bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor regression and pharmacodynamic (PD) biomarker validation in non-small cell lung cancer (NSCLC) patients treated with the ErbB/VEGFR inhibitor BMS-690514
Authors: Bahleda R. , Soria J. , Harbison C. , Park J. , Felip E. , Hanna N. , Laurie S. A. , Armand J. , Shepherd F. A. , Herbst R.
Published: August 2020

8098

Background: BMS-690514 is an oral selective inhibitor of EGFR, HER2, and VEGFR1–3. Previous results from the phase I portion of this phase I/II study established 200 mg/day as safe and tolerable (ASCO 2008; abstr 2564). Methods: Erlotinib-naïve and erlotinib-resistant adult patients with advanced/metastatic, measurable NSCLC received BMS-690514 200 mg/d. Eligible patients had an ECOG PS ≤1 and adequate organ function. Objectives were to assess disease control rate (DCR; CR, PR, SD ≥4 months), safety, PK and potential predictive and PD biomarkers of BMS-690514. Response was assessed every 8 weeks (modified WHO criteria). Predictive biomarkers included EGFR copy number, and EGFR and KRAS mutations. PD biomarkers included immunohistochemistry of EGFR signaling proteins in skin biopsies, circulating sVEGFR2, blood pressure, skin rash and diarrhea. Results: For 60 patients treated, DCR were 11/28 (39%) and 7/32 (22%) for erlotinib-naive and -resistant patients, respectively. DCR was significantly higher among patients harboring an EGFR mutation (6/8) than those with WT EGFR (5/18). One erlotinib-naive patient had PR (57 wks) and subsequent surgical removal of remaining tumor. Regression (48%) was seen in one erlotinib-naive patient harboring a KRAS G13D mutation. One erlotinib-resistant patient had PR (66%, 31 wks). Two erlotinib-resistant patients with EGFR T790M mutations had SD with 6% and 31% decrease in tumor burden. Most frequent treatment-related AES were diarrhea (90%), skin rash (31%), asthenia (29%), anorexia (27%), hypertension (26%), and reversible acute renal insufficiency (11%). sVEGFR2 (14% decrease from baseline, n=14) and decreased pMAPK levels from skin biopsies (14 of 18 pts) were consistent with EGFR and VEGFR2 inhibition. Conclusions: BMS-690514 200 mg/d showed evidence of anti-tumor activity and disease control in patients with NSCLC, including erlotinib-resistant and those with WT EGFR, EGFR T790M or KRAS mutations. Predictive and PD clinical biomarkers confirmed inhibition of both EGFR and VEGFR signaling pathways by BMS-690514. A randomized phase II trial versus erlotinib in NSCLC is underway.

[Table: see text]
Longitudinal evaluation of EGFR mutation in plasma for non-small cell lung cancer patients with front-line chemotherapy
Authors: Hua B. , Zhao J. , Wang S. H. , Yang L. , Duan J. C. , Wu M. N. , Wang J.
Published: August 2020

8099

Background: To investigate longitudinally epidermal growth factor receptor (EGFR) mutation status in the plasma of pre- and post-chemotherapy for patients with advanced non-small cell lung cancer. Methods: Total of 153 advanced lung cancer patients were included in this study. Plasma samples in pre- and post-chemotherapy ( 2 cycles after) were collected. The DNA concentration was determined by real-time PCR. The EGFR exon 19 and 21 were amplified by mutant-enriched PCR and detected by denaturing high performance liquid chromatograph (DHPLC). The associations between EGFR mutation, DNA level and chemotherapeutic response were analyzed. Results: Among the 153 pts, EGFR mutation were detected 41.2% (63/153) and 27.4% (42/153) in plasma of pre-and post-chemotherapy, respectively. The objective response rate was 31.4% (48/153) and the circulating DNA level trend to decrease after chemotherapy in PR group but increase in PD group (p=0.012). 25 and 73 cases showed consistent EGFR mutation and wild-type status in pre-treatment and post-treatment plasma, respectively. Among 38 patients with change from pre-treatment EGFR mutant-type to post-treatment wild-type status, 11 gained PR, 12 SD and 15 PD. While for 17 patients with change from pre-treatment EGFR wild-type to post-treatment mutant-type, PR, SD and PD were 8, 7 and 2, respectively. The change to mutant-type in post-treatment plasma were found to be significantly higher in PR and disease control than PD(P=0.047, P=0.042). Conclusions: The data indicated that chemotherapy could not only affect the DNA concentration but also change the EGFR mutation detection in plasma for pts with advanced NSCLC. Reason for EGFR mutation change related with response of chemotherapy deserves further study.

No significant financial relationships to disclose.
Topoisomerase II, carbonyl reductase I, and chemosensitivity for amrubicin in the treatment of patients with small-cell lung cancer
Authors: Seto T. , Yamanaka T. , Masuda N. , Eguchi K. , Takiguchi Y. , Okamoto H. , Ogura T. , Yokoyama A. , Ichinose Y. , Watanabe K.
Published: August 2020

8104

Background: Amrubicin (AMR) has been suggested to provide a new effective therapeutic option for small-cell lung cancer (SCLC). It is a totally synthetic 9-aminoanthracyclin and converted by carbonyl reductase I (CBR-I) to its active form, amrubicinol, that has higher potent activity than the parent drug and inhibits purified human topoisomerase II (topo-II). We previously reported the promising result of a prospective phase II trial for AMR monotherapy in patients with second-line SCLC (Thoracic Oncology Research Group Study 0301). Using blood samples at enrollment in this trial, the clinical significance of topo-II and CBR-I expression levels on antitumor effect as well as toxicity has been examined. Methods: Total RNA was extracted from the blood with an RNeasy Mini Kit (Qiagen Inc.) and DNase treatment was performed using the RNase-Free DNase Set (Qiagen Inc.). RT-PCR analysis was performed using TaqMan technology. Quantification of target cDNA (Top-II alpha, CBR-I and beta-actin gene) was conducted using an ABI PRISM 7700 Sequence Detection System (Applied Biosystems Inc.). Quantification was performed using the relative standard curve method. Results: The trial registered a total of 60 patients, of which 40 blood samples were available. Nineteen patients achieved a CR or PR to AMR according to the RECIST assessment and 21 did not. Patients with tumor response had a significantly lower Topo-II level than those without (p=0.0465, Wilcoxon test), although there was no association between tumor response and the level of CBR-I (p=0.3229, Wilcoxon test). We did not find any significant association between the levels of the two enzymes and toxicity. Conclusions: Topo-II may be a potential predictor of response in the treatment of AMR for second-line SCLC. Further investigations in larger patient materials are warranted.

No significant financial relationships to disclose.
Complete remissions with weekly dosing of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in a phase I dose-escalation study in patients with relapsed or refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL)
Authors: Bartlett N. , Forero-Torres A. , Rosenblatt J. , Fanale M. , Horning S. J. , Thompson S. , Sievers E. L. , Kennedy D. A.
Published: August 2020

8500

Background: A defining feature of HL and sALCL is CD30 expression on malignant cells. The ADC SGN-35 comprises an anti-CD30 antibody conjugated to the antitubulin agent monomethyl auristatin E (MMAE). SGN-35 causes cell cycle arrest and apoptosis by binding to CD30 on the tumor cell surface, internalizing, and releasing MMAE into the cell. In a previous phase 1 study with q3 wk dosing, 54% of pts achieved an objective response (CR/PR) at SGN-35 doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods: To assess if more frequent dosing might maximize anti-tumor activity with acceptable tolerability, a multicenter, phase 1, weekly dosing, dose-escalation study (3+3 design) was conducted in pts with refractory or recurrent HL or sALCL. SGN-35 was administered weekly at doses of 0.4–1 mg/kg (2-hr IV infusions). Pts with stable disease or better (Cheson 2007) after two 28-day cycles (6 doses) were eligible to continue SGN-35 treatment. Results: In 17 pts, median age was 38 yrs (range 25–67). Pts received a median of 4 prior therapies; 65% received an autologous SCT. MTD has not been defined. One related G3 event (diarrhea) and no related G4 events occurred. The most common related adverse events were G1/G2 rash, nausea, and peripheral neuropathy. Exposure to SGN-35 (AUC) increased relative to dose level. Multiple CRs were observed at higher doses ( table ); observed time to response in the 1 mg/kg dose group was approximately 8 wks. The 7 pts with CRs all remain on treatment. Enrollment to SGN-35 monotherapy continues at 1.2 mg/kg; combination therapy will be subsequently explored. Conclusions: SGN-35 was generally well tolerated and induced CRs in 7 of 8 evaluable pts at the two highest doses in heavily pretreated patients. Pivotal trials of this antibody-drug conjugate will initiate in early 2009.

[Table: see text]

[Table: see text]
A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin's lymphoma
Authors: Cunningham D. , Smith P. , Mouncey P. , Qian W. , Pocock C. , Ardeshna K. M. , Radford J. , Davies J. , McMillan A. , Linch D.
Published: August 2020

8506

Background: The addition of rituximab to standard therapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP21) has resulted in improved survival outcomes in the treatment of diffuse large B-cell non-Hodgkin's lymphoma (DLBC NHL). In addition, the administration of CHOP as a 14 day cycle (CHOP14) has shown benefit over standard CHOP21 chemotherapy. This randomised study was designed to evaluate the toxicity and survival outcomes achieved with the addition of rituximab to CHOP14 (R-CHOP14), as compared to standard therapy (R-CHOP21) in newly diagnosed DLBC NHL. Methods: Patients were randomised to receive either eight cycles of standard R-CHOP21 or six cycles of R-CHOP14 (+ G-CSF) with two additional cycles of single agent rituximab. Randomisation was stratified by age (≤60 vs >60), WHO performance status (0–1 vs 2) and LDH level (normal vs raised). The primary endpoint is overall survival. The study was powered to detect an improvement in 2-year survival in the R-CHOP14 arm of 8% (70% to 78%) with 5% significance and 90% power (2-sided). Results: Recruitment is complete with 1080 patients randomised. Patient characteristics in the R-CHOP21 and R-CHOP14 arms are; IPI score of ≥4 17%:15%, stage III/IV disease 63%:62%, B symptoms 44%:47%, bulk disease 51%:48%. Median age is 61 years in both arms. 82% of patients in the R-CHOP21 arm completed study therapy as compared to 89% in the R-CHOP14 arm. Reported grade III/IV toxicities in the R-CHOP21 and R-CHOP14 arms are; neutropenia 57%:31%, thrombocytopenia 5%:9%, Infection 22%:17%, cardiac 1%:2%, nausea & vomiting 8%:8%, mucositis 2%:3%. The radiological complete response rate (CR/CRu) is 47% in both treatment arms. With a median follow-up 14 months 805 patients remain alive. Conclusions: Results indicate that R-CHOP14 can be delivered as effectively as R-CHOP21 with comparable levels of acute toxicity. Final analysis will be performed when 330 deaths have occurred.

No significant financial relationships to disclose.
Final results of NCCTG N0489: Epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (ER-CHOP) in patients with previously untreated diffuse large B-cell lymphoma
Authors: Micallef I. N. , Maurer M. J. , Nikcevich D. A. , Cannon M. W. , Schaefer E. W. , Moore D. F. , Kurtin P. , Witzig T. E.
Published: August 2020

8508

Background: A prior pilot study of epratuzumab (Immunomedics) and rituximab in combination with CHOP chemotherapy (ER-CHOP) in untreated patients with diffuse large B-cell lymphoma demonstrated feasibility and safety. This multicenter NCCTG phase II study was carried out to assess efficacy. Methods: Patients received immunochemotherapy on the following schedule: epratuzumab 360 mg/m2, rituximab 375 mg/m2, and standard dose CHOP every 3 weeks for 6 cycles. Weekly blood counts were obtained to monitor hematological toxicity. Primary endpoint was 12 month event free survival (EFS12). Secondary endpoints were response rate, progression free survival, functional CR (PET negative) and toxicity. Results: 107 patients were accrued from Feb 2006 to Aug 2007. 29 patients were ineligible resulting in 78 eligible patients. Baseline patient characteristics for the eligible patients included median age 61 (range 21–82); 59% were male. 81% had advanced stage; IPI was 0–1 in 17 pts (22%), 2 in 22 pts (28%), 3 in 29 pts (37%) and 4–5 in 10 pts (13%). Based on the revised IPI (R-IPI) 50% were poor/high risk (IPI 3–5). 71% had an elevated LDH. Performance score was 0–1 in 69 pts and 2–3 in 9 pts. The ORR was 95% (CR/CRu: 73%). For the low risk IPI (0–2), ORR was 95% (CR/CRu: 74%) and for the high risk IPI (3–5), ORR was 95% (CR/CRu: 72%). The EFS at 12 months was 80%. The 12 month progression free survival (PFS12) and overall survival (OS12) is 82% and 88% respectively. EFS12, PFS12 and OS12 by IPI risk category is shown ( Table ). Conclusions: ER-CHOP every 21 days is feasible and safe. The ORR, EFS and PFS compare favorably to studies using R-CHOP especially in the high-intermediate and high risk IPI subgroups. A randomized phase III trial of R-CHOP vs ER-CHOP is needed to prove that dual antibody targeting in combination with CHOP is better.

[Table: see text]

No significant financial relationships to disclose.
Multicenter analysis of 81 solid organ transplant (SOT) recipients with posttransplantation lymphoproliferative disease (PTLD): Examination of survival and prognostic factors
Authors: Evens A. M. , David K. A. , Helenowski I. , Kircher S. M. , Mauro L. , Gimelfarb A. , Hattersley E. , Shammo J. M. , Smith S. E. , Smith S. M.
Published: August 2020

8510

Background: PTLD has a reported 3-year (yr) overall survival (OS) of 35–40% (Leblond, JCO 2001). The impact of rituximab (RTX) on the prognosis or outcome of PTLD is not known. Methods: We examined the clinical features, treatment, and outcomes among a large population-based cohort of SOT-related PTLD patients (pts) at 4 Chicago institutions (1/98–2/08). Prognostic factors were evaluated in univariate and Cox proportional hazards regression for survival. Results: 81 PTLD pts were identified (SOT: 47 kidney ± pancreas, 4 pancreas, 17 liver, 8 heart, 5 lung) with median age at diagnosis (dx) of 48 yrs (range 20–72). Median time from SOT to PTLD was 42 months (mo) (range 1–216 mo). PTLD dx (per WHO) were 55 monomorphic, 22 polymorphic and 4 plasmacytic, while 42 were EBV+ and 30 EBV-negative (9 unknown). 74% of pts (60/81) were treated with rituximab ± chemotherapy (and reduction of immune suppression). With 38-mo median followup for all pts, 3-yr progression-free (PFS) was 58% and 3-yr OS 62%, despite 16% of pts dying ≤ 6 weeks from dx. Most relapses (30/32) occurred ≤ 12 months from dx. Pts receiving RTX as part of therapy had 3-yr PFS of 69% and OS 71% (vs 21% (p=0.0002) and 33% (p=0.001), respectively, without RTX). Univariate analysis identified prognostic factors for PFS/OS (all <0.01): 1) PS, 2) serum albumin, 3) >1 EN site, 4) marrow involvement, 5) CNS disease and 6) RTX as part of initial therapy. Neither histology nor EBV status predicted outcome. On multivariate analysis, 4 factors remained significant ( Table 1a ). Further, a survival model based on 3 factors was constructed ( Table 1b ). Conclusions: This study represents the largest PTLD report in RTX-treated pts. We are the first to identify the prognostic significance of low albumin and a low PTLD relapse rate beyond 1 yr (6.3%). Further, it appears that the introduction of RTX has improved the survival of PTLD. In addition, clinical factors at dx identified pts with markedly divergent outcomes.

[Table: see text]

[Table: see text]

No significant financial relationships to disclose.
Utilization of radiation therapy in early-stage Hodgkin disease and its impact on survival
Authors: Rineer J. , Schreiber D. , Wortham A. , Olsheski M. , Sroufe R. , Sura S. , Katsoulakis E. , Han P. , Choi K. , Rotman M.
Published: August 2020

8511

Background: Despite numerous randomized trials confirming the benefit of consolidation radiation therapy (RT) in the management of early stage Hodgkin disease (HD), utilization of RT in this setting remains variable. We performed a population-based analysis to assess the utilization of RT and its impact on overall and cause specific survival. Methods: The surveillance, epidemiology and end results (SEER) registry was used to identify patients aged 15–75 years diagnosed between 1990–2004 with early stage (stage I-IIA/B) HD, excluding nodular lymphocyte predominant HD. Kaplan-Meier analysis was performed to evaluate the effect of RT on overall survival (OS) and cause-specific survival (CSS). Subgroup survival analyses were also performed by era of treatment (1990–1997 and 1998–2004), sex, and patient age (<30, 30–50, and >50 years). Results: A total of 9729 patients met inclusion criteria. Median age of all patients was 34 years. The majority (71.3%) had nodular sclerosis (NS) type HD. By clinical stage, 3399 (34.9%) were stage I, and 6330 (65.1%) were stage II. 5352 patients (55%) received RT. RT was more likely to be employed during the early era of treatment, in younger patients, females, non-Blacks, and in NS, mixed cellularity and lymphocyte-rich HD. For the entire cohort, RT was associated with a significant (p<0.001) improvement in OS and CSS (hazard ratio of 0.537 and 0.437, respectively). The benefit of RT for OS and CSS remained significant for all subgroups analyzed including the era of treatment, sex, and age (p≤0.001). Conclusions: In this large population-based series of early stage HD patients, the use of RT is associated with a significant OS and CSS benefit across all subgroups. Current efforts in clinical trials have aimed at decreasing the utilization of RT among this patient population. This shift in practice is reflected in the data presented here. The omission of RT from the treatment paradigm, however, appears to be related with diminished survival.

