , one year and two year after CR) Results: : complete remission observed in 121 cases(85.8%) and early mortality rate was14.9%(most common cause of early mortality was APL syndrome,61.9%).Median follow up was 28 months. For patients who achieve to complete remission,one, two and three year disease free survival were 95.6%± 2%, 76.9±4% and 57± 6%,respectively. Many relapsed patients salvaged again with ATO alone so, two and three years overall survival for this cohort was 95.6%±2% and 83.7%±4%. Increasing number of consolidation from one to four couldn’t increase DFS or OS in one and two years after CR. Conclusions: ATO is effective in treatment of new cases of APL. Introduction of ATO in first line treatment of APL(with or without ATRA plus chemotherapy) needs a multi center randomized clinical trial.

No significant financial relationships to disclose.
Baseline predictors of response to treatment with darbepoetin-alpha (DA) in anemic patients with low-risk myelodysplastic syndrome (MDS)
Authors: Gabrilove J. , Paquette R. , Lyons R. , Mushtaq C. , Sekeres M. , Tomita D. , Lillie T.
Published: March 2020

7081

Background: Patients (pts) with MDS often develop anemia, resulting in fatigue and an increased requirement for transfusions. The erythropoiesis-stimulating agent (ESA) DA can raise hemoglobin (Hb) levels in low-risk MDS pts. Previous analyses suggest that baseline (BL) endogenous erythropoietin (eEPO) levels and French-American-British (FAB) disease category are predictors of response to ESAs. Methods: This was a phase 2, open-label, 52-week (wk) study of DA administered 500 mcg every 3 wks (Q3W) to anemic (Hb=11g/dL), low- or intermediate-risk MDS pts. Pts received 500 mcg DA Q2W if they did not respond by wk 7. The last DA dose was at wk 52; end of study was wk 53 or 55 for pts receiving DA Q2W or Q3W, respectively. The primary endpoint was % pts with an erythroid response (International Working Group criteria) by wk 13. Other endpoints included change from BL in Hb and FACT-F score. Exploratory analyses examined the incidence of erythroid responses adjusted by FAB category (refractory anemia [RA], RA with ringed sideroblasts [RARS], or RA with excess blasts [RAEB]). Results: Final 53/55 wk data will be presented. Results were stratified by whether pts received an ESA before enrollment (ESA-naive [ESA-N] vs ESA-treated [ESA-T]). ESA-T pts are a heterogeneous group and their data are difficult to interpret; thus, predictors of response will be presented for ESA-N pts only. Of 144 ESA-N pts, 56% had RA, 37% had RARS, and 7% had RAEB. Most ESA-N pts achieved the target Hb and had a major erythroid response ( Table ). Pts with RA were more likely to achieve a major erythroid response than pts with RARS or RAEB. For ESA-T pts, demographics and type/length of ESA treatment will be presented. Of all pts, serious adverse events (SAEs) were reported in 62 (30%) pts and treatment-related SAEs in 2 (1%) pts. Conclusions: FAB category may affect response to DA in MDS pts. Additional data will be presented on the effect of BL eEPO, transfusion needs, and previous ESA treatment on response and duration of response.

[Table: see text]
A novel denaturing high-performance liquid chromatography (D-HPLC) based method for kit mutation screening of patients (pts) with systemic mastocytosis (SM)
Authors: Colarossi S. , Soverini S. , Gnani A. , Rondoni M. , Gatto S. , Merante S. , Zanotti R. , Martinelli G. , Baccarani M. , Tiribelli M.
Published: March 2020

7085

Background: SM is characterized by activating mutations of Kit tyrosine kinase. While the enzimatic site (ES) type mutation D816V renders Kit resistant to imatinib, regulatory type mutations are sensitive to inhibition. Kit mutations screening with sensitive methods is important for an appropriate therapeutic management of SM. Methods: Our aims were: to set up and optimize a D-HPLC-based screening method for mutations in critical regions of Kit; to assess the sensitivity and reliability of our D-HPLC assay as compared to RFLP analysis; to characterize additional mutations. The analysis was performed on 51 SM pts. Results: For each sample, a RT-PCR product spanning the catalytic and activation loops (ES) was screened in parallel by D-HPLC, followed by sequencing of D-HPLC-positive cases, and by RFLP according to an reported method for the D816V detection. By RFLP analysis, 34/51 pts were positive for the D816V. By D- HPLC analysis, an abnormal eluition profile was seen in 36/51 pts - all the 34 RFLP-positive cases as well as two additional pts. Direct sequencing confirmed the presence of the D816V in all the 34 RFLP-positive cases and showed that in two of these cases a I798I polymorphism was also present. The two pts scored positive by D-HPLC but negative by RFLP were found to have the I798I polymorphism. The 15 pts who did not harbour ES type mutations were further investigated by D-HPLC analysis of a RT-PCR product spanning the transmembrane (TM) and juxtamembrane (JM) domains. D-HPLC showed an abnormal elution profile in 5 pts. By direct sequencing one patient showed the K546K mutation and 4 pts showed the M541L polymorphism. Conclusions: Our D-HPLC-based assay proved a straightforward, reliable and sensitive method for Kit mutation analysis and highlighted the importance of screening for mutations other than the D816V.

