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Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma., Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed., Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab., Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma., Funding: Bristol Myers Squibb and the US National Institutes of Health., Competing Interests: Declaration of interests AOK reports consulting, advisory roles or stock ownership, or both, for Gilead Sciences, Bayer Health, Bristol-Myers Squibb, Exelixis, and Merck; reports research funding to the MD Anderson Cancer Center from Adaptimmune, Bayer/Onyx, Bristol Myers Squibb, Genentech, Hengrui Pharmaceutical, Hengrui Pharmaceutical, and Merck; honoraria from Bayer Health, Bristol Myers Squibb, Exelixis, and Merck; and other expenses from Bayer/Onyx, Bristol Myers Squibb, Exelixis, and Merck. EH reports research funding to the MD Anderson Cancer Center from Conquer Cancer Foundation, Kidney Cancer Association, and International Kidney Cancer Coalation. KPSR reports research funding to the MD Anderson Cancer Center from Bayer, Daiichi, AstraZeneca, Genentech, Guardant, and Merck; and consulting fees from Bayer, Daiichi, AstraZeneca; and honoraria from Bayer, and Daiichi. RS reports consulting fees from Boehringer Ingelheim. CWDT reports consulting fees donated to the MD Anderson Cancer Center from PanTher Therapeutics. RAW reports royalties or licenses from McGraw Hill for the MD Anderson Manual of Medical Oncology, 3rd edition; and travel support from Modern Medicine Emirates Oncology Society. JCY reports consulting fees from Hutchinson Medi Pharma, Ipsen Biopharmaceuticals, Amgen, Chiasma Pharma, Crinetics Pharmaceuticals, Advanced Accelerator Applications International, and Novartis Pharmaceuticals; and leadership roles at the North American Neuroendocrine Tumor Society. PS reports consulting fees from Achelois, Adaptive Biotechnologies, Affini-T, Apricity, BioAtla, BioNTech, Candel Therapeutics, Catalio, Codiak, Constellation, Dragonfly, Earli, Enable Medicine, Glympse, Hummingbird, ImaginAb, Infinity Pharma, Jounce, JSL Health, Lava Therapeutics, Lytix, Marker, Oncolytics, PBM Capital, Phenomic AI, Polaris Pharma, Sporos, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences; and ownership of stocks for Achelois, Adaptive Biotechnologies, Affini-T, Apricity, BioAtla, BioNTech, Candel Therapeutics, Catalio, Codiak, Constellation, Dragonfly, Earli, Enable Medicine, Glympse, Hummingbird, ImaginAb, Infinity Pharma, Jounce, JSL Health, Lava Therapeutics, Lytix, Marker, Oncolytics, PBM Capital, Phenomic AI, Polaris Pharma, Sporos, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences. JPA reports consulting fees from Achelois, Adaptive Biotechnologies, Apricity, BioAtla, BioNTech, Candel Therapeutics, Codiak, Dragonfly, Earli, Enable Medicine, Hummingbird, ImaginAb, Jounce, Lava Therapeutics, Lytix, Marker, PBM Capital, Phenomic AI, Polaris Pharma, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences; ownership of stocks for Achelois, Adaptive Biotechnologies, Apricity, BioAtla, BioNTech, Candel Therapeutics, Codiak, Dragonfly, Earli, Enable Medicine, Hummingbird, ImaginAb, Jounce, Lava Therapeutics, Lytix, Marker, PBM Capital, Phenomic AI, Polaris Pharma, Time Bioventures, Trained Therapeutix, Two Bear Capital, and Venn Biosciences. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML., Materials and Methods: The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML., Results: Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease-negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML., Conclusion: Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation., Competing Interests: Courtney D. DiNardoLeadership: Notable LabsStock and Other Ownership Interests: Notable LabsHonoraria: Agios, Celgene, AbbVie, Jazz Pharmaceuticals, Daiichi Sankyo, Novartis, TakedaConsulting or Advisory Role: Celgene, Agios, AbbVieResearch Funding: AbbVie, Agios, Celgene, Daiichi Sankyo Koichi