Leptin is a peptide hormone, mainly known for its role as a mediator of adipose tissue endocrine functions, such as appetite control and energy homeostasis. In addition, leptin signaling is involved in several physiological processes as modulation of innate and adaptive immune responses and regulation of sex hormone levels. When adipose tissue expands, an imbalance of adipokines secretion may occur and increasing leptin levels contribute to promoting a chronic inflammatory state, which is largely acknowledged as a hallmark of cancer. Indeed, upon binding its receptor (LEPR), leptin activates several oncogenic pathways, such as JAK/STAT, MAPK, and PI3K/AKT, and seems to affect cancer immune response by inducing a proinflammatory immune polarization and eventually enhancing T-cell exhaustion. In particular, obesity-associated hyperleptinemia has been related to breast cancer risk development, although the underlying mechanism is yet to be completely clarified and needs to be deemed in light of multiple variables, such as menopausal state and immune response. The aim of this review is to provide an overview of the potential role of leptin as a bridge between obesity and breast cancer and to establish the physio-pathological basis of the linkage between these major health concerns in order to identify appropriate and novel therapeutic strategies to adopt in daily clinical practice.

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Background. Hematologic and, to a lesser extent, molecular relapsed/refractory in adult acute lymphoblastic leukemia (R/R ALL) is associated with a poor outcome, with low rates of subsequent complete remission (CR) and short survival. Blinatumomab has shown to be effective in both settings. Aims and methods. In this retrospective, single center study we aimed at: 1) evaluating the efficacy of blinatumomab in both hematologic and molecular R/R patients enrolled in clinical trials and in a real life setting; 2) identifying predictive factors impacting on overall and disease free-survival (OS and DFS), and 3) establishing the feasibility and the role of a subsequent allogenic stem cell transplantation (HSCT). Thirty-six adult patients (≥18 years) in hematologic or molecular R/R ALL were treated with blinatumomab between January 2012 and March 2017. Blinatumomab was administered either in the context of a clinical trial (Blast, MT103-211, Tower, Alcantara), in a compassionate use program or according to AIFA (Agenzia Italiana del Farmaco) guidelines. Blinatumomab was administered as continuous infusion for 4 weeks, followed by a 2-week wash out. A stepwise dose of 9 µg/day during the first week of cycle 1 followed by 28 µg/day thereafter, was administered for hematologic R/R cases and a flat dose of 15 µg /m2/day for molecular R/R patients. Patients who witnessed a response received up to 4 additional cycles or underwent a HSCT; patients showing after 1 cycle an increase in the blast count or of minimal residual disease levels, discontinued treatment. Results. Thirty-six patients were analyzed: 21 (58.4%) were in hematologic R/R and 15 (41.6%) in molecular R/R. Four patients had high-risk genetic features (2 BCR/ABL1 and 2 MLL/AF4). Thirteen patient were treated in the context of a clinical trial. All patients received at least one cycle of blinatumomab. At the end of the first cycle, among the 21 hematologic R/R pts, 14 (67%) achieved a CR and 10/14 (71%) also a CMR, while in the molecular R/R group 12/15 (80%) achieved a CMR. As expected, the rate of CMR was significantly higher in the molecular R/R cases as opposed to hematologic R/R (80% vs 52%, p=0.05). Notably, all 4 patients treated for a primary refractory disease, achieved a CR and CMR after the first cycle as opposed to hematologic relapsed cases (p=0.08). With a median follow-up of 33.9 months (range 1-89), the overall OS and DFS at 3 years are 34% and 42.5%, respectively. OS was significantly better for molecular R/R cases than for hematologic R/R cases (54.2% vs 26.1%, p=0.05), while no significant differences were observed in DFS. OS and DFS are 100%, respectively, for refractory cases. Median OS is 6.75 months for hematological R/R, while it is not reached for molecular R/R. Median DFS is 26 months for both groups. Predictive factors for non-response were the status of disease prior to blinatumomab (hematologic vs molecular R/R) and primary refractoriness. A better, though not significant, outcome was observed for patients treated in first rather than in subsequent relapse, and in cases without molecular aberrations (p=0.07, p=0.09). Overall, 14 patients - 9 with molecular and 5 with hematologic R/R at enrollment - underwent a HSCT: 8 are in continuous CR (median follow-up: 17 months, range 5-73). Among the 22 patients who did not receive a HSCT, including 16 molecular and 6 hematologic R/R at enrollment), 7 are in continuous CR (median follow-up: 51 months, range 10-89). Due to the small sample size, we cannot define the role of transplant; transplant-related mortality (TRM) was observed in 3/14 (21.4%). Treatment was well tolerated: the most common adverse events were pyrexia (55%), infectious events (33.3%) and neurotoxicity (19.4%); hematologic toxicity was rare and more frequent in hematologic R/R. Conclusions. Treatment with blinatumomab was safe and effective. As expected, patients treated in molecular R/R had better survival rates than hematologic R/R patients. Despite the small number, all primary refractory patients responded to blinatumomab, suggesting that in these cases immunotherapeutic strategies can be extremely effective, irrespective of a chemo-insensitive disease. HSCT did not impact on OS and DFS, possibly due to the small number of the cohort. Finally, no differences in terms of adverse events, DFS or OS were observed between patients treated in the context of a clinical trial or in a real-life setting. Disclosures Chiaretti: Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Foà:Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees.