International Prognostic Scoring System Risk Research Articles

Risk factors and a prognostic model for postsplenectomy survival in myelofibrosis.

Palliative treatment in myelofibrosis (MF) includes transfusion support, JAK2 inhibitors, involved field radiotherapy and splenectomy. To assist in selecting patients who are likely to benefit from splenectomy, we looked into risk factors for postsplenectomy survival, in 120 consecutive cases (median age 66 years); at the time of splenectomy, 61% displayed red cell transfusion need, 49% platelet count <100 × 10(9)/L, 25% leukocyte count >25 × 10(9)/L, 60% constitutional symptoms and 13% circulating blasts ≥5%; dynamic international prognostic scoring system risk categories were 21% high, 55% intermediate-2, 21% intermediate-1 and 3% low. Among informative cases, karyotype was abnormal in 60% and driver mutational status was JAK2 75%, CALR 15%, MPL 4% and triple-negative 6%. At median follow-up of 1.3 years, from time of splenectomy, 95 (79%) deaths and 30 (25%) leukemic transformations were recorded. Median postsplenectomy survival was 1.5 years; in multivariable analysis, survival was adversely affected by age >65 years, transfusion need, leukocyte count >25 × 10(9)/L and circulating blasts ≥5%; these variables were subsequently used to devise an HR-weighted scoring system with high (3-4 risk factors), intermediate (2 risk factors) and low (0-1 risk factors) risk categories; the corresponding postsplenectomy median survivals were 0.3 (HR 5.9, 95% CI 3.2-11.0), 1.3 (HR 2.9, 95% CI 1.8-4.6) and 2.9 years. Postsplenectomy survival was not affected by driver mutational status or occurrence of leukemic transformation. Leukemia-free survival was predicted by very high risk karyotype. The observations from the current study might help identify appropriate candidates for splenectomy in MF.

Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis.

Analyses suggest iron overload in red blood cell (RBC) transfusion-dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient-related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient-related factors. TD International Prognostic Scoring System (IPSS) low and intermediate-1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease-modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non-ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1years; P<0·0001). By multivariate analysis, not receiving ICT independently predicted inferior OS, (hazard ratio for death 2·0, P=0·03). In matched pair analysis, OS remained superior for ICT patients (P=0·02). In this prospective, non-randomized analysis, receiving ICT was associated with superior OS in lower IPSS risk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease-modifying agents. This provides additional evidence that ICT may confer clinical benefit.

Abstract 2776: Genetic correlations with clinical response to ASTX727 in patients with myelodysplastic syndromes (MDS)

Abstract DNA methyltransferase inhibitors (DNMTis) have been shown to alter the natural history of MDS and reduce related complications; however, many patients do not respond to DNMTi therapy or progress with limited effective secondary options. Therefore, the ability to preselect which patients are most likely to respond to DNMTis would be useful in personalizing MDS therapy. Earlier reports noted a trend toward improved response to therapy in the presence of somatic TET2 mutations (Bejar et al, 2014), and lower response rates in patients with mutations in DNMT3A (Ley et al, 2010). Treatment with the DNMTi decitabine (DAC) requires 5 daily parenteral doses every month administered in the clinic. An orally administered DNMTi provides convenience with the potential for improved compliance, and allows for exploration of different extended dosing schedules which could produce alternative methylation of the genome and improve clinical response. DAC is not readily orally bioavailable due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDA inhibitor, is orally bioavailable with an excellent safety profile in preclinical models. ASTX727 is a combination of E7727 and DAC, and has completed phase 1 dose escalation of 44 MDS or CMML patients in which pharmacokinetic (PK) and pharmacodynamic (PD) parameters of DAC were replicated with the oral agent. During the dose escalation portion of the Phase 1 trial of ASTX727, bone marrow aspirates were obtained pre- and post- treatment from 28 patients (13 clinical responders), and genomic DNA from marrow cells was isolated for next-generation sequencing (NGS) with a panel of 37 myeloid neoplasia-associated genes. Consistent with previous reports, DNMT3A mutations were associated with poor response to ASTX727 (all 4 carriers failed therapy, P = 0.028). Conversely, of the 10 patients with TET2 mutations, a majority responded to treatment (6/10, P=0.444). ASXL1 mutations showed a complex combinatorial effect, as all three ASXL1-mutated patients with BCOR mutations, regardless of International Prognostic Scoring System (IPSS) risk category, were non-responders while all 3 patients ASXL1 who also carried a TET2 mutation responded. ASTX727 is an oral DNMTi that revealed responses in this dose escalation Phase I study exhibiting a similar pharmacokinetic profile and achieving AUC range of IV DAC. As previously observed with DAC, ASTX727 may lead to improved responses in patients with specific gene mutations. This work shows preliminary effects on mutational burden and allele frequency concurrent with activity of ASTX727. Further analyses of patients treated at the RP2D in the Phase 2 trial are ongoing. Citation Format: Haley E. Ramsey, Shilin Zhao, Yaomin Xu, Olatoyosi Otoyosi, Philip Amrein, Amy Dezern, Laura Michaelis, David P. Steensma, Stefan Faderl, Guillermo Garcia-Manero, James Lowder, Pietro Taverna, Michael R. Savona. Genetic correlations with clinical response to ASTX727 in patients with myelodysplastic syndromes (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2776. doi:10.1158/1538-7445.AM2017-2776

Clinical characteristics and outcomes according to age in lenalidomide-treated patients with RBC transfusion-dependent lower-risk MDS and del(5q)

BackgroundParticularly since the advent of lenalidomide, lower-risk myelodysplastic syndromes (MDS) patients with del(5q) have been the focus of many studies; however, the impact of age on disease characteristics and response to lenalidomide has not been analyzed.MethodsWe assessed the effect of age on clinical characteristics and outcomes in 286 lenalidomide-treated MDS patients with del(5q) from two multicenter trials.ResultsA total of 33.9, 34.3, and 31.8% patients were aged <65 years, ≥65 to <75 years, and ≥75 years, respectively. Age <65 years was associated with less favorable International Prognostic Scoring System (IPSS) risk and additional cytopenias at baseline versus older age groups, significantly lower cytogenetic response rates (p = 0.022 vs. ≥65 to <75 years; p = 0.047 vs. ≥75 years), and higher rates of acute myeloid leukemia (AML) progression (Gray’s test, p = 0.013). Lenalidomide was equally well tolerated across age groups, producing consistently high rates of red blood cell transfusion independence ≥26 weeks.ConclusionsBaseline disease characteristics and AML progression appear to be more severe in younger lower-risk MDS patients with del(5q), whereas older age does not seem to compromise the response to lenalidomide.Trial registrationClinicalTrials.gov NCT00065156 and NCT00179621

Presentation and outcome of patients with 2016 WHO diagnosis of prefibrotic and overt primary myelofibrosis

AbstractThe 2016 revision of the World Health Organization (WHO) classification of myeloproliferative neoplasms defines 2 stages of primary myelofibrosis (PMF): prefibrotic/early (pre-PMF) and overt fibrotic (overt PMF) phase. In this work, we studied the clinical and molecular features of patients belonging to these categories of PMF. The diagnosis of 661 PMF patients with a bone marrow biopsy at presentation was revised according to modern criteria; clinical information and annotation of somatic mutations in both driver and selected nondriver myeloid genes were available for all patients. Compared with pre-PMF, overt PMF was enriched in patients with anemia, thrombocytopenia, leukopenia, higher blast count, symptoms, large splenomegaly, and unfavorable karyotype. The different types of driver mutations were similarly distributed between the 2 categories, whereas selected mutations comprising the high mutation risk (HMR) category (any mutations in ASXL1, SRSF2, IDH1/2, EZH2) were more represented in overt PMF. More patients with overt PMF were in higher International Prognostic Scoring System risk categories at diagnosis, and the frequency increased during follow-up, suggesting greater propensity to disease progression compared with pre-PMF. Median survival was significantly shortened in overt PMF (7.2 vs 17.6 years), with triple negativity for driver mutations and presence of HMR mutations representing independent predictors of unfavorable outcome. The findings of this “real-life” study indicate that adherence to 2016 WHO criteria allows for identification of 2 distinct categories of patients with PMF where increased grades of fibrosis are associated with more pronounced disease manifestations, adverse mutation profile, and worse outcome, overall suggesting they might represent a phenotypic continuum.

An miRNA–DNMT1 Axis Is Involved in Azacitidine Resistance and Predicts Survival in Higher-Risk Myelodysplastic Syndrome and Low Blast Count Acute Myeloid Leukemia

Purpose: Azacitidine inhibits DNA methyltransferases, including DNMT1, and is currently the standard of care for patients with higher-risk myelodysplastic syndrome (HRMDS) or low blast count acute myeloid leukemia (AML).Experimental Design: The expression of 754 miRNAs was compared in azacitidine-resistant and azacitidine-sensitive myelodysplastic syndrome cells. We investigated the role of differentially expressed miRNAs on DNMT1 expression and azacitidine resistance in vitro We next evaluated anti-DNMT1 miRNA expression in pretreatment bone marrow samples derived from 75 patients treated with azacitidine for HRMDS or AML.Results: Seven miRNAs, including 5 that in silico targeted the DNMT1 3' UTR, were repressed in azacitidine-resistant cells in which DNMT1 protein levels were significantly higher. Ectopic anti-DNMT1 miRNA expression decreased DNMT1 expression and increased azacitidine sensitivity, whereas specific inhibition of endogenous anti-DNMT1 miRNAs increased DNMT1 expression and triggered azacitidine resistance. In patients treated with azacitidine, decreased expression of anti-DNMT1 miRNAs was associated with poor outcome. miR-126* had the strongest prognostic impact. Patients with miR-126*low myelodysplastic syndrome had significantly lower response rates (P = 0.04) and higher relapse rates (P = 0.03), as well as shorter progression-free (PFS; P = 0.004) and overall survival (OS; P = 0.004). Multivariate analysis showed that age, miR-126* expression, and revised International Prognostic Scoring System risk independently predicted PFS and OS. In 15 patient samples collected over time, decreased miRNA expression levels were associated with secondary resistance.Conclusions: A decreased expression of anti-DNMT1 miRNAs might account for azacitidine resistance in HRMDS and AML, and measuring miRNA expression before and during treatment might help predict primary or secondary azacitidine resistance. Clin Cancer Res; 23(12); 3025-34. ©2016 AACR.

