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Host immune homeostasis as an independent prognostic indicator has been inadequately evaluated in aggressive non-Hodgkin’s lymphomas (NHL). The present study addresses the prognostic significance in aggressive NHLs of the immunologic profile evaluated by pretreatment serum levels of immunoglobulins (Ig) and lymphocyte-monocyte ratio (LMR). In this series of 90 patients with aggressive lymphoma, the median level for IgG was 1,024mg/dl (range 436–2236), and for LMR was 2.2 (range 0.2–13.8). CR rate was higher with IgG levels ≥1,024mg/dL (91% vs 77% p=0.059). LMR ≤ 2.2 was associated with lower 1-year PFS (73% vs. 92%, p 0.016). Patients with good/very good R-IPI showed a reduced PFS if IgG or LMR was low, while patients with poor R-IPI did better if LMR or IgG levels were high. We combined both parameters with the R-IPI and produced a four-risk prognostic score showing one-year PFS of 95% (95% CI 68%–99%), 100% (95% CI 100%–100%), 73% (95% CI 52%–86%), and 59% (95% CI 31%–79%), in patients with zero, one, two and three risk factors, respectively. The results indicate for the first time the value of baseline serum Ig levels in the prognostic assessment of aggressive lymphoma.

Background: Prognosis of acute myeloid leukemia (AML) still represents a clinical challenge, especially in elderly patients. Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor that has demonstrated single-agent activity both in relapsed/refractory (R/R) and newly diagnosed AML. However, the efficacy and safety of venetoclax combinations regimens in the “real-life” setting have not been extensively described. We aimed to report our single-center experience of venetoclax alone or in a combination approach for AML patients not eligible for standard induction therapy. Methods and Results: A retrospective analysis has been performed on 39 consecutive patients affected by treatment-naive (n=13) or R/R AML (n=26) treated with venetoclax alone (n=4) or in association with azacitidine (n=31), decitabine (n=3), or low-dose cytarabine (n=1). Median age was 71 years, with 67% older than 65 years. The majority showed an intermediate genetic risk. Sixteen patients (41%) were treated in the salvage-2 setting or later, and 7 (18%) had received a prior allogeneic stem cell transplantation. Venetoclax was administered at a dose of 400 mg daily (n=22), with dose reductions to 200 mg (n=9) or 100 mg (n=8) in cases of concurrent therapy with CYP3A4 inhibitors. The most common grade 3 or 4 toxicities were hematological or infectious (49% and 51%, respectively). Nineteen patients (49%) achieved a complete response, with median time to best response of 1 month. Six-month overall survival (OS) in the treatment-naive and R/R groups were 92% and 45%, respectively (p=0.0186), with no differences among genetic risk groups. Median disease-free survival was 5 months. The estimated 6-month OS was significantly higher in patients who achieved a response, regardless of disease status at the time of starting treatment (p Conclusions: Our real-world data confirmed that venetoclax-based regimens are a viable and safe option for AML patients unfit for intensive chemotherapy in both first-line and salvage settings. Furthermore, the association of venetoclax and hypomethylating agents proved to be a feasible bridging therapy to transplantation in elderly AML patients.

Background The Revised- International Prognostic Index (R-IPI), the current standard prognostic tool for patients with diffuse large cell lymphoma (DLBCL), considers only patient and clinical disease characteristics. The role of host immune homeostasis as an independent prognostic indicator in different diseases including DLBCL is evolving. Rambaldi et al 2013, showed that the lymphocyte monocyte ratio (LMR) at diagnosis is a simple prognostic biomarker and independent of the R-IPI. Low level of immunoglobulin at diagnosis, in particular IgG, is associated with inferior survival in Hodgkin and Non Hodgkin lymphoma patients (NHL). In DLBCL patients who underwent autologous transplants, Brown et al 2004 documented 18 months relapse free survival of 44% if IgG levels at time of transplant are below 600 mg/dL and 63% if higher. To our knowledge, the prognostic impact of immunoglobulin levels at diagnosis in patients with aggressive B-NHL has not been investigated. Therefore, we aimed to evaluate the prognostic role of the immunologic profile in terms of the pretreatment levels LMR and of immunoglobulins in patients with aggressive B-NHL. Methods and results: We retrospectively patients diagnosed with aggressive B non-Hodgkin lymphoma (NHL) at both the European Institute of Oncology in Milan and the Mauriziano Hospital in Turin from April 2014 to October 2018. Patients with DLBCL, Burkitt, Mantle cell and follicular G3B lymphomas were eligible. All patients were treated with chemo-immunotherapy according to center guidelines and a written informed consent was obtained from all them. A total of 105 patients were included, with male predominance (60%), median age of 64.5 years (range 20-83) and ECOG score 0-1 in 66%. Stage III-IV disease was seen in 58%, extranodal involvement in 73%, bone marrow infiltration in 26%, bulky disease in 39% and high LDH in 66%. Median IgG level was 1003 (range 436-2236) and the median LMR was 2.4 (range 0.2-44.2). By univariate analysis older age, advanced stage, higher ECOG PS, 2 or more extranodal disease sites, poor R-IPI, higher LDH, low LMR ratio as well as low IgG level at diagnosis was associated with a worse 1-year PFS. LMR inferior or equal to 2.4 had 1-year PFS of 70%, compared to 90% if LMR was higher (p 0.025). Patients with IgG levels less than 1003 had 1-year PFS of 70% compared to 90% in higher IgG levels. The later, didn' t reach statistical significance, due to small number of patients, but remains clinically relevant. Interestingly, there was no correlation between the levels of IgG and the LMR. Therefore, we examined the impact of combining each to R-IPI groups. A low IgG at diagnosis worsen the PFS in patients with good or very good R-IPI with 1 year PFS 83% (95% CI 60-93%) compared 97% (95% CI 79%-100%) if IgG levels are higher. Interestingly, patients in the poor IPI risk group and high IgG levels ad 1-year PFS similar to the good risk group with low IgG levels (PFS 84%, 95% CI 57-94%). The worst PFS is seen in the group of patients with poor IPI score and low IgG, PFS 61%, (95% CI 40%-77%). Similar results were seen in case of LMR. We then examined a novel immunologic prognostic score system that includes the three factors: baselines IGg levels, LMR and the R-IPI Figure 1. Because IgG levels and LMR are independent we put the same weight on each factor as well as the R-IPI score. We gave 1 point to each factor R-IPI poor (1 point) + IgG low (1 point) + LMR low (1 point). The sum of the chosen points correlated with four risk groups: group 1 = 0 points, group =2 = 1 point, group 3= 2 points and group 4= 3 points. The 1 year PFS was 95% (95% CI 68%-99%), 94% (95% CI 77%-98%), 75% (95% CI 54%-87%), 52% (95% CI 27%-73%), respectively. Conclusion: To our knowledge, this study is the first to report the prognostic implications of pretreatment levels of immunoglobulin IgG within the immunologic profile of patients with aggressive B-NHL. Our results suggests that IgG level at diagnosis is a clinically important prognostic factor. With the proposed immunologic score, patients are reclassified into four sub-groups with 3 significantly different 1-year PFS of 95% 75%, 50% in patients with no or one poor risk factor, 2 factors or 3 factors, respectively. This study confirms that the addition of baseline immunologic profile to R-IPI in patients with aggressive B-NHL optimizes their prognostic stratification and better identify patients who are at risk of poor outcome compared to the R-IPI alone. Disclosures Saglio: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy.

Introduction: In the revised 2017 World Health Organization (WHO) classification of lymphoid neoplasms, high-grade B-cell lymphoma with C-MYC and BCL2 or BCL6 rearrangements is classified as Double-Hit lymphoma (DHL), while the term Triple Hit lymphoma (THL) is employed when the three genes are rearranged (Swerdlow SH, et al 2017). Amplification of C-MYC plus BCL2 and/or BCL6 rearrangement or amplification are defined as "atypical DHL and THL" (Li S., et al 2015). We will here collectively refer to DHL and THL as DHL. Both true and atypical DHL are resistant to conventional chemo-immunotherapy and are associated with poorer outcome. The median survival is shorter than 12 months with standard regimens (Snuderl M, et al 2010). The success of intensified chemo-immunotherapy protocols in Burkitt lymphoma, encouraged many Centres to include these regimens in the treatment armamentarium of DHL. Among these protocols, the B-ALL/NHL 2002 of the GMALL multicenter group is an effective and well tolerated regimen in the treatment of Burkitt's lymphoma (Pollen M, et al 2011). We have adopted the GMALL protocol, as our guideline for the treatment of patients with true or atypical DHL. The preliminary experience with the GMALL protocol in 18 patients is here reported. Methods: We retrospectively evaluated patients with true or atypical DHL treated with the GMALL protocol at the European Institute of Oncology in Milan from 2015 and at the Mauriziano Hospital in Turin from 2012. The diagnosis was confirmed according to 2017 WHO classification and immunohistochemistry analysis and fluorescent in situ hybridization were performed in all patients. Patients were treated following the R-GMALL protocol according to their age group with less intensified doses applied to patients older than 55 years. The program was part of the treatment guidelines developed at each Center for the management of lymphoma patients and a written informed consent was obtained from all patients. Results: Eighteen patients were included in this analysis, 14 were true DH and 3 atypical DH and 1 was Burkitt like lymphoma. Five were transformed lymphomas, 4 after follicular and 1 after marginal zone lymphoma. The median age of the whole group was 64 years (range 43-77years). Eleven patients were male (61%), 15 patients (83%) had Ann-Arbor stage IV and 5 (28%) had bone marrow infiltration. Median lymphoma cells proliferation fraction assessed by Ki-67 IHC was 90% (range 70-100%). Patients received a median of 6 courses (range 2-6) of the GMALL schedule, as inpatient therapy. No patients died of infectious complications during chemotherapy. Twelve patients (67%) were in complete metabolic response (CR) at end of treatment and another patient in complete response by CT scan. Of the 5 refractory patients, four have died (3 for lymphoma progression, one due to infectious complications after salvage splenectomy plus RT), one is still alive, under salvage therapy at 7 months from end of treatment. Among 12 patients who achieved CR, 3 relapsed at 7, 10, 16 months from end of treatment, they are presently alive under salvage treatment. At a median follow up of 21.7 month, the median PFS is 21.4 months while median OS is not reached. The two-year PFS and OS rates are 42% and 66%, respectively (figure 1 A & B). PFS was significantly worse in patients with bone marrow infiltration with median PFS of 7 months while not reached in the rest of patients. The median PFS was approximately 17 months for patients older than 55 years (n=13) and not reached for younger patients, with PFS at 2 years of 75%. There was no correlation with transformation, or Ki-67. Conclusion: This study indicates that intensive treatment with B-ALL/NHL 2002 GMALL protocol is effective and well tolerated in true and atypical DHL patients aged up to 77 years. In this preliminary series, the OS resulted superior to that commonly reported with standard chemo-immunotherapies, with median 17-month OS in older patients while median OS is not reached in younger patients. In fact, the results were particularly promising in patients younger than 55 years probably reflecting the proper dose schedule delivery in younger patients. Based on these preliminary results, we are continuing to use the GMALL protocol as upfront therapy in DH lymphoma patients and we are exploring the possibility of improving the therapeutic efficacy by supplementing the GMALL schedule with one of the novel non-chemotherapeutic drugs. Figure 1 Disclosures Derenzini: TG-THERAPEUTICS: Research Funding. Saglio:Celgene: Consultancy; Jansen: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy.