bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome after second stem cell transplantation for relapsed multiple myeloma
Authors: Simpson L. , Verma R. , Kumar S. , Lacy M. , Dispenzieri A. , Hayman S. , Rajkumar S. V. , Litzow M. R. , Gertz M. 
Published: March 2020

8118 Background: Autologous stem cell transplantation (ASCT) improves survival and remains the standard of care for patients with newly diagnosed myeloma considered eligible for transplant. However, ASCT is not curative and patients relapse after a median interval of 24–30 months. While new therapeutic options have become available for relapsed MM, repeat ASCT remains an option especially when previously collected stem cells are available. The outcome of pts going to a second SCT in the relapsed setting has not been studied extensively. Methods: We identified pts with myeloma who received a second SCT from a prospectively maintained database. Planned tandem ASCTs were excluded. 56 pts received a second SCT for relapsed MM, including 11 allogeneic SCTs. Among the 45 second ASCTs, 5 were followed by reduced intensity allogeneic SCT and were analyzed with the allogeneic group. Results: The median age at second ASCT was 60.2 yrs (range, 41.3–74.4) and 27 (68%) were males. The median time to second ASCT from diagnosis, first ASCT and relapse were 47.4 mos (22.8–158.6), 36.3 mos (13.5–129.8) and 7.2 mos (1–32) respectively. Among patients receiving second APBSC, 14 (35%) patients were alive with a median follow up of 10.5 mos (1–45 mos). All patients received melphalan conditioning. The median time to neutrophil engraftment was 15 days and platelet engraftment was 16 days. The median hospitalization was 4 days (range 0–33) and there was one transplant related death in the group. The best response included 13 pts with CR (33%), 4 with VGPR (10%), and 19 with PR (48%). MM has relapsed in 22 (55%) pts with a median PFS of 12.5 mos from second ASCT. The median estimated OS from diagnosis, first ASCT and second ASCT were 100.5 mos, 65.9 mos, and 30.6 mos respectively. Among the 16 pts receiving allogeneic SCT, 8 pts (50%) were alive at analysis with a median PFS and OS from transplant of 17.9 mos and 33.5 mos respectively. Conclusions: Second ASCT as salvage therapy for relapsed MM is a viable approach and has a favorable outcome in this selected group of patients. The toxicity, engraftment kinetics, hospitalization and the response rates are comparable to patients undergoing initial ASCT. Allogeneic SCT with or with out a preceding ASCT results in comparable survival in selected patients with high risk disease. No significant financial relationships to disclose.
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Authors: Tarella C. , Zanni M. , Rambaldi A. , Benedetti F. , Passera R. , Gianni A. M. 
Published: March 2020

8123 Background: The high-dose sequential (HDS) chemotherapy approach, including early dose-intensification and autograft with peripheral blood progenitor cells (PBPC), was introduced several years ago (Gianni & Bonadonna, 1989); subsequently, it has been broadly used in the management of both non-Hodgkin s (NHL) and Hodgkin s Lymphoma (HL). The outcome of a large series of lymphoma patients treated with the HDS approach at 10 GITIL Centers is reported. Methods: Data have been collected on 1,266 patients, who received either the original or slightly modified HDS regimens. There were 213 HL and 1,053 NHL (630 intermediate/high-grade, 423 low-grade); median age was 46 yrs. Overall, 671 (53%) patients had refractory/relapsed disease, 595 (47%) were at diagnosis. Most patients were autografted with PBPC; 158 (12%) patients did not undergo autografting due to toxicity, disease progression or poor harvests. Results: Overall, 1,013 (80%) patients reached Complete Remission (CR) following HDS. As to December 2006, 93 (7%) patients died for early/late toxicities, 328 (26%) died for lymphoma, 844 are known to be alive. At a lead follow-up of 18 years, and a median follow-up of 5 yrs, the 5-yr Overall Survival (OS) projection is 64% (S.E.: 2%). The long-term survival was quite favorable in patients achieving a Complete Remission (CR), with a 5-yr OS projection of 76%. The prolonged OS in patients achieving CR was consistent in all lymphoma subtypes, i.e. both low and high-grade NHL (5-yr OS: 77% in both), and HL (5-yr OS: 72%). Patients at diagnosis had a significantly better outcome compared to patients treated for relapsed/refractory disease, again CR achievement was associated with prolonged survival in both subgroups (82% and 69%, respectively, at 5 yrs.). On multivariate Cox survival analysis, CR achievement was the most powerful predictor of long-term survival (HR 0.13, c.i.: 0.10–0.17). Lastly, achieving substantial tumor reduction before autografting had a major influence on the clinical outcome. Conclusions: 1. the HDS program is feasible in a multicenter setting; 2. the long-term outcome is well influenced by the CR status after HDS; 3. the influence of CR achievement on the long-term survival holds true in all lymphoma subtypes, including indolent lymphomas; 4. an adequate pre-autograft tumor debulking may contribute to a favorable long-term outcome. [Table: see text]
Chemokines expressed in melanoma metastases associated with T cell infiltration
Authors: Gajewski T. , Meng Y. , Harlin H. 
Published: March 2020

8501 Background: Despite frequent induction of tumor antigen-specific T cells in melanoma patients following vaccination, tumor regressions remain rare. This observation prompted systematic analysis of the melanoma tumor microenvironment to identify factors that may influence the effector phase of the anti-tumor immune response. Methods: Gene expression profiling using the Affymetrix platform was performed on a series of melanoma metastases, melanoma cell lines, and primary melanocyte cell lines. Confirmatory assays were done by real-time RT-PCR, protein array, immunohistochemistry (IHC), and in vitro chemokine migration assays. Results: Non- supervised hierarchical clustering revealed 3 major subsets of tumors, with the main clustering based on differential expression of T cell-derived transcripts. The presence of CD8+ T cells was confirmed by IHC. Tumors that contained T cells uniquely expressed high levels of multiple chemokines. Protein array confirmed high expression of CCL2, CCL4, and CCL5; real-time RT-PCR additionally confirmed relatively high levels of CXCL9, CXCL10, and CCL3 transcripts. Transwell assays confirmed that each of these 6 chemokines recruited CD8+ effector cells in vitro. Conclusions: We have identified a set of 6 chemokines that likely regulates recruitment of activated T cells into melanoma metastases. Tumors that lack such chemokines might not be capable of supporting the effector phase of the anti-tumor immune response. We suggest that chemokine profiling of tumor sites should be performed in clinical trials of active immunotherapy. No significant financial relationships to disclose.
An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites
Authors: Morton D. L. , Mozzillo N. , Thompson J. F. , Kelley M. C. , Faries M. , Wagner J. , Schneebaum S. , Schuchter L. , Gammon G. , Elashoff R. 
Published: March 2020

8508 Background: Active specific immunotherapy with BCG and an allogeneic, melanoma cell vaccine can induce antibody and T-lymphocyte immune responses to numerous antigens expressed by melanoma cells. This study compared overall and disease-free survival in patients receiving BCG plus placebo versus BCG plus MCV. Methods: Between June 1998 and November 2005, 1,656 patients without evidence of residual disease after resection of stage III (n = 1,160) or stage IV (n = 496) melanoma were randomly assigned to the two treatment arms (1:1). BCG was given as an immunologic adjuvant for the first two injections of both MCV and placebo, which thereafter were administered by intradermal injection every two weeks for the next three injections, every month for the remainder of the first year, every two months for the second year and every three months for years three, four and five. Results: Based on the recommendation of the independent Data and Safety Monitoring Board (DSMB), both studies were terminated after the interim analysis. The recommendation was based on a low probability of demonstrating significant improvement in survival of the BCG plus MCV arm if the study had continued to completion of follow-up and final analysis. Conclusions: This is the largest multicenter clinical trial of postoperative adjuvant immunotherapy after resection of melanoma metastatic to regional lymph nodes or distant sites. It is a landmark study not only because it represents the first randomized multicenter trial to use surgical resection as initial therapy for stage IV melanoma patients with up to five metastatic sites, but also because its results demonstrate excellent survival for the entire study population with 42.3% of stage IV and 63.4% of stage III patients projected to be alive at five years. Updated data for survival and immunologic endpoints which show a significant correlation between immune responses and survival will be provided at the meeting. [Table: see text]
A new paradigm in the management of anorectal melanoma: Trans-anal excision with sphincter preservation and sentinel node biopsy
Authors: Iddings D. M. , Chen S. L. , Faries M. B. , Long L. , Essner R. , Morton D. L. 
Published: March 2020

8513 Background: Anorectal melanoma is rare and highly lethal. Historically this disease has often been treated with abdominoperineal (APR) resection and delayed groin dissection for nodal relapse. As an alternative we have investigated trans-anal excision (TAE) with sphincter preservation and lymphatic mapping with sentinel node biopsy (SNB). We compared the outcomes of this more conservative treatment plan between our institutional data (JWCI) and the Surveillance, Epidemiology and End Results (SEER) data. Methods: JWCI prospective melanoma database (1974–2006) and the SEER database (1973–2003) were searched for pts diagnosed with anorectal melanoma (n=60 vs. n=183, respectively). Treatment, types of recurrence, and survival were recorded. Survival was estimated by the Kaplan-Meier method. Results: Lymphoscintography revealed lymphatic drainage to superficial inguinal nodal basin(s) in all cases. Among JWCI pts, the proportion of pts requiring delayed lymphadenectomy was significantly lower when TAE was performed with SNB versus without SNB (10.0% vs. 58.8%; p=0.018). Among JWCI lymphadenectomy specimens, immediate lymphadenectomy for a positive SNB was associated with fewer metastatic lymph nodes than delayed lymphadenectomy for palpable nodal recurrences (1.6 vs. 2.9; p=0.029), suggesting disease progression during observation. Over the past decade, APR rates were 11.5% for JWCI pts and 43.2% for and SEER pts, (p=0.004). JWCI pts and the SEER pts had median survivals of 33 and 17 months, respectively (p=0.009). TAE versus APR did not adversely affect the survival of JWCI pts (39 vs. 23 months; p=0.010) or SEER pts (18 vs. 16 months; p=0.875). Conclusion: Lymphatic mapping with SNB accurately identified the inguinal nodal basin as the most frequently involved basin and reduced the rate of recurrence and extent of nodal involvement. In this study, the largest to analyze surgical treatment and outcomes for pts with anorectal melanoma in the United States, national TAE rates differed from those at a tertiary melanoma center. TAE did not adversely affect survival in either dataset. Therefore, TAE plus SNB is preferred when negative margins can be obtained; APR should be reserved for locally advanced tumors that cannot be removed by TAE. No significant financial relationships to disclose.
Sequentially-accumulated genetic alterations at chromosome 9p21 play a role in melanoma progression
Authors: Palmieri G. , Rozzo C. , Manca A. , Cossu A. , Lissia A. , Budroni M. , Botti G. , D'Atri S. , Castiglia D. , Sini M. C. 
Published: March 2020

8522 Background: Cytogenetic and molecular studies indicated the chromosome 9p21 and its CDKN locus, with the p16/CDKN2A tumor suppressor genes, as the genomic regions involved into the pathogenesis of malignant melanoma (MM). To further elucidate the role of such regions in melanoma, we evaluated the 9p21-linked molecular alterations during the different phases of melanocytic tumorigenesis. Methods: Paraffin-embedded tissue sections from common nevi, dysplastic nevi, and melanomas, including primary and metastatic MM lesion, as well as melanoma cell lines were evaluated by both fluorescence in situ hybridization (FISH) using probes spanning the entire 9p21 region and immunohistochemistry (IHC) for p16/CDKN2A expression. Results: Allelic deletion at the CDKN locus and p16/CDKN2A gene silencing were both observed at increased rates moving from nevi to early or advanced primary melanomas and to correspondent metastases. Dysplastic nevi, primary and secondary melanomas were instead found to be heterozygously deleted at one or more loci within the 9p21 chromosome in a quite similar fraction (55–62%) of cases. Inactivation of the p16/CDKN2A gene was found at rates higher in melanoma cell lines (67%) than in vivo melanomas (62% secondary and 12.5% primary melanomas), with a normal p16/CDKN2A IHC staining in all analyzed nevi. Conclusions: Our findings indicate a model of sequential accumulation of genetic alterations from normal melanocytes to metastatic melanoma, with a) 9p21 allelic loss playing a role in melanocytic transformation and tumor initiation; b) deletions at CDKN locus and p16/ CDKN2A gene inactivation participating to tumor dissemination. Presence of such alterations could be further evaluated as markers of the different phases of melanoma progression. No significant financial relationships to disclose.
Kinetics of response to ipilimumab (MDX-010) in patients with stage III/IV melanoma
Authors: Hamid O. , Urba W. J. , Yellin M. , Nichol G. M. , Weber J. , Hersh E. M. , Tchekmedyian S. , Hodi F. S. , Weber R. , O'Day S. 
Published: March 2020

8525 Background: Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), enhances immune responses to tumor-associated antigens resulting in durable objective responses (OR). This abstract describes the kinetics of response after ipilimumab treatment. Methods: 5 studies (2 complete; 3 ongoing) in 269 treated patients with stage III/IV melanoma were reviewed and analyzed to determine the kinetics and duration of response after ipilimumab. Patients received ipilimumab alone or with dacarbazine, IL-2 or gp100 peptide vaccine. Ipilimumab doses ranged from 0.3–10mg/kg/dose (single or multiple). Complete and partial response (CR, PR), stable and progressive disease (SD, PD) were evaluated. Results: 41 patients (15%) had a confirmed OR at analysis. CR and PR was of late onset in some patients and occurred from ∼10–106 and ∼5–62 weeks (w) post-treatment initiation, respectively. In 28 patients onset of CR or PR occurred after >∼12w of treatment. PD preceded OR (without additional therapy) in 4 patients. In 2 patients, PD measured at ∼6w post-treatment initiation was followed by a PR at ∼12w. In 1 patient the PR changed to a CR at ∼24w and lasted for ∼188w+; the other patient maintained a PR for ∼17w. In the other 2 patients, PD at ∼12w was followed by SD at ∼17–20w and a PR after ∼30 and 62w; PRs in both patients lasted for ∼17 and 40w+, respectively. Duration of OR ranged from ∼6–187w+; ORs are ongoing in 25 patients. Late onset occurred irrespective of dose, regimen and therapeutic partner. Conclusions: Preliminary results suggest that ORs with ipilimumab may be later in onset and more durable than with traditional chemotherapy and may occur after progression. This late onset of effect likely reflects the immune-related mechanism of action of ipilimumab, and suggests that continued treatment/observation may be beneficial despite initial PD or SD. Acknowledgement: Dr. S. Rosenberg [Table: see text]
Subgroup analysis of efficacy and safety analysis of a randomized, double-blinded controlled phase II study of STA-4783 in combination with paclitaxel in patients with metastatic melanoma
Authors: O'Day S. , Gonzalez R. , Lawson D. , Weber R. , Hutchins L. , Anderson C. , McLeod M. , Hurwitz C. , Haddad J. , Jacobson E. 
Published: March 2020

8528 Background: STA-4783 (S), an inducer of heat shock protein 70 (hsp70) is a bis-thiobenzoylhydrazide compound. S leads to up-regulation of hsp70 in tumor cell lines. Xenograft models of solid tumors showed synergistic anti-tumor activity in combination with paclitaxel (P). The combination P + S, in phase I and II studies, showed dose-related hsp70 induction (evidence of biological activity) and tolerability. Methods: Eligibility was based on a diagnosis of metastatic cutaneous melanoma, ECOG <=2, and prior treatment with 1 or no chemotherapy regimens. A total of 81 patients (pts) were randomized 2:1 (P 80 mg/m2 + S 213 mg/m2:P 80 mg/m2) 3 weeks out of 4 at 21 US clinical sites. The primary endpoint was progression free survival (PFS); secondary endpoints were response rate (RR), and adverse events (AEs). Results: Based on intent-to-treat analysis, the median PFS was 3.68 months (m) for P + S vs. 1.84 m in the P only arm (p=.035). RR was 15.1% in the P + S arm and 3.6% in the P arm. Subgroup analysis showed chemo- naive pts (n=23) with P + S showed a median PFS of 8.28 m vs. 2.40 in the P arm (n=9). For pts with 1 prior chemotherapy, (n=29), PFS on P + S was 3.12 m vs. 1.77 m on P (n=19). Of 19 pts who crossed over at progression, data are available for 14. PFS ranged from 0.72 to 5.5 m. Three of the 14 evaluable pts treated with P alone had rapid progression (0.95, 1.6, and 1.7 m) then significant inversion of the time to progression with the addition of S to P (2.3, 5.5, and 4.2 m) suggesting study drug effect. Scans were done at identical intervals (8 weeks). The proportion of pts with AEs of grade 3 or higher was 54% (n=52) in the P + S group and 57% in the P group (n=28); pts on P received a median of 2 cycles, while pts in the P + S group received a median of 4. Adverse events leading to discontinuation were low in both groups: 10% for the P + S, and 14% for P. Conclusions: The addition of S to P showed an increase in PFS vs. P alone particularly in chemo-naïve pts. A few pts failing single agent P appeared to benefit from P + S. Despite the additional treatment duration in the P + S group the drugs were well- tolerated, and showed mainly P related adverse events. A phase III study is planned to confirm a role for P + S in metastatic melanoma. [Table: see text]
Preliminary results from a phase I/II study of the combination of lenalidomide and DTIC in patients with metastatic malignant melanoma previously untreated with systemic chemotherapy
Authors: Bedikian A. Y. , Kim K. , Papadopoulos N. , Hwu W. , Ervin-Haynes A. , Pietronigro D. , Zeldis J. , Hwu P. 
Published: March 2020

8533 Background: In metastatic melanoma (MM) no single agent has shown objective response greater than 21%, and none have made an impact on overall survival. DTIC is approved for MM with response rates of 7% to 21%. Lenalidomide, an immunomodulatory drug of the IMiDs class, was reported to enhance immune responses in MM patients. This study was designed to assess the safety and activity of lenalidomide in combination with DTIC in patients with metastatic melanoma (MM). Methods: Twenty-eight chemotherapy naive patients with unresectable stage III and IV MM enrolled in the study. All patients received 25 mg lenalidomide orally once daily on days 1–14 every 21 days and continued therapy as tolerated or until disease progression. DTIC was given IV over 1 hour on day 1 every 21 days. There were three dose levels for DTIC: 600 mg/m2, 800 mg/m2 and 1,000 mg/m2. Each dose level had 3–6 patients enrolled. Thirteen additional patients were to be enrolled at the MTD. Response and progression were evaluated using the RECIST criteria every 6 weeks. Results: As of December 21, 2006 twenty-six patients were evaluable for response. Median age was 65 (46–83) and 13 were female. Median ECOG was 1. Two patients (8%) exhibited an objective response (2 partial responses (PR)), 10 had stable disease (SD) for a tumor control rate (TCR) of 46 % and 14 progressive disease (PD). Thirteen patients have been enrolled at the MTD of 25 mg lenalidomide + 800 mg/m2 DTIC and most are still receiving therapy. Grade 3 or 4 adverse events occurred in 12 (43%) of the 28 patients receiving drug. Grade 3 events included: transient elevation of transaminases, increased temperature, headache, dizziness, low hemoglobin, and leg edema. Four patients (14%) experienced a Grade 4 adverse reaction (pulmonary emboli, low hemoglobin, cerebral hemorrhage, and cerebral ischemia). The most common Grade 1/2 adverse events included: fatigue, nausea, pruritis, muscle cramps, taste alteration, skin rash, and constipation. Conclusions: The MTD has been established at 25 mg lenalidomide + 800 mg/m2 DTIC. Preliminary results indicate that lenalidomide in combination with DTIC has manageable side effects in patients with MM. Evaluation of efficacy is ongoing. No significant financial relationships to disclose.
A large first-line, randomized, dose-finding, phase II study on thymosin-alpha 1 (T-alpha 1) plus dacarbazine (DTIC) with or without interferon-alpha (IFN-alpha) compared to DTIC plus IFN-alpha in stage IV melanoma. Tumor response and survival results
Authors: Camerini R. , Mackiewicz A. , Testori A. , Trefzer U. , Jassem J. , Ferraresi V. , Maio M. , Garbe C. , Lange A. , Carminati P. 
Published: March 2020

8535 Background: Thymosin alpha 1 is an immunomodulatory compound that promotes T cell maturation and upregulates T cell response. Ta1 showed clinical potential benefit in a previous pilot study in melanoma patients. Methods: Phase II, randomized, stratified, open-study testing different doses of Ta1 in association with DTIC and IFNa, as first-line therapy in stage IV melanoma patients (AJCC 2001) without brain metastases. The primary endpoint is tumor response and secondary overall survival. Four arms were initially planned: DTIC + IFNa + 1.6 or 3.2 mg Ta1, DTIC + 3.2 mg Ta1, and DTIC + IFNa (control group). A dose-response effect in a preliminary analysis on 142 patients led to the addition of a fifth arm with DTIC + IFNa + 6.4 mg Ta1. Ninety-five patients were allocated to each arm to test the hypothesis that P0 = 0.05 vs the alternative hypothesis that P1 = 0.15 (alpha = 5%, within-group statistical analysis, power = 95%). The five groups were analyzed independently one from the other, nine responses representing the minimal threshold for rejecting the null hypothesis Patients received DTIC (800 mg/m2) iv on day 1, Ta1 (1.6, 3.2 or 6.4 mg) sc on days 8–11 and 15–18, and IFNa (3 MIU) sc on days 11 and 18 during 28d cycles. Tumor response was evaluated every two cycles according to RECIST criteria, utilizing a central review. Results: Data of 483 pts (62% M1c; 25% M1b; 13% M1a) from 64 European sites are given in the table . Thirteen and 10 confirmed responses were observed for the DTIC+ 3.2 mg Ta1 and DTIC+ IFNa + 3.2 mg Ta1 arms (vs 5 in the control group) thus rejecting the null hypothesis that P0 = 0.05. No additional toxicity with the addition of Ta1 was observed. Conclusions: These results suggest a potential survival advantage with the addition of Ta1 to ‘standard‘ treatment of stage IV melanoma patients. The role of Interferon alpha in this therapeutic association is debatable. [Table: see text] [Table: see text]