bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical impact of dose intensity of initial tyrosine kinase inhibitor (TKI) therapy in accelerated-phase CML (CML-AP).
Authors: Ohanian Maro , Kantarjian Hagop , Quintas-Cardama Alfonso , O'Brien Susan Mary , Verstovsek Srdan , Borthakur Gautam , Ravandi Farhad , Garcia-Manero Guillermo , Burton Elizabeth M , Trinh Long , Ferrajoli Alessandra , Jabbour Elias , Kadia Tapan M. , Cortes Jorge E.
Published: March 2020

6587

Background: For patients (pts) presenting with CML-AP, TKIs are recommended. Although generally well tolerated, dose reductions and/or interruptions are often required. The impact of TKI dose intensity (DI) on CML-AP outcome has not been described. Aim: To determine impact of TKI dose interruptions and/or reductions on outcome in de novo CML-AP. Methods: Overall, 58 CML-AP pts (median age 46 yrs) were treated on consecutive or parallel clinical trials with TKIs as initial therapy: imatinib (n=36), dasatinib (n=5), or nilotinib (n=17). CML-AP features included: blasts ≥15% (n=8), basophils ≥20%, (n=22), platelets <100x109/L (n=3), cytogenetic clonal evolution (n=22), or >1 feature (n=3). We examined the impact of dose reductions, treatment interruptions, and DI (ratio of the dose received vs. the intended dose for the entire treatment duration) on event-free (EFS), transformation-free (TFS), and overall survival (OS). Results: Among 58 pts, 37 required treatment interruptions and/or dose reductions (29 required dose reductions). 12 pts required dose reductions and/or interruptions due to hematologic toxicity and 23 for non-hematologic toxicities. Pts were divided into 3 DI tiers: 100% (n= 21), 90-99%, (n=10), and <90% (n=27). Outcomes were analyzed based on DI tiers and presence or absence of dose reductions as shown in the table. Pts with dose reductions and/or interruptions for hematologic toxicities vs. non-hematologic toxicities had a 24-mo EFS rate of 87% vs. 100% (p=0.05). 24-mo EFS by dose reductions and/or interruptions within 6 mo or later were 100% and 91%, respectively (p =0.7). Conclusions: DI has no significant impact on de novo CML-AP outcome. However, dose interruptions and/or reductions for hematologic toxicities are associated with worse 24-mo EFS, suggesting myelosuppression may in some patients be more a feature of the disease than toxicity from therapy. [Table: see text]
Impact of ABL kinase domain mutations on the outcome of patients with chronic myeloid leukemia (CML).
Authors: Sweet Kendra Lynn , Komrokji Rami S. , Al Ali Najla , Crescentini Robert M. , Domingo Gelenis , Chavez Julio C. , Dalia Samir , Tinsley Sara , Lancet Jeffery , Zhang Ling , Pinilla-Ibarz Javier
Published: March 2020

6588

Background: Patients with CML who develop resistance to imatinib commonly have mutations in the BCR-ABL kinase domain (KDM). Studies looking at outcomes in patients with P-loop versus non-P-loop mutations within the ABL-Kinase Domain have produced conflicting results. Methods: The Total Cancer Care (TCC) database was used to identify patients with CML treated at Moffitt Cancer Center (MCC). Descriptive data were reported, chi square test was used for categorical variables, and Kaplan Meier curves were used for OS and PFS. Log rank test was used to compare survival times between groups. Results: Between 1992 and 2011, 540 CML patients were treated at MCC. Of those, 51% were male and 71% were under the age of 60. Sixty percent (n=322) were diagnosed after 2001. Of the 540 patients, 6.5% (n=35) were found to have mutations of which 26 were detected in patients diagnosed after 2001. Of the 35 patients, 74% (n=26) had single mutations and 26% (n=9) had compound mutations. P-loop mutations were seen in 17% (n=6) and 43% (n=15) had T315I mutations. Patients with KDM progressed to accelerated or blast phase in 46% (n=16) of cases compared to 27% (n=136) without mutations (p=0.03). Median OS was 126 months, 109 months, and not reached in patients with P-loop, T315I, and non-P-loop mutations respectively (p=0.17). The corresponding median PFS was 85 months, 89 months, and not reached (p=0.20). In patients with one mutation median OS was not reached compared to 105 months in patients with compound mutations (p=0.27). After 2001, patients with KDM had a median PFS of 75 months and OS of 126 months while neither was reached in the non-mutation cohort (p=0.007, p=0.26 respectively). Median PFS in patients with single mutations was 85 months versus 10 months in those with compound mutations (p=0.037). Patients with KDM had additional Ph+ clones on cytogenetics in 49% of cases compared with 19% of cases in the non-mutation group (P < 0.005). Conclusions: T315I and P-loop KDM predict PFS and OS in CML patients, and convey a trend for worse prognosis. The presence of additional Ph+ clones in patients with BCR-ABL KDM indicates a higher level of genetic instability and clonal evolution, which may be the contributing factor to poor outcomes.
Monitoring and switching patterns in chronic myelogenous leukemia (CML) pts treated with imatinib (IM): A chart review analysis.
Authors: Chen Lei , Guerin Annie , Aberki Clemence , Wu Eric Q. , Ericson Solveig , Jabbour Elias
Published: March 2020

6594

Background: The objective of this study is to evaluate compliance to National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) guidelines regarding monitoring frequency and switching practices in CML patients (pts) treated with IM in community practices. Methods: Physicians treating CML pts were selected from 28 community practices throughout the USA. Each physician reviewed and extracted up to 15 pt charts of CML pts in chronic phase not previously enrolled in clinical trials. Pts were required to have initiated 1st-line IM between 1/2006 - 10/2010. Data on 1st-line IM treatment response monitoring frequency and outcomes, and corresponding therapy switching patterns were extracted. Results: Information was collected on treatment monitoring and response from a total of 297 pt charts. Median IM duration was 320 days. Percentages of pts monitored according to both guidelines are reported. In addition, the proportion of pts who missed milestones and the proportion of pts who did not switch to a 2nd-line tyrosine kinase inhibitor (TKI) when they missed milestones are reported. Conclusions: There is considerable undermonitoring of CML pts receiving IM, which is likely to result in a significant portion of pts with suboptimal response left undetected. The switching rate to 2nd-line TKI among pts with suboptimal response to IM is much lower than recommended by either NCCN or ELN guidelines. [Table: see text]
A phase II study of clofarabine and daunorubicin in patients age 60 or older with newly diagnosed adult acute myeloid leukemia.
Authors: Vigil Carlos Enrique , Griffiths Elizabeth A. , Thompson James E , Tan Wei , Greene Jessica , Ford Laurie Ann , Wang Eunice S. , Wetzler Meir
Published: March 2020

6602

Background: The outcome of acute myeloid leukemia (AML) patients (pts) ≥60 years (yrs) old remains poor, with a median overall survival of a few months. Neither the addition of other drugs during induction of the traditional 7+3 regimen nor an increase of cytarabine or daunorubicin doses has improved their overall survival. We have therefore designed a combination of clofarabine and daunorubicin. Aims: Determine the safety and efficacy of clofarabine and daunorubicin in pts ≥ 60 yrs of age. Methods: Induction-clofarabine 20 mg/m2 /d in a 1-hour IV for 5 days followed 3 hrs later by daunorubicin 50 mg/m2 IV over 5 minutes on days 1, 3, and 5. Pts who did not achieve complete remission (CR) or CR without platelet recovery (CRp) were eligible for a second round of induction as above. Consolidation - 2 cycles of clofarabine 20mg/m2 /d for 3 days and daunorubicin 50 mg/m2/day on days 1 and 3. Results: Twenty-one pts were enrolled. The median age was 69 (range 60-85) yrs. Seven pts (34%) had secondary AML and 52% had complex karyotype. Twenty-one pts completed one induction cycle, one pt received a second induction due to residual disease and 6 pts underwent consolidation therapy. The principal toxicity was grade ≥3 infections and prolonged thrombocytopenia and neutropenia, which occurred in 18% and 21% of pts, respectively. Three deaths were documented from treatment complications (sepsis and fungal infections). Eight (38.1%) pts achieved either a CR or CRp. Responses were observed in 5/11 (45.5%) pts with high risk features (complex karyotype and/or presence of FLT3). The median disease free-survival was 1.9 (range, 0.9-8) months and the median overall survival was 6.5 (range, 4.2-14.2) months. The 1-yr overall survival was 35%. Conclusions: These preliminary results suggest that clofarabine in combination with daunorubicin is safe, well-tolerated with minimal toxicity, and active for the upfront treatment of ≥60 yrs old AML pts, including those with adverse features. Future trials will explore additional modifications to this regimen in order to optimize therapy for this group of pts with high risk features and frequent treatment failure.
Pooled safety analysis of omacetaxine mepesuccinate in patients with chronic myeloid leukemia (CML) resistant to tyrosine-kinase inhibitors (TKIs).
Authors: Wetzler Meir , Kantarjian Hagop , Nicolini Franck E. , Lipton Jeffrey Howard , Akard Luke Paul , Baccarani Michele , Craig Adam , Brown Peter D. , Cortes Jorge E.
Published: March 2020

6604

Background: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a reversible, transient inhibitor of protein elongation that does not depend on BCR-ABL signaling. It showed significant clinical activity in two phase 2, open-label, multicenter studies of patients with CML who were resistant/intolerant to prior TKI therapy. However, omacetaxine tolerability data across the 3 phases of CML are limited. Methods: Safety data were pooled from all patients in the 2 studies plus a small pilot study. Omacetaxine 1.25 mg/m2 was given subcutaneously twice daily: ≤14 successive days per 28-day cycle for induction, ≤7 days/cycle as maintenance. Days of dosing could be adjusted and recombinant growth factors given, as clinically indicated. Results: Of 207 pooled patients (median age, 57 years), 108 were in chronic (CP), 55 in accelerated (AP), and 44 in blast phase (BP). Median treatment was 4 cycles (range, 1–41). On study, 80% of patients had ≥1 hematologic adverse event (AE), 60% had a serious AE (SAE), 30% had a hematologic SAE, 34% had an SAE that resulted in hospitalization, and 15% discontinued treatment due to an SAE (most commonly disease progression). There were 49 (24%) deaths (15 CP, 11 AP, and 23 BP). Of the 8 that were treatment related (5 CP, 2 AP, 1 BP), the most common cause was sepsis (3 patients). The most common AEs were thrombocytopenia (60%), anemia (51%), diarrhea (40%), neutropenia (37%), and nausea (30%). Injection site reactions (eg, injection site pain, erythema) occurred in 32%, with the majority being low grade. Infections (eg, pneumonia, bronchitis) occurred in 51%. Treatment-related grade 3/4 hematologic AEs included thrombocytopenia (52%), neutropenia (31%), anemia (30%), leukopenia (12%), and febrile neutropenia (11%). The most common treatment-related grade 3/4 nonhematologic AE was fatigue (4.3%). Overall, there were 34 (16%) grade 3/4 infections (12 CP, 11 AP, 11 BP). Conclusions: In the largest safety analysis to date, subcutaneous omacetaxine 1.25 mg/m2 showed an acceptable safety profile in all phases of CML. AEs were primarily hematologic, and grade 3/4 nonhematologic AEs were not common. Support: Teva Pharmaceutical Industries Ltd.
Assessment of age as its own risk factor in AML.
Authors: Buchner Thomas , Berdel Wolfgang E. , Haferlach Claudia , Schnittger Susanne , Stelljes Matthias , Silling Gerda , Staib Peter , Grueneisen Andreas , Reichle Albrecht , Balleisen Leopold , Eimermacher Hartmut , Giagounidis Aristoteles , Rasche Herbert , Lengfelder Eva , Krug Utz , Sauerland Maria Cristina , Heinecke Achim , Wormann Bernhard J. , Hiddemann Wolfgang ,   German Acute Myeloid Leukemia Cooperative Group
Published: March 2020

