bluuebunny/crossref_metadata_2025 huggingface dataset:
Allogeneic hematopoietic cell transplantation (alloHCT) in diffuse large B-cell lymphoma (DLBCL) after nonmyeloablative (NMA) or reduced-intensity (RIC) conditioning: Long-term outcome in 116 patients.
Authors: Poon L. M. , Saliba Rima , Rondon Gabriela , Okoroji Grace-Julia , Oki Yasuhiro , Champlin Richard E. , Hosing Chitra , Young Ken H , Turturro Francesco , Khouri Issa F.
Published: March 2020

8561

Background: The role of alloHCT and conditioning intensity in DLBCL remains unclear. In this retrospective study, we determined their effectiveness in 116 patients (pts) with DLBCL (de novo, n=59, transformed, n=57) receiving alloHCT at our institution, between 1998-2011. Methods: Median age was 51years (range, 19-70); median prior therapies was 4 (range 2-12). Disease status at alloHCT was complete response (CR) (n=22), partial response (PR) (n=58), stable (SD) (n=25) or progressive disease (PD) (n=11). 41 (35%) pts had previous autografts. 74 (64%) pts received RIC of melphalan/fludarabine (Flu) or BEAM, and 42 (36%) received a NMA conditioning of Flu/cyclophosphamide or cisplatin/cytarabine/ Flu. Donor source was HLA-identical sibling (MRD) (65%), HLA-matched unrelated (MUD) (31%) or a 1-Ag mismatched donor (4%). Results: With median follow-up among survivors of 63 months (range 5-157), estimated 5-yr OS and PFS for the whole cohort was 41% and 34% respectively. On multivariate (MV) analysis, disease status was most significant predictor for OS, with chemo refractory disease (SD/PD) being associated with higher mortality rate (HR 3.7, 95% CI 1.6-8.6, p=0.002). Combined use of NMA conditioning and MRD was associated with significantly lower mortality rate (HR 0.4, 95% CI 1.6-8.6, p=0.005). OS was highest [69% (95% CI 49-82)} for pts in CR/PR after NMA with a MRD (n=29), and lowest [(12% (95% CI 3-29)] for SD/PD pts after RIC with a non MRD (n=32). Disease status was strongest predictor of PFS on MV analysis, with CR pts having improved PFS compared to SD/PD (5-year estimates of 58% and 13%, respectively (P<0.001). Pts in PR with early disease stage (< Stage 4) and negative PET at alloHCT had PFS comparable to pts in CR (56% at 5 yr HR=1.3, p=0.6), while all other PR pts had PFS comparable to SD/PD pts (PFS=20%, p 0.1). Conclusions: Our study shows disease status, donor type and conditioning intensity are predictors of outcomes after alloHCT in DLBCL. Pts with chemosensitive disease and receiving NMA, MRD had improved survival rates compared to RIC alloHCT. PR pts with low volume PR had similar outcomes to CR pts.
A matched pair analysis of conditioning BuEM versus BEAM in autologous haematopoietic cell transplantation for lymphomas in terms of toxicity and efficacy.
Authors: Sakellari Ioanna , Mallouri Despina , Batsis Ioannis , Apostolou Chryssoula , Konstantinou Varnavas , Abela Elma Maria , Douka Vassiliki , Marvaki Anastasia , Karypidis Kyriakos , Michail Iskas , Baliakas Panayiotis , Kaloyannidis Panayiotis , Yannaki Evangelia , Kouvatseas George , Smias Christos , Anagnostopoulos Achilles
Published: March 2020

8567

Background: In autologous hematopoietic cell transplantation (AHCT) for lymphomas, the optimal conditioning regimen is currently investigated. The standard conditioning used is BEAM. During 2009-2011 a new alternative Busulphan-based conditioning regimen constructed in our unit, consisting of Busilvex (9.6 mg/Kg), Etoposide (9.6 mg/Kg) and Melphalan (140mg/m^2) (BuEM) was used. We retrospectively analysed the outcome of patients (pts) conditioned with BEAM and BuEM regimen, in terms of toxicity and efficacy, in a matched pair analysis. Methods: A matched paired analysis on a 1:2 ratio was performed. Thus, 2 control cases (receiving BEAM regimen) were matched to each patient treated with BuEM according to: phase of transplant, age, lines of previous chemotherapy. The first 50 consecutive pts treated with BuEM were matched to a random sample from the historical BEAM control population. Ninety-three BEAM pts that fulfilled the matching criteria were eventually randomly selected. Concerning pts characteristics there were no statistical significant differences except from more chemoresistant disease in the BuEM cohort (p=0.008). Thus a second matched pair analysis was conducted upon stratification by disease chemosensitivity instead of age as a risk factor. Results: Progression free survival and overall survival (OS) were 70.6% and 81.8% for the BEAM vs 68.9% and 83% for the BuEM cohort respectively (p=ns). In the BuEM cohort a borderline significantly better OS was noted in Hodgkin’s pts receiving BuEM (p=0.05). In terms of early toxicity a significantly faster neutrophil engraftment was found in the BEAM cohort, but there was a significantly less need of red blood cells, platelet transfusions and GCSF infusion in the BuEM cohort. BEAM regimen was also associated with: reduced incidence of infections (p=0.02), less severe (grade 3-4) mucositis (p=0.000) and liver toxicity (p=0.004). Conclusions: BEAM regimen was correlated with a favourable reduced early toxicity profile, ie severe mucositis and liver impairment. On the other hand, BuEM was found to be equally efficacious and moreover offered improved overall survival in Hodgkin’s lymphoma pts.
Impact of rituximab on the course of low-grade follicular lymphoma.
Authors: Krishnamurthy Jairam , Loberiza Fausto R. , Bast Martin , Tandra Pavankumar , Bhatt Vijaya Raj , Bociek Gregory , Bierman Philip Jay , Vose Julie , Armitage James O.
Published: March 2020

8572

Background: Rituximab has revolutionized the treatment of lymphomas and has been shown to improve clinical outcomes in patients with follicular lymphoma. Our study evaluated the progression free survival (PFS) and overall survival (OS) in patients with grades I and II follicular lymphoma when rituximab was used as initial therapy, as salvage or if no rituximab was used. Methods: Patients with grades I and II follicular lymphoma treated between June 1981 and January 2010 were included. Disease and treatment related variables were compared based on type of treatment (No rituximab-Group I, rituximab as salvage-Group II, Rituximab as initial treatment-Group III) using the Kruswal Wallis or chi-square tests. Univariate probabilities of PFS and OS were estimated using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazards regression analysis to evaluate differences in risk of treatment failure and mortality in the three groups while adjusting for covariates. Results: There were 226 patients in group I, 84 in group II and 110 in group III. Significant differences were found in some of the disease and treatment related variables. Univariate analysis is shown in the Table. The relative risk of treatment failure for group II was 0.82 (p=0.26) and 2.63 (p=0.0001) respectively in the first 10 years and after 10 years while it was 0.52 (p=0.0003) and 3.97 (p=0.001) respectively for group III in the first 10 years and after 10 years. The relative risk of mortality in group II was 0.63 (p=0.008) and group III was 0.32 (p<0.0001). Conclusions: Overall survival for patients with low grade follicular lymphoma is significantly improved when rituximab is used as initial treatment or as salvage when compared with no rituximab. [Table: see text]
Single ascending dose escalation study of the specific Syk inhibitor P505-15 investigating pharmacokinetics, pharmacodynamics, and safety in healthy male volunteers.
Authors: Coffey Greg , Rani Aradhana , Betz Andreas , Pak Yvonne , Pandey Anjali , Hollenbach Stanley , Gretler Daniel D. , Mant Tim , Jurcevic Stipo , Sinha Uma
Published: March 2020

