bluuebunny/crossref_metadata_2025 huggingface dataset:
Ligands of EGFR and the insulin-like growth factor family as serum biomarkers for response to EGFR-inhibitors in patients with advanced NSCLC
Authors: Vollebergh M. A. , Kappers I. , van den Heuvel M. M. , Buning-Kager J. C. , Korse C. M. , Bonfrer J. M. , Hauptmann M. , de Visser K. E. , Klomp H. M. , Linn S. C.
Published: August 2020

8100

Background: To determine whether concentrations of transforming growth factor α (TGFa), amphiregulin (ARG), both ligands of the epidermal growth factor receptor (EGFR), insulin-like growth factor 1(IGF1) or IGF-binding protein 3 (IGFBP3) measured in serum of advanced non-small cell lung cancer (NSCLC) patients are predictive of EGFR-inhibitors (EGFRi) response. Methods: We assessed serum levels of marker candidates using ELISA (TGA and ARG) and chemiluminescent (IGF1 and IGFBP3) assays. Sixty-one advanced NSCLC patients treated with EGFRi (gefitinib or erlotinib, >14 days) were matched for gender, age and histology to a control group of 63 EGFRi-untreated advanced NSCLC patients. We dichotomized marker levels at the 20th, 50th or 80th percentile and evaluated whether the effect of EGFRi treatment on overall survival (OS) differed by marker level based on multivariate proportional hazards regression with an interaction term. We adjusted for gender, smoking, stage, histology and prior chemotherapy. Results: While 6-months OS did not appreciably differ between 50 EGFRi treated and 50 control patients whose TGFa levels were below the 80th percentile (39% vs. 54%, multivariate HR 0.78, 95% CI 0.45–1.34, p=0.359), it was substantially worse for 11 EGFRi treated patients compared with 13 control patients whose TGFa levels were high (9% vs. 42%, multivariate HR 2.38, 95% CI 0.87–6.52, p=0.092). The difference of EGFRi effects by TGFa level was statistically significant (interaction p=0.033). There was no evidence that EGFRi treatment effects differed by levels of ARG, IGF1 and IGFBP3. Patients with high concentrations of IGFBP3 (above the median) had significantly longer OS than patients with low IGFBP3 concentrations, independent of treatment (HR 0.46, 95% CI 0.29–0.73, p=0.001). Conclusions: This is the first study in NSCLC patients of Caucasian origin in which serum concentrations of TGFa are predictive for EGFR-inhibitor response, suggesting this is a potential predictive marker for EGFRi treatment. Furthermore, we coincidentally found that levels of IGFBP3 are predictive for overall survival, indicating this might be a prognostic factor in advanced NSCLC patients.

[Table: see text]
Transcriptome-wide mutation discovery in patients in a phase II clinical trial of first-line erlotinib for clinically selected patients with advanced non-small cell lung cancer
Authors: Laskin J. J. , Pugh T. , Jackson C. , Sutcliffe M. , Ionescu D. , Melosky B. , Ho C. , Sun S. , Murray N. , Marra M.
Published: August 2020

8102

Background: The purpose of this study was to clinically select a population of patients (pts) likely to benefit from erlotinib and to perform extensive genetic profiling of fresh tissue tumour to identify predictive biomarkers. Methods: Treatment was erlotinib 150 mg p.o. daily until disease progression. Eligibility criteria included: stage IIIB/IV NSCLC; no prior chemo; ECOG ≤2; at least 2 of the following 4 criteria: women, never-smokers, Southeast Asian origin, adenocarcinoma and/or BAC. All pts had baseline serum samples and a fresh frozen tumour biopsy. EGFR and KRAS were sequenced using traditional methods to identify known mutations of erlotinib. Transcribed coding regions of all other expressed genes were sequenced to uncover novel mutations and other genetic features. Results: From Sept-06 to Oct-08, 65 pts have been enrolled. Of these 60 have completed at least 8 wks of erlotinib (or progressed before 8 wks). 49F and 11M; 45 never smokers. PS 0/1/2: 10/39/11. 18 Caucasian and 42 Asian. Pathology: 44 ACA; 3 BAC;1 squamous carcinoma; 13 NSCLC NOS. Responses: PR - 21 (35%); SD - 24 (DCR 75%); PD - 10; NE - 5. 85% did not progress at 8 weeks. 19 of 51 (37%) pre-treatment samples had an EGFR mutation. 10 of the 28 pts with response data (24pts still on drug) had a PR and 7 of these had either an LREA deletion or L858R point mutation. 1 of 3 post-treatment samples developed a T790M mutation on erlotinib. 3 of 51 pts have KRAS mutations. Analysis of over 21 Giga basepairs of aligned transcriptome sequencing data from 20 tumour samples has uncovered 1089 putative non-conservative gene mutations of which 15 are seen in multiple tumours: TUBA1C, EPS8L1, ARID4B, RPL22, C20orf52, CCT8, HLA-DRB5, TRIP6, and PLP2 in 4 tumours, C20orf52 and CTSL1 in 5 tumours, and SERF2, TMEM173, and an uncharacterized gene in 6 tumours. Conclusions: Clinical selection of pts enriches the EGFR mutation positive and KRAS mutation negative population and leads to high rates of non-progression. Full tumour RNA analysis identified several recurrent mutations that may describe mechanisms of erlotinib response and resistance. The discovery of novel mutations in multiple pts suggests patterns that may shed light on lung cancer specific behaviour.

