bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term outcome with lenalidomide and dexamethasone therapy for newly diagnosed multiple myeloma.
Authors: Srivastava Geetika , Rana Vishal , Lacy Martha , Gertz Morie A. , Dispenzieri Angela , Hayman Suzanne R. , Buadi Francis , Dingli David , Lust John Anthony , Zeldenrust Steven R. , Russell Stephen J. , Rajkumar Vincent , Kumar Shaji 
Published: March 2020

8096 Background: The combination of lenalidomide and dexamethasone (Len-Dex) is a commonly used initial therapy for newly diagnosed multiple myeloma. While the short-term outcomes with respect to response and toxicity is well-known, long-term outcome with this combination as initial therapy is not well described. Methods: We studied 286 consecutive patients with newly diagnosed MM seen at our institution, who received initial therapy with Len-Dex, and who had complete follow up records. Data regarding the clinical course was obtained from medical records. Results: The median (range) age at diagnosis was 63 (28-92) yrs; 166 (58% were ≤ 65 yrs and175 (61%) were male. The median estimated follow-up was 3.9 yrs (95% CI, 3.4, 4.2) and 203 (71%) pts were alive at the time of last follow up. The median estimated duration on Len-Dex was 5.3 mos (95% CI, 4.6, 6.4). The best overall response (≥PR) was 72%, including 26% with VGPR or better and 14 (5%) not being evaluable for a response. At last follow up, 41 (14%) patients were continuing on therapy. There were 93 pts (32%) who stayed on therapy for 12 months or more. Among these patients, the ORR was 86%, including 45% with VGPR or better. The median overall survival (OS) for the entire cohort from diagnosis was 7.4 yrs (95% CI; 5.8, NR) and the estimated 5-yr survival was 67%. There were 16 (5.5%) pts who died within a year of diagnosis. The median time to first disease progression, irrespective of transplant status, was 30.2 mos (95% CI, 25, 42). Overall, 143 (50%) of the patients have gone to stem cell transplant. Censoring those patients who proceeded to SCT prior to relapse at the time of BMT, the median TTP was 25.5 mos (95% CI, 22, 29). The median OS was 7.4 yrs for those ≤65 yrs, compared with 6.2 yrs for the older patients (P=0.01). The 5-yr OS estimate for patients in ISS stage 1, 2 and 3 were 82, 65, and 44 months respectively. Conclusions: The current study provides long-term estimates of responses and survival in a series of patients treated initially with lenalidomide and dexamethasone. The median survival of nearly 8 years reflects the efficacy of the novel agents both at diagnosis and at relapse and confirms the survival improvements seen in MM in the last decade.
Role of immune-related conditions in smoldering myeloma and MGUS.
Authors: Kwok Mary , Korde Neha , Manasanch Elisabet E. , Bhutani Manisha , Maric Irina , Calvo Katherine R. , Zingone Adriana , Costello Rene , Cherry Benjamin M. , Yancey Mary Ann , Mulquin Marcia , Roschewski Mark J. , Landgren Ola 
Published: March 2020

8104 Background: Recent guidelines emphasize tailored follow-up and the need for clinical trials for high-risk smoldering myeloma (SMM). Emerging evidence from epidemiological studies suggests that immune-related conditions play a role in the causation of myeloma precursor disease (SMM and monoclonal gammopathy of undetermined significance; MGUS) and are of clinical importance for the risk of developing multiple myeloma. The aim of our study is to assess whether there is an altered biology in SMM/MGUS patients with preceding immune-related conditions. Methods: From our ongoing prospective SMM/MGUS natural history study, we evaluated 56 SMM and 60 MGUS patients. Information on autoimmunity was identified at baseline. All patients underwent extensive clinical and molecular characterization. At baseline, all patients underwent bone marrow biopsy evaluation using immunohistochemistry and multi-color flow cytometry of plasma cells. We assessed expression patterns of adverse plasma cell markers (CD56 and CD117), and applied risk models based on serum immune markers and bone marrow findings. Results: Among enrolled SMM and MGUS patients, 7 (12%) and 9 (15%) had a preceding autoimmune disorder. We found SMM patients with (vs. without) a preceding autoimmune disorder to have a substantially lower rate of CD56 (28% vs. 61%) and CD117 (28% vs. 61%) expressing plasma cells. When we compared the same markers in MGUS patients, CD56 and CD117 expression patterns were similar among patients with vs. without preceding autoimmunity (10% vs. 17%, and 50% vs. 48%). Using the Mayo Clinic risk model, none of the SMM patients with a preceding autoimmune disorder had high-risk features; in contrast, 3/41 (7%) of those without a preceding autoimmune disorder were high-risk SMM. Using the Mayo Clinic risk model, none of the MGUS patients were high-risk independent of autoimmune status. Conclusions: Our prospective clinical study found SMM patients with preceding immune-related conditions to have less adverse biology, supportive of epidemiological studies suggesting the risk of developing multiple myeloma is substantially lower in these patients.
Participation of BTK in MYD88 signaling in malignant cells expressing the L265P mutation in Waldenstrom’s macroglobulinemia, and effect on tumor cells with BTK-inhibitor PCI-32765 in combination with MYD88 pathway inhibitors.
Authors: Yang Guang , Xu Lian , Zhou Yangsheng , Liu Xia , Cao Yang , Tripsas Christina , Patterson Christopher J , Hunter Zachary R , Tai Yu-Zu , Anderson Kenneth Carl , Treon Steven P. 
Published: March 2020