Efficacy and safety of ruxolitinib in intermediate-1 IPSS risk myelofibrosis patients: Results from an independent study.

Patients with myelofibrosis at intermediate-1 risk according to the International Prognostic Score System are projected to a relatively long survival; nonetheless, they may carry significant splenomegaly and/or systemic constitutional symptoms that hamper quality of life and require treatment. Since registrative COMFORT studies included only patients at intermediate-2/high International Prognostic Score System risk, safety and efficacy data in intermediate-1 patients are limited. We report on 70 intermediate-1 patients treated with ruxolitinib according to standard clinical practice that were evaluated for response using the 2013 IWG-MRT criteria. At 6months, rates of spleen and symptoms response were 54.7% and 80% in 64 and 65 evaluable patients, respectively. At 3months, ruxolitinib-induced grade 3 anemia and thrombocytopenia occurred in 40.6% and 2.9% of evaluable patients, respectively. Notably, 11 (15.9%) patients experienced at least one infectious event ≥grade 2. Most (82.6%) patients were still on therapy after a median follow-up of 27months. These data support the need for standardized guidelines that may guide the decision to initiate ruxolitinib therapy in this risk category, balancing benefit expectations and potential adverse effects.

Azacitidine and Lenalidomide (Combined vs Sequential Treatment) in Higher-Risk Myelodysplastic Syndromes. Long-Term Results of a Randomized Phase II Multicenter Study

▪Introduction. Azacitidine (AZA) is the standard of care of higher-risk myelodysplastic syndromes (MDS), but the duration of clinical response is limited, and outcome after AZA failure is dismal. Several studies have demonstrated the efficacy and safety of combining AZA with Lenalidomide (LEN), either administered concurrently or sequentially, however the optimum dose and schedule for this combination remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts (IPSS score risk: High or INT-2), and to look for possible biomarkers able to predict response. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8.5 (1-37) cycles; in ARM 1: 9 (1-32) cycles, in ARM 2: 8 (1-37) cycles, respectively. 6 pts (ARM 1: 2; ARM 2: 4) are still on treatment. Pts have been followed for a median of 15 (2-37) months for all subjects, for a median of 32 (18-37) months for survivors. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. The median duration of hematologic response was 10.5 months. A grade > 2 non hematologic toxicity was observed in 54.5 % of pts, and an emerging (from grade 0-2 to > 2) hematologic toxicity in 27.3% of pts. In 61.4% of pts LEN dose was reduced because of hematologic or non-hematologic toxicity. 32 pts (72.7%) died , and 17 pts (38.6%) showed progression to AML. Median overall survival (OS) was 15 months. No significant differences between the 2 arms were observed, in terms of ORR, CR rate, toxicity, AML incidence and OS, but there was a trend (although still not significant) towards a longer median duration of response in the sequential arm: ARM 1: 6 months; ARM 2: 18 months (p=0.0847). MDS cells showed alterations of the inositide-dependent signalling as well as an altered microRNA profile. In particular, responder cases showed a frequent downregulation of miR-3613 and mir-4668, that were upregulated in non responder cases. Further analyses are ongoing. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR, although the sequential schedule seems to induce more durable responses. Moreover, possible relationships with signal transduction pathways and microRNA profile are under evaluation. DisclosuresFinelli:Novartis: Other: Speaker fees; Celgene: Other: Speaker fees; Celgene: Research Funding. Gobbi:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Roche: Honoraria; Takeda: Consultancy; Gilead: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study

Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study

Impact of Comorbidities and Body Mass Index in Myelofibrosis Patients Treated with Ruxolitinib: A Retrospective Analysis

Background: Comorbidities and body mass index (BMI) are significantly associated with outcome in patients (pts) who receive continue treatment with tyrosine kinase inhibitors (TKIs), such as in Ph+ leukemias. Ruxolitinib (RUX) is the first JAK1/2 inhibitor that may induce spleen/symptom responses and improve quality of life in pts with myelofibrosis (MF). Up-to-date, no data are available on the impact of comorbidities and BMI on pts treated with RUX.Aims: To evaluate the impact of comorbidities and BMI on responses, overall survival (OS) and maintenance of RUX dose in a large cohort of pts.Methods: Data were extracted from an electronic database that included retrospective data on pts treated before January 2015 in 16 Italian Hematology centers. Response to RUX was evaluated according to IWG-MRT criteria. BMI was calculated at the time of start of RUX and classified according to WHO criteria. Comorbidities were recorded at the time of start of RUX and classified according to the Charlson Comorbidity Index (CCI). Overall survival (OS) was calculated from the date of RUX start to the time of death or to last follow-up, whichever came first.Results: Between June 2011 and Apr 2016, 289 pts with PMF (52.6%), or PET-MF (17%) or PPV-MF (30.4%) were treated with RUX in participating Centers. At RUX start, median age was 68.4 years (range 39-89) with a male prevalence (56.4%); International Prognostic Score System (IPSS) was intermediate (intm)-1 (15.6%), intm-2 (45.3%), high (39.1%). Transfusion dependence and spleen enlargement were present in 26.6% and 96.9% of pts, respectively (69.6% with spleen≥ 10 cm). Median total symptom score (TSS) was 20 (range 0-70). JAK2V617F was present in 80.3% of 234 evaluable pts. Median follow-up from MF diagnosis was 3.8 yr (range 0.3-29.6) and median RUX exposure was 20 months (3-56.2).Overall, comorbidities were evaluable in 275 pts. CCI stratification showed the absence of comorbidities in 100 pts (36.4%), one comorbidity in 63 pts (22.9%) and two or more in 112 pts (40.7%). Compared to pts with CCI <2, pts with CCI ≥2 were more frequently: male (66.1% vs 49.1%, p=0.005), ≥65y (74.1% vs 54%, p=0.001), at intm2/high IPSS risk (90.2% vs 81%, p=0.03) and transfusion-dependent (36.6% vs 20.2%, p=0.003). Notably, the percentage of pts starting RUX >2y from MF diagnosis was lower if CCI≥2 (33.9% vs 54%, p=0.001).Higher CCI did not correlate with lower spleen response (achieved by 45.2% vs 34.7%, p=0.09), TSS response (90.1% vs 83.2%, p=0.11), and higher incidence of RUX-induced anemia (Hb <10 g/dl in pts with baseline Hb ≥10 g/dl) (48% vs 41%, p=0.33). RUX starting and titrated doses at 12-wks were similar in the two groups (p=0.44 and p=0.81, respectively).OS was significantly higher in pts with CCI<2 (96.7% vs 87.8% at 2 yr, p<0.001). After stratification according to CCI (below or above 2) and the achievement of a spleen response, both factors remained significantly associated with survival. Indeed, in pts with CCI<2 OS at 2 yr was 92.7% and 79.1%, depending on the achievement of a spleen response (SR) or not (NR), respectively (p=0.034). Analogously, in pts with CCI≥2 the achievement of a spleen response significantly increased survival (79.2% vs 55.3% in pts without spleen response, p=0.011). Notably, OS was comparable in pts with lower CCI /no spleen response and in pts with higher CCI/spleen response (79.1% vs 79.2%) (Figure 1).BMI was evaluable in 269 pts: 169 pts (62.8%) were classified as under-weight/normal for a BMI <25, whereas 100 pts were overweight/obese (BMI ≥25). Pts with BMI≥25 were more frequently male (71% vs 47.3%, p<0.001) and with a lower incidence of anemia (30% vs 42%, p=0.049). BMI stratification did not correlate with differences in spleen response (p=0.83) and TSS (p=0.18) or onset of anemia/infections during treatment (p=0.49 and p=0.28). Starting and median doses, as well as percentage of pts reducing RUX dose over time, were similar in the two groups.Summary: In MF pts treated with RUX, BMI and comorbidities did not influence the achievement of spleen/symptom responses, maintenance of RUX dose or onset of drug-related anemia. Although CCI stratification correlated with survival, as in Ph+ leukemias treated with TKIs, the achievement of a spleen response was able to counterbalance the negative prognostic effect of a higher CCI. Consequently, higher BMI and CCI should not be regarded as contraindication to RUX therapy. [Display omitted] DisclosuresBreccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding. Cimino:Bristol-Mayer: Honoraria; Celgene: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

A Pooled Overall Survival (OS) Analysis of 5-Year Data from the COMFORT-I and COMFORT-II Trials of Ruxolitinib for the Treatment of Myelofibrosis (MF)

A Pooled Overall Survival (OS) Analysis of 5-Year Data from the COMFORT-I and COMFORT-II Trials of Ruxolitinib for the Treatment of Myelofibrosis (MF)

A Comparison of Levofloxacin and Oral Third Generation Cephalosporins As Antibacterial Prophylaxis in Acute Myeloid Leukemia (AML) during Chemotherapy-Induced Neutropenia

▪Background:There is demonstrated benefit when administering fluoroquinolones as infection prophylaxis in neutropenic patients; however, side effects, drug interactions and increasing drug resistance necessitate investigation toward safe and effective alternative therapies. This study investigates the use of oral third generation cephalosporins as antibacterial prophylaxis during chemotherapy-induced neutropenia to establish knowledge on alternative treatment options.Methods:A retrospective chart review was performed to compare incidence of febrile neutropenia and documented infection rates in Acute Myeloid Leukemia (AML) and intermediate to high International prognostic scoring system (IPSS) risk myelodysplastic syndrome (MDS) patients receiving antibacterial chemoprophylaxis at Mayo Clinic between January 2006 and April 2016. Patients were included if they were 18 years or older, had a diagnosis confirmed on bone marrow biopsy, received induction or first relapse induction-remission chemotherapy regimens and then subsequently were prescribed fluoroquinolone or an oral third generation cephalosporin prophylaxis for anticipated profound and prolonged neutropenia. The main regimens prescribed were cytarabine + anthracycline (7+3), daunorubicin + cytarabine + nilotinib, mitoxantrone + etoposide + cytarabine, all-trans-retinoic acid (ATRA) + anthracycline, all-trans-retinoic acid (ATRA) + arsenic, clofarabine + cytarabine, or an investigational trial. After meeting inclusion criteria the treatment arms were matched via Charlson comorbidity index ( ± 3) and age ( ± 5). Patients with a documented infection 48 hours after switching from either broad spectrum antibiotics to antibacterial prophylaxis, or from levofloxacin prophylaxis to an oral third generation cephalosporin were excluded from the study. All patients provided consent for review of their medical records for research purposes. This study was approved by the Mayo Foundations institutional review board.Results:A total of 565 patients admitted to Mayo Clinic inpatient leukemia service for chemotherapy and concurrently prescribed antibacterial prophylaxis with either levofloxacin or an oral third generation cephalosporin were screened between January 1, 2006 and April 1, 2016. Of those screened 397 patients met the inclusion criteria, and subsequently 123 patients were matched via Charlson comorbidity index and age. Patient characteristics are presented in Table I. Of the 123 study patients, 80 (65%) were male, and the median age was 58.6 years (IQR: 53.3-68.5). The population was comprised of 115 (93.5%) patients with AML, and 8 (6.5%) patients with MDS.By 30 days after prophylaxis start 109 of the 123 patients developed febrile neutropenia (89.9%, 95% CI: (82.8-94.1)). There was no difference in the risk of febrile neutropenia between those on levofloxacin and those on an oral third generation cephalosporin (hazard ratio [HR] = 1.057, 95% CI: 0.64-1.75, p=0.83). The mean ANC value at the time of febrile neutropenia was 0.47 (SD: 1.4). Documented reasons that patients did not receive an oral fluoroquinolone were QTc prolongation (34.2%), rash (21.1%), tendonitis (2.6%), anaphylaxis (5.3%), drug interaction with a treatment study drug (23.7%), or other (13.1%). Three patients died 30 days or less after the last dose of chemoprophylaxis (40 day survival: 96.6%, 95% CI: 92.7-100); two of the reported deaths were due to infection.Of the 111 patients who had a documented febrile episode, 40 (36%) had a culture positive infection. Gram positive organisms caused 27 (71.1%) of the infections, 11 (28.9%) were gram negative organisms, and 1 (2.6%) infection was due to an anaerobic organism. There were 3 (7.5%) polymicrobial infections, and 36 (90%) monomicrobial infections. The majority of the patients had bloodstream as the documented site of infection. Of the documented culture positive infections 15 (39.5%) showed resistance to levofloxacin and 6 (15.8%) had resistance to third generation cephalosporins when susceptibility testing was reported.Conclusions:These findings demonstrate comparable safety and efficacy of oral third generation cephalosporins compared to fluoroquinolones and contribute to the growing body of literature surrounding antibacterial prophylaxis during chemotherapy-induced neutropenia. Further prospective, randomized investigation is warranted. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ruxolitinib Remains Effective in Myelofibrosis after the Necessary Dose Reductions: Real-Life Data from a Multi-Center Observational Study

BACKGROUND - AIMRuxolitinib can be effectively used for the treatment of splenomegaly or constitutional symptoms in patients with myelofibrosis. Its main side effect is myelosuppression which leads to dose modifications. Real-life data from the use of ruxolitinib in every-day practice were analysed to assess efficacy, safety, dose modifications or reasons for treatment discontinuation.PATIENTS - METHODSA retrospective observational study was conducted in patients with primary or secondary myelofibrosis, treated in 13 sites. Statistical analysis was done with non-parametric tests using SPSSv17 software. A total of 116 patients, diagnosed between 1993 and 2016 were included in the analysis. The male:female ratio was 2:1, median age at diagnosis was 63 years (range 27 to 82) and median duration of ruxolitinib therapy was 15.3 months. The study expands over 664.2 patient-years of observation, including 176.7 patient-years while on ruxolitinib.RESULTSThe diagnosis, revisited according to the WHO 2008 criteria, was primary myelofibrosis in 56%, post-essential thrombocythemia myelofibrosis in 22% and post-polycythemia vera myelofibrosis in 22% of patients. At the beginning of ruxolitinib treatment, the international prognostic scoring system (IPSS) risk category was low (6.2%), intermediate-1 (26.5%), intermediate-2 (39.8%), high (23%). Constitutional symptoms were present in 48% of patients at diagnosis and in 73% of them at the onset of ruxolitinib therapy. Median spleen size was 5cm (centimeters) below costal margin at diagnosis and 12cm at onset of ruxolitinib.Ruxolitinib starting dose was 5mg (16%), 10mg (18%), 15mg (31%), 20mg (35%) twice daily (BID), while the final dose was <5mg (5%), 10mg (25%), 15mg (23%), 20mg (23%) and 25mg BID (2%). Starting dose was modified in 77% of patients; the median time to first modification was 3.7 months, while 90% of the modifications had occurred within 14.8 months from onset of therapy.Ruxolitinib was permanently discontinued in 29% of patients, due to progressive disease in 6.4%, transformation to acute leukemia in 2.7% and death in 8.2% of patients. Side effects (including anemia, thrombocytopenia, investigator decision, patient preference) was the reason for treatment discontinuation in 5.5% and lack of response in 2.7% of patients.Efficacy (reduction in constitutional symptoms and spleen size) and hematological toxicity (values of platelets, white blood cell counts, hemoglobin) of ruxolitinib was assessed after 1, 6 and 12 months of treatment (table 1). Thrombocytopenia (PLT<130 x 109/L) was present in 26% of patients at the beginning of treatment, in 46% at 6th month and in 42% at the 12th month, while grade III and IV thrombocytopenia (PLT<50 x 109/L) was present in 4%, 11% and 5% respectively.Constitutional symptoms after 1 month were significantly less frequent with increased doses of ruxolitinib, whereas there was no statistically significant difference among the various doses at 6 and 12 months of treatment. Platelet counts were significantly lower in patients taking 5mg BID at 6 months of treatment (p=0.02), and they also tended to be lower in 1 and 12 months (p=0.07, p=0.08 respectively). White blood cells and hemoglobin values did not differ significantly among the various doses of ruxolitinib in either time point.Table 1. Results at 1, 6, 12 months of treatment, according to different doses.CONCLUSIONSRuxolitinib can effectively improve splenomegaly and alleviate constitutional symptoms in patients with myelofibrosis. The symptoms are relieved slower with the low dosage, whereas the main side effect is thrombocytopenia. It can however be maintained within safety limits (grade < 3), with dose modifications without hampering efficacy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Relationship of JAK2V617F Allelic Burden (AB) to Demographics, Disease Characteristics, and Response to Therapy in Persist-1, a Randomized Phase III Study of Pacritinib (PAC) Versus Best Available Therapy (BAT) in Patients (pts) with Primary and Secondary Myelofibrosis (MF)

Background: The majority of pts with MF present with a mutation in exon 14 of the JAK2 gene (JAK2V617F). Studies have suggested that in pts with MF and this mutation, a lower AB is associated with a myelodepletive phenotype and shortened survival (Tefferi, Leukemia 2008; Guglielmelli Blood 2009; reviewed in Vannucchi, Ther Adv Hematol 2011). For example, in a Cox proportional hazard model for factors predictive of overall survival (OS) in pts with primary MF, a JAK2V617F AB of <25% was associated with a shortened OS (p=0.002; Guglielmelli, Blood 2009). In the phase III trials of ruxolitinib (RUX) therapy in JAK inhibitor-naïve MF, RUX-treated pts had a median decrease in AB of 16% (maximal) in COMFORT-I followed up to 216 weeks and 7% in COMFORT-II at 48 weeks. The median AB at the start of therapy was not reported for COMFORT-I and in COMFORT-II was 84.5% (Cervantes, Blood 2013; Deininger, Blood2015).Methods: In this communication, we report on clinical correlates of quantitative baseline JAK2 mutational status and the effect of treatment on JAK2V617Fmutational burden in the PERSIST-1 trial. This trial enrolled JAK inhibitor-naïve pts with primary or secondary MF without restrictions on baseline platelet counts, randomized 2:1 between PAC and BAT (excluding JAK2 inhibitors) arms. Stratifications included Dynamic International Prognostic Scoring System (DIPSS) risk category, and baseline platelet counts (<50,000/μL, 50,000-100,000/μL, >100,000/μL). Following the 24-week primary analysis, crossover was allowed by physician/pt choice and 90/107 BAT-treated pts (84%) crossed over to receive PAC. Baseline characteristics have been previously reported (Mesa, ASCO 2016) and included 203/327 (62%) pts with Primary MF, 42 (13%) with post-essential thrombocythemia MF and 81 (25%) with post-polycythemia vera MF. 320 of 327 pts had informative PCR testing for JAK2V617F. We report the baseline characteristics of pts with high (≥50%) AB of JAK2V617F, low (<50%) AB of JAK2V617Fand those without a detectable mutation at baseline (<0.1%), as well as the effect of PAC and BAT on AB and correlation with outcome measures.Results: 131 (40.9%) had AB >50% (high AB), 115 (35.9%) had an AB ≥0.1% and ≤50% (low AB), and 74 (23.1%) had AB <0.1% (wild-type JAK2). Median AB values were 80.3% for the high AB group and 30.3% for the low AB group. Baseline characteristics that were significantly different between high and low AB pts are shown in the Table. No differences were noted in the DIPSS risk category or baseline percentage of blasts between pts with low or high AB. There were a higher percentage of pts with a lower AB in the PAC arm (64% vs. 48%; p=0.01). PAC therapy resulted in a median decrement in AB at Week 24 of −15.8% vs −7.9% for pts in the BAT arm (Figure). The median greatest reduction from baseline in AB in PAC-treated pts was −31.6%. Decrease in AB was strongly correlated with spleen volume reduction (p=0.003) and trended towards correlation with improvement in total symptom score (p=0.07) in PAC-treated, but not in BAT-treated pts. Overall survival was shorter in PAC-treated pts with a minimal AB reduction vs pts with greater decreases in AB.Conclusions: In the PERSIST-1 trial, pts with a JAK2V617FAB of <50% had substantially different disease and demographic characteristics when compared with those pts with a >50% AB despite similar distribution of DIPSS scores. In this trial, reduction in AB associated with PAC, but not BAT correlated with clinical benefit. [Display omitted] [Display omitted] DisclosuresVannucchi:Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Mead:Baxalta: Consultancy, Honoraria. Perkins:Novartis Oncology: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Mayer:CTI BioPharma Corp.: Other: Travel, Accommodations, Expenses, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Farber:Alexion: Equity Ownership; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Seattle Genetics: Speakers Bureau; Pharmacyclics: Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Consultancy, Research Funding. Nangalia:Novartis: Consultancy, Other: Travel, Accommodations, Expenses. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Zhou:CTI BioPharma Corp.: Employment, Equity Ownership. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau.

Predictors for Response to Ruxolitinib in Real-Life: An Observational Independent Study on 408 Patients with Myelofibrosis

Background: Response to ruxolitinib (RUX), the only JAK1/2 inhibitor commercially available for the treatment of Myelofibrosis (MF) may vary among patients (pts) and is largely unpredictable at therapy start. Therefore, pts9 selection is based only on clinical needs. Aims: To evaluate the impact of pre-treatment clinical/laboratory factors, as well as RUX dose, on response to RUX in a cohort of "real-life" MF pts. Methods: A multicenter observational study on WHO-defined MF was conducted in 18 Italian Hematology Centers. Data were extracted from a database that included retrospective data on pts treated before January 2015. Subsequently, data were prospectively collected and updated at a 6-month interval.Response to RUX was evaluated according to IWG-MRT criteria. Results: Between June 2011 and Apr 2016, 408 pts with PMF (54.4%), or postET (27.7%) / post-PV (17.9%) were treated with RUX. At RUX start, baseline characteristics were (median): age, 68.5 y (range, 26.5-89); ≥65 y, 63.5%; male, 56.4%; hemoglobin (Hb), 10.7 g/dL (7-16.7); transfusion-dependence 27.9%; PLT, 256×109/L (50-1887); PLT Molecular data were available for 332 pts (81.4%) and was positive in 81% (JAK2V617F), 6.3% (CALR), 1% (MPLW515K/L); 2.7% (triple negative). 30 pts (9%) were JAK2V617Fnegative but did not receive further molecular evaluation. Karyotype was abnormal in 55 (26%) out of 210 evaluable pts (unfavorable: 8.1%). Median follow-up from MF diagnosis was 3.8 yr (0.3-29.6) and median RUX exposure was 20 mos (3-56.2). Overall, 152 out of 365 (42%) pts with spleen ≥5cm achieved a spleen response at any time during RUX therapy. At 3 and 6 mos, the response was achieved by 26.6% and 34.4% of evaluable pts, respectively. In univariate analysis, pre-treatment factors negatively correlating with spleen response were: transfusion dependence, platelet count ≤200x109/l, spleen palpable ≥10 cm below costal margin, grade 3 marrow fibrosis, intm-2/high IPSS risk and interval between MF diagnosis and RUX start ≥2y. Three variables remained significant in multivariate regression logistic analysis: large splenomegaly (HR: 2.05, 95%CI: 1.1-3.7; p=0.02), time-interval ≥2y (HR: 1.78, 95%CI:1.0-3.1; p=0.04) and transfusion dependency (HR: 1.95, 95%CI:1.0-3.7; p=0.04). Spleen response significantly correlated with the average RUX dose in the first 12 wks, with pts treated with doses ≥10 mg BID having better response rates (47.3% vs 26.6% if dose 360 pts had a TSS >10 at RUX start and 319 (88.6%) achieved a symptom response. In multivariate analysis, factors associated with worse responses were: transfusion dependency (HR: 3.15, 95%CI 1.5-6.4, p=0.001) and a baseline TSS >20 (HR: 6.7, 95%CI 3.2-13.8, p Drug-related anemia (acquisition of transfusion dependency or Hb 80 (19.6%) pts discontinued RUX because of: lack/loss of response (28.8%); drug-related toxicity (27.5%, specifically: thrombocytopenia, 16.2%; infection, 6.3%; anemia, 5%); disease progression with/without acute evolution (8.8%); death (13.8%); allogeneic transplant (8.8%); 2ndneoplasia (3.8%); other unrelated causes (8.5%). Summary/Conclusion: In a real-life setting, IWG-MRT-defined spleen and symptoms response rates were observed in 42% and 88.6% of evaluable pts, respectively. Disease severity (in terms of transfusion dependency and large splenomegaly) and a delay in RUX start ≥2yr from diagnosis identified pts with lower spleen response rates. Titrated doses Disclosures Palumbo:Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Bonifacio:Novartis: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy. Tiribelli:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Vitolo:Roche: Membership on an entity9s Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity9s Board of Directors or advisory committees, Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Fanin:Novartis: Speakers Bureau. Merli:Teva Pharmaceuticals Industries: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Cavo:Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Breccia:Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

Inclusion of Patient's Self-Reported Fatigue into a Standard Laboratory Risk Classification Enhances Survival Prediction in Patients with Advanced Myelodysplastic Syndromes

