bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minimal residual disease (MRD) status pre- and post- high-dose therapy/autologous stem (HDC/ASCT) cell transplantation for multiple myeloma (MM) in the era of novel agents.
Authors: Kassim Adetola , McDuffie Jeremy Scott , Mosse Claudio A , Savani Bipin N. , Greer John P. , Oluwole Olalekan O. , Goodman Stacey , Engelhardt Brian G. , Chinratanalab Wichai , Kim Annette S , Jagasia Madan H. 
Published: March 2020

8605 Background: MRD assayed by multi-parameter flow cytometer (MFC), has prognostic significance after HDT/ASCT for MM (Paiva et. al. 2008). The frequency of MRD negativity (-) after induction therapy using novel agents such as immunomodulatory drugs like lenalidomide (IMiDs), and proteasome inhibitors like bortezomib, is unknown. The impact of HDT/ASCT on MRD status in this patient group has not been studied. Methods: We performed a retrospective study of all MM patients undergoing HDT/ASCT (January 2010 - December 2012) in our institution. No restrictions on inclusion were made based on the International Myeloma Working Group response criteria. All patients had novel agents as part of their initial induction regimen. Statistical analysis was by SPSS software (V 12.0). MRD status was determined by MFC on bone marrow samples pre- HDC/ASCT [M1] and post- HDC/ASCT (D100 [M2] and I year [M3]). MFC was done with antibodies against CD45, CD19, CD138, CD38, CD20, CD56, and anti-k and l cytoplasmic antibodies. Results: MRD status was available on 91 patients pre-transplant. Of these patients, 80 had MFC recorded at M2 and 17 patients had MFC recorded at M3. Fifty-eight percent were male and 76% were Caucasian. Forty percent received IMiDs, while 60% got proteasome based therapies. Of the 91 patients with MRD pre-HDC/ASCT, 58% (53/91) were MRD (-), and of these patients 89% (41/46) remained MRD (-) at M2. 48 patients were MRD positive (+) pre-HDC/ASCT, 58% (20/34) became MRD (-) at M2. Age, cytogenetic risk, disease stage, number of chemotherapy cycles or immunofixation status had no impact on MRD status. There were only 6 relapses in the cohort, thus the impact of MRD status on progression-free survival could not be studied. Conclusions: Novel agents improve depth of response pre-transplant. HDC/ASCT increases MRD negativity post-transplant. MRD status could aid better timing of HDC/ASCT or adoption of a risk-adapted strategy for high-risk patients. MRD status validation in a prospective cohort is underway at our center (NCT01215344). With future follow-up, the impact of MRD on progression-free survival in the era of novel agents will be determined.
Survival outcomes of plasma cell leukemia (PCL) in the United States: A SEER analysis.
Authors: Ravipati Hari Prasad , Kaufman Jonathan L. , Langston Amelia A. , Boise Lawrence , Flowers Christopher , Lonial Sagar , Nooka Ajay K. 
Published: March 2020

8609 Background: Plasma cell leukemia (PCL) is an aggressive plasma cell disorder that is associated with poor outcomes. Previous studies have shown improved survival with bortezomib-based regimens in this subset of patients undergoing stem cell transplant (SCT), but this may reflect referral bias. Current knowledge evaluating outcomes of PCL is limited in the era of novel agents. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) database from 18 registries for survival characteristics in PCL stratified by age, sex, race and the era of diagnosis. International Classification of Diseases for Oncology 3rd edition histology code 9733 was used to identify cases. Results: From 1973 to 2009, 74826 cases of myeloma and 479 cases of PCL were recorded. Survival data was available for 397 PCL patients. The median overall survival (OS) was 6 months (95% Confidence Interval (CI): 4.8 months – 7.2 months); and 1-year, 2-year, and 4-year OS rates were 34%, 20%, and 9% compared to corresponding myeloma survival rates of 66%, 52%, and 32%, respectively. Median overall survival differences were observed for women vs. men (7 months vs. 5 months, p=0.026); black vs. white patients (7 months vs. 5 months, p=0.01); and patients aged <60 years vs. ≥ 60 years (9 months vs. 4 months; P=0.01), respectively. In addition, patients diagnosed after 2005 had superior median OS compared with patients diagnosed prior to 2005 (7 months vs. 3 months; P=0.005). Conclusions: Black patients, women and patients aged <60 years have improved OS compared to white patients, males and patients aged ≥ 60 years. The survival benefit seen in patients diagnosed after 2005 may be attributed to the benefit conferred by access to new agents, but OS remains poor. Newer treatment approaches for managing PCL are clearly needed.
Phase II double-blind, randomized study of selumetinib (SEL) plus dacarbazine (DTIC) versus placebo (PBO) plus DTIC as first-line treatment for advanced BRAF-mutant cutaneous or unknown primary melanoma.
Authors: Middleton Mark R. , Dummer Reinhard , Gutzmer Ralf , Lorigan Paul , Kim Kevin , Nyakas Marta , Arance Ana Maria , Liszkay Gabriella , Schadendorf Dirk , Cantarini Mireille Veronique , Spencer Stuart , Robert Caroline 
Published: March 2020

