bluuebunny/crossref_metadata_2025 huggingface dataset:
MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide (POM) plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM).
Authors: San-Miguel Jesùs F. , Weisel Katja C. , Moreau Philippe , Lacy Martha , Song Kevin W. , Delforge Michel , Karlin Lionel , Goldschmidt Hartmut , Banos Anne , Rocafiguera Albert Oriol , Yu Xin , Sternas Lars , Jacques Christian , Zaki Mohamed H. , Dimopoulos Meletios A.
Published: March 2020

8510

Background: RRMM patients (pts) who have exhausted treatment (Tx) with bortezomib (BORT) and lenalidomide (LEN) or thalidomide have a poor prognosis with short overall survival (OS). HiDEX is a well-established standard Tx in RRMM. POM has demonstrated clinical efficacy in pts refractory to LEN and BORT. MM-003 compared POM + LoDEX vs. HiDEX in RRMM pts who failed LEN and BORT and who progressed on their last Tx. Methods: Pts must have been refractory to last prior Tx (progressive disease [PD] during Tx or within 60 days) and failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Pts were randomized 2:1 to receive 28-day cycles of POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20. Tx continued until PD or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS, overall response rate (ORR; ≥ partial response), and safety. Analyses were based on intent to treat. Results: 455 pts were randomized to POM + LoDEX (n = 302) or HiDEX (n = 153). The median number of prior Tx was 5 (range 1-17). 72% were refractory to LEN and BORT. Median follow-up was 4 months. POM + LoDEX significantly extended median PFS (3.6 vs. 1.8 months, HR = 0.45, P < .001) and OS (not reached vs. 7.8 months, HR = 0.53, P < .001) vs. HiDEX. The OS benefit was observed despite 29% of HiDEX pts receiving POM after PD. The trial met the primary endpoint of PFS, crossed the upper boundary for OS superiority, and the Data Monitoring Committee recommended crossover from HiDEX to POM ± DEX. With updated data, the ORR was 21% for POM + LoDEX vs. 3% for HiDEX (P < .001) and 24% vs 3% for pts randomized ≥ 6 months post-enrollment (P < .001). The most frequent grade 3/4 adverse events (AEs) for POM + LoDEX vs. HiDEX were neutropenia (42% vs. 15%), anemia (27% vs. 29%), and infection (24% vs. 23%). Discontinuation due to AEs was infrequent (7% vs. 6%). Updated data will be presented. Conclusions: POM + LoDEX significantly extended PFS and OS vs. HiDEX in pts who failed LEN and BORT. POM + LoDEX should become a standard of care in RRMM pts who have exhausted Tx with LEN and BORT. Clinical trial information: NCT01311687.
Lenalidomide in relapsed/refractory mantle cell lymphoma post-bortezomib: Subgroup analysis of the MCL-001 study.
Authors: Williams Michael E. , Goy Andre , Sinha Rajni , Kalayoglu Besisik Sevgi , Drach Johannes W. , Ramchandren Rod , Zhang Lei , Cicero Sherri , Fu Tommy , Witzig Thomas E
Published: March 2020

8534

Background: Lenalidomide, an immunomodulatory agent with antitumor and antiproliferative effects, demonstrated rapid and durable efficacy in patients with relapsed/refractory mantle cell lymphoma (MCL) post-bortezomib in the phase II multicenter MCL-001 study. The objective of this analysis was to explore the efficacy of lenalidomide across patient subgroups. Methods: Single-agent lenalidomide was administered at 25 mg/d PO on days 1-21 of a 28-day cycle until disease progression or intolerability; primary endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent central review committee per modified IWG criteria. Exploratory analyses of ORR and DOR for subgroups were predefined and prospectively conducted. Results: Patients with relapsed/refractory MCL (N=134) had a median age of 67 y, with a median of 4 prior therapies (range, 2-10). The ORR was 28% (7.5% CR/CRu) and DOR was 16.6 months (95% CI, 7.7-26.7). Lenalidomide treatment provided consistent ORR and DOR across all subgroups analyzed by demographics, baseline disease status and prior therapy (Table). High vs normal baseline LDH was the only significant factor by univariate and multivariate logistic regression analysis of ORR (odds ratio=0.193; p=0.002). Conclusions: Single-agent lenalidomide provided consistent clinical benefit in patients with relapsed/refractory MCL post-bortezomib irrespective of patient subgroups at baseline with the exception of LDH. Clinical trial information: NCT00737529. [Table: see text]
Secondary efficacy subanalysis by histology from the phase III BRIGHT study: First-line bendamustine-rituximab (BR) compared with standard R-CHOP/R-CVP for patients with advanced indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma (MCL).
Authors: Flinn Ian , Van Der Jagt Richard H. C. , Kahl Brad S. , Wood Peter , Hawkins Tim E. , MacDonald David , Hertzberg Mark , Kwan Yiu-Lam , Simpson David , Craig Michael , Kolibaba Kathryn S. , Issa Samar , Clementi Regina , Hallman Doreen M. , Munteanu Mihaela C. , Chen Ling , Burke John M.
Published: March 2020

8537

Background: BR was previously reported to be statistically noninferior to R-CVP/R-CHOP for complete response rate in the treatment of patients with indolent NHL or MCL. Evaluation of time-to-event outcomes is immature. This subanalysis reports response by histology. Methods: Indolent NHL or MCL was histologically confirmed <6 months before study enrollment in patients who were therapy-naïve. Patients were stratified according to predetermined standard treatment (R-CHOP or RECVP) and lymphoma type, then assigned to receive BR (28-day cycles: bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2on day 1) or standard treatment (21-day cycles at standard doses) for 6-8 cycles. Responses were assessed by a blinded independent review committee. The primary efficacy measure was noninferiority of BR complete response (CR) rate for evaluable patients with ≥1 postbaseline efficacy assessment. If the noninferiority threshold was met, superiority was assessed. Secondary measures included tolerability. Results: Of 447 patients enrolled in the study, 213 receiving BR and 206 receiving R-CHOP/R-CVP were evaluable with postbaseline data (Table). BR achieved a statistically noninferior CR rate compared with R-CHOP/R-CVP in patients with indolent NHL and MCL. Conclusions: In patients with treatment-naïve indolent NHL and MCL, BR achieved the primary endpoint of noninferior CR rate. Most CR rates were numerically, but not significantly, higher with BR. Small subgroup results should be interpreted with caution. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00877006. [Table: see text]
Early versus delayed autologous stem cell transplant (ASCT) in patients receiving induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD) for newly diagnosed multiple myeloma (MM).
Authors: Nooka Ajay K. , Langston Amelia A. , Waller Edmund K. , Heffner Leonard T. , Gleason Charise , Muppidi Samatha , Watson Melanie , Casbourne Daniela , Boise Lawrence , Kaufman Jonathan L. , Lonial Sagar
Published: March 2020

8540

Background: Lenalidomide, bortezomib and dexamethasone (RVD) is an active, tolerable induction regimen with superior response rates (≥VGPR rates of 80%) in newly diagnosed MM pts. However, the optimal timing of ASCT with this triplet combination is uncertain. We have evaluated our institutional experience to provide an insight for the best timing of ASCT, where specific patients were offered delayed ASCT based on risk, response and toxicity of therapy. Methods: 222 consecutive transplant-eligible pts with newly diagnosed MM that received at least 3 cycles of RVD and harvested stem cells were included in the analysis from May 2007 until October 2011. Patients underwent early ASCT (received planned ASCT immediately after stem cell harvest, n=136) or delayed transplant (received planned maintenance therapy after collection with intent to proceed with ASCT at first relapse, n=86). Results: Median age of the patients at the time of diagnosis is 60.5 yrs (32-77) vs. 60 yrs (22-73) for early vs. delayed groups. ISS stage 3 disease was seen in 31% patients and 10% patients; high risk cytogenetics were seen in 11% and 7% patients in early vs. delayed groups, respectively. Median time from initiation of induction therapy to ASCT in early group is 5.45 months (range, 3.19-12.68 months). In the delayed SCT group, 28 patients underwent ASCT at a median time of 26.21 months (range, 13.67-41.72 months) from initiation of therapy. At a median follow up of 32 months, 5-year overall survival from diagnosis was 68% and 88% in patients undergoing early and delayed ASCT, respectively (p = 0.106). Conclusions: Transplantation-eligible patients who receive RVD as initial therapy followed by early vs. delayed ASCT result in comparable overall survival. In carefully selected newly diagnosed myeloma patients with lower ISS stage receiving RVD as induction therapy, planned delayed ASCT results in 5-year survival rates close to 90%.
Lenalidomide (LEN)-melphalan-prednisone induction followed by LEN maintenance (MPR-R) in newly diagnosed multiple myeloma (NDMM) elderly patients (Pts) with moderate renal impairment (RI): MM-015 trial post-hoc analysis.
Authors: Catalano John V. , Palumbo Antonio , Weisel Katja C. , Dimopoulos Meletios A. , Delforge Michel , Blade Joan , Petrucci Maria Teresa , Kropff Martin , Hajek Roman , Jacques Christian , Yu Zhinuan , Herbein Lindsay , Cavo Michele
Published: March 2020

8544

Background: The MM-015 pivotal phase III trial showed significant PFS benefit for MPR-R (31 mos) vs. MPR (14 mos) or MP (13 mos; both p < 0.001) followed by placebo in NDMM pts aged ≥ 65 years. As NDMM pts with RI have poor prognosis, this retrospective analysis studied the efficacy and safety of MPR-R in pts with creatinine clearance (CrCl) < 60 mL/min. Methods: LEN starting dose for induction/maintenance was 10 mg/day (D1–21 of a 28-day cycle). Dose adjustments were not recommended for pts with RI. CrCl was calculated using the Cockcroft-Gault equation. Pts with severe RI (serum Cr > 2.5 mg/dL [221 μmol/L]) were excluded from the trial. Results: Pts with CrCl < 60 mL/min (median 47, interquartile range [IQR] 38–55) were included in this analysis: 51% MPR-R, 45% MPR, and 49% MP. Median PFS was significantly higher with MPR-R (26 mos [95% CI 14–48]) vs. MPR (13 mos [95% CI 12–15]) or MP (14 mos [95% CI 12–16]; both p < 0.001). In a Cox proportional model of PFS, CrCl < 60 mL/min was not identified as a negative prognostic factor (p = 0.69). The most common Gr 4 adverse events (AEs) were hematologic and occurred predominantly during induction and are shown in the Table for pts with or without moderate RI. The number of deaths on study was similar: 10% (MPR-R), 7% (MPR), and 8% (MP); deaths associated with RI or disease progression were reported in ≤ 1% of pts with RI across the arms. Conclusions: The benefit of continuous LEN treatment with MPR-R is not compromised in NDMM pts with moderate RI, consistent with the overall trial results. CrCl and AEs should be monitored closely in this population. Clinical trial information: NCT00405756. [Table: see text]
Results after long-term follow-up from the CAN2007 phase I/II study of weekly or twice-weekly bortezomib in patients (pts) with relapsed systemic light-chain (AL) amyloidosis.
Authors: Reece Donna Ellen , Hegenbart Ute , Sanchorawala Vaishali , Merlini Giampaolo , Palladini Giovanni , Blade Joan , Fermand Jean-Paul , Hassoun Hani , Heffner Leonard , Pei Lixia , Enny Christopher , Esseltine Dixie , Van De Velde Helgi , Cakana Andrew , Comenzo Raymond
Published: March 2020

8545

Background: Data from multiple studies suggest that bortezomib alone or in combination regimens is active in newly diagnosed and relapsed AL. CAN2007 (NCT00298766) was the first prospective study of single-agent bortezomib in relapsed AL. Here we report outcome data at study closure after a median follow-up of 51.8 mos (median 46.1–66.1 mos). Methods: 70 pts received bortezomib 0.7, 1.0, 1.3, or 1.6 mg/m2 on days 1, 8, 15, and 22 of 35-day cycles (QW) or 0.7, 1.0, or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles (BIW) for up to 8 cycles (or longer in pts with evidence of ongoing clinical benefit). The maximum tolerated dose was not reached on either schedule; 18 and 34 pts were treated at the maximum planned doses of 1.6 mg/m2 QW and 1.3 mg/m2BIW, respectively, and 18 pts were treated at lower doses. Post-treatment, pts were followed every 6 weeks until disease progression, and then every 3 mos for survival during the long-term follow-up phase. Results: Pts received a median (range) of 8 (1–39), 6 (1–57), and 8 (3–57) cycles of bortezomib in the 1.6 mg/m2 QW, 1.3 mg/m2 BIW, and lower-dose groups, respectively; overall, 32 (46%) pts received ≥8 cycles, and 4 pts were still on treatment and had received ≥39 cycles at study closure. Hematologic responses and outcomes are summarized below. Median (range) follow-up for survival was 51.8 (1–68), 46.1 (1–61), and 66.1 (2–80) mos, and 7, 12, and 9 pts have died, in the 1.6 mg/m2 QW, 1.3 mg/m2BIW, and lower-dose groups, respectively. Median overall survival (OS) in all 70 pts was 62.7 mos, and 4-yr OS rate was 67.3%; data by dose group are shown below. Conclusions: Single-agent bortezomib produces durable hematologic responses and promising long-term OS data in pts with relapsed AL. Clinical trial information: NCT00298766. [Table: see text]
Patterns of failure in advanced-stage diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP chemotherapy and the emerging role of consolidative radiotherapy.
Authors: Shi Zheng Jane , Das Satya , Okwan-Duodu Derick , Esiashvili Natia , Flowers Christopher , Jiang Kun , Chen Zhengjia , Wang Xiaojing , Curran Walter J. , Khan Mohammad K.
Published: March 2020

8546

Background: The role of consolidative radiotherapy (RT) after a complete response (CR) to R-CHOP for stage III-IV DLBCL patients is unclear. The goal of our study is to evaluate the Emory experience when consolidative RT is delivered to initial presenting nodal and extranodal sites or bulky sites in these patients. Methods: From 01/2000 to 05/2012, 211 histologically confirmed DLBCL patients with stage III-IV disease who received R-CHOP were identified at Emory University. Patterns of failure for patients who achieved CR to R-CHOP were analyzed. Local control (LC), distant control (DC), progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method and compared between patients who received R-CHOP alone versus R-CHOP plus consolidative RT using Log-rank test. Multivariate analyses were also performed using Cox proportional hazards model. Results: 163 patients had detailed treatment records. After a median 6 cycles of R-CHOP, 110 patients (67.5%) achieved CR and were entered for analysis. Fourteen patients (12.7%) received consolidative RT to a median dose of 30.6 Gy as part of initial management. With a median follow up time of 32.9 months, 43.8% of patients who received R-CHOP alone failed at the initial presenting sites with or without distant recurrence (DR), whereas isolated DR only occurred in 3.2% of these patients. Consolidative RT was associated with significantly improved LC (91.7% vs 48.8%, p<0.0001), DC (92.9% vs 71.9%, p<0.0001), PFS (85.1% vs 44.2%, p<0.0001) and OS (92.3% vs 68.5%, p<0.0001) at 5-years when compared to patients with R-CHOP alone. In addition, the in-field control rate was 100% within irradiated sites for patients who received consolidative RT. On multivariate analysis, consolidative RT and non-bulky disease were predictive of increased LC and PFS, whereas bone marrow involvement was associated with increased risk of DR and worse OS. Conclusions: 44% of patients with advanced stage DLBCL failed at initial presenting sites despite achieving a CR to R-CHOP. Incorporation of consolidative RT as part of upfront treatment in these patients was associated with improved LC and PFS.
Nodular lymphocyte-predominant and classical Hodgkin lymphoma subtypes: Differences in biology, survival, and impact of radiotherapy.
Authors: Ali Shihab , Olszewski Adam J.
Published: March 2020

8550

Background: Hodgkin lymphoma (HL) is a heterogeneous disease, but differences between nodular lymphocyte predominant (NLPHL) and classical (CHL) subtypes were previously studied in small cohorts preventing adjustment for confounders. We studied those differences based on the Surveillance, Epidemiology and End Results (SEER) program data. Methods: We analyzed SEER HL cases aged 16 years and over, diagnosed between 1995 and 2009. We studied the following endpoints: crude probability of HL-related death (HLRD), relative survival (using individual data in multivariate flexible parametric models) and risk of secondary malignancies (using competing risk regression). We studied the impact of radiotherapy (RT) in early-stage disease using a propensity score, adjusting for treatment selection and immortal time bias. Results: We identified 25,903 patients, with disparate age, race and stage distributions between subtypes. In a multivariate model, NLPHL demonstrated significantly better crude and net survival outcomes (Table), but in contrast to all CHL subtypes, it showed a steady increase in mortality rate after 2 years. The risk of secondary non-Hodgkin lymphoma was significantly higher in both NLPHL (hazard ratio, HR, 2.28, P=0.002) and lymphocyte-rich (LR) CHL (HR 2.08, P=0.01) than in nodular sclerosis (NS). The risk of other secondary malignancies did not differ between subtypes. After balancing confounding factors in treatment arms, RT in stage I/II was associated with improved survival in NS (HR, 0.78, P=0.001) and LR-CHL (HR 0.36, P<0.001), but not in NLPHL (HR 0.98, P=0.94) or in the remaining CHL subtypes. Conclusions: Studies of NLPHL and CHL subtypes should account for their disparate biology and clinical course. Prospective evaluation of NLPHL treatment strategies without RT is justified. [Table: see text]
Interim FDG PET/CT to predict progression-free survival (PFS) better than clinical and baseline metabolic measurements in Hodgkin lymphoma (cHL).
Authors: Knight-Greenfield Ashley , Marshall Richard Aaron , Hutchings Martin , Doucette John , Stern Jamie , Coleman Morton , Kostakoglu Lale
Published: March 2020

