bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of etoposide area under the curve (AUC) in lymphoma patients treated with BEAM regimen and ASCT: Multicenter study of Groupe d’Etudes des Lymphomes de l’Adulte (GELA).
Authors: Bally Olivia , Freyer Gilles , Salles Gilles A. , Michallet Anne-Sophie , Casasnovas Olivier , Tilly Herve , Ribrag Vincent , Sebban Catherine , Falandry Claire , You Benoit
Published: March 2020

8068

Background: The prospective LYMPK study primary objective was to assess the impact of etoposide pharmacokinetic (PK) parameters on toxicity and efficacy in lymphoma patients receiving the BEAM regimen (carmustine, cytarabine, etoposide and melphalan) followed by autologous stem cell transplant (ASCT). We previously showed the high inter-individual variability in etoposide PKs, defined by area under the curve (AUC) and trough concentration (Cmin), among study patients treated with the same doses /m2 (You B et al, Proc. ASCO 2008). Methods: Ninety-six patients with malignant lymphoma at 1st line (n=52) or relapse (n=44) were enrolled in 5 centers. All received BEAM regimen, including high-dose etoposide (100 to 200 mg/m2 bid for 4 days), followed by ASCT. Individual etoposide AUC and Cmin were estimated by population PK approach using NONMEM program. The impact of PK parameters on toxicity and survival was assessed using linear regression and univariate/multivariate analyses. Results: Data from 90 patients were assessable after a 4.2-year median follow-up. The bi-compartment model previously reported was used to characterize PK parameters (You B et al, Proc. ASCO 2008). Etoposide AUC and Cmin correlated with mucositis duration, especially for grade 3-4 toxicity (p< 0.05), but not with other toxicities. Cmin had significant prognostic value regarding 5 year progression free survival (p=0.03). Five year overall survival (OS) was longer in patients with higher AUC (76% vs 56%, if AUC > median, p=0.04) as it was in patients with higher Cmin (78% vs 54%, if Cmin > median, p=0.02). When assessed with available IPI prognostic factors (age; performance status; LDH and stage) using Cox analysis, the only independent prognostic factors of OS and disease specific survival were etoposide AUC (HR= 0.39, 95% CI = 0.16-0.94) and Cmin (HR = 0.32, 95% CI = 0.12-0.80). Conclusions: LYMPK study results suggest that individual etoposide systemic exposure has a strong impact on survival in lymphoma patient receiving BEAM regimen and ASCT. Given the high variability in patient AUCs, plasma concentration-based adjustment of etoposide dose may be considered in future studies.
Ocular adnexal lymphoma (OAL)-outcomes for 82 patients (pts) treated at a single center.
Authors: Portell Craig Anthony , Aronow Mary E , Rybicki Lisa A. , Singh Arun D , Sweetenham John W.
Published: March 2020

8071

Background: OALs comprise 1-2% of NHL and are extranodal marginal zone (EMZL) in 80% of cases. We present a retrospective review of 82 pts with OAL managed at the Cleveland Clinic between January 2004 and November 2011. Methods: 82 pts with NHL of the OA were identified. All biopsies were performed/reviewed at the Cleveland Clinic. Survival and relapse were estimated using the Kaplan-Meier method. Risk factors for relapse and survival were identified using Cox proportional hazards analysis. Risk factors included age at diagnosis (dx), gender, prior autoimmune disease, prior lymphoma history (hx), hx of other malignancy, bilateral disease, and ocular disease site. Results: The table lists pt characteristics. Median follow-up was 25.8 months (range 0.3-307.4). Age at dx (HR=1.45, CI 1.04-2.02) and prior lymphoma hx (HR=3.35, CI 1.33-8.46) were predictive of relapse in a multivariate analysis. There was no difference in relapse rates between pts with EMZL and other lymphoma types (p=0.82). Relapse occurred in 26 (31.7%) pts with most common sites being ipsilateral eye (n=8), contralateral eye (n=3), distant lymph node (n=11), and other organs (n=11). Most common organ was breast (n=4). Of the 10 pts who had eye-only relapses, 8 received rituximab (R) and 2 were observed. Of the 16 with extraocular relapse, 9 received radiation (RT), 2 received R, 3 received other therapies, and 2 were observed. 7 deaths were recorded with a 5 year overall survival of 84.2%. Survival was similar to a matched healthy population (p=0.69). Causes of death were lymphoma in 4, another cancer in 1, and unknown in 2. Conclusions: OAL relapse patterns differ depending on initial treatment. Initial RT was more likely to relapse at distant sites; where as initial R was more likely to relapse in the OA. RT should be used for localized OAL. With bilateral ocular or systemic disease, R results in a high rate of long-term disease control. [Table: see text]
The impact of race, age, and sex in follicular lymphoma (FL): A comprehensive SEER analysis in the pre- and post-rituximab (R) eras.
Authors: Nabhan Chadi , Aschebrook-Kilfoy Briseis , Chiu Brian C-H , Kruczek Kimberly R. , Clemenzi-allen Angelo , Patel Anand , Smith Sonali M. , Evens Andrew M.
Published: March 2020

8072

Background: While racial disparity has been well documented in a number of cancers, the impact of race in FL outcomes is not well defined. Further, the importance of gender in FL has not been fully explored. Methods: We examined population-based FL overall survival (OS) data from SEER 13 (1993-2008) regarding race, sex, age, and socioeconomic status (SES) over two consecutive 8-year (yr) periods: Era 1 (1993-2000, n=7,409) and Era 2 (2001–2008, n=9,083). Results: We identified16,492 FL patients (pts) (white (W): n=13,441; Hispanic (H): n=1,417; Asian/Pacific Islander (A/PI): n=887; and Black (B): n=747). Median ages at diagnosis differed significantly according to: (in yrs, W: 62.1, H: 57.3, A/PI: 60.5, B: 56.6; P<0.01 for each race vs. W). For all pts, OS was superior in Era 2 vs. Era 1 (5-yr OS: 77% vs. 68%, respectively, P<0.0001). Further, OS was significantly improved for all age groups (<50, 50-59, 60-69, and 70-79 yrs) as well as for males (P=0.0019) and females (P<0.0001) across eras. Interestingly, females had superior OS compared with males in Era 1 (P=0.004), but not in Era 2 (P=0.83). We subsequently compared OS within and across races (Table). All races, except A/PI, had improved 5-yr OS rates (age adjusted) from Era 1 to Era 2 (W: <0.001, H: 0.049, A/PI: 0.15, B: 0.003). Notably, A/PIs had the highest OS in Era 1, while H had the poorest OS in Era 2. These differences were more evident in males compared with females within each race. Finally, pts with higher SES had better OS in both eras, although OS was improved across eras for lower and higher SES populations. Conclusions: Collectively, we identified improved OS across eras, which was apparent for all ages, both sexes, and all races. We did not find superior outcome for females in the modern era as has been recently noted. However, several racial disparities persist, including inferior OS for H and superior OS A/PIs in the contemporary era. The disproportionate improvement in outcomes for some, but not all races, warrants continued study of racial disparities in FL. [Table: see text]
Retrospective analysis of second malignancies in patients with multiple myeloma.
Authors: Talamo Giampaolo , Ehmann W. Christopher , Dolloff Nathan G , Malysz Jozef , Drabick Joseph J. , Rybka Witold B.
Published: March 2020

8090

Background: Recent data from patients with multiple myeloma (MM) enrolled in randomized clinical trials have shown an increased incidence of second malignancies after treatment with lenalidomide, but the prevalence of second malignancies in the overall MM population is uncertain. Methods: We retrospectively analyzed the medical records of 320 consecutive MM patients followed at the Penn State Hershey Cancer Institute between 2006 and 2010. We excluded from the analysis basocellular and squamocellular carcinomas of the skin. Results: Forty-three patients (13%) were found to have second malignancies, and 5 of them had a third cancer. One pt had 4 cancers. They included cancers of the prostate (8 pts), breast (8), MDS/leukemia (6), colon/rectum (5), melanoma (5), lung (4), uterus (4), bladder (3), kidneys (2), pancreas (2), testicle (1), myeloproliferative disorders (1), and sarcoma (1). Of 50 cancers, 36 (72%) developed before the diagnosis of MM, at a median of 65 months (range, 1-372), and 14 after that, at a median of 37 months (range, 3-104). Lenalidomide was used in 239 (75%) patients, and in 9 of 14 cases of post-MM second malignancies. Conclusions: Second malignancies usually develop before the diagnosis of MM, i.e., MM is the second malignancy for the majority of patients. The use of lenalidomide could not be indicated as a possible carcinogenic factor for the majority of MM patients with second malignancies.
A phase I/II study of carfilzomib (CFZ) as a replacement for bortezomib (BTZ) for multiple myeloma (MM) patients (Pts) progressing while receiving a BTZ-containing combination regimen.
Authors: Berenson James R. , Yellin Ori , Dichmann Robert , Patel-Donnelly Dipti , Boccia Ralph V. , Hilger James D. , Nassir Youram , Swift Regina A. , Vescio Robert A.
Published: March 2020

8098

Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZ‑containing regimens to which pts have progressed. Methods: Eligible pts had to have progressed while receiving their most recent BTZ‑containing regimen after at least 4 doses of BTZ at > 1.0 mg/m² in < 4 weeks per cycle. Combination regimens containing an alkylating agent, anthracycline, or a glucocorticosteroid were eligible. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZ‑containing regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 19 enrolled pts 13 are evaluable to date and 6 have recently started treatment. Pts received a median of 7 (range, 1-18) prior treatments and 5 (range, 1-5) different BTZ-containing regimens. Pts were treated with CFZ and the following different combinations: bendamustine (BEND) alone, BEND + methylprednisolone, dexamethasone (DEX) alone, DEX + pegylated liposomal doxorubicin, ascorbic acid + cyclophosphamide, and melphalan alone. Pts have completed a median of 3 cycles. Clinical benefit was seen in 10 (77%) pts (complete response = 8%; very good partial response = 8%; partial response = 31%; minor response = 31%) with another 23% showing stable disease. The median time to progression (range: 2-8 months) has not been reached and only 2 pts have progressed. The most common grade 3/4 adverse events were thrombocytopenia occurring in 5 pts (all = grade 3 except 1 event) and fever occurring in two pts (grade 3). Four pts experienced a serious adverse event but no regimen has reached a MTD. Conclusions: These early results suggest that CFZ is an effective and tolerable replacement for BTZ for pts who are refractory to BTZ-containing combination regimens.
Efscalefect of lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy in transplant-eligible patients (Pts) with newly diagnosed multiple myeloma (MM) on CR rates and survival.
Authors: Gleason Charise , Nooka Ajay K. , Muppidi Samatha , Heffner Leonard T. , Steuer Conor E , Kumar Mukesh , Casbourne Daniela , Langston Amelia A. , Watson Melanie , Boise Lawrence , Kaufman Jonathan L. , Lonial Sagar
Published: March 2020

8101

Background: Addition of lenalidomide to bortezomib and dexamethasone (RVD) demonstrated to be an effective and well tolerated regimen in phase II trials with overall response rate (ORR) >95% (Richardson P et al). Given the lack of phase III data, we have evaluated our institutional experience of pts treated with RVD induction therapy, to support this triplet combination. Methods: 286 transplant-eligible pts with newly diagnosed MM were treated with RVD induction therapy [R - 25 mg/day (days1–14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 2008 until January 2012. 148 pts underwent ASCT and 138 pts opted for delayed transplant. Post-ASCT 56% pts are on maintenance therapy tailored to their risk (R-40%; RVD-10%; V-6%). Demographic and outcomes data for the pts that underwent ASCT were collected and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the pts is 60 years (range 32-77). Other pt characteristics include: M/F 55%/45%; ISS I/II/III 40%/30%/30%; Isotype IgG/IgA/FLC/IgM 61%/20%/18%/1%; high risk/standard risk 13%/87%. Pts received a median of 4 cycles (2-9) of RVD. Median CD34+ stem cell collection was 11.24 x 106/kg. 18% pts required dose reductions (R/V/D-5%/9%/2%) and discontinuation in 2% pts for progressive disease. 49%/8% pts had G1-2/G3-4 PN. Median estimated PFS is 47 months and median OS has not been reached. Response rates are included in the table. Conclusions: RVD is an active induction regimen with superior response rates of > 80% ≥VGPR rates post-ASCT and is well tolerated in newly diagnosed MM pts. Incorporation of lenalidomide did not impact the stem cell collection. Until phase III data are available, our institutional experience could provide a perspective in the choice of RVD as an effective induction regimen in improving ORR and prolonging survival. [Table: see text]
miRNA expression profiling of CD20+ plasma cell myeloma (PCM): Upregulation of miR-155 shedding new insight into disease biology and clinicopathologic behavior.
Authors: Kolhe Ravindra , Jillella Anand P. , Natrajan Kavita , Awan Farrukh Tauseef , Manaloor Elizabeth , Kota Vamsi
Published: March 2020

8108

Background: Up to15-20% of patients with PCM have expression of CD20, although the significance of this remains unclear. The prognostic significance of CD20 expression in PCM is unclear. Recently, a class of noncoding RNAs, miRNAs, were identified as critical gene regulators in cell growth, disease, and development. Our study investigates importance of miRNAs in cases of CD20+ PCM and correlates them with clinicopathological parameters. Methods: The miRNA expression profile of CD20+ PCM (n=6), diffuse large B cell lymphoma (DLBCL) (n=6), and CD20 negative PCM (n=8) were evaluated using the Affeymertrix miRNA microarray platform on GeneChip miRNA 2.0 array in paraffin-embedded samples. After hybridization and data acquisition, we used Partek Genomics Suite software for RMA normalization and to determine statistically significant differences in miRNA expression between experimental groups by ANOVA and pairwise comparisons (two-sided α=0.05). Results: miRNA expression profiles of CD20+ PCM, show upto >4 times upregulation of 7 miRNAs and downregulation of 8 miRNAs. miR-155, the miRNA upregulated in various B cell lymphomas and plays a key role in the lymphomagenesis, was amongst the highest miRNAs that were upregulated. Conclusions: miR-155 is known to repress SH2-domain containing inositol-5-phosphatase-1 (SHIP-1), which is a critical phosphatase that negatively down modulates AKT pathway and has functions during normal B-cell development. Physiologically, miR-155 is upregulated during B-cell activation upon antigen stimulation and so plays a role in antibody class switching and plasma cell formation. We propose that this overexpression of miR-155 in CD20+ PCM unblocks AKT activity, inducing cell proliferation and may explain some of the immunophenotypic behavior of CD20+ PCM. This work is intriguing for the new information it provides about the role of miR-155 in CD20+ PCM. Furthermore, the phenotype of miR-155+ve CD20+ PCM might ultimately provide new insights into regulation of poorly understood steps in B cell differentiation and maturation into plasma cell and more importantly the clinicopathological behavior of this entity.
Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): An intergroup study of CALGB, COG, ECOG, and SWOG.
Authors: Flaherty Lawrence E. , Moon James , Atkins Michael B. , Tuthill Ralph , Thompson John A. , Vetto John T. , Haluska Frank G. , Pappo Alberto S. , Sosman Jeffrey Alan , Redman Bruce G. , Ribas Antoni , Kirkwood John M. , Sondak Vernon K.
Published: March 2020

8504

Background: High-dose interferon for one year (HDI) is the FDA approved adjuvant therapy for patients (pts) with high-risk melanoma (HRM). Efforts to modify IFN dose or schedule have not improved efficacy. A meta-analysis demonstrated that biochemotherapy (BCT) produced superior response rates compared with chemotherapy in pts with stage IV melanoma (Wheatley et al J Clin Oncol 25:5426, 2007). We sought to determine whether a short course of BCT would be more effective than HDI as adjuvant treatment in pts with HRM. Methods: S-0008 (an Intergroup Phase III trial) enrolled pts who were high risk (Stage III A-N2a thru Stage III C N3) and randomized them to receive either HDI or BCT consisting of dacarbazine 800 mg/m2 day 1, cisplatin 20 mg/m2/ days 1-4, vinblastine 1.2 mg/m2 days 1-4, IL-2 9 MIU/m2/day continuous IV days 1-4, IFN 5 MU/m2/day sc days 1-4, 8,10,12, and G-CSF 5 ug/kg/day sc days 7-16. BCT cycles were given every 21 days x 3 cycles (9 weeks total). Pts were stratified for number of involved nodes (1-3 v ≥4), micro v macro metastasis, and ulceration of the primary. Co-primary endpoints were relapse free survival (RFS) and overall survival (OS) using a one-sided log rank test at p= 0.05. Results: 432 pts were enrolled between 8/2000 and 11/2007: 30 were ineligible or withdrew consent. Grade 3 and 4 adverse events occurred in 57% and 7% respectively of HDI pts and 36% and 40% of BCT pts. At a median f/up of 6 yrs, BCT improved RFS (p = 0.02, HR 0.77 [90% CI: 0.62 – 0.96]) with median RFS for BCT of 4.0 yrs (90% CI:1.9 – 5.9) v 1.9 yrs (90% CI: 1.4 – 2.5) and 5 yr RFS of 47% v 39%. Median OS was not different between the two arms (p = 0.49 HR 1.0 [90% CI: 0.78 – 1.27]) with median OS not yet reached for BCT v 8.4 yrs (90% CI: 4.5 – 9.3) for HDI and 5 yr survival 56% for both arms. Conclusions: In HRM pts, BCT provides a statistically significant improvement in RFS compared to HDI, but no discernable difference in OS and more grade IV toxicity. BCT represents a shorter, alternative treatment for pts with HRM, and a potential control arm and basis for future combinations in the adjuvant setting.
Safety of ipilimumab in patients (pts) with untreated, advanced melanoma alive beyond 2 years: Results from a phase III study.
Authors: Thomas Luc , Wolchok Jedd D. , Garbe Claus , Lebbe Celeste , Bondarenko Igor , Rodrigues Kristen , Konto Cyril , Chin Kevin M. , Francis Stephen , Robert Caroline
Published: March 2020

8512

Background: Ipilimumab (IPI), a fully human monoclonal antibody, blocks cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response. In a phase 3 study (CA184-024) of previously untreated pts with stage III or IV melanoma, IPI + dacarbazine (DTIC) significantly improved overall survival (OS) vs. DTIC alone (Robert et al. NEJM 2011). We now report safety data of IPI in pts from this study alive > 2 yrs from study initiation. Methods: Pts with untreated advanced melanoma, were randomized to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22. Eligible pts (stable disease or better) received IPI or placebo q 12 wks as maintenance. In the population of subjects alive >2 yrs, the appearance of immune-related adverse events (irAEs) occurring after 2 yrs was evaluated. Within this group was a subset of subjects still receiving IPI dosing after 2 yrs; safety for these pts was evaluated to assess the impact of prolonged IPI exposure. Results: In the IPI + DTIC group 68 (28%) pts survived > 2 yrs compared to 44 (18%) in the DTIC alone group; 11 of the 68 continued IPI dosing for ≥ 2 yrs. Safety assessment beyond 2 yrs showed 3 of the 11 pts had any grade irAEs; 1 pt had grade 3/4 rash, pruritus while low grade events included rash, pruritus (n=2) and elevated ALT / AST (n=1). Overall among all 68 pts in the Ipi + DTIC group, there were 5 pts (7.4%) with any grade irAEs including grade 3/4 rash, pruritus (n=1) and low grade rash (n=3), pruritus (n=2), skin hypopigmentation, and elevated ALT / AST (n=1). No gastrointestinal or endocrine events (any grade) were observed. Conclusions: In Study 024, IPI + DTIC treatment improved OS pts with untreated, advanced melanoma with higher survival rates in the IPI + DTIC group at 1 yr (47.3% vs. 36.3%), 2 yrs (28.5% vs. 17.9%), and 3 yrs (20.8% vs. 12.2%) (HR 0.72, p<0.001). The safety profile of pts alive after 2 yrs suggests that treatment with IPI + DTIC is associated with low rates of irAEs in these pts. Furthermore, in pts still receiving active IPI treatment beyond ≥ 2 yrs, the safety profile appears to be consistent and medically manageable using established safety guidelines (Weber, Oncologist 2007).
Phase II multicenter trial of ipilimumab combined with fotemustine in patients with metastatic melanoma: The Italian Network for Tumor Biotherapy (NIBIT)-M1 trial.
Authors: Di Giacomo Anna Maria , Ascierto Paolo Antonio , Pilla Lorenzo , Ridolfi Ruggero , Santinami Mario , Testori Alessandro , Queirolo Paola , Simeone Ester , Guidoboni Massimo , Del Vecchio Michele , Ferrucci Pier Francesco , Marasco Antonella , Fonsatti Ester , Annesi Diego , Giannarelli Diana , Parmiani Giorgio , Maio Michele
Published: March 2020

8513

Background: Ipilimumab (ipi), an antibody against cytotoxic T-lymphocyte-associated antigen-4, improves survival in patients (pts) with metastatic melanoma (MM); however, objective tumor responses are limited. NIBIT-M1 aims to investigate the efficacy and safety of ipi plus fotemustine (FTM), a cytotoxic alkylating drug, in pts with MM. Methods: Eligible pts, with or without brain metastases, received induction therapy with ipi 10 mg/kg every 3 weeks (Q3W) for four doses and FTM 100 mg/m2 weekly for 3 weeks. Ipi and FTM maintenance therapy was provided Q12W from Week 24 and Q3W from Week 9, respectively. The primary objective was the immune-related (ir) disease control rate (irDCR: pts with complete response [CR], partial response [PR] or stable disease [SD] as determined using the ir response criteria). Secondary objectives included ir objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS); overall survival (OS), and safety. Tumor assessments were performed Q8W from Week 12 to Week 36 and Q12W thereafter. Results: Among 86 pts with unresectable stage III (n=3) or stage IV (n=83) MM treated at 7 NIBIT centers, 42 were previously untreated, 44 had progressed following first-line treatment and 20 had asymptomatic brain metastases. As of December 2011, the irDCR was 46.5% (40/86; 95% CI, 35.7–57.6%); the irORR was 29.1% (95% CI, 19.8–39.8%; 5 CRs and 20 PRs) and with a median 8.3 months follow-up, median irPFS was 5.3 months (95% CI, 3.5–7.1). The 1-year OS rate was 51.8% (95% CI, 37.5–66.1%); median OS was not yet reached. Among all pts, 58.1% and 87% completed ipi or FTM induction, respectively. The most common grade 3/4 drug-related adverse events (AEs) (reported in 54.6% pts overall) were myelotoxicity (43.5%), increased ALT/AST (14.1/10.6%), gastrointestinal (4.7%) and skin-related (2.3%). AEs were generally manageable and reversible per protocol guidance. Conclusions: The study reached its primary objective with 46.5% of pts achieving disease control. The combination of ipi plus FTM is safe; the irDCR, 1-year OS rate and median irPFS warrant its further investigation in MM pts.
SWOG S0826: A phase II trial of SCH 727965 (NSC 747135) in patients with stage IV melanoma.
Authors: Lao Christopher D. , Moon James , Fruehauf John P. , Flaherty Lawrence E. , Bury Martin J. , Ribas Antoni , Sondak Vernon K.
Published: March 2020