9004 Background: BRAF mutations play an oncogenic role in melanomas. Selumetinib (AZD6244, ARRY-142886) inhibits MEK1/2 downstream of B-Raf and may have an additive effect to chemotherapy. We prospectively evaluated SEL + DTIC vs PBO + DTIC in patients with stage III-IV BRAF mutation-positive advanced cutaneous or unknown primary melanoma (NCT00936221). Methods: Eligible patients (pts) received iv DTIC 1000 mg/m2, and po SEL 75 mg or matched PBO bd as first-line treatment. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety and tolerability. Results: A total of 385 pts were screened across 44 centers; 91 patients were randomized (SEL + DTIC, 45; PBO + DTIC, 46). One pt from each group did not receive the randomized treatment. Baseline characteristics were balanced between the two groups, with the exception of histology, gender and previous medications. At data cut-off, 66 deaths had occurred (73% maturity) and median follow-up was 12.3 mo. OS was longer for SEL + DTIC vs PBO + DTIC (median 13.9 vs 10.5 mo), but this did not meet statistical significance (HR 0.93; 80% CI 0.67, 1.28; 1-sided p=0.3873). PFS was significantly improved for SEL + DTIC vs PBO + DTIC, median 5.6 vs 3.0 mo (HR 0.63; 80% CI 0.47, 0.84; 1-sided p=0.021). ORR was 40% with SEL + DTIC vs 26% with PBO + DTIC. Most frequent adverse events (AEs) observed with SEL + DTIC were: nausea (64%), dermatitis acneiform (52%), diarrhea (48%), vomiting (48%), and peripheral edema (43%). AEs that led to hospitalization were higher for SEL + DTIC vs PBO + DTIC (36 vs 13%), and were mostly infections and gastrointestinal disorders. The incidence of grade ≥3 AEs (68 vs 42%), serious AEs (50 vs 18%) and discontinuation of the randomized treatment due to AEs were higher for SEL + DTIC vs PBO + DTIC (16 vs 4%). Conclusions: Clinical activity was observed in patients with BRAF mutation-positive melanoma treated with SEL + DTIC, reflected by a nonsignificant improvement in OS and a significant benefit in PFS. Tolerability of this combination was generally consistent with the monotherapy safety profiles. Clinical trial information: NCT00936221.
NRAS and BRAF mutations in atypical melanocytic lesions arising in melanoma patients treated with vemurafenib.
Authors: Chu Emily Y. , Wilson Melissa , Sobanko Joseph , Miller Christopher , Suh EunRan , Xu Wei , Letrero Richard , Elenitsas Rosalie , Karakousis Giorgos , Xu Xiao wei , Elder David , Amaravadi Ravi K. , Schuchter Lynn Mara , Nathanson Katherine L. 
Published: March 2020

9017 Background: BRAF inhibition with targeted therapy has demonstrated improved overall survival in patients with BRAF mutant melanoma. The use of the selective BRAF inhibitors vemurafenib and dabrafenib are associated with a range of known and predictable cutaneous side effects, including squamous cell carcinomas often associated with RAS mutations. Preclinical evidence indicates that BRAF inhibitors may give rise to non-melanoma tumors by promoting MAPK activation in the tissues that lack mutant BRAF. Here we report atypical melanocytic lesions arising in patients treated with the BRAF inhibitor vemurafenib. Methods: To characterize the mutations of both the melanoma tumors and the atypical melanocytic lesions arising in patients with BRAF V600E/K melanoma treated with vemurafenib, a custom Sequenom panel designed to detect 74 mutations in 12 genes known to play a role in the pathogenesis of melanoma was applied to both melanoma and atypical melanocytic lesions for each patient. Results: We observed a total of six atypical melanocytic lesions (melanoma in situ and severely dysplastic nevi) in three patients undergoing treatment with vemurafenib. Mutations analysis in both pre-treatment tumor samples and on-treatment melanocytic lesions was feasible in two of the three patients. One patient with BRAF V600E metastatic melanoma developed two new melanoma in situ lesions while on vemurafenib, diagnosed 10 and 23 weeks after starting vemurafenib. Both on-treatment melanoma in situ lesions were found by Sequenom analysis to be BRAF wild-type, with a NRAS Q16R detected in one of the two lesions. Another patient’s pre-treatment primary melanoma demonstrated synchronous BRAF kinase domain mutations V600K and G466A, and CTNNB1 D32E mutation; a severely dysplastic nevus which arose after 25 weeks on vemurafenib in this patient showed only a BRAFG466A mutation. Conclusions: We identified an NRAS mutation and a rare BRAF kinase domain mutation in atypical melanocytic lesions that arose in patients treated with vemurafenib. Further studies are warranted to demonstrate a causal relationship between BRAF inhibition and the development or accelerated growth of atypical melanocytic lesions.
Pretreatment levels of absolute and relative eosinophil count to improve overall survival (OS) in patients with metastatic melanoma under treatment with ipilimumab, an anti CTLA-4 antibody.
Authors: Schindler Katja , Harmankaya Kaan , Postow Michael Andrew , Frantal Sophie , Bello Danielle , Ariyan Charlotte Eielson , Michielin Olivier Alain , Hoeller Christoph , Pehamberger Hubert , Wolchok Jedd D. 
Published: March 2020

9024 Background: Ipilimumab, a fully human monoclonal Ab directed against the CTLA-4 receptor on T-cells, has shown significant improvement in OS for patients with metastatic melanoma in randomized phase III trials. Eosinophilia in peripheral blood of those patients has been observed, but its clinical significance as a prognostic factor has not been assessed. Methods: We report on a retrospective multi-center analysis of 123 patients who received ipilimumab in three centers between 2010 and 2013. Patients treated had AJCC unresectable stage III or stage IV melanoma of any origin and received ipilimumab in first- and second-line setting at the approved standard dosage of 3mg/kg (4 times q21d). Four patients were excluded due to missing baseline values in eosinophil count (EC). Results: Median OS for patients in final analysis (n=119) was 9.57 months. Based on cut-offs assessed by ROC curves, OS was estimated by Kaplan-Meier curves. Baseline absolute eosinophil count (AEC) ≥ 0.1 (109/l) was significantly associated with improved OS (p= 0.002) with 6-, 12- and 18-month survival rates of 79%, 60% and 48% compared to rates of 48%, 37% and 19% for pts with baseline AEC below 0.1. Baseline relative eosinophil counts (REC) of ≥ 1.75% showed an even stronger significance (p<0.0001) with 6-, 12- and 18-months survival rates of 79% vs. 52%, 60% vs. 40% and 51% vs. 17.1% respectively. Conclusions: This retrospective analysis elucidates the possible association of baseline EC with OS of patients treated with Ipilimumab. Improvement of OS was highly significant in both analyses considering AEC (p= 0.002) and REC (p<0.0001). Since easily detectable biomarkers could be of great potential value, further effort on understanding the potential role of eosinophil granulocytes as possible effector cells in the immune-mediated response to anti CTLA-4 abs should be undertaken.
Preoperative imaging for staging of cutaneous melanoma in the United States: A population-based analysis.
Authors: Haddad Dana , Etzioni David , Pockaj Barbara A. , Gray Richard J. , Wasif Nabil 
Published: March 2020

9034 Background: Routine imaging for staging of early stage cutaneous melanoma is not recommended by National Comprehensive Cancer Network (NCCN) guidelines. Besides the low probability of finding metastatic disease, detrimental aspects include false-positives and additive cost. We sought to investigate the use of imaging for staging of cutaneous melanoma in the United States. Methods: Patients with newly diagnosed clinically node negative cutaneous melanoma between 2000-2007 were identified from the Surveillance Epidemiology End Results-Medicare registry. Any imaging performed within 90 days following diagnosis was considered a staging study. Patients with metastatic disease were excluded. Results: A total of 25,643 patients were identified, of whom 10,775 (42%) underwent imaging. The mean age was 76.1 years, with the majority being male (61.8%) and Caucasian (98.4%). Breakdown by T classification of the primary was as follows: T1 (63%), T2 (17%), T3 (12%), and T4 (8%). A chest Xray was performed for 9,737 (38.0%), while 3,176 (12.4%) underwent advanced staging imaging studies; PET (7.2%), CT (5.9%), MRI (0.6%), and Ultrasound (0.4%). The use of advanced imaging steadily increased over the period of our study from 9.0% in 2000 to 16.3% in 2007 (p<0.001). When stratified by T classification, advanced imaging was used for 8.9% of T1, 14.5% of T2, 18.8% of T3 and 27.0% of T4 tumors (p<0.001). Similarly, node positive patients (4.7%) underwent advanced imaging 33.4% of the time compared to 11.3% for node negative patients (p<0.001). On multivariate analysis, factors predictive of advanced imaging include higher T classification (OR 3.12 T4 vs. T1, CI 2.77-3.52, p<0.001), node positivity (OR 2.70, CI 2.36-3.09, p<0.001), more recent year of diagnosis (OR 2.01 2007 vs. 2000, CI 1.71-2.37, p=0.006), high school education (OR 1.62, CI 1.43-1.83, p<0.001), non-Caucasian race (OR 1.37, CI 1.05-1.77, p=0.018), and male gender (OR 1.12, CI 1.03-1.21, p=0.006). Conclusions: Contrary to current recommendations, performance of advanced imaging for staging of early stage cutaneous melanoma is increasing in the Medicare population. Further research is needed to identify factors driving this increase.
Ipilimumab retreatment following induction therapy: The expanded access program (EAP) experience.
Authors: Margolin Kim Allyson , Hamid Omid , Weber Jeffrey S. , Pavlick Anna C. , Hodi F. Stephen , Amin Asim , Bennett Kelly , Michener Tracy , Minor David R. 
Published: March 2020

9041 Background: Phase III study MDX010-020 for patients (pts) with advanced melanoma showed that retreatment (ReRx) with ipilimumab (Ipi) upon disease progression could result in further clinical benefit (Hodi et al. NJEM 2010). The Ipi EAP (CA184-045), conducted from 3/2010 to 3/2011, allowed ReRx with Ipi for a subset of pts with progression after benefit from their initial Ipi (SD for ≥3 months or objective response). Methods: Pts with unresectable stage III/IV melanoma who progressed on ≥1 systemic therapies or had no alternative treatment options were eligible for the EAP. Pts who received 3 mg/kg Ipi i.v. q 3 wks up to 4 doses on the EAP were eligible for ReRx using the same regimen if they had not experienced unacceptable toxicity requiring Ipi discontinuation (e.g., grade 4 any severe adverse events (AEs), grade 3/4 immune-related AEs (excluding endocrinopathies)), and had disease progression after clinical benefit defined as ≥3 months SD or objective response, or delayed response following progressive disease not requiring a different interval therapy. Endpoints of this retrospective analysis were clinical benefit defined by objective response or SD ≥3 months and toxicities measured by occurrence of serious adverse events (SAEs), irAEs, or death on study. Results: 108/2155 pts (5%) met the eligibility criteria for ReRx. Among these 108 pts, grade 3 drug-related SAEs during initial therapy were endocrinopathies only (4%). During ReRx, grade 3 drug-related SAEs, all <2%, were colitis, diarrhea, GI hemorrhage, fatigue and dehydration, similar to the toxicities of Ipi in the full EAP cohort of 2155 pts. Three pts (3%) of the 108 in this ReRx cohort had drug-related GI SAEs leading to discontinuation of Ipi. Among these pts who underwent ReRx, the median OS from the 1st initial therapy dose was 21.1 months. Conclusions: In this analysis of EAP pts who experienced benefit from initial Ipi therapy (including those with durable SD who subsequently progressed) and received ReRx with Ipi, no new safety signals were identified. The potential benefit of Ipi ReRx on OS will be prospectively evaluated in an ongoing phase II study in which pts who qualify are randomized to Ipi ReRx or physician’s choice alternative therapy. Clinical trial information: NCT00495066.
Biomarker study in patients with resectable AJCC stage IIIc or stage IV (M1a) melanoma treated in a randomized phase II neoadjuvant trial.
Authors: Chakravarti Nitin , Ivan Doina , Ross Merrick I. , Ilagan Joseph L. , Warneke Carla L. , Kim Kevin , Papadopoulos Nicholas E. , Cain Suzanne , Gershenwald Jeffrey E. , Johnson Marcella M. , Bedikian Agop Y. , Royal Richard E. , Cormier Janice N. , Hanna Ehab Y. , Lee Jeffrey Edwin , Prieto Victor G. , Hwu Wen-Jen 
Published: March 2020

9047 Background: Fewer than 30% of patients with resectable stage IIIC or IV (M1a) metastatic melanoma (MetM) who undergo surgical resection will achieve long-term survival. This study was designed to administer neoadjuvant systemic therapy prior to definitive surgery to explore potential predictive and prognostic biomarkers in patients with MetM. Methods: Fifty patients with resectable MetM were randomized to receive temozolomide (TMZ) alone at 150 mg/m2/day x 7 days every other week (Arm A, n=26) or with pegylated interferon (PGI) at 0.5 mcg/kg weekly (Arm B, n=24). After a pre-treatment tumor biopsy, patients received 8 weeks of neoadjuvant therapy before undergoing surgery. Endpoints were clinical response, tolerability, and biomarker analysis by immunohistochemistry and gene array. In particular, we examined PD-1, PD-L1, pAKT, pMAPK, Ki67, and caspase 3. Patients with response (complete-, partial-, or stable disease) received up to 3 additional cycles of the assigned regimen as adjuvant therapy. Results: Overall response to neoadjuvant therapy was 38% [1 CR, 15 PRs, 3 SDs]: 31% in Arm A (95% CI 14% - 52%) and 46% in Arm B (95% CI 26% - 67%). Estimated 4-year overall survival was 52.52% (95% CI 35.86 - 66.74%). Only 5 patients did not undergo definitive surgery after neoadjuvant treatment due to development of distant metastasis. Preliminary data indicate that in Arm B, responders had higher PD-1 membranous expression in tumor infiltrating lymphocytes (TILs) (p=0.029). Furthermore, low PD-L1 cytoplasmic expression in TILs (p=0.002) as well as low nuclear PD-L1 expression in tumor cells (p=0.025) had better overall survival. Conclusions: Comparing with historical data, neoadjuvant therapy has a potential to improve overall survival in patients with resectable MetM. Biomarker analysis may predict response to neoadjuvant treatment as well as overall survival. Clinical trial information: NCT00525031.
Role of the immunoglobulin constant region in the antitumor activity of antibodies to cytotoxic T-lymphocyte antigen-4 (CTLA-4).
Authors: Korman Alan J. , Engelhardt John , Shahabi Vafa , Yordanova Roumyana , Henning Karla , Chen Timothy , Selby Mark 
Published: March 2020

9055 Background: Anti-CTLA-4 therapy enhances antitumor T-cell responses by both cell-intrinsic and cell-extrinsic mechanisms. Effector T-cell (Teff) activation is increased directly by interfering with CTLA-4-B7 interactions that negatively regulate T cells and by interfering with CTLA-4 expressed on regulatory T cells (Tregs), which function to inhibit immune responses. To analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies (Abs), we examined the role of the immunoglobulin constant region in the antitumor activity of anti-CTLA-4 Abs in mouse tumor models. Methods: The activity of anti-CTLA-4 Abs with different mouse IgG constant regions were compared in several mouse tumor models, and intratumoral and peripheral T cells were analyzed by FACS. DNA samples from 488 patients with metastatic melanoma who received ipilimumab in a phase III clinical trial, MDX010-20, were analyzed for polymorphisms in the IgG fragment c receptor (FcR) at FCGR3A (V158F) and FCGR2A (H131R) loci. Results: In subcutaneous MC38 and CT26 colon tumor models, an anti-CTLA-4 Ab containing the mouse IgG2a constant region exhibited enhanced antitumor activity compared to an anti-CTLA-4 Ab containing the IgG2b constant region, while anti-CTLA-4 Abs containing mouse IgG1 or a mutated mouse IgG1 D265A constant region showed no activity. Anti-CTLA-4-IgG2a caused a dramatic reduction of Tregs at the tumor site that resulted in a greater Teff/Treg ratio. In contrast, all isotypes resulted in expansion of Tregs in the periphery. These results point to an important role for FcR in the action of anti-CTLA-4 Abs. In patients from study MDX010-20, there was no association between the 2 FcR polymorphisms (FCGR3A and FCGR2A) and overall survival. Conclusions: These preclinical studies reveal a novel dual activity of anti-CTLA-4 Abs consisting of intratumoral reduction of Tregs together with activation of Teff cells. This effect is mediated by the constant region and is presumably due to antibody-dependent cellular cytotoxicity. The data suggest that FcR-bearing cells at the tumor site, as well as the presence of intratumoral Tregs, may be important factors in the antitumor activity of anti-CTLA-4 Abs.