bluuebunny/crossref_metadata_2025_split huggingface dataset:
Second autologous stem cell transplantation as a strategy for management of relapsed multiple myeloma.
Authors: Gonsalves Wilson I. , Kumar Shaji , Lacy Martha , Dispenzieri Angela , Hayman Suzanne R. , Buadi Francis , Dingli David , Hogan William J. , Gertz Morie A. 
Published: March 2020

8092 Background: High dose therapy and autologous stem cell transplant (SCT) remain an integral part of the treatment of multiple myeloma (MM). Despite the introduction of several new drugs, disease relapse remains inevitable and a second SCT often allows continued disease control. Methods: We examined the outcomes in 105 patients (pts) undergoing a second SCT (SCT2) for relapsed MM, from among 1033 pts receiving initial transplant between 1994 and 2009. Patients receiving an allogeneic SCT post SCT2 were not included in the survival analysis. Results: Median (range) age at SCT2 was 60 yrs (35-74) and the time between SCTs was 46 mos (10-130). The median follow-up was 5 yrs from SCT2. The median (range) number of regimens between the two SCTs and from diagnosis was 2 (0-7) and 3 (1-11), respectively. Conditioning regimen was Mel 200 in 85 (81%) pts. Median (range) CD34 cells infused was 4.6 (2.5-25 million/kg). Hospitalization was required for 53 pts (50%), median hospital stay was 7 days.. Median time to ANC of 500 and platelets of 50,000 were 13 and 16 days, respectively. Treatment related mortality was seen in 5 (5%) pts. A partial response or better was seen in 95 (90%) pts, including a stringent CR in 10%, CR in 19%, and VGPR in 21%. Stable disease or progression was seen in 7 pts and 3 pts died prior to disease assessment. The median (95% CI) PFS and OS after SCT2 were 10.4 (8, 14) and 33 (28, 51) mos, respectively. The median OS was not reached and 33 mos respectively, for those obtained a CR and those with <CR, P=0.03. FISH pre-SCT2 was available for 73 pts; the PFS and OS were not affected by the presence of high-risk MM. In multivariate analyses, shorter duration of response to SCT1, higher plasma cell (PC) labeling index at SCT2, more regimens used prior to SCT2 all predicted shorter PFS and OS post SCT2. Lack of CR to SCT2 was also significantly associated with shorter PFS. Conclusions: Second SCT is an effective therapy for eligible pts relapsing after other treatments. It provides a meaningful duration of response and appears to be well tolerated. Pts with longer duration of response to first transplant and those achieving a CR appear to have maximum benefit.
BREAK-MB: A phase II study assessing overall intracranial response rate (OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/k mutation-positive melanoma with brain metastases (mets).
Authors: Kirkwood John M. , Long Georgina V. , Trefzer Uwe , Davies Michael A. , Ascierto Paolo Antonio , Chapman Paul B. , Puzanov Igor , Hauschild Axel , Robert Caroline , Kefford Richard , Goodman Vicki L. , Switzky Julie C. , Swann R. Suzanne , Martin Anne-Marie , Guckert Mary E. , Streit Michael R. W. , Schadendorf Dirk 
Published: March 2020

8501 Background: Melanoma brain mets carry a poor prognosis (median survival ≤4 months), for which more effective therapies are needed. Dabrafenib is a potent, selective oral inhibitor of mutated BRAF that has demonstrated clinical efficacy in pts with BRAF V600E/K mutant melanoma and previously untreated brain mets in a phase I study. Therefore, a phase II study (BREAK-MB) was initiated. Methods: Stage IV pts with ≥ 1 intracranial met (0.5 cm–4 cm assessed by MRI) without prior brain therapy (Cohort A) or with progression following prior brain therapy (Cohort B) were eligible with V600E/K mutation. Pts received dabrafenib 150 mg BID. The primary endpoint was investigator-assessed OIRR among V600E mutation-positive pts. Results: Overall, 172 pts were recruited. At interim analysis, of 127 pts enrolled (safety population), 41 (Cohort A n=24; Cohort B n=17) had reached 8-week disease assessment. Unconfirmed OIRR in Cohort A was 10/19, (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed OIRR was 8/15 (53%; 95% CI: 26.6%–78.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. Unconfirmed overall response rate (ORR) in Cohort A was 10/19 (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed ORR was 6/15 (40%; 95% CI: 16.3–67.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. In the safety population, 12/63 pts (19%) in Cohort A reported an SAE; 1 (2%) was fatal (cerebral hemorrhage). In Cohort B 15/64 pts (25%) reported an SAE; 1 (2%) was fatal (seizure). In Cohort A, 47 pts (75%) experienced AEs: 9 grade 3 (14%) and 3 grade 4 (5%). The most common AEs were headache (21%), hyperkeratosis and rash (17% each). In Cohort B, 47 pts (73%) experienced AEs: 12 grade 3 (19%) and 3 grade 4 (5%). The most common AEs were fatigue or nausea (22% each) and pyrexia (17%). Conclusions: Dabrafenib shows high clinical activity both in pts with intra- and extracranial mets with acceptable toxicity. Final data will be presented.
Intermittent high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III malignant melanoma: Final analysis of a randomized phase III DeCOG-trial (NCT00226408).
Authors: Mohr Peter , Hauschild Axel , Trefzer Uwe , Enk Alexander , Tilgen Wolfgang , Loquai Carmen , Gogas Helen , Haalck Thomas , Koller Josef , Schadendorf Dirk , Dummer Reinhard , Gutzmer Ralf , Brockmeyer Norbert , Hölzle Erhard , Sunderkötter Cord , Mauch Cornelia , Stein Anette , Schneider Lars , Podda Maurizio , Weichenthal Michael 
Published: March 2020

8505 Background: Adjuvant high-dose interferon (HDI) treatment of patients (pts) with malignant melanoma (MM) usually consists of 4 weeks initial intravenous (iv) infusion of 20 MU/m² IFNa2b followed by 11 months of 10 MU/m² subcutaneously (sc). It is still unclear, whether both components are necessary for the efficacy of HDI in high-risk MM pts. The adjuvant phase III DeCOG MM-ADJ-5 trial evaluates efficacy, safety, tolerability and quality of life (QoL) of an intermittent (pulsed) high-dose iv IFNa2b regimen as compared to standard HDI. Methods: Patients with stage III (AJCC 2002) resected intransit or lymph node metastasis from cutaneous malignant melanoma were randomly assigned to receive either standard HDI regimen (Arm A), or 3 courses of IFNa2b 20 MU/m² iv on 5 days a week for 4 weeks repeated every 4 months (Arm B). Distant metastasis free survival (DMFS) was the primary endpoint for efficacy analysis. The EORTC QLQ C30 questionnaire was used before and during the study in a standardized way (weeks 0, 4, 16, 24, 40). In addition, patients completed a diary containing global QoL measures every week. Results: Out of 649 patients who were enrolled, 22 patients had to be excluded from the intent-to-treat analysis. The remaining 627 patients were well balanced between both arms according to sex, age, and stage. Median follow-up was similar in both groups (55.4 vs. 55.3 months). Distant metastasis occurred in 138 (Arm A; 44%) vs. 145 (Arm B; 47%) patients without statistical significance (p=0.46). Survival was not significantly different for DMFS (HR 1.1; p=0.39) or OS (HR=1.0; p=0.85). Termination of treatment due to adverse events or QoL related reasons occurred significantly more often in arm A than in arm B (26.0% vs. 14.8%; p<0.001). The pulsed schedule resulted in less cumulative toxicity as compared to the standard regimen, in particular regarding fatigue and neuropsychiatric side effects. Conclusions: The final analysis of pulsed adjuvant HDI treatment showed no significant DMFS or OS differences in comparison to conventional HDI. There is a clearly favorable safety and QoL profile of the pulsed regimen.