No significant financial relationships to disclose.
Long-term follow-up of patients with follicular lymphoma (FL) receiving single agent rituximab at two different schedules in study SAKK 35/98
Authors: Ghielmini M. E. , Hsu Schmitz S. , Martinelli G. , Peccatori F. , Hess U. , Fey M. , Zucca E. , Stahel R. , Ketterer N. , Cerny T.
Published: August 2020

8512

Background: In FL, rituximab as a single agent obtains a response rate of 50–70% with an EFS of 1–3 years depending on the population studied. Some patients respond to this treatment for a prolonged time, so we investigated, in a clinical trial, the proportion of long-term responders and the characteristics predicting long-term response. Methods: Between 1998 and 2002, chemotherapy naïve (n = 64) or pre-treated (n = 138) FL patients received 4 weekly doses of rituximab: those responding or with stable disease were randomized to either no further treatment (observation, n = 78) or 4 additional doses of rituximab given at 2 months intervals (consolidation, n = 73). Results: At a median follow up of 8.9 years, and with all living patients having been followed for at least 5 years, the median event-free survival (EFS: time until progression, relapse, second tumor or death) is 13 months for the observation and 24 months for the consolidation arm (p=0.0012). In the observation arm 10% had no event at 5-years, the figure dropping to 4% (3/78) at 8 years, while in the consolidation arm the EFS was 26% at 5 years and remained 18% (13/73) at 8 years. The only significant prognostic factor for EFS in a multivariate Cox regression was having received consolidation rituximab (hazard ratio = 0.58, CI = 0.44–0.87, p = 0.008), whereas being chemotherapy naïve, presenting with stage < IV and showing a VV phenotype at position 158 of the Fc receptor RIIIA were not any more significantly prognostic in this long term analysis, in contrast to previous data with shorter follow-up. No long-term toxicity from treatment was observed. There were 21 cases of second malignancy: 11 on observation, 10 receiving the consolidation arm. Conclusions: It appears that the EFS advantage of prolonged versus short course rituximab continues for many years after the end of treatment. This seems to hold true independently from previous treatment, stage or 158-phenotype of the Fc receptor. Patients treated with 8 doses of rituximab over 1 year have approximately 25% and 20% chance to remain in remission at 5 and 8 years respectively.

[Table: see text]
A phase III study of VMPT versus VMP in newly diagnosed elderly myeloma patients
Authors: Palumbo A. P. , Bringhen S. , Rossi D. , Berretta S. , Montefusco V. , Peccatori J. , Galli M. , Carella A. , Omedè P. , Boccadoro M.
Published: August 2020

8515

Background: In MM patients VMP is superior to MP. In relapsed-refractory patients the 4 drug combination VMPT induced a high proportion of complete responses (CR). Methods: 500 newly diagnosed MM patients ≥ 65 years were randomly assigned to receive VMPT (N=247) or VMP (N=253). Patients were treated with nine 5-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1, 8, 15, 22; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–35) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described). Primary end-point was progression-free survival (PFS). Assuming the hazard ratio (VMP vs VMPT) of 1.35, the total sample size is 500 (250/arm) subjects (power 80%, 2-side alpha 0.05). Results: 354 patients (median age 71 years), who received at least 1 cycle were evaluated: 177 VMPT and 177 VMP. Data were analyzed in intention-to-treat. The VGPR rate was 55% in the VMPT group and 45% in the VMP group (p<0.001). After a median follow-up of 14.5 months, the 3-year PFS was 74% in the VMPT group and 70% in the VMP group (HR=0.75, 95% CI 0.45–1.26, p=0.28). The 3-year overall survival (OS) was 88% in the VMPT group and 87% in the VMP group (HR=0.89, 95% CI 0.42–1.87, p=0.75). Subgroup analyses did not show any statistical difference between responses/PFS and either ISS or chromosomal abnormalities (t(4;14) or t(14;16) or del17) in both groups. Age > 75 years was associated with lower VGPR rate (p=0.02) in VMPT but not in VMP. Factors predictive of longer PFS were age ≤ 75 years (p=0.003) and the achievement of VGPR (p=0.0005) in VMPT but not in VMP. The incidence of grade 3–4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%) and infections (14% vs 10%), respectively. Conclusions: VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. Both regimens appeared to overcome the poor prognosis of ISS and chromosomal abnormalities. An update of these data will be presented.

[Table: see text]
Phase II study of pegylated liposomal doxorubicin (PLD), low-dose dexamethasone (DEX), and lenalidomide (LEN) in patients with newly diagnosed (ND) multiple myeloma (MM)
Authors: Baz R. , Hussein M. A. , Sullivan D. , Raychaudhuri J. , Ochoa L. , Kosakowski K. , Nardelli L. , Dalton W. S. , Alsina M.
Published: August 2020

8518

Background: We previously reported the results of a phase I/II trial of PLD, low dose DEX and LEN in patients with relapsed and refractory MM in which the MTD of LEN was 10 mg (for 21 of 28 days) and the overall response rate was 75% with 29% of patients achieving nCR or better (Ann Oncol 2006). Accordingly we evaluated this regimen in ND MM. Methods: We hypothesized that patients with ND MM would tolerate this combination better. Accordingly, patients received PLD (40 mg/m2 on day 1), DEX (40 mg on days 1–4) and LEN (25 mg Days 1–21) every 28 days (for 2 cycles beyond best response: 4–8 cycles). Prophylactic low dose aspirin, acyclovir and fluoroquinolone were recommended. Patients not eligible or not wishing to proceed with high dose therapy continued on the tolerated dose of LEN and DEX until disease progression or unacceptable toxicity. Results: Between 2/2008 and 8/2008, 31 of a planned 60 patients were enrolled. 2 patients were screen failures and are not included in subsequent analysis. The mean age was 64 years (41–82) and 58% were males. The median β2microglobulin was 2.8 mg/dL (34% had β2m>3.5). Using the modified SWOG criteria and after a median of 4 cycles of therapy, the overall response rate was 80% with 40% VGPR and better. Two patients had stable disease and 3 patients had progressive disease. Grade 3/4 hematologic toxicity was as follows: neutropenia (48%), anemia (10%), thrombocytopenia (7%). Grade 3/4 non-hematologic toxicity included: Fatigue (21%), infections and febrile neutropenia (20%, only 1 patient with febrile neutropenia), venous thromboembolic events (10%). 14 patients went off study including 8 patients to proceed with high dose therapy. Conclusions: The combination of PLD, LEN and DEX is an active regimen in patients with ND MM. Due to the unexpected higher rates of neutropenia and fatigue, the dose of PLD will be decreased to 30 mg/m2 every 28 days. Updated results will be presented at the time of the meeting.

[Table: see text]
Role of T-cell immunity to embryonal stem (ES) cell antigen SOX2 in the progression of myeloma
Authors: Dhodapkar M. V. , Bolejack V. , Shaughnessy J. , Matthews P. , Pickering R. , Qu P. , Hoering A. , Crowley J. , Barlogie B.
Published: August 2020

8522

Background: Clinical outcome in patients (pts) with asymptomatic plasma-proliferative disorders, monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic myeloma (AMM), is highly variable. There is a need to identify specific tumor or host related features that predict the risk of disease progression. In prior studies, we have shown that patients with MGUS commonly mount a T cell immune response against SOX2, an antigen critical for pluripotency of ES cells. Methods: Patients with MGUS/AMM were enrolled in a prospective observational clinical protocol (SWOG S0120). All patients underwent detailed staging evaluation at registration and were observed without therapy. The presence of T cell immunity to SOX2 in freshly isolated blood / marrow mononuclear cells was analyzed using an overlapping peptide library at study entry. Results: Anti-SOX2 T cell responses were detected in 39/109 (36%) pts tested. Progression to symptomatic MM was observed in only 2 of 39 patients with anti-SOX2 immunity compared to 17 of 59 pts lacking these responses, resulting in 2-yr progression-free survival 96 v 63% (p=0.003). Responses to viral antigens and polyclonal mitogens as controls were preserved in patients lacking SOX2 immunity indicating that the absence of immunity to SOX2 was not due to global immune-suppression. Immunity to SOX2 correlated with features of lower risk including serum-M component < 1.5 g/dL (p=0.008), marrow plasmacytosis < 10% (p<0.001) and normal serum free light chain ratio (p=0.01). Conclusions: These data demonstrate in the context of a prospective trial that T cell immunity to stem cell genes strongly correlates with a reduced risk of progression to clinical myeloma. These data point to SOX2 as a potential target for the prevention of disease progression in MGUS/AMM.

No significant financial relationships to disclose.
Randomized phase III trial of pixantrone compared with other chemotherapeutic agents for third-line single-agent treatment of relapsed aggressive non-Hodgkin's lymphoma
Authors: Pettengell R. , Narayanan G. , Mendoza F. H. , Digumarti R. , Gomez H. , Cernohous P. , Gorbatchevsky I.
Published: August 2020

8523

Background: Currently, treatment options for multiply relapsed aggressive NHL are limited, and response rates are disappointing. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone, has potentially reduced cardiotoxicity and has demonstrated promising clinical activity in phase II studies in heavily pretreated NHL patients. Methods: PIX301 was a controlled, multicenter, open-label phase III study of ≥ third-line treatment of relapsed aggressive (de novo or transformed) NHL. All patients were required to have received ≥ 1 prior anthracycline-containing regimen, with the cumulative doxorubicin-equivalent dose limited to ≤ 450 mg/m2. Randomization was to pixantrone 85 mg/m2 on days 1, 8 and 15 of 28-day cycles, for up to 6 cycles, or to investigator's choice of a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, or mitoxantrone; in the US only, gemcitabine and rituximab were permitted). The primary study endpoint was CR/CRu rate. Secondary objectives included safety, OS, and ORR. Originally planned to enroll 320 patients, PIX301 was amended to 140 patients due to slow enrollment. Results: 140 patients (70 per arm) were randomized. Median age was 60 on the pixantrone arm, 58 on the control arm; patients on both arms had received a median of 3 prior chemotherapeutic regimens. Based on independent review in the ITT population, the CR/CRu rate in patients treated with pixantrone was significantly higher than in those receiving other agents (20.0% vs. 5.7%, p-value = 0.02), and there were no CRs in the control group compared to 8 CRs in the pixantrone group. Conclusions: In this study, single-agent therapy with pixantrone achieved significantly superior CR/CRu and ORR rates in ≥ third-line treatment of relapsed/refractory aggressive NHL.

[Table: see text]

No significant financial relationships to disclose.
Tumor-infiltrating CD163-positive macrophages, clinicopathological parameters, and prognosis in classical Hodgkin lymphoma
Authors: Kamper P. , Bendix K. , Hamilton-Dutoit S. , Honoré B. , d'Amore F.
Published: August 2020

8528

Background: Classical Hodgkin lymphoma (cHL) is characterized by a minority of neoplastic cells surrounded by a heterogeneous background of non-neoplastic cells. A possible prognostic role of LAMs in cHL and follicular lymphomas has been suggested. CD163 is a haemoglobin scavenger receptor expressed by monocytes/macrophages. A high CD163 expression has been observed in macrophages belonging to the “alternative activation” pathway suggested to have pro-tumoral effect. The aim of the present study was to correlate the expression of the tumor-infiltrating CD163+ LAMs with clinico-pathological features and prognosis in a cohort of previously untreated HL patients (pts). Methods: A tissue microarray (TMA) was constructed with paraffin embedded tissue specimens from 286 cHL cases. CD163 expression was assessed immunohistochemically and the degree of intratumoral LAM infiltration was scored semi-quantitatively. Clinical data were obtained from the Danish population-based lymphoma registry and clinical records. All pts were homogeneously treated with either chemo-radiotherapy (localised disease) or ABVD chemotherapy (advanced disease). Results: The median age was 37 yrs (range: 6–86 yrs). The M:F ratio was 1.2. The histological subtypes were: nodular sclerosis (NS)-type I, 167 cases (59 %); NS-type II, 71 (25%); mixed cellularity (MC), 44 (15 %); lymphocyte-rich, lymphocyte-depleted and cHL-NOS, each one case. Of 253 pts with assessable International Prognostic Score (IPS), 204 had a low-risk (≤ 2) and 49 a high risk (>2) profile. A high number of tumour-infiltrating CD163+ cells was associated with a significantly poorer overall and event-free survival (p=0.029 and p=0.018, respectively). Furthermore, a high expression of CD163 strongly correlated to stage IV disease (p=0.035), presence of B-symptoms (p=0.008), lymphocytopenia (p=0.003), hypersedimentation (p=0.009). In a multivariate analysis, IPS score > 2 remained the strongest predictor. Conclusions: In cHL, a high number of intratumoral CD163+ monocytes/macrophages correlates with adverse outcome and with clinical parameters reflecting underlying aggressive disease biology.

No significant financial relationships to disclose.
Lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma (MM): Encouraging outcomes and tolerability in a phase II study
Authors: Anderson K. C. , Jagannath S. , Jakubowiak A. , Lonial S. , Raje N. , Alsina M. , Ghobrial I. , Knight R. , Esseltine D. , Richardson P.
Published: August 2020

8536

Background: Lenalidomide (Revlimid, Len), bortezomib (VELCADE, Bz; maximum tolerated dose [MTD] 15 mg/1.0 mg/m2) ± dexamethasone (Dex; 20–40 mg; RVD) was well tolerated in a phase I study in relapsed/refractory MM patients (pts), with 58% ≥MR. This multicenter phase 2 study evaluated RVD efficacy and safety at the MTD. Methods: Patients received up to eight 21-day cycles of Len 15 mg (days 1–14), Bz 1.0 mg/m2 (days 1, 4, 8, 11), and Dex 40/20 mg (cycles 1–4/5–8, days of/after Bz dosing). After cycle 8, patients with stable/responding disease received maintenance (Len, days 1–14; Bz, days 1, 8; doses per end of cycle 8; Dex 10 mg, days 1, 2, 8, 9) until progression or unacceptable toxicity. Pts with significant peripheral neuropathy were excluded. Results: Among 64 pts, 38 (59%) had relapsed and 26 (41%) refractory/relapsed MM. Median number of prior therapies was two, including Len (8%), Bz (55%), Dex (92%), thalidomide (77%), and stem cell transplant (SCT, 36%). Forty-one pts (64%) completed 8 cycles, 33 continue on maintenance, 22 discontinued early (11 due to progressive disease). Toxicities were manageable, primarily grade (G) 1/2 myelosuppression; 2 developed DVT on aspirin, 2 G3 atrial fibrillation, 1 G3 peripheral neuropathy. One pt died on-study (fungal pneumonia, possibly due to Dex). Overall response rate (62 evaluable patients) was 84% ≥MR, including 21% CR/nCR, 68% ≥PR, which was independent of high-risk features and prior treatment ( Table ). Median duration of response is 24 weeks (range 6–81). Time-to-events data including median time to progression, progression-free survival, and 1-year survival rates will be presented. Conclusions: RVD is active and well tolerated in pts with relapsed/refractory MM, including pts who have received prior Len, Bz, thalidomide, and SCT. Durable responses have been observed and appear independent of adverse cytogenetics and other recognized risk factors.

[Table: see text]

[Table: see text]
Strategies to overcoming rituximab-chemotherapy resistance by targeting the autophagy pathway using bortezomib in combination with the Bcl-2 inhibitor obatoclax in non-Hodgkin's lymphomas (NHL)
Authors: Hernandez-Ilizaliturri F. J. , Khubchandani S. , Olejniczak S. H. , Hoskin P. , Czuczman M. S.
Published: August 2020