8555

Background: Previous studies in cHL have demonstrated that conventional methods to risk stratify patients into various prognostic groups and predict PFS may not be sufficient to individualize therapy. Metabolic parameters using FDG-PET may be helpful for developing a prognostic algorithm and predict PFS. Objectives: To determine the best predictor of PFS among various variables of tm metabolic measurements at baseline and at interim PET/CT compared to conventional methods in cHL patients. Methods: Retrospective evaluation of prospectively acquired data in 58 cHL pts, all stages [IIB-IV:41%, >IPS-3:24%, unfavorable (UF):44%]. Eligibility: PET/CT prior to and after 1 cycle (PET1) ABVD therapy, imaging at 60min+15min, follow-up>24 mo. Baseline PET parameters including metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUVmax, and SULpeak were determined using gradient method (PETVCAR2, GE Healthcare, WI). Data were also evaluated at PET1 for %ΔMTV, %ΔSUVmax, %ΔTLG, PERCIST criteria and visually with Deauville 5-PS. Variables were correlated with PFS. Results: Median follow-up: 32.2 mo. Of 58 pts 14 relapsed (median PFS:6.5 mo). Results for PFS are displayed in the Table. No baseline conventional (stage, IPS, UF vs F) or PET variable was associated with PFS. The best predictor of PFS was Deauville 5-PS at PET1. PERCIST and %ΔTLG using gradient method trended toward significance. Conclusions: Deauville 5-PS best predicts PFS at PET1 in cHL. Neither baseline PET nor conventional prognostic factors correlated with PFS in this group of cHL pts. Risk-stratification of cHL using tumor metabolic volumetry and PERCIST criteria may require a larger sample size and further assessment of various methodologies. [Table: see text]
Correlation of chemotherapy delivery and survival outcomes of follicular lymphoma in the immunchemotherapy era.
Authors: Wudhikarn Kitsada , Button Anna M , Smith Brian J. , Habermann Thomas Matthew , Thompson Carrie A. , Cerhan James Robert , Link Brian K.
Published: March 2020

8563

Background: Optimal initial treatment of follicular lymphoma (FL) is unknown. Rituximab as monotherapy (R) or as a component of immunochemotherapy (R+Chemo) is established as effective and it is now reasonable to re-examine the role of chemotherapy dosing. We explored clinical features, systemic treatment and chemotherapy delivery with comparative effectiveness of delivered dose intensity (DDI) on outcomes. Methods: We reviewed the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource database along with medical records on newly diagnosed grade I-IIIa FL who received systemic therapy from 2002 to 2009. Presenting clinicopathologic factors, outcomes and systemic therapy details including doses of chemotherapy were collected. The event-free (EFS) and overall survival (OS) effects of systemic therapy and chemotherapy DDI were analyzed with multivariate Cox regression. Confounding effects of FLIPI, grade, stage, and age were considered in the analysis. Results: From 2002 to 2009, 631 newly diagnosed FL were enrolled. Median follow up duration was 52.7 months. We identified 322 grade I-IIIa FL treated with systemic therapy including 93 R and 229 R+Chemo. Age and stage were similarly distributed between the R and R+Chemo groups; however, patients in the R group had lower grade (p<0.01) and FLIPI (p=0.03). Multivariate analysis showed no significant differences in EFS (HR=1.24, p=0.28) or OS (HR=0.55, p=0.13) for R compared to R+Chemo. Among R-CVP or R-CHOP treated FL, DDI data were collected for 73 doxorubicin (dox) and 137 cyclophosphamide (cyc) patients. Eighty-five percent of patients received 90% or more pre-planned DDI. After controlling for confounding factors, higher cycDDI was associated with improved EFS (HR 0.55, P=0.04) and OS (HR 0.74, P=0.03). No significant OS or EFS effects of doxDDI were observed. Conclusions: Addition of chemotherapy to rituximab was not associated with a detectable difference in survival outcomes in grade I-IIIa FL at a median follow-up of 52.7 months. Among R+Chemo treated FL, chemotherapy was delivered completely in most patients and more completed delivery of cyclophosphamide was associated with improved EFS and OS.
A phase II study of gemcitabine, ifosfamide, and oxaliplatin (GIFOX) as upfront treatment for high-risk, non-anaplastic large cell, peripheral T-cell lymphomas.
Authors: Corazzelli Gaetano , Marcacci Gianpaolo , Frigeri Ferdinando , Capobianco Gaetana , Volzone Francesco , Becchimanzi Cristina , Donnarumma Daniela , Azzaro Rosa , De Filippi Rosaria , Russo Filippo , Pinto Antonio
Published: March 2020

