bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of stringent complete response (sCR) post-autologous stem cell transplant (SCT) in multiple myeloma (MM)
Authors: Kapoor P. , Kumar S. , Dispenzieri A. , Lacy M. Q. , Hayman S. R. , Buadi F. K. , Dingli D. , Greipp P. R. , Rajkumar S. V. , Gertz M. A.
Published: August 2020

8587

Background: The measurement of serum immunoglobulin free light chains (FLC) has diagnostic and prognostic utility in MM. Normalization of the FLC ratio may define a deeper complete response after therapy than by standard criteria of CR. A sCR requires normalization of the FLC ratio and absence of clonal plasma cells in the bone marrow (BM) in addition to the standard criteria for CR. The objective of our study was to evaluate the impact of specific types of CR [sCR, CR or near CR (nCR/ immunofixation positive CR)] post-SCT on time to progression (TTP) and overall survival (OS). Methods: 468 MM patients who had achieved at least a partial response post-SCT were studied. The results of serum and urine protein studies, serum FLC assay, and BM evaluation, including measurement of marrow plasma cell clonality by immunohistochemistry obtained ≥60 days after SCT were used to determine the best response. TTP was defined as the time from SCT to progression, with non-myeloma related deaths censored. Results: 179 patients achieved varying degrees of CR as their best response. 39, 35 and 105 patients achieved nCR, CR and sCR, respectively. The median estimated follow-up for the entire cohort was 52 months from the diagnosis and 41 months from SCT. The median TTP was 15, 29 and 35 months for patients achieving nCR, CR and sCR, respectively (P<0.0001). The median OS for patients achieving nCR was 53 months from the diagnosis, but not reached for those with a CR or sCR (P=0.0009). The 5-year OS was 80% and 79% for patients with CR and sCR, respectively (P=NS). Similarly, OS from SCT was significantly shorter in patients achieving nCR (42 months vs. not reached for patients in CR and sCR; P<0.001). Conclusions: Achievement of a sCR represents a deeper response state compared to conventional CR, translating to a longer response duration post SCT, validating its inclusion in the modified uniform response criteria. While we did not see a significant improvement in OS with sCR compared to CR in this group, this question needs to be addressed in a larger study. The step wise improvement in the response duration across nCR, CR and sCR highlights the contribution of immunofixation studies, marrow assessment of clonality and FLC estimates.

[Table: see text]
Gene expression profiling (GEP)-defined risk and molecular subgroups assessed at baseline and at relapse: Collective impact on post-relapse survival of multiple myeloma (MM) treated with total therapies 2 and 3
Authors: Nair B. , Shaughnessy J. , Alsayed Y. , Haessler J. , van Rhee F. , Hollmig K. , Pineda-Roman M. , Crowley J. , Barlogie B.
Published: August 2020

8589

Background: GEP-defined risk has evolved as the most robust predictor of overall and event-free survival (OS, EFS) in MM with TT2 and TT3 protocols, distinguishing 85% with low-risk (LR) and 15% with high-risk (HR). Upon relapse, the original risk designation may change typically in the direction LR to HR. Here we examine, among patients with available GEP data at baseline (BL) and relapse (REL), the contributions of both observations on post-relapse survival (PRS). Methods: Paired REL-BL GEP data were available in 77 patients, while information on metaphase cytogenetic abnormalities (CA) was obtained in 76 patients at both time-points. Results: PRS was significantly affected by both BL and REL HR status so that, among the 52 patients with LR at BL, HR status at REL conferred significantly poorer outcome compared to those with LR at REL (p=0.0005) with 30-mo estimates of 71% v 13%; likewise, among the 25 patients with HR at baseline, HR present also at relapse further diminished PRS (p=0.09) with 30-mo estimates in both settings of less than 20%. Similar considerations for CA status revealed, among the 29 patients without CA at BL, marked attrition of PRS with CA v no CA at REL with 30-mo estimates of 29% v 81% (p=0.04); for the 47 patients with CA at BL, CA also at REL further diminished the poor PRS from 46% to 22% (p=0.06). When all standard BL and REL prognostic factors were examined in a multivariate model, GEP-derived HR contributed to poor PRS both when present at BL (HR=2.79, p=0.005) and at REL (HR=2.77, p=0.002), in addition to CA at BL (HR=2.44, p=0.018). Conclusions: In estimating PRS in TT protocols, genetic characteristics at BL (HR, CA) have enduring adverse consequences aggravated further by HR status at REL. Therefore, in HR/CA BL settings, aiming at REL prevention appears as the best overall treatment strategy.

[Table: see text]
Comparison of lenalidomide plus dexamethasone therapy used at first relapse versus later salvage therapy in relapsed or refractory multiple myeloma patients
Authors: Stadtmauer E. A. , Weber D. M. , Nieszvizky R. , Belch A. , Prince H. M. , San Miguel J. F. , Facon T. , Yu Z. , Knight R. D. , Dimopoulos M. A.
Published: August 2020

8594

Background: The benefit of initiating lenalidomide plus dexamethasone at first relapsed was evaluated in this subset analysis from phase III studies in patients with relapsed or refractory multiple myeloma (MM). Methods: Patients from the randomized, multicenter clinical trials MM-009 and MM-010 who had received at least 1 prior treatment and were not resistant to dexamethasone were treated with lenalidomide (25 mg daily for 21 days of every 28 day cycle) plus dexamethasone (40 mg on days 1–4, 9–12, and 17–20 every 28 days for 4 months, then 40 mg on days 1–4 every cycle thereafter until disease progression or intolerance), or dexamethasone (same dose and schedule) plus placebo. Baseline characteristics such as age, sex, ECOG score, and baseline β2-microglobulin levels between the 2 patient groups were similar, however, median time from diagnosis and prior therapy were statistically different. Results: Multivariate analysis showed that more prior therapies is associated with shorter time-to-progression (TTP). Patients who received 1 prior therapy demonstrated a significant improvement in outcomes such as TTP, progression-free survival (PFS), overall response rate (ORR), complete response/very good partial response rate (CR/VGPR), median duration of treatment and overall survival (OS) after first relapse compared with those who received ≥ 2 prior therapies ( Table ). Toxicity, rate of dose reduction, or treatment discontinuation in the cohort with 1 prior therapy did not increase, despite longer treatment. Conclusions: When used at first relapse compared with salvage therapy, lenalidomide plus dexamethasone treatment resulted in significantly prolonged TTP, PFS, and OS, and an improved quality of response. Lenalidomide plus dexamethasone should be considered at an early stage of therapy for patients with MM.