TakahashiHonoraria: Celgene, Novartis, GlaxoSmithKline, SymBio Pharmaceuticals, DAVA PharmaceuticalsConsulting or Advisory Role: SymBio Pharmaceuticals, Novartis, GlaxoSmithKline, CelgeneResearch Funding: Onconova TherapeuticsTravel, Accommodations, Expenses: SymBio Pharmaceuticals, Celgene, GlaxoSmithKline, DAVA Pharmaceuticals Sanam LoghaviStock and Other Ownership Interests: AbbVie, PureTechHonoraria: Curio ScienceConsulting or Advisory Role: Seattle Genetics, Gerson Lehrman Group, Guidepoint GlobalTravel, Accommodations, Expenses: Curio Science Tapan KadiaConsulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Pfizer, AbbVie/Genentech, AgiosResearch Funding: Bristol Myers Squibb, Celgene, Sanofi, Amgen, BiolineRx, Incyte, Genentech/AbbVie, Pfizer, Jazz Pharmaceuticals, AstraZeneca, Astellas Pharma, Ascentage Pharma, Genfleet, Cyclacel Naval DaverHonoraria: BMS, Jazz Pharmaceuticals, Novartis, Incyte, Otsuka, Immunogen, Pfizer, Astellas Pharma, AbbVieConsulting or Advisory Role: Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Otsuka, Incyte, Karyopharm Therapeutics, Sunesis Pharmaceuticals, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium TherapeuticsResearch Funding: Bristol Myers Squibb, Pfizer, Immunogen, Genentech, Nohla Therapeutics, AbbVie, Astellas Pharma, Servier, Daiichi Sankyo, Novartis, Karyopharm Therapeutics, Incyte, Sunesis Pharmaceuticals, Sobi Nicholas J. ShortHonoraria: AmgenConsulting or Advisory Role: AstraZenecaResearch Funding: Takeda, Astellas Pharma Koji SasakiHonoraria: OtsukaConsulting or Advisory Role: Novartis, Pfizer, TakedaResearch Funding: NovartisTravel, Accommodations, Expenses: Otsuka Sa WangConsulting or Advisory Role: Boston Biomedical, GlaxoSmithKline, Blueprint Medicines, CapricoResearch Funding: GlaxoSmithKline, Autolus Ltd, Genmab Gautam BorthakurConsulting or Advisory Role: Argenx, PTC Therapeutics, BiolineRx, BioTheryX, Nkarta, Treadwell Therapeutics, Novartis, Catamaran Bio, TakedaResearch Funding: Incyte, GlaxoSmithKline, Cyclacel, BiolineRx, MedImmune, Lilly, Oncoceutics, Ryvu Therapeutics, Janssen Scientific Affairs, Bristol Myers Squibb, AbbVie, Novartis, AstraZeneca, Mundipharma Research, PTC Therapeutics, BioTheryX, XBiotech, Arvinas, Astex Pharmaceuticals, TCR2 Therapeutics, Nkarta, Treadwell Therapeutics, Cellestia Biotech Ghayas IssaConsulting or Advisory Role: Novartis, Kura OncologyResearch Funding: Novartis, Syndax, Kura Oncology Abhishek MaitiResearch Funding: Celgene Yesid AlvaradoResearch Funding: Jazz Pharmaceuticals, FibroGen, Sun Pharma, BerGenBio, Daiichi Sankyo/Lilly, Astex Pharmaceuticals Naveen PemmarajuEmployment: MD Anderson Cancer CenterLeadership: ASH, ASCOHonoraria: Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Molecular Diagnostics, Blueprint Medicines, DAVA Pharmaceuticals, SpringerConsulting or Advisory Role: Blueprint Medicines, Pacylex, Immunogen, Bristol Myers SquibbResearch Funding: Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix/Thermo Fisher Scientific, Daiichi Sankyo, PlexxikonTravel, Accommodations, Expenses: Stemline Therapeutics, Celgene, AbbVie, DAVA Oncology, MustangBioUncompensated Relationships: Dan's House of Hope, Oncology Times Guillermo BravoResearch Funding: IFM Therapeutics Musa YilmazResearch Funding: Daiichi Sankyo, Pfizer Nitin JainHonoraria: Pharmacyclics, ADC Therapeutics, Adaptive Biotechnologies, AbbVie/Genentech, Janssen, AstraZeneca/MedImmune, Servier, Precision Biosciences, BeiGene, TG Therapeutics, Cellectis, Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Pharmacyclics, ADC Therapeutics, Adaptive Biotechnologies, AbbVie/Genentech, Janssen, AstraZeneca/MedImmune, Servier, Precision Biosciences, BeiGene, TG Therapeutics, Cellectis, Bristol Myers Squibb/CelgeneResearch Funding: Pfizer, Pharmacyclics, AbbVie, Genentech/Roche, Incyte, Infinity Pharmaceuticals, Bristol Myers Squibb, Seattle Genetics, Celgene, ADC Therapeutics, Servier, AstraZeneca/MedImmune, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Aprea Therapeutics, Fate Therapeutics, Kite, a Gilead company Michael AndreefStock and Other Ownership Interests: Reata Pharmaceuticals, Aptose Biosciences, Eutropics, Senti Biosciences, Oncoceutics, OncolyzeConsulting or Advisory Role: Daiichi Sankyo, Jazz Pharmaceuticals, Celgene, Amgen, AstraZenecaResearch Funding: Daiichi Sankyo, Breast Cancer Research Foundation, United Therapeutics, Ono Pharmaceutical, Karyopharm Therapeutics, CPRIT, NIH/NCI, Amgen, AstraZenecaPatents, Royalties, Other Intellectual Property: Patent with ReataTravel, Accommodations, Expenses: Aptose Biosciences, Oncoceutics, Amgen, AstraZeneca Elias JabbourConsulting or Advisory Role: Pfizer, Takeda, Amgen, AbbVie, Bristol Myers Squibb, Incyte, Adaptive Biotechnologies, Astellas Pharma, GenentechResearch Funding: Pfizer, AbbVie, Amgen, Takeda, Adaptive Biotechnologies, Ascentage Pharma Group Guillermo Garcia-ManeroHonoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, AbbVieConsulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals, Bristol Myers Squibb, Helsinn TherapeuticsResearch Funding: Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, AbbVie, Bristol Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck Farhad RavandiHonoraria: Amgen, Pfizer, Astellas Pharma, Orsenix, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, NovartisConsulting or Advisory Role: Amgen, Astellas Pharma, Orsenix, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, Certara IncResearch Funding: Bristol Myers Squibb, Amgen, Macrogenics, Xencor, Selvita, Cellerant Marina Y. KonoplevaHonoraria: AbbVie, Genentech, Roche, Amgen, Stemline Therapeutics, KisoJi BiotechnologyConsulting or Advisory Role: AbbVie, Genentech/Roche, Stemline Therapeutics, Amgen, Forty Seven, KisoJi Biotechnology, Roche, JanssenResearch Funding: AbbVie, Genentech, Roche, Lilly, Cellectis, Calithera Biosciences, Ablynx, Agios, Ascentage Pharma, AstraZeneca, SanofiPatents, Royalties, Other Intellectual Property: Novartis—Pending, Eli Lilly—Research Funding; Issued/Licensed, Reata Pharmaceutical—Research Funding (Issued, Licensed, Royalities) Hagop M. KantarjianHonoraria: AbbVie, Amgen, ARIAD, Bristol Myers Squibb, Immunogen, Orsenix, Pfizer, Agios, Takeda, Actinium PharmaceuticalsResearch Funding: Pfizer, Amgen, Bristol Myers Squibb, Novartis, ARIAD, Astex Pharmaceuticals, AbbVie, Agios, Cyclacel, Immunogen, Jazz PharmaceuticalsNo other potential conflicts of interest were reported.

Introduction: Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches., Methods: We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1., Results: We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event., Conclusion: To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

CPX-351 is a liposomal formulation of cytarabine/daunorubicin with a 5:1 fixed molar ratio. We investigated the safety and efficacy of escalating doses of CPX-351 in patients with acute myeloid leukemia (AML) at high risk of induction mortality with standard chemotherapy determined through assessment of leukemia and patient-related risk factors for intensive chemotherapy in an open-label, phase II trial. Patients were randomized to receive 50 or 75 units/m 2 on days 1, 3, and 5. Once safety was established, a 100 units/m 2 arm was opened. Fifty-six patients were enrolled, 16, 24, and 16 in the 50, 75, and 100 units/m 2 arms, respectively. The composite complete remission rate (complete remission + complete remission with incomplete blood count recovery) was lowest with 50 units/m 2 (19%) compared with 75 units/m 2 (38%) and 100 units/m 2 (44%) (P = 0.35). The 50 units/m 2 arm had a median OS of 4.3 months, compared with 8.6 and 6.2 months for the 75 and 100 units/m 2 respectively (P = 0.04). Nonhematologic grade 3/4 treatment-emergent adverse events included febrile neutropenia (34%), pneumonia (23%), and sepsis (16%). CPX-351 at 75 units/m 2 has favorable safety and efficacy for AML patients at high risk of induction mortality with some tolerating the standard dose of 100 units/m 2 .