[Table: see text]
Results of a phase II trial of single-agent amrubicin (AMR) in patients with extensive disease small cell lung cancer (ED-SCLC) refractory to first-line platinum-based chemotherapy: An update
Authors: Ettinger D. S. , Jotte R. , Lorigan P. , Gupta V. , Garbo L. , Conkling P. , Spigel D. , McNally R. , Renschler M. , Oliver J.
Published: August 2020

8103

Background: Amrubicin (AMR), a third-generation synthetic anthracycline and potent topoisomerase II inhibitor, is approved in Japan for the treatment of lung cancer. Patients (pts) with SCLC, who are refractory to first-line chemotherapy or progress within 3 months (mos) of treatment completion, are less likely to respond to additional chemotherapy and have an expected median survival of 3–5 mos. Here, we investigate the efficacy and safety of single-agent AMR in the treatment of Western pts with refractory ED-SCLC. Methods: In this phase II trial, pts with ED-SCLC refractory to prior 1st-line platinum-based chemotherapy (defined as progression (PD) while on therapy or relapse within 90 days of treatment completion) and ECOG performance status (PS) ≤2 were eligible. Patients were treated with intravenous AMR 40 mg/m2/day x 3 days every 21 days until PD or intolerable toxicity. The primary endpoint was response rate (ORR, by RECIST), with a goal to demonstrate an ORR ≥18% (point estimate). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: In all, 75 pts were enrolled with a median age of 63 years (range 43–88), 52% female, 17% PS 2. Response to 1st-line therapy was 5% complete remission (CR), 36% partial remission (PR) and 28% PD. Median time from completion of 1st-line therapy to PD was 1.3 mos. Sixty-nine pts received AMR for a median of 4 cycles (range 1–12). Six pts died or discontinued before receiving treatment. The primary endpoint was met with an ORR of 21% (16/75, 95% confidence interval [CI] 13.6% - 31.9%), including CR in 1 pt (1%) and PR in 15 pts (20%). Stable disease was achieved in 40% of pts. Two pts with PD as best response to 1st line chemotherapy achieved a PR. Median OS was 6.0 mos (95% CI 4.8–7.1 mos). Median PFS was 3.2 mos (95% CI 2.4–4.0 mos). The most common grade 3 or 4 adverse events were neutropenia (65%), thrombocytopenia (39%), and leukopenia (35%). Seven (10%) patients experienced febrile neutropenia. Dose reductions were required in 26 patients (38%). Conclusions: AMR shows promising activity, with an ORR of 21%, and an acceptable safety profile in patients with refractory ED-SCLC, and warrants further study in these pts.

[Table: see text]
Phase II study of RAD001 (everolimus) in previously treated small cell lung cancer (SCLC)
Authors: Kotsakis A. P. , Tarhini A. , Petro D. , Flaugh R. , Vallabhaneni G. , Belani C. P. , Friedland D. , Argiris A.
Published: August 2020

8107

Background: Everolimus (E) is an oral inhibitor of mammalian target of rapamycin (mTOR), a novel target for anti-cancer therapy that plays a central role in the PI3K/AKT signaling pathway and other pathways that mediate tumor growth, proliferation, and angiogenesis. E has shown preclinical activity in SCLC cell lines and xenograft models. Methods: Eligibility included SCLC with disease progression after up to 2 prior chemotherapy regimens, ECOG performance status (PS) 0–2, and adequate bone marrow, liver, and kidney function. Patients (pts) were treated with E 10 mg, orally, once daily. Primary endpoint was the disease control rate (DCR), i.e. complete response (CR), partial response (PR) and stable disease (SD), after 2 cycles of E (6 weeks) in pts who received at least 1 cycle. A 2-stage design was followed. PI3K/AKT signaling pathway molecular biomarkers (AKT, pAKT, PTEN, P-S6, p-4E- BP1) will be evaluated on baseline tumor tissue. Results: 40 pts were enrolled; 14 males/26 females; median age 64 years (44–80); PS 0: 17, PS 1: 23; prior chemotherapy status: 1 prior regimen/sensitive relapse (i.e. relapse >60 days from completion of first-line chemotherapy): 23 pts; 1 prior regimen/refractory: 4 pts; 2 prior regimens: 13 pts. 28 pts (70%) received ≥ 2 cycles of E, 7 (18%) 1 cycle and 5 (12%) did not complete the first cycle of E due to adverse events or early progression. Best response in 35 evaluable patients: 1 (3%) PR, 8 (23%) SD and 26 (74%) progression; DCR at 6 weeks was 26% with a duration of disease control of 2.7–6.3 months; median progression-free survival 1.4 months; and median overall survival 5.5 months. No grade 4 toxicity was seen. Grade 3 toxicities included thrombocytopenia (2), neutropenia (2), infection (1), pneumonitis (1), fatigue (1), elevated transaminases (1), hyperglycemia (1), diarrhea (1), and acute renal failure due to dehydration from diarrhea and poor oral intake (1). Conclusions: E is well tolerated but has limited single-agent antitumor activity in unselected patients with pretreated SCLC.

[Table: see text]
R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by autologous stem cell transplantation: CORAL study
Authors: Gisselbrecht C. , Glass B. , Mounier N. , Gill D. , Linch D. , Trneny M. , Bosly A. , Shpilberg O. , Ketterer N. , Moskowitz C. , Schmitz N.
Published: August 2020

8509

Background: Salvage chemotherapy followed by high dose therapy and autologous stem cell transplantation (ASCT) is the standard of treatment for chemosensitive relapses in diffuse large B cell lymphoma. This intergroup trial compared the association rituximab, ifosfamide, etoposide, carboplatinum, R-ICE and rituximab dexamethasone aracytine and cisplatinum R-DHAP. Methods: DLBCL CD 20+ in first relapse or pts refractory after first line therapy were randomized between R-DHAP and R-ICE. Responding patients received BEAM and ASCT and were randomized between observation or maintenance with rituximab for 1 yr. Results: Intent to treat analysis was made on the first 396 pts randomized in 11 countries (R ICE:202; R DHAP:194): median age 55 yrs.; 225 relapses >12months, 166 refractory/early relapses; 244 pts with prior exposure to rituximab; Stage 3–4: 240 pts; elevated LDH: 198 pts; secondary IPI 0–1: 226 pts/ 2–3:149 pts. Patients with prior exposure to rituximab had more refractory disease and adverse prognostic factors. The overall response rate was 63%, with 38% complete remission. There was no difference in response rate between R-ICE 63.5% (CI 56–70%) and R-DHAP 62.8% (CI 55–69%), and in mobilization adjusted response rate. ASCT was performed in 206 pts. 90 SAE were reported in the R-ICE arm and 120 in the R-DHAP with 14 deaths. Factors significantly affecting response rate (p<.0001) were: refractory/relapse < 12 months:46 % vs 88 %, secondary IPI >1:52% vs 71% and prior exposure to rituximab:51% vs 83%. There was not significant difference between R-ICE and R-DHAP for 3 yr EFS (26% vs 35% p=0.6) and OS (47% vs 51%, p=0.5). Three yrs EFS was affected by: prior treatment with rituximab, 21% vs none 47% (p<.0001); early relapse< 12 m 20% vs >12m 45% (p <.0001); secondary IPI 2–3: 18% vs 0–1: 40% (p=.0001). In Cox model, all these parameters were significant (p<.0001) for EFS, PFS and OS but not the treatment arm. Longer follow up is necessary to evaluate the second randomization. Conclusions: There was no difference between R-ICE and R-DHAP. In pts without adverse prognostic factors a response rate > 80% was observed. However, early relapses/ refractory pts to upfront rituximab-based chemotherapy have a poor response rate and prognosis.