6610

Background: Patients’ age is an important issue in treatment decisions for AML, while its role in this disease remains poorly explained. Methods: In the AMLCG 1999 trial 1223 patients (pts) were 16-59y and 1470 pts were 60-85y of age. Their treatment was randomized between TAD-HAM vs HAM-HAM induction (TAD, standard dose thioguanine, cytarabine, daunorubicin 60mg/m² x 3; HAM, high-dose cytarabine 3g/m² x 6, mitoxantrone 10mg/m² x 3), TAD consolidation and monthly maintenance vs autologous SCT, any chemotherapy + vs - G-CSF priming. All randomization was done upfront. Pts of <60y received routine double induction and full dose HAM while pts of 60+y preferentially received only one course induction and HAM at 1g instead of 3g cytarabine /m² x 6. Results: With little differences according randomizations, pts <60y and 60+y achieved a complete remission rate (CR) of 70.2% and 53.5% (p<.001), overall survival (OS) at 5y of 41.3% and 12.9% (p<.001) and a relapse rate (RR) of 49.0 and 72.0% (p<.001). We also focussed on pts around 60y of age and compared the 172 pts of 57-59y with the 261 pts of 60-62y excluding pts undergoing allogeneic stem cell transplantation. According to their similar age the two groups showed similar baseline characteristics. In contrast and due to the cut-off point for age adaption at 60y they differed considerably in treatment. Expressed by the cumulative dosage of cytarabine, the difference between the two groups was by factor 2.9. This difference, however, did not translate into a different outcome being 62% vs 60% CR, 28% vs 21% 5y OS (p=0.25), and 73% vs 73% RR at 5y. A multivariable analysis in all pts between 16 and 85y of age identified cytogenetik/ molecular risk and age as a continuous variable, to be risk factors predicting CR, OS, as well as RR. In pts of 16-60y those below and above the median age of 47y differed in their CR rate by 75% vs 66% (p<.001), their OS by 49% vs 35% (p<.001) and in their RR by 45% vs 53% (p=.007). In pts of 60-85y those below and above the median age of 67y differed in their CR rate by 57% vs 51% (p=.023), and their OS by 16% vs 11% (p<.001), while their RR was similarly 71%. Conclusions: The outcome in pts with AML is substantially determined by patients’ age as its own risk factor, and not by treatment intensity.
High frequency of BCR-ABL oncogene in pediatric acute lymphoblastic leukemia (ALL) patients as revealed by RT-PCR and interphase FISH: Association with disease biology and treatment outcome.
Authors: Iqbal Zafar , Awan Tashfin , Iqbal Mudassar , Sabir Noreen , Asad Sultan , Siddique Mohammad Hasan , Sahar Sumrin , Tahir Ammara H , Aleem Aamer , Akhtar Tanveer ,   H.O.P.E.S. Group
Published: March 2020

6612

Background: ALL is a complex genetic disease involving many fusion oncogenes (FGs)1 frequency of which can vary in different ethnic groups2,3 thus having implication in differential diagnosis, prognosis and treatment. Methods: We studied FGs in 101 pediatric ALL patients using RT-PCR1 at Day 0, Day 15 and Day 29 and Interphase FISH, and their association with clinical features and treatment outcome. Results: Five most common FGs i.e. BCRABL (t 22; 9), TCF3-PBX1 (t 1; 19), ETV6-RUNX1 (t 12; 21), MLL-AF4 (t 4; 11) and SIL-TAL1 (del 1p32) were found in 88.1% (89/101) patients. Frequency of BCR-ABL was 44.5% (45/101). Patients with BCR-ABL had significantly lower survival (43.733 weeks ±4.241) as compared to others except MLL-AF4 and significantly higher TLC count. Overall survival was lower (52.2±3.75) than the patients with ETV6-RUN X 1 (65.2± 9.9) which may be due to overall high frequency of poor prognostic FGs (71%) as compared to ETV6-RUNX 1 (17.1%) (p=0.01). Conclusions: This is the first study from Pakistan correlating molecular markers, disease biology and treatment response. It is the highest reported frequency of BCR-ABL in pediatric ALL and was associated with disease biology and survival. Some authors have reported BCR-ABL frequency higher than in West2,4,5 while others reported 45% frequency of ETV6-RUNX16. These and our data reflect strong interplay of genetic and environmental factors in biology of pediatric ALL and its correlation with disease biology and treatment2,3. Our data indicates immediate need for large clinical trials of imatinib, dasatinib and nilotinib in paediatric ALL treatment in our ethnic group. This study will lead to unravel the mechanisms of BCR-ABL Leukemogenesis and to find population-specific biomarkers and drug targets. References: 1) van Dongen JJ, et al., Leukemia. 1999 Dec; 13(12):1901-28. 2) Iqbal Z, et al. J Pediatr Hematol Oncol. 2007 Aug; 29(8):585. 3) Ariffin H, et al. J Pediatr Hematol Oncol. 2007 Jan; 29(1):27-31. 4) Ramos C, et al. 2011 Sep; 139(9):1135-42. 5) Artigas A CG, et al. Rev Med Chil. 2006 Nov; 134(11):1367-76. 6) Karrman K, et al. Br J Haematol. 2006 Nov; 135(3):352-4.
Epigenetically induced expression of CD30 in T-PLL: A rationale for the use of brentuximab vedotin.
Authors: Hasanali Zainul , Sharma Kamal , Shimko Sara , Stuart August , Liu Xin , Epner Elliot E , Loughran Thomas P.
Published: March 2020

