bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma viral DNA as a marker of tumor response in EBV(+) Hodgkin lymphoma in a phase III study (E2496).
Authors: Kanakry Jennifer Ann , Li Hailun , Gellert Lan L. , Lemas M. Victor , Hsieh Wen Son , Tan King L. , Gascoyne Randy D. , Gordon Leo I. , Horning Sandra J. , Kahl Brad S. , Ambinder Richard F. 
Published: March 2020

8003 Background: Epstein-Barr virus (EBV) is associated with Hodgkin lymphoma (HL) and can be detected by in situ hybridization (ISH) of viral nucleic acid (EBER) in tumor cells. Studies have suggested a correlation in HL between plasma EBV DNA and EBER ISH. We previously studied the DNase sensitivity of plasma EBV DNA and found plasma EBV of patients with EBV(+) HL was not protected from DNase digestion, consistent with tumor-derived DNA, while plasma EBV of patients with HIV without EBV(+) tumors was protected from DNase digestion, consistent with virion DNA. We sought to determine whether plasma EBV could serve as a surrogate for EBER ISH and whether reappearance of plasma EBV predicts treatment failure. Methods: Specimens from a Cancer Cooperative Intergroup Trial (E2496/Stanford V versus ABVD for HL) were used to compare pretreatment plasma EBV DNA copy number, assessed by real-time quantitative PCR, with EBV status by EBER ISH. An ROC analysis was performed using patients with both pretreatment plasma EBV and EBER results (n=121), identifying a cutoff of 60 viral copies/100 µL plasma (95% concordance, 92% sensitivity, 96% specificity for EBV status by EBER). Using this cutoff, pretreatment plasma specimens (n=274) were designated EBV(+) (n=54) or EBV(-) (n=220), as were serial follow-up specimens. Cox proportional hazard models were constructed to evaluate plasma EBV as a prognostic factor for failure-free survival (FFS). FFS was estimated by the Kaplan-Meier method. Results: Pretreatment EBV(+) plasma was associated with treatment failure with a hazard ratio of 2.1 (95% CI 1.2-3.6, p=0.01) after adjusting for International Prognostic Score, treatment arm, and histology. Of the EBV(+) patients with follow-up specimens (n=45), patients with EBV(+) plasma beyond 1 month of therapy (n=9) had inferior FFS compared to those who cleared their plasma of EBV (n=36), (3-year FFS 44% versus 69%, respectively; log rank p=0.03). Conclusions: HL patients with EBV(+) plasma at baseline have inferior FFS compared to others. Among patients with EBV(+) plasma at baseline, those in whom plasma EBV persists or reappears after initiation of therapy have inferior FFS. Such patients may benefit from experimental or intensified therapies.
Stringent complete response (sCR) in patients (pts) with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX).
Authors: Jakubowiak Andrzej J. , Griffith Kent A. , Dytfeld Dominik , Vesole David H. , Jagannath Sundar , Anderson Tara B. , Nordgren Brian K. , Detweiler-Short Kristen , Lebovic Daniel , Stockerl-Goldstein Keith , Jobkar Terri L. , Wear Sandra Marija , Al-Zoubi Ammar , Ahmed Asra Z. , Mietzel Melissa A , Couriel Daniel R. , Kaminski Mark Stefan , Hussein Mohamad A. , Yeganegi Homa , Vij Ravi 
Published: March 2020

8011 Background: Combination treatment (tx) with CFZ, LEN, and DEX (CRd) is well tolerated and highly active in NDMM. In a phase 1/2 study, CRd provided rapid reduction of disease by 68% after cycle (C) 1 and 94% ≥partial response (PR) at a median of 8C, including 65% ≥very good PR and 53% ≥near CR (nCR), which improved to 79% ≥nCR after C12 (ASH 2011, Abstr 631). Here, we examine the clinical significance of the response rates with longer follow-up. Methods: Pts with NDMM were treated in 28-day (d) C with CFZ 20–36 mg/m2 IV (d1, 2, 8, 9, 15, 16), LEN 25 mg PO (d1–21) and DEX 40/20 mg PO weekly (C1–4/5–8). After C4, autologous stem cell transplant (ASCT) candidates achieving ≥PR could collect stem cells but then continued CRd with the option to proceed to ASCT. After C8, pts received CRd maintenance, using the last tolerated doses, with LEN/DEX at the same schedule but a modified CFZ schedule (d1, 2, 15, 16). Response was assessed by IMWG criteria plus nCR. Results: As of Nov 30, 2011, median follow-up was 14 mo (range 4–25) with 33/53 (62%) pts achieving ≥nCR and 42% sCR. After a median of 13C (range 1–25), 36 pts completed C8 and continued CRd maintenance, 64% achieving sCR. 20/22 pts in CR evaluated for minimal residual disease (MRD) by multiparameter flow cytometry had no MRD. Progression-free survival (PFS) rate was 97% at 12 and 92% at 24 mo. All pts who achieved sCR have maintained response for a median of 9 mo (range 1–20). Extended CRd tx was well tolerated. During CRd maintenance, the most common toxicities (all grades) were lymphopenia (30%), leukopenia (26%), and fatigue (25%), and peripheral neuropathy remained limited (11%, all G1/2). There were no tx discontinuations due to toxicity during maintenance and limited dose modifications (CFZ 19%, LEN 28%, DEX 31%). Conclusions: CRd is highly active in NDMM, providing rapid and deep responses. Extended tx was well tolerated and resulted in improved depth of response with a high sCR rate and a significant proportion of pts without evidence of MRD. Responses were durable with very promising PFS. All pts who achieved sCR remained on CRd with sustained sCR. These results compare favorably to other frontline regimens.
Phase I trial of obatoclax mesylate in combination with bortezomib for treatment of relapsed multiple myeloma.
Authors: Stewart A. Keith , Trudel Suzanne , Zonder Jeffrey A. , Hayman Suzanne R. , Erlichman Charles , Fruth Briant , LaPlant Betsy , Sullivan Daniel 
Published: March 2020

8013 Background: Obatoclax mesylate (GX15-070MS) is a BH3 mimetic that inhibits Bcl-2 protein family members including MCL-1, a dominant target in myeloma (MM). Obatoclax (OBX) inhibited viability of 14 MM cell lines (mean IC50 215 nM) and primary MM samples while exhibiting pre clinical synergy with bortezomib (BTZ). Sensitivity correlated with basal levels of Mcl-1 and Bcl-XL, but not Bcl2, Bim, Bax or Bak expression. Methods: We report a phase I trial of OBX in combination with BTZ. Eligibility required measureable disease, > 1 prior MM therapy, ≤10 cycles of prior BTZ and did not progress on prior BTZ therapy, creatinine ≤2 ULN. Starting dose level 1 was OBX 14 mg/m2 24-hour continuous iv. infusion days 1, 8, 15 of a 21-day cycle. BTZ given at 1.3mg/m2 iv. days 1, 4, 8 and 11. After protocol amendment OBX level 1 dosing was 30 mg/m2, level 2 was 40 mg/m2 IV both by continuous 3 hour infusion days 1, 8 and 15 on a 21 day schedule. Pre med. with famotidine was required. Results: Eleven patients were accrued, median age 62 (range: 46-77), median time from diagnosis was 4.7 years. Median of 2.5 cycles (range: 1-10). Median follow-up for patients still alive is 11.6 months (range: 0.9-35.5). At dose level 1, there were 2 DLTs. After amendment 8 patients were accrued (3 hour infusion): 4 at amended dose level 1 and 4 at dose level 2. All patients are now off treatment. 10 patients are evaluable for response: 2 patients at original dose level 1 (2 PR), 3 patients at dose level 1 (2 PR, 1 MR), no patients at dose level 2 responded: overall PR of 40%, clinical benefit response in 50% (95% CI: 19-81%). 6 patients had disease progression and 2 patients died. 4 DLTs were seen: at original dose level 1 grade 4 thrombocytopenia and delay of therapy > 15 days. At dose level 2, 1 patient had grade 3 somnolence, a 2nd patient grade 3 euphoria and grade 4 thrombocytopenia. No DLTs were seen at amended dose level 1. Common adverse events of any grade included GI, hematologic and neurologic e.g. euphoria, decreased level of consciousness, psychosis, speech. Conclusions: In summary MTD is OBX 30mg/m2 by 3 hour iv infusion once weekly, BTZ 1.3 mg/m2 days 1,4,8, and 11. Major toxicities were central neurologic and hematologic. This P2C consortium study was supported by NCI N01-CM62205.