[Table: see text]

[Table: see text]
MDS-associated cytogenetic abnormalities (MDS-CA) after total therapy (TT) regimens for newly diagnosed multiple myeloma (MM): Apparent surge after introduction of post-transplant consolidation chemotherapy (CONS) in TT2 and TT3
Authors: Hollmig K. , Waheed S. , Nair B. , Haessler J. , Petty N. , Pineda-Roman M. , Alsayed Y. , van Rhee F. , Crowley J. , Barlogie B.
Published: August 2020

8595

Background: We have previously reported on the variables associated with the development of MDS-CA in the context of autologous transplant-supported high-dose therapy regimens for MM (Barlogie et al, Blood 2008). Methods: Due to a perceived increase in MDS-CA frequency, our MM data base was reviewed again to determine the potential effect of CONS introduced in TT2 and retained in TT3 trials. The frequency of MDS-CA post-transplant was determined, using Kaplan-Meier estimate plots, for 183 patients who received TT1, 554 enrolled in TT2 and 305 receiving TT3. Persistence of MDS-CA implied their documentation on 3 successive occasions. Results: 3-year MDS-CA estimates were 2% for both TT1 and TT2 and 4% for TT3 (TT3 v TT2, p=0.04; TT3 v TT1, p=0.11); persistent MDS-CA were also more frequently observed in TT3 in comparison with TT2 and TT1 (2% v 0% v 0%, both p=0.01). Multivariate analysis of features associated with transient and persistent MDS-CA revealed TT3 as an adverse feature (HR=2.84, p=0.043), along with incomplete platelet recovery of <165,000/uL 3mo after 1st transplant. Conclusions: Despite reduced induction chemotherapy prior to and CONS after tandem melphalan (200mg/m2)-based autotransplants from 4 in TT2 to 2 in TT3, overall and persistent MDS-CA increased significantly in TT3. Clinical MDS and AML were rarely observed and a full account of hematopathologic findings will be presented.

[Table: see text]
Prognostic impact of bone marrow CD138 immunohistochemistry (IHC) prior to autologous stem cell transplant (ASCT) for multiple myeloma (MM)
Authors: Foster M. C. , Christensen R. , Egan J. , Whitley J. , Chiu W. K. , Serody J. , Gabriel D. , Ivanova A. , Dunphy C. H. , Shea T. C.
Published: August 2020

8600

Background: Low bone marrow plasma cell (BMPC) burden prior to ASCT for MM is associated with favorable outcomes, but is usually determined by morphologic evaluation of marrow aspirates, a method subject to variability in sampling and interpretation. It is unknown if CD138 IHC, a more sensitive measure of BMPC, predicts progression-free survival (PFS), overall survival (OS) or post-ASCT response. Methods: Consecutive patients (n=93) who underwent single ASCT for MM from 2001 to 2008 and had available, stainable bone marrow core biopsies (BMB) obtained <90 days prior to ASCT were included in this single-center retrospective cohort study. BMB and/or clot CD138 IHC staining were reviewed by blinded hematopathologists. Post-ASCT response, PFS, and OS were determined using the International Myeloma Working Group uniform response criteria. Results: Patients were highly cytoreduced prior to ASCT, with 50.5% of pts having 0–5%, 21.5% having 6–10%, 20.4% having 11–20%, and 7.5% having >20% BMPC by CD138 analysis. BMPC% by CD138 IHC correlated with aspirate BMPC% [Pearson correlation coefficient=0.48, 95%CI (0.30, 0.63)]. In 12.6% of patients, BMPC% by CD138 IHC was ≥10% more than the aspirate count. Patients with ≤5% BMPC were more likely to achieve or maintain a CR or VGPR at initial post-ASCT restaging than those with >5% BMPC: Odds Ratio (95% CI) 6.91 (2.12, 22.57), p=. 0005 (chi-squared). With median follow up of 15.4 months for the ≤5% BMPC group and 19.3 months for the >5% BMPC group, 34/93 patients have progressed or died, with no difference between groups. By Kaplan-Meier analysis, PFS was similar regardless of BMPC [3 year estimated PFS (95%CI): ≤5%BMPC, 49.9% (29.4, 70.4) vs. >5%BMPC, 45.5% (26.7, 64.3); HR=1.24 (0.62, 2.49), p=.55, log-rank]. There was no difference in OS [3 year estimated OS (95%CI): ≤5%BMPC, 71.0% (49.7, 92.3) vs. >5%BMPC, 81.8% (66.2, 97.4); HR=0.61 (0.21, 1.78), p=.36, log-rank]. Conclusions: Detection of ≤5% BMPC by CD138 IHC prior to ASCT predicts attainment or maintenance of post-transplant CR/VGPR and correlates with plasma cell morphology. Differences in PFS or OS may emerge with additional follow-up, or if more patients with a higher content of residual plasma cells were transplanted.