6616

Background: T-cell prolymphocytic leukemia (T-PLL) is characterized by high lymphocyte counts, skin involvement and enlarged organs. Treatment with alemtuzumab (alem) induces complete remission (CR) in >50% of patients, duration is short (median: 6 mos). Therapy with the histone deacetylase inhibitors (HDACi) vorinostat (SAHA) or romidepsin (romi) and cladribine (2-CdA), may augment mAb activity. Methods: Five T-PLL patients were studied (Table). Diagnosis was made by pathology, flow cytometry and TCR studies. Alem (30 mg sq d1,3,5) and 2-CdA (5mg/m2 d1-5), followed by alem, 2-CdA and SAHA (400mg q d X 5 days) or romi (14mg/m2d 1,8,15) was given. One patient with skin lesions expressed CD30 and received brentuximab vedotin (SGN-35). Results: All patients achieved CR (mean: 10; median: 8 mos). Relapsed patients responded with repeat dosing. Genes assayed indicate involvement of the MAPK pathway (p53, DUSP2, TRIB1, C/EBP). mRNA expression of the membrane receptor CD30 (TNFRSF8) increased following therapy in 4/5 patients (mean: 14; Range: 1.3-69 fold). CD30 protein was confirmed by IHC and Western blotting. One patient with relapsed T-PLL involving skin had a dramatic clearing of lesions and blood counts after one dose of SGN35. Conclusions: Therapy with HDACi and 2-CdA overcomes resistance and augments clinical activity of alem and SGN-35, as evidenced by derepression of CD30 and response to treatment. We present a rationale for epigenetic resensitization to mAbs and their drug conjugates (ADC) in T-PLL. A prospective multicenter clinical trial is warranted. [Table: see text]
Phase I dose escalation study of bortezomib in combination with lenalidomide in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
Authors: Amrein Philip C. , Attar Eyal C. , Fathi Amir Tahmasb , McAfee Steven L , Wadleigh Martha , DeAngelo Daniel J. , Steensma David P. , Foster Julia , Stone Richard M. , Neuberg Donna S. , Ballen Karen K. ,   Massachusetts General Hospital/Dana-Farber Cancer Institute/Harvard Cancer Center
Published: March 2020

6621

Background: Both bortezomib (Bz) and lenalidomide have clinical activity in patients with MDS and AML. We conducted a phase I dose escalation study to determine the maximal tolerated dose (MTD) of Bz in combination with lenalidomide. Methods: Patients with MDS (IPSS score ≥ 0.5 or therapy-related) received Bz by IV bolus on Days 1, 4, 8, and 11 and lenalidomide 10 mg/day PO on Days 1-21 in 28 day cycles for up to 9 cycles. Three doses of Bz were tested (0.7, 1.0, or 1.3 mg/m2). Cohorts consisted of 3-6 patients; the dose of Bz was escalated if there were < 2 dose limiting toxicities (DLTs). Growth factor support and transfusions were permitted. Dose limiting toxicities (DLTs) were assessed during the first cycle and were defined as severe neutropenia (absolute neutrophil count ≤ 250/ul), thrombocytopenia (platelet count < 10,000/ul), grade ≥ 2 neurotoxicity, or other grade ≥ 3 non-hematologic toxicity. Following determination of the MTD, enrollment opened to patients with relapsed and refractory AML and those with untreated high risk disease for whom induction therapy was not indicated. Responses were assessed by IWG 2006 criteria for MDS and IWG 2003 criteria for AML. Results: 23 patients (14 men) were enrolled; one patient was inevaluable due to disease progression prior to starting protocol therapy. The median age was 73 years (range 54-87). There was 1 DLT observed, neutropenia, in 6 patients treated with 1.0 mg/m2 Bz and no DLTs at 0.7 or 1.3 mg/m2. The median number of cycles was 2 (range 2-9). Grade ≥ 3 toxicities possibly attributable to the treatment at any dose level were: anemia (2), thrombocytopenia (10), leukopenia (3), infection (1), rash (2), dyspnea (1), dizziness (1), hypotension (1), pneumonia (2) and neuropathy (1). Among the 14 patients with MDS, 1 patient with RARS experienced a CR and 2 with RAEB-2 experienced marrow CR (mCR). Among the 8 patients with AML, there was 1 CR. Conclusions: The maximal tested dose of Bz (1.3 mg/m2) in combination with lenalidomide is safe. Responses were seen in MDS and high risk AML. Future testing of this regimen is planned.
Regional variation in treatment costs and survival for elderly patients with myelodysplastic syndromes.
Authors: Ma Xiaomei , Wang Rong , Long Jessica B. , Gold Heather Taffet , Halene Stephanie , Gross Cary P.
Published: March 2020

6628

Background: Myelodysplastic syndromes (MDS) occur primarily in the elderly (≥65 years). The expected 5-year cost for an elderly MDS patient tops $63,200 in 2009 US$. This study assessed regional variation in the cost of care and survival for elderly MDS patients. Methods: Using the Surveillance Epidemiology and End Results–Medicare data, we identified primary MDS patients aged 66-99 years diagnosed from 2001-2007, had continuous fee-for-service coverage for Parts A and B, and had no history of other cancer. We assigned patients to Dartmouth Atlas of Health Care Hospital Referral Regions (HRRs) based on their residence at time of diagnosis. We also selected controls from a 5% sample of Medicare beneficiaries without cancer and matched controls 1:1 to patients by HRR, age, sex, pre-diagnosis cost and comorbidity. All Medicare claims through 2009 were tallied, and MDS-related costs were defined as the difference between the payments for a patient and a matched control. Results: With 6244 patients in 73 HRRs, the average 3-year MDS-related cost varied across HRRs, ranging from $12,900 to $83,600 (2009 US$). Patients in high-spending regions had more comorbidities and higher Medicare costs before diagnosis and were more likely to be racial minorities and live in lower-income areas. Three-year survival ranged from 13.0% to 62.1%. However, there was no significant correlation between 3-year costs and 3-year survival (ρ=-0.06, p=0.61). The hazard ratios (HR) for higher spending regions compared to the lowest-expenditure region were near 1, after controlling for covariates including MDS subtype (2nd quartile: HR=1.03, 95% CI: 0.94-1.12; 2nd quartile: HR=1.04, 95% CI: 0.95-1.14; 4th quartile: HR=0.98, 95% CI: 0.90-1.08). Conclusions: We observed considerable regional variation in Medicare expenditure on elderly MDS patients during the first 3 years post-diagnosis. However, patients in higher cost regions had similar 3-year survival to patients in lower cost regions. Given the substantial economic burden of MDS and Medicare’s current fiscal challenges, it is important to further assess the factors associated with higher regional costs and to improve the care of MDS patients in a cost-efficient way.
Phase II study of pemetrexed (P) plus carboplatin (Cb) or cisplatin (C) with concurrent radiation therapy followed by pemetrexed consolidation in patients (pts) with favorable-prognosis inoperable stage IIIA/B non-small cell lung cancer (NSCLC).
Authors: Choy Hak , Schwartzberg Lee Steven , Dakhil Shaker R. , Garon Edward B. , Choksi Janak K. , Govindan Ramaswamy , Peng Guangbin , Koustenis Andrew , Treat Joseph , Obasaju Coleman K.
Published: March 2020

7002

Background: There is no consensus chemotherapy regimen with concurrent radiation therapy (CRT) for inoperable stage IIIA/B NSCLC. P synergizes with ionizing radiation, as well as with Cb and C in preclinical models. These doublets have shown efficacy and favorable toxicity profiles in phase II/III trials. Methods: In this open-label randomized phase II trial, 98pts with inoperable stage IIIA/B NSCLC (all histologies) were randomized (1:1) to P 500 mg/m2 plus Cb AUC 5 (PCb) or P 500 mg/m2 plus C 75 mg/m2 (PC) intravenously (IV) every 21 days for 3 cycles. All pts received CRT 64–68 Gy (2 Gy/day, 5 days/week, Days 1–45). Consolidation P 500 mg/m2 IV every 21 days for 3 cycles began 3 weeks after completion of CRT. The primary endpoint was 2-year overall survival (OS); secondary endpoints included median OS, time to progression (TTP), overall response rate (ORR), and toxicity. Results: Since Jun 2007, 98 pts were enrolled (PCb: 46; PC: 52).Pts were followed until Oct 2011. Mean dose compliance was PCb: 95.7% P, 97.1% Cb; PC: 89.7% P, 89.1% C. Mean dose compliance for CRT was PCb: 95.7%; PC: 88.1%. CRT dose interruptions occurred in PCb: 32.6% and PC: 40.4%. Two-year OS was PCb: 45.2% (95% confidence interval [CI], 29.3-59.8); PC: 57.6% (95% CI, 41.6-70.7); p=0.270. Median OS (months) was PCb: 18.7 (95% CI, 12.9-not assessable [N/A]); PC: 27.0 (95% CI, 23.2-N/A). Median TTP (months) was PCb: 8.8 (95% CI, 6.0-10.7); PC: 13.1 (95% CI, 8.3-N/A); p=0.057. The ORR rates were PCb: 52.2% (complete response [CR], 6.5%; partial response [PR], 45.7%); PC: 46.2% (CR, 3.8%; PR, 42.3%). Grade 4 treatment-related toxicities (% PCb/% PC) were: anemia, 0/1.9; neutropenia, 6.5/3.8; thrombocytopenia, 4.3/1.9; and esophagitis, 0/1.9. No drug-related deaths were reported. Conclusions: While conclusions are limited by the size of the trial, this study suggests OS and TTP advantages for the C-containing arm. Both combinations with CRT appear well tolerated.
Quantitating pathologic response to neoadjuvant chemotherapy in KRAS-mutated versus nonmutated lung cancers.
Authors: Chaft Jamie E. , Paik Paul K. , Sima Camelia S. , Kris Mark G. , Krug Lee M. , Azzoli Christopher G. , Riely Gregory J. , Pietanza Maria Catherine , Rusch Valerie W. , Travis William D , Rizvi Naiyer A.
Published: March 2020

7014

Background: Trials of neoadjuvant chemotherapy in non-small cell lung cancers (NSCLC) have demonstrated that pathologic response correlates with downstaging and survival. There is controversy as to whether KRAS mutated patients (pts) have the same benefit with adjuvant chemotherapy as non-mutated pts however the impact of KRAS mutations on response to neoadjuvant therapy has not been reported. Methods: Pts with resectable stage I-III non-squamous NSCLCs were treated with 4 cycles of cisplatin, docetaxel, and bevacizumab, followed by surgical resection. Tumors were tested for KRAS mutations. Percent treatment effect (necrosis, inflammation, fibrosis) was quantified histologically. Pts were followed until disease recurrence and/or death. Binary variables were compared using the Fisher’s Exact Test. Survival was assessed by pathological response based on the literature (≥90 vs <90%) using the Kaplan-Meier method, stratified by stage (IB-IIB vs. III) and by KRAS mutation. Results: We accrued 51 pts. 34/51 (67%) had clinical stage IIIA disease. 48 had molecular testing: 14/48 (29%) had KRAS mutations and 4/48 (8%) had EGFR mutations. The median follow-up was 2 years (yr) (range, 3-63 months). 41 pts had resection and analysis for pathological response. The 2 yr disease free survival (DFS) and overall survival (OS) were superior in the 11/41 (27%) with ≥90% versus those with <90% treatment effect: DFS 91% vs. 56%, p=0.029 and OS 100% vs. 60%, p=0.013. These outcomes remained significant when adjusted for stage. For pts with KRAS mutations, 0 of 10 tumors analyzed had ≥90% treatment effect whereas 11 of 31 (35%) pts with wild-type KRAS had ≥90%, p=0.039. There was an inferior median OS for KRAS mutated pts (22 months) compared to pts without a known KRAS mutation, (Not Reached, p=0.03). Conclusions: Following neoadjuvant chemotherapy, pts with tumors having ≥90% necrosis had improved survival. There were no patients with KRAS mutation that achieved ≥90% treatment effect in response to cisplatin, docetaxel, and bevacizumab. Adaptive adjuvant trial strategies to improve upon outcomes of those with <90% necrosis at resection and new approaches specifically targeting KRAS-mutated NSCLCs are needed.
Prognostic impact of the number of examined lymph nodes (LNs) in resected node negative (pNo) non-small cell lung cancer (NSCLC).
Authors: Ogbata Obiageli Uchenna , Yu Xinhua , Osarogiagbon Raymond U
Published: March 2020