8574

Background: The spleen tyrosine kinase (Syk) regulates immune cell activation in response to ligation of a variety of receptors, making it an intriguing target for inflammatory and autoimmune disorders, as well as certain B cell malignancies. Here we present data from our first human study aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of P505-15, a selective Syk inhibitor in male volunteers following single oral administration. Methods: This study was a single center, blinded, randomized, placebo-controlled, ascending, single dose study of oral P505-15 suspension or its matching placebo, administered to healthy male volunteers. Dosing was initiated at 3mg and escalated to 400mg over seven cohorts. Serial blood samples for PK and PD evaluations were analyzed. The PD assays were designed to determine the potency and specificity of Syk inhibition. Potency for Syk inhibition was determined by measuring B cell receptor- (BCR) mediated ERK Y204 phosphorylation and cellular activation (CD69), as well as FcεRI-mediated basophil degranulation. Results: PK data indicate that P505-15 has a long terminal half life (~50-60 hrs), a Tmax of about 2 hrs, and oral exposure more than dose proportional up to the 200mg dose. Complete inhibition of all three Syk-dependent assays was observed in the 200mg and greater dose levels. PD effect in the basotest approximated IC50 at 24 hours post-dose, and returned to pre-dose levels by 72 hours. At all dose levels, no inhibition of PMA or fMLP induced signaling and leukocyte activation was observed, consistent with a high degree of selectivity for Syk. Analysis of the PK/PD relationship indicated an IC50of 208nM (95% confidence interval of 190-225) for inhibition of BCR-mediated B cell activation, and 124nM (95% confidence interval of 117-131) for inhibition of FcεRI-mediated basophil degranulation. Conclusions: P505-15 was safe and well tolerated across the entire range of doses. These data show that P505-15 has a favorable PK profile, and demonstrate its utility to safely and potently suppress Syk kinase function in humans.
Whole genome sequencing of sporadic Burkitt lymphoma in HIV-infected and uninfected patients.
Authors: Ritter Deborah , Walker Kimberly , Kwon Myoung , Lulla Premal , Bollard Catherine M. , Sheehan Andrea , Heslop Helen E. , Gibbs Richard A. , Wheeler David A. , Mims Martha P.
Published: March 2020

8577

Background: Burkitt Lymphoma is defined by canonical translocations between MYC and immunoglobulin IgH, IgK or IgL (8:14, 8:2, 8:22, respectively), and is commonly associated with HIV. The identification of HIV from sequenced samples is critical to understanding HIV-associated Burkitt Lymphoma. While recent novel gene mutations (ID3 and TCF3) have been implicated in functional roles, concomitant genomic structural variants and the interaction of HIV with structural variation is less well defined. Methods: We sequenced the whole genomes of 15 patients with 100bp paired-end reads on Illumina Hi-Seq platform, resulting in an average insert size of 278 (+/- 63) and coverage of 60X tumor and 30X normal. We included 7 HIV-negative, and 8 HIV-positive subjects. Sequencing reads were mapped to the reference genome using BWA. Large-scale structural variation was detected by the BreakDancer and Crest programs. Functional annotation was used to prioritize structural variants for validation. Single nucleotide variants and small insertions and deletions were detected by CARNAC, a somatic variation discovery pipeline. The subset of WGS reads that failed to align to the human reference genome were tested for the presence of HIV sequences by comparing the unmapped reads to a database of viral DNA sequences which included the common subtypes of HIV defined by Los Alamos. Reads matching HIV or EBV with an expectation value of <10-4 were analyzed to determine virus coverage and viral integration sites. Results: Canonical MYC-IgH translocations were identified in 9/15 (60%) tumor samples, with 2 additional subjects harboring either a deletion or an inversion near exon1 of MYC; 4 had no MYC rearrangement. MYC translocations occurred equally in both groups. TP53 and SMARC4 point mutations were observed recurrently in the HIV uninfected group but not in the HIV infected patients. Variable levels of HIV DNA sequence were observed in normal tissue of all HIV infected patients. Conclusions: Whole genome sequencing has identified known somatic variants in HIV infected and uninfected patients. Two genes, TP53 and SMARC4, appear to be differentially mutated, but additional samples are needed to achieve statistical significance.
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.
Health behaviors and survivorship needs of short- versus long-term melanoma survivors.
Authors: Swetter Susan M. , Gerry Arianna Aldridge , Bugos Kelly , Greco Ralph Steven , McGurk Katherine L. , Palesh Oxana
Published: March 2020

9061

Background: Little is known about melanoma survivors and their long-term symptoms, sun protection practices and support needs from health professionals. Methods: Melanoma survivors previously treated at Stanford Cancer Center completed a quality improvement survey to explore the value of a melanoma survivorship clinic, as part of the Stanford Cancer Survivorship Program. The survey period ranged from July 2012 to September 2012, and 17% of the 893 invited survivors responded. We compared responses of melanoma survivors diagnosed between 2006-2011 (short-term) and 1995-2005 (long-term). Results: 153 cancer survivors (41% short- and 59% long-term) completed the survey. On average, they were 62 years of age (SD=15.1), 94% Caucasian, 47% female, and 68% underwent local excision alone. Long- vs. short-term survivors were less likely to receive routine skin screening every 3-6 months (38% vs. 83%, p<0.001) or follow-up for their melanoma in the last 6 months (54% vs. 76% p=0.045). Sun protection practices were similar between groups; however, long-term survivors decreased their use of tanning beds (33% vs. 18%, p=0.03) and time seeking a tan relative to short-term survivors (72% vs. 48%, p=0.002). Overall, survivors rated anxiety as the most prevalent symptom (33%), followed by numbness of the scar site (31%), forgetfulness (26%), sleep problems and depression (23%), pain and fatigue (17%). Sixty-eight percent of all survivors reported their symptoms were not addressed by their health provider, and of those stating their provider addressed their symptoms (32%), the survivor initiated the conversation 71% of the time. In general, survivors desired education about the long-term effects of melanoma (41%), family risk of skin cancer (28%), and protecting their skin from further damage (20%). Twenty percent of all survivors requested treatment for the long term effects of melanoma, and 12% wanted emotional support. Conclusions: Melanoma survivors experience continuing symptoms long after treatment, namely anxiety, and express a need for information about long-term melanoma effects, psychosocial support, and prevention of further skin cancer. Clinicians should routinely assess survivorship needs to improve quality of life.
Efficacy, safety, and pharmacokinetics (PK) of the BRAF inhibitor dabrafenib (D) hydroxypropyl methylcellulose (HPMC) capsule formulation in combination with the MEK1/2 inhibitor trametinib (T) in patients (pts) with BRAF mutation-positive metastatic melanoma (MM).
Authors: Schuchter Lynn Mara , Kudchadkar Ragini Reiney , Gonzalez Rene , Lawrence Donald P. , Sosman Jeffrey Alan , Infante Jeffrey R. , Daud Adil , Kefford Richard , Cebon Jonathan S. , Sharfman William Howard , Amaravadi Ravi K. , Boasberg Peter D. , Lewis Karl D. , Flaherty Keith , Ouellet Danielle , Little Shonda M , Clark Jennifer , Gibney Geoffrey Thomas , Patel Kiran , Hamid Omid
Published: March 2020

9066

Background: Preclinical studies ofD + T show enhanced activity in BRAF mutant MM vs either drug alone. D + T safety and efficacy were evaluated in a 4-part (A–D) phase I/II study. Part D assessed the impact on efficacy, safety and PK of a more stable HPMC capsule formulation of D alone, and in combination with T, instead of the gelatin capsule used in Parts A–C. Methods: 110BRAFV600E/KMM pts with RECIST measurable disease were randomized to 4 cohorts. Dose-limiting toxicities (DLTs) were evaluated for the first 3 weeks of treatment. PK sampling was done on Days 1 and 21. Primary endpoints were PK and safety; secondary endpoints were response rate (RR) and overall survival (OS). Results: Median age was 54 years, 58% male, 65% ECOG PS 0, 88% V600E, 68% M1c stage, 97% no prior brain metastases, and 45% LDH > ULN. Treatment (tx) with D HPMC + T had little impact on ratio of D Cmax (1.16) and D AUC (1.23) vs D tx alone; but led to higher ratio of D Cmax(1.51) but similar D AUC (1.10) vs D gelatin + T seen in Part B. Median progression-free survival (PFS) and RR are in Table. Median PFS not reached in D4. No DLTs occurred in the first 15 subjects enrolled in D4. Most common AEs (≥40%) for all cohorts were pyrexia, nausea, chills, vomiting, arthralgia, and fatigue. Most common grade >3 AEs (all 5%) were hypertension, pyrexia, increased GGT, and hyponatremia. 11% of pts discontinued treatment due to an AE. There were no major differences in toxicities between cohorts and Parts A–C. Conclusions: The D + T combination had an acceptable safety profile with clinically manageable side effects. D HPMC + T had little impact on D Cmax and D AUC vs D alone. D HPMC led to higher D Cmaxbut similar D AUC vs gelatin + T. Meaningful clinical activity was seen in all dose combinations with D HPMC +T; PFS, RR, and duration of response were consistent with other study parts. Phase 3 studies with D HPMC + T are ongoing. Clinical trial information: NCT01072175. [Table: see text]
A phase I study of high-dose calcitriol in combination with temozolomide for patients (Pts) with metastatic melanoma (MM).
Authors: Pettijohn Erin , Rademaker Alfred , Martone Brenda K. , Poast Erica , Weitner Bing Bing , Eklund John W. , Kuzel Timothy
Published: March 2020

9087

Background: Temozolomide (Tem) has demonstrated efficacy as an oral alternative for pts with MM on traditional and extended dosing schedules. Calcitriol has known antiproliferative properties in vitro, and has shown synergistic effects with chemotherapy. Additionally, vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and disease progression. Specifically, the VDR genotype tt/ff (Taq1 and Fok1 polymorphisms) has been associated with tumors >3.5mm, though no studies have focused on survival. Methods: Tem 150mg/m2was administered on days 2-8 and 16-22 every 28 days until progression or significant toxicity. Calcitriol was given on days 1 and 15 every 28 days with 3 pts at a dose of 0.2mcg/kg, 3 pts at 0.3mcg/kg, 3 pts at 0.5mcg/kg, and an additional 11 pts at a maximum dose of 0.5mcg/kg. VDR gene analysis was completed on 17/20 pts using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (PFS) and overall survival (OS), both as a whole and by VDR genotype. Results: Twenty pts (males=15) with MM treated with at least one prior systemic therapy or who were not candidates for interleukin-2 (conducted pre BRAF and anti CTLA agents), were accrued. Median age was 58. The regimen was well-tolerated with leukopenia, lymphopenia, thrombocytopenia, anemia, and thrombosis as the most common grade 3 or 4 toxicities at 10% incidence each, less than observed in prior studies (Patel et al Eur J Ca 2011). Obj RR was 10%. Median PFS was 1.8 mo with a mean of 2.7 cycles given. Pts with low-risk VDR genotype non-tt or ff (n= 11) had a median OS of 7.4 mo compared to 3.8 mo for tt or ff or both (n=6)(median ratio=1.95) from time of enrollment, although not statistically significant given small sample sizes. Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated oral regimen in MM. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness. Whether this represents a benefit of the inclusion of calcitriol should be studied further. Clinical trial information: NCT00301067.
Frequency of BRAF V600E variant in circulating free DNA compared with the single melanoma biopsy.
Authors: Di Guardo Lorenza , Vallacchi Viviana , Frigerio Simona , Cova Agata , Squarcina Paola , Giardino Felicetta , Frati Paola , Colonna Valentina , Patuzzo Roberto , De Braud Filippo G. , Santinami Mario , Rivoltini Licia , Rodolfo Monica
Published: March 2020

9092

Background: To select melanoma patients for treatment with BRAF inhibitors, the BRAF mutational status is determined in the most recent tumor biopsy. However, tumor specimens are not always available for the analysis, and relying on a single biopsy specimen can potentially exclude from treatment patients with heterogeneity among metastatic tumors due to polyclonality of BRAF mutation, which appears as a rather common condition. As an alternative approach we explored a blood-based mutation detection assay. Methods: We developed a method including enrichment for the BRAV600E variant by selective elimination of the wild type allele by TspRI digestion and BRAFV600E detection by TaqMan Mutation Detection Assay (BRAF_476_mu, Life Technologies). Sensitivity testing showed that BRAFV600E variant was detected starting from 6.25X10-5 ng of DNA, and specificity testing showed that the variant can be detected when diluted in 8X105 copies of wild-type alleles. Results: Mutational analysis performed by Sanger sequencing of exon15 in 114 melanoma biopsies showed that 4 (3%) harbored the c.1798_1799GT>AA (V600K) mutation, 1 (1%) the c.1799_1800TG>AA mutation (V600E), and 56 (49%) the most common c.1799T>A mutation (V600E), while by the novel method the latter mutation was detected in 9 additional specimens (8% increment) and confirmed by sequencing the PCR product after TspRI digestion. Pre-surgery plasma was available for 50/114 patients at advanced stages, 26/50 (52%) showing a mutated specimen, including 4 with a double nucleotide substitution (V600K and V600E). The matched plasma samples resulted mutated in 25/26 cases with mutated biopsy and in further 14/25 samples with biopsy resulting wild type; in contrast, plasma of 50 healthy controls tested negative. Taken together, these results indicate that V600E circulating variant was detectable in 39/50 (78%) plasma samples and in 22/50 (44%) tumor specimens. Conclusions: Detection of BRAF V600E variant in circulating free DNA may represent a more sensitive approach for patient selection and decision making process during the treatment with BRAF inhibitors.
Identification of functional DNA methylation aberrations associated with outcome in melanoma patients with brain metastasis.
Authors: Marzese Diego M , Huynh Jamie L , Huang Sharon , Hirose Hajime , Kiyohara Eiji , Morton Donald L. , Kelly Daniel F. , Hoon Dave S. B.
Published: March 2020

9095

Background: Brain metastasis (MBM) represents one of the most significant causes of death in melanoma patients. Identification of clinically relevant markers is necessary to recognize patients with high risk of MBM development. Alterations in DNA methylation patterns have been recognized as a major epigenetic hallmark of metastasis initiation and progression. Methods: To generate a comprehensive genomic DNA methylation landscape of MBM, we performed genome-wide data integrative analyses examining the DNA methylation (Illumina HumanMethylation 450K), gene expression (Affymetrix HumanExon 1.0), and genotype (Affymetrix SNP 6.0) of specimens related to melanoma progression from normal to MBM (n=65). Results: We observed significant genome-wide hypomethylation and CpG island hypermethylation according to melanoma progression to the brain. To identify significant differentially methylated CpG sites between lymph node metastasis and MBM, we applied a strict statistical threshold (β-value difference >0.3 and FDR-corrected p <0.005). We identified the homeobox D (HOXD) gene family members amongst the most significantly affected genes. The influence on gene expression and the frequency of HOXD hypermethylation were verified using integrative analysis of publicly available data generated from 168 melanoma specimens. In a cohort of clinically annotated melanoma patients (n = 159), we demonstrated that hypermethylation of a genomic region in the HOXD gene cluster was significantly associated with shorter disease-free survival (p = 0.004) and overall survival (p = 0.002).Multivariate analysis confirmed the association with poorer survival (p = 0.01 and HR = 2.8; CI95%: 1.3-6.1). Conclusions: The use of genome-wide DNA methylation, gene expression, and genotyping integrative analyses allowed the identification of novel markers with functional and clinical implications for melanoma patients with brain metastasis.