bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of the tolerability and activity of weekly vincristine sulfate liposomes injection (VSLI) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second relapse or progressing following two antileukemia treatment lines
Authors: Heffner L. T. , Damon L. E. , Larson M. L. , Schiller G. , Stock W. , Kantarjian H. M. , Lu B. , Imperiale S. M. , O'Brien S.
Published: August 2020

7046

Background: VSLI (Marqibo) is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol liposomes called Optisomes. The optisomal formulation lends itself to an improved pharmacokinetic profile and enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus standard VCR in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 with no dose cap, while conventional VCR is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study in relapsed ALL showed a complete response rate of 19%, warranting further study. Methods: Eligible adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. This international, multicenter, single-arm study will enroll approximately 56 subjects. Major endpoints include response rate and overall survival (OS). An interim analysis was planned following enrollment of 29 evaluable subjects. Results: 29 heavily pretreated subjects received ≥ 1 dose of VSLI. To date, at least 9 of 29 subjects had clearing of leukemic blasts and achievement of an M1 bone marrow. Based on preliminary data, the median OS is estimated to be 7.5 months (95% CI: 4.7–10.5) using the Kaplan-Meier method. The most frequent related adverse event (AE) was peripheral neuropathy (PN) (48%), half of which was grade 3. No grade 4 PN was reported. Six subjects had 8 treatment-associated grade 4 AEs of neutropenia (4), thrombocytopenia (2), anemia (1), and inappropriate antidiuretic hormone secretion (1). Conclusions: These results are encouraging, as VSLI was given as a single agent to a heavily pretreated patient population who nearly universally received prior VCR. This population typically has a very low response rate to anti-leukemia therapies. Early OS data compares favorably to an historical median OS of ∼ 2 months (8.7 weeks) in a second salvage population (data on file, M. D. Anderson). VSLI was well tolerated in these patients in the context of universal prior vincristine treatment.

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Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib
Authors: Gallagher N. J. , Fischer D. , Demirhan E. , Zhou W. , Golor G. , Schran H. , Yin O.
Published: August 2020

7053

Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of CML-CP and CML-AP patients resistant or intolerant to prior therapy including imatinib. The solubility of nilotinib is pH dependent, with lower solubility at higher pH. We evaluated whether esomeprazole, a potent proton pump inhibitor (PPI) that can significantly increase gastric pH, could affect the oral absorption and pharmacokinetics of nilotinib in healthy subjects. Methods: Twenty-two subjects (6 F, 16M, age range 18–64 years) were enrolled to receive nilotinib alone or in the presence of steady-state esomeprazole during two treatment periods. Nilotinib was given as a single oral 400 mg dose on days 1 and 13, and esomeprazole 40 mg once-daily on day 8 through day 13. Serial blood samples were collected up to 72 hours after nilotinib dosing for determination of nilotinib serum concentrations by a validated liquid chromatography-tandem mass spectrometry assay. Gastric pH was monitored in all subjects at baseline (prior to nilotinib and esomeprazole dosing), before and during the first 4 hrs of esomeprazole steady state dosing (fifth dose on Day 12). Results: When coadministered with esomeprazole, nilotinib Cmax was decreased by 27% (397±89 vs 303±157ng/mL) and AUC0-∞ decreased by 34% (11515±6140 vs 7164±3752ng*hr/mL) respectively. The median time to reach nilotinib Cmax was slightly prolonged from 4.0 hrs to 6.0 hrs, but its elimination half-life was not altered (17.3±10.7 vs 15.9±6.6 hrs). Median gastric pH was increased from 0.8 at baseline to 2.0 at pre-dose, and to 3.9, 5.8, 5.5, and 5.7 at 1, 2, 3, and 4 hrs after esomeprazole dosing. Administration of nilotinib alone or in combination with esomeprazole was generally well tolerated in the study subjects. Conclusions: The study results demonstrate a modest reduction in the rate and extent of nilotinib absorption when co-administered with esomeprazole. Such an effect is unlikely to cause a significant clinical consequence for nilotinib therapy, and thus nilotinib can be used with esomeprazole or other PPIs without the risk of substantial decrease in nilotinib systemic exposure.

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Pretransplant comorbidity as an outcome predictor in adult patients younger than 60 years of age receiving standard induction chemotherapy for de novo acute myeloid leukemia
Authors: Kim S. , Lee J. , Lee J. , Kim D. , Lim S. , Lee Y. , Kang Y. , Seol M. , Ryu S. , Lee K.
Published: August 2020

7055

Background: Comorbidity has been evaluated as an outcome predictor in elderly patients receiving induction chemotherapy for acute myeloid leukemia (AML) as well as in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematologic disorders. In this single-institute retrospective study, we investigated the prognostic significance of comorbidity in younger AML patients. Methods: A total of 276 patients, aged 14 to 59 years, who received standard induction chemotherapy consisting of cytarabine plus daunorubicin or idarubicin for de novo AML excluding M3 subtype between 2000 and 2007 were included. Pre-treatment comorbidity score, assessed by the HCT specific comorbidity index (HCT-CI), was calculated using clinico- pathologic data, which were retrieved from Asan Medical Center Leukemia Registry Database. The HCT-CI score was 0 in 113 patients (40.9%), 1 in 94 (34.1%), and ≥ 2 in 69 (25.0%). Results: In the univariate analyses, the HCT-CI score was not a significant prognostic factor for induction of complete remission (CR), whereas survival outcomes such as overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS) were significantly different according to the HCT-CI scores (Table). The multivariate models showed that the HCT-CI score was an independent prognostic factor for EFS (P=0.044), but not for OS (P=0.301) and RFS (P=0.119). Other independent prognostic factors were age (P=0.001 for OS, P=0.002 for RFS, P=0.006 for EFS), initial leukocyte counts (P=0.006 for CR, P<0.001 for OS, P=0.039 for RFS), initial uric acid levels (P=0.004 for RFS, P=0.001 for EFS), and cytogenetic risk groups (P=0.012 for CR, P<0.001 for OS, P<0.001 for RFS, P=0.005 for EFS). Conclusions: Pre-treatment comorbidity may provide additional prognostic information over established prognostic factors in patients younger than 60 years of age receiving standard induction chemotherapy for de novo AML.

[Table: see text]

No significant financial relationships to disclose.
Monitoring chronic myeloid leukemia (CML) response to tyrosine kinase inhibitors (TKI) and homoharringtonine (HHT) using peripheral blood (PB) fluorescence in situ hybridization (FISH) and quantitative RT-PCR (Q-PCR): Are bone marrow biopsies still needed?
Authors: Khoury H. J. , Lima L. , Saxe D. , Mann K. P. , Arellano M. , Heffner L. , Bernal-Mizrachi L. , McLemore M. , Langston A. , Winton E.
Published: August 2020

7064

Background: The purpose of this study is to compare simultaneously obtained PB and bone marrow (BM) BCR-ABL FISH and Q-PCR to monitor response to TKI and HHT in CML. Methods: Between January 2005 and December 2008, 52 patients (pts) with chronic (n = 37, 80%), accelerated (n = 6, 7%), and blast phase (n = 9, 14%) CML had 112 simultaneous PB and BM FISH and Q-PCR before and/or after start of imatinib (IM, n = 27), dasatinib (n = 9), nilotinib (n = 1), bosutinib (n = 13), or HHT (n = 2) for newly diagnosed (n = 27), IM resistant (n = 20), or IM intolerant (n = 5) CML. 13 (26%) had chromosomal abnormalities in addition to the Philadelphia chromosome, and 10 (20%) had a detectable BCR-ABL mutation including the T315I in 2 pts. Results: 24 (46%) had simultaneous PB and BM FISH and/or Q-PCR measurements obtained at 1 time point, 9 (17%) at 2; 9 (17%) at 3; 10 (20%) at > 4 time points before and/or post-initiation of TKI or HHT. Excellent concordance was observed between PB and BM at all time points for both FISH (r = 0.96; p = 0.0003) and Q-PCR (r = 0.88; p= 0.0015). Correlation was not affected by the presence of additional chromosomal abnormalities, phase of the disease, treatment (TKI or HHT), or the number of prior therapies. Conclusions: FISH and Q-PCR are reliable methods to monitor CML response to TKI and HHT in patients with CML and may render the need for BM biopsy monitoring obsolete.

No significant financial relationships to disclose.
Patterns of imatinib resistance mutation analysis in chronic myeloid leukemia (CML) patients on imatinib at the time of loss of response to the drug in Asian Indian subjects
Authors: Prabhash K. , Vora T. , Ghadyalpatil N. S. , Rangarajan B. , Hingmire S. S. , Menon H. , Jain P. , Kurkure P. A. , Parikh P. M.
Published: August 2020

7079

Background: The treatment of (CML) has undergone major changes in the past decade with the introduction of tyrosine kinase inhibitors (TKI). However the initial enthusiasm is waning with increasing recognition of drug resistance. There is an urgent need to identify the types of receptor mutations which lead to drug resistance and their significance in salvage therapy. Methods: We identified 17 males and 8 female patients with median age 40 yrs (range 9–55 years) with CML who were on imatinib at the time of loss of hematologic response (HR), cytogenetic (CyR), or molecular response (MR) and performed imatinib-resistance mutation analysis. The sequencing was done on ABI machine by direct sequencing method. Results: This group included 22 patients with chronic phase (CP) disease, 2 patients with accelerated phase (AP), and 1 patient with extramedullary blast crisis (BC). Fourteen patients received treatment with agents other than imatinib as the first-line therapy due to either nonavailability of the drug at the time of diagnosis in India, but were started on imatinib when drug became available. The other 11 patients received imatinib as first-line therapy. The best response to imatinib included major CyR in 14 patients which included 3 patients with complete CyR and minor CyR in 6 patients. Lack of HR was noted in 2 patients in whom CyR was not evaluated. Imatinib resistance mutation analysis was prompted by no HR (n = 2); loss of HR after achieving CyR (n = 9); failure to achieve CyR milestones (n = 3); loss of CyR (n = 9); development of extramedullary BC (n = 1). The analysis revealed no mutations-11 patients, M351T-4 patients, G250E-3 patients, F317L-2 patients, M244V- 1 patient, T315I-1 patient, F382L-1 patient, results awaited in 4 patients with 2 patients showing 2 mutations. Conclusions: The majority of patients 11/25 had no detectable mutations while T315I which confers resistance to all TKIs was detected only in 1/25 patients who demonstrated loss of response in our population. The correlation of the other mutations to loss of response and the response to second line TKI needs to be studied in further detail. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment.

No significant financial relationships to disclose.
Outcomes following induction chemotherapy in patients with AML arising from MDS: Analysis of prognostic factors
Authors: Bello C. M. , Yu D. , Zhu W. , Wetzstein G. A. , Lancet J. E.
Published: August 2020

7088

Background: Secondary acute myeloid leukemia (sAML) arising from myelodysplasia (MDS) or a myeloproliferative neoplasm (MPN) has a poor prognosis. To date, there is limited knowledge about risk factors that determine how sAML will respond to treatment. This analysis evaluated possible prognostic factors in patients with sAML that were treated with anthracycline-based induction therapy. Methods: Retrospective chart review of patients with untreated AML from MDS/MPN treated with standard induction therapy from January 2004 to September 2008. Age, IPSS, ECOG PS, cytogenetics, duration of MDS, and prior MDS treatment were evaluated for their impact on obtaining complete remission (CR) or CR with low platelets (CRp) and overall survival (OS). Results: Sixty-one patients with sAML who received induction therapy were evaluated: median age (range) = 66 (36–82) years; M = 67%, ECOG PS 0 or 1 = 86%; poor-risk (PR) cytogenetics = 33%; IPSS > 1 = 43%; prior therapy for MDS with decitabine or azacitidine (DM) or lenalidomide (L) = 41% (25 pts). Of the entire group, 59% (36 pts) achieved CR/CRp (95% CI: 46%-71%) and the median OS was 6.5 (95% CI: 3.9–8.1) mo. Multivariable analysis indicated that the same three factors were significantly negatively associated with CR/CRp as well as OS: PR cytogenetics, prior treatment with DM/L, and long transformation to AML on log scale. Only 32% of the group that received prior treatment with a DM/L achieved CR/CRp compared to 78% in non DM/L-treated patients (OR = 0.13, 95% CI: 0.04–0.42). The CR/CRp rate for those with intermediate risk (IR) cytogenetics was 70% compared to only 35% for those with PR cytogenetics (OR = 4.33, 95% CI: 1.38–13.6). Those with PR cytogenetics had a median OS of 2.8 mo compared to 7.5 mo for IR (p = 0.01). The median OS for those treated with a DM/L was 3.7 mo compared to 10.5 mo for non DM/L-treated patients (p < 0.0001). Conclusions: Prior MDS treatment with a DM/L, PR cytogenetics and long transformation to AML are independent negative prognostic factors for response and OS in patients with sAML following induction therapy, suggesting that such patients may be better served by novel approaches, and that stratification for these risk factors should be considered in future clinical trials. Larger-scale confirmation of these data is ongoing.

No significant financial relationships to disclose.
Feasibility of hypomethylating therapy in patients with renal insufficiency
Authors: Batty G. , Kantarjian H. , Issa J. J. , Garcia-Manero G. , Pierce S. , O'Brien S. , Jabbour E. , Cortes J. , Ravandi F.
Published: August 2020

7089

Background: Epigenetic therapy with hypomethylating agents (HA) is the standard of care in patients (pts) with myelodysplastic syndrome (MDS). Although neither 5-azacytidine (5AZA) nor 2'-deoxy azacytidine (decitabine; DAC) are excreted by the kidneys, many studies exclude pts with a serum creatinine level (sCr) ≥ 1.5 mg/dL. Moreover, there are no reports of use of these agents in pts with renal insufficiency (RI) commonly seen in pts with MDS. Methods: We investigated the outcomes of pts with RI and MDS, chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML) receiving therapy with HA. RI was defined by a sCr ≥ 1.5 mg/dL. We examined the compliance, dose adjustments (DA), and complications of treatment with DAC and 5AZA given at standard doses. We used the International Working Group criteria to evaluate the response rates. Data for pts with sCr > 2 mg/dL were compared to pts with sCr ≤ 2 mg/dL (Kantarjian H, et al, Blood. 2007). Results: Forty-two pts with sCr ≥ 1.5 mg/dL (including 17 with MDS, 16 with AML, and 9 with CMML) were treated with DAC or 5AZA alone or in combination with other agents (primarily histone deacetylase inhibitors). 14 (33%) and 28 (67%) of the pts received 5AZA and DAC, respectively. The median number of courses was 4.5 (range 1–19). 9 pts (21%) required treatment delay or discontinuation, and 12 pts (28%) required dose reduction (DR). Overall, 25 (62%) had an objective response (OR), and 4 pts (9%) had complete response (CR). 15 (36%) and 7 (17%) of the pts experienced episodes of therapy-related infections and bleeding, respectively. Among 12 pts who had sCr > 2.0 mg/dL, 7 pts (58%) required DR due to myelosuppression (n = 3) and to worsening of renal function (n = 4). The incidence of complications, DA, and the response rate were not significantly different for pts with sCr > 2.0 mg/dL. Conclusions: The use of HA is well tolerated in pts with MDS and AML and RI who achieved comparable OR rates to those without RI. Dose adjustment might be required in some pts.

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Patients with secondary myelodysplastic syndromes (MDS) who are enrolled in AVIDA, a longitudinal registry for patients receiving azacitidine (AZA)
Authors: Grinblatt D. L. , Narang M. , Malone J. M. , Sweet D. A. , Dunne T. S. , Sullivan K. A.
Published: August 2020

7094

Background: Prevalence of secondary MDS (sMDS) is increasing because of improved survival of patients treated with chemotherapy or radiotherapy and aging of the population. Methylation of cell cycle regulators is common in sMDS, thus the hypomethylating agent AZA may have a role in the treatment of these patients. AVIDA is a longitudinal, multicenter patient registry designed to prospectively collect data from community-based hematology clinics on the natural history and management of patients receiving AZA. AVIDA patients with sMDS were investigated and compared with registry patients with primary MDS (pMDS). Methods: Baseline demographics and disease characteristics were obtained at enrollment. Transfusion requirements and onset of transfusion independence were recorded. Transfusion independence was defined as no transfusions for at least 56 days. The first day of the 56-day period with no transfusions was noted as the time at which patients first achieved transfusion independence. Results: As of October 8, 2008, 23 patients with sMDS due to exposure to radioiodine (18), benzene (2), radiation (1), or other (2) have received AZA. Median time since diagnosis was 1 month versus 4 months for pMDS patients (n = 203). At baseline, patients with sMDS had a similar median age (71 yrs) compared with pMDS patients (75 yrs). However, a higher proportion of patients with sMDS had a poor-risk karyotype (44% vs. 11%), 2 to 3 cytopenias (78% vs. 52%), and an International Prognostic Scoring System (IPSS) risk score of intermediate-2/high (57% vs. 23%) compared with pMDS patients. Patients with sMDS have received 93 cycles of AZA, and as of this analysis, have received a median of 4 cycles (range, 1–13). Most common dose and schedule was 75 mg/m2 (81%), 7 days on treatment (39%) for patients with sMDS vs 75 mg/m2 (88%), 5 days on (47%) for pMDS patients. Six of 15 (40%) sMDS patients with ≥ 56 days treatment duration had received a red blood cell (RBC) transfusion during the 6 months prior to AVIDA. Of these patients, 4/6 (67%) have achieved RBC transfusion independence. Conclusions: Patients with sMDS are being treated with AZA in the community-based setting with early data demonstrating substantial benefit in transfusion independence.

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Exploratory analysis describing ultrasonic (US) evaluation of spleen size during peripheral blood progenitor cell (PBPC) mobilization by filgrastim in normal donors
Authors: Stiff P. J. , Hansen K. S. , Dreiling L. , Guo M. , Artz A. S.
Published: August 2020

7102

Background: Filgrastim is used to mobilize CD34+ cells into the peripheral blood that are collected by apheresis for allogeneic transplantation. We prospectively evaluated spleen size during PBPC mobilization Methods: Donors ≥18 yrs eligible to be PBPC donors per institutional guidelines enrolled. Splenic assessments were done before, during, and after PBPC mobilization. Filgrastim dose and schedule and leukapheresis (LK) procedures were per local practice. Spleen size by US was measured in 3 dimensions: longitudinal (craniocaudal), transverse, and diagonal (perpendicular to transverse). Splenic volume was estimated by taking the cross-product of 3 dimensions and multiplying by 0.52, approximating an ellipse volume. Stiff (ASH 2007) reported the primary endpoint, fold change from baseline in splenic volume during mobilization. Exploratory analyses, including a linear regression evaluating the effect of age and baseline spleen size on fold-change, were performed. Results: 309 enrolled, median age 44yrs, 56% male. Median fold volume change from baseline to first LK was 1.47, resolving to near baseline 1 week after last LK. No significant clinical sequelae, including splenic rupture, were reported. Older donors appeared to have the smallest baseline spleen volume and the largest fold change (table). Linear regression analyses indicated age was a significant predictor for both baseline spleen volume (p=0.0031) and spleen volume fold change from baseline at first LK (p=0.0499). Conclusions: During mobilization, spleen volume transiently increased from baseline to day of 1st LK and returned to near baseline 1 week after last LK. Older donors tended to have smaller baseline splenic volume and greater fold changes in spleen size. Preclinical models suggest decreasing hematopoietic stem cell homing after mobilization with aging (Morrison 1996; Wagers 2002), which could result in splenic accumulation of progenitor and stem cells.

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Effects of glucocorticoid treatment on the functional capacity of stem cell transplant recipients entering a rehabilitation program
Authors: Scheetz J. S. , Morris G. S. , Brueilly K. E. , Brannan E. A. , Del Fabbro E.
Published: August 2020

7104

Background: Emerging data strongly supports the concept that stem cell transplant (SCT) recipients derive psychological and physiological benefit from participation in exercise training programs. Many SCT recipients receive glucocorticoids (GC) for prolonged periods, increasing their risk for proximal muscle damage and raising the possibility that SCT recipients on GC may differ from those SCT recipients not receiving GC in terms of their exercise/functional capacity. This becomes an important reconditioning issue because exercise prescription and progression is predicated on initial exercise capacity. Therefore the purpose of this study was to compare the initial functional capacity of outpatient STC recipients receiving GC to STC recipients not receiving GC. Methods: The medical records of 163 successive SCT recipients referred to Rehabilitation Services for reconditioning were retrospectively reviewed for demographic information and measures of exercise/functional capacity (6-min walk test, 50-ft fast walk, and repeated sit-to-stand times) collected at the initial physical therapy visit. Data from SCT recipients on GC (ON) were compared with that of SCT recipients not on GC (OFF) by means of an unpaired t-test (α=0.05). Data are presented as mean + standard deviation. Results: Demographic and functional measures are presented in the following tables. Significant differences between group means are denoted by an asterisk. Conclusions: STC recipients on steroids have comparable endurance capacity to those STC recipients not on steroids, but are less capable of performing lower extremity activities requiring rapid movement and receive rehabilitation services later in the post transplant recovery course. These results suggest rehabilitation strategies are 1) needed for STC patients, 2) should be individualized according to the patient's drug regime, and 3) should be initiated soon after the stem cell transplant.

[Table: see text]

No significant financial relationships to disclose.
Phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407
Authors: Govindan R. , Bogart J. , Wang X. , Hodgson L. , Kratzke R. , Vokes E. E.
Published: August 2020