7025

Background: In the US, 29% of patients undergo curative-intent surgery for NSCLC. Absence of LN metastasis and the extent of LN examination influence survival. 44% of patients with pathological node negative (pN0) disease die within 5 years. There is no consensus on the optimal number of LNs to be examined to determine pN0 stage. We hypothesized that patients with few examined nodes may have missed nodal metastasis and increasing the number of LNs examined would improve survival. Methods: Retrospective SEER database analysis of NSCLC resections from 1998 to 2002, with survival updated to 2008. Patients with first primary, pN0 NSCLC, with one or more LNs examined, met our study criteria. Cox regression and competing risk models were used for survival analysis. A p value <0.05 was considered statistically significant. Results: 8,137 patients met inclusion criteria and were evaluated. A median of 6 LNs were examined in this cohort. Patients who underwent pneumonectomy and lobectomy had more LNs examined than those who had sub-lobar resections. Higher number of LNs examined was associated with better overall survival (OS) and lung cancer specific survival (LCSS), at a plateau of 8 LNs for both outcomes (Table). Having mediastinal LNs examined also resulted in increased OS and LCSS (p<0.05). Conclusions: The pathologic assessment of LNs in surgical specimens is often suboptimal. Examining more LNs may have increased the likelihood of correct staging. Lower numbers of LNs examined probably result in understaging. Examining 8 or more total LNs and mediastinal LNs examined improved both OS and LCSS. [Table: see text]
Randomized phase II trial comparing two schedules of thoracic radiotherapy (TRT) in limited disease small-cell lung cancer (LD SCLC).
Authors: Grønberg Bjørn Henning , Halvorsen Tarje Onsoien , Fløtten Øystein , Brustugun Odd Terje , Brunsvig Paal , Aasebø Ulf , Bremnes Roy M. , Tollali Terje , Hornslien Kjersti , Aksnessæther Bjørg Yksnøy , Liaaen Erik Dyb , Sundstrøm Stein ,   Norwegian Lung Cancer Study Group
Published: March 2020

7027

Background: Concurrent chemotherapy and TRT is standard therapy for SCLC if all lesions can be included in a radiotherapy field (LD). Several schedules of TRT are used. One study showed that two fractions a day improved local control and overall survival (OS), but this schedule has not been compared to a commonly used 3 wks schedule. Methods: Eligible pts had LD SCLC and PS 0-2. Pleural fluid was accepted if negative cytology. Pts received 4 cycles of PE (cisplatin 75 mg/m2 IV day 1 and etoposide 100 mg/m2 IV day 1-3 q 3 wks) and were randomly assigned to 3 wks of 3D conformal TRT [A] 42 Gy (2.8 Gy x 1/day) or [B] 45 Gy (1.5 Gy x 2/day). TRT started 3-4 wks after the first PE. All responders received prophylactic cranial irradiation (PCI) 2 Gy x 15 ≤ 6 wks after last PE. Pts reported health related quality of life (HRQoL) on EORTC QLQ C30 + LC13. Primary endpoint: 1-year local failure. Secondary: OS, toxicity and HRQoL (dysphagia and dyspnea; a difference ≥ 10 points was considered significant). 75 pts were required in each arm to show a 30% improvement of local disease control with α=.05 and β=.8. Results: 159 eligible pts were enrolled at 18 sites in Norway May 05 – Jan 11 (A: 85, B: 74). Median age 60 (40-85); 52% men, 84 % PS 0-1, 11% pleural fluid. Mean no. of PE-cycles was 3.8, 97% completed TRT, 82 % PCI (no difference between arms). Response rates were similar (A: 92%, B: 94%; p=.8), but more pts on Arm B had CR (A: 13%, B: 35%; p=.01). There was no difference in local failure as first site of progression at 1 year (A: 17%, B: 12%; p=.4) or 1-year PFS (A: 44%, B: 50% ; p=.4). There was similar grade 3-4 esofagitis (A: 33%, B: 37 %; p=.7) and pneumonitis (A: 6 %, B: 7 %; p=.9). 2 pts (1 on each arm) died from pneumonitis. Pts in Arm B reported more dysphagia (A: 64 points, B: 73 points), but not more dyspnea (A: 29 points, B: 28 points). 1-year OS was similar (A: 77%, B: 76%; p=.9). Currently, 2-year survival among those followed ≥ 2 years (n=130) favors Arm B (A: 40%, B: 55%; p=.09) and so far (all pts followed ≥ 1-year; 103 events) median OS favors Arm B (A: 18.7 mos, B: 26.6 mos; p=.34). Conclusions: Twice daily TRT resulted in more CRs, slightly more dysphagia, similar 1-year local control and 1-year PFS. There are indications of improved 2-year and median OS in this arm.
Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma (MPM).
Authors: Krug Lee M. , Wozniak Antoinette J. , Kindler Hedy Lee , Feld Ronald , Koczywas Marianna , Morero Jose Luis , Rodriguez Cristina P. , Ross Helen J. , Bauman Julie E. , Orlov Sergey V , Ruckdeschel John C. , Mita Alain C. , Fein Luis , Fernandez Cristian , Hall Robert , Kawabe Takumi , Sharma Sunil
Published: March 2020

7029

Background: CBP501, a synthetic duodecapeptide, enhances the cytotoxicity of cisplatin in cell lines and xenografts, including NCI-H226 human mesothelioma. CBP501 increases cisplatin influx into tumor cells through an interaction with calmodulin, and inhibits cell cycle progression by abrogating DNA repair at the G2 checkpoint. Phase I clinical trials combining CBP501 with cisplatin alone or with pemetrexed showed acceptable safety profiles and suggested activity. The most common toxicity of CBP501 is infusion-related urticaria, which is easily managed with diphenhydramine. Methods: Chemotherapy-naive patients with unresectable MPM were stratified by histology (epithelioid vs other) and performance status (PS 0-1 vs 2) and randomized 2:1 to Arm A: pemetrexed/cisplatin plus CBP501 25 mg/m2 IV (42 pts planned), or Arm B: pemetrexed/cisplatin alone at standard doses (21 pts planned). Patients continued on treatment until progression or intolerance; no maintenance therapy was delivered. The primary endpoint is progression free survival (PFS) in Arm A; if > 23 of the 42 patients remain free of progression more than 4 months, the combination will be deemed worthy of further study. In addition to standard CT imaging to assess response and PFS, PET scans, pulmonary function tests, and mesothelin levels were performed. Results: Enrollment was completed in October 2011. 65 pts from 14 institutions were randomized, and 63 were treated. Patient characteristics in the two arms were similar and as follows: median age 65, 82% male, 71% epithelioid histology, 8% PS2. Grade 3/4 treatment-related toxicities were uncommon, no different than expected from standard chemotherapy, and comparable in the two arms. 70% of patients treated with CBP501 had infusion reactions, all grade 1-2. The best overall response rate in evaluable patients (modified RECIST, investigator assessed) was 12/37 (32%) (95% CI 18-50) in Arm A, and 3/22 (14%) (95% CI 3-35) in Arm B. The median number of chemotherapy cycles was 5.5 in Arm A, 5 in Arm B. Conclusions: Data on the primary endpoint of PFS in Arm A are maturing and will be presented at the meeting.
Phase II study of cixutumumab (IMC-A12) in thymic malignancies.
Authors: Rajan Arun , Riely Gregory J. , Carter Corey Allan , Thomas Anish , Khozin Sean , Bergagnini Isabella , Berman Arlene W , Scepura Barbara , Szabo Eva , Lee Min-Jung , Trepel Jane B. , Browne Sarah K , Pancholi Minjal J , Cao Liang , Chen Helen X. , Giaccone Giuseppe
Published: March 2020

7033

Background: The IGF-1 receptor (IGF-IR) is expressed in thymoma (T) and thymic carcinoma (TC). Prolonged SD has been seen with anti-IGF-IR therapy in thymic tumors in phase I trials. Cixutumumab (C) is a fully human IgG1 monoclonal antibody (ab) that targets IGF-IR. Methods: Patients (pts) with recurrent T or TC, PS 0-2, measurable disease, and normal organ function received C at 20 mg/kg IV q3wks until progression or intolerable toxicity. Primary endpoint was response rate. Correlative studies included immune cell subset (central memory, effector memory, naïve and regulatory T cells), circulating endothelial progenitor (CEP) cell, serum IGF-1 and IGF-IR in PBMCs, anticytokine ab, and tumor mutational analysis. Results: Forty-five pts enrolled from two centers (20 female, T=33, med age 52 yrs, range, 26-86). Median number of prior systemic treatments: 3 (range, 1-11). Median number of cycles of C administered: 6 (range, 1-41). In 30 evaluable T pts there were 4 (13%) PR, 23 (77%) SD, and 3 (10%) PD. Corresponding numbers in 12 TC pts were 0, 5 (42%) and 7 (58%). Median PFS for T and TC was 40 and 9 wks respectively. C-related grade 3/4 AEs were hyperglycemia (8%), hyperuricemia, weight loss, lipase elevation, chest wall pain (5% each) and AST elevation (3%). Two pts died while on study: one due to respiratory insufficiency related to T after 5 cycles and one due to worsening myasthenia and an acute coronary event after 13 cycles. In 8 of 33 T pts autoimmune (AI) symptoms developed (4 new-onset) due to immune thrombocytopenic purpura, myositis, myocarditis, colitis, PRCA and food allergy. In the first 13 pts a trend towards increased numbers of central and effector memory T cells and a decrease in naïve T cells and CEPs was seen. High-titer anticytokine abs, including anti-IFNa, anti-IL-12, and anti-IL-17A, were found in 13/27 pts tested. No EGFR, KRAS or BRAF mutation, HER2 amplification or ALK translocations were detected in 11 tumors analyzed. Conclusions: C monotherapy is well tolerated and active in T. Accrual will continue until 37 T pts are enrolled. Activity in TC is unworthy of further investigation. CEP and immune cell subset analysis suggests therapy may impact angiogenesis and immune response. Development of AI symptoms during treatment needs further evaluation.
FGFR1 amplification in squamous cell lung cancers.
Authors: Cote Michele L , Bepler Gerold , Land Susan , Bollig-Fischer Aliccia , Schwartz Ann G. , Gadgeel Shirish M.
Published: March 2020

7063

Background: Squamous cell carcinoma of the lung (SqCCL) is the second most common type of lung cancer. There are currently no established targeted therapies that take advantage of SqCCL-specific genetic abnormalities. Amplification of the fibroblast growth factor receptor type 1 gene (FGFR1) has been identified as a driver event in breast cancers and in SqCCL. The demographic characteristics and prognosis of patients with these tumors remains to be defined. Methods: DNA from 123 surgically resected, fresh frozen, and clinically annotated SqCCLs was extracted using a resin-based or phenol-based methodology. DNA quantity and quality was assessed using the Quantifiler kit (ABI). Specimen histology was validated, and the proportion of tumor cells was >60%. Copy number variation (CNV) analysis was performed using quantitative PCR with primers specific for exons 12 and 16 of FGFR1 and data analysis using CopyCaller (ABI). Samples with a predicted CNV of at 2 or greater in at least one exon were scored as amplified. Chi-squared tests were used to examine clinical and demographic differences between patients with and without amplification of FGFR1. Survival differences were examined by Kaplan Meier and Cox regression models. Results: Men comprised the majority of the population (n=91, 74%) and most cases were pathological stage I (n=75, 61%) or stage II (n=32, 26%). Thirty (24.4%) tumors showed amplification of FGFR1. There was no association between amplification and sex (p=0.18) or stage (p=0.37). The majority of the patients were white (n=114, 92.7%), but the proportion of tumors that were amplified was higher among non-whites (5/9, 55.5%) than whites (25/114, 21.9%, p=0.02). Overall, median survival was 32.2 months. In univariate survival analysis, amplification was associated with an increased hazard of death (HR=1.55, Wilcoxon p=0.03). Tumor stage at diagnosis was also associated with increased risk of death (HR=1.67, p=0.0009). Only stage remained a significant predictor of death in the multivariate survival models (HR=1.65, p=0.004). Conclusions: Somatic amplification of FGFR1 is a relatively common event in SqCCL and may be associated with race and overall survival.
Multicenter phase II study of concurrent high-dose (72Gy) three-dimensional conformal radiotherapy (3D-CRT) without elective nodal irradiation with chemotherapy using cisplatin and vinorelbine for unresectable stage III non-small cell lung cancer (NSCLC).
Authors: Horinouchi Hidehito , Sekine Ikuo , Sumi Minako , Satouchi Miyako , Isobe Hiroshi , Harada Masao , Niho Seiji , Mori Kiyoshi , Tamura Tomohide
Published: March 2020

7070

Background: The optimal dose of radiotherapy remains unclear in concurrent chemoradiotherapy for unresectable stage III NSCLC. We previously concluded that the recommended dose for further trial was 72Gy in a phase I study (Sekine et al., Int J Radiat Oncol Biol Phys. 953-959, 2012). Methods: Eligible patients (unresectable stage III NSCLC, age between 20 and 74, PS 0-1, V20 ≤ 30%) received cisplatin (80 mg/m2 day 1) and vinorelbine (20 mg/m2 days 1 and 8) repeated every 4 weeks for 3-4 cycles. The 3D-CRT started at the first day of chemotherapy at a total dose of 72 Gy in 36 fractions. The primary endpoint was a 2-year survival rate and the planned sample size was 60 to reject the rate of 45% under the expectation of 65% with a power of 90% and an alpha error of 5%. Results: Thirty-one patients from 4 institutions were enrolled between May 2009 and March 2010. This trial was terminated early due to slow accrual and grade 5 pulmonary toxicities in 2 patients. There were 25 men and 6 women with a median (range) age of 59 (32-72) years. Of these, 23 had adenocarcinoma and 21 had stage IIIA disease. The median (range) V20 value was 20 (9-30). The full planned dose of radiotherapy could be administered in 30 (97%) patients, and 26 (84%) of the patients received 3-4 cycles of chemotherapy. During the chemoradiotherapy, grade 3-4 febrile neutropenia, infection and esophagitis were noted in 5, 4 and 1 of the 31 patients, respectively. After completion of the planned chemoradiotherapy, 5 patients had grade 3 or higher radiation pneumonitis, and 2 (6%) of these patients died at 6.6 and 7.3 months after the treatment started. The overall response rate was 97% (95% confidence interval: 83.3-99.9). Twenty-four patients are alive and thirteen patients experienced recurrence (2 had loco-regional recurrences, 7 had distant recurrence and 4 had mixed recurrence pattern) at a median follow up of 16.4 months. Conclusions: Concurrent high-dose (72Gy) 3D-CRT with chemotherapy using cisplatin and vinorelbine may have a too excessive incidence of pulmonary toxicities to warrant any further evaluation.
Size distribution and metastasis in discarded intrapulmonary lymph nodes (LN) after lung cancer resection.
Authors: Miller Laura Elizabeth , Ramirez Robert A. , Wang Christopher Gene , Adair Courtney A , Berry Allen , O'Brien Thomas , Osarogiagbon Raymond U
Published: March 2020

7072^

Background: Lymph node (LN) status is the most important prognostic determinant after resection of lung cancer. 18% of a SEER cohort and 12% of a Memphis cohort had no LNs examined (pNx). Patients with pNx have inferior survival to T-category matched pN0 patients with at least 1 LN examined. The optimal number of LN needed to safely declare a patient pN0 may be >10. Less than 20% of resections in SEER achieve this. We hypothesized that a significant number of intrapulmonary LNs are left unexamined and some may harbor metastatic disease. We report the size characteristics of materials examined in a re-dissection protocol to test this hypothesis. Methods: Prospective study of lung resection specimens re-dissected after signout of the final pathology report. Remnant lung material was dissected with thin cuts and all LN-like material was retrieved for microscopic examination, irrespective of size or location. The size of non-LN tissue, LN without metastasis and LN with metastases were compared using the Wilcoxon-Mann-Whitney test. Results: 112 specimens were examined and 1,094 LN-like materials were retrieved. 749 (69%) proved to be LN tissue. 71 (10%) LNs retrieved had metastasis. Non-LN tissue was significantly smaller than LN tissue (p<0.0001). LNs with metastasis were significantly larger than those without metastasis (p <0.0001). 60% of materials >2cm were LNs with metastasis. 7% of materials <1cm were LN with metastasis. 52% of LNs with metastasis, and 55% of LNs without metastasis measured from 0.5 to 1.5cm (Table). Majority of LNs >2cm had metastatic disease, but 40% did not; a notable proportion of LNs with metastasis were small. Nearly equal percentages of LNs with and without metastasis were found in the range of 0.5-1.5cm. Conclusions: Statistical differences in size between lymph nodes with and without metastasis is clinically meaningless due to broad overlap. LN size alone is not an adequate predictor of LN metastasis. [Table: see text]
The Lung Cancer Symptom Scale (LCSS) as a prognostic indicator of overall survival in malignant pleural mesothelioma (MPM) patients: Post hoc analysis of a phase III study.
Authors: Wang Ping , Bowman Lee , Shen Wei , Winfree Katherine B. , Peterson Patrick , John William J.
Published: March 2020

7075

Background: To determine the patients likely to benefit from therapy, clinicians seek factors associated with outcomes. This analysis investigates prognostic effect of baseline patient-reported symptoms on overall survival (OS) in the presence of demographic/clinical factors among MPM patients. Methods: Intent-to-treat patients (N=448) were included in the analysis. LCSS consists of 6 symptom items and 3 general items, each ranging from 0 (no symptoms) to 100 (worst). Average symptom burden index (ASBI) was the mean of 6 symptom items. Patients were classified into subgroups based on ASBI: low symptom burden (LSB; ASBI<25) and high symptom burden (HSB; ASBI ≥25). Univariate Cox models were used to determine the prognostic effect of 7 demographic/clinical factors, 9 LCSS items, and ASBI on OS. Multivariate Cox model was used to determine the prognostic effect of ASBI in the presence of 7 demographic/clinical factors. Kaplan-Meier curves of OS were generated for patients with LSB and HSB and compared using both univariate and multivariate Cox models. Results: In the univariate analysis, significant prognostic effects on OS were observed for baseline Karnofsky performance status (KPS; 90-100 vs. 70-80, hazard ratio [HR]=0.45, p<0.0001) and baseline stage (I/II/III vs. IV, HR=0.63, p<0.0001). In addition, significant prognostic effects were observed for 5 LCSS symptom items (anorexia, cough, dyspnea, fatigue, and pain), 3 LCSS general items (interference with activity level, symptom distress, and quality of life; HRs=1.08-1.20 for every 10 points worsening, all p<0.02), as well as ASBI (HR=1.32, p<0.0001). In the multivariate Cox model, ASBI remained a significant prognostic factor of OS (HR=1.22, p<0.0001), along with baseline KPS and stage. Patients with LSB (N=265) had significantly better OS than those with HSB (N=181) (12.9 vs. 6.9 months, HR=0.46, unadjusted p<0.0001; HR=0.59, p<0.0001 adjusted for the 7 demographic/clinical variables). Conclusions: The results suggest that baseline patient-reported symptoms as measured by LCSS provide distinct prognostic information in the presence of demographic and clinical measures in MPM.