8564

Background: Patients (pts) with peripheral T/NK cell lymphomas (PTCL) and intermediate-high/high IPI risk have a 5-yr overall survival < 20%. Current chemotherapy is unsatisfactory while benefit of upfront autologous transplantation (ASCT) is limited by high pre-transplant progression rates and pts advanced age. We evaluated efficacy and stem cells (SCs)-mobilizing activity of a biweekly regimen of gemcitabine (G), ifosfamide (Ifo) and oxaliplatin (Ox) (GIFOX), as an upfront strategy ensuring fast cytoreduction and early ASCT access or an effective alternative to CHOP-like programs in transplant-inelegible pts. Methods: Six biweekly courses of GIFOX [G 1000 mg/m2 D1, Ox 130 mg/m2 D2, Ifo 5 g/m2 D2 as 24h infusion (fractionated over days 2-4 in pts>65 yrs), G-CSF DD 7-11] were planned for all pts, with SCs mobilization at course 3 in ASCT-eligible pts. Simon's minimax two-stage design was adopted with the primary and secondary endpoints of response rate (RR) and progression-free survival (PFS), respectively. Results: Thirty-four pts (median age 63 yrs, r 42-80) [PTCL, nos (n=16), AITL (n=7), extranodal NK/T-cell (n=5), SS (n=6)], with IPI score intermediate-high (62%) or high (38%) were accrued [stage IV: 71%; BM involvement: 38%; E-site >1: 47%; hi LDH: 71%; ECOG>1: 38%; B-symptoms: 44%]. A total of 172 courses was delivered (median 6, r 2-6). Only 5 pts received <4 courses, due to progression (n=4) or early death (n=1). Overall RR was 82% [95% CI, 66-92; 22 complete (CR) and 6 partial (PR) responses]. Twelve pts mobilized SCs (median CD34+ cells harvest: 4.36x106/kg) and 8 (7CRs,1PR) underwent ASCT, 6 to 13 weeks after the 6th course. Estimated 5-yr PFS was 48% (95%CI: 28-65); median PFS for non-transplanted pts was 15 mo.s. Estimated 4-yr disease-free survival was 58%. Relevant toxicities were G4 thrombocytopenia (13%), G4 anemia (23%), G3/G4 infection (29%/6%), G3 encephalopathy (6%). Conclusions: Response and survival rates of GIFOX in high-risk PTCL compared more than favorably to CHOP-based regimens. Effective cytoreduction and prompt access to ASCT were ensured, together with safe delivery of a full induction program to transplant-ineligible pts.
The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial diffuse large B-cell lymphoma.
Authors: Murawski Niels , Zeynalova Samira , Held Gerhard , Ziepert Marita , Kempf Barbara , Viardot Andreas , Haenel Mathias , Witzens-Harig Mathias , Ruebe Christian , Fleckenstein Jochen , Zwick Carsten , Glass Bertram , Schmitz Norbert , Pfreundschuh Michael ,   German Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8566

Background: The role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement of aggressive B-cell lymphoma remains to be determined in the rituximab era. Methods: In a retrospective subgroup analysis of 9 consecutive prospective DSHNHL trials covering all DLBCL risk groups from 18 to 60 years of age, patients with and without craniofacial involvement were compared with respect to clinical presentation, event-free and overall survival. Results: 336 sites of extralymphatic craniofacial involvement were observed in 284/3840 (7.4%) patients (orbita: 30, paranasal sinuses: 90; main nasal cavity: 38, tongue: 26, remaining oral cavity: 99, salivary glands: 53). In a multivariable analysis adjusting for IPI risk factors the addition of rituximab improved EFS and OS in both patients with and without craniofacial involvement. The 141 responding patients who received radiotherapy to sites of craniofacial involvement had a similar 3-year event-free (79% vs 79%; p=0.835) and 3-year overall survival (88% vs. 85%; p=0.311) when compared with the 56 patients who did not receive radiotherapy. Without rituximab, the 2-year-rate of cumulative risk of CNS disease was increased in 205 patients with compared to 2586 patients without craniofacial involvement (4.2% vs. 2.8%; p=0.038), while this difference disappeared in patients who received CHOP(like) chemotherapy in combination with rituximab (1.7% in 77 patients with compared to 2.9% in 946 patients without craniofacial involvement; p=0.868). Of 85 patients with craniofacial involvement who received intrathecal prophylaxis with methotrexate, the 2-year-rate of cumulative risk of CNS disease was 4.3% compared to 2.3% in 189 patients who did not (p=0.995). Conclusions: Rituximab eliminates the increased risk for CNS disease in patients with craniofacial involvement. As a practical consequence intrathecal prophylaxis and radiotherapy to sites of craniofacial involvement should not be given any more.
Screening for coronary artery disease after mediastinal irradiation in Hodgkin lymphoma survivors.
Authors: Daniëls Laurien Aletta , Krol Augustinus , de Graaf Michiel A , Scholte Arthur JHA , Putter Hein , van t Veer Mars B , de Roos Albert , Schalij Martin J , Creutzberg Carien L.
Published: March 2020

8568

Background: Cardiovascular diseases are the most common non-malignant cause of death in Hodgkin Lymphoma (HL) survivors, especially those who had mediastinal irradiation as part of their treatment. We investigated the role of CT coronary angiography (CTA) as a screening tool for coronary artery disease (CAD) in asymptomatic HL survivors, related findings to stress testing and subsequent interventions. We also evaluated acceptance of screening. Methods: Patients were eligible if at least 10 years disease-free and treated with mediastinal radiotherapy. All patients were screened with ECG, stress testing and CTA. Primary endpoint was significant CAD (stenosis >50%) on CTA. A sample size of 50 patients would achieve ≥80% power to detect a difference of 13% (≥20% vs a population proportion of 7%) using a two-sided binominal test. Allowing for non-evaluable and false-positive scans, we considered CTA screening to be indicated for testing in a larger population if in ≥six patients revascularization would be necessary. Results: Fifty-two patients were included, 48 patients underwent CTA. Median age was 47 years, time since HL diagnosis 21 years. Most patients had no risk factors for CAD. There were 45 evaluable scans. Prevalence of significant CAD on CTA was found in 20% (N=9), and significantly increased compared to the 7% expected abnormalities (p=0.01, 95% CI 8.3-31.7%). In 5 of the 8 patients who underwent conventional angiography, significant CAD was confirmed, and revascularization performed. Two patients were started on medication. Stress testing was inaccurate for determining CAD: all participants were asymptomatic and 1 patient with significant CAD had signs of ischemia. Ninety percent of the participants were content with the screening offered in this study, regardless whether the CTA showed abnormalities or not. Conclusions: Prevalence of significant CAD among HL survivors is high. In our participants even the most severe and life-threatening CAD was not preceded by typical symptoms. In symptomatic cardiac patients revascularization improves survival. This might justify both screening by CTA and intervention in this asymptomatic population, but needs to be further evaluated in a larger cohort. Clinical trial information: NCT01271127.
A phase I dose-escalation trial of ublituximab (TG-1101), a novel anti-CD20 monoclonal antibody (mAb), for rituximab relapsed/refractory B-cell lymphoma patients.
Authors: Deng Changchun , Amengual Jennifer Effie , Schreeder Marshall T. , Clark-Garvey Sean , Patterson Molly , Miskin Hari , Sportelli Peter , O'Connor Owen A.
Published: March 2020

