bluuebunny/crossref_metadata_2025 huggingface dataset:
A first-in-human phase I/II study of ALK inhibitor CH5424802 in patients with ALK-positive NSCLC.
Authors: Kiura Katsuyuki , Seto Takashi , Yamamoto Nobuyuki , Nishio Makoto , Nakagawa Kazuhiko , Tamura Tomohide
Published: March 2020

7602

Background: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively activated in a subset of non-small cell lung cancer (NSCLC) following chromosomal gene translocation. CH5424802 was identified as a potent, selective, and oral ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against NSCLC cells expressing EML4-ALK fusion in vitro and in vivo (Cancer Cell, 2011). Our results support the potential of CH5424802 as a new therapeutic opportunity for patients (pts) with ALK-positive NSCLC. Methods: Pts with ALK-positive NSCLC received CH5424802 twice daily orally until progressive disease or toxicity was observed. In the phase I portion, dose was escalated using an accelerated titration scheme. The primary objectives were to investigate the safety, tolerability and pharmacokinetic (PK) parameters under fasting conditions, and to determine the recommended dose (RD) for use in the phase II portion. The primary objectives of the phase II portion were to investigate the efficacy and safety at the RD. The phase I portion was amended to include an investigation under non-fasting conditions in addition to fasting conditions. Results: 15 pts (M/F: 9/6) were treated with CH5424802 under fasting conditions in 6 cohorts (20 mg bid to 300 mg bid) and 9 pts (M/F: 2/7) were treated under non-fasting conditions in 2 cohorts (240 mg bid and 300 mg bid). Median age was 42.5 years. The highest dose level defined in the protocol (300 mg bid) did not reach the MTD. Thus, a DLT was not determined. Toxicities were mild to moderate. The most frequent toxicity was grade 1 myalgia. Grade 3 toxicity (cases) occurred as follows; hypophosphatemia (2), neutropenia (2), blood CPK increased (1) and hypermagnesemia (1). PK data from the fasting cohorts showed dose-dependent increases of Cmax and AUC. All pts at all dose levels achieved tumor regression. At dose levels 240 mg bid or more under fasting conditions, all 7 pts with measurable lesions achieved a partial response. So far, 11 pts have been on study treatment ≥ 6 months. Conclusions: CH5424802 was well tolerated with promising efficacy in pts with ALK-positive NSCLC. The phase II portion is ongoing.
Metastatic NSCLC: Treatment patterns, outcomes, and costs of newer agents.
Authors: Sacher Adrian G. , Le Lisa W. , Lau Anthea , Earle Craig , Leighl Natasha B.
Published: March 2020

7606

Background: New therapies for metastatic NSCLC have improved survival in clinical trials. The increased cost of these agents has led to variable drug funding and treatment across jurisdictions. Here we review patterns, real-world outcomes and costs of metastatic NSCLC treatment in the province of Ontario. Methods: All patients diagnosed with metastatic NSCLC from 2005-2009 were identified from the Ontario Cancer Registry with demographic, histologic and mortality data. Treatment records from the Ontario New Drug Funding Program and centralized treatment database were linked. Statistical analysis involved Wilcoxon rank sum, Kruskal-Wallis, Cochran-Armitage trend and likelihood ratio tests where appropriate. Results: 8113 metastatic NSCLC patients were identified. The median age was 68; 39% had adenocarcinoma, 14% squamous carcinoma and 43% histology not otherwise specified. Most were treated in regional cancer centers (92%). The majority (76%) did not receive systemic therapy; 23% received first-line chemotherapy, most commonly platinum doublets. More patients received systemic therapy over time (19% in 2005 v 26% in 2009, p <0.0001). Older patients (p <0.0001) and those with squamous histology (p <0.0001) were less likely to receive systemic therapy. Center of diagnosis did not affect the likelihood of treatment (p=0.46). The median time from diagnosis to death was significantly greater among patients selected to receive chemotherapy (9.3 v 3.2 months, p <0.0001), and with cisplatin/gemcitabine compared to other doublets (10.7 v 8.2 months, p=0.004). 31% of treated patients received second-line chemotherapy, predominantly with docetaxel (52%) or pemetrexed (41%). Pemetrexed use increased significantly over time (8% in 2005 v 71% in 2009, p<0.0001), as did the mean drug cost of second-line therapy ($5939/patient in 2005 v $10,057 in 2009). A longer median survival was also seen with pemetrexed in adenocarcinoma (17.9 v 15.2 months for docetaxel, p =0.02). Conclusions: Most metastatic NSCLC patients do not undergo systemic treatment. First- and second-line treatment outcomes in this population-based study were similar to clinical trials, confirming better outcomes with new agents at greater cost.
Three-year survival in stage IV non-small cell lung cancer (NSCLC): The importance of metastatic distribution.
Authors: Karp Daniel D. , Hanneken Jan M , Taylor Sarah H , Men Taoyan , Wu Xifeng , Pu Xia
Published: March 2020

7608

Background: Although long term survival (LTS) is an important goal of lung cancer treatment, those with metastatic disease at presentation have a median of only 8-9 months in most series with a small “tail” on the survival curve. We analyzed a large cohort of Stage IV pts by performance status (PS), smoking history, number and sites of disease to assess factors associated with 36 month survival. Methods: From 2004–2008, 526 newly diagnosed untreated pts with Stage IV NSCLC received initial treatment at our institution. Sites of disease were analyzed according to lung, brain, bone, liver, adrenal, skin, malignant effusion, lymphangitic, bulky pleural disease, and “other”. No patient had definitive surgery. Results: Overall, 58/526 pts (10.8%) survived 36 months or more. 453 pts died within 36 months. 15 pts alive with follow-up time less than 36 months were removed from further analysis. Of those, 38/58 (65.5%) had only 1 metastatic site (p<0.001). 14 (24.1%) had 2 sites, only 6 (10.3%) had 3 or more sites. Those 19 pts with lung to lung spread were the most common (32.8%) with LTS – reflecting the M1 status in the new International Staging System. Only 1 LTS pt had liver mets at diagnosis – a solitary lesion treated with radiofrequency ablation. 20 pts had PS=0 (0.019) and 29 had PS=1 (NS). PS=2 pts made up 6. 2 pts had PS=3 initially. 1 unknown. Only 6/58 (10.3%) were current smokers, 23 (39.7%) were never-smokers (p<0.001). Adenocarcinoma made up 65.5%. Conclusions: Progress in lung cancer survival has been slow. Very few LTS pts have more than 1 site of metastatic disease at presentation, virtually none with liver disease (p=0.02). Number of metastatic sites and presence of liver metastases appear to be important stratification variables for lung cancer clinical trials.
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.
The utility of serum lactate dehydrogenase (LDH) in the follow-up of patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Bongu Navneeth Rao , William Basem M. , Bast Martin , Bociek Gregory , Bierman Philip Jay , Vose Julie , Armitage James O.
Published: March 2020

8047

Background: The prognostic significance of high serum LDH is well established for both indolent and aggressive lymphomas at diagnosis. The performance characteristics of LDH in predicting relapse after treatment in patients (pts) with DLBCL has not been well studied. The determination of utility of LDH monitoring in pts with DLBCL would have widespread practice implications. Methods: We searched the Nebraska Lymphoma Study Group database to identify pts with DLBCL who were treated with a rituximab-based regimen, from 2000 to 2010, and sustained a complete response (CR). For the pts who relapsed (RP), after sustaining a CR, we collected the LDH level at relapse and the LDH level 3 months prior (considered baseline). For pts who never relapsed (NR), we collected the last 2 LDH levels at follow-up; levels had to be at least 3 months apart. The relative increase of LDH was compared, to baseline, among RP vs. NR. Results: We identified 129 pts, 15 pts were excluded from the analysis as their LDH results were not available, 27 relapsed and 87 didn’t. Median age of pts was 57 years. Only 9/27 RP (33%) had increase in LDH above upper limit of normal (ULN) at relapse. The mean increase in LDH at relapse was 1.2 fold above the ULN for RP vs. 0.83 for NR (p=0.59). The mean increase in LDH, from baseline, was 1.1 fold in NR vs. 1.3 in RP (p=0.3). The likelihood ratio (LR) of relapse was 4.65 for pts who had 1.5 fold increase in LDH above baseline (1.5xLDH) vs. those who didn’t (p=0.03). The sensitivity, specificity, positive and negative predictive values of 1.5xLDH for detecting relapse, compared to clinical and imaging findings were 0.18, 0.95, 0.55, and 0.79 respectively. Also, 1.5xLDH at relapse was significantly associated with the presence of fever (LR=5.74; p=0.03) but not with other symptoms including drenching night sweats, anemia, or new/progressive lymphadenopathy. Conclusions: A 1.5 fold increase in LDH, over a period of 3 months, is associated with increased likelihood of relapse from DLBCL. Modest elevations in LDH (<1.5 fold of baseline) doesn’t seem to be associated with relapse. LDH, when elevated at least 1.5 fold of baseline, is a specific (i.e. 56%), but not a sensitive (i.e. 19%) marker, for relapse of DLBCL.
Association of low expression of VEGF121 soluble isoform with prognostic impact and survival in patients with activated B-cell-like (ABC-like) diffuse large B-cell lymphoma (DLBCL) from the CORAL trial.
Authors: Thieblemont Catherine , Mounier Nicolas , Mourah Samia , Houlgatte Remi , Hirchaud Edouard , Cuccuini Wendy , Ysebeart Loic , Bron Dominique , Gaulard Philippe , Gisselbrecht Christian , Briere Josette
Published: March 2020

8048

Background: Gene expression profiling (GEP) has demonstrated that survival of DLBCL is influenced by the origin of the tumor cells (COO), germinal center-like (GC-like) vs ABC-like (Alizadeh et al. 2000), but also by the tumor microenvironment, particularly the angiogenesis (Lenz et al., 2008). To further understand the prognostic impact of these tumoral characteristics, we analysed the prognostic impact of COO and the expression of biomarkers involved in angiogenesis, in a selected population of 36 patients with relapsed/refractory DLBCL included in CORAL (Gisselbrecht, ASCO 2011). Methods: Expression of 5 biomarkers including VEGF (isoforms 121, 165, and 189), and their receptors (VEGFR-1 and R-2) was assessed by quantitative qRT-PCR after total RNA extraction and cDNA synthesis of tumor samples. COO was determined by GEP, and progression free- (PFS) and overall- (OS) survivals were analysed. Results: In the study population, VEGF121 expression below the median was associated to a better outcome, with 4 year-PFS at 63% vs 33% (p=.053), and a 4-year-OS at 79% vs 37% (p = 0.032), respectively. VEGF-165 -189, VEGF-R1, -R2 did not have any significant impact. Eighteen patients were predicted as ABC-like DLBCL and 18 as GCB-like DLBCL. In patients with ABC-like DLBCL, low VEGF121 level was associated to a significantly better survival than in those with high VEGF121 level: 4-year OS at 100% vs 36% (p=.011). The type of induction treatment, R-ICE or R-DHAP, did not influence the outcome. The differences in outcome according to VEGF isoforms were not significant among CGB patients. Conclusions: Our data suggest that angiogenesis plays a central role in ABC-like DLBCL. VEGF121 seemed to be a key player in this context and should be proposed as a target in the treatment of patients with ABC-like DLBCL.
Transformation of follicular lymphoma in the era of immunochemotherapy: A population-based study from British Columbia.
Authors: Al-Tourah Abdulwahab J. , Sehn Laurie Helen , Moccia Alden A , Gascoyne Randy D. , Connors Joseph M.
Published: March 2020

8049

Background: Several published series have established that the risk of transformation of follicular lymphoma (FL) to aggressive lymphoma is approximately 3% /year (15%-20% at 5 years). The addition of rituximab (R) to chemotherapy (immuno-chemotherapy) has significantly improved the outcome of patients with FL. The impact of immuno-chemotherapy on the risk of transformation remains unknown. We assessed whether the introduction of immuno-chemotherapy has altered this risk. Methods: We examined the Lymphoid Cancer Database of the British Columbia Cancer Agency for FL patients treated with immuno-chemotherapy. Inclusion criteria: FL grades 1-3A by WHO criteria; only patients requiring treatment at diagnosis were included. Exclusion criteria: FL grade 3B or composite histology (FL and DLBCL) at diagnosis; pts who received anthracycline-based chemotherapy; and HIV positivity. The diagnosis of transformation was confirmed by biopsy when possible (n=19; 79%) but patients who were considered to have transformed based on pre-defined clinical assessment (n=5; 21%) were also included in the analysis. Results: We identified 261 pts with FL grade 1-3A requiring treatment at diagnosis, who received immuno-chemotherapy; median f/u 47 months (0.2-116), median age, 61 y (34-86). Treatment: 243 (93%), R-CVP of which 145 (59%) also received maintenance R; 9 (4%), R-Fludarabine combination. 24 pts developed transformed aggressive lymphoma. The risk of transformation for the entire group was approximately 2% per year or 10% at 5 years. However, pts treated with maintenance R (n=151) had a lower risk of transformation compared to pts who only received R-chemo at induction (n= 110), 8% vs 20% at 5 years respectively, (P= 0.003). The post-transformation outcome remains poor with a median survival of 6 months. Conclusions: We and other groups have demonstrated that the risk of transformation from FL to aggressive lymphoma is approximately 15% to 20% by 5 years. Our study suggests that the introduction of immuno-chemotherapy has reduced this risk to less than 10%. This effect is particularly apparent when patients receive maintenance R. The outcome for patients who develop transformation remains poor.
LR-CD: Lenalidomide combination therapy for untreated low-grade B-cell NHL.
Authors: Reeder Craig B. , Tiedemann Rodger Edwin , Gano Katherine , Dueck Amylou C. , Conley Christoher R , Ansell Stephen Maxted , Nowakowski Grzegorz S. , Curtis Kelly Kevelin , Camoriano John Kelly , Leis Jose Francisco , Slack James L. , Valdez Riccardo , Stewart A. Keith , Witzig Thomas E.
Published: March 2020

8053

Background: Lenalidomide (LEN) is an immunomodulatory agent that has shown significant single-agent anti-lymphoma activity in patients with relapsed disease and in combination may enhance the efficacy of rituximab by various mechanisms. There is limited data on the role of LEN in combination regimens for treatment-naïve patients. This phase II single arm trial was designed to evaluate tumor response, toxicity (AE) and survival with a combination of LEN, rituximab, cyclophosphamide (CTX) and dexamethasone (DEX) (LR-CD) in symptomatic untreated patients with low grade B-cell non-Hodgkin lymphoma. Methods: Eligibility required age ≥18, ECOG PS ≤2, confirmed diagnosis of low-grade B-cell lymphoma (FL1-2, SLL, MZL or LPL/WM), measurable nodes ≥2cm or IgM ≥400mg/dL(LPL/WM), ANC ≥1400/mm3, platelets ≥100,000/mm3, creatinine ≤2mg/dL, signed informed consent and in need of therapy. Treatment consisted of IV rituximab 375mg/m2 D1, oral LEN 20mg D1-21, CTX 250mg/m2 D1, 8, 15, DEX 40mg D1, 8, 15, 22 and ASA 325 mg daily in a 28 day cycle. Treatment continued 2 cycles beyond best response (max 12). Toxicity was assessed by NCI CTCAE v3.0. Results: 28 patients have enrolled at Mayo Clinic with 25 evaluable for toxicity and 21 for response: Median age 65(43-83), 72% male, FL 24%, MZL 28%, LPL/WM 38%, and SLL 4%. Median number of cycles given was 5. Overall response in 21 patients with response data is 95% (95% CI 76-100%) with 19% CR (95% CI 5-42%), and 76% PR (confirmed and unconfirmed, 95% CI 53-92%). The ORR in 8 patients with LPL/WM with response data was 88%, all PR (95% CI 47-100%). At a median f/u of 14.7 months 96% are alive without progression. 1 death (unrelated) occurred 7.7 months after completing 12 cycles of treatment. The most common grade ≥3 AEs were neutropenia (37.5%), leukopenia (16.7%), anemia (12.5%) and fatigue (12.5%). Conclusions: The combination LR-CD with the novel agent LEN is feasible, well tolerated and produces high response rates in symptomatic patients with low grade B-cell NHL. Toxicities are manageable and similar to reported data of single agent LEN.
MLN9708, an investigational proteasome inhibitor, in patients (pts) with relapsed/refractory lymphoma: Emerging data from a phase I dose-escalation study.
Authors: Martin Peter , Chang Julie E. , Rifkin Robert M. , Hui Ai-Min , Berg Deborah , Gupta Neeraj , Liu Guohui , Di Bacco Alessandra , Assouline Sarit E.
Published: March 2020

8064

Background: MLN9708 is a reversible, orally bioavailable, specific 20S proteasome inhibitor. This study (NCT00893464) studied the safety and determined the MTD of IV MLN9708 in pts with relapsed/refractory lymphoma, and characterized pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Pts aged ≥18 yrs who had failed ≥2 chemotherapeutic regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. One pt was enrolled at the 0.125 mg/m2 starting dose; dose doubling proceeded with 1 pt at each dose up to 1.0 mg/m2. Dose escalation occurred in ≤40% increments using a standard 3+3 scheme based on DLT occurrence in cycle 1. Blood samples were collected at multiple time points after dosing on days 1 and 15 of cycle 1 for PK/PD analyses. Results: At data cut-off (Dec 1 2011), 21 pts had been enrolled and treated: 1 each at 0.125, 0.25, 0.5 and 1 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, and 6 at 2.34 mg/m2. Median age was 57 yrs (range 23–78); 57% were male. Median number of prior therapies was 5; 29% had prior radiation, 24% prior stem cell transplant. Histologies included T-cell lymphoma (n=5), Hodgkin lymphoma (n=3), follicular lymphoma (n=2), DLBCL (n=1) and other indolent B-cell lymphoma (n=7). Pts had received a median of 2 cycles (range 1–22); 2 DLTs were seen (neutropenia at 1.76 and 2.34 mg/m2). All pts experienced drug-related AEs, including fatigue (48%), nausea (29%), diarrhea (29%), pyrexia, thrombocytopenia, and vomiting (each 24%). 43% had drug-related grade ≥3 AEs, 1 pt discontinued due to drug-related grade 3 neutropenia (2.34 mg/m2). Three pts had drug-related peripheral neuropathy (1 grade 1, 2 grade 2). There were no on-study deaths. Of 18 response-evaluable pts, 3 achieved PR (including 2 who remain in response and on-study for >1 yr) and 4 SD. PK analyses showed linear PK (0.5–2.34 mg/m2) and a terminal half-life of ~6–9 days. There was a dose-dependent increase in maximal whole blood 20S proteasome inhibition. Conclusions: These data suggest IV MLN9708 is generally well tolerated, with infrequent PN, and is clinically active in pretreated lymphoma pts. The trial is ongoing and updated data will be presented.
Phase I/II study of MEDI-551, a humanized monoclonal antibody targeting CD19, in subjects with relapsed or refractory advanced B-cell malignancies.
Authors: Goswami Trishna , Forero Andres , Hamadani Mehdi , Sonet Anne , Verhoef Gregor , Fanale Michelle A. , Bello Celeste M. , Huang Wenmei , Cheson Bruce D.
Published: March 2020

8065

Background: Novel B-cell targeting agents, including monoclonal antibodies such as rituximab, are among recent advances in treatment of B-cell malignancies. New approaches are needed for patients progressing after rituximab-based therapies. MEDI-551 is an afucosylated monoclonal antibody targeting CD-19, a B-cell restricted transmembrane protein with enhanced affinity and antibody-dependent cellular cytotoxicity. Methods: Pts with relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia, or multiple myeloma received single agent MEDI-551 at dosages ranging from 0.5 mg/kg to 12 mg/kg via intravenous infusion over 28-day cycles; cohorts 1-6 received 0.5, 1, 2, 4, 8, and 12 mg/kg, respectively. Results: 25 pts were enrolled in the phase I portion Jun 2010–Aug 2011. No maximum tolerated dose (MTD) was achieved. Most AEs were grade 1/2 with dose-independent frequency and severity (Table). Six pts had grade 3 toxicities including tumor lysis syndrome, infusion reaction, thrombocytopenia, and neutropenia, or grade 4 neutropenia. No grade 5 AEs were seen. All pts recovered. Three partial responses (PR) and 2 complete responses (CR) were seen in DLBCL and FL pts at 0.5, 4, and 8 mg/kg. Activity included a CR lasting 9 mo. in a FL pt in cohort 1, who is currently being retreated with MEDI-551 on relapse. Conclusions: MEDI-551 demonstrated a safety profile warranting further study and showed no MTD reached at the highest dose studied. Anti-tumor activity is suggested by the responses achieved across dose levels. Phase II is currently enrolling subjects. This study is funded by MedImmune, LLC. [Table: see text]
Comparison of the international prognostic factors index (IPI) with the absolute monocyte and lymphocyte prognostic index (AMLPI) for patients (Pts) with diffuse large b-cell lymphoma (DLBCL) receiving R-CHOP.
Authors: Batty Nicolas , Ghonimi Elham , Feng Lei , Fayad Luis , Younes Anas , Rodriguez Maria Alma , Romaguera Jorge Enrique , McLaughlin Peter , Samaniego Felipe , Kwak Larry W. , Hagemeister Fredrick B.
Published: March 2020

8067

Background: We studied the value of a proposed prognostic index (PI) generated by baseline absolute monocyte (AMC) and lymphocyte (ALC) counts for pts with DLBCL, using values as previously reported (Leukemia 25:1502-9, 2011). Methods: From 03/07 to 01/09, 245 consecutive pts with untreated DLBCL receiving standard R-CHOP from the MDACC database were evaluated. Baseline AMC and ALC were retrospectively recorded. High AMC (≥610/uL) and a low ALC (≤1000/uL) were examined as dichotomized variables for progression-free (PFS) and overall survival (OS). An AMLPI was generated, stratifying pts into 3 risk groups (RGs): low-(AMC <610/uL and ALC >1000/uL), intermediate-(AMC ≥610/uL or ALC ≤1000/uL), and high-risk(AMC ≥610/uL and ALC ≤1000/uL). The prognostic effect of the AMLPI and the IPI were examined by multivariate analysis (MVA). Results: Ninety (37%) had high AMC and 71 (29%) had low ALC. By univariate analysis, a high AMC was associated with inferior PFS (p=0.01) and OS (p=0.03). The frequencies of AMLPI RGs were: low-105 pts (43%), intermediate-119 (48%), and high risk-21 (9%). With a median follow-up of 22 months (range <1-42), 3-year PFS and OS rates for these RGs were 80%, 61%, and 46% (p=0.007) and 92%, 76%, and 60% (p=0.006), respectively. Three-year PFS rates for IPI 0-2 and 3-5 RGs were 73% and 58%, respectively (p=0.0004); comparable OS rates were 88% and 68%(p<0.0001). For pts with IPI 0-2, 1-year PFS rates for AMLPI low, intermediate, and high RGs were 92%, 89% and 80% (p=0.022); comparable 1-year OS rates were 96%, 95% and 80% (p=0.049). By MVA, AMLPI effect (low vs. high RGs) on PFS was significant (p=0.046) as was IPI effect (0-2 vs 3-5, p=0.005); similar results were observed for OS (p=0.052 and p=0.003, respectively). Conclusions: Baseline AMC and AMLPI are significant variables for PFS and OS for pts with DLBCL receiving R-CHOP. AMLPI can identify pts with low, intermediate, and high-risk disease for PFS and OS, particularly for those with IPI 0-2. AMLPI may also add prognostic value beyond that of the IPI.