No significant financial relationships to disclose.
Dasatinib therapy for patients with Philadelphia-negative (ph-) myeloproliferative disorders (MPDs), including systemic mastocytosis
Authors: Verstovsek S. , Atallah E. , Thomas D. , Cortes J. , Ravanid-Kashami F. , Nicaise C. , Sams I. , GIles F. , Kantarjian H.
Published: March 2020

7086

There are no curative medical therapies for Ph- MPDs. Over last several years several of the MPDs have been associated with the abnormal expression of selected tyrosine kinases (e.g. c-kit in SM) and others are suspected to be involved too. Therefore, we engaged in conducting a Phase II study with dasatinib, an orally available multi targeted kinase inhibitor, for patient with Ph- MPDs. Dasatinib is administered at 70 mg PO BID continuously (one month equals one cycle). Response is assessed every 3 cycles, and the therapy is discontinued in those without response after 6 cycles of therapy. Patients are observed for any toxicity; in such cases the dose of dasatinib is adjusted to 50 mg PO BID, then to 40 mg PO BID, or discontinued. The study is ongoing and has enrolled 55 patients; 44 are evaluable for response and toxicity, including 24 with SM (6 with aggressive SM, 4 with SM and associated hematologic non-mast cell disease and 14 with indolent SM with uncontrolled symptoms despite optimal supportive care measures), 10 CIMF, 6 HES, 3 unclassifiable MPD and one PV. Median age is 65 years (range, 27–75); 25 males and 19 females. The overall response rate in SM was 42% (10 pts). Of those, two patients (8%) achieved complete remission, one with SM-CIMF, and one with SM-HES. Both were c-KIT mutation negative and had low, not significant tryptase levels. Both were anemic (Hb 9.4g/dL) and failed erythropoietin therapy, and had abnormal WBC differential; one had low platelets (90×109/L). Symptoms related to SM improved significantly in additional 8 patients, however, no significant response in percentage of bone marrow mast cells or blood tryptase levels have been observed so far. The 6 patients with HES had previously failed imatinib therapy and had no evidence of the FIP1L1-PDGFRA fusion transcript; one achieved complete remission (normalization of blood and bone marrow eosinophil percentage) while others did not respond. No responses have been recorded in patients with CIMF, PV and unclassifiable MPD. No grade 4 toxicity has been observed. Dasatinib is active in SM (overall response rate 42%) mainly by improving symptoms. Updated clinical results on all enrolled patients will be presented.

No significant financial relationships to disclose.
Phase II trial of cladribine (2-CdA) and rituximab in patients with CLL and SLL: Preliminary report of a single institution
Authors: Bertazzoni P. , Laszlo D. , Gigli F. , Bassi S. , Calabrese L. , Saronni L. , Quarna J. , Alietti A. , Cocorocchio E. , Martinelli G.
Published: March 2020

7093

Background: Byrd et al (Blood 2003) confirmed the synergistic effect of Rituximab and Fludarabine in the treatment of CLL patients (pts). The choice of purine analogue still remains controversial. We evaluated feasibility, efficacy, and toxicity of 2-CdA-Rituximab combination in the treatment of CLL and SLL pts requiring treatment. Methods: The combination therapy consisted of intravenous Rituximab at a dose of 375 mg/m2 on Day 1 and 2-CdA at a dose of 0.1 mg/kg (sc injection) per day on Days 2 through 6. The course was repeated at 4-week intervals for 4 times. 31 pts (21 CLL and 10 SLL) was enrolled in the study and the median age was 59 years (31–73); 42% of pts were pre-treated. A CT scan was abnormal in 95% of CLL pts. Immunophenotypic evaluation by ZAP-70 was positive in 70% of pts while no evaluable pts showed an adverse prognostic cytogenetic features by FISH. Minimal residual disease (MRD) assessment was performed by flow-cytometry and PCR methods. Results: 2 pts had to discontinue therapy after 2 cycle: one due to herpes zoster reactivation and the other one to the progression disease (PD). We observed grade 3 and 4 neutropenia in 4 pts (12%), major infections in 4 pts (12%) and no episodes of grade 3–4 thrombocytopenia. 24 pts were evaluable for response with an ORR of 96%. At the end of therapy 10 pts (42%), 7 CLL and 3 SLL, achieved a CR, with negative MRD (by PCR) in 4 pts (3 untreated); 13 pts (54%) obtained a PR and 1 patient had no response. With a median follow-up of 12 months (range 3–34) 7 pts (2 pts with MRD+CR and 5 pts with PR after treatment) experimented a PD; 5 of these pts were pre-treated and 2 died because of PD. Conclusions: The combination of 2- CDA and Rituximab seems to be tolerable and active principally for untreated pts and able to induce a molecular clearance also in pre-treated pts. The achieving of a CR with negative MRD seems to be the most important issue to improve the outcome.

No significant financial relationships to disclose.
Assessing the impact of comorbidities on autologous hematopoietic cell transplant (AHCT) outcomes using the hematopoietic cell transplant-comorbidity index (HCT-CI) in lymphoma
Authors: Kassar M. , Gregory S. A. , Shell K. , Venugopal P. , Shammo J. , Farhat M. I. , Batus M. , Law A. , Fung H. C.
Published: March 2020

7102

Background: Sorror et al. has identified HCT-CI as a valid scoring of pretransplant comorbidities that predicted nonrelapse mortality and survival after allogeniec HCT. We recently reported on the validity of HCT-CI in predicting morbidity outcomes after AHCT for lymphoma (BBMT in press). High HCT-CI score predicted for prolonged hospitalization and high incidence of hospital re-admission after AHCT. The objective of this study is to evaluate the impact of HCT-CI on mortality risk after AHCT. Methods: We included pts above age of 40 with advanced HL or NHL, who underwent AHCT in our institution between 01/98 & 05/06. Median follow up was 29.4 mo. Pts were assigned scores based on the HCT-CI. Defenition of comorbidities were recently reported (Kassar et al, BBMT in press). Results: 80 pts were included (NHL: 74, HL: 6). 61 pts were male. Median age was 56 years (42–76). Comorbidities (points, prevalence%): mild hepatic (1,14), cardiac (1,15), cerebrovascular (1,4), arrhythmia (1,9), moderate pulmonary (2,11), severe pulmonary (3,8), rheumatologic (2,5), DM (1,23), inflammatory bowel disease (1,3), psychiatric (1,11), infection (1,6), obesity (1,11), and renal (2,1). Median HCT-CI was 1 (0: 37 %, 1: 26%, 2–7: 37%). 22 pts died: 15 from relapse and 7 from non relapse mortality (NRM) causes. Cumulative day-100 NRM and 1-year NRM rates are: 1.3% and 4%, respectively. Pts were categorized into 2 groups: low-risk (scores of 0–1) and high-risk (scores 2–7). Using Cox Regression model and adjusting for age and histology, low-risk group had a significantly better OS (1 wk-58.6 mo, median 34.1 mo) compared to high-risk group (5 days-23.6 mo, median 6 mo) (HR: 3.73, p = .01, 95% CI 1.32, 10.54). 1-year OS rate was 75% vs. 25%, respectively (p=.04). Conclusion: HCT-CI is a valid scoring of pre-transplant comorbidities that predicted mortality after AHCT for pts with lymphoma. The physiologic burden of comorbidities is likely to impact the tolerance to AHCT or to other therapies administered upon relapse after transplant. HCT-CI can serve as important tool for both the transplant administrator when planning for resources allocation and clinical trials, and for pts during pre-transplant evaluation and counseling.

No significant financial relationships to disclose.
Correlations among vitality, physical competence, lipid profile and measures of inflammation in transplant survivors with chronic graft versus host disease
Authors: Gerber L. , Mitchell S. , Li L. , Diao G. , Odom J. , Atlam N. , Cowen E. , Sportes C. , Bishop M. , Pavletic S.
Published: March 2020

7108

Background: Chronic graft vs. host disease (cGVHD) is a multi-system disorder and a late complication of cancer therapy experienced by more than 50% of survivors after allogeneic hematopoietic stem cell transplantation. An improved understanding of the underlying biology and its relation to clinical symptoms may guide the development of better treatments for cGVHD. Methods: In a prospective, cross-sectional natural history protocol we examined the associations among organ/system dysfunction, measures of physical performance and health status with clinical measures of inflammation and fat metabolism. Variables included: 1. a composite severity score (CAS) rated by clinician-specialists (skin, eyes, mouth, gastrointestinal/liver, hematological, gynecological, pulmonary function evaluations); 2.functional measures [2 minute walk time (WT), grip strength (GS), SF-36 physical component summary score (PCS), vitality (VT) subscale, maximal activity score (MAS) of the Human Activity Profile]; 3.Laboratory tests (glucose, LDH, hemoglobin, ferritin, platelets, lymphocytes, pre-albumin, cholesterol, lipoproteins (HDL, LDL), triglycerides (TG), beta-2microglobulin (B2), and CRP. Results: 43 pts (mean age 47 yrs) with prior hematologic malignancy participated (mean 3 yrs post transplant). An average of 3.5 organ systems were affected, 77% were on systemic treatment for cGVHD, and 67% had prior acute GVHD. The mean body mass index (BMI) was 25, TG 255, cholesterol 222, LDL 132. They were moderately disabled by self-report (MAS), had slower than normal WT (540 ft/min), lower than normal GS (63 pounds), PCS (36) and VT (46) than a healthy population. Using a backward selection model with a significance of 0.1, low lung diffusing capacity (p<.001) and low PCS (p=0.01) correlated with high CAS. VT correlated negatively with LDH, platelets, B2 and LDL (all p<0.01). Low GS correlated with high LDH and B2 (p=0.01). Conclusions: Reported physical function and vitality in cGVHD patients are associated with abnormal lipid profiles and markers of inflammation. Establishment of such profiles is a critical step in the development of testable and validated outcome measures and for evaluation of new therapies in cGVHD.

No significant financial relationships to disclose.
Pemetrexed + carboplatin versus gemcitabine + carboplatin in the treatment of stage IIIB/IV non-small cell lung cancer
Authors: Gronberg B. H. , Bremnes R. , Aasebø U. , Brunsvig P. , Fløtten Ø. , Hjelde H. , Wammer F. , Stornes F. , Tollåli T. , Sundstrøm S. H.
Published: March 2020

7517

Background: A prospective, randomized, multicentre study was conducted to compare pemetrexed + carboplatin (PC) with a standard regimen, gemcitabine + carboplatin (GC). Methods: Chemonaive patients with verified non-small cell lung cancer, stage IIIB (ineligible for curative radiotherapy) or stage IV, WHO performance status (PS) 0–2, adequate hematology and creatinine-clearance > 45 ml/min were eligible. All patients were supplemented with folic acid 0.4 mg OD and vitamin B12 1 mg IM every 9 weeks, from >= 5 days before and through the treatment period. Patients were randomized to receive either pemetrexed 500 mg/m2 + carboplatin AUC=5 (Calvert) day 1 or gemcitabine 1,000 mg/m2 day 1 & 8 + carboplatin AUC=5 (Calvert) day 1. Maximum 4 courses every 3 weeks were given. Primary endpoints: QoL defined as global health status, nausea/vomiting, dyspnea and fatigue - measured by the EORTC QLQ-C30 and LC13 before every cycle and 3 & 11 weeks after the last cycle. Secondary endpoints: Overall survival (OS) and toxicity measured by the CTCAE v3.0. Stratification was done for age (−75 vs +75 years), stage (IIIB vs IV) and PS (0–1 vs 2). 190 evaluable patients in each arm were required to detect a 15% improvement on predefined QoL parameters with an a of 0.05 and β of 0.80. A 15% loss to follow up was expected. Results: 446 patients were included from Apr 05 - Jul 06. The two arms were well balanced with respect to age, sex, stage, PS and histological classification. 436 patients were eligible for the primary QoL-analyses. No statistical significant differences in mean score of the QoL-scales were observed between the arms. So far, 384 patients have been analysed for toxicity. Significantly more patients in the GC arm experienced grade 3–4 thrombocytopenia (48 vs 107, p<0.001), leucopenia (44 vs 89, p<0.001) and granulocytopenia (78 vs 98, p=0.02). No difference in the frequency of neutropenic fever was recorded. More patients in the GC arm received transfusion of platelets (5 vs 19, p=0.02). At present, 291 patients are deceased. We expect to present complete OS analyses for a minimum of 380 patients at the annual meeting. Conclusions: No differences were detected between the two arms with respect to the primary QoL outcome. Patients in the PC arm experienced less toxicity.

No significant financial relationships to disclose.
IFCT0002 phase III study comparing a preoperative (PRE) and a perioperative (PERI) chemotherapy with two different CT regimens in resectable non-small cell lung cancer (NSCLC): Early results
Authors: Milleron B. , Quoix E. , Westeel V. , Puyraveau M. , Braun D. , Breton J. L. , Bigay Game L. , Pujol J. L. , Morin F. , Depierre A.
Published: March 2020

7519

Background: Recent trials have shown a survival benefit of CT in resectable NSCLC. The primary objective was to define the best timing of CT (all before surgery versus perioperative). Another objective was to compare two regimens, gemcitabine-cisplatin (GP) and paclitaxel-carboplatin (TC). Methods: Between May 2001 and Dec 2005, 528 patients (pts) with a stage IA-II resectable NSCLC were randomized to 4 parallel arms: A: 2 GP + 2 GP in responders, then surgery, B: 2 GP - surgery + 2 GP in responders, C: 2 TC + 2 TC in responders then surgery, D: 2 TC - surgery + 2 TC in responders (GP: Gemcitabine 1250 mg/m2/d1, 8 and cisplatin 75 mg/m2/d1 q3 wk; TC: Paclitaxel 200 mg/m2/d1 and carboplatin AUC 6, q3 wk). Results: Pathological tumor volume and pathological complete response rate did not differ with the number of preoperative cycles. Proportions of pts receiving cycles 3 and 4 were higher when all CT was given before surgery. There were several significant differences in the main toxicities between GP and TC. Conclusions: 1- GP and TC were effective and safe. 2- Results of pathological response suggested that 2 cycles might be as effective as 4 cycles. 3- Dose intensity was higher when all chemotherapy was given before surgery compared to both before and after surgery.

No significant financial relationships to disclose.

[Table: see text]
Outcomes for elderly advanced stage non-small cell lung cancer (NSCLC) patients (pts) treated with bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P): Analysis of Eastern Cooperative Oncology Group (ECOG) 4599 study
Authors: Ramalingam S. S. , Dahlberg S. E. , Langer C. J. , Gray R. , Belani C. P. , Brahmer J. R. , Sandler A. , Schiller J. H. , Johnson D. H.
Published: March 2020