[Table: see text]
Plasma cell leukemia: A SEER database analysis
Authors: Ramsingh G. , Mehan P. , Luo J. , Vij R. , Morgensztern D.
Published: August 2020

8605

Background: Primary plasma cell leukemia (PCL) is a rare plasma cell disorder with clinical information limited to small series of patients. Methods: We analyzed the Surveillance Epidemiology and End Results (SEER) database to evaluate the patient characteristic and survival data for patients with PCL. Patients were divided into cohorts based upon age, gender, race and time period of diagnosis. Kaplan-Meier product limit method was used to estimate survival functions for group in each risk factor. Demographics and survival over different periods of time from 1973 and 2004 were compared with multiple myeloma. Results: Among the 291 patients with PCL, median age was 67 years (range 19–98), and the male/female distribution was equal and the most common race was white (79.4%). Median overall survival (OS) and disease specific survivals (DSS, defined by interval from diagnosis to the event of death from PCL) were 4 months and 6 months respectively. The 1 year, 2 year and 5 year overall survival rates were 22.7%, 10.2% and 3.8% respectively. The survival did not differ between gender and race. Patients ≤60 years had a better median overall survival compared to older patients (median OS: 7 months Vs 3 months, p=0.007), although 5-year overall survival was equally poor for either group (6.9% Vs 6.7%). During the same period, we identified 49,106 patients with MM. Demographics for MM showed a slightly increased median age of 70 years, but similar race and gender distribution. Unlike MM, where there has been a modest but statistically significant survival improvement over time, both OS and DSS remained stable in PCL ( Table ). Conclusions: This is the largest study to analyze demographic and survival data on patients with PCL. The poor long term outcome and the lack of improvement in survival of patients with PCL despite small gains in MM suggest a more aggressive disease, for which further therapeutic agents are needed.

[Table: see text]

No significant financial relationships to disclose.
Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer
Authors: Flaherty K. , Puzanov I. , Sosman J. , Kim K. , Ribas A. , McArthur G. , Lee R. J. , Grippo J. F. , Nolop K. , Chapman P.
Published: August 2020

9000

Background: PLX4032 is an oral, selective inhibitor of the oncogenic V600E mutant BRAF kinase with preclinical activity. V600E BRAF is the most common kinase mutation in melanoma (60%), also found in colorectal carcinomas (10%), most anaplastic and papillary thyroid carcinomas, and low-grade serous ovarian carcinomas. Methods: Phase I, dose-escalation study designed to determine maximum tolerated dose (MTD), safety, pharmacokinetic (PK) / pharmacodynamic (PD), and efficacy (RECIST evaluation every 8 wks) of PLX4032 in sequential cohorts of 3 to 6 patients (pts). Plasma PK samples were collected on days 1, 8 and 15. Results: 54 pts have been enrolled: metastatic melanoma (n=49), thyroid (n=3), rectal (n=1), or ovarian carcinoma (n=1). 26 pts received a crystalline formulation (CF) continuously at doses from 100 mg BID to 1600 mg BID with associated exposures below target plasma levels. 28 pts received an optimized formulation with increased bioavailability, predicted to have 10-fold greater bioavailability, at doses from 160 mg BID to 1120 mg BID. AUC was dose-proportional and above target levels at 240 mg BID and higher. There was 1 DLT at 720 mg BID (G4 pancytopenia); treatment was restarted at 360 mg BID without myelosuppression. At 1120 mg BID, 3 of 5 pts had DLT (rash and fatigue). One pt had grade 3 increased ALT at 360 mg BID. 13 melanoma pts (77 %M1C) treated at doses of 240 mg BID or higher of the increased bioavailability formulation have a minimum follow-up of 8 weeks. 5 of the 7 BRAF V600E+ pts treated at ≥ 240 mg BID had tumor regression, up to 83%, with 1 confirmed partial response (PR) and 1 unconfirmed PR (too early); 2 of 4 pts with unknown V600E status had tumor regression, up to 50%, with 1 confirmed PR; 2 BRAF wild-type pts had progressive disease. All 7 pts with tumor regression remain progression-free, ranging from 4 to 14 months. 3 thyroid cancer pts with V600E mutations have tumor regression (range 9–16%) and are progression-free (4–7 months). Conclusions: Dose escalation of PLX4032 reached DLTs at 1120 mg BID. 720 mg BID is the current MTD, but 960 mg BID may be explored. PLX4032 exhibits antitumor activity in V600E BRAF mutant tumors. These observations confirm that V600E BRAF is a valid therapeutic target in human cancer.

[Table: see text]
A phase II trial of dasatinib in advanced melanoma
Authors: Kluger H. M. , Dudek A. , McCann C. , Rink L. , Ritacco J. , Adrada C. , Phouyaphone N. , Southard N. , Sznol M.
Published: August 2020

9010

Background: Direct or indirect inhibition of Src kinases (non-receptor tyrosine kinase signaling intermediates) reduces melanoma cell proliferation in vitro. Dasatinib is a well tolerated, small molecule inhibitor of src kinase family members c-Src, c-Yes, Lck, and also inhibits c-KIT, PDGFβR and EPHA2. We initiated a CTEP-sponsored phase 2 trial of dasatinib in melanoma to assess response rate, PFS and toxicity. The secondary objective is to evaluate the association between clinical response and expression of dasatinib targets in tumors obtained pre-treatment. Methods: Adults with stage III/IV unresectable melanoma with a PS of 0- 1, who have not received prior chemotherapy are eligible. Dasatinib was administered at 100mg PO BID continuously to the first 18 patients. Subsequently, the starting dose was decreased to 70mg BID. Cycles are 4 weeks, tumor assessments occur q2 cycles. Results: Thirty patients have been accrued, five are too early to evaluate. Five, four and three patients had acral-lentiginous, ocular or mucosal primaries, respectively. Median age was 62, M:F 18:12, six received prior non-cytotoxic therapy. Three patients had confirmed partial responses lasting 16, 6, and 5 months, and one had a non-confirmed partial response, progressing after 4 cycles. One patient had a minor response and remains on study after 24 cycles. A patient with an exon 13 mutation in c-KIT responded to therapy, while another with a c-KIT exon 11 deletion mutation did not. Common toxicities are grade II fatigue, grade II-III dyspnea and pleural effusions. Chronic toxicities required reduction of the starting dose, and have been observed in all patients on dasatinib for over two months, all of whom required two dose reductions. Conclusions: Daily dasatinib has modest activity in melanoma. Accrual is almost complete. Toxicities are frequent, alternate schedules providing breaks in dosing might be better tolerated and should be evaluated. Combination studies may be warranted based on preclinical evaluation in molecularly defined subsets of patients.

[Table: see text]
First analysis of an international pediatric melanoma and atypical melanocytic neoplasm database
Authors: Averbook B. J. , Jukic D. , Rao J. S. , Panneerselvam A. , Delman K. , Zager J. S. , Sabel M. , Pittelkow M. R. , Swetter S. , Kirkwood J. M.
Published: August 2020

9013

Background: Pediatric melanoma (PM) care has been extrapolated from adult melanoma data. PM and atypical melanocytic neoplasms (AMNs) appear to have different biology. An international database (DB) was developed to clarify their behavior. Methods: IRB approval was obtained at 12 institutions. An SQL-DB was developed for web entry of de-identified demographic and pathologic data for PM and AMN patients (pts) < 21yr through an honest broker system at the University of Pittsburgh. Institutions retained a key of pts entered with assigned numbers for quality assurance and updates. Statistical analysis used Kaplan-Meier survival curves, univariate linear trends and log rank tests. In situ melanoma was excluded from PM survival analysis. Results: 828 pts were registered as of 31 Oct 2008 (ages 11mo-23; median 15yr). 34 pts 21–23yr entered were left in the DB for statistical comparison. Diagnosis years ranged from 1936–2008. 455 pts had complete follow-up. Too few AMN pts had complete follow-up for analysis (18/208). After excluding 32 in situ and 40 with other incomplete data, 365 PM out of 415 total PM were evaluable for OS and 351 for DFS (Stage IV removed). Mean/median age for evaluable PM pts was 16.44/17-yrs (range 1–21yr). 591 pts were age 10–20 while 203 were < 10. Sentinel lymph node (SLN) biopsy showed spread in 30.1 % PM pts (compared to 50% [4/8] of AMN SLN pts). 10-yr PM OS was 80.6%, and pts 0–10 yr had 100% 10-yr OS compared to 69.6% for pts age 10–15 and 79.49% for age 15–20 (p= 0.1473). OS did not differ significantly by gender. Stage predicted OS (p<0.0001). 10-yr OS was 94.13% for Stage I (n=174), 79.62% for stage II (n=67) & 77.14% for stage III (n=75). Thickness affected 10-yr OS: 0–1mm=97% (n=147), 1.1–2mm 70% (n=84), 2.01–4mm 78% (n=71) & >4mm 81% (n=25), p= 0.0099. Survival was similar for pts with PM > 1mm of the several T stage groupings. Ulceration adversely affected OS (p=0.022). Mitosis, defined as present/absent did not alter survival. Nodal metastasis correlated with worse OS (p= 0.170). Conclusions: Stage, thickness, ulceration, and nodal status are significant predictors of OS for PM. Further study will focus on multivariable analysis of PM and AMNs after updating pts, increasing accrual, and cleaning data.

No significant financial relationships to disclose.
The biology and prognostic value of lymphatic vessel density (LD) and lymphatic invasion (LI) in regression in melanoma
Authors: Yun S. , Gimotty P. , Hwang W. , Dawson P. , VanBelle P. , Elder D. , Elenitsas R. , Guerry D. , Schuchter L. , Xu X.
Published: August 2020

9017

Background: Regression in melanoma is characterized by increased vascularity, lymphocytic infiltrate and fibroplasia in the papillary dermis, accompanied by the absence (complete regression, CoR) or presence (partial regression, PaR) of melanoma cells in the epidermis. The prognostic value of regression is controversial. We noticed that LD and LI were increased in the areas of regression (AR) or areas with brisk lymphocytic infiltration (AB). Our goal was to clarify the prognostic value of regression in melanoma. Methods: Dual immunohistochemical staining was done using antibodies to podoplanin (lymphatic vessels) and S100 (melanoma cells) on paraffin tissues from 321 patients with vertical growth phase (VGP) primary melanomas who had 10 years or more of follow-up. LD in AR (both CoR and PaR) was compared with that of normal dermis adjacent and distant, as well as LD in the AB. LI in these areas was also scored. Unadjusted and adjusted hazard rates were obtained from univariate and multivariate Cox models for time to melanoma-specific death using established melanoma prognostic factors. Results: 116 patients (36%) had regression: 75 CoR (23%) and 41 PaR (13%). LD significantly decreased stepwise from CoR (mean ± se, 23.7 ± 2.7) to PaR (15.5 ± 1.1), adjacent normal dermis (7.3 ± 0.28) and distant normal dermis (5.4±0.31) and it was significantly elevated in the AB (18.5±0.78). Melanomas with CoR had the highest percentage of LI in both AR and AB. In addition, the percentage of LI in AB was highest for men and for those with VGP tumor infiltrating lymphocytes (TILs). Both high LD in AR and more LI in AB were associated with poor prognosis (p=0.004 and p=0.002, respectively). Six factors were significant in the final multivariate model: LI in AB (HR=2.3), LD in AR (HR=1.04), thickness (HR=1.44), axial (HR=7.7), ulceration (HR=2.5) and no VGP TILs (HR=2.8). Conclusions: AR and AB were associated with increased LD and higher incidence of LI in primary melanomas. LD and LI in AR or AB are independent prognostic factors. Our data suggest that the effects of regression on prognosis are mediated at least in part through lymphangiogenesis and LI.

No significant financial relationships to disclose.
Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multipeptide vaccine for resected stages IIIC and IV melanoma
Authors: Weber J. S. , Sarnaik A. , Targan S. , Yu B. , Morelli D. , Urbas P. , Maker N. , Yellin M. , Nichol G.
Published: August 2020

9023

Background: Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma that is associated with immune-related adverse events (IrAEs). Methods: 50 HLA A*0201 positive patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times subcutaneously with Ipilimumab at 3 or 10 mg/kg intravenously every 8 weeks for 12 months, and 25 HLA A *0201 negative patients received Ipilimumab alone at 10 mg/kg. Primary endpoints were toxicity and the achievement of a 40% rate of tolerable IrAEs. Immune responses measured by ELISPOT and tetramer assays, and time to relapse were also assessed. 3 melanoma peptides were administered at 1000 mcg/dose each. Results: Median age was 58, with 44 men and 31 women. 46 patients had stage IV, and 29 had stage IIIC resected disease. 19/75 (25%) patients had grades 3–4 IrAEs that were dose-limiting. No patient with dose limiting toxicity required hospitalization and all returned to baseline status with the use of systemic steroids. Assays of induction of IL-17 secreting T cells showed a positive association with freedom from relapse (p=0.049). Change in slope of the increase in total lymphocyte count at four weeks was also associated with a trend toward freedom from relapse and development of an IrAE. 27 of 75 patients have relapsed with a median of 23 months of follow-up. 10 were again rendered NED surgically and are alive without disease. 68 patients are alive, 10 with disease. Only 1/19 patients with grade 3/4 IrAE has died of disease, compared to 6/56 without a dose limiting IBE. 23 of 27 relapses occurred without a grade 3/4 IrAE, compared with 15 IrAEs in 48 patients without a relapse. ELISPOT assays showed that patients at 10 mg/kg actually had decreased responsiveness in fresh PBMC to PHA and the CEF (CMV, EBV, FLU) pool of peptides. Conclusions: IrAEs are associated with clinical benefit in patients with resected high-risk melanoma receiving Ipilimumab with or without a peptide vaccine. Increases in IL-17 secreting CD4 T cells and the slope of increase in total lymphocytes over 4 weeks are associated with freedom from relapse. These data support testing the current regimen at 10 mg/kg in a larger randomized trial.

[Table: see text]
Phase II trial of bevacizumab and everolimus in the treatment of patients with metastatic melanoma: Preliminary results
Authors: Peyton J. D. , Spigel D. R. , Burris H. A. , Lane C. , Rubin M. , Browning M. , Trent D. , Hainsworth J. D.
Published: August 2020

9027

Background: Metastatic melanoma remains resistant to therapy. Anti-angiogenesis agents and m-TOR inhibitors have shown modest activity as single agents. In this multicenter phase II trial, we evaluated the combination of bevacizumab and everolimus in the treatment of patients with metastatic melanoma. Methods: Patients with unresectable metastatic melanoma with ECOG PS 0–2 were eligible. Up to 2 previous treatment regimens were allowed; patients previously treated with angiogenesis or m-TOR inhibitors were excluded. Additional eligibility requirements: adequate organ function, no CNS involvement, standard bevacizumab exclusions. All patients received bevacizumab 15mg/kg IV q 3 weeks, and everolimus 10mg po daily. Patients were evaluated every 6 weeks, and treatment continued until disease progression. Results: Between February 2008 and October 2008, 56 patients were enrolled; the first 31 patients are included in this interim report. The median age was 71 years (range 36 to 89 years); 19 patients (61%) had visceral metastases; 0/1/2 previous regimens, 12/11/8 patients; ECOG PS 0/1/2, 17/11/1. 28 patients (90%) received at least 6 weeks of treatment; 3 patients withdrew prior to 6 weeks (toxicity, 2 patients; intercurrent illness, 1 patient). 1 of 28 evaluable patients (4%) had a PR. However, 19 additional patients (68%) had stable disease (15 of these patients had measurable decrease in tumor size), for a disease control rate of 72%. 14 patients remain on treatment, after treatment durations of 2 - 7.5 months. After a median followup of 5 months, the median progression-free survival is 3.5 months (95% CI 2.4 - 5.4 months). Bevacizumab/everolimus was generally well tolerated. 1 patient withdrew because of interstitial pneumonitis (reversible) and 1 patient had a fatal MI, possibly bevacizumab-related. Grade 3 mucositis occurred in 13%; other grade 3 toxicities occurred in < 10% of patients. Conclusions: The combination of bevacizumab and everolimus was well tolerated and has activity in patients with metastatic melanoma. Updated results in all 56 patients will be presented.

[Table: see text]
Phase I/II study of arginine deiminase (ADI-PEG 20) in patients with advanced malignant melanoma (MM)
Authors: Ott P. A. , Carvajal R. D. , Pandit-Taskar N. , Jungbluth A. A. , Hoffman E. , Venhaus R. , Pan L. , Old L. , Pavlick A. C. , Wolchok J. D.
Published: August 2020

9030

Background: ADI-PEG 20 is an enzyme that degrades arginine, a crucial amino acid central to metabolism and biosynthesis of growth and development of normal and neoplastic cells. Melanoma is auxotrophic for arginine because it lacks argininosuccinate synthetase (ASS), a key enzyme required for synthesis of arginine from citrulline via the urea cycle. This study evaluates the safety and clinical efficacy of ADI-PEG 20 in patients with MM. Methods: Patients with histologically confirmed stage III (unresectable)/ IV cutaneous, uveal or mucosal MM were treated with 40, 80 or 160 IU/m2 ADI-PEG 20 i.m. weekly for 9 weeks in a phase I setting. In a phase II component, 16–25 pts receiving 160 IU/m2 will be evaluated for tumor response (TR) by RECIST. Secondary endpoints for all patients included metabolic response by 18FDG-PET, pharmacodynamics (PD), immunogenicity and ASS tumor expression by immunohistochemistry. Results: As of Nov. 2008, 24 pts were enrolled (40 IU/m2, n=6, 80 IU/m2, n=6, 160 IU/m2, n=12): 14 males, 10 females. Median age: 66 yrs (range 29- 83 yrs). Toxicity consisted primarily of Grade 1/2 adverse events (AE) (injection site pain, myalgia, arthralgia, fatigue, flushing, rash/itch, nausea, diarrhea, hyperuricemia, taste alteration). One dose limiting toxicity (DLT) of G3 arthralgia was observed at 80 IU/m2. Two DLTs (G3 seizure and G3 lymphedema) were reported, at 160 IU/m2. No grade 4 or 5 AEs were observed. Of 22 patients evaluable for TR, 8 had stable disease (SD) with 2 of these durable for ≥ 6 months. Notably, 3 SD were uveal melanoma. 14 patients had progressive disease. PD analysis showed plasma arginine depletion during study weeks 1–6 regardless of dose. Immunohistochemical ASS expression analysis in tumor tissue: negative= 13 pts, < 5% cells positive= 5 pts. Conclusions: ADI-PEG 20 as a single agent is well tolerated in advanced MM leading to consistent arginine depletion. The extent of clinical activity has yet to be shown. Combination therapy of ADI-PEG20 with other treatments such as pro-apoptotic reagents during the first 6 weeks of ADI-PEG 20 treatment while arginine is depleted could lead to synergistic anti-cancer activity.

No significant financial relationships to disclose.
Reduction of circulating regulatory T cell (Treg) by intravenous high-dose interferon (HDI) treatment in melanoma patients
Authors: Ascierto P. A. , Napolitano M. , Celentano E. , Simeone E. , Gentilcore G. , Capone M. , Ciccarelli L. , Palmieri G. , Castello G. , Mozzillo N.
Published: August 2020

9040

Background: T regulatory (Treg) cells are an immunoregulatory cell type which express high levels of surface CD25, CTLA-4, and GITR. Tregs have been shown to be present in tumor and tumor-draining lymph nodes, acting as an inhibitory population blocking effector cell function. Depletion or blockade of Tregs might be able to enhance antitumor immunity. Recent evidence has been reported about the possibility of High Dose Interferon (HDI) to act through an indirect immunomodulatory mechanism (Gogas, NEJM 2006; Moschos JCO 2006). We started a study to verify if iv HDI treatment in melanoma patients could be able to reduce the number of Treg cells in peripheral blood. Methods: Analysis was performed on melanoma pts referring to the National Cancer Institute of Naples since July 2006 and who addressed to Neoadjuvant or Adjuvant treatment with iv HDI (20 MUI/m2, 5 days per week) for 4 wks. Peripheral blood mononuclear cells (PBMC) were obtained from 22 consecutive melanoma pts. Blood draw was performed at days 0, 8, 15, 22 and 29. PBMC were thawed and labeled with anti-CD4 and anti-CD25hi (BD, San Diego, CA) and anti-FoxP3 (eBioscience, San Diego, CA). Labeled cells were analyzed using a FACScalibur (Becton Dickinson). Results: Fifteen (68.2%) out of 22 pts showed a decrease of Treg cells in peripheral blood. The average value at day 0 for circulating Treg (cTreg) was 2.7%. The average percentage at day 29 was 1.4%. The average reduction was 1,4 (50% reduction in the average value of cTreg). Statistical analysis showed an average decrease of 0.29% per week of treatment. Despite of this clear trend in reducing cTreg by HDI, statistical significance was not reached (probably due to the power of the study). Moreover, it has been observed great differences between the disease status, the prognosis (recurred/not recurred pts, alive/deceased) and an increased basal percentage of cTreg. Our preliminary data are consistent for an effect of HDI on reducing cTreg, although no conclusion about the role of such reduction in terms of response to treatment or as prognostic markers of better/worse disease can be inferred. Further data are awaited in order to verify if the Treg reduction after a HDI treatment may indeed contribute to the antitumor response.

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Association between HU177 serum level and prognosis in patients with primary melanoma
Authors: Hamilton H. , Krich D. , Christos P. J. , Shapiro R. L. , Berman R. S. , Pavlick A. C. , Polsky D. , Liebes L. , Brooks P. C. , Osman I.
Published: August 2020

9044

Background: Cleavage of type IV collagen during extracellular matrix (ECM) remodeling leads to exposure of cryptic regulatory sites within the ECM shown to be involved in tumor angiogenesis. Increased levels of a soluble form of the cryptic epitope HU177 in sera of melanoma patients have been shown to be associated with greater tumor thickness and nodular histological subtype. In this study, we investigate the association between HU177 serum levels and melanoma patients' clinical outcomes. Methods: Sera from 209 patients with primary melanoma prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the New York University Langone Medical Center (85 females, 124 males, mean age=58, mean thickness=2.09 mm, Stage I n=140, Stage II n=40, Stage III n=29) were analyzed for HU177 level. HU177 serum levels at the time of diagnosis were then correlated with disease-free survival (DFS) and overall survival (OS). Results: Median follow-up time for survivors was 54.9 months (range 2–81 months). Thirty-eight of the 209 (18%) patients developed recurrences, and 34 of the 209 (16%) patients died during follow-up. HU177 sera levels ranged from 0–139.9 ng/ml (mean=6.2 ng/ml; median=3.7 ng/ml). Because the distribution of HU177 levels was positively skewed, we analyzed the data using the median in addition to the mean. HU177 level > 3.7 ng/ml (the median) was associated with a higher rate of melanoma recurrence (p=0.04) and increasing mortality (p=0.01) in a Kaplan Meier analysis. HU177 remained an independent prognostic factor for DFS and OS when controlling for tumor thickness and histological subtype in multivariate Cox proportional hazards regression models. In the DFS hazard model controlling for tumor thickness and histology, the hazard ratio for HU177 >3.7 ng/ml (the median) was 2.01 (95% CI= 1.002, 4.04; p=0.049). In the OS hazard model controlling for tumor thickness and histology, the hazard ratio for HU177 >3.7 ng/ml (the median) was 2.23 (95% CI=1.06, 4.70; p=0.03). Conclusions: Increased serum level of HU177 identifies a subset of primary melanoma patients with worse prognosis and suggests that anti-angiogenic therapy in the adjuvant setting may be a rational approach.

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The prognostic significance of lymphatic invasion in primary melanoma
Authors: Xu X. , Chen L. , Hwang W. , Dawson P. , Guerry D. , VanBelle P. , Elder D. , Schuchter L. , Gimotty P.
Published: August 2020

9050

Background: Lymphatic invasion (LI) is an under-observed phenomenon in primary malignancies that can be better detected by immunostaining and that may associate with prognosis. In this study we sought to test the hypothesis that LI was associated with melanoma-specific survival (MSS) and was an independent prognostic factor. Methods: This study included 277 patients with stage I/II melanomas in vertical growth phase (VGP) who had at least 10 years of follow up. The log-rank test was used to test the study hypothesis - 72 melanoma-specific deaths were needed for 80% power to detect an odds ratio of 2.1. Paraffin sections were stained with antibodies to podoplanin (lymphatic vessels) and S-100 (melanoma cells) to identify LI. Univariate and multivariate Cox models were used to evaluate the prognostic significance of LI. An independent cohort of 106 similar patients was used for validation of the 10-year MSS rates. Results: LI was observed in 44.5% (95% CI: 38.6% - 50.4%) of the melanomas and its presence was significantly associated with thickness, mitotic rate, gender, age, and ulceration (U). The Kaplan-Meier survival curves for those with and without LI were significantly different (log-rank test p=0.022). The final multivariate model for time to MSD identified 4 independent prognostic factors: thickness (HR=1.5, p<0.001), U (HR=2.2 p=0.013), site (HR=3.9, p<0.001) and LI (HR=1.9, p=0.015). These factors were used to define a prognostic tree with 5 risk groups defined by melanomas that were thin (≤1.0mm) with no LI or U; thin with LI but no U; 1–3mm with no U; 1–3mm with U; and >3mm. Respectively, MSS rates were 100%, 88.6%, 77%, 48% and 42%. In the validation set, observed 10-year MSS rates in each risk group were not significantly different from those predicted from the survival curves for the tree-based risk groups. Conclusions: LI is an independent prognostic factor for MSS. Among patients with thin melanomas without U the 10-year MSS was lower for those patients with LI (89%, 95% CI=78% - 99%; n=41) compared to those without (100%, n=78). LI is an important prognostic factor that needs further validation in a population of patients from the sentinel node biopsy era.

No significant financial relationships to disclose.
Plitidepsin alone or with dacarbazine (DTIC) as first-line treatment for advanced unresectable melanoma (AUM)
Authors: Plummer R. , Hayward L. , Lorigan P. , Soriano V. , Moiseyenko V. , Szyldergemajn S. , Prados R. , Smyth J. , Calvert H.
Published: August 2020

9059

Background: AUM remains incurable in most patients (pts). DTIC alone had a 8–15% response rate (RR), while plitidepsin (Aplidin [APL]) showed a 6% RR and a 14% stable disease (SD) in a Phase (Ph) II study in 35 relapsed/refractory pts after DTIC failure. Furthermore, APL + DTIC has additive activity in preclinical models. Methods: This multicenter Ph Ib study aim to determine the safe recommended dose (RD) of APL on days 1, 8 & 15 + DTIC only day 1 q4wk. RD was defined as the highest dose with >5 days G4 neutropenia or G4 thrombocytopenia (TC) and/or febrile neutropenia (FN); any drug-related ≥ G3 toxicity (except nausea/vomiting or hypersensitivity reaction) in cycle 1. Results: Of 28pts with AUM, 23 were evaluable for DLT; 57% were males, median (med) age was 48 y (20–77), med ECOG 0 (0–2) and med LDH was 226 IU/l (126–983). Most pts (96%) had metastasis with a median of 2 sites involved (1–5). Dose levels of APL + DICT (mg/m2), were: DL1 (1.8 + 800), 7 pts; DL2 (2.4 + 800), 8 pts; DL 2b (2.4 + 1000), 5 pts; DL3 (3.0 + 800), 8 pts. Pts received 4 (2–6), 2 (2–5), 2 (1–2), 2 (1–8) median cycles respectively. The number of DLTs were 1/6, 1/7, 2/4, 2/6, respectively. DLTs were G3 ALT in 4 pts and FN + TC in 1 pt. The MTD was at DL 2B and the RD was at DL 2. There were 3 partial responses (PR, 14%) and 4 SD > 3 months (19%); all PR at DL2/3. Five pts were not evaluable, 2 pts had G3 hypersensitivity reactions related to Cremophor oil (APL formulation) and 1 pt had a idiosyncratic reaction to DTIC with prolonged pancytopenia. One pt had a wrong diagnosis and 1 pt had early progressive disease (PD). Conclusions: APL + DTIC can be safely combined at ≥ 70% of their respective single- agent RD in AUM. Main DLTs were asymptomatic, transient and reversible ALT elevations. Ph Ib showed 14 % PR and 19% clinically meaningful SD. A randomised Ph II study of DTIC + APL vs APL alone is ongoing.

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Pharmacokinetics (PK) of CR011-vcMMAE, an antibody-drug conjugate (ADC), in a phase (Ph) I study of patients (pts) with advanced melanoma
Authors: Sznol M. , Hamid O. , Hwu P. , Kluger H. , Hawthorne T. , Crowley E. , Simantov R. , Pavlick A.
Published: August 2020