[Table: see text]
Lenalidomide, bortezomib, pegylated liposomal doxorubicin hydrochloride, and dexamethasone in newly diagnosed multiple myeloma: Initial results of phase I/II MMRC trial
Authors: Jakubowiak A. J. , Hofmeister C. C. , Campagnaro E. L. , Zimmerman T. M. , Schlossman R. L. , Lonial S. , Reece D. E. , Kaminski M. S. , Anderson K. C. , Richardson P. G.
Published: August 2020

8517

Background: Three-drug combinations with lenalidomide (Revlimid, Rev) and bortezomib (Velcade, Vel) are highly active in previously untreated multiple myeloma (MM). Among the most active are RVD (Revlimid, Velcade, Dexamethasone) and VDD (Velcade, Doxil, Dexamethasone) with ≥ PR rate of 100% and 93%, and a CR/nCR rate of 44% and 40%, respectively. Pre-clinical evaluations suggest that adding pegylated liposomal doxorubicin hydrochloride (Doxil, Dox) to RVD (RVDD) may have higher activity. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of RVDD, assess safety and evaluate efficacy of this 4-drug regimen in newly diagnosed MM. Methods: Four dose levels are being evaluated: Rev 15–25 mg (days 1–14), Vel 1.3 mg/m2 (days 1, 4, 8, 11), dexamethasone (Dex) 20/10 mg (cycles 1–4/5–8; days of and after Vel), Dox 20 and 30 mg/m2 (day 4), with dose assignment for patients (pts) according to the TITE-CRM algorithm. Eight 21-day cycles are planned with 38 pts to be treated at the MTD in phase II. Pts who achieve ≥ PR can proceed to autologus stem cell transplant (ASCT) after ≥ 4 cycles, while all others receive 21-day maintenance cycles with Rev (days 1–14), Vel (day 1 and 8), and Dex (days of and after Vel) at the doses tolerated by the end of initial treatment. Results: The study has enrolled 23 pts to date. Four pts received level 1 (Rev/Dox 15/20), 11 pts level 2 (Rev/Dox 20/20, and 8 pts level 3 (Rev/Dox 25/20). Nineteen pts are evaluable for toxicity after completion of a median of 4 cycles (range 1–8). Two pts developed DLT at dose level 2, consisting of grade (G) 3 asymptomatic neutropenia and G3 elevation of transaminase. The MTD has not been reached. Overall, toxicities have been manageable with no additional G3 hematologic events. There have been 4 additional G3 non-hematologic events including one case each of pneumonia, DVT, fatigue, and hypotension. After a median of 12 (range 3–24) weeks of treatment, preliminary response rates by modified EBMT/UC in 19 evaluable pts are: 95% ≥ PR, 47% ≥ VGPR, 26% CR/nCR. Conclusions: RVDD is well tolerated in newly diagnosed MM and appears highly active with an overall response (≥ PR) of 95%. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting.

[Table: see text]
Bone marrow microenvironment (ME) associated genes identified prior to all altered 48 hours after bortexomib test-dose application and prognosis of multiple myeloma (MM) treated with total therapy 3 (TT3)
Authors: Qu P. , Haessler J. , Barlogie B. , Shaughnessy J.
Published: August 2020

8520

Background: Total Therapy 3 (TT3) incorporated bortezomib (BOR) to co-target ME that plays an important role in MM progression and drug resistance. Consenting patients received a BOR test dose of 1mg/m2 to determine whether ME alterations induced 48hr post-BOR could clarify the drug's in-vivo mechanism of action in the context of achieving MM control. Methods: Bone marrow biopsies were obtained at baseline (BL) prior to and 48hr after BOR (PB) in 70 of 303 patients receiving TT3a (training set) and in 45 of 177 patients enrolled in TT3b (test set). Among 608 ME genes distinguishing BL and PB training samples, 58 were identified as being significantly linked to short event-free survival (EFS). A summary score was computed based on the percent change of these 58 genes (PB-ME-S). Additionally, 20 ME genes were selected whose BL expression predicted OS, arriving at a BL score (BL-ME-S). Results: Applying the PB-ME-S score, 3-yr OS and EFS estimates were 96% and 96% among the 49 patients with low PB-ME-S and 50% and 38% in the 21 with high PB-ME-S (both p<0.0001). Follow-up is too short to validate the PB-ME-S model in the test set of 45 patients in TT3b. The BL-ME-S distinguished OS and EFS in the training set of 70 patients, with 3-yr OS and EFS estimates of 92% and 91% among the 50 patients with low and 54% and 45% in the 20 patients with high BL-ME-S (both P<0.0001). These data were validated in 113 patients with only BL-ME data: 3-yr OS and EFS were 90% and 85% among the 89 patients with low as opposed to 70% and 55% among the 14 patients with high BL-ME-S (p=0.001, p=0.002). TT3 survival was independently significantly affected by PB-ME-S (OS: HR=12.74, p=0.002; EFS: HR=14.32, p<0.001) and BL-ME-S (EFS: HR=3.10, p=0.045), whereas the univariately significant role of BL-PC-S for both endpoints could not be confirmed on multivariate analysis. Conclusions: To our knowledge, this is the first report documenting a validated prognostic role of ME for cancer survival. Key genes shared by both PB-ME-S and BL-ME-S models are involved in endothelial and mesenchymal stem-cell signaling, the details of which will be reported at the meeting.

[Table: see text]
The multi-institutional myeloma group clinico-genomic risk stratification system: A blinded validation
Authors: Tuchman S. A. , Chng W. , Anguiano A. , Barry W. T. , Zhan F. , Gasparetto C. , Fonseca R. , Shaughnessy J. D. , Potti A.
Published: August 2020

8521

Background: Several clinical and molecular prognostic factors (e.g, International Staging System [ISS] stage, plasma cell labeling index, genomic models) exist for multiple myeloma (MM). We hypothesized that exploiting gene signatures representative of oncogenic pathway deregulation (i.e., Ras, Myc, etc.), would improve MM prognostication and also aid with the identification of novel therapeutic targets. Methods: Using a discovery cohort (n=47) of patients with MM and corresponding gene expression data, we built upon current molecular risk-stratification and devised a Bayesian genomic (“metagene”) model for prognosis. We validated that model in an independent patient cohort (n=207). Finally, we incorporated ISS staging and clinical variables to construct a combined Clinico-Genomic Risk Stratification System. We further validated the combined model in a separate cohort (n=72), in a blinded manner. Results: Using gene signatures predictive of oncogenic pathway activation in the discovery cohort, we identified specific patterns (metagenes) of signaling pathway activation with prognostic relevance. In an independent validation cohort, this metagene-based model accurately predicted event free survival (EFS) independently of ISS (multivariate hazard ratio [HR] 3.4 for ISS stage, and 5.4 for the metagene model, p=0.002). Using multivariate risk modeling, we incorporated ISS staging and the metagene model into a Clinico-Genomic System and successfully stratified the validation cohort into three groups (low, intermediate, and high risk) with markedly different EFS (HR 4.2 for intermediate risk and 14.0 for high risk vs. the low risk cohort, p<0.0001). In an additional blinded validation, the Clinico-Genomic System again accurately predicted median overall survival (68.7 [low risk] vs 24.7 [intermediate risk] vs 18.7 months [high risk], p<0.0001); more accurately than either ISS or other reported genomic models. Conclusions: A combined Clinico-Genomic Risk Stratification System, building on patterns of oncogenic pathway activation and ISS staging system, improves upon current prognostic models in MM and identifies novel pathway targets for future therapeutic consideration.

No significant financial relationships to disclose.
Expression of programmed death ligand 1 (PD-L1) by non-Hodgkin's lymphomas (NHL) and effect on tumor-associated T cells
Authors: Andorsky D. J. , Yamada R. , Steward K. , De Vos S. , Said J. , Timmerman J.
Published: August 2020

8526

Background: PD-L1 is expressed on antigen presenting cells and inhibits activation of T cells through its receptor, PD-1. PD-L1 is aberrantly expressed on epithelial malignancies and may prevent an effective host anti-tumor immune response. The role of PD-L1 in NHL is unknown. Methods: PD-L1 expression was analyzed in 16 NHL cell lines by flow cytometry (FC) and in 111 lymphoma specimens by immunohistochemistry (IHC) (n=92) or FC (n=19). In functional studies, irradiated anaplastic large cell lymphoma (ALCL) cells were co-cultured with allogeneic T cells in the presence of anti-PD-L1 blocking antibody, and IFNγ secretion and thymidine incorporation was used to assess T cell function and proliferation. To further test tumor-T cell interactions, malignant ascites from a patient with ALK+ ALCL and peripheral blood mononuclear cells from a patient with leukemic mantle cell lymphoma, both containing PD-L1-expressing tumor cells and tumor-associated T cells, were stimulated with phytohemagglutinin (a polyclonal T cell activator) and incubated with anti-PD-L1 antibody. Levels of 16 inflammatory cytokines were measured as an assessment of T cell activity. Results: All 9 B cell lymphoma lines were negative for PD-L1, while all 5 ALCL cell lines were strongly positive. One T-cell ALL line was positive, and one peripheral T cell lymphoma was negative. Strong PD-L1 staining was detected by IHC in all 14 ALCL specimens and in 83% of diffuse large B cell lymphomas (DLBCL) analyzed (n=35). Activity of allogeneic T cells co-cultured with irradiated ALCL cells, as measured by IFNγ secretion and proliferation, was markedly enhanced in the presence of anti-PD-L1 blocking antibody. In the autologous setting using cultures of ALCL and mantle cell lymphoma specimens containing host T cells, secretion of inflammatory cytokines by tumor-associated T cells, including GMCSF, IFNγ, IL-1, IL-6, IL-8, TNFα, and MIP1α, were increased by incubation with anti-PD-L1 antibody. Conclusions: PD-L1 is highly expressed in ALCL and in a majority of DLBCL. Blockade of tumor-associated PD-L1 promoted activation of adjacent T cells. PD-L1 may play a role in thwarting an effective anti-tumor immune response and represents an attractive target for lymphoma immunotherapy.

No significant financial relationships to disclose.
A phase II multicenter study of CNTO 328, an anti-IL-6 monoclonal antibody, in patients (pts) with relapsed or refractory multiple myeloma (MM)
Authors: Voorhees P. M. , Manges R. F. , Somlo G. , Lentzsch S. , Jagannath S. , Sonneveld P. , Frank R. C. , Zweegman S. , Wijermans P. W. , Thomas S.
Published: August 2020

8527

Background: Relapsed/refractory MM constitutes a specific and unmet medical need with poor overall response and survival. Interleukin-6 (IL-6) plays an important role in MM cell proliferation, survival, and corticosteroid resistance and previous studies have shown clinical benefit from anti-IL-6 therapy. We therefore evaluated the combination of CNTO328, a chimeric monoclonal antibody with high affinity for human IL-6, and dexamethasone (dex) in pts with relapsed/refractory MM. Methods: Pts were treated with 6 mg/kg CNTO328 IV Q2 weeks. Oral dex (40mg) was given once daily, days 1–4, 9–12, and 17–20 for a max of 4 cycles; and on days 1–4 for subsequent cycles. Inclusion criteria were > 2 prior lines of systemic therapy, creatinine clearance >20 ml/min, platelets >50,000/mm3, and neutrophils >1000/mm3. Primary endpoint was overall response with secondary endpoints of time to progression, incidence of AEs and SAEs. Results: Thirty-nine pts received at least 1 infusion of CNTO328 in combination with dex - median age 66 yrs (range 43–89), median disease duration 4.2 yrs (1–13), median lines of prior therapy 5 (2–9) including bortezomib (100%), IMIDs (87%), and ASCT (59%). The median duration of therapy was 3.3 months (0.5–21+). Of the 36 pts who were evaluable, the overall response rate (CR+PR+MR) using EBMT criteria was 31% (7PR, 4MR). An additional 4 uMR and 4 SD lasting ≥3 months have been reported. PRs were durable; 6 out of 7 pts had responses ranging from 3 months to up to more than 1 year (with 1 still ongoing for more than 1 year). Duration of MRs ranged from 2–5 months. Responses were seen in pts relapsing after and refractory to at least one other prior treatment including bortezomib, IMIDs, or steroids. Median time to disease progression (PD) was 3.7 months (0.3–18+). Main reasons for treatment discontinuation were PD (24) and AEs (6). Hematologic toxicities Grade ≥ 3 were common though not dose-limiting. Three pts had Grade ≥ 3 infections considered reasonably related to CNTO328. Conclusions: CNTO 328 in combination with dex shows promising preliminary activity in this heavily pretreated patient population with an acceptable safety profile. Further investigation is ongoing.

No significant financial relationships to disclose.
Subcutaneous injections of low doses of veltuzumab (humanized anti-CD20 antibody): Objective responses in B-cell malignancies
Authors: Allen S. L. , Rai K. R. , Elstrom R. , Negrea O. G. , Farber C. M. , Abbasi R. , Teoh N. , Horne H. , Wegener W. A. , Goldenberg D. M.
Published: August 2020

8530

Background: Low IV doses of veltuzumab, a second-generation anti-CD20 monoclonal antibody with structure-function differences from chimeric rituximab, have shown clinical activity, thus justifying subcutaneous (SC) injections. Methods: A phase I/II study was initiated in patients (pts) with previously untreated or relapsed CD20+ indolent NHL or CLL who received 4 SC injections of veltuzumab 2 weeks apart at dose levels of 80, 160, or 320 mg. Efficacy was assessed by CT-based IWG (NHL) or hematology-based NCI/IWCLL (CLL) criteria 4 and 12 weeks later, with responding pts continuing follow-up. Other evaluations included AEs, safety laboratories, B-cell blood levels (CD19), serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers. Results: Nineteen pts (8M/11F, median age 63), including 14 NHL pts (11 follicular, 3 other indolent NHL; 5 treatment naive) most with stage III or IV disease (11/14) and 5 CLL pts (4 treatment naïve) all with Rai stage II or III disease, have now received SC veltuzumab at 80 mg (3 NHL, 3 CLL), 160 mg (9 NHL, 2 CLL) or 320 mg (2 NHL) dose levels. Pre-treatment with antihistamines or steroids has not been required, and SC veltuzumab was well tolerated with only mild, transient injection site reactions and tenderness. To date, all HAHA results have been negative. In NHL pts, SC veltuzumab demonstrates good bio-availability, with a slow release pattern over several days and depletion of circulating B cells starting after 1st injection. Initial response information is currently available for 10 pts. For 7 NHL pts, 4 weeks after treatment with 80 or 160 mg doses, 2 pts had partial responses, 3 pts showed stable disease, and 2 pts had disease progression. For 3 CLL pts who received 80 mg doses, serum veltuzumab levels were lower, but all pts still achieved 65–75% decreases in circulating leukemic cells over the course of treatment. Conclusions: SC administration of veltuzumab is well tolerated, achieves slow but efficient delivery into the blood, and is pharmacologically active. The low doses currently evaluated in B-cell malignancies show evidence of therapeutic activity, achieving objective responses in NHL and notable reductions in circulating leukemic cells in CLL.

[Table: see text]
Use of bortezomib (BOR) pharmacogenomics (PG) to identify mechanisms of drug resistance and predict survival in multiple myeloma (MM) treated with total therapy 3 (TT3)
Authors: Shaughnessy J. D. , Qu P. , Haessler J. , Crowley J. , Barlogie B.
Published: August 2020

8538

Background: The prognosis of patients with MM is best captured by gene expression profiling (GEP) analysis of CD138-purified plasma cells (PC), distinguishing a high-risk group of 15% with dismal survival using a 70-gene baseline risk model (BLR). Translational research in TT3 was designed to investigate whether short-term BOR-induced GEP alterations could advance our understanding of BOR's novel mechanism of action. Methods: PG studies were performed as part of two TT3 trials (TT3a, n=303; TT3b, n=177), obtaining PC prior to and 48hr after a BOR test-dose (1.0mg/m2), which was accomplished in 142 patients in TT3a (training set) and 127 in TT3b (test set). Among 1051 genes significantly altered post-BOR in TT3a, 80 were identified as being significantly associated with EFS. A continuous risk score was calculated and an optimal cut-point for EFS separation determined. The independent prognostic power of the binary risk score was tested in TT3b. Multivariate analyses (MV) were employed to determine post-BOR risk (PBR) in relationship to standard prognostic variables and BLR. Results: The discriminatory power in TT3a (3-yr OS: 95% v 45%, p<0.0001; 3-yr EFS: 90% v 35%, p<0.0001) was confirmed in TT3b (18-mo OS: 100% v 65%, p=0.0004; 18-mo EFS: 95% v 45%, p<0.0001). Evaluating PBR in the context of BLR, 12/26 in TT3a and 7/21 in TT3b deemed as having low BLR had high PBR; conversely, 8/126 in TT3a and 14/106 in TT3b deemed as having high BLR had low PBR. In the context of our 8 molecular subgroup model, high PBR was over-represented in the Proliferation (PR) subgroup (7/15 in TT3a, 8/18 in TT3b) and absent in the Low Bone disease (LB) group (0/28). On MV, PBR was an independent adverse variable for both OS and EFS in TT3a (OS: HR=3.17, p=0.006, R2=55%; EFS: HR=4.40, p<0.001, R2=48%) and in TT3b (OS: HR=13.00, p=0.002, R2=48%; EFS: HR=15.57, p<0.001, R2=55%). Proteasome genes ranked first among those differentially up-regulated by BOR. Conclusions: PG identified a powerful 80-gene PBR model with unprecedented prognosis-discriminating power, dispelling BLR from MV analysis by altering BLR designation mainly from low to high risk. High PBR (18%) could be traced to up-regulation of proteasome genes, the target of BOR.

[Table: see text]
PX-171–006: Phase Ib multicenter dose escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) and low-dose dexamethasone (loDex) in relapsed and refractory multiple myeloma (MM): Preliminary results
Authors: Niesvizky R. , Bensinger W. , Vallone M. , Gutierrez A. , Kunkel L.
Published: August 2020

8541

Background: CFZ is a highly specific proteasome inhibitor with single agent activity in relapsed/refractory MM (ASH 2008). The purpose of this study is to evaluate the safety and activity of CFZ in combination with LEN and loDex. Methods: This phase Ib trial evaluates 4 dose levels (≥ 3 pts each) to define the maximum tolerated dose (MTD) of CFZ/LEN/loDex in relapsed/refractory MM pts who failed 1–3 prior therapies, including prior LEN or bortezomib (BTZ). CFZ IV 15- 20 mg/m2 (d1,2,8,9,15,16), LEN 10–20 mg po (d1–21) and loDex 40 mg po (d1, 8, 15, 22) in 28-day cycles (C). An additional 10–15 pts will be evaluated at the highest dose level reached. Dose limiting toxicity (DLT) has been defined as grade (G) ≥ 3 non- hematologic; G4 neutropenia for > 7d and/or neutropenic fever; G4 thrombocytopenia > 7d or G3-G4 thrombocytopenia in association with bleeding. Overall response (CR/sCR, VGPR/PR) is assessed by IWG criteria, with secondary assessment by modified EBMT criteria which includes MR. Results: 11 pts have been enrolled. 8/11 are evaluable for response and toxicity. Median prior lines of therapy was 2 (range 2–3). Prior therapies included DEX (8/8), BTZ (6/8), LEN (7/8), alkylators (6/8), anthracyclines (5/8), stem cell transplant (5/8), and thalidomide (1/8); 6/8 pts had received both LEN and BTZ. MTD has not yet been reached after the first 2 dose cohorts. No drug related SAEs or G3/4 treatment emergent AEs were reported. Responses to date with a median of 2 C (range 1–4) are shown below. Responses were rapid and occurred within the first 28-day cycle. Conclusions: CFZ/LEN/loDex in combination was well tolerated in the first 2 cohorts. There have been no myleosuppressive or renal DLTs. The combination has achieved early encouraging responses in pts who had failed both LEN and BTZ at doses well below the single agent MTD of either LEN or CFZ. Dose escalation is ongoing. Updated data will be presented at the meeting.

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Eight cycles of BEACOPP escalated compared with 4 cycles of BEACOPP escalated followed by 4 cycles of BEACOPP baseline with or without radiotherapy in patients in advanced stage Hodgkin lymphoma (HL): Final analysis of the HD12 trial of the German Hodgkin Study Group (GHSG)
Authors: Diehl V. , Haverkamp H. , Mueller R. , Mueller-Hermelink H. , Cerny T. , Markova J. , Ho A. D. , Kanz L. , Greil R. , Engert A.
Published: August 2020

8544

Background: The GHSG HD9 trial had established BEACOPP escalated (BE) as new standard of care for advanced-stage HL patients. The successor study, HD12, evaluated a possible reduction in toxicity by comparing 8 cycles of BE with 4 cycles BE followed by 4 cycles BB. The second question in this trial related to the need of additional radiotherapy (RT) to initial bulk and residual disease. Methods: HL patients in stage IIB with large mediastinal mass and/or E-lesions or stage III/IV were randomised according to a 2x2-factorial design between: 8BE + RT, 8BE no RT, 4BE+4BB + RT, 4BE+4BB no RT. Primary endpoint of the trial was FFTF. Between 9/1999 and 1/2003, a total of 1,670 patients aged 16–65 were randomized. For this final analysis at a median follow up of 78 months, 99 patients were excluded for various reasons resulting in 1,571 eligible patients. Results: Patient characteristics in the 4 groups were comparable. Treatment-related toxicity of WHO grade III/IV was observed in 97% of patients. Most prominent differences between pooled chemotherapy arms were anemia (65% 8BE vs 51% 4BE+4BB) and thrombopenia (65% vs 51%). Treatment outcome: complete remission 92.4%; early progression 2.2%; progression/relapse 7.8% (6.6% and 8.5%). A total of 156 (9.9%) deaths (72 vs 84) have been observed (22 vs 32 acute or salvage treatment toxicity; 15 vs 24 HL; 22 vs 13 secondary neoplasia). Most treatment related deaths occurred in the >60 years age group, the first 4 cycles and the IPS> 3 RF groups. Secondary neoplasias were observed in 77 patients (4.9%). At 5 years, OS was 91%, FFTF 85.5% and progression free survival (PFS) 86.2% (Kaplan-Meier estimates). Estimates for the difference at 5 years are 1.8% for OS, 2.3% for FFTF and 2.7% for PFS favoring BE. However, there was no statistical difference between 8x BE and 4BE+4BB in all outcome parameters (p>0.19, log rank test). There is also no significant difference between the RT or no-RT arms in this study. Conclusions: The adoption of 4BE+4BB as a new standard in the future GHSG studies will depend on a refined analysis of the total data set and will be presented.