7505

Background: Cisplatin, etoposide and concurrent thoracic radiation has remained the standard treatment for locally advanced unresectable non small cell lung cancer (NSCLC) over the past two decades. The Cancer and Leukemia Group B (CALGB) conducted a phase II study using a novel chemotherapy regimen administered in systemically active doses with thoracic radiation (CALGB 30407). We previously reported the preliminary safety results (ASCO 2008, abstract 7518). Methods: Eligible patients with previously untreated stage III NSCLC received thoracic radiation (70 Gy) along with carboplatin (AUC 5) and pemetrexed 500 mg/m2 on day 1 administered intravenously every 21 days for 4 cycles (arm A) or the same chemotherapy regimen with weekly cetuximab for 6 weeks concurrent with radiation (arm B). All patients received four additional cycles of pemetrexed (500 mg/m2 every 21 days) as consolidation therapy. The primary endpoint was the percentage of patients who lived longer than 18 months after starting initial treatment. We planned to study the regimen (s) further if the 18 month survival rates equaled or exceeded 55%. Results: Characteristics of the 99 eligible pts (48 in arm A and 51 arm B) enrolled from 09/05 to 1/08: male 62%, 22% were 70 yrs or older. The most common histological type was adenocarcinoma (46% in Arm A and 41% in Arm B). Updated toxicity data (grade 3 or greater, %) by arms (arm A/arm B) for 106 pts: neutropenia 40/47; febrile neutropenia 8/6, thrombocytopenia 36/34, nausea/vomiting 8/10, esophagitis 32/24, skin rash 2/21 and fatigue 22/17. The median follow up time is 17 months. Preliminary efficacy data by arms (arm A/arm B) for 99 pts: complete or partial response 73% (95% CI 59–83)/71% (95% CI 57–81%), median failure free survival (months) 12.9 (95% CI 8.6–18.0)/10.3 (95% CI 8.7–18.9); 18 month survival 57% (95% CI 41–79)/47% (95% CI 33–67) and median survival (months) 22.3/18.7. Conclusions: The combination of pemetrexed, carboplatin and thoracic radiation has met the protocol-specified criteria for further study. Although it does not appear that the addition of cetuximab confers additional benefit in this setting, further follow-up is necessary.

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Phase II feasibility trial of induction chemotherapy (ICT) followed by extrapleural pneumonectomy (EPP) and postoperative radiotherapy (PORT) for cT3N1M0 or less malignant pleural mesothelioma (MPM) (EORTC 08031)
Authors: Van Schil P. E. , Baas P. , Gaafar R. , Maat A. P. , van de Pol M. , Hasan B. , Klomp H. M. , Abdelrahman A. M. , Welch J. , Van Meerbeeck J.
Published: August 2020

7509

Background: MPM is a highly lethal disease and the role of EPP in the treatment of early stage, potentially resectable MPM remains controversial. EORTC 08031 phase II trial investigated the feasibility of trimodality therapy (TMT) consisting of ICT followed by EPP and PORT. Methods: Eligibility criteria were cT3N1M0 or less, proven MPM, < 70 years, PS 0–1, fit for TMT. ICT consisted of 3 courses of cisplatin 75mg/m2 and pemetrexed 500mg/m2 q3weeks. Non-progressing patients (pts) underwent EPP followed by PORT (54Gy, 30 fractions). Primary endpoint was “success of treatment” defined as a patient receiving the full protocol treatment, still alive 90 days after end of treatment without progression and without grade (G) 3–4 toxicity. Using a one step Fleming design 52 patients and 26 successes were required. Secondary endpoints were toxicity of TMT, overall and progression-free survival. Results: 59 pts were registered between 07/26/05 and 08/24/07, 1 was ineligible. Median age was 57 years (range 26–67), M/F 46/12, all proven MPM (31 epithelial, 18 mixed, 9 other). All pts underwent mediastinoscopy, cT1/T2/T3: 36/16/6, cN0/N1: 57/1. 55 pts received 3 cycles of ICT. G3–4 toxicity related to ICT was rare. 46 pts (79%) were operated, 42 (74%) had EPP. R0/1/2: 30/10/3, 6 were re-operated, pT0/1/2/3/4: 2/5/19/15/4, pN0/1/2/3: 34/2/6/2, 90-day mortality: 3 pts (6.5%); in 38 pts (83%) postoperative complications occurred. PORT was initiated in 38 pts and completed in 37 (65%). After PORT 2 pts (3.5%) died due to infection. Persisting G3/4 toxicity after 90 days: 3 pts (5.3%) due to radiation pneumonitis and bronchopleural fistula. After median follow- up of 19.3 months (mos) median overall survival time was 18.4 mos (95% CI 14.8-NR) and median progression-free survival was 13.9 mos (95% CI 10.9–17.1). Only 24 pts (42%) met the definition of success (one-sided 90% CI 0.36–1.00). Conclusions: EORTC 08031 investigated the feasibility of TMT in pts with proven MPM. Due to the low proportion of “successes” this TMT is not considered to be feasible. Although overall results were similar to other series, adjustments to this TMT are necessary.

No significant financial relationships to disclose.
Integration of mRNA and microRNA profiles as prognostic and predictive markers in lung adenocarcinoma
Authors: Strickler J. H. , Mostertz W. , Kim W. , Walters K. , Stevenson M. , Acharya C. , Onaitis M. , Nevins J. , Potti A.
Published: August 2020

7522

Background: Lung adenocarcinoma (ADC) is a distinct biologic entity with unique gene amplifications (Weir B, Nature 2008). Yet, comprehensive transcriptomic analysis, including microRNAs, specific to lung ADC are lacking. Methods: Using mRNA expression data from a discovery cohort of 154 patients with histologically proven early stage (I and II) lung ADC, signatures of oncogenic pathway and tumor microenvironment status were applied and further organized by hierarchical clustering to develop a metagene model. Further, using in vitro assays in a large cohort of lung ADC cell lines (n = 42) with corresponding mRNA and microRNA data, novel microRNAs associated with a poor prognosis and their relationship to cisplatin resistance was elucidated. Results: In the discovery cohort of 154 patients with early stage disease, activation of oncogenic pathways associated with wound healing (angiogenesis), chromosomal instability, and STAT signaling were associated with an increased risk of recurrence (p<0.001). Utilizing the extremes of survival to identify cohorts of patients as high and low risk phenotypes, using bayesian regression, a 100 gene signature (‘metagene') that captured the diversity of signaling pathways unique to patients at increased risk of recurrence was identified and validated in an independent cohort (n = 364) of lung ADC samples with 78.3% accuracy. Kaplan Meier survival analysis and multivariate analysis further confirmed the independent prognostic value of the 100 gene signature (p= 0.007). Using in vitro cell proliferation assays, predicted high risk lung ADC cell lines were identified as being more resistant to cisplatin therapy than those predicted to be low risk (p=0.001). In a novel manner, we also identified several microRNAs (miR-215, miR-98, miR- 643, let-7b, miR-665, miR-629) associated with a high risk of recurrence and more importantly cisplatin resistance. Conclusions: mRNA and microRNA profiles reflect unique aspects of individual tumors and may characterize histology-specific tumor heterogeneity in lung ADC, providing an opportunity to better characterize the oncogenic process and refine therapeutic options.

