bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I/II (P1/P2) study of AT-101 in combination with topotecan (T) in patients with relapsed or refractory small cell lung cancer (SCLC) after prior platinum-containing first-line chemotherapy
Authors: Heist R. S. , Fain J. , Chinnasami B. , Khan W. , Molina J. , Brainerd V. , Leopold L. , Lynch T. 
Published: August 2020

8106 Background: Bcl-2 family proteins are expressed in SCLC and are associated with chemotherapy resistance. AT-101 is an oral, pan Bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, and Bcl-w) and potent inducer of proapoptotic proteins. AT-101 has demonstrated activity in SCLC models, including those that express Mcl-1 and are resistant to other Bcl-2 inhibitors. The P1 portion of the study was previously reported. Methods: Pts ≥18 years of age, PS 0–1, with relapsed or refractory SCLC after first line chemotherapy with measurable disease per RECIST were eligible. Pts were stratified into 2 cohorts; cohort A ≥ 60 days and cohort B < 60 days relapse from prior chemotherapy and treated with T 1.25 mg/m2 daily and AT-101 40 mgs daily on days 1–5, q21 along with the use of myeloid growth factors. Adverse Events (AEs) were graded by the NCI CTCAE v. 3.0. Efficacy assessments (RECIST) were performed every 6-weeks. A 2-stage design was used with power/alpha of 80%/0.05 to detect a RR of > 25% and > 5%, in cohort A and B respectively. Results: 36 pts enrolled: ages 41–76; cohort A/B 23/13. The PR/SD/PD/NE rates were 17%/70%/9%/4% and 8%/54%/23%/15%, in cohorts A/B respectively. The median times to progression (TTP) were 18 and 13 weeks, respectively. The most common (>20 %) AEs (all grades): anemia (64%); neutropenia (53%); nausea (47%); fatigue (44%); thrombocytopenia (42%); dyspnoea (25%); and vomiting (22%). Most common Grade 3/4 related events (>5%): neutropenia (31%); thrombocytopenia (25%); anemia (14%); and asthenia (6%). No ileus was reported. Conclusions: AT-101 can be safely combined with T. The observed toxicities were consistent with the known rates of G4 cytopenias of T alone. The response rates observed did not meet the criteria for additional enrolment; however, many patients had a best response of SD and the median TTP in both cohorts was favorable compared to historical controls. Additional trials of AT-101 in SCLC are ongoing. [Table: see text]
Novel organic arsenic molecule darinaparsin: Development of IV and oral forms
Authors: Lossos I. , Craig M. D. , Tallman M. S. , Boccia R. V. , Conkling P. R. , Becerra C. , Komarnitsky P. B. , Hamilton B. L. , Lewis J. , Miller W. H. 
Published: August 2020

8501 Background: Darinaparsin (ZIO-101) is a novel organic arsenical active against diverse cancers in vitro, and in vivo. Darinaparsin i.v. activity in lymphoma is being evaluated in a phase II study. Darinaparsin is orally bioavailable; the oral form is being investigated in two phase I studies in patients with advanced malignancies. Methods: Phase II trial is being conducted in patients diagnosed with advanced lymphomas who had ≥ 1 prior therapy. Patients receive 300 mg/m2/day of darinaparsin i.v. for 5 consecutive days every 28 days. Efficacy and safety are evaluated by standard criteria. Phase I oral dose escalation studies are being conducted in patients with advanced malignancies and explore safety, MTD, DLTs and preliminary efficacy of continuous and intermittent dosing schedules. Starting continuous dose is 100 mg BID for 3 weeks with 1 week rest, starting intermittent dose is 300 mg twice weekly for 3 weeks followed by 1 week rest. Results: The phase II study has accrued 28 lymphoma patients (21 non-Hodgkin's, 7 Hodgkin's); median age at baseline 61 years, ECOG ≤2, median number of prior therapies 3. Seventeen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 subject (PTCL) has achieved a complete response, 3 - partial responses (2 marginal zone, 1 Hodgkin's), and 4 stable disease (2 PTCL, 1 DLBCL, 1 Hodgkin's). A total of 63 cycles of darinaparsin have been administered to subjects with lymphoma. No Gr. 3 or higher drug-related AEs were reported. Two SAEs were considered possibly drug-related (fall; neutropenic fever). Phase I studies accrued 35 patients; median age at baseline 58 years, ECOG ≤2, median number of prior therapies 3. Predominant tumor types include: colorectal (17), pancreatic (3), NHL (3). Current darinaparsin dose levels: continuous 200 mg BID, 2× weekly 900 mg. Of 18 patients evaluable for efficacy, 10 demonstrate SD ≥ 3 cycles. Oral darinaparsin bioavailability is 58%. Drug-related AEs include nausea/vomiting, fatigue, decreased appetite/anorexia. Conclusions: Darinaparsin is active in heavily pretreated patients with advanced lymphoma and has been very well tolerated. Oral darinaparsin is also well tolerated, and shows early activity. [Table: see text]
Benefit of rituximab combined to ACVBP (R-ACVBP) over ACVBP in 209 poor- risk BDLC NHL patients treated with up-front consolidative autotransplantation: A GELA phase II trial (LNH 2003–3)
Authors: Mounier N. , Gisselbrecht C. , Fitoussi O. , Belhadj K. , Feugier P. , Coiffier B. , Tilly H. , Casasnovas O. , Fermé C. , Briere J. , Haioun C. 
Published: August 2020

8507 Background: Rituximab (R) combined with CHOP improves survival in DLBCL pts. More intensive regimen followed by auto transplantation have been used in patients < 60y with 2–3 adverse age-adjusted International-Prognostic-Index (aa-IPI) factors, providing a 5y OS of 65% (CI 60–68%), (Haioun LNH 98–3B, ASCO 2007). The objective of the present study was to assess whether or not combining R (375 mg/m2) to the dose intense ACVBP (doxorubicin 75 mg/m2 d1, cyclophosphamide 1,200 mg/m2 d1, vindesine 2 mg/m2 and bleomycin 10 mg d1 and d5, prednisone 60 mg/m2 d1-d5) also translates into a survival benefit. Methods: From 01/2004 to 12/2005, 209 DLCBL pts < 60y with DLBCL and aaIPI 2 or 3 received 4 cycles of R-ACVBP every 15 days. CR and PR pts received a consolidative BEAM and peripheral blood stem cell rescue (LNH2003–3 trial, # NCT00144807 ). Median age was 49 years, 22 % of patients presented with aa-IPI 3, 58% with IPI 3–5 (93% with elevated LDH and 54 % with extranodal sites >1). CR rate after induction was 61%, PR rate 24% leading to an overall response rate of 84% (176 pts). Collection failure was observed in 18 pts (10%). 155 pts received auto transplantation, representing 75% of the study population. Results: With a median follow-up of 27 months, according to the updated IWC 2007, 3y PFS and OS were estimated at 76% (CI 69–81%) and 81% (CI 75–86%), respectively. A case-controlled study was performed by matching the present R-ACVBP population with ACVBP patients selected from the LNH-98–3 trial. Patients were fully matched (1:1) on histology, aa-IPI score, gender, age and follow-up duration. 3y PFS was higher in R-ACVBP than in ACVBP patients: 75% (CI 67–81%) vs 58% (CI 50–65%), p=0.0003. 3y OS were estimated at 78% (CI 71–84%) vs 67% (CI 58–74%), p=0.05. The gain in 3y OS was significant in patients who received auto transplantation: 89% (CI 81–93%) vs 77% (CI 67–84%), p=0.02. Conclusions: These results with R-ACVBP induction and consolidative auto-transplantation suggest a major survival benefit which needs confirmatory prospective study. No significant financial relationships to disclose.
Long-term follow-up of autotransplant (AT)-supported high-dose melphalan (hdm) for multiple myeloma (MM): Update of Intergroup Francophone du Myelome (IFM), Southwest Oncology Group (SWOG), and Arkansas (ARK) Total Therapy (TT) trials
Authors: Barlogie B. , Attal M. , Crowley J. , Harousseau J. 
Published: August 2020

8519 Background: Clinical trial outcomes are usually published when statistical protocol objectives have been met, with short median follow-up not exceeding 5 years. Due to treatment innovations, MM survival beyond 10 years has become more common but formal long-term results are seldom reported. Methods: IFM, SWOG and ARK provide an update of their major trials. IFM-90: 1 AT v standard therapy (STD), IFM-94: 2 v 1 AT, IFM-9902: 2AT ± THAL, IFM-9904: 2AT for high-risk MM; SWOG-9321: 1 AT v STD; TT1: 2 AT with interferon, TT2: 2AT ± THAL, TT3: 2AT + THAL + bortezomib. Results: OS clustered in 3 groups with superior outcomes for TT3/TT2/IFM-99 v TT1 v IFM-94/ IFM-90/SWOG-9321 with 5/10/15-yr estimates of 70%/50%/TE v 57%/35%/20% v 43%/25%/15% (p<0.0001). EFS also clustered in 3 groups with superior outcomes for TT3 v TT2 v remainder with estimates of 71%/TE/TE v 50%/35%/TE v 27%/ 15%/10% (p<0.0001). Among phase III trials, added THAL in TT2 increased 10-yr OS/EFS from 40%/25% to 60%/40% (p=0.04/p=0.0005); 10-yr OS was 30% v 8% with 1 v 0 AT in IFM-90 (p=0.005), 31% v 21% with 2 AT v 1 AT in IFM-94 (p=0.08), and 20% for both arms of S9321. On multivariate analysis involving 2962 patients, OS was adversely affected by B2M >=3.5mg/L (p<0.001), LDH >=ULN (p<0.001), hemoglobin <10g/dL (p=0.001) and albumin <3.5g/dL (p=0.02). 2AT (65%) and THAL (21%) both contributed independently to superior OS (p<0.001, p=0.002); among individual trials, IFM-9902 (19%) and TT2/TT3 (33%) both improved OS significantly (both p<0.001). For each of the 3 major OS clusters, 228 patients could be matched on B2M, LDH, hemoglobin and albumin, with 10-yr OS/EFS estimates of 65%/30% for the TT3/TT2/IFM-9902 group significantly exceeding 30%/15% each for the other 2 groups (p=0.001/p=0.001). Conclusions: A 15-yr EFS plateau of 10% with older trials and superior 10-yr EFS/OS estimates of 50%/35% with recent studies emphasize that cure should be a realistic trial objective in contemporary MM therapy, requiring however very long-term follow-up beyond 15 years. [Table: see text]
Phase I study of an anti-CD30 Fc engineered humanized monoclonal antibody in Hodgkin lymphoma (HL) or anaplastic large cell lymphoma (ALCL) patients: Safety, pharmacokinetics (PK), immunogenicity, and efficacy
Authors: Blum K. A. , Smith M. , Fung H. , Zalevsky J. , Combs D. , Ramies D. A. , Younes A. 
Published: August 2020

8531 Background: XmAb2513 is a novel 2nd-generation humanized monoclonal antibody (mAb) directed against CD30 (a cell surface antigen expressed on Reed-Sternberg cells of HL and ALCL), with an Fc region engineered to have increased binding affinity to Fcγ receptors (FcγRs) leading to improved FcγR-dependent effector cell functions. In vitro, XmAb2513 was more potent and more efficacious than 1st-generation anti-CD30 mAbs (e.g., SGN-30 & MDX-060). In cynomolgus monkeys (cynos), XmAb2513 exposure was dose-proportional with half-lives ranging from 12 - 17d in repeat dose studies, which suggested biweekly (QOW) dosing in man. A Phase 1 study has been initiated to examine the safety and efficacy of XmAb2513 in patients (pts) with relapsed HL and ALCL. Methods: Phase 1 open-label study with QOW dosing of XmAb2513; dose-escalation study design with doses of 0.3, 1, 3, 6, 9, and 12 mg/kg via IV-infusion to establish the maximum tolerated dose (MTD). Pts receive up to 4 cycles (8 infusions) with sample collections at regular intervals for safety, PK, soluble CD30 (sCD30) and detection of immunogenicity [i.e., human Abs to humanized Abs (HAHA)]. Tumor response is assessed every 2 cycles. Results: 13 HL pts have been enrolled in the 1st 4 dose levels (0.3 to 6 mg/kg). XmAb2513 has been well tolerated. The MTD has not been achieved. 1 pt with an extensive treatment history and chronic immunosuppression died due to fungal pneumonia after a single 3 mg/kg dose. The event was considered unrelated to XmAb2513. PK parameters were computed for the 1st dose alone and for the entire course of XmAb2513 treatment. PK parameters appeared non-linear across the dose range from 0.3 - 3 mg/kg. Half-life appeared to increase after multiple infusions and ranged from 5.3 - 30.2 days in the 1 and 3 mg/kg cohorts. Immunogenicity (HAHA) results have been negative. Tumor reduction has been observed in 1 pt in the 1 mg/kg cohort and 2 in the 3 mg/kg cohort. Conclusions: The MTD of XmAb2513 has not yet been reached due to its tolerability and lack of immunogenicity. PK results are on track with simulations based on PK results from cynos. XmAb2513 has demonstrated encouraging biologic activity in patients with refractory HL. [Table: see text]
Prognostic implications of comprehensive imaging with PET-CT, MRI, and X-rays and their biological and molecular correlates in multiple myeloma (MM) treated with total therapy 3 (TT3)
Authors: Bartel T. B. , Brown T. , Haessler J. , Shaughnessy J. , Angtuaco E. , Anaissie E. , van Rhee F. , Walker R. , Crowley J. , Barlogie B. 
Published: August 2020

8532 Background: PET and MRI can reveal intramedullary focal lesions (FL) before osteolysis is detected on metastatic bone survey (MBS). Diagnostic merits, biological/molecular correlates, and outcome implications of the imaging techniques were prospectively and serially evaluated in 269 of 303 newly-diagnosed patients receiving TT3. Methods: Examined were FL number identified by PET (FDG-FL), CT portion of PET (CT-FL), MRI (MRI-FL), and MBS (MBS-FL); additionally, max-SUV of FL (SUV-FL), diffusely-involved bone marrow (SUV-DI), and extramedullary disease (EMD) on PET-CT. Results were compared, laboratory correlates examined (eg: gene expression profiling [GEP]-derived risk, molecular subgroups), and outcome implications determined. Results: Comparing anatomic sites, PET detected the highest mean FL followed by MRI and MBS (p<0.0001). Univariately significant implications on overall and event-free survival (OS, EFS) of FDG-FL, MBS-FL, and EMD may be explained by their link to other prognostic variables. Applying tertile frequency distributions of all imaging parameters, significant associations were seen for B2M with MBS-FL, FDG-FL, SUV-DI; CRP with MRI-FL, FDG-FL, CT-FL; GEP-defined high-risk with MRI-FL, FDG-FL, MBS-FL, SUV-FL; GEP low bone (LB) disease with MRI-FL, FDG-FL, SUV-FL; GEP Proliferation (PR) subgroup with MRI-FL, FDG-FL, MBS-FL, CT-FL. Yet on multivariate analysis, OS was independently adversely affected by both SUV-FL (>11) (p=0.001) and MRI >23 (p=0.043) in addition to cytogenetic abnormalities (CA) (p=0.005), B2M (>5.5mg/L) (p=0.005), and LDH ((ULN) (p=0.017). Even with GEP-defined high-risk (p=0.008), SUV-FL (>11) (p=0.009) retained independent significance in addition to CA (P<0.001) and CRP (>8mg/L) (p=0.020). Conclusions: This first prospective comprehensive imaging approach to MM showed that high SUV-FL had significant survival implications even after adjusting for powerful prognostic variables, especially GEP-defined risk. Multifaceted correlations of imaging variables also with molecular features of MM underscore the key role of bone (“soil”) for MM (“seed”) development and progression. [Table: see text]
Adjuvant bortezomib and dexamethasone following risk-adapted melphalan and stem cell transplant in patients with light-chain amyloidosis (AL)
Authors: Landau H. J. , Hoffman J. , Hassoun H. , Elizabeth H. , Riedel E. , Nimer S. D. , Cohen A. , Comenzo R. L. 
Published: August 2020

8540 Background: Melphalan (MEL) and autologous stem cell transplant (SCT) induces both hematologic and clinical remissions in AL, and prolongs overall survival (OS) when complete hematologic remissions (CR) are achieved. We have reported improved responses (including 39% CR) at 12 mos post-SCT using risk-adapted MEL followed by adjuvant dexamethasone (Dex) and thalidomide (Thal) (BJH 2007;139:224). In this phase II trial we use bortezomib (Bort) in place of Thal in an effort to further improve frequency and depth of response. Methods: Pts with newly diagnosed AL involving ≤2 organs were assigned to MEL 100, 140 or 200mg/m2 with SCT, based on age, renal function and cardiac involvement. Response was assessed at 2–3 months (mos) and 12 mos following SCT. Pts who did not achieve hematologic CR at 2–3 mos post-SCT received adjuvant therapy with Bort and Dex for up to 6 cycles (26 weeks). The impact of heart disease on OS was determined using the log-rank test; BNP and Trop-I were correlated with OS using the Cox proportional hazards model. Results: Of 27 pts enrolled, organ involvement was kidney (63%), heart (44%), liver/GI (15%) and peripheral nervous system (7%); 33% have 2 organs involved. Two pts were removed from study prior to SCT (1 due to 3 organ involvement and 1 for comorbid illness that resulted in ineligibility for SCT). Transplant related mortality was 12% (3/25) and was restricted to pts with cardiac AL. Of 21 pts evaluable post-SCT, 5 achieved CR and 16<CR, 15 receiving adjuvant therapy. At 12 mos post-SCT, 12 pts are evaluable. In these 12 pts, the ORR was 92% (11/12) with 67% (8/12) achieving CR. Fifty percent of pts had organ improvement. Adjuvant therapy resulted in improved responses in 7/8 (88%) of pts. Cardiac involvement, BNP and trop-I were all significantly associated with OS. As either BNP or Trop-I increases, the risk of death increased (p=0.006 and p=0.007, respectively). Conclusions: Adjuvant Bort and Dex effectively eradicates clonal plasma cell disease in pts with AL following SCT and results in an unprecedented CR rate at 12 mos post-SCT. Pts with cardiac AL continue to do poorly. Baseline BNP and Trop-I both predict survival. A revised risk-adapted treatment approach incorporating these cardiac biomarkers may be warranted. [Table: see text]
Late mortality and morbidity of patients with Hodgkin lymphoma treated in adulthood
Authors: Matasar M. J. , McCallen L. N. , Riedel E. R. , Ford J. S. , Oeffinger K. C. , Straus D. J. 
Published: August 2020

8547 Background: Increased late mortality and morbidity have been observed among adult survivors of Hodgkin lymphoma (HL) treated in childhood, but are less well characterized for patients treated in adulthood. Methods: We investigated the late mortality and morbidity of adult patients treated at our center from 1975 to 2000. The study population consisted of all patients treated on one of 6 consecutive first-line trials of combined modality therapy (CMT), one of which included a chemotherapy-only arm. Cause-specific mortality was determined by chart review and National Death Index. Survival was estimated using the method of Kaplan-Meier, and cause-specific mortality using competing risk methodology. Self-report surveys were distributed to surviving patients to assess the prevalence of late morbidity; severity of morbidity was scored based on a published adaptation of the Common Terminology Criteria for Adverse Events. Results: 746 patients were eligible for assessment. At time of survey, 227 patients (30.4%) had died: 107 deaths from HL, 100 from causes other than HL, and 20 from unknown cause ( Table 1 ). 20-year OS for the cohort was 71%. Cumulative risk of death due to HL is surpassed by causes other than HL by 22 years post-treatment. Among the 521 survivors, survey data were available for 233 (44.7%), with a median follow-up of 21.6y. Late morbidity was common: 94% reported any morbidity, 48% reported at least one severe (grade 3/4) late morbidity and 22% reported two or more severe late morbidities. The most prevalent severe morbidities included second primary malignancy (SPM) (17%), cardiovascular (CV) (18%) and neurologic (18%) disease. Conclusions: Among adults treated on trials of CMT, by 22y post-treatment the risk of death due to HL is surpassed by risk of death due to other causes. Survivors of HL treated during adulthood experience substantial late morbidity. These findings underscore the importance of efforts directed at prevention of and early intervention for late morbidity in adult survivors of HL. [Table: see text] No significant financial relationships to disclose.
Lenalidomide and rituximab for untreated indolent non-Hodgkin's lymphoma
Authors: Fowler N. H. , McLaughlin P. , Kwak L. , Hagemeister F. , Fanale M. , Fayad L. , Pro B. , Samaniego F. 
Published: August 2020

8548 Background: Despite advances in therapy and a better understanding of the natural history of indolent non-Hodgkins lymphomas (NHL), the optimal treatment for newly diagnosed patients (pts) has not been determined. While several combination chemotherapy regimens have response rates approaching 90%, toxicity is common with genotoxic drugs and secondary malignancies is a concern. Lenalidomide has been shown to have single agent activity in indolent NHL, and is approved for the treatment of multiple myeloma and myelodysplastic syndrome. Rituximab is effective as a single agent and in combination with chemotherapy for indolent NHL. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, stage III, or IV indolent NHL. Methods: Pts with indolent NHL who were previously untreated, with measurable disease (>1.5 cm), were eligible for enrollment. Pts received 20mg of lenalidomide orally once daily on days 1–21 and rituximab 375mg/m2 intravenously on day 1 of each 28 day cycle. Pts could receive up to 6 cycles of therapy. Response was assessed after 3 cycles and at the end of therapy using the International Working Group Response Criteria. Results: At time of this report 17 pts have been enrolled and 14 are eligible for safety evaluation. The median age was 55 (33–77) years and 53% were male. Therapy was well tolerated with the following grade 3 adverse events (AE) reported; myalgia (1 pt), rash (1 pt), peripheral neuropathy (1pt). There were no grade 4 AEs. There have been no reported grade 3/4 hematologic AEs. There has been no tumor flare observed. In the 5 pts eligible for response assessment, 4 pts (80%) attained a complete response (CR), 1 patient (20%) had stable disease (SD). After 3 cycles, one patient had unconfirmed stable disease who also was previously treated with combination chemotherapy for Hodgkin's lymphoma. Updates for response will be presented. Conclusions: The combination of lenalidomide and rituximab has activity and is well tolerated with minimal toxicity in patients with newly diagnosed indolent lymphoma. [Table: see text]