No significant financial relationships to disclose.
Pooled analyses of two international, multicenter clinical studies of romidepsin in 167 patients with cutaneous T-cell lymphoma (CTCL)
Authors: Demierre M. , Whittaker S. , Kim Y. , Kim E. , Piekarz R. , Prince M. , Nichols J. , Balser J. , Prentice A. , Bates S.
Published: August 2020

8546

Background: Romidepsin is a novel pan-HDAC inhibitor with demonstrated single-agent activity in 2 open-label clinical studies of 167 patients (pts) with CTCL [mycosis fungoides or Sézary Syndrome (SS)]. Data for these 2 studies were pooled for more accurate estimates of endpoints and investigation of subpopulations. Methods: GPI-04–0001 (pivotal study) enrolled 96 pts with confirmed CTCL who had recieved ≥1 prior systemic therapy. NCI 1312 (supportive study) enrolled 71 pts with CTCL. Pts recieved romidepsin, 14mg/m2 as a 4-hr infusion on days 1, 8, and 15 every 28 days until disease progression (≥25% increase). The primary efficacy endpoint for both studies was overall response rate (ORR) using a composite endpoint that included skin assessment, lymph node and visceral involvement and abnormal circulating T-cells/Sézary cells. Results: 167 pts received romidepsin (as-treated); 135 pts (81%) were in the efficacy evaluable population. Mean age was 57±12 yrs, 67% men, 87% white. 103 pts (76%) had stage ≥IIB disease. Median number of prior systemic therapies was 2 (range 1–8). ORR in the table. Responses were noted in: 42% of pts with stage ≥IIB; 11 (58%) of 19 pts with SS (erythroderma + Sézary cells, >1000/ml or >20% ); and 20 (38%) of 52 pts who received prior bexarotene and 8 (40%) of 20 pts who had received denileukin diftitox. Most common drug-related adverse events (AE), all grades, included: nausea (67%), fatigue (49%), anorexia (37%), ECG T-wave changes (29%), anemia (26%), dysgeusia (23%), neutropenia (22%), leucopenia (20%). Related serious AEs in 2% of pts: supraventicular arrhythmia, ventricular arrhythmia, infection, neutropenia, WBC decreased, hyperuricemia, hypotension; all other serious AEs in ≤1 pt. 3 deaths reported as possibly related. Conclusions: Romidepsin is a valuable new therapy for pts with CTCL based on the ORR, CR, durability of response, improvement in all disease compartments and responses at all stages and in all subpopulations analyzed.

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Application of the mantle international prognostic index (MIPI) to patients with mantle cell lymphoma treated with fludarabine/cyclophosphamide: Results from a UK NCRI Lymphoma Group study
Authors: Rule S. , Smith P. , Qian W. , Gambell J. , Curtis N. , Johnson P. , Linch D.
Published: August 2020

8555

Background: Mantle cell lymphoma (MCL) remains an incurable malignancy with conventional chemotherapeutic options with little randomised evidence to help direct therapy. The International Prognostic Index (IPI) for diffuse large cell lymphoma or Follicular Lymphoma International Prognostic Index (FLIPI) showed poor separation of survival curves in MCL patients. A new prognostic index (MIPI) based on age, performance status, lactate dehydrogenase (LDH), and leukocyte count was developed for patients with advanced stage MCL. Data from a randomised phase II NCRI trial designed to assess the effect of adding rituximab to an all oral chemotherapy regimen has been used to validate the MIPI. Methods: Patients with advanced stage, newly diagnosed MCL were randomised to receive either oral fludarabine 40mg/m2 and cyclophosphamide 250mg/m2 daily x 3 repeated every 28 days (FC) or FC with standard dose rituximab (375mg/m2 on day 1 of every cycle) (FCR). Patients could receive up to 8 cycles of treatment but no consolidation therapy was permitted. The primary outcome measures were response rate and the feasibility of a phase III randomised study. Results: 156 patients were randomised. Median age 64 (36–88) with a significant male predominance. With median follow up of 49 months for survivors the five year overall survival (OS) is 39%. 117 patients had complete data for calculating the simplified Mantle International Prognostic Index (MIPI) .There was equal distribution between the 3 risk groups (low risk 35%, intermediate risk 33% and high risk 31%). The median OS (months) for the 3 groups is; low not reached, intermediate 55.7 and high 20.4 (p of log rank test = 0.0048). However there is no difference between the 3 groups with regard to progression free survival (p=0.31). Conclusions: This large study of patients treated with an oral purine analogue combination confirms that the MIPI is predictive for OS. However MIPI does not discriminate for PFS suggesting that those patients with high scores have an inferior response to subsequent therapy post relapse after FC based therapy.

No significant financial relationships to disclose.
Effects of FCGR3A and FCGR2A polymorphisms on outcomes of patients with diffuse large B-cell lymphoma treated with CHOP-like chemotherapy versus CHOP-rituximab
Authors: Vose J. , Loberiza F. , Armitage J. , Bierman P. , Bociek R. , Dornan D.
Published: August 2020

8567

Background: The addition of rituximab to cyclophosphamide/ doxorubicin/ vincristine/ prednisone (R-CHOP) therapy for diffuse large B-cell lymphoma (DLBCL) has significantly improved the outcome for many patients (pts). We evaluated the impact of single nucleotide polymorphisms (SNPs) of Fc receptor (FcR) genes FCGR3A and FCGR2A on the outcomes of patients with DLBCL treated with R-CHOP compared to a historical control patientss treated with CHOP-like chemotherapy alone. Methods: 199 patients with DLBCL who had received CHOP or CHOP-like chemo (N=99) or R-CHOP (N=100) had tissue blocks assayed for FCGR3A and FCGR2A polymorphisms. The patient characteristics, progression-free survival (PFS), and overall survivals (OS) were compared and analyzed with respect to the polymorphisms. Results: In the univariate analysis, the probability of PFS of pts according to polymorphisms in the FCGR2A gene treated with CHOP-like chemotherapy; H/H (n=25), H/R (n=39), and R/R (n=35) and those treated with R-CHOP; H/H (n=24), H/R (n=41), and R/R (n=35) were both not statistically different; log-rank p=0.47 and p=0.86, respectively. The probability of PFS in the FCGR3A gene treated with CHOP-like chemotherapy; V/V (n=10), F/V (n=40), F/F (n=49) and those treated with R-CHOP; V/V (n=12), F/V (N=40), F/F (n=48) were also not statistically different; log-rank p=0.32 and p=0.22, respectively. In a multivariate analysis for risk of progression or death: FCGR2A : H/H vs. H/R or R/R by treatment type: CHOP-like [RR 0.63 (95% CI 0.37–1.08), p=0.10] and R-CHOP [RR 0.59 (0.36–0.96), p=0.04] and for FCGR3A V/V vs. F/V or F/F by treatment arm: CHOP-like [RR 0.75 (0.36–1.54), p=0.43] and R-CHOP [RR 2.28(0.70–7.44), p=0.17]. Conclusions: Generally, the addition of rituximab to CHOP chemotherapy results in better outcomes than patients who receive CHOP-like regimen regardless of polymorphisms. However, our study also suggests that a trend toward association of certain polymorphisms with clinical outcomes. Additional, larger studies are needed to confirm this data. This information may assist in targeting additional therapies in patients with less favorable outcomes.