8521

Background: Cyclin-dependent kinases (cdks) function to regulate cell cycle control and agents that can target cdks in malignant progression remain viable therapeutic strategies. Selective inhibition of cdk2, in particular, may be of therapeutic value in a subset of patients with melanoma. Methods: 60 patients with metastatic melanoma of cutaneous or mucosal origin were planned to be recruited to a multicenter, single-arm phase II trial of the cdk inhibitor, SCH 727965 (NSC747135).  Patients were potentially eligible if they had 0-1 previous treatments, PS of 0-1, and adequate organ function. Ocular melanoma patients and patients with a history of brain metastases were excluded.  SCH 727965 50 mg IV every 3 weeks was given until progression with disease assessment occurring every 2 cycles.  Co-primary endpoints were 1-year overall survival (OS) and 6-month progression free survival (PFS). Results: 72 patients were enrolled from July 1, 2009 to November 1, 2010 at 24 institutions.  68% of patients had M1c disease and 43% had LDH elevation. 19% had prior therapy for metastatic disease. 28 patients (39%) experienced Grade 4 adverse events, including 20 cases of neutropenia, one case each of cardiac ischemia/infarction, cardiac troponin I elevation, dehydration, abdominal pain, leukopenia, muscle weakness, headache, syncope, and anterior ischemic optic neuropathy.  65 patients are currently evaluable for response. The response rate was 0/65 (95% C.I. (0-6%)). Stable disease was observed in 22%.  The estimated median PFS was 1.5 months (95% CI: 1.4 – 1.5); 6-month PFS was 11% (5-20%).  Median OS was 8 months (95% CI: 5-11 months); 1-year OS was 36% (95% CI: 24-48%). The null hypothesis of 1-year overall survival=25% was rejected (p=0.04) but 6-month PFS=11% was not (p=0.8). Data Analysis will be updated when missing data are received. Correlative studies of Rb phosphorylation and cyclin expression will be pursued. Conclusions: SCH 727965 appears to be reasonably well tolerated although grade 4 events were relatively common, particularly near the time of infusion. There were no responses but few patients had prolonged disease stabilization that may have resulted in improvement in the 1-year OS rate.
Sensitivity rate of ultrasound (US)-guided fine-needle aspiration cytology (FNAC) using the Berlin morphology criteria for lymph node metastases to reduce the need for surgical sentinel node (SN) staging in melanoma.
Authors: Voit Christiane A. , Van Akkooi Alexander Christopher Jonathan , Gooskens Saskia , Siegel Petra , Schaefer-Hesterberg Gregor , Schoengen Alfred , Roewert-Huber Joachim , Sterry Wolfram , Eggermont Alexander M.
Published: March 2020

8535

Background: US-guided-FNAC prior to surgical SN staging is emerging as a possible cost-effective addition to the staging of melanoma patients (pts). Formerly, sensitivity (sens) rates of lymph node US in melanoma were disappointing (20–40%). The introduction of the Berlin Morphology Criteria has significantly improved sens rates for US-FNAC (J Clin Oncol 2010;28(5):847-52). The aim of the current study was to report on 1000 patients the sens, specificity (spec), positive (PPV) and negative (NPV) predictive value rates of US-FNAC from our prospective database with prolonged follow-up. Methods: Since 2001, >1000 stage I / II consecutive melanoma pts have undergone US-FNAC prior to SN. All patients underwent lymphoscintigraphy. Peripheral Perfusion (PP), Loss of Central Echoes (LCE), Balloon Shaped (BS) were the Berlin Morphology Criteria which were registered. FNAC was performed in case of presence of any of these factors. SN tumor burden was measured according to the Rotterdam Criteria. All patients underwent SN or LND in case of positive FNAC. Results: Mean/median Breslow thickness was 2.56 / 1.57 mm (0.2 – 44 mm).Mean/median follow-up was 39 / 32 months (0 – 115). Ulceration was present in 24 %. SN positivity rates were 20 % (202 / 1000). Sens was 51 %. Spec, PPV and NPV were 99%, 91% and 89%. Sensitivity was highest for T4 tumors (77%). PP, LCE, BS had sens of 69%, 24%, 25%. SN tumor burden > 1 mm in largest diameter according to the Rotterdam Criteria was identified by US-FNAC in 86%. Threshold for positive FNAC was 0.4 mm in maximum diameter. Conclusions: The new criterion of Periferal Perfusion is of key importance to achieve the high sensitivity of US-FNAC according to the Berlin Morphology Criteria (J Clin Oncol 2010; 28:847-852) to identify lymph node metastases. Especially for T4 patients and in patients with advanced SN tumor burden it can reduce significantly the need for surgical SN staging. The EORTC Melanoma Group will launch the prospective validation study, USE FNAC, in 2012.
Outcomes of ipilimumab treatment-related adverse events in patients with metastatic melanoma (MM) who received systemic corticosteroids in a phase III trial.
Authors: Baurain Jean-Francois , Smylie Michael , Ascierto Paolo Antonio , Roman Laslo , Houston Stephen , Konto Cyril , Chin Kevin M. , Chen Tai-Tsang , Francis Stephen , Wolchok Jedd D.
Published: March 2020

8539

Background: Ipilimumab (ipi) is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses. In a phase III trial, ipi at 10 mg/kg plus dacarbazine (DTIC) improved overall survival in previously untreated patients (pts) with MM. In ipi studies, the most common drug-related adverse events (AEs) were immune-related, which were generally reversible using treatment guidelines involving prompt recognition, intervention (corticosteroids, and rarely, alternative immunosuppressive agents), and possible discontinuation of therapy. The purpose of this analysis is to evaluate outcomes of ipi treatment-related AEs with use of systemic corticosteroids. Methods: AEs were reported from the first ipi dose up to 70 days after the last dose. Immune-mediated adverse reactions (imARs) were used to characterize inflammatory AEs in previously untreated pts with MM who received ipi plus DTIC in a phase III trial. This analysis includes the imAR categories of hepatitis, dermatitis, enterocolitis, and endocrinopathies. Results: More than 70% of pts who received corticosteroids had complete resolution of the imAR, ie, last reported Grade (Gr) of 0 (Table). In pts for whom a high-grade imAR had not completely resolved at the last report, ≥50% had improved to Gr 1. Conclusions: In the majority of pts treated with ipi at 10 mg/kg plus DTIC who received corticosteroids for the management of imARs, as recommended per treatment guidelines, the most common imARs had completely resolved or improved to Gr 1. [Table: see text]
Characterization of ipilimumab exposure-efficacy/safety response relationships in subjects with previously treated or untreated advanced melanoma.
Authors: Feng Yan , Godfrey CJ , Chu Hui-May , Masson Eric , Williams Daphne , Berman David Mark , Roy Amit
Published: March 2020

8541

Background: Ipilimumab (IPI) is a fully human monoclonal antibody directed against CTLA-4 that is being developed as a novel immunotherapeutic agent against melanoma and other solid tumors. The objective of this analysis was to retrospectively characterize the exposure-response (E-R) relationships for efficacy (overall survival, OS) in subjects with previously untreated advanced melanoma (pu-MEL), and safety (immune related adverse-events, irAEs) in subjects with previously treated advanced melanoma (pt-MEL) or pu-MEL. Methods: The E-R analysis of OS included 498 pu-MEL from a phase III study (CA184024) of IPI administered at 10 mg/kg + dacarbazine (DTIC) or DTIC + placebo; and the E-R analyses of irAE included 1036 subjects from a phase I study (CA184078), 4 phase IIstudies (CA184004/007/008/022) and CA184024 of IPI administered at doses of 0.3, 3 or 10 mg/kg. The relationship between steady‑state IPI trough concentration (Cminss) and OS was described using a Cox proportional hazards model, and the relationships between Cminss and incidence of irAEs were described by ordinal logistic regression models (separate models for any irAE, as well as skin, liver and GI irAE). Results: The risk of death decreased with increasing Cminss, and is higher for subjects with elevated baseline LDH level. The risk of death was higher for subjects with baseline ECOG status > 0 and was higher with increasing stage of disease (M1C>M1B>M1A>M0). The hazard ratio for OS corresponding to the median Cminss of 49.99 µg/mL was 0.745 relative to subjects in DTIC + placebo group. The probability of Grade 2+ or Grade 3+ GI, skin, liver and any irAEs also increases with Cminss. Prior anti-cancer therapy (including prior DTIC) or concomitant DTIC were the only significant covariates in the E-R irAE models. Conclusions: These model-based analyses suggest that higher Cminss of IPI appears to be associated with improved survival in pu-MEL (based on data from CA184024) and higher Cminss also appears to be associated with increased probability of irAEs in pu-MEL or pt-MEL.
BRAF mutation as a pejorative marker in metastatic melanoma.
Authors: Brissy Sophie , Gaudy-Marqueste Caroline , Mallet Stéphanie , Monestier Sandrine , Hesse Sylvie , Koeppel Marie-Christine , Rojat-Habib Marie-Christine , Nanni Isabelle , Loundou Anderson , Ouafik L'houcine , Bonnet Nathalie , Richard Marie-Aleth , Grob Jean Jacques
Published: March 2020

8555

Background: BRAF mutation in melanoma has been shown to be associated with a trend in favour of a spontaneous worse outcome after metastases in a series of 197 patients in Australia. Objective: To correlate BRAF status in metastatic melanoma with clinicopathologic features and outcome. Methods: In our department in France 182 patients with metastatic melanoma have been tested for BRAF mutation between September 2009 and September 2011. Survival was assessed by log-rank test. Multivariate analysis was performed with Cox model. Results: From 182 patients, 88 (48.3%) were B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other mutation subtypes. BRAF-mutant patients were younger than BRAF wild-type patients at diagnosis of primary melanoma (median age 52.3 vs 60.7 years, respectively, p=0.003), and at diagnosis of distant metastasis (median age 53.6 vs 64.1 years respectively, p=0.002). 34 patients were treated by B-RAF inhibitors. There was no significant difference in other demographic features of patients with metastatic melanoma by mutation status. Features of the primary melanoma significantly associated with a BRAF mutation (p<0.05) were histopathologic subtype (SSM), high mitotic rate (≥1/mm2), lower Breslow thickness (median Breslow: 2.2 vs 3.5 mm for BRAF mutant and BRAF-wild-type patients respectively, p=0.016), truncal location and location on occasionally exposed at sun site.The interval from diagnosis of first ever melanoma to first distant metastasis was not significantly different in BRAF-mutant and wild-type patients. The median overall survival (OS) from diagnosis of primary melanoma was 6.5 years for BRAF wild-type patients. Median OS was not reached in BRAF-mutant patients treated (34 of 88) with a BRAF inhibitor, but also in those not treated (p=0.24, and p=0.06 for treated BRAF-mutant vs BRAF wild-type). The overall survival from diagnosis of first distant metastasis was not significantly different (p=0.75). These results remained unchanged in a multivariate analysis. Conclusions: Our results confirm the characteristics of BRAF-mutant metastatic patients, and the efficacy of B-RAF inhibitors, but not that the presence of mutant-BRAF is per se a pejorative predictive marker.
High-risk uveal melanoma: A prospective study evaluating the role of magnetic resonance imaging of the liver.
Authors: Marshall Ernest , Romaniuk Chris , Ghaneh Paula , Wong Helen , McKay Marie , Chopra Mona , Coupland Sarah , Damato Bertil
Published: March 2020

8564

Background: Almost 50% of uveal melanomas are fatal. Metastatic death occurs almost exclusively with tumours showing chromosome 3 loss and 8q gain. Metastases, which almost always involve the liver, are resectable in some patients. They are rarely detectable when the patient presents with the primary ocular tumour. Screening is therefore necessary, but there is no consensus as to who should be screened, how often, and for how long. Methods: Uveal melanoma patients with ECOG performance status 0-2 were eligible if their risk of metastatic death at 5 years exceeded 50%. Survival probability was estimated by multivariate analysis of tumour stage, histological grade and genetic tumour type. Patients underwent screening 6monthly, clinical examination, non-contrast liver MRI and liver function tests for at least five years. Results: Between Jan 2000 and November 2010, 279 high-risk patients were referred for screening. Of these, 188 (84 male, 104 female) accepted screening and underwent as least 1 MRI. The median age was 63 years (IQR 16.5). Median basal tumour diameter was 16.5mm (IQR 5.25). Chromosome 3 loss was detected in 175 tumours. Median follow up time was 28.8 months (IQR 29.1). Median relapse-free survival was 33 months (95% CI 28-38) with a 35% relapse-free survival at 5 years. After a median of 18 months (IQR 20), screening detected metastases in 90/188 (48%), 83 of whom were asymptomatic. 12 patients underwent R0 liver resection, which increased the median survival from 10 (95% CI 8.1 - 11.9) to 24 (95% CI 20.2- 27.8) months. The screening programme stimulated a UK NCRI portfolio of clinical trials in which 23 of these patients were subsequently treated. Conclusions: Six-monthly liver MRI detects metastases from uveal melanoma at an early stage, thereby enhancing opportunities for surgical metastatectomy, clinical trial participation and prolonging life.
Biomarker for benefit from ipilimumab: Correlation of breadth of humoral tumor-antigen-specific immunity with outcome.
Authors: Ellis Sarah Gabrielle , Wheater Matthew , Tier Katherine , Cazaly Angelica , Smart James , Theaker Jeffrey , Hepburne-Scott Henry , Bonner-Ferraby Phoebe , Ottensmeier Christian H.H
Published: March 2020

8566

Background: Checkpoint blockade through CTLA4 with ipilimumab has for the first time improved survival in patients with advanced melanoma. Immune-mediated toxicity and increase in humoral and T-cell anti-NY-ESO-1 immune responses after treatment are both linked with benefit. However there is currently no broadly relevant, immunological biomarker for predicting outcome prior to initiation of therapy. Methods: Using a novel immunological assay developed by Serametrix Corporation we analysed the presence of antibodies to a proprietary panel of tumour associated antigens (TAAs) in 34 patients with advanced melanoma, given ipilimumab at 3mg/kg as second or subsequent line of treatment. Results: 34 patients were consented and analysed, 22 females, 13 males. With a median age of 63 years median overall survival was 24 weeks; 6/34 patients had an objective response to ipilimumab (17.6%, median survival not reached). Antibody (AB) responses were tested against the panel of 26 TAAs. This panel includes BRAF, Cancer/Testis and other described or novel TAAs. We observed a wide range in the incidence and levels of antibody response. 12 patients had no detectable immunity, 6 an AB response to a single antigen, 5 AB response to 2, and 11 patients to 3 or more TAA. Five patients had either pre-existing anti-BRAF antibodies or developed these after CTLA4-blockade. Survival was significantly longer in those patients with pre-existing antibodies to 2 or more TAA, compared to those with 0 or 1 specificities (median survival 39.4 vs 16.4 weeks p=0.02). Conclusions: Patients with advanced melanoma had variable levels of humoral immunity to a large number of TAA, including to BRAF. The presence of antibody response to 2 or more TAA correlated with longer survival following treatment with ipilimumab and appears to provide a biomarker for identifying those patients that are most likely to respond to checkpoint blockade with ipilimumab.
Ipilimumab-induced hypophysitis in melanoma patients.
Authors: CarrÃ© Typhanie , Gaudy-Marqueste Caroline , Albarel Frédérique , Monestier Sandrine , Mallet Stéphanie , Brue Thierry , Richard Marie-Aleth , Grob Jean Jacques
Published: March 2020

8568

Background: Ipilimumab (Ipi) is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigene-4 (CTLA-4) recently approved for the treatment of metastatic melanoma (MM) and currently under investigation in the adjuvant setting. Methods: Retrospective analysis of patients treated with ipi between June 2006 and September 2011 in our department in Marseille. As some patients are still blinded in trials, the exact number of patient under ipi is unknown. We present a minimal percentage (>%) assuming that the 120 patients received ipi. Results: A total of 120 patients were treated: 76 stages IV MM, from which 16 in the BMS clinical trials (CA184-022, -024, and-025 and MDX 010-20) and 44 stages III MM (in the BMS CA184-029 trial). Stage IV MM were administered 0.3, 3 or 10mg/kg IV dosage, while stages III MM were randomly assigned to receive 10 mg/ kg or placebo (1:1 ratio). Hypophysitis was diagnosed in 12 patients (>10%): 2/76 patients with stage IV MM (>2. 6 %) and 10/44 patients with stage III MM (>22.7). Diagnosis was performed at the 1st, 3rd and 4th administration in respectively 2 (1.6%), 6 (50%) and 4 patients (33.3%). Clinical symptoms included headaches (n=11; 91.6%), asthenia (n=7; 58.3%) and decreased libido (n=2; 1.6%). Adrenal, thyroidal and gonadal axis were affected in respectively 6 (50%), 9 (75%) and 7 patients (58.3%). MRI changes were observed in 7 patients (58.3%): pituitary swelling in 5 patients (41.6%) and heterogeneous enhancement in 4 patients (33.3%) including 2 patients with normal biology. Corticosteroids supplementation was required in 11 patients and thyroidian supplementation in 4 patients. Clinical symptoms regressed within one week in 8 patients (66.6%). Conclusions: Ipi-induced hypophysitis is detectable only if clinicians are aware of these unspecific signs. Only MRI can make diagnosis in some patients without clinical and/or biological signs. Our data suggest that it develops especially for 10mg/kg dosage, after the third administration, and that the rate could be higher in patients with a normal immune system (adjuvant treatment), than in metastatic ones. Hormonal supplementation usually controls the disease.
Assessment of germ-line and somatic alterations in main candidate genes among patients with multiple primary melanoma.
Authors: Palmieri Giuseppe , Sini MariaCristina , De Giorgi Vincenzo , Lissia Amelia , Massi Daniela , Rubino Corrado , Cossu Antonio , Stanganelli Ignazio , Palomba Grazia , Botti Gerardo , Caraco Corrado , Mozzillo Nicola , Ascierto Paolo Antonio , Colombino Maria
Published: March 2020

8581

Background: We have studied a series of patients with multiple primary melanoma (MPM) for the involvement of the key-regulator genes in susceptibility (CDKN2A) and pathogenesis (BRAF, cKIT, CyclinD1) of such a disease. Methods: Genomic DNA from peripheral blood of 63 MPM patients (54 cases with two primary melanomas, 8 with three, and 1 with four) were screened for germline mutations in p16CDKN2A and p14CDKN2A genes by automated DNA sequencing. Melanoma families were identified according to standardized criteria: 9 (14%) patients were classified as familial cases. Paired synchronous and/or asynchronous MPM tissues (N=100) from same patients (N=46) were analyzed for somatic mutations in BRAF gene and FISH-based amplifications in cKIT and CyclynD1 genes. Results: Overall, 6 (10%) different CDKN2A germline mutations were identified: 5 in p16CDKN2A and 1 in p14CDKN2A. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were significantly more frequent in patients with familial history of melanoma (5/9; 56%) compared with patients without (1/54; 2%) (P<0.001), and in patients with more than two melanomas (3/9; 33%) compared with patients with only two melanomas (3/54; 6%) (P=0.012). The debated A148T polymorphism was found at low level (2/54; 4%) in our series. Regarding genetic alterations at somatic level, BRAF mutations were identified in 36/100 (36%) primary melanoma tissues, whereas amplification of cKIT and CyclinD1 genes was observed in 2/88 (2%) and 10/88 (11%) analyzed tissue samples, respectively. Considering all types of genetic events, paired samples presented a poorly consistent distribution of somatic alterations in same patients (52% consistency). Conclusions: Coexistence of MPM and familial recurrence of melanoma as well as the presence of more than two melanomas seem to be strong indications to address patients to CDKN2A mutational screening. The low consistency in genetic patterns of primary tumors from the same patients provide additional evidence that pathogenetic mechanisms of melanomagenesis are heterogeneous and molecularly different cell types may be generated in multiple primary melanoma.
Phase I trial of extended-dose anti-PD-1 antibody BMS-936558 with a multipeptide vaccine for previously treated stage IV melanoma.
Authors: Kudchadkar Ragini Reiney , Gallenstein Donna , Martinez Alberto J , Yu Bin , Weber Jeffrey S.
Published: March 2020

8582

Background: BMS-936558, a fully human IgG4 anti-PD-1 antibody, has shown clinical activity in melanoma and renal cancer. Methods: 30 HLA A*0201 positive patients with unresectable, previously treated stage IV melanoma received MART-1/gp100/NY-ESO-1 peptides with adjuvant Montanide ISA 51 injected subcutaneously with BMS-936558 at 1, 3 or 10 mg/kg intravenously every 2 weeks for 24 weeks, followed by BMS-936558 alone every 3 months. No patient had prior ipilimumab. Endpoints were toxicity, correlative studies of immunity measured by ELISPOT and T-cell phenotype assays, and response by RECIST. Results: Median age was 62, with 14 men and 16 women. 73% of patients had M1c disease. One patient had dose limiting optic neuritis; one patient had dose limiting grade 3 interstitial pneumonitis. Of 10 patients at 1 mg/kg, 2 had confirmed partial responses (PR), both one year from initiation of study. 13 patients were treated at the 3 mg/kg cohort; 3 patients did not complete more than 3 doses secondary to progressive disease and one withdrew consent. Of 12 evaluable patients, 3 had confirmed PRs and 2 unconfirmed PRs. In the 10 mg/kg cohort, thus far 6 patients completed one cycle with 2 unconfirmed PRs and one patient stable. Only 2 of the 9 responders after one cycle have progressed with a median follow-up of 7 months. 2/6 patients failing BMS-936558 responded to ipilimumab. At week 12, patients in all cohorts had decreased PD-1 on CD4 and CD8 T-cells (p<0.0001), increased CD4 CTLA-4 levels (p=0.01) and dose related decreases in CD8 T-cells whereas CD4 T-cells increased (both p<0.05). ELISPOT assays showed that patients at all doses had no increased responses in fresh PBMC to MART-1/gp100, but showed dose related decreased responses to viral (CMV, EBV, FLU) peptides over time (p=0.04). Conclusions: BMS-936558 in combination with a peptide vaccine is well tolerated at 1 and 3mg/kg. Accural to the 10mg/kg cohort is on-going. Responses have been observed at all dose levels. PD-1 levels on T-cells decreased, and CTLA-4 levels increased in CD4 T cells in all cohorts. There was a dose-related decrease in CD8 T-cells and in viral-specific T-cells. Further study of BM-936558 is warranted to determine its optimal dose.