No significant financial relationships to disclose.
Evaluation of class III beta-tubulin (bTubIII) expression as a prognostic marker in patients with resectable non-small cell lung cancer (NSCLC) treated by perioperative chemotherapy (CT) in the phase III trial IFCT-0002
Authors: Zalcman G. , Levallet G. , Bergot E. , Antoine M. , Creveuil C. , Brambilla E. , Dumontet C. , Morin F. , Depierre A. , Milleron B.
Published: August 2020

7526

Background: IFCT-0002 phase III trial compared two timings of CT in early lung cancer, all before surgery (PRE) versus PERIoperative, and two CT regimens, CDDP-Gem vs. CBDCA-Pac. 528 patients were randomized. Paraffin embedded post- chemo pathological specimens were collected in the 490 non complete responder patients for tissue expression of the putative biomarker beta-tubulin III (bTubIII). Methods: 423 surgical pathological specimens with enough remaining viable tumor tissue after neoadjuvant chemo were processed for immunohistochemistry as published in the Bio-IALT study. A semi-quantitative score was attributed taking account the number of stained cells and the intensity of staining. Semi-quantitative scores were studied as continuous variables, without any pre- determined cut-off. Multivariate analysis for progression-free (PFS) and overall survival (OS) were corrected with Bonferroni-Holm method for multiple analyses. Median follow-up was 42 months. Results: bTubIII was the only IHC marker significantly associated with poor PFS in univariate (p=0.014) or multivariate analysis, adjusted for histology, T and stage (HR= 1.50 [1.07–2.10]; p=0.020). In patients with a pathological specimen showing a bTubIII positive immunostaining, median PFS was 30.6 months, versus 60.1 months (HR=1.46 [1.08–1.99]) for bTubIII negative patients. bTubIII IHC score remained predictive of poor OS in univariate (p= 0.0065) as in multivariate analysis (p=0.019 with Bonferroni correction, HR=1.75 [1.15–2.68] ). Median OS was not reached for bTubIII negative patients whereas it was 71.7 months in patients with bTubIII immunostaining of any intensity score (HR=1.61, [1.11–2.35]). Conclusions: This study showed a dramatic negative prognostic impact for bTubIII immunostaining in resectable early lung cancer. A subset of bTubIII expressing patients with poor prognosis did not take any advantage from perioperative chemo. Hence, those patients could rather have beneficiated from personalized adjuvant treatment with alternative approaches.

No significant financial relationships to disclose.
The association between clinical characteristics, treatment modality, and outcomes of non-small cell lung cancer
Authors: Yorio J. , Xie Y. , Yan J. , Gerber D. E.
Published: August 2020

7534

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death in the United States. NSCLC outcomes vary widely among patients. The degree to which these disparate outcomes reflect differences in treatment modality remains unclear. We therefore examined these associations at a medical center providing care to a diverse patient population. Methods: We performed a retrospective analysis of consecutive patients diagnosed with NSCLC stages I-III from 2000 to 2005 at the University of Texas Southwestern Medical Center. We recorded patient, disease, and treatment characteristics. The association between these characteristics and outcome was assessed using univariate analysis, multivariate logistic regression, and survival analysis. Results: A total of 482 patients met criteria for analysis. Mean age was 64 y, and 52 percent were men. For stage I/II disease, median survival was 6.7 y for patients aged < 65 y vs 4.4 y for age ≥ 65 y (P=0.01); 3.1 y for men vs >5.8 y for women (P=0.0002); 5.6 y for patients with household income below the national median ($41,995) vs 5.6 y for above-median income (P not significant). For stage III, median survival was 1.1 y for age < 65 y vs 0.7 y for age ≥ 65 y (P=0.02); 0.8 y for men vs 1.2 y for women (P=0.02); 0.7 y for below-median income vs 1.2 y for above-median income (P=0.02). Race and hospital setting (public versus private) were not associated with survival. For stage I/II, patients treated with surgery had a median survival of 5.8 y, vs 1.7 y for non-surgical treatment (P<0.0001). For stage III, patients who received surgery and/or radiation had a median survival of 1.2 y vs 0.5 y for other patients (P<0.0001). For stage I/II, treatment modality was associated with hospital setting, race, and income. For stage III, treatment modality was associated with age, gender, hospital setting, race, and income. In multivariate analysis, age (for stage I/II), gender (for stage I/II), and treatment modality (for all stages) were associated with survival. Conclusions: For stages I-III NSCLC, a number of clinical characteristics are associated with outcomes. Differences in treatment modality may account in part for these disparities. These findings warrant further study.