8543

We found that repeated rituximab exposure leads to deregulation of Bcl-2 proteins and concomitant chemotherapy resistance. We demonstrated that obatoclax (O), a potent Bcl-2 inhibitor, enhanced the anti-tumor activity of rituximab or chemotherapy agents. The proteasome is known to regulate Bcl-2 family members expression. In the current work we study the interactions between bortezomib (B) and O against B-cell NHL. Studies were conducted in rituximab sensitive (RSCL) and resistant cell lines (RRCL), as well as in malignant B-cells derived from patients with NHL (n = 20). Cells were exposed in vitro to escalating doses of O with/without B. Cell death was determined by the Cell glow luminescent assay and DNA synthesis by [3H]-Thymidine incorporation. To further study the mechanisms of O and/or B action, RSCL or RRCL were exposed to O or B with or without caspase inhibitors; viability was evaluated as above and apoptosis by flow cytometry and PARP cleavage. Autophagy was detected by LC3 conversion and electron microscopy (EM). Changes in p53 or BH3 domain proteins were evaluated by Western blot. To determine the role of p53 and/or autophagy in O or B activity, SiRNA assays were performed. O or B monotherapy induced time- and dose-dependent cell death of all cells tested. In vitro exposure of RRCL, RSCL and lymphoma specimens to O and B resulted in significant synergistic activity. In vitro exposure of NHL cells to O lead to p53 degradation and Noxa or PUMA induction; while exposure to B resulted in Bax upregulation and Mcl-1 downregulation. The ability of O or B to induce PARP cleavage varied between patient samples and was not observed in RRCL. Inhibition of caspase activity did not affect the ability of O or B to kill NHL cells. Induction of autophagy was detected by LC3 conversion and EM not only in RSCL or RRCL but also in patient-derived tumor cells. Additionally, cell death induced by O could be inhibited by knock-down of Beclin-1 or p53. Our data suggest that O and B have a dual mechanism of action. We also provide data suggesting that both p53 and Beclin-1 have a pivotal role in response to O. Our findings strongly suggest that O added to B may result in a novel and potent therapeutic strategy against aggressive NHL.

No significant financial relationships to disclose.
Retrospective analysis of CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) treated with chemotherapy with or without rituximab
Authors: Miyazaki K. , Yamaguchi M. , Suzuki R. , Niitsu N. , Ennishi D. , Tamaru J. , Kagami Y. , Katayama N. , Kinoshita T. , Nakamura S.
Published: August 2020

8551

Background: CD5+ DLBCL comprises 5–10% of DLBCL, and shows a high incidence of central nervous system (CNS) relapse. It has been included in the 4th WHO classification as an immunohistochemical subgroup. To clarify the prognosis and incidence of CNS relapse of CD5+ DLBCL in the rituximab-era, we conducted a multicenter retrospective study. Methods: We analyzed 313 patients (pts) with CD5+ DLBCL who received chemotherapy with (n=164) or without rituximab (n=149). The current series includes 107 out of 120 pts described in our previous study (Haematologica, 2008). Intravascular large B-cell lymphoma, primary CNS DLBCL, and secondary CD5+ DLBCL were excluded from the study population. Results: 313 pts showed the following clinical features: median age, 67 (range: 15–93); M:F=163:150; elevated serum LDH level, 71%; stage III/IV, 64%; IPI HI/H, 53%. No significant difference in clinical background such as the IPI and its five components, B symptom, male sex, and bone marrow involvement was found between pts who were treated with and without rituximab. Pts treated without rituximab received more dose-intensive chemotherapies (CHOP14, third-generation regimen, and high dose cytarabine-based regimen) than those treated with rituximab (24% vs. 7%, P<0.0001). The CR rate was higher in pts received rituximab than those without (81% vs. 65%; P=0.0014). The median follow-up was 28 months in pts who received rituximab (range: 7–77) and 68 months in those who did not (range: 6–187). Overall survival (OS) was significantly superior for pts with rituximab than for those without (2-yr OS: 68% vs. 54%, P=0.003). Multivariate analysis revealed that the use of rituximab was favorably associated with OS (HR=1.81, 95% CI: 1.26–2.58, P=0.001), but dose-intensive chemotherapies did not affect OS. However, the incidence of CNS relapse was not different between the two groups (2-yr CNS relapse rate: 11.9% vs. 11.4%, P=0.91). 16 of the 20 pts (80%) with CNS relapse in the rituximab group had brain parenchymal disease. Conclusions: Our data show that rituximab improves OS of pts with CD5+ DLBCL, but does not prevent CNS relapse. Future prospective studies to decrease CNS disease for CD5+ DLBCL are warranted.

No significant financial relationships to disclose.
PROPEL: Results of the pivotal, multicenter, phase II study of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL)
Authors: O'Connor O. , Pro B. , Pinter-Brown L. , Popplewell L. , Bartlett N. , Lechowicz M. , Savage K. , Coiffier B. , Saunders M. , Horwitz S.
Published: August 2020

8561

Background: Pralatrexate is a novel targeted antifolate designed to accumulate preferentially in cancer cells. PROPEL, a pivotal phase 2, non-randomized, open-label, international study, is the largest prospective study in patients (pts) with relapsed or refractory PTCL. Methods: Pts received 30 mg/m2 of pralatrexate intravenously weekly for 6 of 7 weeks, supplemented with B12 and folic acid. Primary endpoint = objective response rate (ORR); secondary endpoints = response duration, progression-free survival, and overall survival. Eligibility criteria: histologically confirmed PTCL, disease progression after ≥ 1 prior treatment, and ECOG performance status ≤ 2. Pathology was confirmed by independent central review, response to therapy was assessed by independent central review using International Workshop Criteria (IWC). Results: 115 pts were enrolled, 109 were evaluable for efficacy. 111 treated pts included 76 males (68%) and 35 females (32%). Pts had failed a median of 3 prior regimens and thus were heavily pre-treated. 78 pts (70%) failed CHOP, 18 (16%) had previous autologous stem cell transplant. 25% of pts never responded to any prior therapy; 53% did not respond to last prior therapy. The majority (59 pts, 53%) had PTCL not-otherwise specified. The ORR by central review was 27% (n = 29). 11 pts (10% overall, 38% of responders) had a complete response (CR), 18 pts (17%) had a partial response (PR), and 23 (21%) had stable disease. ORR by investigators assessment was 39% (n = 42). The median duration of response cannot be accurately estimated at this time, though responses of > 1 year have been observed. 69% of responses were after just 1 cycle. 5 responding pts went on to transplant. The most frequent Grade (Gr) 3–4 adverse events were mucosal inflammation (Gr 3 = 17%, Gr 4 = 4%) and thrombocytopenia (Gr 3 = 14%, Gr 4 = 19%). Conclusions: The results of PROPEL show that pralatrexate exhibits substantial activity in pts with relapsed or refractory PTCL, as assessed by a rigorous central review, with durable CRs /PRs, irrespective of the amount of prior therapy.