Background: Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m 2 IV over 30 minutes + NabP 125 mg/m 2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM-NabP given every two-weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen., Methods: Metastatic PDAC patients (pts) who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression-free survival, and the incidence of dose delays and/or adjustments., Results: From a total of 235 patients, 140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line. Median dosing was 600 mg/m 2 at fixed-dose rate for GEM and 125 mg/m 2 for NabP given predominantly (~90%) every two-weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6 months and when given second-line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front-line progression-free survival (PFS) of 5.3 months and 2.8 months and second-line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications., Conclusion: Our analysis revealed safety with every two-week low dose GEM-NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade., Methods: This was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed., Results: A total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1-6). Grade 3-4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway., Conclusions: The combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue., Trial Registration Number: NCT02362048., Competing Interests: Competing interests: MO reports research funding from Merck. SN reports fees and research support from Allogene, Celgene, Kite (a Gilead Company), Merck and Unum Therapeutics; research support from Acerta Pharma, Bristol-Myers Squibb, Cellectis, Karus and Poseida and fees from Cell Medica, Incyte, Novartis, Pfizer and Precision Biosciences. NBM receives research funding to institution from Amgen, ARMO Biosciences, BMS, Genentech, Incyte, MedImmune and OncoMed and research funding from the Lustgarten Foundation. LT, VM and PP are employees of Acerta Pharma. VM owns stock in AstraZeneca and Gilead Sciences. MJ, RED, CK-S, PV, CDL, ERP and LX report no relevant conflicts of interest. AM receives royalties from Cosmos Wisdom Biotechnology for a biomarker test related to pancreatic cancer early detection., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Advanced unresectable gastroesophageal cancers continue to confer a dismal patient prognosis. Limited options remain once the cancer is refractory to cytotoxics/biologics (like irinotecan, taxane, and ramucirumab). Recently, anti-programmed death-1 (anti-PD-1) inhibitors have been used with limited efficacy in select patients with adenocarcinoma. Similarly, irinotecan-based therapy has marginal efficacy. We combined irinotecan plus a fluoropyrimidine with an anti-PD-1 antibody, nivolumab, with hopes of having a higher advantage for patients., Objectives: Primary objective was to assess safety judged by toxicities, dose delays, or dose reductions. Secondary endpoints included the assessment of response, overall survival (OS), and progression-free survival (PFS)., Methods: We treated 15 patients with this combination during July 2017 to April 2019. Patients were included if they had follow-up at our institution., Results: Median doses given were nivolumab 240 mg + irinotecan 120 mg/m2 + 5-FU 2,000 mg/m2 over 46-48 h (or capecitabine 1,250 mg/m2/day; 7 days on, 7 days off) given every 2 weeks. Median age of the patients was 55 years, and all patients had an ECOG performance status of 0-1. The patients had a median of 1 prior therapy. Slightly over half of the patients had PD-L1 expression. The median number of cycles was 7. Five patients (33%) had a dose delay or dose adjustment. The most common reason for dose delay or adjustment was grade 2 fatigue. Disease control (response or stability) on first scan was 73.3% (n = 11). Median PFS and OS for the entire group was 7 and 13.3 months, respectively., Conclusion: In this small cohort of patients, we conclude that this combination is quite feasible and resulted in prolonged stability in some patients. Further development of this regimen is warranted., (© 2020 S. Karger AG, Basel.)

Background: Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer., Methods: We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m 2 and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m 2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868., Findings: Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m 2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths., Interpretation: Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned., Funding: Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Importance: Administration of gemcitabine-cisplatin, the current standard therapy for advanced biliary tract cancers, results in median progression-free survival and overall survival of 8.0 and 11.7 months, respectively. New treatments offering improved survival outcomes are therefore needed., Objective: To evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer., Design, Setting, and Participants: This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017., Interventions: Patients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients., Main Outcomes and Measures: The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population., Results: Of 60 patients who started treatment, the mean (SD) age was 58.4 (11.0) years, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 (95% CI, 9.4-19.4) months, and median progression-free survival was 11.8 (95% CI, 6.0 to 15.6) months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months (95% CI, 13.2 months to not estimable). Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment., Conclusions and Relevance: Treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. These findings will be tested in a phase 3 randomized clinical trial., Trial Registration: ClinicalTrials.gov identifier: NCT02392637.