No significant financial relationships to disclose.
Phase II pilot study of neoadjuvant docetaxel and cisplatin followed by adjuvant erlotinib in patients with stage I-III non-small cell lung cancer (NSCLC)
Authors: Gold K. A. , Lee J. J. , Rice D. , Tse W. , Stewart D. , Wistuba I. , Herbst R. S. , Lippman S. M. , Hong W. K. , Kim E. S.
Published: August 2020

7566

Background: Pts with early stage NSCLC, especially with nodal disease, have a poor prognosis despite curative intent therapy. It is unclear which pts may derive the benefit of chemotherapy. The primary endpoint of the study was to assess the tolerability of the regimen. In addition, the clinical response of the chemotherapy regimen as well as tumor biomarkers modulation will be examined. Methods: Pts had previously untreated, potentially surgically resectable, stage I-III NSCLC with ECOG performance status (PS) 0–1 and adequate laboratory parameters. After baseline tissue was obtained, chemotherapy was administered (docetaxel [T] 75 mg/m2 and cisplatin [P] 80 mg/m2 every 3 wks) for 3 cycles. Subsequently, pts underwent restaging, then planned definitive therapy with surgical resection. Pts were then offered treatment for 1 year with erlotinib (E) 150 mg PO daily. Bronchoscopic biopsies were performed at 6 months and 1 year post- surgery. Results: 41 pts were enrolled between 2/07 and 11/08. 3 were not eligible and did not receive treatment. Of the 38 eligible pts: median age was 65 years (42–80); 24 (63.2%) were male; 26 (68%) were PS 1. Stage IB 18% (7), IIB 37% (14), IIIA 39% (15), IIIB 5% (2). 31 pts completed all 3 cycles (35 pts completed at least 2 cycles). 32 pts underwent definitive surgical resection with 1 pt pending for surgery. 5 others did not undergo surgery: pneumonia (1), progressive disease (1), definitive chemo-radiation (3). For pts completing at least 2 cycles of chemotherapy, the radiographic response rate was 57% (20) by RECIST criteria with 40% (14) having stable disease. 1 pt had a complete pathologic response. 16 pts have started adjuvant E, 4 have completed 1 yr of treatment. Grade 3/4 toxicities included neutropenia (6 pts) and hypokalemia (4 pts). Blood and tissue specimens will be analyzed to assess sensitivity to chemotherapy. Conclusions: Neoadjuvant T and P is a tolerable and active regimen with an encouraging response rate in stage I- III resectable NSCLC. In addition to clinical characteristics, determining which patients will benefit from chemotherapy by analyzing their tumor biomarkers may help improve overall outcomes of curative lung cancer pts. Supported by grant DoD# W81XWH-07–1-0306.

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Phase II trial of extrapleural pneumonectomy followed by adjuvant radiotherapy in malignant pleural mesothelioma
Authors: Peigaud C. , Cellerin L. , Roussel J. , Sagan C. , Bordenave S. , Trogrlic S. , Mahé M. , Bennouna J. , Michaud J. , Despins P.
Published: August 2020

7579

Background: This phase II clinical study was conducted to evaluate the effectiveness of the association of extrapleural pneumonectomy followed by radiation therapy in patients with potentially resectable malignant pleural mesothelioma (MPM). Methods: Eligible patients had histologically proven epithelial or mixed MPM with clinical stage T1–3, N0–2, M0 disease considered to be completely resectable and a WHO performance status of 0 or 1. Surgery had to consist of a complete extrapleural pneumonectomy including resection of pericardium and diaphragm. Postoperative radiotherapy (40 Gy) was delivered through anterior and posterior fields, with a 10 to 20 Gy boost dose if necessary. Results: Thirty seven patients were included in this study. Extrapleural pneumonectomy was completed in 35 patients. Overall hospital mortality was 5,7 %. Major post operative complications were: 3 acute lung injury, 1 bronchopleural fistula, 1 stroke, 1 chylothorax and one diaphragmatic patch dehiscence. IMIG post-operative staging was: stage II = 5 patients; stage III = 25 patients; stage IV = 5 patients. Adjuvant radiation was administered to 29 patients. Survival for the 35 patients with complete resection was 47 ± 8 % at 2 years. Median overall survival time was 22 months. Survival without recurrence was 37 ± 8 % at 2 years. Median time to progression was 15 months. Locoregional recurrence is the most common form of relapse. Conclusions: In the era of surgical neoadjuvant therapy in MPM treatment, extrapleural pneumonectomy followed by radiation therapy in patients with resectable epithelial or mixed MPM can achieve acceptable results.

No significant financial relationships to disclose.
Phase II study of NGR-hTNF, a selective vascular targeting agent (VTA), in previously treated patients with malignant pleural mesothelioma (MPM)
Authors: Gregorc V. , Ceresoli G. L. , Zucali P. A. , De Braud F. G. , Bajetta E. , Santoro A. , Viganò M. G. , Caligaris-Cappio F. , Lambiase A. , Bordignon C.
Published: August 2020

7582

Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to an aminopeptidase N (CD13) overexpressed on tumor blood vessels. In preclinical models, NGR-hTNF has shown potent anti-vascular and antitumor activity, both at low and at high doses. Methods: Patients with advanced MPM were treated with a low-dose of NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and a total of 27 patients to be enrolled after first and second stage, respectively. Primary endpoint was progression-free survival (PFS) with restaging performed q6w according to MPM-modified RECIST criteria. Results: From May 2007 to January 2008, forty-three patients with radiologically-documented progressive disease after a pemetrexed-based regimen were evaluated over 167 cycles (range, 1 to 17). Patient characteristics were: median age 64 years (range, 54 to 80); male/female 27/16; epithelial/non-epithelial histology 34/9; PS 0/1/2 24/10/9; EORTC score good/poor 34/9. Main grade 1–2 toxicity was chills (71%), transiently occurring after the first infusions. Only one grade 3 treatment-related toxicity was observed. One patient (2%) had a partial response lasting 7.1+ months and 17 patients (40%) maintained stable disease for a median duration of 4.4 months (range, 1.3 to 12.4+ months). The median and 3-month PFS were 2.8 months and 43%, respectively, whereas the median and 1-year overall survival were 11.6 months and 48%, respectively. In an additional 14 patients treated at same dose with a weekly schedule, there was any suggestion of toxicity exacerbation. In this cohort, the PFS rate at 6 months was 36%, with 7 patients (50%) experiencing stable disease for a median duration of 6.9 months (range, 2.4 to 9.3+ months). Conclusions: NGR-hTNF 0.8 μg/m2 weekly is well tolerated, showing prolonged disease control in previously treated MPM patients, and will be further developed in this setting.