8575

Background: Anti-CD20 therapy (rituximab or RTX) in treating patients (pts) with B-cell lymphomas has resulted in significant improvement in treatment response and clinical outcomes. Despite advances, pts continue to relapse from, or are refractory to, RTX-based regimens. Ublituximab (UTX) is a novel, chimeric mAb targeting a unique epitope on the CD20 antigen. UTX has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, and therefore demonstrates greater ADCC activity than RTX (Le Garff-Tavernier, 2011). UTX displayed greater antitumor activity compared to RTX in NHL in vivo models and in low CD20 expressing tumors (ASH 2011). A phase I trial with UTX used as a single agent in pts with relapsed/refractory CLL reported a response rate of 45%. Herein we report on the phase I dose-escalation of UTX in pts with RTX relapsed/refractory B-cell lymphoma. Methods: Eligible pts have B-cell lymphoma relapsed or refractory to a RTX containing regimen. Pts are required to have measurable/evaluable disease, ECOG PS < 2 and no active hepatitis B/C. The phase I dose-escalation uses a sequential 3+3 design in dose cohorts of 450mg, 600mg and 900mg respectively. UTX is administered once weekly for 4 infusions followed by monthly maintenance therapy. PK and correlative PD data are being collected. Primary endpoint: Maximum Tolerated Dose (MTD) and Dose Limiting Toxicities (DLT). Efficacy is a secondary endpoint. Results: Nine pts (5 FL, 3 MZL, 1 MCL) have been enrolled (3 each cohort). Median age 63; 3/6 (M/F). Median prior Rx = 4 (2-6). RTX refractory (44%). 8/9 pts are evaluable for safety; no DLT’s observed and no Grade 3/4 AE’s to date. 7/9 pts have had at least one response assessment (8 wk scan), which includes: 1 CR (rituximab refractory MZL); 2 PR’s (1 MZL, 1 FL); 2 SD (FL) and 2 PD (1 transformed FL, 1 MCL). PK analysis is ongoing. Conclusions: UTX has been well tolerated to date with no G 3/4 AE’s with demonstrated early clinical activity at all doses. 7/9 patients continue to receive UTX treatment (range 1–25 wks). Enrollment in the 900mg expansion cohort is now open with an emphasis on RTX relapsed/refractory indolent or low CD20-expressing lymphomas. Clinical trial information: NCT01647971.
Effect of phosphotidylinositol 3-kinase-delta inhibitor idelalisib (GS-1101) on signaling in primary non-Hodgkin lymphoma cells: Correlative studies from NCT01306643.
Authors: Arita Adriana , Hanlon Katherine , Chkourko Halina , Lannutti Brian Joseph , Johnson David Michael , Gabrilove Janice Lynn , Scigliano Eileen , Parekh Samir S. , Brody Joshua
Published: March 2020

8579

Background: Studies of GS-1101, an oral phosphatidylinositol 3-kinase (PI3K)d-specific inhibitor, in heavily pre-treated patients with indolent-non-Hodgkin's lymphomas (iNHL) have shown marked clinical activity [Kahl BS, et al., Blood 2010]. We have shown that GS-1101 blocks both constitutive and inducible signaling events proximally downstream of PI3K [Lannutti BJ, et al., Blood 2011]. We hypothesized that flow-cytometric interrogation of PI3Kd-inhibition in iNHL samples might demonstrate signaling differences between patients that can be correlated with clinical outcomes. Methods: Single-cell suspensions of biopsy specimens from patients were incubated with or without GS-1101, B-cell receptor stimulated and stained with lineage markers and phospho-specific antibodies targeting signaling nodes proximally (e.g. pAkt S473) or distally (e.g. pS6 S235/6) downstream, or "parallel" to (e.g. pErk1/2) described PI3K pathways. Results: Healthy and iNHL B cells demonstrated complete or near-complete inhibition of PI3K proximal downstream signaling by GS-1101. PI3K distal downstream signaling was completely inhibited by GS-1101 in healthy B cells. The degree inhibition of distal downstream signaling was variable between iNHL patients. iNHL showed marked variability in the degree of PI3K distal downstream signaling amongst tumor cells within the same sample, suggesting an admixture of "PI3K-dependent“ and "PI3K-independent" tumor cells. We also observe variable PI3K-independence amongst other NHL histologies such as mantle cell lymphoma. Additionally, combining inhibition of PI3K with that of other signaling nodes shows additive distal downstream effects. Conclusions: We demonstrate that GS-1101 blocked both constitutive and invoked signaling proximally downstream of PI3K in primary iNHL cells. By correlating clinical outcomes in the ongoing study with signaling readouts between patients we may develop predictive rules for response. Ongoing studies will focus on studying the change in intratumoral cell subsets which develop in vivo as patients progress on PI3Kd inhibitor therapy.
Effect of a novel agent, SL-401, targeting interleukin-3 (IL-3)-receptor on plasmacytoid dendritic cell (pDC)-induced myeloma cell growth and drug resistance.
Authors: Chauhan Dharminder , Ray Arghya , Brooks Christopher , Rowinsky Eric K. , Anderson Kenneth Carl
Published: March 2020

8582

Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and drug resistance. The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in MM cells. Our recent study utilized in vitro and in vivo MM xenograft models to show that plasmacytoid dendritic cells (pDCs) were significantly increased in MM BM and promote MM growth (Chauhan et al., Cancer Cell 2009, 16:309). Importantly, we found increased IL-3 levels upon pDC-MM interaction, which in turn, trigger MM cell growth and pDCs survival. IL-3R is highly expressed on pDCs. We utilized SL-401, a novel biologic conjugate that targets IL-3R, to examine whether abrogation of IL-3–IL-3R signaling axis affects pDC-MM interaction and its tumor promoting sequelae. Methods: MM cell lines, patient MM cells, and pDCs from healthy donors or MM patients were utilized to study the anti-MM activity of SL-401. MM cells and pDCs were cultured alone or together in the presence or absence of SL-401, followed by analysis of cell growth or viability. Results: SL-401 significantly decreased the viability of pDCs at low concentrations (IC50: 0.83 ng/ml; P < 0.005, n = 3). SL-401 also decreased the viability of MM cells at clinically achievable doses. Co-culture of pDCs with MM cells induced growth of MM cell lines; and importantly, low doses (0.8 ng/ml) of SL-401 blocked MM cell growth-promoting activity of pDCs. MM patient-derived pDCs induced growth of MM cell lines and primary MM cells as well; conversely, SL-401 inhibited pDC-triggered MM cell growth (P < 0.005, n= 5). Tumor cells from 3 of the 5 patients were from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. In agreement with these results, SL-401 blocked pDC-induced growth of dexamethasone-resistant MM cell lines. Conclusions: Our study therefore provides the basis for directly targeting pDCs or blocking the pDC-MM interaction, as well as targeting MM, in novel therapeutic strategies with SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.
Quality of life (QOL) improvements for pomalidomide plus low-dose dexamethasone (POM + LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients (pts) enrolled in MM-003.
Authors: Song Kevin W. , Dimopoulos Meletios A. , Weisel Katja C. , Moreau Philippe , Lacy Martha , Delforge Michel , Karlin Lionel , Goldschmidt Hartmut , Banos Anne , Rocafiguera Albert Oriol , Hudgens Stacie , Yu Zhinuan , Sternas Lars , Jacques Christian , Zaki Mohamed H. , San-Miguel Jesùs F.
Published: March 2020

8583

Background: Poor prognosis and therapy exhaustion have been associated with reduced QOL in RRMM. In MM-003, a randomized, multicenter, open-label phase 3 trial, POM + LoDEX (n = 302) significantly improved progression-free and overall survival vs. high-dose dexamethasone (HiDEX; n = 153) in pts who failed lenalidomide (LEN) and bortezomib (BORT) and progressed on their last therapy. This analysis evaluated QOL changes in these pts. Methods: To assess pt-reported outcomes, cross-sectional and longitudinal analyses were performed. Minimal important differences for 5 clinically relevant EORTC QLQ-C30 domains (Global Health Status, Physical Functioning, Fatigue, Emotional Functioning, and Pain) were calculated as meaningful change thresholds (1 standard error of measurement) from baseline through cycle (C) 5. Time to QOL worsening was compared between arms using the Kaplan-Meier method. Results: Favorable trends were observed for POM + LoDEX vs. HiDEX in each of the 5 relevant domains. The cross-sectional analysis indicated statistically or marginally significant (P < .10) differences favoring POM + LoDEX in Global Health Status (C2, 4), Physical Function (C2, 3, 4), Emotional Function (C2, 3, 4), and Fatigue (C2) scores. Longitudinal comparisons between arms confirmed the significance of score changes for Global Health Status (C2; P = .01), Physical Functioning (C3 and 4; P = .018 and .028, respectively), Emotional Functioning (C3; P = .018), and Fatigue (C5; P = .008) for POM + LoDEX vs. HiDEX. HiDEX pts exhibited clinically meaningful worsening in Global Health Status and Physical Functioning scores vs. POM + LoDEX by C2 (P = .04) and C3 (P = .02), respectively. POM + LoDEX extended median time to meaningful worsening vs. HiDEX for Global Health Status (114 vs. 85 days, P = .05), Physical Functioning (174 vs. 106 days; P = .09), Fatigue (113 vs. 60 days; P = .02), Emotional Functioning (190 vs. 124 days; P = .04), and Pain (147 vs. 113 days; P = .2). Conclusions: In heavily pretreated pts who failed LEN and BORT, POM + LoDEX resulted in better clinical outcomes as well as improvement in clinically relevant QOL measurements over the course of treatment. Clinical trial information: NCT01311687.
MM-008 trial: Pharmacokinetics (PK) and tolerability of pomalidomide plus low-dose dexamethasone (POM plus LoDEX) in relapsed/refractory multiple myeloma (RRMM) patients with renal impairment (RI).
Authors: Matous Jeffrey , Siegel David Samuel DiCapua , Duong Hien Kim , Kasserra Claudia , Sternas Lars , Jacques Christian , Klesczewski Kenneth , Zaki Mohamed H. , Shah Jatin J.
Published: March 2020

8585^

Background: POM + LoDEX has shown significant clinical activity in RRMM pts including those refractory to lenalidomide and bortezomib. Renal impairment is a common comorbidity for MM pts, occurring in > 40%. POM is extensively metabolized with less than 5% renally eliminated as parent drug. Thus, renal function may not substantively affect parent drug exposure. Previous POM trials excluded pts with severe renal impairment. MM-008 is a phase 1, multicenter, open-label study designed to assess the PK and safety of POM + LoDEX in RRMM pts and normal or impaired renal function. Methods: RRMM pts (≥ 1 prior therapy [Tx]) with creatinine clearance (CrCl) ≥ 60 ml/min (cohort A) or severe renal impairment (CrCl < 30 ml/min [cohort B]) not requiring dialysis were included. Cohort A received POM 4 mg and cohort B received POM 2 mg or 4 mg D1-21/28-day cycle following a standard 3 + 3 dose-escalation design. Both cohorts received DEX 40 mg (20 mg for pts aged > 75 y) D1, 8, 15, and 22. Cohort C will assess pts with severe renal impairment (CrCl < 30 ml/min) requiring dialysis (up to 14 pts planned). Pts were not permitted to enroll in more than 1 cohort. G-CSF was not permitted in cycle 1. Tx continued until progressive disease or unacceptable toxicity. Results: As of Feb 5, 2013, 11 pts have been treated (8 pts in cohort A; 3 pts in cohort B at 2 mg). Age ranged from 46-71 y (cohort A) and 57-64 (cohort B). 5 pts were aged > 65 y in cohort A (aged 66, 69 [n = 3], and 71 y); none in cohort B. 7 pts in cohort A have received > 1 cycle of Tx; 5 pts have received ≥ 3 cycles. One pt in cohort B has received > 3 cycles. All 3 pts in cohort B have completed 1 full cycle of Tx with no dose-limiting toxicities reported. Dose escalation is planned. The most common grade 3/4 adverse events (AEs) in cohort A were neutropenia (n = 3) and pneumonia (n = 2). No grade 3/4 AEs have been observed for pts in cohort B to date. POM dose reduction due to AE occurred in 2 pts (both in cohort A), all pts remain on study. PK and updated AE data will be presented at the meeting. Conclusions: MM-008 is an ongoing trial evaluating PK and safety in pts with renal impairment. Early tolerability data are encouraging. Clinical trial information: NCT01575925.
Profile of multiple myeloma in the inner city: Disease presentation and clinical course.
Authors: Goldrich Adam , Melanthiou Andriane , Kriplani Anuja , Helzner Elizabeth , Babu Arvind , Fein Daniel , Sidhu Juhee , Gonsky Jason Parker , Batuman Olcay
Published: March 2020

8594

Background: Multiple myeloma (MM) is the most common hematologic neoplasm in blacks in the US. Based on SEER data of all Americans, the disease is more common in men, has a median diagnosis age of 70 and median survival of 3-6 years. The subclinical syndrome MGUS precedes MM, and blacks have a 2-3-fold higher risk of developing MGUS and MM. Further, recent improvements in survival observed for white patients are not observed in blacks. To gain new insight into pathogenesis and to optimize patient care, we characterized our inner city, largely Caribbean-African population in Brooklyn, NY, in terms of disease presentation and course. Methods: MM patients were identified by tumor registries based on histopathology. Data including survival were collected from records of patients diagnosed between 2001-2011 (n=242). Data analysis was performed using SPSS Advanced Statistics. Results: Median age was 64 (range 35-91), male: female ratio was 0.70. The most common presenting pathology was the presence of multiple skeletal lesions with fractures (67% of patients). Spinal cord compression and spinal compression fractures occurred in 33% and 32% of patients, respectively. Renal disease was present in 26%, indicated by serum creatinine >2 mg/dL. Consistent with advanced stage and renal failure, median serum beta-2 microglobulin was 4.25 (range 0.96-82.8). Chromosome banding and FISH was available on 133 patients and showed no cytogenetic abnormalities in 53%; hyperdiploidy (30.4%). Common trisomies included chr 1, 5, 15 and 19. Other abnormalities were del 13 (13%) and chr 14 translocations (11%). Comorbidities include hypertension (65%), diabetes (35%) and obesity (BMI over 30 in 24%). While recent improvements in acquiring health insurance have improved access, less than 10% of patients received HDCT and ASCT. As of October 1, 2012, 36% of all patients are living. Survival analyses are underway. Conclusions: MM presents at an advanced stage and affects younger AA’s in the Downstate community. Strategies for identifying and treating patients with progressive MGUS and at earlier disease stages may enhance survival.
Altered cytokine profiles in multiple myeloma (MM) and precursor disease: Predictors of progression and potential targets for treatment.
Authors: Tageja Nishant , Wang Weixin , Plyler Ryan , Corrigan-Cummins Meghan , Korde Neha , Manasanch Elisabet E. , Bhutani Manisha , Kwok Mary , Flanders Aaron W. , Zuchlinski Diamond , Mulquin Marcia , Costello Rene , Roschewski Mark J. , Landgren Ola , Calvo Katherine R. , Zingone Adriana
Published: March 2020

8597

Background: Presently, there is no reliable biomarker for predicting clinical progression from smoldering (SMM) to symptomatic MM for individual patients. To improve our understanding on the pathogenesis from SMM to MM, we conducted a screening study of circulating cytokines using peripheral blood (PB) and bone marrow supernatant (BM) collected from treatment naïve SMM and MM patients as well as healthy donors as controls. Methods: PB samples from 14 SMM and 38 MM patients and 7 controls and BM obtained from 17 MM patients and 9 controls were assayed in duplicates using ultra-sensitive Human TH1/TH2 10-plex multi-spot plate and multi-array plate for interleukin-(IL)-6. Two-tailed Mann-Whitney test was used for statistical analysis. Results: PB of SMM patients (vs controls) had increased levels of several cytokines, including IL-8 (p=0.008) and IFN-gamma (p=0.002). In PB, MM patients (compared to SMM patient and controls) had increased levels of IL-6 (p=0.006 and 0.001, respectively), IL-8 (p=0.0001 and 0.008), IL-10 (p=0.02 and 0.02), TNF-alpha (p=0.01 and 0.009), and IFN-gamma (p=0.01 and 0.02). Analysis of BM revealed a similar profile with increased levels of IL-2, IL-6, IL-8, and TNF-alpha in MM patients compared with controls (p=0.007, p=0.0003, p=0.0001 and p=0.0008). Conclusions: We found significantly increased levels of key cytokines associated with progressive disease state (controls→SMM→MM). Patterns of cytokines were similar in BM and PB, suggesting that serum based cytokines may have a future role as biomarkers for disease progression, and could potentially be assessed as novel targets for treatment.