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Rituximab plus gemcitabine, ifosfamide, oxaliplatin (R-GIFOX) as salvage therapy for recurrent Hodgkin lymphoma
Authors: Corazzelli G. , Frigeri F. , Marcacci G. , Capobianco G. , Arcamone M. , Becchimanzi C. , Russo F. , Pinto A.
Published: August 2020

8579

Background: Gemcitabine (G), ifosfamide (Ifo), oxaliplatin (Ox) and rituximab (R) have been accounted of cross-synergy in preclinical and early clinical studies in Hodgkin lymphoma (HL). We assessed activity, toxicity and stem cells (SCs) mobilizing capacity of a bi-weekly salvage combination with these agents in HL recurring after conventional or high dose therapy (HDT). Methods: Patients were scheduled to receive 3 R-GIFOX courses followed by SCs mobilization and HDT if elegible for autologous transplantation (ASCT) or 3 more courses if not. R-GIFOX consisted of R 375 mg/m2 D1, G 1000 mg/m2 D2, Ox 130 mg/m2 D3 and Ifo 5 g/m2 D3, as a 24-h single infusion, G-CSF 5 mcg/kg/d DD 7–11 (10 mcg/kg/d, 3rd course until SCs mobilization). Results: Twenty-one patients (median age 33 yrs, r 22–64) with relapsed (n = 16) [post-ASCT (n=6), <12 mo.s (n=7), > 12 mo.s (n=3)] or primary progressive (n = 5) HL, were prospectively accrued. Ten patients (48%) had received ≥ 2 previous CHT lines and 15 (78%) had GHLSG recurring HL prognostic score ≥ 2. Eighty-three total courses were delivered (median 3, r 3–6). CTCAE v3.0 G4 thrombocytopenia occurred in 18% of courses, G4 infection in 11%. Ifosfamide was withdrawn at the 4th course in 2 patients, both aged 64 yrs, due to tachyarrhythmia and encephalopathy. Actual dose intensity of the first 3 courses was 82%, 86%, 92 % for G, Ifo and Ox, respectively. The overall response according to FDG-PET/IWC criteria after 3 courses was 86%, with 2 partial and 16 complete responses (CRs) (76%; CR=10, CRu=6). Four CRs were achieved among the 6 patients with post-ASCT relapses. Eight of 14 eligible patients had effective CD34+ cells harvest [median 4,35 × 106/kg (r 2,91–11.45)] and proceeded to subsequent ASCT. Five ’bad mobilizers’ had previously undergone radiation therapy (n=3) and radioimmunotherapy (n=2). At 42 mo.s. Failure Free Survival was 57%. At a median f.u. of 12 mo.s for CRs, Disease Free Survival was 79% in patients eligible for ASCT and 41% in those unfit treated with additional R-GIFOX. Conclusions: R-GIFOX retains an attractive therapeutic potential in recurring HL, enabling pre-ABMT cytoreduction and mobilization, and also a safe delivery of a full salvage program to patients unfit for HDT.

No significant financial relationships to disclose.
Relationship of rapid M protein reduction to outcomes in a trial of pegylated liposomal doxorubicin (PLD) plus bortezomib (B) versus B alone in previously treated multiple myeloma (MM)
Authors: Shah J. J. , Londhe A. , Lantz K. C. , Lowery C. , Orlowski R. Z.
Published: August 2020

8591

Background: An early response in MM results in rapid improvement in symptoms and may benefit outcomes. To investigate the relationship between rapid response and outcomes, we retrospectively evaluated early reduction in M protein (MProt) in a trial of pegylated liposomal doxorubicin + bortezomib (PLD+B) vs B alone in relapsed/refractory multiple myeloma (MM). (Orlowski, JCO 2007) Methods: Patients (pts) were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, & 11 of each 3-week cycle (N=322) or to the same B regimen + IV PLD 30 mg/m2 on day 4 (N=324) of each cycle. % decrease from baseline of MProt was evaluated using a landmark analysis at the end of cycles 2 and 4. Pts were categorized into 4 groups by reduction in MProt at the landmark timepoints. 199 PLD+B and 205 B pts were included in the analysis at end of cycle 2. Time to progression (TTP) post-landmark was evaluated using a Cox proportional hazard model with treatment and the three ≥25% MProt reduction groups compared to the <25% group as factors. Results: Regardless of treatment, a decrease in risk of TTP was observed for greater reduction in MProt. This was significant for the 50–75% and ≥75% MProt reduction groups. Hazard ratios (95% CI) were: [0.84 (0.55, 1.30), P=.438] for 25-<50% vs 25%; [0.41 (0.26, 0.64), P=.001] for 50-<75% vs <25%; and [0.26 (0.15, 0.45), P=.001] for ≥75% vs <25%. PLD+B had a significant benefit over B alone in extending TTP [1.68 (1.19, 2.37), P=.003]. TTP was longer as MProt decreased and improved for PLD+B vs B. Similar results were observed at the end of cycle 4 landmark. Safety profiles for the 2 regimens were consistent with known toxicities of the agents. Conclusions: PLD+B had significant benefit over B alone in extending TTP in landmark analyses similar to the overall study. A >50% reduction in MProt resulted in a significant risk reduction for progression. These data suggest that early reductions in MProt may provide better outcomes.

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