A randomized phase II study of elotuzumab with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma.
Authors: Moreau Philippe , Richardson Paul Gerard Guy , Jakubowiak Andrzej J. , Jagannath Sundar , Raab Marc , Facon Thierry , Vij Ravi , Reece Donna Ellen , White Darrell , Benboubker Lotfi , Zonder Jeffrey A. , Rossi Jean-Francois , Tsao Claire , Parli Teresa , Kroog Glenn Scott , Singhal Anil , Lonial Sagar 
Published: March 2020

8020 Background: Elotuzumab (Elo) is a humanized monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein. CS1 is highly expressed on >95% of multiple myeloma (MM) cells, with lower expression on natural killer cells and little to no expression on normal tissues. A phase 1 trial of Elo plus lenalidomide and low-dose dexamethasone (Elo/Len/Dex) demonstrated an 82% objective response rate (ORR) in patients (pts) with relapsed/refractory (RR) MM (Lonial et al. J Clin Oncol, in press). Methods: In this phase 2 study, previously treated pts with MM were randomized to Elo 10 or 20 mg/kg IV (days 1, 8, 15, and 22 every 28-days in first 2 cycles and days 1 and 15 of subsequent cycles), Len 25 mg PO (days 1-21) and Dex 40 mg PO weekly. Prophylaxis for infusion-related reactions (IRs) was administered prior to each Elo infusion. Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess efficacy (ORR ≥partial response [PR]) according to IMWG criteria. Results: Among73 pts (median age 63 years; range, 39-82), 55% had received ≥2 prior therapies, 60% had received prior bortezomib, and 62% prior thalidomide. ORR was 82% for all pts including 48% ≥ very good PR (VGPR). The ORRs were 92% in the 10 mg/kg group (n=36) and 73% in the 20 mg/kg group (n=37). Median time to best response was 2.2 months (range, 0.7-17.5). After a median follow-up of 14.1 months, median progression-free survival (PFS) has not been reached, with PFS rates of 75% (10 mg/kg) and 65% (20 mg/kg). Elo/Len/Dex also showed encouraging activity in pts with high-risk cytogenetics (ORR 80%) and/or Stage 2-3 MM (ORR 81%). The most common grade 3/4 toxicities were neutropenia (16%), lymphopenia (16%), and thrombocytopenia (16%). Investigator-designated IRs were reported in 12% of pts (all grades); 1 pt (1.4%) had grade 3 IR (rash). Conclusions: Elo/Len/Dex was generally well tolerated and resulted in a high ORR, and PFS not reached after 14.1 months of median follow-up in pts with RR MM. Updated results will be presented at the meeting. Two phase 3 trials of 10 mg/kg Elo/Len/Dex are ongoing in newly diagnosed MM (ELOQUENT1; CA204-006; NCT01335399) and RR MM (ELOQUENT2; CA204-004; NCT01239797).
Everolimus (EVE) for relapsed/refractory classical Hodgkin lymphoma (cHL): Open-label, single-arm, phase II study.
Authors: Johnston Patrick B. , Pinter-Brown Lauren C. , Rogerio Jaqueline Willemann , Warsi Ghulam , Chau Quincy , Ramchandren Rod 
Published: March 2020

8028 Background: Effective treatment for relapsed/refractory cHL is lacking. The oral mammalian target of rapamycin inhibitor EVE showed promising efficacy and acceptable toxicity in cHL. We conducted a study to confirm EVE safety and efficacy in relapsed/refractory cHL. Methods: In this multicenter, open-label, 2-step, phase 2 study, adults with cHL that progressed after high-dose chemotherapy with autologous hematopoietic stem cell transplant (AHSCT) or a gemcitabine-, vinorelbine-, or vinblastine-containing regimen received EVE 10 mg/d until disease progression or unacceptable toxicity. Response was assessed every 12 wk via integrated positron emission tomography/computed tomography (CT) with contrast or CT with contrast. Primary endpoint was overall response rate (ORR) per modified response criteria for malignant lymphoma. Adverse events (AEs) were assessed during, and for ≥4 wk after, EVE treatment. Results: 55 patients were enrolled. Of the 38 currently evaluable patients, 37% were men, median age was 32.5 y, 53% were pretreated with AHSCT, and 95% were pretreated with gemcitabine, vinorelbine, or vinblastine; 71% had disease progression during previous therapies or discontinued previous treatment due to progression. 23 patients discontinued treatment, most commonly due to disease progression (n = 11). ORR was 37% (Table). Median progression-free survival (PFS) was 7.2 mo. The most common hematologic AEs were thrombocytopenia (39%) and anemia (24%); the most common nonhematologic AEs were fatigue (47%), cough (29%), dyspnea (26%), headache (21%), and rash (21%). Grade 3/4 AEs, most commonly thrombocytopenia (18%), were observed in 45% of patients. Conclusions: EVE showed a favorable ORR and median PFS in the first 38 evaluable patients with highly pretreated, relapsed/refractory cHL. The AE profile was consistent with that previously observed for EVE. These preliminary results confirm those of an earlier study and support further evaluation of EVE in cHL. [Table: see text]
CNS-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT) for CNS relapse of aggressive lymphomas: Final analysis of a phase II study.
Authors: Korfel Agnieszka , Illerhaus Gerald , Haenel Mathias , Moehle Robert , Schroers Roland , Elter Thomas , Reiser Marcel , Dreyling Martin H. , Eucker Jan , Scholz Christian Winfried , Metzner Bernd , Roeth Alexander , Birkmann Josef , Schlegel Uwe S. , Martus Peter , Thiel Eckhard , Fischer Lars 
Published: March 2020

8031 Background: The outcome of patients with CNS relapse of aggressive lymphoma (secondary CNS lymphoma, SCNSL) is poor with no standard therapy established thus far. Here we present the final analysis of a prospective multicenter phase II study using an intensive induction regimen followed by high-dose chemotherapy and autologous stem-cell transplantation. Methods: Adult immunocompetent patients ≤65 years with SCNSL were eligible. Induction chemotherapy consisted of two cycles MTX/IFO (methotrexate 4g/m2 iv. d1, ifosfamide 2g/m2 iv. d3-5 and i.th. liposomal cytarabine 50mg d6) and one cycle AraC/TT (cytarabine 3g/m2 d1-2, thiotepa 40mg/m2 iv. d2 and i.th. liposomal cytarabine 50mg d3). Then, patients without progression received high-dose chemotherapy with carmustine 400mg/m2 iv. d -5, thiotepa 2x5mg/kg iv. d -4 to -3 and etoposide 150mg/m2 iv. d -5 to -3 followed by ASCT d0. Results: Thirty eligible patients (median age 58 years) were enrolled. Three patients had T-cell and 27 aggressive B-cell lymphoma. Pre-treatment was CHOP-like in 29 patients, including rituximab in 26. CNS relapse occurred after a median of 8.5 (3-80) months and was intracerebral in 23 and meningeal in13 patients (combined in 7); 6 had concomitant systemic lymphoma. After induction therapy CNS response was found in 22 (73%) patients (8xCR, 14xPR), 3 patients had SD, 4 patients PD and 1 patient no response evaluation. HD-ASCT was performed in 24 patients; resulting in 15 CR (63%), 2 PR (8%) and 7 PD (29%). Myelotoxicity was the most frequent WHO grade 3-4 adverse event with infections in 8/30 pts on MTX/IFO (27%), 5/23 (22%) on AraC/TT and 11/20(55%) on HD-ASCT. One patient died due to septic diverticulitis and one developed persisting fecal incontinence. The median follow up was 21 months. The median PFS was 12.1 months (95% CI 6.4-17.7) in all patients and 30.4 (95%CI 2.5-58.3) months after HD-ASCT, the median overall survival was 27.4 months and not reached, respectively. Conclusions: This first prospective study on SCNSL demonstrates that lasting remissions can be achieved with CNS-directed HD-ASCT in a large proportion of patients and probably cure in some.
Connect MM: The multiple myeloma (MM) disease registry—Incidence of second primary malignancies (SPM).
Authors: Rifkin Robert M. , Abonour Rafat , Fonseca Rafael , Gasparetto Cristina , Mehta Jayesh , Narang Mohit , Pashos Chris L , Thomas Sachdev P , Shah Jatin J. , Terebelo Howard R. , Toomey Kathleen , Minton Neil , Srinivasan Shankar , Street Thomas , Sullivan Kristen , Durie Brian G. 
Published: March 2020

8037 Background: Advances in the treatment of MM have greatly improved clinical outcomes for patients (pts). SPM occurrence has been observed in early and late stage MM as well as with increasing age. US SEER Cancer Registry reports a background incidence rate of SPM 2.1/100 person-yrs (PY) among persons ≥ 65 yrs of age. However, incidence of SPM in MM pts and the relationship to therapy still warrants further exploration. Methods: Connect MM is a US-based observational registry designed to characterize pts with newly diagnosed MM from 266 US sites. Initiated in Sep 2009, patient data were collected at baseline and each subsequent quarter with a standardized form. On Dec 14, 2011, Connect MM reached full enrollment at 1,500 pts. Results: As of Jan 13, 2012, preliminary retrospective SPM data is available for 1015 pts. Median age was 67 yrs, 56.8% male, and median follow-up was 10.6 mo (0.03-24.9 mo). 12 pts (7 male) with median age of 68.5 yrs developed SPM. Median time to SPM was 8.5 mo (0.8-17.7 mo) after treatment initiation. 11 invasive SPM were observed - 4 hematological (heme): 1 AML, 1 MDS, 1 CMML and 1 DLBCL, and 7 solid: 2 melanoma skin, 1 bronchus, 1 breast, 1 prostate, 1 tonsil, and 1 gastric carcinoid. Also, 1 pt had non-melanoma skin cancer (NMSC), and 1 pt with invasive skin cancer also had NMSC. Of the 4 pts developing heme SPM, 3 had bortezomib (BORT), 1 had thalidomide (THAL), 1 had lenalidomide (LEN), 2 had melphalan (MEL), and all 4 pts had steroids. Of the 7 pts who developed solid tumor SPM, 5 had BORT, 5 had LEN, 2 had doxorubicin, 1 had MEL, 5 had steroids, 1 had irradiation, and 1 had not received MM treatment. 2 pts with prior history of invasive malignancy developed solid tumor SPM (1 pt also developed NMSC).1 pt who received irradiation developed NMSC. Early overall incidence of invasive SPM was 1.21/100 PY (95% CI 0.60, 2.16) for all pts and 1.20/100 PY (95% CI 0.44,2.62) for pts ≥ 65 yrs of age. Conclusions: This preliminary analysis shows that SPM occurred at an expected rate in this disease specific registry of patients with NDMM and appeared to occur irrespective of MM treatment administered. Incidence rates of SPM may increase over time as patients receive transplantation and alkylators. Prospective observation will continue.
Metronomic therapy for heavily pretreated relapsed/refractory multiple myeloma (RRMM).
Authors: Papanikolaou Xenofon , Szymonifka Jackie , Mitchell Alan , Keller Jason , Heuck Christoph Johann , Waheed Sarah , Usmani Saad Zafar , Nair Bijay , Van Rhee Frits , Medlin Stephen Charles , Bailey Clyde , Petty Nathan , Hoering Antje , Crowley John , Barlogie Bart 
Published: March 2020

8041 Background: RRMM represents a true challenge in MM therapy. Based on the effectiveness of metronomic therapy in solid tumors, we developed a treatment of metronomically scheduled therapy (MT) for RRMM (Hollmig, ASH 2004). We are now updating our experience with a median follow up of 25.6 months. Methods: We identified 187 patients treated with MT from 03/2004 to 11/2011. Results: The median age was 61 years (range 36-83); the median number of prior therapies was 14 (range 1-51). 79% of patients had prior HDT, 99% had a prior exposure to bortezomib, 98% to an IMiD, and 95% to their combination . The median number of completed MT cycles was 1 (range 1-5). 63% of patients had a response of MR or better (6% CR ,7% VGPR, 36% PR, 16% MR). The median overall (OS) and progression free (PFS) survivals were 11.3 and 3.7 months respectively. 91 of 187 patients had gene expression profiling (GEP) prior to initiation of MT, of which 53% were high risk according to the 70-gene (GEP70) risk model. OS was affected by elevated CRP (> 8mg/L, HR=1.71, p=0.009) and cytogenetic abnormalities within 6 months of initiation of MT (HR=2.45, p<0.001). For the 91 patients with GEP data available, OS was correlated with elevated CRP > 8mg/L (HR=2.11, p=0.009) and GEP70 high-risk (HR=2.65, p<0.001), which also showed a trend towards shorter PFS. Hematological toxicity grading was difficult as 69% of patients presented with grade >=3 thrombocytopenia within 90 days prior to starting MT. Grade 4 leucopenia , anemia thrombocytopenia due to MT occurred in 74%, 17%, 89% of patients respectively. Incidence of grade 4 neutropenic fever was 1%. Grade 4 or worse incidence of all non-hematological toxicities was below 9%. Most patients were treated in the outpatient setting (95%) and secondary admissions due to regimen toxicity occurred in 20%. Conclusions: MT is an effective salvage treatment in RRMM, with a high ORR and a favorable toxicity profile. [Table: see text]
Detection of the MYD88 L265P mutation in Waldenström’s macroglobulinemia using a highly sensitive allele-specific PCR assay.
Authors: Xu Lian , Hunter Zachary R , Yang Guang , Cao Yang , Liu Xia , Zhou Yangsheng , Patterson Christopher J , Manning Robert J , Tripsas Christina , Sheehy Patricia S , Lindeman Neal Ian , Treon Steven P. 
Published: March 2020

8042 Background: Waldenström’s macroglobulinemia (WM) is a B-cell malignancy characterized by bone marrow (BM) infiltration with lymphoplasmacytic cells and production of an IgM paraprotein. By whole genome sequencing, we recently identified a somatic mutation (L265P) in the MYD88 gene in 27/30 (90%) WM patients (Treon et al, ASH 2011). To expand this finding for possible diagnostic testing, we developed an allele-specific PCR assay for MYD88 L265P and evaluated this assay in a large cohort of WM patients. Methods: An allele-specific PCR assay was developed with a threshold of detection of 0.125% for MYD88 L265P. DNA from bone marrow aspirates from 99 patients with the clinicopathological diagnosis of WM was used for assessment of MYD88 L265P expression by both allele-specific PCR and Sanger sequencing. Findings were correlated with clinical parameters using ANOVA. Results: We observed that 85/99 (86%) WM patients were positive for MYD88 L265P using the allele-specific PCR assay. Of the 85 allele-specific PCR positive patients, 81 demonstrated a detectable mutation peak by Sanger sequencing. All 14 allele-specific PCR negative patients remained negative by Sanger sequencing. By the allele-specific PCR assay, MYD88 L265P positive patients showed greater bone marrow involvement, higher serum IgM and lower serum IgA and IgG levels versus MYD88 L265P negative patients (p<0.008). Conclusions: MYD88 L265P is highly expressed in BM samples of WM patients using an allele-specific PCR assay, and is associated with greater bone marrow disease burden and serum IgM levels. Use of allele-specific PCR provides a simple and sensitive diagnostic tool for detection of the MYD88 L265P mutation.