7535

Background: PC administered in combination with bevacizumab extends survival for advanced non-squamous NSCLC pts. Based on SEER data, elderly pts (age ≥70 years) represent >50% of all new cases of lung cancer and present unique therapeutic challenges. The ECOG 4599 database was analyzed to compare the outcomes in elderly pts treated with PCB vs. PC alone. Methods: Pts ≥ 70 years at study entry constituted the elderly cohort. Each arm (PCB vs. PC) and age group (≥70 vs. <70) was compared with respect to baseline pt characteristics, response rate (RR), progression-free survival (PFS), survival and toxicity. Results: Out of 850 eligible pts, 26% (N=224) were ≥ 70 years of age (1.6% ≥ 80 years). Median age for the elderly was 74 yrs; 44% were ≥ 75 yrs. Baseline characteristics of the elderly cohort were similar to the younger group except for a higher proportion of males (62% vs. 52%, P = 0.005). For the elderly pts, there was a trend towards superior response rate (29% vs. 17%, P = 0.067) and median PFS (5.9 mos vs. 4.9 mos, P = 0.063) with PCB when compared to PC, though there was no difference in overall survival (PCB = 11.3 mos; PC = 12.1 mos; P = 0.4). Grades 3–5 toxicities (CTC version 2.0) were noted in 87% of elderly pts treated with PCB compared to 61% with PC (P < 0.001). Treatment-related death rates with PCB vs. PC were 6.3% vs. 1.8% (NS) for the elderly. Febrile neutropenia (6% vs. 0.9%), proteinuria (8% vs. 0) and hypertension (6% vs. 0.9%) were more common with PCB than PC among the elderly. When compared to younger pts, the elderly experienced more neutropenia (34% vs. 22%), bleeding (7.9% vs. 3.2%), proteinuria (7.9% vs. 1.3%), muscle weakness (7.9% vs. 2.2%) and motor neuropathy (3.5% vs. 0.6%) with PCB. Conclusions: The proportion of elderly patients in ECOG 4599 is the highest recorded among ECOG phase III studies for advanced NSCLC. Increased toxicity with the addition of bevacizumab in those ≥ 70 yrs may have contributed to the absence of survival benefit for PCB vs PC, but this observation is limited by its post-hoc, retrospective nature.

No significant financial relationships to disclose.
Can baseline complete geriatric assessment (CGA) predict toxicity in elderly non-small cell lung cancer (NSCLC) patients (pts) receiving combination chemotherapy? Results from the first 100 pts in the prospective multicenter NVALT-3 study
Authors: Wymenga M. , Biesma B. , Vincent A. , Dalesio O. , Stigt J. , Smit H. , Groen H.
Published: March 2020

7537

Background: Nearly 50% of NSCLC pts are aged over 70 years, but only few receive combination chemotherapy. Undertreatment results from a fear of associated toxicities. CGA may predict which patients are prone to toxicities, and thus allow patient selection for such treatment. Methods: A total of 182 NSCLC pts = 70 years with stage IIIb/IV disease were randomized to 4 cycles carboplatin/gemcitabine (group 1) or carboplatin/paclitaxel (group 2). Before treatment, CGA was performed using the following instruments: WHO Performance Scale (PS), Charlson comorbidity index (CCI), Cumulative Illness Rating Scale-Geriatrics (CIRS-G), Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Timed “Up&Go” (TUG), Mini-Mental State Examination (MMSE), Geriatric Depression Score (GDS-15), Groningen Frailty Indicator (GFI). Toxicity was scored using NCI-CTC v2. Toxicity related outcomes were defined as all grade III/IV toxicities, toxicity related SAEs, = grade II neurological toxicity and the ability to finish all cycles. Results: In the first 100 pts mean age was 75 yrs (range 70–85). PS was 0 in 30%, 1 in 56% and 2 in 14%. 57% completed all 4 cycles. 11% stopped treatment prematurely due to toxicity and 12% due to PD. Overall, grade III/IV toxicity occurred in 66% of pts, toxicity related SAEs in 12%, and 35% experienced = grade 2 neurological toxicity (n=13 group 1, n=22 group 2). Median (range) baseline CGA scores were as follows: CCI 1.0 (0–7), CIRS-G 3.0 (0–14), ADL independent 72%, IADL independent 50%, TUG 12.0 sec.(5–40), MMSE 29 (19–30), GDS-15 normal (score 0–4) 71%, GFI 3.0 (0–10). Multivariate logistic regression indicated that, for experiencing toxicity related SAEs CIRS-G provided extra information, for experiencing neurological toxicities MMSE was predictive and for finishing all cycles, IADL provided extra information in addition to PS and stage. Conclusions: CGA can predict toxicity in elderly NSCLC pts receiving combination chemotherapy. Data on all 182 patients will be presented.

No significant financial relationships to disclose.
Gemcitabine/platinum alone or in combination with cetuximab as first-line treatment for advanced non-small cell lung cancer (NSCLC)
Authors: Butts C. A. , Bodkin D. , Middleman E. L. , Englund C. W. , Ellison D. , Alam Y. Z. , Pautret V. , Weber M. , Kreisman H. , Shepherd F. A.
Published: March 2020

7539

Background: This randomized phase II study was conducted to evaluate the benefit of adding cetuximab, an IgG1 monoclonal antibody targeting the EGF receptor, to gemcitabine/platinum chemotherapy in patients with recurrent or metastatic NSCLC. Methods: Patients with previously untreated stage IIIB (malignant pleural effusion) or stage IV NSCLC irrespective of their EGF receptor status were eligible for this study. Patients on arm A received cetuximab (400 mg/m2 IV on day 1 followed by 250 mg/m2 weekly) combined with either cisplatin (75 mg/m2 IV q3 weeks) and gemcitabine (1,250 mg/m2 IV days 1 and 8) or carboplatin (AUC 5 IV q3 weeks) and gemcitabine (1,000 mg/m2 IV days 1 and 8). Patients on Arm B received the same chemotherapy regimen without cetuximab. The primary endpoint was tumor response rate with progression-free (PFS) and overall survival (OS) as secondary endpoints. Results: 73 women and 58 men, median age 66 years (35–88) were randomized to arm A (n=65) or arm B (n=66). Partial responses occurred in 18 (27.7%, 95% CI: 17.3–40.2) patients in arm A and 12 (18.2%, 95% CI 9.8–29.6) in arm B. Median PFS was 5.09 months for arm A (95% CI: 4.17–5.98) and 4.21 months (95% CI: 3.81–5.49) in arm B; median OS was 11.99 (95% CI: 8.80–15.20) and 9.26 months (95% CI: 7.43–11.79) respectively. The incidence of drug related infusion reactions (any grade) in arm A was 15.6% and 1.5% in arm B. Three patients in arm A had grade 3–4 cetuximab related infusion reactions. Severe acneform rash was observed in 14.1% of patients in arm A and none in arm B. Other toxicities were similar and only 18.5% of patients in arm A and 10.6% patients in arm B discontinued treatment for toxicity. Conclusions: These data confirm the previously observed benefit for the combination of cetuximab with a platinum based doublet chemotherapy regimen patients with metastatic NSCLC. The difference of 2.7 months in median OS between treatment arms seems to suggest a more substantial clinical benefit. Fully powered phase III studies addressing this question are on- going and results will become available in 2007.

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Accelerated conformal radiotherapy for stage I non-small cell lung cancer (NSCLC) in patients with pulmonary dysfunction: A CALGB phase I study
Authors: Bogart J. , Watson D. , Seagren S. , Blackstock A. W. , Wang X. , Lenox R. , Vokes E. , Turrisi A. T. , Green M. R.
Published: March 2020

7556

Background: The optimal treatment for medically inoperable stage I NSCLC has not been defined. Methods: CALGB 39904 is a prospective phase I study assessing accelerated once-daily radiotherapy for early stage NSCLC. The primary objectives were to define the maximally accelerated course of conformal radiotherapy; and to describe the short-term and long-term toxicity of therapy. Entry was limited to patients with clinical stage T1N0 and T2N0 NSCLC (< 4 cm) with pulmonary dysfunction (FEV1 <40% predicted, DLCO 45mmHg, V02 max <15m1/kg/min, O2 requirement). The nominal total radiotherapy dose was held constant at 70 Gy, while the number of daily fractions in each successive cohort was reduced (table). Results: The study was activated on 12/15/2000, and closed on 7/29/2005. Forty patients were accrued with 8 on each cohort. One patient on cohort 5 declined protocol treatment leaving 39 eligible patients. Patients were generally female (53%), white (83%), and ECOG performance status = 1 (67%). The median age was 74 (range 48 to 87), and the majority of the patients (73%) had T1N0M0 disease. Treatment was well tolerated without grade 4+ toxicity. There was one hematologic toxicity (lymphopenia) in cohort 2, and one non-hematologic toxicity each in cohort 3 (dyspnea) and cohort 4 (pain).The major repsonse rate was 74% (31% complete response, 43 % partial response), and 26% of patients had stable disease. After a median follow-up of 38.1 months, 21 patients remain alive. The actuarial median survival of all eligible patients is 38.5 months (95% confidence interval= 19.45 to NE). Conclusion: Accelerated conformal radiotherapy was well tolerated in a high-risk population with clinical stage I NSCLC. Outcomes are comparable to prospective reports of alternative therapies, including stereotactic body radiosurgery and limited resection,with less apparent severe toxicity. Further investigation of this approach is warranted.

No significant financial relationships to disclose.

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IFCT0401 trial: Phase II study of gefitinib administered as first-line treatment in non-resectable adenocarcinoma with bronchioloalveolar carcinoma features (ADC-BAC): Final results on efficacy and survival
Authors: Cadranel J. , Quoix E. , Debove P. , Moro-Sibilot D. , Brechot J. M. , Souquet P. J. , Soria J. C. , Morin F. , Milleron B.
Published: March 2020

7560

Background: ADC-BACs are distinguished from other ADCs by epidemiological, clinical and CT scan presentations as well as molecular biology, leading to some responses to EGF receptor tyrosine kinase inhibitors. We therefore conducted a prospective, multicentric, phase II trial to evaluate gefitinib (250 mg/d) as first-line treatment in non-resectable ADC-BAC. Methods: Inclusion criteria were previously untreated, non-resectable cyto/pathologically proven ADC-BAC. Primary objective was disease control rate (DCR) at 3 months. Secondary objectives were progression free survival (PFS), survival, and identification of markers associated with efficacy and survival using multivariate logistic regression and cox model analyses. Results: From 04/04 to 06/05, 88/90 enrolled patients were eligible. All had stage IV disease, with pulmonary (n=86) and/or extra-thoracic metastasis (n=10). All were caucasians, median age 64 yrs (27–84), PS less than 2 in 80.7%, 48 females and 38 never-smokers. Tissue biopsies were centrally reviewed and 85/88 patients evaluable for response by a clinical trial panel. DC was achieved in 25/85 patients (DCR=29.4%, CI=[20–39]). Median PFS was 2.9 months (CI=[2.4–3.2]) and median survival 13.3 months (CI=[13.3–21.8]) with a 1-year survival of 55.7% (CI=[44.4–65.5]). DC was independently associated with age >70 yrs (OR=4.9, p=0.047); never-smoking (OR=8.1, p=0.015); teeter score (clinical pulmonary symptoms score) <9 (OR=18.7, p=0.002); non-mucinous BAC (OR=15.1, p=0.006) and rash (OR=2.1, p=0.02). Shorter PFS and survival were independently associated with teeter clinical score <9 (HR=1.9, p=0.03 and HR=3.3, p=0.006); mucinous BAC (HR=2.7, p=0.008 and HR=2.8, p=0.04), and absence of rash (HR=2.3, p=.004 and HR=2.4, p=0.02). Conclusions: Gefitinib seems active as first-line treatment of non-resectable ADC-BAC. Non-smoking patients, fewer pulmonary symptoms, non-mucinous histological subtype are predicting factors of efficacy and increased survival. Cutaneous rash is associated with efficacy and better survival. In other patients, especially with mucinous BAC, alternative therapies should be offered.

