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We report a case of a young patient suffering from very-high risk B-acute lymphoblastic leukemia (ALL) refractory to first-line therapy with early central nervous system relapse, sequentially treated with inotuzumab. At this timepoint, the patient showed persistent transfusion-refractory thrombocytopenia (platelets < 5000/uL), fever and cytomegalovirus infection. A bone marrow revaluation showed complete remission of ALL, but hemophagocytic elements and activated macrophages were present. At physical examination, the spleen was palpable. Blood chemistry showed hyperferritinemia (1419 ng/mL, normal range 24–336), NK cells suppression (11 cells/microL, minimum value 90) and IL-6 increase (119.1 pg/dL, normal values < 1.8). Triglycerides and fibrinogen were normal. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made according to HLH-2004 criteria. The patient was treated with the IL-1 inhibitor anakinra at escalating dosage. After an initial improvement in altered HLH parameters, a clinical worsening occurred with progressing thrombocytopenia and anemia and a remarkable increase in ferritin (4066 ng/mL). The patient then underwent rituximab-based salvage treatment but died due to HLH and B-ALL progression. HLH could be a rare complication in ALL patients. Despite increasing biological knowledge, prognosis remains poor, and more efforts are needed in order to improve survival in these patients.

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase family member. Mutations in

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase family member. Mutations in FLT3, as well known, represent the most common genomic alteration in acute myeloid leukemia (AML), identified in approximately one-third of newly diagnosed adult patients. In recent years, this has represented an important therapeutic target. Drugs such as midostaurin, gilteritinib, and sorafenib, either alone in association with conventional chemotherapy, play a pivotal role in AML therapy with the mutated FLT3 gene. A current challenge lies in treating forms of AML with extramedullary localization. Here, we describe the general features of myeloid sarcoma and the ability of a targeted drug, i.e., gilteritinib, approved for relapsed or refractory disease, to induce remission of these extramedullary leukemic localizations in AML patients with FLT3 mutation, analyzing how in the literature, there is an important development of cases describing this promising potential for care.

Simple Summary Venetoclax (VEN) is a potent oral inhibitor of the anti-apoptotic molecule BCL2, approved for adults with chronic lymphocytic leukemia (CLL), and recently for naïve acute myeloid leukemia (AML) unfit for intensive chemotherapy. Therefore, VEN is not approved for relapsed/refractory (R/R) AML patients; consequently, this use falls within the so-called off-label use. This review provides evidence of the role of VEN-based therapy in R/R AML patients, including data from clinical trials and from retrospective studies. Abstract Despite the progress in the development of new therapeutic strategies, relapsed/refractory (R/R) acute myeloid leukemia (AML) still represents a high unmet medical need. Treatment options in this setting include enrollment into clinical trials, allogeneic stem cell transplantation and/or targeted therapy. Nevertheless, it is associated with poor outcomes. Thus, the development of new treatments, which could ameliorate the prognosis of these patients with a good safety profile are highly demanded. Recently, venetoclax (VEN) has been approved for naïve AML patients unfit for intensive chemotherapy. In this regard, regimens including VEN could represent a valuable treatment option even in those with R/R disease and several studies have been conducted to demonstrate its role in this clinical setting. This review aims to summarize the current evidence on the use of VEN regimens in the treatment of R/R AML.

Background: The ASPIRE (NCT01080391) phase 3 trial showed the efficacy of carfilzomib, lenalidomide and dexamethasone (KRd) triplet for relapse and refractory multiple myeloma (RRMM). However, little is known about safety and efficacy of KRd outside a clinical trial context. Methods: Herein we report real life results of KRd given to 130 RRMM patients from 12 Sicilian Centers. Results: Median age was 62 years, patients had received a median of two previous lines of treatment (range 1&ndash, 10) and 52% were refractory to previous treatment. Median number of KRd cycles was 12 (2&ndash, 29), with a mean duration of treatment of 12 months, 21 patients had received at least 18 cycles. Overall response rate was 61%, including 18% complete response. Median PFS was 22.9 months, median OS was not reached. Creatinine clearance &gt, 30 mL/min, quality of the best achieved response and standard Fluorescence In Situ Hybridization (FISH) risk were independent predictors of favorable outcome. Patients who received the full-dosage of carfilzomib in the first two cycles had a better outcome. Conclusions: KRd was effective and well tolerated and in a considerable proportion of patients, therapy continued beyond the 18th cycle. The finding of a better outcome in patients with the higher cumulative dose of carfilzomib in the first two cycle encourages to maintain the maximum tolerated dose.

INTRODUCTION: Gaucher disease (GD) is a rare, autosomal recessive genetic disorder. It is due to a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in tissue macrophage with damage to hematological, visceral, and skeletal organ systems. Although GD has a continuous spectrum of severity, it is traditionally classified into three forms: type 1 (chronic; lacking early onset neuronopathy), type 2 (acute; with early onset neuronopathy),and type 3 (chronic; with early onsetneuronopathy). Type 1GD accounts for more than 90% all GD patients. Its prevalence world-wide is 1 in 50,000-100,000 but it is as high as ~1 in 850 in individuals of Ashkenazi heritage. Type 1 GD is frequently associated to monoclonal gammopathies; despite the emergence of theories advanced to explain these observations, the cause remains unknown. OBJECTIVE: Aim of the ongoing observational study is to determine the prevalence of unrecognized type I GD in a selected Italian population with MGUS. MATERIALS AND METHODS: From January 2018, dried blood spots (DBS) sample from patients with laboratory evidence of MGUS coming from five hematology units of Sicily and Calabria were collected and tested for the acid β-glucosidase enzyme activity. The study was approved by the local institutional review board. All patients provided informed consent for the prospective collection of their data. In case of DBS positive result, a confirmatory test was carried over and, if GD was confirmed, the patient was referred to one of the Regional Reference Centers for Metabolic Disease, as for current clinical practice in Italy. RESULTS: To date, 308 patients with MGUS were enrolled; acid β-glucosidase enzyme activity was low in 22 patients (7%). Sequence analysis of GBA gene was performed in these selected patients, but we have found only 4 patients with heterozygous mutation in the GBA1 gene, 1 homozygous(c.1226A>G -N370S) and 1 compound heterozygous (c.1226A>G -N370S and c.1448T>C -L444P); the last 2 patients had signs of GD (hepato-splenomegaly and mild thrombocytopenia). CONCLUSIONS: Type 1 GD remains a rare lysosomal storage disorder but preliminary results of our observational study show that it should be considered in the diagnostic framework of patients with MGUS, particularly when other GD symptoms are present. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Di Raimondo:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding.

Background: Triplet-based lenalidomide plus dexamethasone (Rd) combinations have become the new standard of care for early relapse and refractory multiple myeloma (RRMM). Carfilzomib is a novel selective proteasome inhibitor (PI) with high efficacy in RRMM. The ASPIRE phase 3 trial showed the superiority of carfilzomib-based triplet (KRd compared to Rd), leading to approval of K for RRMM. However, little is known about safety and efficacy of KRd outside a clinical trial context. Experimental design and aims: In 11 Sicilian Centers belonging to the Sicilian Myeloma Network, from November 2016, when KRd regimen was approved in Italy, to June 2018, 103 consecutive RRMM patients (previous lines 1-10) have received KRd regimen, according to ASPIRE schedule. Lenalidomide dosage was reduced in patients with a low count of platelet and/or renal failure according to manufacturer guidelines. Since previous studies have demonstrated that increased cumulative dose of first generation PI bortezomib significantly improved overall survival of patients treated with VMP regimen, we studied the effect of cumulative dose of Carfilzomib in RRMM patients receiving KRd. Results: Clinical and demographic characteristics of patients included in the study are summarized in Table 1. Median age was 65 years (range 33-86), most patients were males (54%). About half of the patients included in the survey were refractory to previous treatment (54%); Sixty-five (63%) patients received at least 5 cycles of KRd and 38 (36%) received at least 10 cycles. Overall response rate was 34% (35 patients); 18 patients (17%) achieved a complete response (CR), 6 patients minimal response (MR), 13 (12%) patients achieved PR, 16 patients achieved MR and then progressed; progression occurred in 20 patients, among them 3 did not reached any response. Delays due to adverse events were 33%, mainly due to febrile neutropenia (22%), thromboembolic events (4.5%), heart failure (3%), or thrombocytopenia (4.5%). To prevent hematological toxicities, 24% of patients received granulocyte growth factors, 15% erythropoietin. In 30 patients treatment was reduced (mainly due to lenalidomide toxicity) and in 5 patients discontinued for toxicity. Thus, median cumulative carfizomib doses at 2, 3, 4 and 6 cycles were respectively 480 mg (282 mg/m2), 735 mg (435 mg/m2), 995 mg (589 mg/m2) and 1522mg (890 mg/m2). After a median follow up of 16.2 months, PFS at 12 months was 67.3%. We found that median PFS was significantly longer in patients who received at least 480 mg (282 mg/m2) within first two months of treatment compared to those that could not receive full-dose KRd (respectively, undefined vs 11 months p=0.04). To identify patients that could obtain the most advantage by KRd treatment, 65 patients who had received at least six cycles were distinguished in two groups, based on previous treatments. In group A, 27 patients were heavily pretreated (median previous lines 4, range 2-10) and had previously received lenalidomide while 38 patients included in group B were less pretreated (median previous lines 3, range 1-5) and lenalidomide- naïve. We found that group A had lower PFS than group B although duration of PFS from the previous treatment was similar in both groups. Conclusions: In our cohort of patients rate of VGPR or better obtained with KRd combination was high with an overall response rate of 34%, with an acceptable safety profile. It is therefore reasonable that approaches to achieve a higher cumulative dose, such as continuing therapy in responding patients and/or proactive adverse events management, influence efficacy. In addition, it is likely that patients not previously exposed to several lines of treatment including lenalidomide are the best candidate for a favorable outcome with KRd regimen. Disclosures Di Raimondo: Celgene: Honoraria; Takeda: Honoraria, Research Funding.

Patients with chronic obstructive pulmonary disease (COPD) are prone to clinical exacerbations that are associated with increased airway inflammation, a potent pro-thrombotic stimulus. Limited information is available on the mechanisms underlying the putative alterations of the endothelial-coagulative system during acute exacerbations. The aim was to investigate whether the activation of the endothelial-coagulative system occurs in association with the acute inflammatory response of COPD exacerbation. We monitored the blood levels of surrogate markers of inflammation: interleukin-6 (IL-6); endothelium damage: von Willebrand’s factor (vWF); clotting activation: D-dimer (D-D), and prothrombin fragment 1+2 (F1+2); fibrinolytic response: plasminogen activator inhibitor 1 (PAI-1), in COPD subjects, during hospital admission and after clinical resolution. In 30 COPD subjects, IL-6, vWF, D-D and F1+2 levels were elevated during exacerbation and decreased significantly at clinical stability (IL-6, p = 0.005; vWF, p < 0.001; D-D, p < 0.001; F1+2, p < 0.001). PAI-1 levels did not change at exacerbation compared to clinically stable situations. Positive correlations were observed between several of the markers measured. Elevation of IL-6, vWF, D-D and F1+2 levels during COPD exacerbations implies a strict association between acute inflammation, endothelial activation and clotting initiation. This was not associated with a change in PAI-1, implying an increase in the fibrinolytic response to inflammation. The pro-thrombotic nature of COPD exacerbations sustained by enhanced clotting activation appears to be mitigated by excessive fibrinolysis.

The recent advances in cytogenetic and molecular diagnostic techniques has provided a better understanding of biology of CLL and a better prediction of disease progression and refractoriness but they are not easily accessible to all Institutions. CLL cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. An increased number of studies describe the emerging role of neutrophils and monocytes as mediators of the inflammation process and antitumor immunity modulation that support tumorigenesis and tumor progression. The neutrophil to lymphocyte ratio (NLR), has been recently published as new marker of systemic inflammation associated with outcome in different cancer types. In our study we retrospectively evaluated the prognostic significance of peripheral blood neutrophils, monocytes and non-neoplastic lymphocytes in a unicentric, unselected, CLL cohort of 400 CLL patients (160 were treated). The study was approved by the institutional board review;informed consent was obtained from patients. Using the blood count and the Flow cytometric analysis reports, peripheral blood absolute neutrophil count (ANC), absolute monocyte count (AMC) and absolute T-lymphocyte count (ALC-CD3+) were evaluated and the neutrophil to T-lymphocyte ratio (NLR), the monocyte to T-lymphocyte ratio (MLR) and the neutrophil to monocyte ratio (NMR) were calculated. Clinical and biological data from all patients were also retrieved. Serial count and ratio were evaluated at diagnosis, during follow up and at relapse to make a better comparison with the major clinical and prognostic markers commonly used. The median ratio for NLR 2.67 and patients with pre-treatment NLR > 3 had a shorter time from diagnosis to treatment initiation. CLL patients showed an increase in the absolute number of monocytes compared to normal controls (788±65 cells/μL vs 469±51 cells/μL, p=0.005) and MLR appeared higher in advanced stage (stage Binet C) and bulky disease (p=0.06). High level of both NLR and MLR (cut off >3) correlated with the presence of a complex karyotype detected by FISH (p=0.03, p=0.016). NLR ratio was associated with the absence of serum prognostic markers, such as the expression of CD38, ZAP-70 and CD49d. This result, apparently conflicting, could strengthen the NLR as an independent prognostic factor. NMR was higher in asymptomatic patients (absence vs. presence of B symptoms, p=0.02) and this data resulted independent from disease stage. NMR median value was significantly higher in untreated patients than in patients who received treatment (p=0.01), strengthening the hypothesis that this ratio is associated with a more indolent form of disease. In this contest, the subset of patients with CD49d positive disease showed the lowest NMR value. This data seems of relevance, being CD49d a recently discovered and validated prognostic marker. ANC/ALC and AMC/ALC ratio significantly increased at relapse compare to baseline (NLR average onset 2.3±0.4 vs 3.4±0.6 at relapse). The median NMR value showed conversely the opposite trend: NMR is reduced in first relapse (NMR average onset 7.2±0.4 vs. 5.4±0.5 at relapse). These combined ratios reflect both the inflammatory status, the immune response and the microenviromental network that contribute to aggressive tumor biology and disease progression. They are simple, cheap, easily measured and reproducible and can be integrated into daily clinical practice as new prognostic markers for CLL. Disclosures Chiarenza: Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy.