bluuebunny/crossref_metadata_2025 huggingface dataset:
Tolerability and activity of combinations of the PI3Kδ inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL): Updated results from a phase I study.
Authors: Leonard John , Wagner-Johnston Nina D. , Coutre Steven E. , Flinn Ian , Schreeder Marshall T. , Fowler Nathan Hale , Sharman Jeff Porter , Boccia Ralph V. , Barrientos Jacqueline Claudia , Rai Kanti Roop , Boyd Thomas E. , Furman Richard R. , Holes Leanne , Johnson David Michael , Kim Yeonhee , Dansey Roger D. , Godfrey Wayne R. , De Vos Sven
Published: March 2020

8500

Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in recurrent iNHL (Kahl, ICML 2011), as well as combination therapy (Fowler, ASCO 2012). Methods: This phase I study evaluated the activity of continuous (48 weeks) idelalisib (Id), 100/150 mg BID, in combination with rituximab (R) (375 mg/m2 weekly x 8 doses) (Id+R), with bendamustine (B) (90 mg/m2 x 2, for 6 cycles) (Id+B), or in combination with R (375 mg/m2 monthly x 6) and B (90 mg/m2 x 2), for 6 cycles (Id+BR). Investigators assessed response according to standard criteria (Cheson 2007). Patients who continued to benefit were able to enroll on an extension study. Results: Study enrolled 78 pts with relapsed/refractory iNHL, with 34 (44%) pts continuing on treatment in the ongoing extension protocol. The 3 cohorts included Id+R (N=30), Id+B (N=34), and Id+BR (N=14). Pts were 67% male, median age [range] of 62 [37E84] years, 41% with refractory disease, 88% stage III/IV, and 36% of FL with high FLIPI scores. The median [range] number of prior therapies was 3 [1E10]. The median [range] duration of treatment was 10.6 [0.5-29.2] months. Overall response rate (ORR) was 63/78 (81%), with 22/78 (28%) CR. The ORR/CR for Id+R was 77%/20%, Id+B was 85%/29%, and Id+BR was 79%/43%. At 20 months, the PFS was 66%. For responders, 73% were progression-free at 20 months. Most common adverse events included (total%/≥G3%) pyrexia (56/4), fatigue (45/4), nausea (41/0), rash (40/8), cough (37/0), diarrhea (36/8), chills (18/0), URI (18/1), and pneumonia (17/15). Lab abnormalities included (total%/≥G3%) ALT/AST elevations (56/17). Conclusions: Idelalisib-based combination therapy is highly active and well tolerated in patients with relapsed/refractory iNHL. These data support further clinical development. Phase III trials evaluating the efficacy of idelalisib in combination with R, or BR in iNHL are ongoing (NCT01732913, NCT01732926). Clinical trial information: NCT01732913, NCT01732929.
Preventing hepatitis B reactivation in HBsAg-positive patients with untreated diffuse large B-cell lymphoma with R-CHOP chemotherapy: A prospective study to compare entecavir and lamivudine.
Authors: Huang He , Li Xue Ying , Li Hao Ran , Shrestha Dr.Prem Raj , Guo Cheng-cheng , Liang Chao Yong , Liu Tingzhi , Zhang Mengping , Hong Huang Ming , Lin Jia Tian , Huang Jia Jia , Tian Ying , Lin Tongyu
Published: March 2020

8503

Background: Hepatitis B reactivation is a serious complication in lymphoma patients treated with rituximab-contained chemotherapy despite lamivudine prophylaxis. The optimal prophylactic antiviral protocol is undetermined. This prospective study was designed to compare the efficacy of prophylactic entecavir and lamivudine in preventing hepatitis B reactivation in HbsAg-positive patients with untreated diffuse large B cell lymphoma (DLBCL) under R-CHOP treatment. Methods: HBsAg carriers with untreated DLBCL, normal liver function and low serum HBV DNA levels (less than 103copys/ml)were randomized to receive entecavir or lamivudine during R-CHOP treatment and for 6 months after completion of chemotherapy. HBsAg, HBsAb, HBeAg, HBeAb and HBcAb were performed prior to initiation of treatment. Serum alanine aminotransferase (ALT), and HBV-DNA levels were prospectively monitored before every cycle of chemo and every month after completion of chemotherapy. Results: Between February 2008 and December 2012, a total of 229 patients older than 18y with newly diagnosed DLBCL were included. The present analysis is based on 121 HBsAg-positive patients, including 61 patients randomly assigned to entecavir and 60 patients to lamivudine .The primary efficacy end point was the incidence of HBV-related hepatitis. The secondary end point was chemotherapy disruption due to hepatitis. Compared with the lamivadine group, the entecavir group had significantly lower rates of hepatitis(8.2% vs 23.3%,P=0.022), hepatitis B reactivation (0 vs 13.3%,P=0.003),HBV reactiviation(6.6% vs 30.0%,P=0.001), delayed HBV-related hepatitis (0 vs 8.3%,P=0.027) and disruption of chemotherapy (1.6% vs 18.3%,P=0.002). 7 of 8 patients with hepatitis B reactivation had advanced stage(III–IV) disease. Conclusions: In HBsAg-positive DLBCL patients undergoing R-CHOP chemotherapy, entecavir is more effective than lamivudine in preventing hepatitis B reactivation. For patients with advanced stage disease, entecavir should be considered the primary preventive therapy. Clinical trial information: CTR-TRC-11001687.
Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients.
Authors: Boccadoro Mario , Cavallo Federica , Gay Francesca Maria , Di Raimondo Francesco , Nagler Arnon , Montefusco Vittorio , Patriarca Francesca , Tacchetti Paola , Guglielmelli Tommasina , Musto Pellegrino , Baldini Luca , Crippa Claudia , Ruggeri Marina , Gentilini Fabiana , Cavalli Maide , Ben Yehuda Dina , Caravita Tommaso , Ciccone Giovannino , Hardan Izhar , Palumbo Antonio
Published: March 2020

8509

Background: The incorporation of new drugs into induction, consolidation, and maintenance therapy is changing the treatment paradigm of MM. Methods: At diagnosis, 402 pts (< 65 years) were randomly assigned to receive six MPR cycles (N=202) or tandem MEL200 (N=200). After MPR or MEL200, pts were further randomized, within each group, for no maintenance (N=204) or lenalidomide maintenance (N=198). A 2x2 factorial randomized trial was designed. The primary end point was PFS. An enrolment of 170 pts/arm was required to demonstrate a 15% improvement of PFS at 2 years (2-sides a = 0.05, 1- β 80%). Results: After a median follow-up of 45 mos from diagnosis, the median PFS was 25 mos with MPR and 39 mos with MEL200 (p=.0002). Median PFS were 37.5 mos for maintenance and 25.7 mos for no maintenance (p=.0008). The 4-year OS from diagnosis was 71% with MPR and 72% with MEL200 (p=0.71), 76% for maintenance and 68% for no maintenance (p=.08). After a median follow-up of 32 mos from start of maintenance, the median PFS was for 41 mos for maintenance and 18 mos for no maintenance (p<.0001). The 3-year OS from start of maintenance was 81% for maintenance and 72% for no maintenance (p=.04). Conclusions: MEL200 significantly prolonged PFS in comparison with MPR. Lenalidomide maintenance significantly reduced the risk of progression independently from the previous treatment. OS is similar between MPR and MEL200, with a trend for an improved OS in pts receiving lenalidomide as maintenance therapy. Clinical trial information: NCT00551928. [Table: see text]
Prognostic value of deep sequencing method for minimal residual disease (MRD) detection in multiple myeloma.
Authors: Martinez-Lopez Joaquin , Garcia-Sanz Ramon , Pepin Francois , Ayala Rosa , Montalban Maria Angeles , Paiva Bruno , Weng Li , Barrio Santiago , Montejano Laura , Rapado Immaculada , Martinez Rafael , Blachard Maria Jesus , Sanchez-Godoy Pedro , Blade Joan , San-Miguel Jesùs F. , Faham Malek , Lahuerta Juan José
Published: March 2020

8511

Background: Most multiple myeloma (MM) patients will relapse due to persistence of residual tumor cells, or MRD. We compared the prognostic value of traditional response criteria and MRD measurement by a sequencing-based method, LymphoSIGHT, and multiparameter flow cytometry (MFC) in a cohort of 68 uniformly-treated MM patients from the Spanish Myeloma Group trials. Methods: Bone marrow samples were obtained from 68 patients at diagnostic and post-treatment time points on GEM clinical trials (GEM00 and GEM05). All patients were in CR or VGPR at the post-treatment time point. Using sequencing, we identified clonal rearrangements of immunoglobulin (IGH-VDJ, IGH-DJ, and IGK) genes in diagnostic samples. We assessed MRD in follow-up samples, analyzed concordance between sequencing and MFC MRD results, and compared the prognostic value of each method with traditional response criteria. Results: The sequencing assay detected a myeloma-specific gene rearrangement in diagnostic samples from 59 of 68 (87%) patients. We tested MRD in follow-up time points in 56 of the 59 patients. We observed high correlation between MFC and sequencing MRD results (r2=0.86), with MFC underestimating the myeloma burden (Slope=0.4). Of the 56 patients, 45 were positive by sequencing at MRD levels of 10-5 or higher and 11 were MRD negative. There was significantly improved overall survival (OS) in the MRD negative group versus the MRD positive group (median not reached vs. 86 mos, p=0.026). Similar differences were found in progression free survival. When limiting the analysis to the 35 patients in conventional CR, 24 of 35 patients were positive by sequencing at MRD levels at 10-5 and higher and 10 were MRD negative. There was significantly improved OS in the MRD negative group versus the MRD positive group (median not reached vs. 80.92 mos, p=0.041). Conclusions: Our data shows high correlation between MFC and sequencing MRD levels in MM patients. For patients in CR by traditional response criteria, the presence or absence of MRD by sequencing delineated 2 groups of patients with significantly different OS. MRD negativity by sequencing may be a better prognostic indicator than CR by traditional response criteria.
Final results of a phase I study of idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase P110δ (PI3Kδ), in patients with relapsed or refractory mantle cell lymphoma (MCL).
Authors: Spurgeon Stephen Edward Forbes , Wagner-Johnston Nina D. , Furman Richard R. , Flinn Ian , Coutre Steven E. , Brown Jennifer R. , Benson Don M. , Byrd John C. , Leonard John , Peterman Sissy , Johnson David Michael , Gu Jessie , Dansey Roger D. , Godfrey Wayne R. , Kahl Brad S.
Published: March 2020

8519

Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ. Initial response rate of 42% was previously reported in MCL (Kahl, ICML 2011). Long-term follow-up is now presented. Methods: This phase 1 study evaluated the activity of continuous (48 weeks) idelalisib monotherapy in pts with relapsed or refractory hematologic malignancies. Doses ranged from 50 mg BID to 350 mg BID in 8 cohorts. Response was based on investigator assessments using standard criteria (Cheson et al, 2007). Patients who continued to benefit were able to enroll in an extension study. Results: 40 patients with recurrent MCL enrolled. Patients were 88% male, median age [range] of 69 [52-83] years, 43% with refractory disease. The median [range] number of prior therapies was 4 [1E14]. The median [range] duration of idelalisib treatment was 3.5 [1-26+] months, with 6 (15%) patients continuing on treatment in the extension protocol. Overall response rate (ORR) was 16/40 (40%), with 2/40 CR (5%). The median duration of response (mDOR) was 2.7 months, and median PFS (mPFS) was 3.7 months. The 1-year PFS was 22%. For patients dosed with ≥100 mg BID, ORR was 12/23 (52%), for patients dosed with ≥150 mg BID, ORR was 11/16 (69%) including both CR (12.5%). Most common adverse events included (total%/≥G3%); diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (25/3), decreased appetite (20/15), URI (20/0), and pneumonia (13/13). Abnormal lab values included (total%/≥G3%) ALT/AST elevations (65/20). 6/40 (15%) patients discontinued therapy due to AEs, potentially treatment related. Conclusions: The oral PI3Kδ inhibitor idelalisib (GSE1101) is active and well tolerated in heavily pre-treated pts with MCL. A proportion of patients have long-term (>1 year) clinical benefit. These data support further clinical evaluation of idelalisib in MCL. Clinical trials with idelalisib in combination with other agents are in progress. Clinical trial information: NCT00710528.
Final results of a phase I study of idelalisib, a selective inhibitor of PI3Kδ, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL).
Authors: Benson Don M. , Kahl Brad S. , Furman Richard R. , Brown Jennifer R. , Wagner-Johnston Nina D. , Coutre Steven E. , Spurgeon Stephen Edward Forbes , Byrd John C. , Leonard John , Peterman Sissy , Johnson David Michael , Cho Yoonjin , Dansey Roger D. , Godfrey Wayne R. , Flinn Ian
Published: March 2020

8526

Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells, plays a role in homing and retention in lymphoid tissues, and is hyperactive in many B-cell malignancies. Idelalisib (GS-1101) is a first-in-class, selective, oral inhibitor of PI3Kδ. Initial response rate of 38% was reported previously in iNHL (Kahl, ICML 2011). Long-term follow-up is now presented. Methods: This phase 1 study evaluated the activity of continuous idelalisib monotherapy in pts with relapsed hematologic malignancies. Doses ranged from 50 to 350 mg QD or BID in 8 cohorts. Response was evaluated based on investigator assessments using standard criteria (Cheson, 2007). Pts who continued to benefit were able to enroll in an ongoing extension study. Results: Study enrolled 64 pts with indolent iNHL. iNHL subtypes included 38 FL, 11 SLL, 9 LPL/WM, and 6 MZL. Pts were 69% male, median age [range] of 64 [32E91] years, 58% with refractory disease and 53% with bulky disease (LN diameter ≥5 cm). The median [range] number of prior therapies was 4 [1E10]. The median [range] duration of treatment was 3.8 [0-41] months, with 19 (30%) pts continuing on treatment extension protocol. ORR across all cohorts were 31/64 (48%), with 1 CR (1.6%). The median duration of response (mDOR) was 18.4 months, and median PFS (mPFS) was 7.6 months. For pts dosed with ≥100 mg BID (N=36); the ORR was 24/36 (67%), the mDOR was 15.4 months, and the mPFS was 16.6 months. The ORR for iNHL subtypes was: FL (45%), SLL (64%), LPL/WM (56%), and MZL (33%). Adverse events included (total%/≥G3%) diarrhea (36/8), fatigue (36/3), rash (27/3), nausea (25/2), pyrexia (20/3), chills (20/0), cough (19/2), pneumonia (17/16), and URI (17/0). Lab abnormalities included (total%/≥G3%) ALT/AST elevations (56/25). 8/64 (12.5%) pts discontinued therapy due to potentially treatment-related adverse events. Conclusions: The oral PI3Kδ inhibitor idelalisib is active in heavily pretreated pts with iNHL, can produce durable responses, and has a favorable safety profile. These data support further clinical development; phase 2 and 3 trials in iNHL are ongoing (NCT01732913, NCT01732926). Clinical trial information: NCT00710528.
Pomalidomide plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM): MM-003 analysis of patients (pts) with moderate renal impairment (RI).
Authors: Weisel Katja C. , Dimopoulos Meletios A. , 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. , San-Miguel Jesùs F.
Published: March 2020

8527

Background: Pts who have exhausted lenalidomide (LEN) and bortezomib (BORT) treatment (Tx) have a poor prognosis. A significant proportion of pts have RI with increasing incidence during disease course. POM + LoDEX has demonstrated efficacy in pts with prior LEN and BORT, including those with RI. MM-003 is an open-label, multicenter, phase 3 trial comparing POM + LoDEX vs HiDEX in RRMM pts who failed LEN and BORT and progressed on their last Tx. Methods: Pts must have failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination) and must have been refractory to last prior Tx (progressive disease [PD] during Tx or within 60 days). Pts with creatinine clearance (CrCl) < 45 mL/min were excluded. Randomization was 2:1 to POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) qw; or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20 (28-D cycles). Tx continued until PD or unacceptable adverse event (AE). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and AEs. This analysis examined pts with or without moderate RI (CrCl < 60 vs ≥ 60mL/min). Results: 302 pts received POM + LoDEX; 153 pts received HiDEX, 31% and 39% had moderate RI, respectively. Pts with moderate RI were more likely to be older (64% vs 36% aged > 65 y) vs no RI. Median follow-up was 4 mo. Median PFS and OS were significantly longer with POM + LoDEX vs HiDEX regardless of RI (Table). Similar AE rates for POM + LoDEX as well as HiDEX Tx were seen in pts with and without moderate RI (Table). Discontinuation due to AE was 5% vs 7% (no moderate RI) and 11% vs 5% (moderate RI). Conclusions: POM + LoDEX significantly extended PFS and OS vs HiDEX in pts with or without moderate RI. Tolerability of POM + LoDEX was acceptable across subgroups, with few discontinuations due to AE. Clinical trial information: NCT01311687. [Table: see text]
Final results from the phase Ib/II study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in patients with relapsed or progressive multiple myeloma.
Authors: Wang Michael , Martin Thomas , Bensinger William , Alsina Melissa , Siegel David Samuel DiCapua , Kavalerchik Edward , Niesvizky Ruben
Published: March 2020

8529

Background: Carfilzomib (CFZ) is approved in the US as single-agent treatment for patients with multiple myeloma (MM) who have progressed after bortezomib (BTZ) and an IMiD and are refractory to last line of treatment. We previously reported interim data from PX-171-006 (NCT00603447), a Ph 1b/2 study of CRd in relapsed or progressive MM (Wang et al. ASCO 2011). Herein we report final results. Methods: Patients (1–3 prior treatments) received CRd in 28-day (D) cycles—CFZ IV on D1, 2, 8, 9, 15, 16, lenalidomide (LEN) PO D1–21, and dexamethasone (dex) wkly. In phase 1, CFZ (15–27 mg/m2) and LEN (10–25 mg) doses were escalated to determine the maximum tolerated dose (MTD) with a maximum planned dose (MPD) of CFZ 20 mg/m2 D1, 2 of Cycle 1 and 27 mg/m2 thereafter, LEN 25 mg/d, and dex 40 mg/wk, followed by phase 2 expansion at MTD/MPD. Endpoints included IMWG overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled since June 2008. Overall, prior treatment included BTZ (77%/18% refractory) and LEN (70%/35% refractory); 20% had high-risk cytogenetics/FISH. MTD was not reached in Ph 1, supporting expansion at the MPD (n=52, 23% BTZ refractory and 42% LEN refractory). As of Nov 2012 (median follow-up 24.4 mo): ORR was 69% overall and 76.9% at MPD with very good partial response in 36.9% and 38.5% and stringent complete response in 3.6% and 3.8%, respectively; median DOR was 18.8 (95% CI 9.7–41.5) and 22.1 mo (95% CI 9.5–NE) respectively; median PFS was 11.8 (95% CI 7.6–20.7) and 15.4 mo (95% CI 7.9–NE), respectively. Seven responders at MPD pursued other therapy and were censored for PFS.A median of 8.5 (range 1−46) CFZ cycles were started; 4% required CFZ dose reductions; 15% discontinued CFZ due to adverse events (AEs). Grade 3/4 AEs were generally consistent with earlier studies in advanced MM that used similar doses of single-agent CFZ; grade 3/4 peripheral neuropathy was 1%. Conclusions: CRd was well tolerated, providing robust and durable responses in this pt population where 35% were LEN refractory. This combination is being further evaluated in several ongoing phase 2/3 trials. Clinical trial information: NCT00603447.
Changes in the tumor microenvironment associated with transformation in follicular lymphoma.
Authors: Smeltzer Jacob Paul , Jones Jason Michael , Ziesmer Steven , Grote Deanna , Yang Zhi Zhang , Novak Anne , Xiu Bing , Ristow Kay , Ansell Stephen Maxted
Published: March 2020

8538

Background: Follicular lymphoma (FL) is a heterogeneous disease with a variable prognosis. Transformation to an aggressive lymphoma is associated with a poor prognosis. Previous studies have identified tumor microenvironment cells such as CD68+ macrophages, PD-1+ and FOXP3+ cells as prognostic in FL. However, results have been conflicting and infrequently address the risk of transformation. In this study we analyzed various components of the microenvironment and their association with transformation. Methods: Patients with FL that later transformed were identified through Mayo Clinic lymphoma database. Tissue specimens at diagnosis were stained with CD68, CD11c, CD21, CXCL13, FOXP3, PD-1 and CD14 and characterized by pattern of location and semi-quantitative cell content. Time to transformation (TTT) and overall survival (OS) were assessed by Kaplan-Meir analysis. Significant variables were further analyzed by cox proportional hazards model. Results: 58 patients were included with a median TTT of 4.7 years (range, 0.4-20). Presence of CD14+ cells vs absence and their location (follicular vs non-follicular) were associated with shorter TTT (4.5 vs 6.2 yrs., p=0.037 and 3.8 vs 5.9 yrs. p= 0.027, respectively). The quantity of PD-1+ cell content was not associated with TTT or OS. However, localization of PD-1 to the follicle compared to diffuse was associated with a longer TTT (6.1 vs 3.6 yrs. p=0.033) and superior OS (9.7 vs 4.6 yrs. p=0.009). On multivariate analysis, the pattern of CD14 and PD-1 staining remained significantly associated with shorter TTT (Table). Conclusions: In follicular lymphoma, a diffuse pattern of PD-1+ cells is associated with inferior TTT and OS. CD14+ cells localized to the follicle is associated with a shorter TTT. After accounting for FLIPI score, both these factors remained significant. These results identify two independent predictors of the rate of transformation in follicular lymphoma and suggest it is location rather than quantity of CD14+ or PD-1+ cells that influence outcomes. [Table: see text]
Total therapy 5 (TT5) for newly diagnosed high-risk multiple myeloma (HRMM): Comparison with predecessor trials total therapy 3a and 3b (TT3 a/b).
Authors: Usmani Saad Zafar , Waheed Sarah , Van Rhee Frits , Mitchell Alan , Restrepo Alejandro , Grazziutti Monica , Crowley John , Barlogie Bart
Published: March 2020

8539

Background: HRMM has not benefited from advances achieved in the remainder 85% with low-risk MM. In order to guard against relapses during previous drug-free intervals in TT3, TT5 was designed as a dose-dense and less dose-intense program. Here we are reporting for the first time on the TT5 outcomes in comparison with TT3a/b results in HRMM. Methods: TT5 called for M-VTD-PACE induction with HPC collection. This was followed by tandem autologous stem cell transplants (ASCT) with hybrid regimens Mel80 plus VRD-PACE, sandwiched in between were 2 inter-transplant cycles of MEL20-VTD-PACE. Maintenance consisted of 3 years of alternating VRD and VMD (M, melphalan). As relapses were observed during maintenance, bortezomib was increased from 1.3mg/m2 to 1.5mg/m2 weekly. Results were compared with HRMM treated with TT3a/b (n=40/37). Data were compared with TT3 HRMM, involving 77 patients. Overall survival and progression free survival was analyzed employing Kaplan-Meier curves. Cox regression modeling was done for univariate and multivariate analyses. Results: Of 59 patients enrolled in TT5, CR was 66% including 10% with s-CR. The 18-mo OS was 92% v 74% with TT3 (p=0.009), whereas PFS was similar at 67% and 69%, respectively. A newly developed GEP-5 model distinguished 8 patients with a 36-mo OS estimate of 20% versus almost 90% for the remainder (p=0.04). On multivariate analysis that included TT5 and TT3, our GEP80 low-risk score, TT5 (vs TT3) and age <65yr were independent features linked to superior OS. Conclusions: This isthe first report of a dose-dense chemotherapeutic approach for newly diagnosed HRMM, which also introduced a hybrid Mel80-VRDPACE hybrid preparative regimen for ASCT. TT5 represents an advance in the management of GEP70-defined HRMM compared to predecessor trials TT3a/b for similar patients, with significant improvement in overall survival and tolerability compared with TT3 a/b. Clinical trial information: NCT00081939, NCT00572169, NCT00869232.
The LIMD1-MYBL1 index as a composite marker for subtype classification and survival prediction for diffuse large B-cell lymphoma patients.
Authors: Xu Qinghua , Tan Cong , Ni Shujuan , Yuan Lin , Wu Fei , Liu Fang , Ye Xun , Meng Xia , Sheng Weiqi , Du Xiang
Published: March 2020

8547

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas with wide variations in patient survival. Through gene expression profiling, DLBCL can be stratified into two major cell-of-origin subtypes with distinct prognoses: the favorable germinal center B-cell-like (GCB) and the unfavorable activated B-cell-like (ABC) DLBCLs. However, the current cell-of-origin signatures are not suitable for use in routine clinical practice. Our study aimed to identify a novel biomarker to facilitate the translation of research into clinical practice. Methods: We performed an integrative analysis of seven independent cohorts comprising 1,682 patients. The DLBCL-1 cohort was used for signature identification. The identified signature was then tested in the DLBCL-2 to DLBCL-7 cohorts. Results: Two genes (LIMD1 and MYBL1) were significantly differentially expressed between the ABC and GCB subtypes. We integrated these genes into a composite marker, the LIMD1-MYBL1 Index. In seven independent cohorts, the average concordance rate between the LIMD1-MYBL1 Index and the cell-of-origin signature classification was 87% (range, 77% to 94%). Furthermore, the LIMD1-MYBL1 index is an independent prognostic factor for patients from different populations and for patients treated with a variety of therapies (Table). Conclusions: We identified the LIMD1-MYBL1 Index that has clinical value for DLBCL subtype classification and prognosis. Although little is known about the oncogenic roles of these genes, our findings prompt further research on the molecular mechanisms of DLBCL. [Table: see text]
Dexabeam versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T-cell lymphoma: A retrospective evaluation of parallel patient cohorts of one center.
Authors: Mikesch Jan-Henrik , Kuhlmann Mareike , Demant Angela , Krug Utz , Schmidt Eva , Kessler Torsten , Schliemann Christoph , Pohlen Michele , Mohr Michael , Koehler Gabriele , Wessling Johannes , Mesters Rolf M. , Mueller-Tidow Carsten , Berdel Wolfgang E. , Thoennissen Nils Heinrich
Published: March 2020

8548

Background: High-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T-cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. Methods: We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline based first-line chemotherapy who received either DexaBEAM (n=16) or ICE (n=15) regimen as first salvage chemotherapy followed by HDT and ASCT between 1996 and 2009. The median patient age was 46 years (range, 18-66) in the DexaBEAM group and 40 years (range, 17-59) in the ICE group. Patients were included independent of WHO stage and IPI score. Results: The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%) as compared to the ICE group (20%; P=0.01), with higher complete response (CR; 38% vs. 7%) as well as partial response (PR; 31% vs. 13%) rate. Changing regimen due to failure of the first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in 3 patients receiving ICE after DexaBEAM failure only 1 patient achieved an OR (1 PR). Median progression-free survival (PFS) was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P=0.01). Median overall survival (OS) was not different between the two groups (22.8 vs. 29.8 months; P=0.72), most likely due to the good response rate of patients to DexaBEAM as 2nd salvage regimen after failure of ICE chemotherapy. Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. Conclusions: In this retrospective comparison DexaBEAM salvage chemotherapy was superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.
Phase I study of a novel humanized anti-CD20 antibody, BM-ca, in patients (pts) with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) pretreated with rituximab.
Authors: Tobinai Kensei , Ogura Michinori , Maruyama Dai , Suzuki Tatsuya , Kobayashi Yukio , Uchida Toshiki , Fukuhara Suguru , Oyama Takashi , Fukuzaki Tomoharu , Komatsu Yasuhiko
Published: March 2020

8551

Background: BM-ca is a novel humanized type-I/II anti-CD20 antibody, which is effective against rituximab-resistant cell line RC-K8, and has more potent anti-cell-proliferation activity than rituximab or ofatumumab when combined with cancer chemotherapeutics. The aim of this study was to evaluate the safety, efficacy, and PK profile of BM-ca in pts with indolent B-NHL. Methods: A total of 12 pts {age: median 61 (50-73), number of prior regimens: median 2 (1-13)} with indolent B-NHL relapsed after or refractory to rituximab-containing therapy underwent treatment by IV infusion of BM-ca weekly for 4 weeks at a dose of 5, 10, or 15 mg/kg. Initially, 3 pts were to undergo BM-ca therapy at a dose of 5 mg/kg using the conventional 3+3 dose escalation design. To minimize infusion reactions (IRs), pts were pretreated with acetaminophen and d-chlorpheniramine maleate. Allopurinol and/or hydrocortisone were also administered if necessary. Infusion was started at 50 or 100 mg/h and was gradually increased to a maximum of 400 mg/h. Since no DLTs were observed, all 12 pts completed weekly 4 doses of BM-ca. Results: The most frequent AE was IRs (11 of 12 pts), which occurred mostly in the first infusion, and the highest grade of AE was neutropenia (grade 4 in one pt of 15 mg/kg after the last infusion). Anti-BM-ca antibodies were not detected. Of the 12 pts examined, 2 achieved CR (10 mg/kg) and 2 PR (15 mg/kg); these 4 pts had follicular histology. The remaining 8 pts including one each of extranodal marginal zone, nodal marginal zone, and small lymphocytic histology were judged to achieve SD. The CR states in 2 pts continued at least >14 and >11 months, respectively. The PK properties of BM-ca were comparable to those of other naked anti-CD20 antibodies including rituximab (AUC and Cmax were proportional to the doses; Vdss≈4 L; t1/2≈750 h). Since at 10 mg/kg the response was the best and no grade 4 AE observed, 10 mg/kg was suggested as a recommended phase II dose. Conclusions: Four weekly IV administration of BM-ca up to 15 mg/kg was well tolerated and safe with promising preliminary anti-lymphoma activity in pts with indolent B-NHL. Further evaluation is warranted. Clinical trial information: 000004805.
Long-term survival with 90yttrium ibritumomab tiuxetan and rituximab as treatment for relapsed or refractory diffuse large B-cell lymphoma.
Authors: Arnason Jon E. , Luptakova Katarina , Rosenblatt Jacalyn , Zwicker Jeffrey , Levine James D. , Boussiotis Vassiliki , Kim Michelle , Avigan David , Joyce Robin
Published: March 2020

8558

Background: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) are salvaged with high dose chemotherapy followed by autologous stem cell rescue. Ibritumomab tiuxetan is an anti-CD20 antibody conjugated to the radionuclide 90yttrium. 90Y ibritumomab tiuxetan has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile relative to transplant. Methods: This phase II trial investigated the overall response rate (ORR), event free survival (EFS), overall survival (OS) and toxicity of treatment with ibritumomab followed by rituximab in patients with relapsed or refractory DLBCL, not candidates for transplant. Patients were treated with an initial dose of rituximab (250 mg/m2) followed one week later by ibritumomab (0.4 mCi90Y/kg or 0.3 mCi90Y/kg based on plateles) followed by 4 weekly doses of rituximab (375mg/m2). All non-progressing patients received maintenance rituximab (375 mg/m2) weekly for 4 doses every 6 months for 4 cycles. Results: 25 patients were enrolled. Median age was 79 (range 45-95). 12 of 25 (48%) had stage 3 or 4 disease. 13 (52%) had 2 or more prior regimens. At 12 weeks 5 patients (21%) had a complete response (CR), 3 (13%) a partial response, 2 (8%) stable disease and 14 (58%) progressed for an ORR of 32% (8/25). At best response 7 patients obtained a CR. Median EFS was 2.5 months. Median OS was 8.1 months. No patient who obtained CR later relapsed, with follow up of 18.3-100.1 months. Deaths unrelated to treatment occurred in remission in 5 patients. 2 patients remain free of disease at 67.4 and 100.1 months. 11 (65%) patients had grade 3 or 4 thrombocytopenia, but no significant bleeding was observed. 9 (36%) patients had grade 3 non-hematologic toxicity. Grade 1 and 2 fatigue occurred in 41%. Patients who progressed through a rituximab containing regimen were at high risk of early progression. Conclusions: The ORR of ibritumomab as salvage therapy for DLBCL compares favorably to other regimens with acceptable toxicity. Those patients with disease refractory to rituximab are not likely to benefit. For a subset of patients not candidates for salvage with autologous transplant, this treatment can produce a durable remission. Clinical trial information: NCT00110149.
Markers of angiogenesis and hypoxia to cell of origin (COO) subtypes of DLBCL: Correlative studies from S0515, a phase II trial of R-CHOP plus bevacizumab.
Authors: Badari Ambuga R. , Abu Zaid Mohammad , Unger Joseph M. , Rimsza Lisa M. , Marron Marilyn , Fisher Richard I. , Miller Thomas P. , Stopeck Alison
Published: March 2020