No significant financial relationships to disclose.
FISHing for lung cancer: Promising findings using multi-targeted interphase fluorescence in situ hybridization (FISH) for lung cancer detection in sputum
Authors: Franklin W. A. , Byers T. , Wolf H. J. , Braudich S. , Hirsch F. R. , Miller Y. E. , Keith R. L. , Kennedy T. C. , Belinsky S. , Varella-Garcia M.
Published: March 2020

7567

Background: Lung CT imaging shows promise for early lung cancer detection, but may be insensitive for central lesions and will create a need for complementary biomarkers to guide clinical decisions. Methods: We have been conducting a prospective study to assess the performance of various biomarkers in sputum to detect lung cancer. Within a cohort of 3,269 people at high risk for lung cancer (over 30 pack-years of cigarette use and chronic obstructive lung disease) we have conducted a nested case-control study to assay stored samples from 85 incident lung cancer cases and 73 controls for cytologic morphology, DNA methylation, and multi-targeted FISH assays (LAVysion, Vysis/Abbott Molecular). The FISH assay targeted DNA sequences from centromere 6, 5p15.2, 7p12 (EGFR), and 8q24 (cMYC). Cytology was classified as abnormal if moderate or greater atypia was observed, methylation was abnormal if three or more of 8 selected genes were methylated, and FISH was abnormal if two or more scored cells were observed to contain chromosomal aneuploidy indicated by signal gain for at least two targets or signal gain for one and signal loss for two or more targets. Results: Among all subjects, regardless of the time between sputum collection and diagnosis, FISH was abnormal in 49/87 cases (56%) and 5/73 controls (7%) (odds ratio (OR) = 17.5, 95% CI = 6.4 to 47.8). Considering only the cases for which sputum had been collected within 18 months before the lung cancer diagnosis, FISH was abnormal in 37/49 cases (75%) and in 3/38 controls (8%) (OR = 36.0, 95% CI = 9.4 to 138). For this same time period, cytological atypia was abnormal in 37% of cases and 22% of controls (OR = 2.1, 95% CI = 0.8 to 5.3) and methylation was abnormal in 64% of cases and 36% of controls (OR = 4.5, 95% CI = 1.0 to 19.8). Conclusions: The LAVysion FISH assay is more sensitive than other currently available sputum tests for the prediction of invasive carcinoma in subjects and is highly specific with a low frequency of false positive and false negative results. The results suggest that chromosomal aneuploidy and by extrapolation, missegregation, are features of advanced premalignancy and should identify patients who are proximate to clinically overt lung cancer.

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What we could know from the semiannually repeated screening with low-dose helical CT in a high-risk cohort over 10 years: Update of Anti-Lung Cancer Association project
Authors: Seki N. , Eguchi K. , Kaneko M. , Ohmatsu H. , Kakinuma R. , Matsui E. , Kusumoto M. , Tsuchida T. , Nishiyama H. , Moriyama N.
Published: March 2020

7568

Background: There have been several randomized trials of low-dose helical CT (LDCT) screening for lung cancer. However, all trials are in progress. Therefore, before they are completed, we summarized what we could know from an update of Anti-Lung Cancer Association project, which was regarded as a longer-term study with LDCT performed at shorter intervals and with a larger number of detected cancers than any other single-armed studies. Methods: Among 2,120 participants, 1,877 (mean age 64 years, 88% male, and 84% smoker) underwent semiannually repeated screening from 1993 to 2004 (median, 3.5 years). We investigated (1) survival of patients with screening detected lung cancers, (2) presence of a stage shift (indicator of a mortality benefit), (3) appropriate duration of repeated screening, (4) identification of high-risk group by age, sex, and smoking, and (5) appropriate screening intervals by high-risk group (6 months or 1 year). Results: (1) The 5- and 10-year survival rates were 84.5% and 84.5%, respectively, in repeated screening group (n = 57) and were 68.7% and 38.1%, respectively, in initial screening group (n = 19) (P = 0.208). (2) Only in invasive adenocarcinoma, both proportion of stage II to IV and tumor size were negatively correlated with duration of repeated screening (r = −0.77, P = 0.007 and r = − 0.60, P = 0.029, respectively). (3) Detection rate of all incidence cancers were positively correlated with duration of repeated screening (r = 0.50, P = 0.020). However, detection rate remained unchanged until 5 years of repeated screening. Moreover, stage shift did not occur until 5 years of repeated screening. (4) Female sex (HR 2.9, P = 0.015) and smoking (HR 2.7, P = 0.046) were demographic risk factors for lung cancer detection at repeated screening. The accumulated 10-year detection rates for female smokers (n = 91), male smokers (n = 1,557), and non-smokers (n = 229) were 15.1%, 6.2%, and 4.3%, respectively (P = 0.002). (5) The estimated relative cancer detection powers of annual screening to semiannual screening were 50% and 57% for female and male smokers with lung cancer, respectively. Conclusions: Semiannually repeated LDCT screening over 5 years might be beneficial to smokers, especially female smokers.

No significant financial relationships to disclose.
Smoking history and frequency of somatic KRAS mutations in adenocarcinoma of the lung
Authors: Miller V. A. , Riely G. J. , Kris M. G. , Rosenbaum D. , Marks J. , Li A. , Chitale D. , Nafa K. , Pao W. , Ladanyi M.
Published: March 2020

7573

Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are more common in patients with adenocarcinoma, especially those who smoked < 15 pack years (py). KRAS mutations are found in ∼25% of lung adenocarcinomas, most commonly in codons 12 and 13 of exon 2 (∼85%) and have been associated with poor prognosis in resected disease [Winton NEJM 2005] and resistance to EGFR tyrosine kinase inhibitors [Pao PLoS Med 2005]. KRAS mutations are uncommon in non-small cell lung cancer histologies other than adenocarcinoma. We sought to determine the association between quantitative measures of cigarette smoking and presence of KRAS mutations in lung adenocarcinomas. Methods: Standard direct sequencing techniques were used to identify KRAS codon 12 and 13 mutations in lung adenocarcinoma specimens from surgical resections between 2001 and 2006 and tumor specimens sent for KRAS molecular analysis in 2006. Surgical specimens were obtained from an institutional tumor bank. Detailed smoking history (age at first cigarette, packs per day, years smoked, years since quitting smoking) was obtained from the medical record and a patient-completed smoking questionnaire. Results: KRAS mutational analysis was performed on 408 lung adenocarcinomas from 242 women and 166 men. Median age was 68 (range 33–89). KRAS mutations were present in 19% (78/408, 95% CI 15 to 23%). The frequency of KRAS mutation was not associated with age or gender. The presence of KRAS mutations was not related to smoking history with 15% (9/61) of never smokers having KRAS mutations compared with 19% (51/275) of former smokers. When compared with never smokers, there was no significant difference in frequency of KRAS mutations for tumors from patients with 1–5 py (5%, p=0.44), 6- 10 py (12%, p=0.99), 11–15 py (25%, p=0.45), 16–25 py (16%, p=0.99), 26–50 py (25%, p=0.129), 51–75 py (20%, p=0.48), >75 py (20%, p=0.47) history of cigarette smoking. Conclusions: While the incidence of EGFR mutations has a strong inverse relationship with the amount of cigarettes smoked, allowing the selective molecular testing for EGFR mutations, the frequency of KRAS mutations cannot be predicted by age, gender, or smoking history. KRAS mutational analysis of all adenocarcinomas is required to reliably identify patients with KRAS mutations.

No significant financial relationships to disclose.
Paraffin-based molecular diagnosis of lung cancer reproduces morphologic and molecular subtypes of lung cancer
Authors: Hayes D. N. , Schallheim J. , Roberts P. , Lee C. , Thorne L. , Perou C. , Parsons A. , Socinski M. A. , Funkhouser W. , Bernard P.
Published: March 2020

7579

Background: Molecular profiling of lung cancer by gene expression analyses has documented potential to guide therapy. However, quality ‘fresh’ tissue for RNA analyses is generally unavailable in clinical practice. We introduce a (q)RT-PCR assay and analytic method for profiling lung cancers from clinically obtained formalin-fixed paraffin-embedded tissues. Methods: Approximately 1,000 DNA microarrays were analyzed to select genes distinguishing the major histological variants (adenocarcinoma, small cell carcinoma, etc) and previously described molecular subtypes of lung cancer. Based on gene expression, a classifier of 62 genes was constructed to assign each sample to its morphologic tumor type, as well as to risk stratify by molecular subtypes. A real-time qRT-PCR assay was developed to evaluate the expression of the 62 genes from paraffin-embedded samples. This assay was used to profile RNA extracted from a cohort of surgically treated lung cancer patients. Samples were procured as fresh frozen and formalin-fixed, paraffin-embedded and were archived between 1–15 years. Results: Fifty-eight of 62 genes passed performance criteria and were used for analyses. Normalized gene expression was used for sample classification. The cohort contained a broad spectrum of tumors in proportions consistent with clinical practice. Gene amplification was successful in 139 of 142 (98%) lung cancer samples. Matched frozen-paraffin and replicate paraffin samples had mean correlations of approximately 80%. Linear discriminant analysis of gene expression data agreed with morphologic classification by light microscopy in >99% of cases. More importantly, the method successfully re-identified molecular subtypes of lung cancer for the first time through the use of a paraffin-based assay. Clinical outcomes previously associated with molecular tumor subtypes, including differential survival and metastatic patterns, were again seen in our cohort. Conclusions: We describe for the first time a clinically meaningful and robust molecular diagnosis of a clinical cohort of lung cancer patients which is complementary to morphologic cancer diagnosis. This assay is easily implemented using specimens routinely collected in current patient care.

No significant financial relationships to disclose.