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Simple Summary Immunotherapy and targeted therapy represent effective therapeutic opportunities that radically changed the available armamentarium for the treatment of melanoma. In about 50% of patients with advanced disease, long-term survival can be achieved; unfortunately, the other half of patients still have limited benefit from such innovative therapies and experience complications that affect their quality of life. Affordable, reliable and easily-to-detect biomarkers are urgently needed to facilitate the decision-making process, in order to identify patients best suited to receive immune or targeted therapy, with the aims of reducing toxicities, enhancing efficacy and preventing recurrences. Abstract Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient’s possible response to treatment or development of toxicities.

Germline variants of the melanocortin-1-receptor (MC1R) gene are the most common genetic trait predisposing to cutaneous melanoma (CM). Here, we performed a literature review and meta-analysis of the association between MC1R gene variants and the frequency of somatic mutations of the BRAF, NRAS, and TERT genes in CM patients. We included studies published until January 2020 in MEDLINE, EMBASE, Ovid Medline, and two grey literature databases. Random effect models were used to pool study-specific estimates into summary odds ratio (SOR) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity and assess the robustness of pooled estimates. Twelve studies published between 2006 and 2018 (encompassing 3566 CM, mostly on nonacral sites) were included. MC1R gene variants were not significantly associated with the frequency of somatic mutations of the BRAF and NRAS genes. Only three studies focused on somatic mutations of the TERT gene promoter, all of which reported moderate-to-strong positive associations with MC1R germline variants. MC1R gene variants appear to make only moderate changes, if any, to the risk of BRAF- or NRAS-mutant CM. The association with TERT promoter mutations is suggestive, yet it warrants confirmation as it is based on a still limited number of studies.

The outbreak of COVID-19 pandemia is a major health worldwide concern. Patients with cancer might have a worse outcome, because of the immunosuppression determined by the tumor itself and anti-cancer treatments, including chemotherapy and radiotherapy. The impact and course of viral infection in patients receiving immunotherapy remains unknown. We report the case of a patient with metastatic melanoma, long responder to anti PD-1 blockade who got infected with Sars CoV-2, recovering without sequelae. A critical review of literature was performed. Limited data available in literature support the possibility to continue the immunotherapy in patients with cancer under control.

Proto-oncogene KIT is the gene encoding the receptor tyrosine kinase protein KIT. Activating mutations are found in 2.9% of neoplasms, with the highest prevalence in gastrointestinal stromal tumour. Exon 17 mutations typically alter the kinase activation loop and are relatively rare, representing 11.7% of all activating KIT mutations. Recently, KIT exon 17 mutants turned out to be a potential molecular target for the type 1 kinase inhibitor avapritinib (BLU-285).In this framework, we aimed at investigating the potential activity of avapritinib in mucosal melanoma and thymic carcinoma, two disease histologies with dismal prognosis, currently lacking evidence-based second line treatment options and in which KIT exon 17 activating mutations could represent a relevant therapeutic target.In this series, we report the only four cases of patients affected by exon 17 mutant mucosal melanoma and thymic carcinoma that have been treated in Italy with avapritinib within a Compassionate Use Program. Two patients harboured mucosal melanoma and the other two were diagnosed with thymic carcinoma. We describe a differential activity of avapritinib (3/4 patients responded, 1/4 did not respond), along with possible hypotheses to justify such differences and potential implications for precision oncology.Taken together, the inactivity of imatinib on KIT exon 17 mutations, the general low clinical efficacy of immunotherapy, as well as the consequent formal lack of standard available and active second line systemic treatments in both mucosal melanoma and thymic carcinoma, support the implementation of avapritinib in the therapeutic armamentarium, even though further prospective evidence is warranted.

Efficacy, safety, together with molecular and immunological biomarkers were studied in a sequential clinical trial of neoadjuvant immunotherapy, surgery and adjuvant immunotherapy in locally advanced or oligometastatic melanoma patients (pts), within an open label, single arm and two sites study. Treatment schedule consisted in four primary cycles of inverted dose ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 3 weeks, followed by radical surgery and adjuvant nivolumab 480 mg every 4 weeks for 6 cycles. Primary objective was pathological complete remission (pCR) rate, according to International Neoadjuvant Melanoma Consortium (INMC) criteria, while secondary objectives were: safety, feasibility and efficacy; QoL; identification of biomarkers of response and resistance; degree of immune activation; longitudinal evaluation of the gut microbiome. From March 2019 to April 2021, 43 pts were enrolled in the trial and, with an intent to treat of 35 pts, 34 completed the primary phase, 31 received surgery and 28 completed the adjuvant phase. Four pts were withdrawn during primary phase for progression (2), toxicity (1) and consent withdrawal (1). Study primary endpoint has been met since 20/31 pts undergoing surgery reached a pCR/near pCR (65%), 4/31 (13%) a pathological partial remission (pPR) and 7/31 (22%) pts a pathological no response. With a median follow-up of 17 months, 33/35 pts are alive. Treatment failure occurred in 9 pts: 2 pts progressed during primary phase and did not undergo surgery; 7 pts progressed during adjuvant (3 pts) or follow-up phase (4 pts). Six out of these 7 pts were classified as pNR at surgery, while the other, classified as pCR, did not receive adjuvant therapy. Both pts in stage IV relapsed. Unfortunately, one pt died for ischemic stroke after 5 months from adjuvant therapy while on CR. Treatment related toxicities were mainly G1-2 and only 6 pts (17%) developed G3-4 adverse events (AE): 3 transaminitis, 1 pneumonitis, 1 myocarditis, 1 CPK increase and 1 dermatomyositis. Translational studies on samples collected before, during therapy and at progression have been performed: whole exome sequencing and gut microbiota dynamics on longitudinal samples showed some relationships with responses and developing resistances. These data, never presented elsewhere previously, are in part new and in part confirmatory of immunological or molecular signatures described by other groups. In conclusion, primary immunotherapy with Ipilimumab/Nivolumab in pts affected by locally advanced/oligometastatic melanoma is able to achieve an elevated pCR/near pCR rate which appears to be predictive of long term relapse free survival. Translational data analyzed longitudinally on each patient can allow for a better selection of pts, giving new insight on the mechanisms of melanoma progression and resistance. Citation Format: Pier Francesco Ferrucci, Bruno Achutti Duso, Luigi Nezi, Luca Mazzarella, Fiorenza Lotti, Sara Gandini, Gianmarco Orsolini, Elisabetta Pennacchioli, Patrizia Gnagnarella, Teresa Manzo, Simone Ribero, Maria Teresa Fierro, Rebecca Senetta, Concetta Riviello, Virginia Caliendo, Pietro Quaglino, Massino Barberis, Giuseppina Bonizzi, Emilia Cocorocchio. Neoadjuvant ipilimumab/nivolumab in locally advanced or oligometastatic melanoma: An open label, single arm, multi-institutional clinical study with molecular and immunological biomarker’s analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT167.

9574 Background: The aim of neo-adjuvant therapy in locally advanced or oligometastatic melanoma is to facilitate radical resection, improve outcomes and undertake research to identify biomarkers of response and resistance. The optimal schedule to balance efficacy vs toxicity in dual PD1/CTLA4 blockade regimens remains a matter of debate. We initiated an open- label, single arm study to investigate the Nivo 3/ Ipi 1 schedule as primary treatment of locally advanced or oligometastatic melanoma patients (pts). Methods: Treatment schedule consists in 4 neoadjuvant cycles of Ipilimumab 1 mg/kg and Nivolumab 3 mg/kg every 3 weeks, followed by surgery and adjuvant Nivolumab 480 mg every 4 weeks for 6 cycles. Primary objective is pathological complete remission (pCR) rate, according to Neoadjuvant Melanoma Consortium criteria. Secondary objectives are: safety, feasibility and efficacy; QoL; identification of molecular and immunological biomarkers of response and resistance (somatic genetic drivers, tumor mutational burden, mutational signatures, predicted neoantigens, germline HLA typing, somatic HLA mutations and liquid biopsy); degree of immune activation; evaluation of microbioma Results: From March 2019 to April 2021, 35 pts were included within the trial. All pts completed the treatment program. 6 pts (17%) developed immune-related (IR) G3-4 adverse events (AE): 3 transaminitis, 1 pneumonitis, 1 myocarditis and 1 CPK increase; all of them but one underwent surgery after toxicity resolution. 4 pts (11%) experienced G3-4 non-IR AE. 31 pts underwent surgery after neoadjuvant phase: pCR, near pCR, pathological partial remission (pPR) and pathological no response (pNR) were achieved in 18 (58%), 2 (7%), 4 (13%) and 7 (22%) cases, respectively. 2 pts progressed before surgery and 8 pts progressed during/after adjuvant phase (6/8 in NR at surgery). 4 pts died, 3 after disease progression and 1 for ischemic stroke 5 months after the end of therapy. At 18 months, progression free survival (PFS) and overall survival (OS) were 80 and 85%, respectively (median follow-up: 23 months); non responders (pNR) have a higher risk of relapse or death vs responders (pCR+near pCR+pPR) [HR= 4.11, 95%CI (0.96 -17) adjusted for age, p=0.06]. Conclusions: Our study lends further support to the adoption of the Nivo 3/ Ipi 1 schedule as primary treatment for locally advanced/oligometastatic melanoma, as this regimen achieved a pCR/near pCR rate of 65% with a rate of severe IR-AEs (17%) lower than previously reported in CheckMate 511 trial (34%) using Nivo3/Ipi1 schedule. Available translational data on potential genomic biomarkers of response, gut microbiome and systemic inflammatory landscape evaluated longitudinally during therapy on each patient will be presented. Clinical trial information: 2018-002172-40.

9541 Background: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF -V600 metastatic melanoma (B-mut MM) patients. However, still more than 50% of those patients do not respond or relapse to these current strategies. Preclinical and translational data suggest that ICI plus TT may improve treatment outcomes in patients with B-mut MM, but with conflicting results in the clinical setting. Methods: We performed a systematic review and meta-analysis of randomized phase II-III studies published until January 2022 comparing first-line ICI+TT vs TT alone in B-mut MM. We obtained summary estimates through random-effects models. Overall survival (OS) and progression-free survival (PFS) were the main outcomes retrieved but we look also at difference in responses and adverse events. Results: We summarized data from 3 independent trials and we showed a significant advantage in terms of PFS and OS for the experimental arms in B-mut MM patients treated with ICI+TT rather than TT alone. The summary estimate indicates a significant 23% decrease in risk of progression (SHR = 0.77, 95%CI: 0.66-0.89, with no between-study heterogeneity I2= 0%) and a significant 21% reduction in risk of death (SHR = 0.79, 95%CI: 0.66-0.96, with no heterogeneity I2= 0%). However, no difference was shown (p-value = 0.56) between arms in terms of summary Objective Response Rate (ORR) estimates (Summary ORR doublet = 65.4% [61.5%; 69.2%] and Summary ORR triplet = 67% [63%; 70.9%], respectively). From the subgroup analysis on PFS risk estimates, no significant differences were observed in summary HRs by age ( < 65 vs ≥65 years, p-value = 0.11), sex (female vs male, p-value = 0.58), ECOG PS (0 vs 1, p-value = 0.36), LDH levels (lower vs upper, p-value = 0.59) and PDL1 status (positive vs negative, p-value = 0.89). Significant differences were found in frequencies of grade 3 or more adverse events with higher number of events occurring in B-mut MM vs TT alone (Summary Odd Ratio = 2.01, 95%CI: 1.16-3.47, I2= 74%), whereas no significant differences were found in terms of any adverse event between arms (SOR = 1.83, 95%CI: 0.70-4.78, I2= 0%). Conclusions: This study supports and extend the discussion on first-line available combinations to be offered to B-mut MM patients. Combining ICI with TT demonstrated an effective advantage on both PFS and OS, although augmenting toxicities. Further biomarker-driven investigation may identify patient subpopulations who could benefit from ICI+TT combinations in order to expand their window of therapeutic opportunities.

Purpose: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. Experimental Design: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.

Background: The high resistance of melanoma to targeted therapy has made it a persistently lethal cancer type. Although the advent of immune checkpoint inhibition (ICI) therapy markedly improved outcome for melanoma in recent years, response remains heterogenous, with only 20-40% of patients achieving clinical response for anti-CTLA4 or anti-PD1 therapy. This variability in response has urged research towards host factors that drive response to immunotherapy, and studies have come out to show that the gut microbiota influences immunotherapy response. More importantly, mouse studies and more recent human clinical trials demonstrate that transplantation of responder (R) microbiota improves host immunity and alleviates tumor growth during immunotherapy. Although these findings confirm a close relationship between the gut microbiota and antitumor host immunity, FMT human clinical trials on melanoma patients report success in only 30-40% of patients, suggesting that current knowledge of underlying immunomodulatory mechanisms of the gut microbiota are still limited, and that analysis of data collected only before start of therapy is insufficient. Notably, there is a lack of published longitudinal studies that monitor gut microbiome changes during melanoma immunotherapy. Methods: We performed longitudinal analysis of the gut microbiota in melanoma patients undergoing NEOAJUVANT immunotherapy, revealing distinct dynamics between R and non-responders (NR) over the course of treatment. Sequencing data were paralleled with a quantitative analysis of circulating inflammatory molecules, suggesting a dynamic interaction between the gut microbiota and immune system. Here, we will present key modulators of the immune cell compartment. Conclusions: Overall, our results highlight the importance of longitudinal analysis to dissect the role of the gut microbiota on response to immunotherapy. Citation Format: Angeli Dominique Macandog, Carlotta Catozzi, Ester Cassano, Sara Gandini, Pier Francesco Ferrucci, Emilia Cocorocchio, Teresa Manzo, Luigi Nezi. Gut microbiota shift in melanoma patients undergoing immunotherapy is associated with clinical response [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P073.

Simple Summary Vitamin D has been extensively studied in relation to cancer risk at several body sites, but its relationship with non-melanoma skin cancer (NMSC), the most frequent malignancy in humans, is still unclear. Here, we performed a systematic literature search and meta-analysis of published studies and did not find convincing evidence that a causal association exists between vitamin D intake (from foods and supplements), vitamin D blood concentration, or polymorphisms of the genes coding for the vitamin D receptor and binding protein, and NMSC risk. Abstract We aimed to provide a comprehensive overview of the link between vitamin D and non-melanoma skin cancer (NMSC). For this purpose, we conducted a systematic literature review (updated to 3 February 2021) and meta-analysis of the studies reporting on the association between vitamin D intake (from diet and supplements) and blood concentration, polymorphisms of the vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genes, and the risk of NMSC. Random effects meta-analysis models were fitted to merge study-specific risk estimates into summary relative risk (SRR) and corresponding 95% confidence intervals (CI). Twenty-four studies altogether were included. There was a suggestive association between increasing serum/plasma vitamin D concentration and NMSC risk (SRR for highest vs. lowest concentration 1.67, 95%CI 0.61–4.56), although with large heterogeneity across studies (I2 = 91%). NMSC risk was associated with highest vitamin D intake in observational studies but not in clinical trials. Finally, there was no significant association between any polymorphism of the VDR and VDBP genes and NMSC risk. In conclusion, no strong relationship between vitamin D metabolism and NMSC risk appears to exist according to our systematic review and meta-analysis, although some findings are worthy of further investigation.

Mucosal melanoma is rare and accounts for 1.3-1.4% of all melanomas. Kit mutations are found in approximately 15-20% of mucosal melanomas. Immunotherapy with anti cytotoxic T-lymphocyte associated protein 4 and antiprogrammed cell death protein 1 have reported low clinical efficacy in this melanoma subtype. Studies with Kit inhibitor Imatinib showed response rates ranging from 20 to 30%. We present the case of a patient with a c-kit mutated metastatic melanoma who developed autoimmune vitiligo during treatment with oral tyrosine kinase inhibitor Masitinib.

The aim of this study is to verify if baseline hematological markers, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies, are independently associated with progression free survival (PFS) and overall survival (OS).We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites.The median PFS was 9.1 and 3.5 months, respectively, for patients with baseline NLR 5 and NLR ≥ 5, while median OS was 17.2 and 5.5 months, respectively, for patients with NLR 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28-0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23-0.76; p = 0.004), independent of age, sex, stage, LDH 2xULN, previous treatments, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN, NLR 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13-0.62; p = 0.002,) and OS (HR = 0.23; 95% CI = 0.10-0.55; p = 0.001).These biomarkers are easily reproducible, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.

Background Checkpoint inhibitors in melanoma can lead to self-immune side-effects such as vitiligo-like depigmentation (VLD). Beyond the reported association with favorable prognosis, there are limited data regarding VLD patient features and their echo on the therapeutic outcomes. Methods To assess the association between VLD and a series of clinical and biological features as well as therapeutic outcomes, we built an observational cohort study by recruiting patients who developed VLD during checkpoint inhibitors. Results A total of 148 patients from 15 centers (101 men, median age 66 years, BRAF mutated 23%, M1c 42%, Eastern Cooperative Oncology Group (ECOG) status 0/1 99%, normal lactate dehydrogenase 74%) were enrolled. VLD was induced by ipilimumab, programmed cell death-1 (PD-1) inhibitors, and their combination in 32%, 56%, and 12%, respectively. The median onset was 26 weeks and it was associated with other skin and nonskin toxicities in 27% and 28%, respectively. After 3 years of VLD onset, 52% (95% confidence interval 39% to 63%) were progression free and 82% (95% confidence interval 70% to 89%) were still alive. The overall response rate was 73% with 26% complete response. Univariable analysis indicated that BRAF V600 mutation was associated with a better overall survival (P = 0.028), while in multivariable analysis a longer progression-free survival was associated with BRAF V600 (P = 0.093), female sex (P = 0.008), and M stage other than 1a (P = 0.024). When VLD occurred, there was a significant decrease of white blood cell (WBC) count (P = 0.05) and derived WBC-to-lymphocytes ratio (dWLR; P = 0.003). A lower monocyte count (P = 0.02) and dWLR (P = 0.01) were also reported in responder patients. Conclusions Among VLD population, some features might help to identify patients with an effective response to immunotherapy, allowing clinicians to make more appropriate choices in terms of therapeutic options and duration., Highlights • This multicentric retrospective study outlined the melanoma profile of 148 patients with vitiligo-like depigmentation (VLD) induced by checkpoint inhibitors. • Median VLD onset was 26 weeks and it was associated with other immune toxicities in one-third of cases. • After 3 years of VLD onset, 52% and 82% of patients, respectively, were progression free and still alive with a response rate of 73%. • Some features such as BRAF V600, female sex, and M stage were associated with better outcomes as well as a specific blood profile.

Simple Summary Talimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is the first oncolytic viral immunotherapy to be approved for the local treatment of unresectable metastatic stage IIIB/C–IVM1a melanoma. Its direct intratumoral injection aim to trigger local and systemic immunologic responses leading to tumor cell lysis, followed by release of tumor-derived antigens and subsequent activation of tumor-specific effector T-cells. Its approval has fueled the interest to study its possible sinergy with other immunotherapeutics in preclinical models as well as in clinical contextes. In fact, it has been shown that intratumoral administration of this immunostimulatory agent successfully synergizes with immune checkpoint inhibitors. The objectives of this review are to resume the current state of the art of T-VEC treatment when used in monotherapy or in combination with immune checkpoint inhibitors, describing the strong rationale of its development, the adverse events of interest and the clinical outcome in selected patient’s populations. Abstract Direct intralesional injection of specific or even generic agents, has been proposed over the years as cancer immunotherapy, in order to treat cutaneous or subcutaneous metastasis. Such treatments usually induce an effective control of disease in injected lesions, but only occasionally were able to demonstrate a systemic abscopal effect on distant metastases. The usual availability of tissue for basic and translational research is a plus in utilizing this approach, which has been used in primis for the treatment of locally advanced melanoma. Melanoma is an immunogenic tumor that could often spread superficially causing in-transit metastasis and involving draining lymph nodes, being an interesting model to study new drugs with different modality of administration from normal available routes. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for intratumoral injection, that produces granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhances local and systemic antitumor immune responses. After infection, selected viral replication happens in tumor cells leading to tumor cell lysis and activating a specific T-cell driven immune response. For this reason, a probable synergistic effect with immune checkpoints inhibition have been described. Pre-clinical studies in melanoma confirmed that T-VEC preferentially infects melanoma cells and exerts its antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has been assessed in monotherapy in Phase II and III clinical trials demonstrating a tolerable side-effect profile, a promising efficacy in both injected and uninjected lesions, but a mild effect at a systemic level. In fact, despite improved local disease control and a trend toward superior overall survival in respect to the comparator GM-CSF (which was injected subcutaneously daily for two weeks), responses as a single agent therapy have been uncommon in patients with visceral metastases. For this reason, T-VEC is currently being evaluated in combinations with other immune checkpoint inhibitors such as ipilimumab and pembrolizumab, with interesting confirmation of activity even systemically.

Cancer-related inflammation may play an important role in disease progression and patient outcome, and could be easily monitored through indirect parameters routinely evaluated at diagnosis. Here, we investigated if peripheral blood cells and the ratios of neutrophils to lymphocytes (NLR) and of lymphocytes to monocytes (LMR) as surrogate markers of cancer related inflammation are associated with disease progression and survival of melanoma patients at any stage of the disease. Records of 1,182 melanoma patients included in an Institutional tumor registry in the period 2000-2010, were reviewed. Among them, 584 patients with a cutaneous or unknown primary melanoma and available pre-operative blood tests were analyzed. Survival was estimated with the Kaplan-Meier method, and analyzed using Log-rank test, Cox regression and multivariate Cox proportional hazard models. We found that patients presenting with distant metastases had higher leukocytes, neutrophils and monocytes, and lower lymphocytes compared to Stage I-III patients. Furthermore, at a single-patient level, hematological profiles changed on disease progression from regional to distant metastatic, with significantly increased circulating leukocytes, neutrophils and monocytes, and decreased lymphocytes. Peripheral blood cell counts were not associated with survival of patients with a localized or regionally metastasized melanoma. Instead, in Stage IV patients, leukocytes (p = 0.001), neutrophils (p = 0.0002), monocytes (p = 0.002), NLR (p

BackgroundWe previously showed that therapy with anti–checkpoints T-lymphocyte-associated protein 4 (anti–CTLA-4) or antiprogrammed cell death protein 1 (anti–PD-1) agents was more effective for men as compared with women. However, because the sex-dimorphism of the immune system is complex, involving multiple elements of immune responses, it is possible that women could derive larger benefit than men from strategies other than therapy with immune checkpoint inhibitors (ICIs) alone. Here we investigated whether women could derive larger benefit than men from the combination of chemotherapy and anti-PD-1 or anti-PD-L1.MethodsWe performed two meta-analyses. The first included all randomized controlled trials (RCTs) testing anti-PD1 and anti–PD-L1 plus chemotherapy vs chemotherapy to assess different efficacy between men and women. The second included all RCTs of first-line systemic treatment in advanced non-small cell lung cancer testing anti–PD-1/PD-L1 given either alone or combined with chemotherapy to assess the different efficacy of these two immunotherapeutic strategies according to patients’ sex. For each RCT included in the two meta-analyses, first, a trial-specific ratio of hazard ratios (HRs) was calculated from the ratio of the reported hazard ratios in men and in women; second, these trial-specific ratios of hazard ratios were combined across trials using a random-effects model to obtain a pooled hazard ratios ratio. A pooled HRs ratio estimate lower than 1 indicates a greater treatment effect in men, and higher than 1 a greater effect in women.ResultsEight RCTs were included in the first meta-analysis. The pooled overall survival hazard ratios (OS-HRs) comparing anti–PD-1/PD-L1 plus chemotherapy vs chemotherapy was 0.76 (95% confidence interval [CI] = 0.66 to 0.87) for men and 0.48 (95% CI = 0.35 to 0.67) for women. The pooled ratio of the overall survival hazard ratios reported in men vs women was 1.56 (95% CI = 1.21 to 2.01), indicating a statistically significant greater effect for women. Six RCTs were included in the second meta-analysis: three tested an anti-PD-1 alone, whereas three RCTs tested anti-PD-1/PD-L1 plus chemotherapy. The pooled overall survival hazard ratios were 0.78 (95% CI = 0.60 to 1.00) in men and 0.97 (95% CI = 0.79 to 1.19) in women for anti–PD-1 alone, compared with 0.76 (95% CI = 0.64 to 0.91) in men and 0.44 (95% CI = 0.25 to 0.76) in women for anti–PD-1/PD-L1 plus chemotherapy. The pooled ratio of overall survival hazard ratios was 0.83 (95% CI = 0.65 to 1.06) for anti–PD-1 alone, indicating a greater effect in men, and 1.70 (95% CI = 1.16 to 2.49) for anti–PD-1/PD-L1 plus chemotherapy, indicating a greater effect in women.ConclusionWomen with advanced lung cancer derived a statistically significantly larger benefit from the addition of chemotherapy to anti–PD-1/PD-L1 as compared with men.

The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2±13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents.

CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan–Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03–1.88) and 89% (OR = 0.11; 95%CL = 0.02–0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02–19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39–0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.

Dabrafenib is a potent BRAF-kinase inhibitor. Its activity was evaluated on 40 consecutive metastatic melanoma patients (pts) harboring the V600BRAF mutations. Dabrafenib was administered orally at the dosage of 150 mg b.i.d. daily. ORR was 82%, with 7% CR, 62% PR, 13% SD and 18% PD. The median PFS and OS were seven and 17 months, respectively (median follow-up: 8.5 months). Increased risk of progression was found in pts with elevated LDH, ECOG PS >1 and more than two metastatic sites. Grade 3–4 adverse events were recorded in 4 pts. In this retrospective analysis, Dabrafenib confirmed its role as the standard clinical option in metastatic melanoma pts.

High-dose chemotherapy (HDCT) has a consolidated role in the treatment of patients with refractory or relapsed Hodgkin lymphoma (HL). We report clinical results of 97 HL patients who underwent HDCT for refractory (62 patients) or relapsed (35 patients) diseases in Istituto Europeo di Oncologia, from 1995 to 2009. Treatment included high-dose carmustine, etoposide, cytarabine and melphalan in 84 patients and high-dose idarubicin and melphalan in 13 patients with subsequent peripheral hemopoietic stem cells transplant. Outcomes were evaluated in terms of progression-free survival (PFS) and overall survival (OS). In order to identify prognostic factors for outcome, a multivariate analysis for age, sex, disease status (refractory/relapsed), disease stage, B symptoms, presence of extranodal involvement, bulky disease, elevated lactate dehydrogenase, number of previous chemotherapy lines, remission status before transplant, 18F-fluoro-deoxy-d-glucose positron emission tomography (18FDG-PET) status before and after transplant was done. A clinical response was achieved in 91% of patients, with complete remissions in 76/97 patients. With a median follow-up of 45 months (range 1–164 months), 5-year PFS and OS were 64% and 71%, respectively. Remission status after induction therapy, 18F-fluoro-deoxy-d-glucose positron emission tomography status before and after transplant were the most important prognostic factors for PFS and OS in univariate or multivariate analyses. HDCT is able to induce a high remission rate and a prolonged PFS in more than 50% of the patients with refractory and relapsed HL. Copyright © 2012 John Wiley & Sons, Ltd.

Background: Ipilimumab improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to benefit from treatment. The aim of this study was to identify an upfront marker for treatment benefit. Methods: A total of 187 metastatic melanoma patients treated in three Italian Institutions with 3 mg kg−1 ipilimumab, and 27 patients treated with 10 mg kg−1 ipilimumab, were evaluated. Neutrophil-to-lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan–Meier method, and multivariate Cox models were applied, adjusting for confounders and other prognostic factors. Results: In the training cohort of 69 patients treated at European Institute of Oncology, pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in multivariate analyses. Patients with baseline NLR

Background: Elderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients. Data from clinical trials and expanded access programmes (EAPs) suggest ipilimumab confers a consistent survival benefit and has a similar safety profile across different age groups of patients with metastatic melanoma. Here we report the efficacy and safety of ipilimumab 3 mg/kg in elderly patients enrolled in an EAP in Italy. Methods: Patients aged > 70 years with pretreated melanoma received ipilimumab 3 mg/kg every 3 weeks for four doses through an EAP. Tumour response was evaluated at baseline and after completion of induction therapy using immune-related response criteria and patients were monitored throughout the treatment period for adverse events (AEs), including immune-related AEs. Results: The immune-related disease control rate among 188 evaluable patients was 38%, including four patients with an immune-related complete response, 24 with an immune-related partial response and 44 with immune-related stable disease. Median progression-free survival (PFS) was 4.0 months and the 1- and 2-year PFS rates were 21% and 12%, respectively. Median overall survival (OS) was 8.9 months; 1- and 2-year OS rates were 38% and 22%, respectively. The safety profile of ipilimumab was consistent with that observed in the general population of the Italian EAP and treatment-related AEs generally resolved within a median of 2 weeks with treatment as per protocol-specific guidelines. Conclusions: These results suggest ipilimumab is a feasible treatment option in elderly patients with metastatic melanoma. Ipilimumab treatment was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated at centres in Italy.

Background: Lymphocyte-predominant Hodgkin disease (LPHD) differs in biology and clinical behaviour from classic Hodgkin disease. Almost 100% of LPHD neoplastic cells express CD20 and thus rituximab could be effective; yet limited data are available. Patients and Methods: We performed a retrospective analysis on patients with LPHD who were treated with rituximab at our institution to determine the magnitude of benefit offered by this drug. Results: Seven patients were identified; 4 received the drug as single agent while the rest received it in combination with chemotherapy. All except 2 received the drug in the salvage setting. Response rate was 100% with 6 of 7 patients achieving complete remission. At a median follow-up of 2 years, 4 patients are still disease free while the rest relapsed at a median time of 27 months. Conclusion: Rituximab is effective in LPHD and should be considered; however, the optimal schedule remains to be determined.

Background: Ipilimumab, a recently approved immunomodulatory drug, improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to obtain clinical benefit from treatment. The aim of this study was to identify a criterion to select patients best suited to receive this drug. Methods: Sixty-nine metastatic melanoma patients treated at the European Institute of Oncology with 3 mg/kg ipilimumab, were evaluated. Neutrophil to lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied. Findings were independently validated on a cohort of 27 patients treated with 10 mg/kg ipilimumab at the University Hospital of Siena and on a cohort of 88 treated in Rome. Results: Best overall response and disease control rates were 9% and 27%, respectively. Median PFS and OS were 3 and 5 months, respectively. Pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in univariate and multivariate analyses. Patients with baseline NLR Conclusions: Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve as a selection criterion for this therapy. Citation Format: Pier Francesco Ferrucci, Sara Gandini, Angelo Battaglia, Salvatore Alfieri, Laura Pala, Annamaria Di Giacomo, Giovanni Amato, Gian Carlo Antonini Cappellini, Diana Giannarelli, Emilia Cocorocchio, Chiara Martinoli. Baseline neutrophil to lymphocyte ratio as a selection criterion for ipilimumab treatment in metastatic melanoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-115. doi:10.1158/1538-7445.AM2015-LB-115

9034 Background: Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely to benefit from treatment is a major...

Vinblastine, bleomycin, methotrexate (VBM) combination chemotherapy (CT) with involved field radiotherapy (IFRT) was first described by the Stanford group as an active regimen in early stage Hodgkin's disease (HD). Here, we report our retrospective experience of a modified VBM schedule + IFRT in a similar group of patients. From 1988, 49 patients with stage I-IIA HD received vinblastine (VBL) 6 mg/m2, bleomycin (BLM) 10 IU/m2, methotrexate (MTX) 30 mg/m2 day 1,8 every four weeks for three cycles; IFRT was delivered four weeks later followed by three additional cycles of VBM with a dose reduction of BLM (6 IU/m2). The regimen was well tolerated, with grade 3-4 neutropenia occurring in 20 patients. No acute or late pulmonary toxicity was recorded in our series. Estimated Freedom from Progression (FFP) and Overall Survival (OS) at five years are 75% (95% CI, 60.1%-92.2%) and 85% (95% CI, 73.6%-98.1%), respectively. In this retrospective analysis, VBM + IFRT treatment with bleomycin dose reduction seems safe and active. Such combination could be considered as first line treatment for early stage HD patients with favorable prognosis and/or not suitable for anthracyclines-containing regimens.

The aim of this study is to verify the feasibility and the clinical activity of a new CHOP-like schedule (ACOD) with a fractionated days 1 and 8 administration in elderly patients. This regimen was chosen in the attempt to allow a sufficient dose intensity (DI) of each drug with better compliance. Fifty-two patients, (74 years, median age), with diffuse large B cell non-Hodgkin's lymphoma were retrospectively evaluated. Patients received ADM 25 mg/sqm, CTX 500 mg/sqm, VCR 1.2 mg/sqm (max 2 mg intravenously) days 1 and 8 and PDN 50 mg orally, days 1-8. Results showed that 54% of patients reached a complete remission, 21% a partial remission with an overall response rate of 75%. Two-thirds of the patients received at least 70% of the planned dose of cyclophosphamide and doxorubicin and 50% of vincristine and prednisone. The median duration of follow up was 12.6 months (range 0.7-61.4). The estimated median OS was 15.2 months (95%CI = [11.6, not estimable]); the estimated median PFS was 5.7 months (95%CI = [5.12, not estimable]). After 2 years, the proportion of patients alive was 47% (95%CI = 34-64%) and the proportion of patients free from progression was 39% (95%CI = 27-57%). Grade 3-4 leukopenia was observed in 61% of patients with 11% of febrile neutropenia. In conclusion, the ACOD chemotherapy regimen seems safe and feasible in elderly patients. This schedule allowed a sufficient DI of chemotherapic agents with clinical results very similar to those recorded with the standard CHOP regimen in young adults.

Purpose: Chemotherapy (CT) with Dacarbazine (DTIC) in association with an anti-VEGF treatment could be an intriguing exploiting path, since metastatic melanoma (MM) in vitro models showed VEGF as a possible target, due to its transcription up-regulation by DTIC. The purpose of this study was to indentify modulated circulating factors which may be used as specific biomarkers in patients (pts) affected by MM undergoing DTIC plus Bevacizumab (B = Avastin) combination and to test its tolerability and efficacy. Patients and Methods: Between July 2006-September 2009, 40 untreated MM pts underwent CT with DTIC (800mg/mq q4w) + B (10mg/kg q2w). Clinical benefit, response duration, safety and feasibility were analyzed. Moreover, 13 pts participating to the clinical study agreed to provide blood for translational research. The blood samples for this study were drawn at the same time points as for regular follow-up tests and were evaluated for the following several soluble factors: vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-R1, VEGF-R2, angiopoietin (Ang)-2, E-cadherin, E-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, matrix metalloproteinase (MMP)-2 and -9, tissue inhibitor of metalloproteinase (TIMP)-1 and -2. Correlations with pts clinical outcome were performed as well. Results: 36/40 pts were evaluated at the analysis-time. Median age was 57yr (male 60yr; female 47yr) and 23 were male. Three pts (8.3%) experienced a complete remission (CR), 3 pts (8.3%) developed partial response (PR), 13 (36.1%) stable disease (SD); 17 (47.2%) progressive disease (PD). Clinical benefit (CR+PR+SD) was 52.7% and treatment was well tolerated. Time to progression (months) was 10.9, respectively 22.6 for PR pts, 8.2 for SD pts and 2 for PD pts. Median-survival in the whole group was 16.5 months (PR pts 22.6; SD pts 17; PD pts 4.23). DTIC/B treatment modulates not only VEGF-A, but also VEGF-C, Ang-2 VEGF-R1 and VEGF-R2. Among soluble adhesion molecules, we observed an increase of VCAM-1 in non responder pts. Conclusions: Long-lasting responses obtained in both SD and CR/PR pts and mild side effects make DTIC/B a promising combination in advanced melanoma. The companion translational study partially clarified these clinical results by molecularly characterizing and profiling responders vs non-responders pts. Citation Format: Pier Francesco Ferrucci, Chiara Martinoli, Emilia Cocorocchio, Andrea Anichini, Sara Gandini. Translational study on circulating markers in advanced melanoma patients undergoing Dacarbazine and Bevacizumab treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2550. doi:10.1158/1538-7445.AM2014-2550

e20037 Title: Brain metastasis in melanoma patients: associations with BRAFstatus and age. Background: Somatic BRAF mutations are found in 40-50% melanoma patients. While associations with patient ...

e20042 Background: Elettrochemotherapy (ECT) is a consolidated treatment in Europe for the treatment of cutaneous and non-cutaneous cancers. The aim of this study was to analyse the effects of ECT ...

e19036 Background: Vulvar melanoma (VM) represents 3-7% of melanoma in women. The 5-year survival rate ranges from 8 to 55%. Surgical excision represents the best definitive therapy but surgical radicality does not impact on recurrence or survival. Methods: Thirty women with histologically confirmed VM diagnosed between 1993 and 2009 were selected for this monocentric retrospective study. One patient with metastases at time of diagnosis was excluded from the statistical analysis. Clinical, pathological and follow-up data were collected. Cumulative incidences of events were calculated and compared across subgroups by means of the Gray test. Results: Average age at diagnosis was 62 years. Average Breslow thickness was 4.91 mm. Ulceration was present in 11 cases and was unknown in 5. One case of VM was multifocal at presentation. Eleven patients underwent a wide local excision, 11 a hemivulvectomy and 7 a radical vulvectomy Sentinel node biopsy was performed in 23 patients and at least one positive sentinel node was found in 8 cases. Eight patients received adjuvant therapy. Ten patients had a second tumor (other than melanoma); of these, a breast cancer was recorded in 5 cases. Four patients had a second primary melanoma: of the vulva (n=2), vagina (n=1), and urethra (n=1). Median follow-up among ongoing survivors was 79 months and median overall survival was 69 months. The 5-year overall survival was 55.4%. Median event free survival 34 months. Positive lymph nodal status was associated with an increased risk of loco-regional recurrences (P=0.04). Positive lymph nodal status (P=0.06), Breslow thickness > 2mm (P=0.05) and number of mitoses > 10/mm2 (P=0.04) increased the risk of distant metastases. Age, ulceration and type of surgery were not significantly associated with any type of event. Conclusions: Lymph node involvement, elevated depth of invasion and a high number of mitoses were the most important prognostic factors for locoregional recurrence and distant metastases. The same trends were observed for the overall survival, but results were not statistically significant. Conservative surgery in the form of wide local excision with adequate margins may replace vulvectomy. Sentinel node biopsy is feasible and its role in VM should be further investigated.

e19520 Background: The role of FDG-PET for staging and response assessment in Hodgkin lymphoma (HL) is still evolving. We report our experience with the intent of evaluate prognostic role of 18FDG-PET in terms of long term complete remission (CR). Methods: We retrospectively analysed 65 consecutive pts affected by newly diagnosed HL. Median age was 36 yrs. Histology included 50 classical and 10 lymphocyte predominance HL. According to Hasenclever index, 58 out of 65 pts were considered at low risk, 5 at intermediate and 2 at high risk. 30/65 pts showed good prognosis (defined as IA-IIA, < 3 nodal sites, ERS < 50) and received 4 cycles of VBM followed by involved field (IF) radiotherapy (RT); the remaining 35 pts received hybrid ChlVPP/ABVVP for 6 cycles followed by IF RT in case of bulky disease. All patients underwent 18FDG-PET scans at diagnosis, after the fourth cycle in the VBM group, after the third cycle in the ChlVPP/ABVVP (interim 18FDG-PET), at the end of treatment in all patients. Fisher exact test was used to compare percentages between groups. Results: CR was recorded in 60 (92%) pts. Interim 18FDG-PET was negative in 52 out of 65 pts (80%), all in CR at the end of treatment. Eight out of 13 pts with positive interim 18FDG-PET obtained a CR at the end of treatment (100% versus 62%, Fisher exact text p18FDG-PET was negative in 5 of them, positive in 1 case. Two deaths occurred, one among pts with negative and one with positive interim 18FDG-PET. After a median follow-up of 30 months, 3-year freedom from treatment failure was 83% and 62% in pts with negative and positive interim 18FDG-PET, respectively (Log-rank test p18FDG-PET demonstrate a predictive role regarding the achievement of CR and treatment failure, at least as relevant as Hasenclever index, but failed to predict clinical result in 12 (18%) pts. Its role in defining the best therapeutical approach in HL pts must be further investigated in randomized clinical trials. No significant financial relationships to disclose.

7093 Background: Byrd et al (Blood 2003) confirmed the synergistic effect of Rituximab and Fludarabine in the treatment of CLL patients (pts). The choice of purine analogue still remains controversial. We evaluated feasibility, efficacy, and toxicity of 2-CdA-Rituximab combination in the treatment of CLL and SLL pts requiring treatment. Methods: The combination therapy consisted of intravenous Rituximab at a dose of 375 mg/m2 on Day 1 and 2-CdA at a dose of 0.1 mg/kg (sc injection) per day on Days 2 through 6. The course was repeated at 4-week intervals for 4 times. 31 pts (21 CLL and 10 SLL) was enrolled in the study and the median age was 59 years (31–73); 42% of pts were pre-treated. A CT scan was abnormal in 95% of CLL pts. Immunophenotypic evaluation by ZAP-70 was positive in 70% of pts while no evaluable pts showed an adverse prognostic cytogenetic features by FISH. Minimal residual disease (MRD) assessment was performed by flow-cytometry and PCR methods. Results: 2 pts had to discontinue therapy after 2 cycle: one due to herpes zoster reactivation and the other one to the progression disease (PD). We observed grade 3 and 4 neutropenia in 4 pts (12%), major infections in 4 pts (12%) and no episodes of grade 3–4 thrombocytopenia. 24 pts were evaluable for response with an ORR of 96%. At the end of therapy 10 pts (42%), 7 CLL and 3 SLL, achieved a CR, with negative MRD (by PCR) in 4 pts (3 untreated); 13 pts (54%) obtained a PR and 1 patient had no response. With a median follow-up of 12 months (range 3–34) 7 pts (2 pts with MRD+CR and 5 pts with PR after treatment) experimented a PD; 5 of these pts were pre-treated and 2 died because of PD. Conclusions: The combination of 2- CDA and Rituximab seems to be tolerable and active principally for untreated pts and able to induce a molecular clearance also in pre-treated pts. The achieving of a CR with negative MRD seems to be the most important issue to improve the outcome. No significant financial relationships to disclose.

6699 Background: Pegfilgrastim (PEG) is a new growth factor able to stimulate granulocyte production with a single injection. Basing on a biomathematical model showing a relationship between PEG se...

9596 Background: We investigated the incidence and prognostic relevance of tumor cell detection (TCD) in G-CSF-mobilized peripheral blood progenitor cells collections (PBPCC), using Cytokeratyn (CK...

9548 Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Here we evaluate the safety and efficacy of ipilimumab treatment outside of clinical trials in elderly (>70 years old) patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Disease evaluation was performed at baseline and after completion of induction therapy using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, using Common Terminology Criteria for Adverse Events v.3.0. Results: Out of 855 Italian pts participating in the EAP from June 2010 to January 2012 across 55 centres, 193 (22.6%) were over 70 years old (median 75; 70-88). Of these, 132 pts (68.4%) received all 4 doses of ipilimumab, 24 (12.4%) 3 doses, 17 (8.8%) 2 doses and 20 pts (10.4%) received 1 dose. With a median follow-up of 7.6 months (range 1-26), the disease control rate among 188 pts evaluable for response was 38.3%, including 4 pts (2.1%) with a complete response, 24 (12.8%) with a partial response and 44 (23.4%) with stable disease. As of December 2012, median progression-free survival and overall survival were 3.7 months and 8.9 months respectively, with 1-year survival rate of 38%. In total, 96 pts (49.7%) reported an AE of any grade, which were considered treatment-related in 69 pts (35.7%), with a safety profile comparable to the general population. Grade 3/4 AEs were reported by 19 pts (9.8%) and drug-related in 11 pts (5.7%). AEs were generally reversible with treatment as per protocol-specific guidelines with a median time to resolution of 2.0 weeks. Conclusions: Based on the data from EAP, ipilimumab is a feasible treatment in the elderly population; efficacy and safety results were similar to those observed in the general population.