[Table: see text]
Randomized, double-blind, placebo-controlled phase II study of carboplatin and paclitaxel with or without vorinostat, a histone deacetylase inhibitor (HDAC), for first-line therapy of advanced non-small cell lung cancer (NCI 7863)
Authors: Ramalingam S. S. , Maitland M. , Frankel P. , Argiris A. E. , Koczywas M. , Gitlitz B. , Espinoza-Delgado I. , Vokes E. E. , Gandara D. R. , Belani C. P.
Published: August 2020

8004

Background: Vorinostat, a HDAC inhibitor, enhances paclitaxel and platinum-mediated anti-cancer activity in preclinical studies by enhanced tubulin acetylation and DNA fragmentation respectively. Promising activity with carboplatin (C), paclitaxel (P), and vorinostat in patients with advanced NSCLC in the phase I study (Ramalingam et al, Clin Cancer Res, 2007) prompted this placebo-controlled, randomized phase II study. Methods: Pts. with stage IIIB (wet) or IV NSCLC, performance status (PS) 0/1, no prior therapy and adequate bone marrow, renal and hepatic function were randomized (2:1) for therapy with PC with either vorinostat or placebo. Treatment consisted of C: AUC=6 mg/ml.min; and P 200 mg/m2 both given on day 3 along with either vorinostat (400 mg PO QD) or placebo on days 1–14 of each 3 wk cycle to a maximum of 6 cycles. The estimated sample size to demonstrate a 50% improvement in response rate for vorinostat over placebo was 93 pts. (one-sided P, type I error 10%). Results: Ninety-four pts. were enrolled (vorinostat-64; placebo-32). Pts. baseline characteristics were similar between the two arms (median age 64, male 60%, PS 0 40%, brain mets 16%). Median # cycles: vorinostat-3.5; placebo - 4. The confirmed response rate was superior with vorinostat over placebo (34% vs. 12.5%, P = 0.02). At the time of analysis, the preliminary median PFS for vorinostat and placebo were 5.75 and 4.1 m respectively (ITT). Follow up for survival is ongoing. Common grade 3/4 toxicities (vorinostat vs. placebo): neutropenia (44% vs. 47%); thrombocytopenia (33% vs. 16%); fatigue (13% vs. 3%); hyponatremia (21% vs. 6%); diarrhea (5% vs. 0). Discontinuation from study after cycle 1 was higher with vorinostat (27% vs. 16%). Biomarker studies on baseline tumor tissue and peripheral blood cells are ongoing. Conclusions: Administration of vorinostat with carboplatin and paclitaxel resulted in a significantly superior response rate for pts.with advanced NSCLC. HDAC inhibition is a novel therapeutic strategy for treatment of NSCLC. Supported by ASCO Career Development Award to S.S.Ramalingam, and NCI NO1-CM-62209, NO1-CM-62201, NO1-CM-62208.

[Table: see text]
Molecular and clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): Data from the FLEX study
Authors: O'Byrne K. J. , Bondarenko I. , Barrios C. , Eschbach C. , Martens U. , Hotko Y. , Kortsik C. , Celik I. , Stroh C. , Pirker R.
Published: August 2020

8007

Background: The multinational, randomized, phase III FLEX study compared cisplatin/vinorelbine (CT) plus the EGFR- antibody, cetuximab (Erbitux), with CT alone in the 1st-line treatment of patients (pts) with advanced EGFR-expressing NSCLC and demonstrated a statistically significant OS benefit for the cetuximab combination. We hypothesized that KRAS mutation status is predictive for cetuximab efficacy and enables optimal use of cetuximab. The relationship between early-onset acne-like rash (ie rash that developed ≤21 days of treatment initiation) and OS time of pts treated with CT and cetuximab was also evaluated. Methods: Archived tumor samples from 554/1125 pts were available. Genomic DNA derived from formalin-fixed paraffin embedded tumor tissue was analyzed for KRAS using an LNA-mediated qPCR clamping assay capable of detecting oncogenic mutations at codons 12 and 13. The Kaplan-Meier method was used to estimate OS time and PFS time in pts with KRAS wild-type (wt) and mutant (mt) tumors for each treatment arm. All pts treated with cisplatin/vinorelbine plus cetuximab who were alive at 21 days were included in a landmark analysis evaluating the relationship between early-onset acne-like rash and OS time. Results: KRAS results were obtained from 379 pts. A KRAS mutation was detected in 72 (19%) pts. The comparison of the cetuximab treatment effects in pts with KRAS wt tumors and pts with KRAS mt tumors showed no marked differences with regard to OS or PFS. A total of 518 pts were included in the landmark analysis. Pts treated with cetuximab who developed early acne-like rash of any grade (grade 1–3; 56%, n=290) had a longer median OS than those without acne-like rash (n=228) (median [95% CI]: 15.0 months [12.8–16.4] vs 8.8 months [7.6–11.1]; HR [95% CI]: 0.63 [0.52–0.77]; p<0.001). Analysis of EGFR FISH is ongoing and results will be presented. Conclusions: Clinical data from the FLEX study do not support the hypothesis that KRAS mutation status is predictive for cetuximab efficacy when combined with 1st- line chemotherapy in advanced NSCLC, whereas early acne-like rash of any grade appears to be associated with better outcome in pts treated with platinum-based chemotherapy plus cetuximab in this setting.

[Table: see text]