Background: The RAINBOW trial established ramucirumab combined with paclitaxel as a second-line option in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma. Ramucirumab was given on days 1 and 15 with paclitaxel on days 1, 8, and 15 of a 28-day cycle. The median overall survival (OS) was significantly longer with ramuciru-mab plus paclitaxel (p = 0.017), and it led to 41% grade 3 or higher neutropenia. We review our experience with both ramucirumab plus paclitaxel given biweekly (mRAINBOW) to assess efficacy and safety., Objectives: The primary objective was to assess OS. Secondary end points were progression-free survival (PFS), overall response, and safety., Methods: We identified 129 patients retrospectively from our database between November 2014 and May 2017. Patients were included if they were followed up at our institution., Results: Median doses given were ramucirumab 8 mg/kg i.v. plus paclitaxel 110 mg/m2 i.v. given once every 2 weeks. The median performance status was 1, and ∼60% had poorly differentiated histology; 55.8% had progression in < 6 months on first-line therapy, and the majority had measurable cancer. Median overall OS and PFS for the entire cohort was 9.4 months (95% CI: 8.05-10.74) and 3.68 months (95% CI: 2.73-4.5), respectively. Median OS was 9.46 months (95% CI: 8.05-14.95) and median PFS was 4.14 months (95% CI: 2.96-5.29) in those patients that received ramucirumab plus paclitaxel in the second-line setting., Conclusion: Biweekly administration of ramucirumab plus paclitaxel did not compromise efficacy. Delays, adjustments, or doses held were similar to the RAINBOW trial, with 31% requiring a dose or schedule modification., (© 2019 S. Karger AG, Basel.)

The purine nucleoside analogues clofarabine and fludarabine are active in acute myeloid leukemia (AML). We conducted a phase I/II randomized study of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) for relapsed or refractory AML. Clofarabine 15 mg/m 2 was identified as the recommended phase II dose. Eighty-one patients were assigned using adaptive randomization to CIA (n = 48) or FIA (n = 33). The complete response (CR)/CR without platelet recovery rate did not differ between CIA and FIA (38% versus 30%, respectively; p = .50). In both arms, more than half of patients who had received only one prior line of therapy achieved remission. The median event-free survival for CIA and FIA was 2.0 and 1.9 months (p = .48), and the median overall survival was 6.3 and 4.7 months, respectively (p = .28). No significant differences in adverse events or early mortality rates were observed. Overall, CIA and FIA resulted in similar response rates and survival in patients with relapsed/refractory AML.

Background: Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma that primarily affects adolescents and young adults. Patients can present with many peritoneal implants. We conducted a phase 2 clinical trial utilizing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) with cisplatin for DSRCT and pediatric-type abdominal sarcomas., Patients and Methods: A prospective cohort study was performed on 20 patients, who underwent CRS-HIPEC procedures, with cisplatin from 2012 to 2013. All patients were enrolled in the phase 2 clinical trial. Patients with extraabdominal disease and in whom complete cytoreduction (CCR0-1) could not be achieved were excluded. All outcomes were recorded., Results: Fourteen patients had DSRCT, while five patients had other sarcomas. One patient had repeat HIPEC. Patients with DSRCT had significantly longer median overall survival after surgery than patients with other tumors (44.3 vs. 12.5 months, p = 0.0013). The 3-year overall survival from time of diagnosis for DSRCT patients was 79 %. Estimated median recurrence-free survival (RFS) was 14.0 months. However, RFS for patients with DSRCT was significantly longer than for non-DSRCT patients (14.9 vs. 4.5 months, p = 0.0012). Among DSRCT patients, those without hepatic or portal metastases had longer median RFS than those with tumors at these sites (37.9 vs. 14.3 months, p = 0.02). In 100 % of patients without hepatic or portal metastasis, there was no peritoneal disease recurrence after CRS-HIPEC., Conclusions: Complete CRS-HIPEC with cisplatin is effective in select DSRCT patients. DSRCT patients with hepatic or portal metastasis have poorer outcomes.

Background: High-risk non-muscle-invasive bladder cancer (NMIBC) that invades into the lamina propria is frequently understaged and is associated with a risk of lymph node metastasis and death., Objective: To identify high-risk features (HRFs) for NMIBC that may identify patients with poorer prognosis who may benefit from neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC)., Design, Setting, and Participants: We performed a single-center retrospective review of patients who underwent RC for NMIBC with invasion into the lamina propria between 1995 and 2013. HRFs included hydronephrosis, abnormal examination under anesthesia, lymphovascular invasion, or variant histology., Outcome Measurements and Statistical Analysis: Pathology at RC, and overall (OS) and disease-specific (DSS) survival were evaluated and analyzed by Fisher's exact test, Student t test, Cox proportional hazards regression analysis, and the Kaplan-Meier method., Results and Limitations: We identified 336 patients with a median follow-up of 130 mo. Of these, 159 (47%) had no HRF, 140 (41.5%) had one HRF, and 37 (11%) had ≥2 HRFs. At RC, patients with ≥2 HRFs had a significantly higher rate of pathologic T stage upstaging and lymph node metastasis (p<0.05). Median OS was 139 mo for those with no HRF, 127 mo for those with one HRF, and 56 mo for those with ≥2 HRF (p=0.0057). HRFs are also associated with a decreased DSS (p=0.0009). Patients with ≥2 HRFs (11/37) who received NAC showed improved OS (21% vs 55% 5-yr OS, p=0.0353) and trended toward an improvement in DSS (25% vs 56% 5-yr OS, p=0.0716) compared with RC alone., Conclusions: The presence of ≥2 HRFs in NMIBC invading the lamina propria is associated with worse pathology at RC and a significant decrease in OS and DSS. NAC appears to provide benefit for these patients. Limitations include retrospective design and limited sample size., Patient Summary: The presence of high-risk features in urothelial cancer with invasion into the lamina propria has a worse prognosis that may be mitigated by neoadjuvant chemotherapy., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML)., Methods: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine., Results: The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009])., Conclusions: CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile. Cancer 2017;123:4430-9. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Older patients with localized gastric adenocarcinoma (LGAC) have substantial postoperative morbidity and mortality; however, postoperative outcomes of the patients who receive preoperative chemotherapy and/or chemoradiation have not been reported. We examined the impact of age at baseline on potential predictors of postoperative outcomes., Methods: Patients with LGAC who were treated with chemotherapy and/or chemoradiation followed by surgery (n = 203) formed two groups: (1) ≥65 years old (n = 70) and (2) <65 years old (n = 133). We assessed postoperative morbidity and mortality as well as overall survival (OS) and progression-free survival (PFS). Potential predictors of 90-day postoperative outcomes were identified i) by age groups and ii) other clinical covariates. Descriptive statistics and survival analyses were utilized., Results: 90-day postoperative morbidity was similar in older and younger patients (61 % vs 58 %; P = 0.655). 90-day mortality was similar (3 % vs 0 %; P = 0.118). Major Clavien grade III/IV complications were similar (17 % vs 12 %; P = 0.392). OS and PFS were also similar for both groups (P = 0.863 and P = 0.558, respectively). Other factors, such as Charlson comorbidity index (P < 0.001) and median operative time (P = 0.002) were strongly associated with postoperative complications., Conclusion: Our data show that older patients with LGAC generally have similar outcomes as do younger patients after preoperative therapy but comorbidity indices have significant impact on complications and the long-term outcomes rather than age.

Background: A high pretreatment β2 -microglobulin (B2M) level is associated with inferior survival outcomes in patients with chronic lymphocytic leukemia. However, to the authors' knowledge, the prognostic and predictive significance of changes in B2M during treatment have not been reported to date., Methods: The authors analyzed 83 patients treated with ibrutinib-based regimens (66 with recurrent/refractory disease) and 198 treatment-naive patients who were treated with combined fludarabine, cyclophosphamide, and rituximab (FCR) to characterize changes in B2M and their relationship with clinical outcomes., Results: B2M rapidly decreased during treatment with ibrutinib; on multivariable analysis, patients who received FCR (odds ratio, 0.40; 95% confidence interval [95% CI], 0.18-0.90 [P = .027]) were less likely to have normalized B2M at 6 months than patients treated with ibrutinib. On univariable analysis, normalization of B2M was associated with superior progression-free survival (PFS) from the 6-month landmark in patients treated with ibrutinib-based regimens and FCR. On multivariable analysis, failure to achieve normalized B2M at 6 months of treatment was associated with inferior PFS (hazard ratio, 16.9; 95% CI, 1.3-220.0 [P = .031]) for patients treated with ibrutinib, after adjusting for the effects of baseline B2M, stage of disease, fludarabine-refractory disease, and del(17p). In contrast, in patients treated with FCR, negative minimal residual disease status in the bone marrow was the only variable found to be significantly associated with superior PFS (hazard ratio, 0.28; 95% CI, 0.12-0.67 [P = .004])., Conclusions: Normalization of B2M at 6 months in patients treated with ibrutinib was found to be a useful predictor of subsequent PFS and may assist in clinical decision-making., (© 2015 American Cancer Society.)

Importance: Different adjuvant chemotherapy regimens are available for early-stage breast cancer. Because conventional meta-analysis does not allow comparing all regimens, we performed a network meta-analysis to identify the most effective adjuvant chemotherapy regimen., Objective: To find the most effective adjuvant therapy regimen for early-stage breast cancer., Data Sources: We searched MEDLINE, Embase, and the Cochrane Library for articles published before June 2015; the American Society of Clinical Oncology annual meeting abstracts from January 1983 through December 2014; and the American Association for Cancer Research annual meeting abstracts from January 1916 through December 2014. Additionally, we manually searched bibliographies for related references., Study Selection: We included randomized clinical trials of adjuvant treatments for early-stage breast cancer that compared 2 or more of the following: no adjuvant chemotherapy; sequential anthracycline-cyclophosphamide and taxane (AC-T); concurrent anthracycline-cyclophosphamide and taxane (ACT); anthracycline-cyclophosphamide without taxane (AC); docetaxel and cyclophosphamide (TC); cyclophosphamide, methotrexate, and fluorouracil (CMF); and platinum-containing regimens., Data Extraction and Synthesis: We followed the PRISMA guidelines. Two investigators independently selected the articles and extracted information. Disagreements were resolved by discussion with another author. Quality was assessed by Cochrane risk-of-bias method. Data were pooled using random-effects models., Main Outcomes and Measures: We used network meta-analysis to test the most effective adjuvant therapy regimen in terms of overall survival (OS) by comparing regimens listed in the National Comprehensive Cancer Network guidelines and platinum-containing regimens., Results: We identified 24 trials. The TC and platinum-containing regimens had OS benefit similar to that of sequential AC-T (TC hazard ratio [HR], 0.93; 95% CI, 0.62-1.40; and platinum HR, 0.93; 95% CI, 0.66-1.31). Patients treated with CMF or AC had significantly worse OS than those treated with sequential AC-T (CMF HR, 1.56; 95% CI, 1.32-1.85; and AC HR, 1.22; 95% CI, 1.10-1.37). Platinum-containing regimens tended to be more toxic than sequential AC-T. The toxicity of TC was similar to or less than that of sequential AC-T. Meta-regression analysis showed that hormone receptor status did not impact the HRs for OS for any regimen., Conclusions and Relevance: Sequential AC-T is likely to be the most effective adjuvant therapy regimen for early-stage breast cancer regardless of hormone receptor status.

Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL)., Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD., Results: The median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders., Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL., (©2015 American Association for Cancer Research.)

Background: The mechanisms responsible for chemoresistance in patients with refractory classical Hodgkin lymphoma (CHL) are unknown. ATP-binding cassette (ABC) transporters confer multidrug resistance in various cancers and ABCC1 overexpression has been shown to contribute to drug resistance in the CHL cell line, KMH2., Findings: We analyzed for expression of five ABC transporters ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2 using immunohistochemistry in 103 pre-treatment tumor specimens obtained from patients with CHL. All patients received first-line standard chemotherapy with doxorubicin (Adriamycin®), bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens. ABCC1 was expressed in Hodgkin and Reed-Sternberg (HRS) cells in 16 of 82 cases (19.5%) and ABCG2 was expressed by HRS cells in 25 of 77 cases (32.5%). All tumors were negative for ABCB1, ABCC2 and ABCC3. ABCC1 expression was associated with refractory disease (p = 0.01) and was marginally associated with poorer failure-free survival (p = 0.06). Multivariate analysis after adjusting for hemoglobin and albumin levels and age showed that patients with CHL with HRS cells positive for ABCC1 had a higher risk of not responding to treatment (HR = 2.84, 95%, CI: 1.12-7.19 p = 0.028)., Conclusions: Expression of ABCC1 by HRS cells in CHL patients predicts a higher risk of treatment failure and is marginally associated with poorer failure-free survival using standard frontline chemotherapy regimens.

Background: We previously introduced a classification system for patients with localized pancreatic adenocarcinoma that integrates assessments of tumor anatomy, cancer biology, and patient physiology. By means of this system, we sought to analyze outcomes of patients with resectable anatomy but heterogeneous biology and physiology who were treated with neoadjuvant therapy., Methods: We evaluated consecutive patients (2002-2007) with anatomically potentially resectable cancers treated with chemotherapy or chemoradiation before potential pancreatectomy. We compared clinical factors and outcomes of patients classified as having disease that was clinically resectable (CR; no extrapancreatic disease, preserved performance status); suspicion for extrapancreatic disease (BR-B); or marginal performance status or significant comorbidity (BR-C). Patients with borderline resectable anatomy (BR-A) were excluded., Results: Resection rates for 138 CR, 41 BR-B, and 38 BR-C patients were 75, 46, and 37%, respectively (P < 0.001). Metastases, detected during treatment in 23% of patients, were the most common contraindication to resection among CR (15%) and BR-B (46%) patients. Performance status rarely precluded surgery except among BR-C (32%) patients. Factors associated with selection against surgery were older age, poor performance status, pain, and therapeutic complications (P < 0.05). The median overall survival of all patients was 21 months. Resected and unresected BR-B and BR-C patients had median overall survival durations similar to those of resected and unresected CR patients, respectively (P > 0.22)., Conclusions: This system describes discrete clinical subgroups of patients with pancreatic cancer who have similar, potentially resectable tumor anatomy but heterogeneous physiology and cancer biology. It may be used with neoadjuvant therapy to predict outcomes, individualize treatment algorithms, and optimize survival.

The optimal pretransplant regimen for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in patients ≥ 55 years of age remains to be determined. The myeloablative reduced-toxicity 4-day regimen i.v. busulfan (Bu) (130 mg/m(2)) and i.v. fludarabine (Flu) (40 mg/m(2)) is associated with low morbidity and mortality. We analyzed 79 patients ≥ 55 years of age (median, 58 years) with AML (n = 63) or MDS (n = 16) treated with i.v. Bu-Flu conditioning regimens between 2001 and 2009 (median follow-up, 24 months). The patients who received this regimen had a good performance status. The 2-year overall survival (OS) rates for patients in first complete remission (CR1), second CR (CR2), or refractory disease and for all patients at time of transplantation were 71%, 44%, 32%, and 46%, respectively; 2-year event-free survival (EFS) rates for patients in CR1, CR2, or refractory disease at time of transplantation and for all patients were 68%, 42%, 30%, and 44%, respectively. One-year transplant-related mortality (TRM) rates for patients who were in CR or who had active disease at the time of transplantation were 19% and 20%, respectively. Grade II-IV acute graft-versus-host (aGVHD) disease was diagnosed in 40% of the patients. Our results suggest that age alone should not be the primary reason for exclusion from receiving myeloablative reduced-toxicity conditioning with i.v. Bu-Flu preceding transplantation in patients with AML/MDS., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Disseminated gynecologic cancers are usually fatal due to chemoresistance. Recently, rationally developed, targeted agents are entering the early clinical trials setting. We assessed patients with metastatic gynecologic cancers in a dedicated phase I clinical trials clinic in order to determine their outcome., Methods: We reviewed records for 89 consecutive patients with gynecologic cancers referred to the Phase I Clinical Trials Program, 85 (96%) of whom were treated on > or = 1 trial., Results: Cancer diagnoses were ovarian (N=43), uterine (N=19), cervix (N=17), and other. Median age was 58 years; median number of prior cytotoxic regimens, five. Two patients (2.4%) achieved a CR; four (4.7%), a PR; and eight (9.4%), SD > or = 6 months (total CR/PR/SD > or = 6 months=16.5%) for the first phase I trial. Twenty-five patients enrolled on a second trial and three, on a third (N=113 trials total). Combining response data for all trials, of the 85 patients, two achieved CR (2.4%), nine achieved PR (10.6%), and 12 (14%) had SD for > or = 6 months. One-year survival was 30% (95% CI, 21% to 44%). There was no difference in time-to-treatment failure (TTF) on phase I versus the patient's last standard treatment., Conclusion: Twenty-three of 85 patients (27%) with advanced, heavily pretreated, gynecologic cancers achieved CR/PR/SD > or = 6 months on a phase I trial, and overall TTF on phase I was comparable to that of last conventional therapy, suggesting that participation in a phase I trial is a reasonable option for these patients., (Copyright 2010 Elsevier Inc. All rights reserved.)