Hypersensitivity skin reactions in melanoma patients treated with vemurafenib after ipilimumab therapy.
Authors: Harding James J. , Lacouture Mario E. , Pulitzer Melissa , Callahan Margaret , Postow Michael Andrew , Carvajal Richard D. , Wolchok Jedd D. , Chapman Paul B. 
Published: March 2020

8515 Background: Ipilimumab (IPI) and vemurafenib (VEM) each improve overall survival for patients (pts) with metastatic melanoma. Both are FDA-approved and are being used in pts with BRAFV600E-mutated metastatic melanoma. We previously described cases of prominent skin eruptions associated with VEM in pts who had previously received IPI. Methods: We have updated our experience of BRAFV600E-mutated melanoma pts treated with VEM who had previously received IPI. Pts were treated at our center from January 2007 to January 2012. Data were collected under an approved IRB waiver. Results: Sixteen melanoma pts were treated with VEM after having received IPI. The most common drug-related adverse event (AE) associated with VEM was rash, occurring in 13/16 patients (81.3%, 95% CI 56.5-93.2). Four pts developed a severe, Grade 3, maculopapular rash within 8 days of starting VEM. Biopsies in 2 pts revealed spongiotic and perivascular dermatitis with eosinophils consistent with a drug hypersensitivity reaction. Hypersensitivity reactions did not progress to life-threatening reactions such as anaphylaxis or Stevens-Johnson syndrome, nor did they result in VEM dose discontinuation. Reactions were managed with corticosteroids and dose modifications. Grade 3 rash strongly correlated with initiating VEM within one month of IPI (Fisher’s exact test, p = 0.007) and was not associated with the dose of prior IPI, the number of prior doses, or immune-related AEs. The incidence of Grade 3 rash in this pt cohort was significantly higher than in pts treated on the phase III trial of VEM (4/16, 25% versus 28/336, 8%; χ2 = 5.13, Df = 1, p = 0.02). The objective overall response for VEM was 50% (95% CI 26.5-73.4), which is similar to response rates seen on the phase II and III trials. Conclusions: In pts receiving VEM who have previously received IPI, dermatologic AEs appear to be more common. This effect seemed most pronounced if VEM was given within one month of completing IPI. Although more data are necessary to confirm this apparent association, we speculate that the release of immune checkpoint inhibition by IPI may predispose pts to hypersensitivity skin reactions to VEM.
Predicting early relapse in patients with BRAFV600E melanoma with a highly sensitive blood BRAF assay.
Authors: Sullivan Ryan J. , Lawrence Donald P. , Flaherty Keith T. , McDermott David F. , Aldridge Julie , Cho Daniel C. , Simonson Rachel , Seery Virginia Jean , Hodi F. Stephen , Atkins Michael B. , Mier James Walter , Panka David J 
Published: March 2020

8516 Background: Many patients (pts) with metastatic melanoma (MM) who progress on BRAF inhibitors (BRAFi) develop rapidly progressive disease (PD) which is difficult to manage. Identification of an early marker of PD may allow for therapeutic intervention prior to clinical deterioration. We have developed a highly sensitive and inexpensive assay in our laboratory which can detect as little as 1 BRAFV600E mutant melanoma cell in 400,000 peripheral blood lymphocytes (PBL). We aimed to determine the utility of our assay as a tool to follow pts with BRAF mutant MM who are being treated with a BRAFi. Methods: Every pt had a BRAFV600E mutation detected from a tumor sample in a CLIA-approved laboratory prior to commencing BRAFi therapy. 20 pts with stage IV BRAFV600E MM underwent serial venopunctures before and every 4 weeks during treatment with a BRAFi. BRAFV600E level was quantified using our proprietary assay (Panka et al Melanoma Research 2010). Serial BRAFV600E levels were generated for every pt and normalized to the pre-treatment value. BRAFV600E level was then correlated with response to therapy and PD. Results: BRAFV600E was detected in the PBL of each pt. To date, 10 pts have had BRAFV600E levels quantified at 3 or more time points (data for all 20 pts will be available at time of presentation). Relative BRAFV600E levels reduced by half following the first and second cycles of treatment in 7 pts, which correlated with disease regression in each pt. Following the third cycle of treatment, the relative BRAFV600E levels varied greatly with a subset of pts having continued suppression while others having a rise in their BRAFV600E levels. In each pt with PD, the BRAF assay showed an increase > 4 wks in advance of clinically or radiographically defined PD. Conclusions: Our assay is able to quantify changes in BRAFV600E levels in the blood of pts with BRAF mutant MM receiving BRAFi therapy. In these pts, the BRAFV600E levels are reduced in the setting of initial disease regression and increase well in advance of clinical or radiographic PD. While further development is necessary, such a test could be used to identify pts who may be selected to receive alternative therapy prior to clinical or radiographic PD.