8106 Background: Bruton’s tyrosine kinase (BTK) promotes B-cell receptor signaling along with B-cell expansion and survival through NF-κB and MAPK. MYD88 L265P is a widely expressed somatic mutation in tumor cells from WM patients. MYD88 L265P promotes enhanced tumor cell survival through IRAK 1/4 mediated NF-κB and MAPK signaling. We therefore sought to clarify the role of BTK signaling in MYD88 L265P expressing WM cells, and the impact of BTK and MYD88/IRAK inhibition on WM cell signaling and survival. Methods: Western blot analysis was performed using total and phospho-specific BTK antibodies in MYD88 L265P expressing primary WM patient cells, BCWM.1 and MCWL-1 WM cell lines following MYD88 knockdown by lentiviral transduction, and/or use of MYD88 or IRAK signal inhibitors. Cells were also treated with the BTK inhibitor PCI-32765, in the presence or absence of MYD88 homodimerization or IRAK1/4 inhibitors. Annexin V / PI staining was used to assess cell survival, and synergism assessed with CalcuSyn software. Results: BTK was phosphorylated in MYD88 L265P expressing WM cells. Knockdown of MYD88 by lentiviral transduction, and/or use of MYD88 or IRAK 1/4 kinase inhibitors led to decreased BTK phosphorylation. Phosphorylation of BTK, TIRAP, a major TLR adapter protein for MYD88 signaling, IRAK1, IKBα, ERK1/2 and STAT3 were significantly reduced following treatment with PCI-32765. Treatment with PCI-32765 also induced apoptosis of MYD88 L265P expressing WM cells, and showed synergistic tumor cell killing in the presence of either MYD88 homodimerization or IRAK 1/4 kinase inhibitors. Conclusions: BTK activation is facilitated by MYD88 pathway signaling in L265P expressing WM cells, and participates in MYD88 downstream signaling. Inhibition of BTK by PCI-327625 led to robust tumor cell killing of MYD88 L265P expressing WM,cells, which was potentiated by MYD88 pathway inhibitors. These studies provide the framework for the investigation of BTK inhibitors in WM, as single agents and in combination with MYD88 pathway inhibitors.
Phase II randomized study of high-dose interferon alfa-2b (HDI) versus chemotherapy as adjuvant therapy in patients with resected mucosal melanoma.
Authors: Lian Bin , Mao Li Li , Cui Chuan Liang , Chi Zhi Hong , Si Lu , Sheng Xi Nan , Li Si Ming , Tang Bi Xia , Guo Jun 
Published: March 2020

8506 Background: High-dose interferon alfa-2b regimen has been demonstrated as the standard of adjuvant therapy for resected melanoma. But the subgroup of mucosal melanoma seems more aggressive and insensitive to immunotherapy. So we conducted a phase II study (ChiCTR-TRC-11001798) to compare Interferon regimen with chemotherapy as adjuvant therapy for this particular subgroup pts. Methods: Resected mucosal melanoma pts were randomized to observation (Group A) or receive postoperative adjuvant Interferon (IFN) alfa2b 15 MU/m2/day for 5 days/week X 4 weeks followed by 9 MU/m2 three times each week for 48 weeks (Group B), or chemotherapy with temozolomide 200 mg/m2 d1-5 + cisplatin 25 mg/m2 d1-3, repeated every 3 Weeks X 6 cycles (Group C). Results: 189 patients were enrolled and 184 patients were eligible for survival analysis. With a median follow-up of 26.8 months, the median RFS for Group A, B and C were 5.4, 9.4 and 20.8 months, respectively (P<0.001). Estimated median OS for Group A, B and C were 21.2, 41.1 and 49.6 months (P<0.001), respectively. Toxicities were generally mild to moderate. Conclusions: Chemotherapy significantly improved RFS and OS as adjuvant therapy for mucosal melanoma pts over HDI regimen or observation. This trial suggests that different subgroup of melanoma may need different adjuvant therapy.
Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma.
Authors: Patel Sapna Pradyuman , Hwu Wen-Jen , Kim Kevin B. , Papadopoulos Nicholas E. , Hwu Patrick , Radvanyi Laszlo George , Mahoney Sandy , Deburr Tawania L , Liu Ping , Bedikian Agop Y. 
Published: March 2020

8514 Background: Ipilimumab (Ipi) alters the immune system balance by inhibiting the suppression of T-cell function. In two phase III trials, Ipi has shown an overall survival benefit alone and in combination with dacarbazine in previously treated and treatment-naïve patients (pts) with metastatic melanoma (MM), respectively. We performed a single-institution, phase II clinical trial of Ipi plus temozolomide (Tem) in pts with MM. Methods: Pts between the ages of 18 and 75 with previously untreated unresectable stage III or stage IV MM and an ECOG Performance Status of 0 to 1 were enrolled in a phase II trial of Ipi plus Tem. Induction phase consisted of Ipi 10mg/kg intravenous on Day 1 and oral Tem 200 mg/m2 on Days 1 – 4 every 3 weeks for 4 doses. Maintenance consisted of Ipi 10 mg/kg intravenous on Day 1 starting week 12 and repeated every 12 weeks and oral Tem 200 mg/m2 on Days 1 – 5 starting week 12 and repeated every 4 weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS) rate at 6 months. Responses were evaluated using immune-related response criteria. Results: Sixty-four pts were enrolled and received at least one dose of study drug. All pts were included in the analysis. With a median follow-up of 8.5 months, the PFS rate at 6 months was 43%, exceeding the proposed rate of 30%, and the median PFS was 5.1 months. There were 10 (15.6%) confirmed complete responses and 8 (12.5%) confirmed partial responses. At the time of this analysis, median overall survival has not been reached. Immune-related adverse events (irAEs) were experienced by 88% of pts, most commonly pruritus (88%), rash (83%), diarrhea (56%), transaminitis (45%), and colitis (11%). Grade 3/4 irAEs seen in more than one patient were skin rash (11%), diarrhea (9%), pruritus (6%), and transaminitis (5%). Constipation occurred in 70% of pts and was the most common gastrointestinal (GI) toxicity. There were no GI perforations or deaths on study due to treatment. Conclusions: At a median follow-up of 8.5 months, the best overall response rate in this study is 28%. Ipi at 10 mg/kg in combination with Tem given in an induction followed by maintenance fashion is safe, well-tolerated, and efficacious in MM.
Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases.
Authors: Meier Friedegund Elke , Forschner Andrea , Klumpp Bernhard , Flaherty Keith T. , Honegger Juergen Bernd , Witte Maria , Bornemann Antje , Dummer Reinhard , Bauer Juergen , Tabatabai Ghazaleh , Weide Benjamin , Eigentler Thomas K. , Schadendorf Dirk , Quintanilla-Fend Leticia , Niessner Heike , Garbe Claus 
Published: March 2020

8526 Background: Brain metastases are a major contributor to mortality in stage IV melanoma patients. In melanoma, the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways play a major role in tumor progression and therapy resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib recently gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, ongoing clinical studies suggest short-lived responses to BRAF inhibitors in melanoma brain metastases. Methods: We observed in several melanoma patients that chemotherapeutics or BRAF inhibitors yielded a significant regression of extracerebral metastases while brain metastases progressed or newly occurred. We therefore aimed at identifying factors that may contribute to treatment resistance of brain metastases. Results: Immunohistochemistry of matched brain and extracerebral melanoma metastases demonstrated an identical pattern of ERK, p-ERK and AKT staining but a different pattern of p-AKT and PTEN staining with hyperactivation of AKT and loss of PTEN expression in brain metastases. Mutation analysis revealed no difference in BRAF, NRAS or KIT mutation status in matched brain and extracerebral metastases. By contrast, in monolayer culture expression of ERK, p-ERK, AKT, p-AKT and PTEN was identical in cell lines derived from brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed hyperactivation of AKT compared to melanoma cells stimulated by fibroblast-conditioned medium. When inhibiting the MAPK and AKT signaling pathways at different levels in cells freshly isolated from melanoma brain metastases, growth inhibition and apoptosis induction was most pronounced with novel PI3K inhibitors such as BKM120 and BEZ235. Conclusions: These data suggest that 1) hyperactivation of the AKT survival pathway is brain environment-induced and relevant for the survival of melanoma cells in the brain parenchyma and that 2) inhibition of AKT signaling may be a suitable strategy to enhance and/or prolong the antitumor effect of chemotherapeutics or BRAF inhibitors in melanoma brain metastases.
CNS metastases as a site of progression on SWOG intergroup study S0008: A phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 (BCT) versus high-dose interferon (HDI) in patients with high-risk melanoma.
Authors: Samlowski Wolfram E. , Moon James , Witter Merle , Atkins Michael B. , Kirkwood John M. , Othus Megan , Ribas Antoni , Sondak Vernon K. , Flaherty Lawrence E. 
Published: March 2020

8527 Background: Central nervous system (CNS) metastases (mets) are common in stage IV melanoma patients (pts). However, the incidence of CNS mets in pts with high-risk regional melanoma (HRM; stages IIIA-N2a thru IIIC N3) is not well described. A recent large prospective S0008 trial provided an opportunity to evaluate the contribution of CNS mets to treatment failure and survival. Methods: All pts had HRM treated with wide excision and full regional lymphadenectomy. Pts were then randomized to receive treatment with either BCT or HDI. All eligible pts were included in the analysis. Relapse/progression in the CNS (PCNS) was retrospectively identified only if clearly documented in case report forms. The cumulative incidence of PCNS in the presence of the competing hazard of death was estimated and potential risk factors were explored using the methods of Fine and Gray. Survival from PCNS was measured from date of PCNS to date of death. Results: 402 patients were evaluated (BCT: 200, HDI: 202), with median follow (if alive) of 6 years. The site of progression was identified in 162 (78 %) of 208 pts relapsing on study. Clearly documented PCNS occurred in 53/402 pts (13%). PCNS as a component of initial relapse/progression occurred in 34 patients (8%) and an additional 19 patients (5%) had delayed PCNS following initial systemic relapse. Most PCNS (85%) occurred within 3 years of initial surgery. Differences between arms were not significant (22 on BCT, and 31 on HDI)(p=0.21). Lymph node macromets demonstrated a strong correlation with development of PCNS (p=0.01). Neither primary tumor ulceration nor head and neck primary site were significant risk factors. Survival from diagnosis of brain mets was short (median 6 mo BCS, 5 mo HDI, p=0.93). Conclusions: Although the S0008 trial was not specifically designed to evaluate PCNS, a retrospective analysis identified a high CNS failure rate (at least 13%) in HRM pts, including 8% as the initial site of relapse. Further studies are needed to evaluate if screening for CNS mets in high-risk pts is useful and whether early treatment improves survival.
Neoadjuvant ipilimumab in locally/regionally advanced melanoma: Clinical outcome and immune monitoring.
Authors: Tarhini Ahmad A. , Edington Howard , Butterfield Lisa H. , Tawbi Hussein , Moschos Stergios J. , Shuai Yongli , Lin Yan , Horak Mary , Sarkisian Saro , Shipe-Spotloe Janice , Milburn Christy , Sander Cindy , Johnson Jonas Talmadge , Kirkwood John M. ,   University of Pittsburgh Cancer Institute
Published: March 2020

8533 Background: Neoadjuvant ipilimumab (ipi) for stage IIIB-C melanoma may improve the clinical outcomes and provide access to pre/post ipi blood and tumor to gain insight into host effector and suppressor immune response mechanisms. Methods: Patients were treated with ipi (10 mg/kg IV q3weeks x 4doses total) bracketing definitive surgery. Tissue samples were obtained at baseline and at definitive surgery (week ≥ 6) and serum/PBMC collected at baseline, 6 weeks, then at 3, 6, 9, 12 months and/or progression. Flow cytometry was used to monitor the host effector and suppressor immune response in blood and evaluable tumor. Results: Thirty pts (21 male, 9 female), age 40-87 were enrolled (25 cutaneous primary, 1 unknown, 4 mucosal). Six had AJCC stage IIIB (N2b, N2c) and 24 IIIC (N3) melanoma. Ninety-three cycles have been delivered (median 4). Worst toxicities included grade 3 diarrhea/colitis (5 patients; 17%), hepatic enzyme elevations (2; 7%), rash (2; 7%), lipase (1; 3%), all manageable. Median follow up is 14 months: among 29 evaluable pts 15 (52%) continue disease free. Median PFS is 15.5 months, 95% CI = (8.1,-). The probability of 6 and 12 month PFS is 82.4% (95% CI=0.63, 0.92) and 53% (95% CI=0.31, 0.70) respectively. Peripherally, a significant increase in frequency of circulating T-regs (CD4+CD25hi+ Foxp3+; p=0.02 CD4+CD25hi+CD39+; p=0.001) from baseline to 6 weeks was observed. Greater increases in T-regs were associated with improved PFS (p=0.045; HR=0.54). Significant decreases in circulating MDSCs, were observed in monocytic HLA-DR+/low/CD14+ MDSC subtype (p<0.0001). Spontaneous in vivo cross presentation was observed resulting in Th1 CD4 and CD8 antigen specific T-cell immunity (gp-100, MART-1, NY-ESO-1 peptides) with increase in frequency after ipi. Activated TIL in tumor increased after ipi (CD3+/CD4+/CD69+;p=0.06 and CD3+/CD8+/CD69+) with significant induction/potentiation of T-cell memory (CD8+/CD45RO+/TNF-α+;p=0.03). Conclusions: Neoadjuvant ipi exhibits promising clinical activity and significantly modulates the host effector and suppressor immune response. Full analysis of this completed trial and its correlates will be presented. Support: BMS, P30CA047904 and P50CA121973.
Suppression of apoptosis by BRAF inhibitors through off-target inhibition of JNK signaling.
Authors: Tsai Kenneth Yee , Vin Harina , Leung Marco , Chitsazzadeh Vida , Ojeda Sandra , Dwyer David , Richards Kristen , Stewart Larissa , Curry Jonathan , Kim Kevin B. , Ciurea Ana , Duvic Madeleine , Prieto Victor , Ullrich Stephen , Flores Elsa 
Published: March 2020

8537 Background: The advent of targeted therapy has revolutionized the treatment of cancer. The mutant BRAFV600E protein is found in over 50% of melanomas and thyroid carcinomas, resulting in elevated kinase activity, increased mitogen-activated protein kinase (MAPK) pathway signaling, and cell proliferation. Vemurafenib and PLX4720 were designed to selectively inhibit the BRAF kinase, and clinical trials of vemurafenib in metastatic melanoma have demonstrated a response rate of over 50% and an overall survival advantage over standard dacarbazine therapy. Approximately 20-30% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) highlighting the importance of understanding toxicities associated with this drug. Paradoxical ERK activation in BRAF wild-type, RAS-mutant cells is thought to be the major mechanism by which this occurs, as evidenced by the presence of RAS mutations in 60% of such lesions. Methods: Using a combination of BRAF-wild-type cSCC cell lines, primary human keratinocytes, as well as a UV mouse model of cSCC and human cSCC samples, we identified novel effects of BRAFi on apoptosis. Results: Here we show an unexpected and novel effect of vemurafenib and PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases. JNK signaling and apoptosis are suppressed in cSCC lesions arising in vemurafenib-treated patients as well as in irradiated mouse skin. This occurs independently of paradoxical ERK signaling and in the presence of MEK inhibitor. Treatment with PLX4720 greatly accelerates the development of UV-induced cSCC in mice without Ras mutations. Kinome screening identified ZAK and MKK4 (MEK4 / MAP2K4) kinases as inhibited by vemurafenib, leading to suppression of MKK4 and MKK7 (MAP2K7) phosphorylation. Knockdown of inhibited off-target kinases recapitulates these anti-apoptotic effects of vemurafenib. Conclusions: Our results implicate suppression of JNK signaling, independent of ERK activation, as an additional, complementary mechanism of adverse effects of vemurafenib. This has broad implications for combination therapies with other modalities that induce apoptosis and for the long-term use of vemurafenib in the adjuvant setting.