9063

Background: CR011-vcMMAE, an ADC of fully-human monoclonal anti-GPNMB antibody (Ab) with monomethylauristatin E (MMAE), is in Ph I/II trials in pts with melanoma and breast cancer. We report PK and toxicity data from a Ph I study in melanoma pts treated every (q) 3 weeks (w), qw, or 2 of 3w. Methods: Enzyme-linked immunosorbent assays were used to measure ADC, total Ab (TA), soluble GPNMB (sGPNMB), and anti-ADC Ab in pt samples. Free MMAE was measured by liquid chromatography/mass spectrometry. Results: Initially, 32 pts were treated in 9 cohorts of 0.03 to 2.63 mg/kg iv q3w using standard 3+3 dose escalation. Noncompartmental PK analysis showed dose-proportional TA, ADC and free MMAE levels. As previously reported, maximum tolerated dose (MTD) was 1.88 mg/kg iv q3w; dose limiting toxicity (DLT) was rash. At MTD (n=15), terminal phase half life (T½) of TA was 41 ± 25h and T½ of ADC was 29 ± 13h. Mean maximum plasma concentrations of free MMAE was 1.3–2.9% of TA concentration across all doses. Mean sGPNMB at baseline was 12 ng/ml (range 1.3–32 ng/ml), corresponding to 0.024 % of TA concentration at MTD. Anti-ADC Ab were detectible in 8/240 (3.3%) samples (n=54). Based on the T½, two additional dose schedules (qw and 2 out of 3w) were initiated (n=14). Pts received 0.75 mg/kg (n=3) and 1.0 mg/kg (n=5) in the qw schedule and 1.25 mg/kg (n=3) and 1.5 mg/kg (n=3) in 2 of 3w. The most common adverse events (AEs) were rash (n=6), pruritus (n=5) and fatigue (n=4). 1 DLT (Gr 3 rash) was observed at 1.0 mg/kg qw. Enrollment is ongoing in both schedules. Conclusions: The relatively short T½ of CR011-vcMMAE (∼40h) does not appear to be due to immunogenicity or sGPNMB-mediated clearance. Preliminary data suggest that weekly dosing is tolerated at higher per-cycle cumulative doses than the q3w schedule.

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Tailoring end-of-life discussions to advanced cancer patients’ state of grief
Authors: Prigerson H. G. , Wright A. A. , Block S. D. , Maciejewski P. K.
Published: August 2020

9500

Background: Prior research has shown end-of-life (EOL) discussions are not associated with significant psychological distress, but are associated with earlier referrals to hospice and lower rates of intensive care. Nevertheless, associations between EOL discussions and care received may vary depending on patients’ state of grief over their cancer diagnosis. The aim of this study was to determine how Kubler-Ross’ proposed 5 states of grief –numbness, anger, bargaining, depression, and acceptance –modify the effects of EOL discussions on EOL care received. We hypothesized that the early grief state of numbness would interfere with patients’ processing of an EOL discussion, thereby, reducing its association with care received. Methods: Coping with Cancer is an NCI/NIMH-funded, multi-site prospective, longitudinal cohort study of patients with advanced cancer, conducted from September 2002-February 2008. Analyses were based upon 316 deceased patients who were interviewed at baseline and followed until death 4.4 months later. Patients were assessed at baseline on 5 grief states in response to their cancer diagnosis (i.e., numbness, anger, bargaining, depression, and acceptance) and whether an EOL discussion with their physician had occurred. Information on medical care received in the last week of life was obtained from chart review, and regressed on the interaction between each of the 5 grief states and the patient's report of an EOL discussion. Results: Of the 5 grief states, only numbness significantly moderated the effect of EOL discussions on medical care received. For patients with higher than average numbness (i.e., ≥ 1 on the 0–4 numbness score continuum), the effect of EOL discussions on ventilation or resuscitation in the last week of life was significantly reduced by a factor of 10 [OR=9.96, 95% CI (1.21–82.2)]; the effect of EOL discussions on death in the ICU was significantly reduced by a factor of three [OR=2.98, 95% CI (1.01–8.78)]. Conclusions: Associations between EOL discussions and care received are much reduced among patients who are high on numbness (i.e., those who have not resolved the 1st grief state). Physicians should consider their patients’ grief state (i.e., numbness) when deciding whether to engage in EOL discussions.

No significant financial relationships to disclose.
Geriatric medication management: Evaluation of pharmacist interventions and potentially inappropriate medication (PIM) use in older (≥65 years) cancer patients
Authors: Lichtman S. M. , Boparai M. K.
Published: August 2020

9507

Background: Polypharmacy and inappropriate drug use are risk factors for adverse drug reactions (ADR) and poor compliance in older cancer patients. Drug evaluations in the past have not focused on this group. An evaluation of the prevalence of PIMs, pharmacist interventions, and the number and type of medications was performed. An educational component helped patients with drug management to increase adherence, avoid drug-drug and drug-disease interactions. Methods: A geriatric clinical pharmacist reviewed patient's medications, assessed understanding of their drugs, evaluated adherence, reviewed for PIMs (Beer's criteria), identified possible ADR and side effects, and provided detailed instructions. The pharmacist collaborated with the oncologist to determine appropriate therapy for the patient. Only patients over the age of 65 were eligible for this clinic. Consults were performed from March 2008 to June 2008, this includes new and follow up visits. An additional retrospective chart review was performed on 100 patients ≥ 65 years of age seen from July 2007 to November 2007. Results: There were 154 patients who underwent a prospective consultations; 74 yrs (65–91; 58% female). The interventions were: an alternative agent was recommended (31pts/20%), drug - drug interactions identified (15/10%), problems with adherence (58/37%), drugs discontinued (54/35%), additional medication (64/42%), dose change (17/11%), pain management (28/18%) and cost issues (19/12%). More then one issue was addressed during visits. In the retrospective study, median age 72 (65 - 90), 48% were females; medications: median 8 (range 0–23). Most common classes of medications were anti-hypertensives (52%), vitamins/herbals (46%), proton pump inhibitors (32%) and lipid lowering agents (29%). The prevalence of PIMs was 11%. The most common were propoxyphene, high doses of long-acting benzodiazepines and diphenhydramine. Conclusions: A geriatric medication management evaluation resulted in 50% of patients requiring specific interventions and identification of PIMs in 11% of patients. This type of intervention can optimize care by increasing adherence and avoiding adverse drug events and their serious sequelae.

No significant financial relationships to disclose.