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In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality–infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01–0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality.

Infections represent one of the most frequent complications during the treatment of patients with Acute Lymphoblastic Leukemia (ALL): of these, almost half develop an infectious event in the majority of cases in induction. The new monoclonal and bispecific antibodies and CAR-T, besides offering new perspectives in the overall survival and disease-free survival of patients, may also transform the epidemiology of infections in ALL by improving the toxicity of treatments. In this review, we examined studies published in the literature over the past 12 years and described the infectious complications of therapy with Blinatumomab, Inotuzumab, Rituximab and CAR-T in adult and pediatric patients with ALL. Infections are less frequent than in traditional chemotherapy treatment with vincristine, corticosteroids and anthracyclines, which has been the backbone of therapy for patients with ALL for years. On the other hand, the infection scenario in the CAR-T setting is quite peculiar: In these patients, infections are more frequent in the first month after infusion and are predominantly bacterial. As the time moves away from day zero, viral infections become more frequent, occurring mainly in patients who have had prolonged cytopenia and major cytokine release syndrome.

Elderly patients represent the most challenging and hard-to-treat patient population due to dismal characteristics of the disease, such as secondary-acute myeloid leukemia (AML), enrichment of unfavorable molecular genes (TP53) and comorbidities. We conducted a multicentric retrospective study to evaluate activity and safety in a real-life setting of hypomethylating drugs (HMAs) in patients older than 75 years with AML. Between September 2010 and December 2021, 220 patients were treated, 164 (74.5%) received AZAcitidine and 56 DECitabine; most patients (57.8%), received more than four cycles of HMAs. The best response obtained was CR in 51 patients (23.2%), PR in 23 (10.5%) and SD in 45 (20.5%); overall transfusion independence was obtained in 47 patients (34%), after a median of 3.5 months. The median OS (mOs) was 8 months (95% CI 5.9–10.2), with 1- and 2-years OS of 39.4% (95% CI 32.7–46) and 17.4% (95% CI 11.7–23.1), respectively; similar mOS was observed according to HMA treatment (AZA 8.3 vs. DEC 7.8 months, p = 0.810). A subset of 57 long survivors (44 in AZA group and 13 in DEC group) received at least 12 cycles of HMAs, their mOS was 24.3 months. In multivariate analysis, age (≥80), Charlson comorbidity index (≥3), creatinine clearance and the type of best response (≥PR) during treatment maintained independent significance in predicting survival. Infectious complications, most frequently pneumonia (35) and septic shock (12), were lethal in 49 patients (22.2%). Our data show that HMAs have similar efficacy compared to pivotal trials and are well tolerated in a setting of very elderly patients with several co-comorbidities.

We compared the efficacy of azacitidine (AZA) and decitabine (DEC) in elderly patients with untreated AML, diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS) and disease free survival (DFS). The AZA and DEC groups included 139 and 186 patients, respectively. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 136 patient pairs. In the AZA and DEC cohort, median age was 75 years in both, (IQR, 71–78 and 71–77), median WBCc at treatment onset 2.5x109/L (IQR, 1.6–5.8 ) and 2.9x 109/L (IQR, 1.5–8.1), median bone marrow (BM) blast count 30% (IQR, 24–41%) and 49% (IQR, 30–67%), 59 (43%) and 63 (46%) patients had a secondary AML, respectively. Karyotype was evaluable in 115 and 120 patients: 80 (59%) and 87 (64%) had intermediate-risk, 35 (26%) and 33 (24%) an adverse risk karyotype, respectively. Median number of cycles delivered was 6 (IQR, 3.0–11.0) and 4 (IQR, 2.0–9.0), CR rate was 24% vs 29%, median OS and 2-year OS rates 11.3 (95% CI 9.5–13.8) vs 12.0 (95% CI 7.1–16.5) months and 20% vs 24%, respectively. No differences in CR and OS were found within the following subgroup: intermediate- and adverse-risk cytogenetic, frequency of WBCc at treatment ≥ 5x10^9L and

Aims: To define the peculiar features of patients with the deletion of the chromosome 20 long arm (del20q), data from 69 patients with myelodysplastic syndromes (MDSs) and isolated del20q, followed by the Gruppo Romano-Laziale Sindromi Mielodisplastiche (GROM-L) and Ospedale Torrette of Ancona, were collected and compared with those of 502 MDS patients with normal karyotype (NK-MDS). Results: Compared to the NK-MDS group, patients with del20q at diagnosis were older (p = 0.020) and mainly male (p = 0.006). They also had a higher rate of bone marrow blast < 5% (p = 0.004), a higher proportion of low and int-1 risk according to IPSS score (p = 0.023), and lower median platelet (PLT) count (p < 0.001). To date, in the del20q cohort, 21 patients (30.4%) received no treatment, 42 (61.0%) were treated with erythropoiesis-stimulating agents (ESA), 3 (4.3%) with hypomethylating agents, and 3 (4.3%) with other treatments. Among 34 patients evaluable for response to ESA, 21 (61.7%) achieved stable erythroid response according to IWG 2006 criteria and 13 (38.2%) were resistant. Nine patients (13.0%) progressed to acute myeloid leukaemia (AML) after a median time from diagnosis of 28 months (IR 4.1–51.7). The median overall survival (OS) of the entire cohort was 60.6 months (95% CI 54.7–66.4). the 5-year cumulative OS was 55.9% (95% CI 40.6–71.2). Conclusion: According to our results, we hypothesize that MDSs with isolated del 20q may represent a distinct biological entity, with peculiar clinical and prognostic features. The physio-pathological mechanisms underlying the deletion of the chromosome 20 long arm are still unclear and warrant future molecular analysis.

BACKGROUND Acute myeloid leukaemia (AML) patients are at high risk of invasive aspergillosis (IA) after first induction chemotherapy (CHT). Although IA risk factors have been identified, few data are available on impact of IA, occurring during induction phase, on overall AML outcome. PATIENTS AND RESULTS The end point of this multicentre, case-control, study was to evaluate whether IA, occurring after first induction CHT, can affect treatment schedule and patient's outcome. We identified 40 AML patients (cases) who developed IA during first induction phase, 31 probable (77.5%) and 9 proven (22.5%). These cases were matched with a control group (80 AML) without IA, balanced according to age, type of CHT, AML characteristics and cytogenetic-molecular risk factors. The overall response rate to induction CHT was the same in the 2 groups. In the 40 cases with IA, the overall response rate to antifungal treatment was favourable (80%) but it was significantly affected by the achievement of leukaemia complete remission (CR) with induction CHT. In fact, in cases with AML responsive to induction CHT, responses of IA to antifungal therapy were 96% compared to 21% in cases of AML not responsive to induction treatment (P

COVID-19 continues to be a relevant issue among patients with haematological malignancies (HM). Vaccines are frequently not effective in subjects on active treatment. In this multicentre retrospective study of Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA), we collected data from 91 paucisymptomatic HM patients treated with anti-spike neutralizing monoclonal antibodies (nMoAbs) to determine time to viral clearance, referencing it to the expected value of 28 days from an historical group of untreated paucisymptomatic patients. Secondary endpoints included rate of hospitalization, intensive care unit (ICU) admission, COVID-19 related death and safety. SARS-CoV-2 molecular swab negativity was obtained in 86 patients (95%), with a median time of 18 days (IQR 13-26; p 0.0001). We did not find significant variations according to age, diagnosis, treatment type, vaccination status or nMoAbs type. Rate of hospitalization due to COVID-19 progression was 12% (11/91), with 2 patients (2.2%) requiring ICU admission. With a median follow-up of 2.33 months, the overall mortality was 5.5% (5/91), with 3 deaths due to COVID-19. Side effects were rare and self-limiting. Our data suggest that nMoAbs can limit the detrimental effect of immunosuppressive treatments on COVID-19 clinical progression and time to viral clearance. The original trial was registered at www.clinicaltrials.gov as #NCT04932967.

The incidence, risk factors, and prognostic significance of extramedullary involvement (EMI) in adult patients with acute myeloid leukemia (AML) have not been established yet. This study analyzed clinical and biological characteristics, the impact on prognosis, and the cumulative incidence of EMI in a monocentric retrospective series. All adult patients diagnosed with AML observed in our institution between January 2010 and December 2017 were included in the analysis. Overall, 346 AMLs were analyzed. The incidence of EMI was 11% (38 patients). The involved sites were: skin (66%), central nervous system (CNS) (23%), pleura (7%), lymph nodes (5%), peritoneum (2%), spleen (2%), pancreas (2%), breasts (2%) and bones (2%). Most patients (91%) had only one EMI site, while 9% had multiple sites affected at the same time. Twenty-four (63%) patients showed signs of EMI at presentation, while extramedullary relapse occurred in 10 patients (26%); 4 patients had EMI both at presentation and relapse. EMI had a significantly higher frequency in patients with monocytic and myelo-monocytic leukemia subtypes (p

Invasive fungal infection (IFI) remains the major complication in patients with either acute leukemia, allogeneic stem cell transplantation setting, or both, especially regarding pulmonary localization. We report an experience of a 74-year-old Caucasian male with a Philadelphia-positive (BCR-ABL p190) Common B-acute lymphoblastic leukemia (ALL) who developed a pulmonary infection due to Geosmithia argillacea. Furthermore, we describe the management of this complication and the results of microbiological tests useful to guide the treatment. All cases reported show failure of voriconazole treatment. In the majority of cases a good susceptibility to posaconazole has been reported, which seems to have a good clinical impact; however, only L-AmB shows a clinical effect to produce quick clinical improvement and so it should be a drug of choice. A literature revision shows that only a few papers have thus far described this infection, at present only one case was reported in a hematological setting like a gastrointestinal graft versus host disease in an allogeneic HSCT recipient. The severity of clinical conditions in hematological malignancy settings requires improving the management of this emerging invasive fungal infection. Indeed, a molecular diagnostic approach with a tight laboratory collaboration and targeted therapy should become the gold standard.

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a twostage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk., Instituto de Salud Carlos III PI17/02276, ERA-NET PathoGenoMics PIM2010EPA-00756 0315900A, Collaborative Research Center/Transregio 124 FungiNet, Portuguese Foundation for Science and Technology PTDC/SAU-SER/29635/2017 PTDC/MED-GEN/28778/2017 CEECIND/03628/2017 CEECIND/04058/2018, European Union (EU) 847507, La Caixa Foundation ID 100010434, Portuguese Foundation for Science and Technology LCF/PR/HP17/52190003, PI20/01845, PI12/02688

PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion–dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.

Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.

We aimed to compare fatigue of newly diagnosed patients with myelodysplastic syndromes (MDS) with that of the general population (GP). We also investigated the ability of the IPSS and IPSS-R to capture severity of patient-reported fatigue at diagnostic workup. A sample of 927 newly diagnosed patients with MDS was consecutively enrolled in a large international observational study and all patients completed the FACIT-Fatigue questionnaire at baseline. Fatigue was compared with that of the GP (N = 1075) and a 3-point difference in mean scores was considered as clinically meaningful. Fatigue of MDS patients was on average 4.6 points below the mean of the GP (95% CI, −5.9 to −3.2, p < 0.001), reflecting clinically meaningful worse fatigue. Unlike the IPSS, the IPSS-R identified clearly distinct subgroups with regard to burden of fatigue. Mean scores differences compared with GP ranged from nonclinically relevant for very low risk (Δ = −1.8, 95% CI, −4.0 to 0.5, p = 0.119) to large clinically meaningful differences for very highrisk IPSS-R patients (Δ = −8.2, 95% CI, −10.3 to −6.2, p < 0.001). At diagnostic workup, fatigue of MDS is clinically meaningful worse than that reported by the GP. Compared with the IPSS classification, the IPSS-R provides a better stratification of patients with regard to fatigue severity.

Thrombocytopenia is a severe complication for patients with myelodysplastic syndrome (MDS). Eltrombopag increases platelet count in MDS patients but its combination with azacitidine elicited controversial results. We aimed to quantify the colony forming units of megakaryocytes (CFU-Mk) obtained from CD34+ bone marrow cells isolated from patients with MDS and from healthy donors that were cultured in vitro in the presence or absence of azacitidine and with or without the sequential addition of eltrombopag to the culture medium. CD34+ bone marrow cells from 6 MDS patients and 3 controls were expanded in vitro and cultured for 3 days with or without azacitidine. Subsequently, a CFU-Mk assay was performed in presence or absence of eltrombopag. The addition of eltrombopag in the CFU-Mk assay after mock treatment of CD34+ cells increased the number of CFU-Mk in both controls and patients. On the contrary, using azacitidine pretreated CD34+ cells, eltrombopag minimally increased CFU-Mk in controls and produced heterogeneous response in MDS patients with no change in two patients and CFU-Mk increase in four patients. In vitro CFU-Mk assay suggest that some MDS patients are likely to benefit from the sequential addition of eltrombopag after azacitidine treatment, in the context of a personalized medicine.

We are deeply grateful to the study participants. We also thank Astella Pharma Inc. and Mrs. Consuelo González Moreno (AML survivor) for supporting this work., The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk., Astella Pharma Inc., Instituto de Salud Carlos III PI12/02688 PI17/02276, Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) NORTE-01-0145-FEDER-000013, Portuguese Foundation for Science and Technology CEECIND/04601/2017 CEECIND/03628/2017, Astellas Pharmaceuticals

Luana Fianchi,1 Marianna Criscuolo,1 Emiliano Fabiani,2 Giulia Falconi,2 Alessio Maria Edoardo Maraglino,1 Maria Teresa Voso,2 Livio Pagano1 1Department of Radiological Sciences, Radiotherapy, and Hematology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy; 2Department of Biomedicine and Prevention, Università di Roma Tor Vergata, Rome, Italy Abstract: Therapy-related myeloid neoplasms (t-MNs) are a complication of cytotoxic treatment for primary tumors and autoimmune diseases. t-MNs result from a complex interaction between individual predisposition and exposition to toxic agents. Some different biological and clinical characteristics can be recognized according to the type of anticancer drug. Compared to de novo myeloid neoplasms, prognosis of t-MN is dismal. Age and karyotype are the most important prognostic factors for t-MN, which should be treated with frontline chemotherapy treatments that are appropriate for patients with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) with similar disease characteristics. Allogeneic stem cell transplantation should be considered particularly for unfavorable karyotypes and younger patients with aggressive disease. Keywords: therapy-related myeloid neoplasm, leukemia, prognosis, secondary leukemia, secondary myelodysplastic syndrome

We performed a retrospective analysis of 88 adult patients with B-ALL diagnosed in our center by a flow-cytometric assessment. Immunophenotypic expression of leukemic cells was explored by simultaneous evaluation of positivity, percentage of expressing cells and median fluorescence intensity (MFI). BCR/ABL1 fusion transcripts were assessed by RT-PCR analysis and were identified in 36 patients (40.9%). CD10 and CD34 were positive in the totality of BCR/ABL1-positive cases. Patients with gene rearrangement had a greater frequency of CD66c, CD13 and CD33 positivity compared with BCR/ABL1-negative cases. Moreover, BCR/ABL1-positive cases exhibited a greater median percentage and MFI values of CD13, CD33, CD66c, CD10, CD34 and CD25 expressions, but a lower median percentage and MFI values of CD38 and CD22 expressions than patients without gene rearrangement. Multivariate logistic regression analysis showed that CD10, CD38 and CD13 expressions were independent predictors for the presence of BCR/ABL1 rearrangement. Predictive probabilities of molecular occurrence based on these markers are proposed. © 2017 International Clinical Cytometry Society.

Background Current prognostic systems for myelodysplastic syndromes (MDS) are based on clinical, pathologic, and laboratory indicators. The objective of the current study was to develop a new patient-centered prognostic index for patients with advanced MDS by including self-reported fatigue severity into a well-established clinical risk classification: the International Prognostic Scoring System (IPSS). Methods A total of 469 patients with advanced (ie, IPSS intermediate-2 or high-risk) MDS were analyzed. Untreated patients (280 patients) were recruited into an international prospective cohort observational study to create the index. The index then was applied to an independent cohort including pretreated patients with MDS from the Dana-Farber Cancer Institute in Boston, Massachusetts (189 patients). At baseline, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Results A new prognostic index was developed: the FA-IPSS(h), in which FA stands for fatigue and h for higher-risk. This new risk classification enabled the authors to distinguish 3 subgroups of patients with distinct survival outcomes (ie, risk-1, risk-2, and risk-3). Patients classified as FA-IPSS(h) risk-1 had a median overall survival (OS) of 23 months (95% confidence interval [95% CI], 19-29 months), whereas those with risk-2 had a median OS of 16 months (95% CI, 12-17 months) and those with risk-3 had a median OS of 10 months (95% CI, 4-13 months). The predictive accuracy of this new index was higher than that of the IPSS alone in both the development cohort as well as in the independent cohort including pretreated patients. Conclusions The FA-IPSS(h) is a novel patient-centered prognostic index that includes patients' self-reported fatigue severity. The authors believe its use might enhance physicians' ability to predict survival more accurately in patients with advanced MDS. Cancer 2018;124:1251-9. © 2017 American Cancer Society.

Introduction: The outcome of patients with acute myeloid leukemia (AML) secondary to myelodisplastic syndrome (MDS) or therapy-related (t-AML) receiving conventional treatment and allogeneic stem cell transplantation consolidation (HSCT) is poor. CPX-351 is a new drug composed by liposomal encapsulated cytarabine and daunorubicin, at a fixed molecular ratio of 5:1. It showed superior results, compared to standard 3+7 induction, in a phase III trial (Lancet et al, JCO 2018) in patients affected by t-AML or AML with myelodisplasia-related changes and it is now commercially available for secondary AML (sAML). We recently published results from CPX-351 Italian Named (Compassionate) Use Program (CUP) which enrolled 73 elderly sAML patients (Guolo et al, Blood Cancer J. 2020) showing that CPX-351 is an effective induction regimen for high risk AML patients treated with a curative aim. With a limited follow up, our data suggested the good activity and tolerability of CPX-351. Good quality remissions with acceptable toxicity in the majority of patients was achieved and CPX-351 increased the feasibility of HSCT in a poor risk AML cohort. Scarce data are available on long term outcome of high risk patients receiving CPX-351 in the real life setting. Here we report the results from the extended follow up analysis of the Italian CUP. Results: Seventy three patients were enrolled between December 2018 and June 2019 in a compassionate use program (CUP) in 33 Italian Hematology Centers. Data collection began on July 2019 and included 71/73 patients (97.2%), enrolled in 31 Centers. As previously reported, median age was 65.5 years (52-79). Sixty-two (88%) patients had at least one relevant comorbidity upon enrollment. Six patients (9%) presented with ECOG 3-4 upon enrollment. With a median follow up of 22 months, median overall survival (OS) was 13 months (21.2 - 22.8 95% IC). Two-years OS was 28.6% in the whole cohort. In order to confirm the positive impact of HSCT in first complete remission (CR) and the correlation with the other variables, a landmark model was applied, including only patients alive and in CR at day 90. In landmark analysis, HSCT performed in first CR after CPX-351 was the only significant predictor of longer survival: median OS was not reached for patients transplanted in first CR Vs 12 months for patients who did not undergo HSCT, p < 0.05, Figure1). Two-year OS for patients who received HSCT was 57.6% vs 15.8% for patients who did not undergo HSCT. Conclusions: Results from the extended follow up of Italian CPX-351 CUP confirm the good activity CPX-351 in such a difficult cohort as sAML. Two-year OS for transplanted patients is high despite the high median age, the high frequency of severe comorbidities in this real life cohort of patients and the high frequency of high risk AML. On the contrary, non-transplanted patients show a poor outcome, thus confirming that CPX-351 induction as an optimal bridge to transplant induction therapy. Figure 1 Figure 1. Disclosures Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Marco: Insight,: Consultancy; Jazz: Consultancy; Janssen: Consultancy. Fracchiolla: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Speakers Bureau. Tafuri: Roche: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Rossi: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Pagano: Gilead Science, MSD, Pfizer, Basilea, Janssen, Novartis, Jazz Pharmaceutical, Cidara: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Gilead Sciences, MSD, Pfizer Pharmaceuticals, Astellas Pharma: Speakers Bureau.

Background: In ‘real-life', the Nordic score guides ESA use in lower-risk MDS with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed. Objectives: To validate existing ESA predictive scores and develop a new score that identifies non-responders. Methods: ESA-treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, MDS-CAN 208). Clinical and disease-related variables were captured. Nordic, MDS-CAN and IPSS-R-based ESA scores were calculated and documented ESA responses compared. Results: 996 ESA-treated patients were identified. Overall response rate(ORR) was 59%. The database was randomly divided into balanced derivation (n=463) and validation (n=462) cohorts. By multivariate analysis, transfusion independence, erythropoietin level