A phase II trial of dasatinib in patients with unresectable locally advanced or stage IV mucosal, acral, and solar melanomas: An Eastern Cooperative Oncology Group study (E2607).
Authors: Kalinsky Kevin , Lee Sandra J. , Lawrence Donald P. , Iafrate A. John , Borger Darrell R. , Averbook Bruce Jeffrey , Tarhini Ahmad A. , Kirkwood John M. 
Published: March 2020

8522 Background: Pre-clinical studies report a critical role of c-KIT mutations in mucosal, acral, and solar melanomas. Clinical trials of KIT-directed therapy with imatinib and sunitinib demonstrate activity in these subtypes. Unlike other TKIs, dasatinib inhibitory activity is seen in melanoma cell lines with the most common KIT mutation at exon 11L576P. E2607 tests the efficacy of dasatinib in treatment-naïve or previously treated patients (pts) with these unresectable subtypes. Methods: Pts receive dasatinib 70 mg PO twice daily for this two-stage phase II trial. The primary objective is response rate (RR: RECIST). Stage I was open to KIT mutated (KIT+) and wild-type (KIT-) tumors with these subtypes (n=56). Depending upon the interim analysis, stage II would pre-select for KIT+. If the overall response rate were < 5%, the study would be terminated. Secondary objectives include progression-free survival (PFS), overall survival (OS), safety, and KIT mutation status. Results: Between May 2009-Dec 2010, 57 pts have been accrued to stage I. Of 54 (2 no therapy, 1 ineligible), 26 have mucosal (48%), 13 acral (24%), and 15 solar melanomas (28%). As of Jan 2012, the median f/u is 15 months (mo, range: 4-24 mo). Best responses (n=52) are 1 complete (CR: 2%), 3 partial (PR: 6%), 13 stable disease (25%), 29 progression (56%), and 6 unevaluable (11%). 51/52 have progressed (median PFS: 1.9 mo, 95% CI: 1.5-2.8) and 40/54 died (median OS: 7.4 mo, 5.7-10.8). KIT status has been assessed in 42 pts: 39 KIT- (93%) and 3 KIT+ (7%). PR is seen in 1/39 KIT-. All KIT- have died: median PFS (1.8 mo, 95% CI: 1.4-2.9) and OS (6.8 mo, 95% CI: 5.2-10.8). Of the 3 KIT+ (1 acral, 2 mucosal), 2 have died (PFS 1.4-2.5 mo, OS: 1.4-10.5 mo), and 1 refused f/u (OS: 13.3+ mo). The pt with a CR is alive at 14.4+ mo (unknown KIT status). Toxicities include 1 grade IV (elevated lipase) and grade III dyspnea (n=7), nausea (n=6), and vomiting (n=3). Conclusions: Further evaluation of dasatinib should be pursued in pts selected for KIT+ and subtype, given the lack of promising results in Kit-(<5% RR). The current trial is revised to enroll only KIT+ acral, mucosal, and vulvovaginal melanomas and available via CTSU.
Phase II trial of RO4929097 Notch gamma-secretase inhibitor in metastatic melanoma: SWOG S0933.
Authors: Margolin Kim Allyson , Moon James , Redman Bruce G. , Chidiac Tarek , Othus Megan , Ribas Antoni , Flaherty Lawrence E. , Sondak Vernon K. , Gajewski Thomas 
Published: March 2020

8525 Background: The Notch pathway regulates expression of genes for cell cycle, tissue-specific differentiation, and vasculogenesis. Notch target genes affect melanomagenesis, and Notch levels can influence stemlike versus differentiated tumor cells. Gamma-secretase, which activates intracellular Notch, can be inhibited to kill melanoma cells. We designed this trial to test RO4929097 in pts with melanoma and its effects on T lymphocytes and tumor gene expression. Methods: To assess 6-month progression-free survival (PFS) and 1-year overall survival (OS) in advanced, untreated melanoma patients (pts), a 2-stage accrual design was used. Correlative studies: markers of Notch pathway activation in archived or fresh tumor and T cell functional assays pre-treatment (Rx) and at week 3. Rx dose was 20 mg orally on 3 consecutive days, weekly. Results: 33 pts were Rx’d in stage 1 (median age 61 [range 32-85]; 70% male; 42% elevated LDH; 30% unknown primary; 24% bone mets; 36% liver; 55% lung; 55% lymph node, skin or soft tissue). The clinical outcomes did not meet criteria for stage 2 accrual. One pt had a confirmed PR of 7 months’ (mo) duration. The median PFS was 1.4 mo, [95% confidence interval, c.i. 1.3-2.7], the 6-mo PFS was 11% [95% c.i 3%-33%], and the 1-year OS was 45% [95% c.i. 23%-90%]. Treatment was well-tolerated with no grade (gr) 4-5 tox. The most common gr 2 drug tox were fatigue and nausea in 4 patients (12%) each, and only 4 of 7 gr 3 tox were considered drug-related (1 increased ALT, 1 QTc prolongation, 1 bradycardia, 1 lymphopenia). Pre- and week 3 on-Rx peripheral T cell samples assayed for IL-2 (23 pts) and IFN-γ (22 pts) secretion to Staphylococcal enterotoxin A showed no significant change, in contrast to in vitro gamma-secretase inhibitors which blocked T cell activation. Pre- and on-Rx tumor biopsies in one pt showed no decrease in the Notch target Hey1. Conclusions: RO4929097 at this dose and schedule has limited activity in molecularly-unselected pts with melanoma. Lack of effect on T cell function and tumor Hey1 expression suggests that sustained target inhibition might not have been achieved. Supported in part by PHS Cooperative Agreements, NCI, DHHS CA32102 and CA38926. ClinicalTrials.gov identifier: NCT01120275.
Association of high T-cell immune infiltrate and low hemorrhage in melanoma brain metastases (MBMs) with prolonged survival.
Authors: Krauze Michal Tadeusz , Hamilton Ronald H. , Romkes Marjorie , Bortoluzzi Stephanie , Harasymczuk Malgorzata , Reinhard Todd , Junecko Beth Fallert , Nukui Tomoko , Konstantinopoulos Panagiotis , Becker Dorothea , Kondziolka Douglas , Tarhini Ahmad A. , Whiteside Theresa , Mintz Arlan H. , Tawbi Hussein , Ferrone Soldano , Kirkwood John M. , Moschos Stergios J 
Published: March 2020

8528 Background: Despite the poor prognosis of patients (pts) with MBM several pts have prolonged survival. We hypothesized that the heterogeneity of BrMM is determined by differences in melanoma biology and its brain microenvironment. Methods: We identified pts who have undergone craniotomy for MBMs. Evaluation entailed complete clinical information, acquisition of archived melanoma brain metastases, histopathologic analysis of hematoxylin and eosin-stained sections (n=101), whole genome expression profiling (WGEP, Illumina DASL) in 29 archived tissues. Results were validated by immunohistochemistry (IHC) or in situ hybridization (ISH). Results: In univariate analysis (log-rank) factors significantly associated with prolonged survival were high immune infiltrate (HII) plus low hemorrhage (hazard ratio, HR, 2.71, p<0.001), present melanin (1.67, p=0.03), and recursive partitioning analysis (RPA) class 1 (0.37, p<0.0001). No association between HII and use of immunotherapy prior to craniotomy was noted. Only RPA class 1 (p=0.029) and HII plus low hemorrhage (p=0.002) remained significant in Cox proportional hazards model analysis. Gene set analysis of WGEP data confirmed that Encarta pathways related with T-cell activation and differentiation were significantly associated with prolonged survival whereas Y branching of actin filaments, presenilin action in Notch and Wnt signaling, G-protein signaling through tubby protein, lissencephaly gene in neuronal migration and development are among the gene categories associated with worse survival. IHC and ISH analysis of tumor sections for various markers (n=40) showed that high peritumoral CD3+ (3.31, p=0.009), high peritumoral CD4+ (4.41, p=0.014), and high peritumoral CD8+ (3.02, p=0.030) are associated with prolonged survival whereas neither CD14+ nor FoxP3+ infiltrate, nor high melanoma expression of antigen presentation molecules are associated with survival. Conclusions: Our study is the first to document that high peritumoral T-cell infiltrates are associated with prolonged survival. High tumor hemorrhage, an adverse prognostic sign, reflects aggressive melanoma cells that migrate and invade in the brain.
Long-term cure after complete resection and adjuvant immunotherapy for distant melanoma metastases.
Authors: Morton Donald L. , Mozzillo Nicola , Kashani-Sabet Mohammed , Thompson John F , Kelley Mark C. , De Conti Ronald C. , Lee Jeffrey Edwin , Huth James F. , Faries Mark B. , Dalgleish Angus George , Wagner Jeffrey D. , Hersh Evan , Schneebaum Schlomo , Anderson Clay M. , Smithers Mark , Schuchter Lynn Mara , McMasters Kelly M. , Testori Alessandro , Karakousis C. P. , Elashoff Robert ,   MMAIT-IV Clinical Trial Group
Published: March 2020

8534 Background: In phase II trials, postoperative therapy with Canvaxin allogeneic melanoma cell vaccine plus Bacillus Calmette-Guerin (BCG) improved the survival of patients with stage IV melanoma. A multicenter, phase III placebo-controlled study was undertaken to investigate the vaccine’s efficacy. Methods: After complete resection of melanoma involving up to 5 distant sites, patients were randomized to treatment with BCG plus Canvaxin (BCG-Canvaxin) or BCG plus placebo (BCG-placebo). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS) and skin test responsiveness to the study agent. Results: Between May 1998 and April 2005, 496 patients were randomized. In April 2005, entry to the study was terminated due to low probability of demonstrating treatment differences. However, 256 patients from sites enrolled in a follow-up study were monitored until March 2010. Median OS and 5-year and 10-year rates of OS were 39.1 months, 43.3% and 33.3%, respectively, in the BCG-placebo group, versus 34.9 months, 42.5% and 36.4%, respectively, in the BCG-Canvaxin group (hazard ratio, 1.053; 95% confidence interval, 0.81 to 1.36; p=0.6964). Median DFS, 5-year DFS, and 10-year DFS were 7.6 months, 23.8% and 21.7%, respectively, for the BCG-placebo group, versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG-Canvaxin group (hazard ratio, 0.882; 95% confidence interval, 0.708 to 1.097; p=0.2595). Positive skin test results correlated with improved survival. Conclusions: BCG-Canvaxin was not superior to BCG-placebo, but the highly favorable long-term survival for combined groups indicates that complete metastasectomy should be considered as initial therapy for patients with resectable stage IV melanoma (ClinicalTrials.gov identifier: NCT00052156).