8562

Background: S0515 was a nonrandomized phase 2 trial of R-CHOP + bevacizumab in 64 patients with newly diagnosed DLBCL. No significant improvement in PFS or OS was observed compared with historic controls.Patients with higher baseline levels of plasma VCAM and urine VEGF had worse PFS and OS. Tumor-associated carbonic anhydrase, CA IX, is induced by hypoxia in various tumors and part of the hypoxia inducible factor -1/ hypoxia responsive element (HIF-1/HRE) system. We present additional correlative studies from S0515 including longitudinal plasma CAIX levels, and correlate expression of VEGF and VEGF receptors (VEGFR) to COO subtype [GCB vs. non-GCB] and urine VEGF and plasma VCAM. Methods: COO subtypes were determined by immunohistochemistry (IHC) using the Hans classification. VEGF and VEGFR expression was determined by IHC and scored on a scale of 0 (none) to +3 (strong). Plasma VCAM, CAIX, urine VEGF levels were measured by ELISA and samples collected at baseline and before cycles 4 and 8 of therapy. Results: Baseline CAIX levels did not predict PFS (p = 0.95) or OS (p=.66) or change with therapy. Patients with lower baseline CAIX levels (below the median) had a statistically significant increase in CAIX over the course of therapy (median 34.1 to 52.4, p=.002), whereas in patients with higher baseline CAIX, levels decreased (median 96.7 to 78.2, p=.20). CAIX correlated with plasma VCAM (P=.006), but not COO subtype. 33 lymphoma samples were classified as GCB (n = 21) or non-GCB (n=12). COO subtype did not predict difference in PFS (p=.56) or OS (p=.67). Median urine VEGF and plasma VEGF levels trended higher in non-GCB vs GCB tumors (181 vs 144pg/mL and 1499 and 821ng/mL, respectively). Lymphoma expression of VEGF did not correlate with plasma VCAM or urine VEGF. VEGR2 expression was higher in non-GCB vs GCB tumors (33% vs 5% expression). Conclusions: Plasma CAIX levels, a marker of hypoxia and HIF1alpha activation, increased only in those patients with lower baseline levels in response to therapy. COO by IHC did not predict PFS or OS. However, non-GCB tumors had higher expression of VEGFR2, plasma VCAM, and urine VEGF compared to GCB tumors consistent with increased angiogenesis. Clinical trial information: SWOG S-0515.
Association of 25-OH vitamin D deficiency with worse outcome for elderly patients with aggressive B-cell lymphomas treated with CHOP plus rituximab (R): An analysis of the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).
Authors: Bittenbring Joerg Thomas , Achenbach Marina , Altmann Bettina , Ziepert Marita , Reichrath Joerg , Geisel Juergen , Regitz Evi , Murawski Niels , Zwick Carsten , Held Gerhard , Pfreundschuh Michael
Published: March 2020

8569

Background: Vitamin D deficiency was shown to be is associated with a worse outcome in patients with non-Hodgkin's lymphoma (Drake et al., 2010) To study whether this observation could be confirmed in patients with aggressive B-cell lymphomas treated uniformly within a prospective trial, we analyzed 25-OH vitamin D serum levels in patients treated within the RICOVER-60 trial of the DSHNHL. Methods: 25-OH Vitamin D serum levels were determined with a commercial chemoluminescence immunoassay in the serum from elderly patients of the RICOVER-60 trial which compared 6 or 8 cycles of CHOP, both with and without rituximab. Results: 193 of 359 pts (53.8%) had vitamin D deficiency (<10 ng/ml) and 165/359 patients (46.0%) had vitamin D insufficiency (10-30 ng/ml) according to current definitions. When treated with R-CHOP, patients with vitamin D levels ≤8 ng/ml had a 3-year EFS of 59% compared to 79% of patients with vitamin D serum levels >8 ng/ml; the respective figures for 3-year overall survival were 70% and 82%, respectively. In R-CHOP pts these differences were significant in a multivariable analysis adjusting for IPI risk factors with a hazard ratio (HR) of 2.1 (p=0.008) for EFS and a HR of 1.9 (p=0.040) for OS. In pts treated without R effects of vitamin D deficiency were significant only for OS (HR 1.8; p=0.025), but not with respect to EFS (HR 1.2; p=0.388). These results were confirmed in an independent validation set of 63 patients treated within the prospective RICOVER-noRx study. Conclusions: Vitamin D deficiency is a significant risk factor for patients with aggressive B-cell lymphomas treated with R-CHOP. The stronger adverse effect of vitamin D deficiency in patients receiving rituximab suggests that vitamin D deficiency interferes with the R mechanisms of this antibody. A prospective study evaluating the effects of vitamin D substitution on outcome of patients receiving R-CHOP is warranted. Supported by Deutsche Krebshilfe.
Infectious disease associations in advanced stage, indolent lymphoma (follicular, FL, and nonfollicular, nFL): A prospective trial of antibiotic therapy.
Authors: Portlock Carol S. , Hamlin Paul A. , Gerecitano John F. , Noy Ariela , Palomba Maria Lia , Walkley Janelle , Corcoran Stacie , Papanicolaou Genovefa A , Markowitz Arnold
Published: March 2020

