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Objectives During the lockdown that started in Italy on 10 March 2020 to address the COVID-19 pandemic, aggressive procedures were implemented to prevent SARS-CoV-2 transmission in SARS-CoV-2-negative patients with haematological malignancies. These efforts progressively reduced Klebsiella pneumonia carbapenemase-producing K. pneumoniae (KPC-KP) spread among these patients. Here we evaluated the potential effects of measures against COVID-19 that reduced KPC-KP transmission. Patients and methods We analysed KPC-KP spread among 123 patients with haematological malignancies, hospitalized between March and August 2020, who were managed using measures against COVID-19. Their outcomes were compared with those of 80 patients hospitalized during the preceding 4 months (November 2019–February 2020). Results During March–August 2020, 15.5% of hospitalized patients were KPC-KP positive, compared with 52.5% in November 2019–February 2020 (P Conclusions Aggressive strategies to prevent SARS-CoV-2 transmission were applied to all hospitalized patients, characterized by high levels of KPC-KP endemicity and nosocomial transmission. Such measures prevented SARS-CoV-2 infection acquisition and KPC-KP horizontal transmission. Reduced KPC-KP spread, fewer associated clinical complications and decreased ceftazidime/avibactam consumption represented unexpected ‘collateral benefits’ of strategies to prevent COVID-19.

Simple Summary Roughly 85–90% of adult and pediatric acute myeloid leukemia (AML) are CD33-positive. Gemtuzumab ozogamicin (GO), a humanized murine IgG4 anti-CD33 antibody, is the first target therapy approved in AML therapeutic scenario. This review focuses on current biological information and clinical data from several studies investigating the use of GO in patients with AML. Over the years, flow cytometry, cytogenetics, molecular techniques, and genotyping studies of CD33 SNPs have provided a comprehensive analysis of promising biomarkers for GO responses and have potentially helped to identify subgroups of patients that may benefit from GO addition to standard chemotherapies. Increased understanding of molecular mutations, altered intracellular pathways, and their potential relationship with CD33 expression may open new therapeutic landscapes based on combinatorial regimens in an AML scenario. Abstract Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, has been historically treated with infusional cytarabine (ara-c) + daunorubicin (3 + 7) for at least 40 years. The first “target therapy” to be introduced was the monoclonal anti-CD33 gemtuzumab ozogamicin (GO) in 2004. Unfortunately, in 2010 it was voluntarily withdrawn from the market both for safety reasons related to potential liver toxicity and veno-occlusive disease (VOD) and because clinical studies failed to confirm the clinical benefit during induction and maintenance. Seven years later, GO was re-approved based on new data, including insights into its mechanism of action on its target receptor CD33 expressed on myeloid cells. The present review focuses on current biological information and clinical data from several studies investigating GO. Cytogenetic, molecular, and immunophenotypic data are now able to predict the potential positive advantages of GO, with the exception of high-risk AML patients who do not seem to benefit. GO can be considered a ‘repurposed drug’ that could be beneficial for some patients with AML, mostly in combination with new drugs already approved or currently in testing.

Introduction: The broadening of targeted and immunotherapeutic strategies markedly impacted on the management of acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKIs) changed the history of Philadelphia-chromosome positive (Ph+) ALL. Nowadays, almost all Ph+ ALL patients treated with TKIs achieve a complete hematologic response, and most become minimal residual disease negative. In Ph- ALL, genomic profiling studies have identified a subtype associated with a high relapse risk and a transcriptional profile similar to that of Ph+ ALL, the so-called Ph-like ALL. Given the high prevalence of kinase-activating lesions in this subset, there is compelling evidence from experimental models and clinical observations favoring TKI administration.Areas covered: We discuss the main findings exploring the efficacy of TKIs in ALL.Expert opinion: The use of more potent TKIs will further enhance the inhibitory activity on leukemia cells and increase the possibility of eradicating the disease at a molecular level. In the future, 'combined' approaches of different inhibitors may be considered to prevent/avoid resistance and/or mutations. A rapid identification of Ph-like ALL patients is needed to propose early TKI-based intervention. Several questions remain open, including the initial TKI choice in Ph+ ALL and whether Ph-like ALL patients might benefit from immunotherapy.

Objective The aim of this study was to evaluate the addition of cyclophosphamide in relapsed-refractory multiple myeloma patients (RRMM) who experienced biochemical relapse or progression without CRAB, during treatment with lenalidomide and dexamethasone (Rd), to slow down the progression in active relapse. Methods This analysis included 31 patients with RRMM treated with Rd who received cyclophosphamide (CRd) at biochemical relapse. The CRd regimen was continued until disease progression. Results The median number of CRd cycles administered was 8 (range: 1-35). A response was observed in 9 (29%) patients. After a median observation time of 11 months, the median overall survival (OS) from the beginning of CRd was 17.7 months. The median progression-free survival (PFS) from the beginning of CRd was 13.1 months. Conclusion The addition of cyclophosphamide delays the progression in patients who present a biochemical relapse during Rd treatment. The response rate and the duration of PFS obtained with minimal toxicities and low costs induced us to setting up a randomized clinical trial.

Background Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined. Methods Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated. Results Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed. Conclusions Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.

Background: In elderly patients with chronic myeloid leukemia (CML) responsive to imatinib, the incidence of clinically significant (CS) late chronic anemia is still unknown. Materials and Methods: To highlight this issue, we revised retrospectively 81 CML patients aged >60 years treated at our Institution with front-line imatinib for at least 24 months in durable complete cytogenetic response (CCyR). CS late chronic anemia was defined as the presence of persistent (>6 months) and otherwise unexplained Hb levels ≤10 g/dL, which occurred >6 months from imatinib start. Results: A condition of CS late chronic anemia occurred in 22 out of 81 patients (27.2%) at different intervals from imatinib start. Seven out of 22 patients (31.8%) needed packed red cell transfusions during the follow-up. At diagnosis, patients who developed CS late chronic anemia were significantly older and had a lower Hb median level. Six out of 22 patients with CS late chronic anemia received subcutaneous recombinant alpha-erythropoietin (EPO) at the standard dosage of 40,000 IU weekly: all 6 patients achieved an erythroid response. A significantly worse event-free survival (EFS) in patients with untreated CS late chronic anemia was observed (p = 0.012). Conclusions: CS late chronic anemia during long-term treatment with imatinib is a common complication in responsive elderly patients, with worse EFS if untreated. Results with EPO are encouraging, but larger studies are warranted to define its role.

Pulmonary infections (PIs) are a major complication of patients with myelodysplastic syndromes (MDS). We retrospectively evaluated 234 MDS patients treated with azacytidine (AZA). The total number of AZA cycles was 2886 (median 8 cycles per patient). There were 111 episodes of PI (3.8% of AZA cycles) in 81 patients (34.6%). PIs were considered of fungal origin in 27 cases (24.3%), associated to bacteremia in 11 cases (9.9%), to influenza infection in two cases (1.8%) and of unknown origin in the remaining 71 cases (64.0%). Forty-five PI episodes were documented in cycles 1 to 4 of AZA (5.1% of 875 cycles) and the remaining 66 episodes beyond the fourth cycle (3.2% of 2011 cycles) (P = .017). Overall, a fungal PI was documented in 13/875 (1.5%) cycles 1 to 4 and in 13/2011 (0.6%) cycles beyond the fourth cycle (P = .001). A baseline chronic pulmonary disease was significantly associated to a higher risk of severe PIs. In the survival analysis, cases of PI in patients who progressed to acute leukemia (PAL) were excluded, in view of the predominant influence of PAL on the outcome of the patients. A PI unrelated to PAL documented during the first 4 AZA cycles was an independent factor predicting lower survival (OR, 2.13; 95% CI, 1.37-3.33; P = .001). In conclusion, PIs are common in MDS patients receiving AZA, in particular during the first cycles of treatment and are associated with an unfavorable outcome. The results of our study raise the issue of the need of a tailored infection prevention strategy.