[Table: see text]
Phase I/II study of a hybrid schedule of flavopiridol in relapsed/refractory mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL)
Authors: Tay K. , Shapiro G. , Disinski M. , Chirieac L. R. , Pittaluga S. , Jaffe E. S. , Janik J. E. , Wiestner A. , Wilson W. H. , Dunleavy K.
Published: August 2020

8563

Background: Continuous infusion and bolus schedules of flavopiridol in MCL have yielded disappointing results. However, a pharmacologically derived hybrid schedule of administration is effective in refractory, genetically high-risk CLL, though life-threatening tumor lysis syndrome (TLS) may occur in patients with very high lymphocyte counts. Because flavopiridol decreases cyclin D1 and mcl-1 and induces apoptosis in MCL cells, is significantly toxic for cell lines derived from the activated B-cell-like type of DLBCL (OCI-Ly3) and down-regulates NF-kappa B, we investigated the hybrid schedule in MCL and DLBCL. Methods: Flavopiridol was administered as a 30-minute bolus (mg/m2) followed by a 4-hour continuous infusion (mg/m2), weekly for 4 doses every 6 weeks. Separate escalation rules applied to cycle 1 week 1 (C1W1) and all other weeks of treatment. Dose levels on C1W1 were DL1: 25/25 (4 pts); DL2: 30/30 (10 pts) and DL3: 30/50 (6 pts). Dose escalation on subsequent weeks was not possible due to toxicity and all pts received 30/50. All patients received TLS prophylaxis. Paired biopsy samples obtained before and after the first dose were analyzed for cdk targets. Results: Patient (n=20) characteristics: median age: 59 (r 24–80); male 15 (75%); median prior regimens 2 (r 1–6). 10 had MCL and 10 had DLBCL. Responses were PR in 2 (1 MCL; 1 DLBCL) pts (10%); SD in 5 (25%); and PD in 13 (65%). DLTs were TLS and severe vomiting/diarrhea in 2 pts at DL3. The MTD and phase II dose has not yet been defined. Other toxicities were grade 4 ANC (10 pts) requiring prophylactic G-CSF, TLS (1 pt) and bowel perforation (1 pt). Decreased Rb staining at the S807/811 phospho-site was noted in 8 of 9 paired samples analyzed (r 20–75%; p = 0.027) and at the S780 site in 7 of 8 paired samples (r 38–91%; p = 0.00016), suggestive of G1 cdk inhibition. In 1 sample in which p53 was detected, there was an increase post-treatment, suggestive of cdk9 inhibition. Conclusions: The hybrid schedule of flavopiridol has modest activity in relapsed MCL and DLBCL. TLS occurred infrequently and was reversible. DLTs were TLS and gastrointestinal toxicity. Accrual continues. Analysis of cell cycle and transcriptional cdk targets is ongoing.

No significant financial relationships to disclose.
Prediction of treatment response in subtypes of non-Hodgkin's lymphoma by in vivo 31P MR spectroscopy before treatment
Authors: Arias-Mendoza F. , Leach M. O. , Koutcher J. A. , Griffiths J. R. , Heerschap A. , Glickson J. D. , O'Connor O. A. , Brown T. R.
Published: August 2020

8565

Background: To determine if the intracellular tumor marker of phosphoethanolamine plus phosphocholine normalized by nucleotide triphosphates (PPN) monitored non-invasively by phosphorus MR spectroscopy (31P-MRS) correlate with indicators of treatment response in non-Hodgkin's lymphoma (NHL) subtypes. Methods: The PPN value was obtained in 33 diffuse large B-cell lymphomas (DLBCL), 18 follicular lymphomas (FL) and 16 other types (OT) of NHL using in vivo 3D-localized, 1H-irradiated 31P-MRS prior to standard treatment. Results: The PPN values (mean ± standard error) for complete responses (CR) and not complete responses (NCR) in DLBCL were significantly different (CR: 1.42±0.10, n=19 and NCR: 2.25±0.15, n=14; p<0.00002). A Fisher test with a cutoff maximizing PPN sensitivity and specificity (1.78) showed a p<0.004 (sensitivity=0.6, specificity=1.0). Further, when the PPN was combined with the international prognostic index (IPI) to predict treatment response, the Fisher test increased significance (p<0.0002; sensitivity and specificity=0.9). In addition, the two groups dichotomized by the PPN-IPI combination showed a significant difference for drug-free survival (p<0.0001)with one group with survival below 20 months. FL patients did not show PPN significance (CR: 1.40±0.16, n=4 and NCR: 1.75±0.15, n=14). Although this could be due to the lower number of patients, the mean PPN value of the NCR group of FL was significantly lower than that of DLBCL (p<0.01). In the OT group there was only one CR observation but the PPN of its NCR cases was 2.51±0.25, n=13. This value was not significantly different from that of DLBCL but was against that of FL (p<0.007). Conclusions: Our results show that: 1) the pretreatment PPN can predict treatment response in DLBCL identifying a group of DLBCL patients with DFS below 20 months; 2) FL and DLBCL showed distinctive metabolic behaviors; and 3) the number of CR cases was low for FL and OT limiting analysis of PPN until larger cohorts of patients are accrued.

No significant financial relationships to disclose.