8571

Background: The antigen-drive association of gastric MALT with H. pylori (HP) is well recognized. Successful antibiotic (Ab) can result in lymphoma remission. We have studied a 3 mo course of clarithromycin (substituting lansoprazole/amoxicillin/clarithromycin, Prevpak, in the first 2 wks if HP +) in non-bulky, advanced stage indolent lymphoma as the first step to such a lymphoma treatment/prevention strategy. Methods: Patients with new diagnosis indolent lymphoma (FL and nFL), stages II (abdominal), III and IV fulfilling GELF criteria for observation were eligible. Stool HP done in all patients. Hepatitis B and C positive excluded. All patients had CT and PET prior to and 1 mo post Ab. Results: 32 evaluable patients were enrolled: 14 females, 18 males; median age, 53.5 years (36- 81); 22 FL, 10 nFL; stage II (2), III (16), and IV (14). HP + patients: 4 (3 FL, 1 nFL). We have observed lymphoma responses 1 mo post Ab in 7 of 32 (Table). With continued followup post Ab, best response to date in 9 of 32: PET CR ( 2 FL; 2 nFL); CT CR/PR ( 1/3 FL, 1/0 nFL). Median followup for all patients, 23.7 mos; and for those not needing lymphoma treatment, 54.9 mos. To date, no patient with PET CR has required lymphoma treatment (22.5+ to 62.8+ mos). Among 22 with FL, 8 have progressed, 3 had histologic transformation, possibly suggesting a different biology. Conclusions: H pylori eradication/3 mos clarithromycin has achieved lymphoma responses in advanced stage indolent lymphoma. PET negative CRs have been durable for 22.5 – 62.8 + mos following Ab alone. This prospective study may be a first step toward developing a lymphoma prevention strategy and deserves further clinical/biological study. Clinical trial information: NCT00461084. [Table: see text]
Use of stem cell transplantation (SCT) as initial therapy in multiple myeloma (MM) and impact of sociodemographic factors in the era of novel agents: Analysis of 137,409 patients using the National Cancer Data Base (NCDB).
Authors: Al-Hamadani Mohammed , Go Ronald S.
Published: March 2020

8580

Background: Novel agents for MM became available in the past decade. Our study aim was to determine whether the rate of SCT utilization as part of initial therapy in patients with MM had changed in the US after the introduction of novel agents. We also determined the impact of various sociodemographic factors. Methods: De-identified patient level data were obtained from the NCDB bParticipant User File. NCDB is a nationwide oncology outcomes database, which comprises approximately 70% of all newly diagnosed cancer cases in the United States. Results: A total of 137,409 MM patients were included in the study. The median age was 68 years (range, 18-90+). The population was predominantly male (54%), white (79%), non-Hispanic (87%), and living in a metro (78%), low- or middle-income (annual income < $46,000; 63%), and low- or moderate-education (> 14% without high school diploma; 66%) areas. Most patients had minimal or no co-morbidities (Charlson-Deyo score of 0-1; 93%) and treated in the community setting (62%). The rate of SCT use as initial therapy consistently increased annually from 5% in 1998 to 12% in 2010. This was true for all socio-demographic subgroups except for those who were age > 75 years, treated in the Northeast, and the medically uninsured. Multivariate logistic regression showed that the following characteristics were significant main predictors of lower likelihood of SCT use (odds ratio): age > 65 years (0.18), non-white race (0.57), Hispanic ethnicity (0.68), lack of high education (0.89), annual income < $30,000 (0.76), diagnosed before the era of novel agents (1998-2003) (0.70), covered by a non-managed care insurance (0.57), treatment in a non-academic facility (0.28), residence at a non-metro area (0.88), and treatment facility located outside of the Midwest or West (0.62). In contrast, sex was not significant. Conclusions: Even after the introduction of novel agents, the rate of SCT as initial therapy in MM continues to increase annually in the US. Significant disparity exists in the rate of SCT use by demographic, social, and geographic factors as well as the type of treatment facility.
Changes in patient-reported outcomes in patients diagnosed with and treated for multiple myeloma in the Connect MM registry.
Authors: Pashos Chris L. , Shah Jatin J. , Terebelo Howard R. , Durie Brian G. , Abonour Rafat , Gasparetto Cristina , Mehta Jayesh , Narang Mohit , Thomas Sachdev , Toomey Kathleen , Swern Arlene S. , Sullivan Kristen A. , Street Thomas K. , Khan Zeba M. , Nourbakhsh Ali , Hardin James , Wildes Tanya Marya , Rifkin Robert M.
Published: March 2020

8586

Background: Little is known about the impact of treatment on patient-reported outcomes (PROs) and health-related quality of life (HRQoL) in multiple myeloma (MM) patients (pts). The change in PROs of MM pts between baseline and 1 year was assessed relative to their baseline International Staging System (ISS) stage and Eastern Cooperative Oncology Group (ECOG) performance status (PS) score. Methods: Connect MM is a prospective US registry of MM pts initiated in 2009. Clinicians reported pt demographics, ECOG PS score, and ISS stage. PROs were collected at baseline and at 1 year utilizing the Functional Assessment of Cancer Therapy (FACT)-MM, EQ-5D, and Brief Pain Inventory (BPI). Changes in FACT-MM, EQ-5D, and BPI scores were analyzed by ISS stage and ECOG PS score in 636 pts meeting CRAB criteria from 189 centers. Results: Most pts were male (58%) and white (84%). Mean age was 66 years (± 11). Pts were treated in community (81%), academic (17%), or veterans/military (2%) settings. ISS stages of pts were: I (29%), II (35%), and III (35%). ECOG PS scores were 0 (37%), 1 (49%), 2 (11%), and 3 (3%). Improvements in overall HRQoL as shown by the FACT-MM and FACT-General (G) total scores, were observed across all ISS stages (P = 0.03 to < 0.0001) with no significant differences between stages. Improvements in FACT-MM and FACT-G total scores were observed with ECOG PS scores 1–3 (P = 0.03 to 0.005). Pts with poorer ECOG PS scores tended to have greater improvement in EQ-5D domains of mobility, self-care, and usual activities. HRQoL/functional ability improved in 4 of 5 FACT domains (except social/family; all others P < 0.0001), and in 4 of 5 EQ-5D domains (except pain/discomfort; all others, P = 0.01 to < 0.0001). BPI showed that overall average pain improved (P < 0.0005) over 1 year, but statistically significant differences by ISS stage or ECOG PS score were not observed. Conclusions: Connect MM data showed that overall HRQoL of MM pts improved between baseline and 1 year, with a consistent benefit observed across pts with different ISS stages and ECOG PS scores. Additional analysis should examine which disease- and treatment-related factors are associated with these HRQoL improvements.