OBJECTIVES To evaluate differences in clinical results according to age among patients with chronic myeloid leukemia (CML). METHODS 207 consecutive CML patients treated with imatinib frontline were revised, dividing them in young adults (>20

Ibrutinib is a tyrosine kinase inhibitor used in the treatment of a variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Drugs inhibiting B-cell-receptor (BCR)-associated kinases, including BTK inhibitors, act on B cells and on a wide spectrum of tissues and cells, including innate immunity cells. Thus, alterations in the Bruton's tyrosine kinase (BTK) kinase function could lead to an impairment of innate immune cells functions and to an increased infectious risk in patients receiving BTK inhibitors. We analyzed in vivo neutrophils oxidative burst, neutrophils granules release and cytokine production in relapsed/refractory CLL patients treated over time with ibrutinib as single-agent. We observed a dramatic reduction of neutrophils oxidative burst, Fc gamma receptors (FcγRs)-mediated degranulation and IL-8 plasma levels already after the first forty-eight hours of therapy with ibrutinib. However, ibrutinib treatment did not alter the surface expression of CD11b nor cytokine and proteinases release not mediated by FcγRs engagement. After three weeks, oxidative burst was still impaired, while degranulation and IL-8 levels were restored. In a group of CLL patients who survived for more than three years, all processes triggered by FcγRs completely recovered except the release of neutrophil elastase (NE) and IL-8. In conclusion, during the initial phases of ibrutinib therapy, the reduction of IL-8, NE, myeloperoxidase (MPO) levels and oxidative burst negatively impacted on mechanisms involved in neutrophils microbicidal activity.

BACKGROUD. The B-cell receptor inhibitor ibrutinib has significantly improved treatment and overall management of chronic lymphocytic leukemia (CLL). Although several data derived from clinical trials suggest that ibrutinib increases the risk of atrial fibrillation (AF), the incidence of AF in a real-life cohort of CLL patients is unknown. Furthermore, it would be clinically relevant to identify patients at high risk of AF during ibrutinib. The aim of this study is to report the prevalence and risk factors of AF in ibrutinib-naive CLL, in order to define a predictive model for the development of AF and to test it in a cohort of subjects receiving ibrutinib. METHODS. We retrospectively analyzed data from 860 ibrutinib-naive CLL patients, referred to the Padua University hospital. Comorbidities, clinical and biological prognostic markers were analyzed using the Mann-Whiney, Fisher exact or Chi-square tests, when appropriated. Time to AF (TTAF) and overall survival (OS) were evaluated with Kaplan-Meier method. Univariate and multivariate Cox models were run to identify independent factors associated with AF. Then, risk values were obtained based on the hazard ratios. The score for AF was calculated as the sum of each risk values. Subsequently, the model was evaluated in a cohort of 354 ibrutinib-treated patients referred from 8 Italian hematological centers. RESULTS. Among the 860 patients from Padua hospital, 60% were male, 49% were older than 65 years, 73% were Binet A stage at diagnosis and 41% underwent at least one line of treatment. A prior history of AF was present in 21 patients (2.4%) at CLL diagnosis, while, among the remaining 839 patients without a previous history of AF, 47 (5.6%) developed it after a median follow-up of 9.4 years, resulting in an estimated incidence of almost 0.8% cases/year. Moreover, the median OS for patients with AF was significantly shorter than that patients without AF (12 vs 22 years, p65 years (p=0.001, 1 point), male gender (p=0.003, 1 point), valvular hearth diseases (p=0.001, 2 points), cardiopathy (p Subsequently, we applied our AF model to a cohort of 354 ibrutinib-treated patients, 64% were male, the median age was 69 years, 88 were treatment-naive, 70% U-IGHV and 39% harbored TP53 abnormalities. Forty-four subjects developed AF after a median observation of 25 months, with an estimated 2-year TTAF of 12%. Only 9 out of the 44 patients (20%) discontinued ibrutinib. Sixteen patients (4%) were classified as AF score 0, 218 (62%) score 1-2, 73 (21%) score 3-4 and 46 (13%) at least score 5. Our model was also able to identify patients at a higher risk AF during ibrutinib, in fact the 2-year risk of AF was 0%, 5%, 17% and 40% for patients with score 0, 1-2, 3-4, and ≥5 respectively (p CONCLUSIONS. In this study, variables associated with an increased risk of developing AF were identified and recapitulated into a scoring system. Our model proved to be a valid tool to identify patients at a higher risk of developing AF, including ibrutinib-treated patients. Taking these data into account, patients with a score ≥5 should be carefully monitored during ibrutinib treatment given the very high-risk of developing AF or should be considered for alternative therapies. Disclosures Visentin: janssen: Consultancy, Honoraria. Mauro:abbvie: Other: board member; janssen: Other: board member. Reda:Janssen and Cilag: Consultancy; ABBVIE: Consultancy; Gilead: Consultancy; Celgene: Consultancy. Molica:Jansen: Other: Advisory board; Gilead: Other: Advisory board; Roche: Other: Advisory board; AbbVie: Other: Advisory board. Rigolin:Gilead: Research Funding. Tedeschi:Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; AbbVie: Consultancy. Cortelezzi:novartis: Consultancy; abbvie: Consultancy; roche: Consultancy; janssen: Consultancy. Coscia:Abbvie, Gilead, Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen, Karyopharm: Research Funding. Cuneo:Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:CELGENE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Trentin:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Gilead: Research Funding; Janssen: Research Funding.

Peripheral neuropathy is one of the most important complications of multiple myeloma treatment. Neurological damage can be observed at the onset of the disease, due to the effect of monoclonal protein or radicular compression, but more often is treatment related. Vinca alkaloids in the past era, and more recently, thalidomide and bortezomib are mainly responsible. Degeneration of dorsal root ganglion is common, prevalently related to angiogenesis inhibition and cytokine modulation in the case of thalidomide and inhibition of the ubiquitin proteasome system in the case of bortezomib. Sensory neuropathy and neuropathic pain are more common; motor neuropathy and autonomic damage are less frequently observed. Neurotoxicity often affects patient’s quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, alcohol abuse, vitamin deficiencies, or viral infections) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Effective management of treatment at the emergence of peripheral neuropathy can minimize the incidence and severity of this complication and preserve therapeutic efficacy. Dose adjustment could be necessary during treatment; moreover, gabapentin or pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, carbamazepine, and opioid-type analgesics are suggested according to the pain severity. Some authors reported that patients who develop peripheral neuropathy during their multiple myeloma treatments presented a particular gene expression profile; therefore, future studies could be helpful for a better understanding of possible biological pathways underlying neurotoxicity.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare diseases, characterized by an aggressive behavior and a poor clinical outcome. High-dose therapy followed by autologous stem cell transplantation (ASCT) has been used as salvage and upfront treatment with conflicting results. However, no standard therapy has so far been established due to the lack of randomized studies. The records of 54 untreated patients with a confirmed diagnosis of PTCL managed at our Institute between 2001 and 2011 were reviewed. The histologic subtypes were: 37 (68%) peripheral T-cell lymphomas unspecified (PTCL-U), 13 (24%) anaplastic large cell lymphomas (ALCL), of which 4 (30%) ALK-positive, 2 (4%) angio-immunoblastic lymphomas (AITL) and 2 (4%) enteropathy-associated T-cell lymphomas (EATL). The clinical characteristics were: median age 56 years (range 18-79); 40 men and 14 women; 13 (24%) and 41 (76%) patients were, respectively, in Ann Arbor stages I-II and III-IV. An elevated serum LDH was present in 33% of patients, 48% had B symptoms and 24% had a bone marrow involvement. The ECOG performance status was 2-3 in 28% of patients. According to the International Prognostic Index (IPI) and the prognostic index for T-cell lymphomas (PIT), 11% and 22% were classified as low risk, 30% and 33% as low-intermediate risk, 12% and 33% as high-intermediate risk and 29% and 12% as high risk, respectively. CHOP-like regimens were given to 32 (59%) patients, 14 of whom received the CHOEP regimen. The remaining 22 (41%) patients were treated with more intensive third generation regimens (MACOP-B like). ASCT was planned as upfront consolidation therapy for 16/54 (30%) patients. A complete response (CR) was obtained in 30/54 (55.5%) patients, a partial response in 7 (13%), while 17 (31.5%) patients showed a lymphoma progression during induction therapy. No difference in terms of CR rate was observed between the CHOP-like and MACOP-B-like regimens. At a median follow-up of 19 months (range 3-138), the 5-years OS and 5-years PFS were 32% (95% CI 25.3-38.5) and 27% (95% CI 20.2-34.5), respectively. At univariate analysis, bone marrow involvement (p=0.003), PIT high risk group (p The prognosis of PTCLs remains poor despite the use of intensive chemotherapy regimen including upfront ASCT. More active induction chemotherapy regimens, including novel agents, should be designed in an attempt to increase the quality of response before ASCT consolidation therapy. Disclosures: No relevant conflicts of interest to declare.

Background: Several trials and analysis have explored the efficacy of bortezomib re-use in relapsed patients with multiple myeloma (MM), notably in those who have experienced good response and late relapse after the end of frontline treatments including the same drug. However, very few specific evidences on bortezomib re-challenge at first relapse are available. Patients and methods: This observational, retrospective study enrolled 135 MM patients treated from January 2002 to May 2015 in 12 Italian centres with bortezomib-based regimens as first line therapy (both in daily practice or clinical trials) and who had received again a salvage treatment containing bortezomib at first relapse, according to current clinical practice and/or guidelines recommendations. Results: Median age was 61 years (range 28-95) and 60% of patients were males. At diagnosis, ISS was 30% stage I, 30% stage II and 40% stage III; r-ISS (available in 45 cases) was 25% stage I, 44% stage II and 31% stage III. Two patients presented as primary plasma cell leukemia (PCL). First line induction treatments included VD (27%), VTD (25%), VMP (23%), PAD (10%), and further combinations of bortezomib with cyclophosphamide (11%) or other drugs (4%). Eighty-two percent of patients received a twice-week schedule and 18% once-a-week administration of bortezomib, which was initially given i.v. in 71% and s.c. in 29% of patients, respectively. Seventy-five patients (56%) underwent single (72%) or double (28%) autologous stem cell transplantation (AuSCT) as part of their frontline therapy. Consolidation or maintenance with borteomib were performed in 17 and 4 patients, respectively. As per inclusion criteria, all patients achieved PR or better response (according to IMWG criteria), including at least VGPR in 36%, CR in 20% and sCR in 1% of cases. Median duration of PFS1 was 33 months (95% CI 28-36), while median treatment free-interval (TFI) was 23 months (95% CI 22-28). Median PFS1 was 35 months (95% CI 31-43) and 27 months (95% CI 20-33) for patients undergoing or not AuSCT, respectively (p n.s.). At first relapse (clinical 65%, only biochemical 35%), anemia, neutropenia and thrombocytopenia were present in 42%, 5% and 9% of patients, respectively. Median bone marrow plasma cell infiltration was 40% (range 2-99). Bone lesions were present in 74%, hypercalcemia in 7%, high LDH values in 15% of patients. Serum beta2-microglobulin levels were increased in 48%, while albumin was decreased in 17%. Renal failure was observed in 14%, with a median value of serum creatinine of 2.2 mg/dl (range 1.4-7). PCL occurred in 3 patients. Second line regimens included VD (44%), VCD (11%), PAD (9%), VTD (7%), BVD (7%), VMP (7%), VRD (4%), VRCD (2%), or other combinations (9%). Six patients had maintenance therapy with bortezomib. Twenty-one patients (16%) received AuSCT as part of their salvage therapy, while 4 patients (3%) underwent allogeneic transplantation (AlloSCT) and 5 (4%) a tandem sequence of AuSCT followed by AlloSCT. Seventy-four percent of patients received bortezomib once-a-week, 26% twice-weekly, 35% i.v. and 65% s.c. A total of 782 cycles (median 6, range 1-13) were given. Grade 3-4 hematological and non-hematological toxicities occurred in 27% and 10% of patients, respectively. No patient reported grade 3-4 neuropathy. Bortezomib dose reductions were needed in 12%. SPM occurred in 1 patient. Overall response rate was 70%, with 24% at least VGPR and 7% CR (sCR/nCR 1.5%). Improvement of renal failure (13 cases) was complete in 4 and partial in 6 patients. Bone disease improved in 31% of patients with osteolytic lesions. Median duration of second PFS was 19 months (95% CI 13-23), while that of second TFI was 14 months (95% CI 8-17). Median PFS2 was 56 months (95% CI 50-70); it was 60 months (95% CI 54-78) for patients who underwent AuSCT and 50 months (95% CI 45-68) for those who did not (p n.s.). Median OS was 94 months (95% CI 80-121) for the entire cohort, 94 months (95% CI 75-107) for patients undergoing AuSCT, and 86 months (95% CI 76-92) for those who did not receive AuSCT. After a median follow up of 56 months, 85 patients (63%) are alive, with 41 of them in response after second line therapies containing bortezomib. Conclusions: This real-life survey indicates that re-treatments including bortezomib as first salvage therapy should be considered for selected MM patients achieving prolonged response after initial exposure to first line, bortezomib-based regimens. Disclosures Musto: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cascavilla:Janssen-Cilag: Honoraria. Falcone:Janssen-Cilag: Honoraria. Petrucci:Janssen-Cilag: Honoraria. Di Raimondo:Janssen-Cilag: Honoraria. Ria:Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau; Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau. Mastrullo:Janssen-Cilag: Honoraria. D'Arena:Janssen-Cilag: Honoraria. Bringhen:Janssen-Cilag: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Di Renzo:Janssen-Cilag: Honoraria. Caravita:Janssen-Cilag: Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Corso:Janssen-Cilag: Honoraria.

Background Early occurrence of severe (≤ 10 g/dl) anemia has been reported in about 5% of newly diagnosed patients with Chronic Myeloid Leukemia (CML) treated with imatinib and is generally transient: in patients responsive to imatinib, however, severe late anemia seems to occur in a higher rate and seems to be more common in elderly patients. Methods To highlight this issue, we revised retrospectively 81 CML patients aged > 60 years treated at our Institution with frontline imatinib for at least 24 months who achieved a durable complete cytogenetic response (CCyR). The main clinical features of the patients at diagnosis were as follows: male/female 42/39 (51.9%/48.1%), median age 70.5 years [interquartile range (IQR) 64.5 - 76.5], median Hb 12.8 g/dl (IQR 11.2 - 13.7), median WBC 42.5 x 109/l (IQR 25.4 - 78.9), median PLTS 448 x 109/l (IQR 282 - 717). According to Sokal risk classification, 12 patients (14.8%) were low risk, 58 (71.6%) intermediate risk, 11 (13.6%) high risk. Severe late chronic anemia was defined as the presence of persistent (> 6 months) and otherwise unexplained (creatinine level < 2 mg/dl, normal iron balance, bilirubin level < 2 mg/dl, folate and Vitamin B12 in the normal range) Hb levels ≤ 10 g/dl which occurred > 6 months from imatinib start. Results On the whole, a condition of late chronic anemia occurred in 22 out 81 patients (27.2%) at different intervals from imatinib start: the incidence was 13.5% (11/81 patients) at the 12th month, 14.8% (12/81 patients) at the 24th month, 12.3% (9/73 patients) at the 36th month, 7.0% (4/57 patients) at the 48th month and 5.9% (3/51 patients) at the 60th month. Seven out 22 patients (31.8%) needed packed red cell transfusions during the follow-up. Clinical features at diagnosis of patients who had severe late chronic anemia compared to the remaining 59 patients without anemia are shown in the Table: Among the 22 patients with severe late chronic anemia, 6 were treated with subcutaneous recombinant alpha-erythropoietin (EPO) at the standard dosage of 40,000 UI weekly, after a median time from imatinib start of 44.7 months (absolute range 26.8 - 73.8): in all 6 patients, baseline endogenous EPO levels were < 100 mUI/ml. All 6 patients achieved erythroid response, which was complete (achievement of stable Hb levels > 12 g/dl) in 4 patients and partial (stable increment > 1.5 g/dl of Hb levels with Hb levels < 12 g/dl) in 2 patients: one patient had a relapse of anemia after 24.1 months from EPO start and stopped EPO treatment, the remaining 5 patients are still in response and in treatment with EPO. No EPO-related toxicity was observed. Cumulative 4-year Event-Free Survival (EFS) for patients with severe late chronic anemia was 69.7% (CI95% 49.3 - 90.1) compared to 86.2% (CI95% 77.4 - 95.0) for patients without anemia (p=0.075): cumulative 4-year Overall Survival (OS) for patients with severe late chronic anemia was 89.6% (CI95% 75.9 - 100) compared to 94.8% (CI95% 89.1 - 100) for patients without anemia (p=0.204). Conclusions The occurrence of a late severe chronic anemia during long-lasting treatment with imatinib has been observed in > 25% of our responsive elderly patients, with a trend for a worse EFS: its occurrence seems more common in very elderly patients with lower Hb levels at diagnosis. Results with EPO are encouraging, but larger studies are warranted to define the role of such an approach in treating this common late complication of prolonged imatinib therapy. Table Table. Disclosures Breccia: Celgene: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Azacytidine (AZA) is a demethylating agent widely used in the treatment of patients with high-risk Myelodysplastic Syndromes (MDS). Pulmonary infections are often reported in these patients during AZA treatment, however, their incidence, etiology and impact in the overall outcome are still unclear. A major problem is represented by the low level of clinical and microbiological documentation, as most of patients treated with AZA are managed on an outpatient basis. This study aims to evaluate the incidence and clinical impact of pulmonary infections in MDS patients treated with AZA in 5 hematological Institutes in Rome, with a relatively homogeneous infective diagnostic work-up in the presence of fever or other infective clinical signs. We retrospectively evaluated 146 MDS patients [M/F 93/53, median age 69.5 years, interquartile range (IQR) 65.0 - 75.6] treated with AZA at our Institutions from 04/2009 to 01/2016. All patients received AZA cycles at standard dosage (75 mg/m2 for 7 days every 28 days) as outpatients. In the event of febrile neutropenia or other infectious episodes patients underwent blood cultures, culture from other sites, and chest x-ray or (preferably) pulmonary CT-scan. Galactomannan assay from serum and from sputum/bronchoalveolar lavage was performed as indicated. The total number of AZA cycles was 1712, with a median per patient of 9 cycles (IQR 5 - 17 cycles). There were 75 episodes of lung infection (4.1% of AZA cycles), with 58 patients (39.7%) presenting at least 1 episode. Based on the above diagnostic work-up, pulmonary infiltrates were considered of fungal origin in 21 cases (28.0%), associated to bacteremia in 5 cases (6.7%) and of unknown origin in the remaining 49 cases (65.3%). As to the time of occurrence of lung infections, 29 episodes were documented in the first 4 cycles of AZA treatment (5.4% of 535 cycles) and the remaining 46 episodes beyond the 4th cycle of AZA treatment (3.9% of 1177 cycles). Overall, a pulmonary fungal disease was documented in 10 of 535 (1.9%) cycles 1-4 and in 11 of 1177 (0.9%) cycles beyond the 4th (p=0.001). Several clinical features (age, gender, Hb level, WBC and PLT counts, time from diagnosis) were evaluated as predictive factors for the occurrence of pulmonary infection, but none was significant. Out of 58 patients who developed at least one pulmonary infection, 39 (67.2%) definitively discontinued the AZA treatment within 3 months from the infectious episode due to deterioration of clinical conditions, hematologic disease progression and/or death. Attributable mortality rate of patients with pulmonary infection was 22.4% (13 of 58). The median Overall Survival (OS) of the whole cohort was 18.0 months (95%CI 14.4 - 21.5): the median OS of patients with pulmonary infection was 15.6 months (95%CI 13.1 - 18.0) compared with 21.5 months (95%CI 16.3 - 26.6) of patients without pulmonary infection (p=0.031). In conclusion, pulmonary infections are a common complication in MDS patients receiving AZA treatment, and are often associated to an interruption of AZA therapy. Pulmonary fungal infections are more frequently observed early during the first cycles of treatment. It should be defined if the poor outcome of patients who develop pulmonary infections during AZA therapy is an epiphenomenon of an immunologic deterioration associated to the hematologic disease progression or is independently related to the complication. If confirmed in other experiences, the results of our study raise the issue of the need of an antibacterial and/or antifungal prophylaxis particularly during the first months of AZA therapy. Disclosures Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Breccia:Celgene: Honoraria; Novartis: Consultancy, Honoraria; Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

Background: New active classes of drugs such as proteasome inhibitors (e.g., bortezomib) and immunomodulatory drugs-IMiDs (e.g., thalidomide and lenalidomide) are nowadays the standard treatment for multiple myeloma (MM) patients, alone or in association with old agents. The achievement of deeper responses, using novel agents instead of conventional treatment, is a significant prognostic factor for the outcome of these patients, resulting in an improved overall survival (OS) and progression-free survival (PFS). Here, we report the single center real life comparison between the outcome achieved with old agents with that obtained with novel agents in young MM patients treated at first relapse over a 25-year period. Patients and Methods: We analyzed a cohort of 258 young (median age 55 years; range 19-69) newly diagnosed MM patients treated at our Center between August 1989 and November 2014. All patients received old or novel agents followed by autologous hematopoietic stem cell transplantation (single or tandem) as first line treatment. Of the 258 patients, 144 experienced a progression of disease after a median of 34 months (range 7-195) and received old or novel agents as second line therapy. Old agents used as first and second line treatment were prevalently vincristine, doxorubicin and dexamethasone (VAD), melphalan and prednisone (MP) or cyclophosphamide and dexamethasone (CD); novel agents included velcade-based or IMiD-based regimens. Our cohort was divided into four different groups: 1) 51 patients treated with old agents as first and second line therapy (35.4%);2) 79 patients treated with old agents as first line therapy and novel agents as second line therapy (54.8%);3) 2 patients treated with novel agents in induction therapy and subsequently with old agents as second line therapy (1.4%);4) 12 patients treated with novel agents both in first and second line (8.3%). Our analysis focused on groups 1 and 2; group 3 was not considered for the small number of patients and because the choice of treatment was based exclusively on a worsening of the clinical condition; group 4 was not included for the small number of patients and because of the short follow-up. Our aim was to compare the results obtained in patients treated only with old agents both as first and second line treatment with the outcome of patients who received old agents as first treatment and novel agents as second line treatment, to assess the impact of novel agents in real life MM patients' management. Results: The OS at 5 years for patients of group 2 was significantly higher than that of group 1 patients (41.6% vs 14.1%); even at 10 years, the OS was significantly better for group 2 (20.4% vs 2.4%, p Conclusions: We analyzed the effect of the introduction of novel agents in a cohort of young MM patients treated at our Center over a 25-year period, between 1989 and 2014. Patients treated in the earlier years received old agents both as first and second line treatment, while in more recent years all patients who experienced a relapse were treated with novel agents as second line treatment. Our analysis underlines that patients receiving novel agents witnessed a significantly better OS and PFS compared to patients treated only with old agents. When focusing on PFS2, we could determine that the duration of response obtained with proteasome inhibitors and IMiDs was significantly longer than that obtained with conventional chemotherapy. This currently ongoing study and a longer follow-up in a larger number of group 4 patients will allow to conclusively define the true real life impact of novel agents when used both as first and second line treatment for the management of young MM patients. Disclosures Petrucci: Celgene, Janssen-Cilag, Amgen, Mundipharma, BMS: Honoraria.