BACKGROUND: Patients with higher risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS) have poor life expectancy making accurate prediction of overall survival (OS) a critical issue for optimal and personalized patients' management.PURPOSE: The primary objective of this study was to develop a patient-based prognostic index for higher risk-disease, that would include self-reported fatigue into the widely used IPSS classification. A secondary objective was to examine whether this patient-based index would provide more accurate OS prediction than the standard IPSS classification.PATIENTS AND METHODS: Analysis is based on 280 newly diagnosed patients with MDS classified with an intermediate-2 or high-risk score (i.e., higher-risk) according to the IPSS. Patients were recruited in an international prospective cohort observational study involving 37 centers. OS was defined as the date of diagnosis of IPSS intermediate-2 or high risk MDS up to death for any cause. Patients were censored at the date of last follow up if not dead at the time of analysis. Before treatment start, all patients completed the EORTC QLQ-C30 questionnaire and the fatigue scale was a priori selected for possible inclusion into the IPSS. Among all observed values of the fatigue score (range: 0-100) we looked for a threshold defining four risk groups, formed by patients reporting either low or high fatigue respectively in intermediate-2 and high risk IPSS groups. The final prognostic index was developed based on univariate and multivariate Cox models. Differences among Kaplan-Meier OS estimation of new risk categories were assessed by log-rank test. Sensitivity analyses were performed, 1) assessing differences in patients’ baseline characteristics among risk groups, by Kruskal-Wallis and Fisher’s exact tests 2) accounting for several potential confounding factors (baseline and time-dependent) in a multivariate extended Cox model, including treatment received after baseline assessment and further evolution into acute myeloid leukemia, 3) performing a bootstrap resampling procedure to internally validate the final prognostic index. Discrimination and calibration of the new index were evaluated. For all analyses, α=0.05.RESULTS: With a median follow- up of 15 months (IQR 8-27) we observed 113 deaths. The median OS of the overall population was 17 months (95% CI, 15-19). The majority of patients (N=165, 59%) received treatment with hypomethylating agents. The final cut-off value selected for the EORTC QLQ-C30 fatigue scale was 45 points discriminating between patients with low (<45 points) or high fatigue (≥45 points). A new risk score classification was then developed, namely, the Fatigue(FA)-IPSS(h), enabling to distinguish three risk group categories (i.e., risk-1, risk-2 and risk-3) in contrast to the two categories of the IPSS (intemediate-2 and high-risk). Patients with the most favorable prognosis according to the FA-IPSS(h) (i.e., risk-1) had a median OS of 23 months (95% CI, 19-29), those with risk-2 had a median survival of 16 months (95% CI, 12-17) and those with the least favorable prognosis (risk-3) had median OS of 10 months (95% CI, 4-13). In contrast, median OS was 20 months (95% CI, 17-24 months) and 13 months (95% CI, 9-16 months) for patients with an IPSS intermediate-2 and high risk scores, respectively. Survival rates at 6 months, one and two years were markedly different amongst the three groups of the FA-IPSS(h). For example, one-year OS for patients with the most favorable prognosis (risk-1) was 80.2% (95% CI, 73.4-87.8) and only 37.5% (95% CI, 23.8-59.1) for those with the poorest prognosis (risk-3). Sensitivity analyses supported our findings. The FA-IPSS(h) index showed very good predictive performance (bootstrap-corrected c-index=0.911).CONCLUSION: The FA-IPSS(h) is a new prognostic index that integrates patient's self-reported fatigue into the well established IPSS index. Its use might enhance physicians' ability to more accurately predict OS in higher-risk MDS. Also, implementation of this index into standard practice might have important implications to elicit a more active patient participation during initial consultations. DisclosuresEfficace:Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding. Gaidano:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria. Bonnetain:Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgène: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria; Integragen: Consultancy, Honoraria; Nestle: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; Merck Serono: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Fianchi:Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Breccia:Novartis: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Platzbecker:Celgene Corporation: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding.

Wilms Tumor 1 (WT1) mRNA Expression Level at Diagnosis Is a Significant Prognostic Marker in Elderly Patients with Myelodysplastic Syndrome

Background/Aims: A high expression of Wilms tumor 1 (WT1) mRNA occurs in most cases of acute leukemia and myelodysplastic syndrome (MDS). Although there are many reports suggesting that acute myeloid leukemia patients with high expression levels of WT1 mRNA have a relatively poor long-term survival, there are few reports addressing the relationship between WT1 levels and prognosis in MDS. Methods: We retrospectively analyzed 42 elderly patients with MDS whose WT1 levels at diagnosis were available, and we assessed the relationships between WT1 levels in peripheral blood and preexisting prognostic factors such as World Health Organization prognostic scores and Revised International Prognostic Scoring System risk categories, bone marrow blast percentages, and chromosomal abnormalities linked to a poor prognosis. We also evaluated the relationship between WT1 levels and prognosis. Results:WT1 levels were significantly different between high- and low-risk MDS patients (p < 0.05). There was a trend towards a significant difference between those with and those without poor prognostic chromosomal rearrangements (p = 0.051). Moreover, the overall survival and progression-free survival were significantly worse in elderly patients with higher levels of WT1 (p = 0.00039 and p = 0.00077, respectively). Conclusions: The WT1 mRNA expression level at diagnosis may be a significant independent prognostic marker for elderly patients with MDS.

Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations.

Ruxolitinib is an oral Janus-activated kinase 1 (JAK1)/JAK2 inhibitor approved for the treatment of patients with myelofibrosis based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of the three clinical outcomes: (a) splenomegaly, (b) disease-related symptoms, and (c) survival. Ruxolitinib was strongly recommended for improving symptomatic or severe (>15 cm below the costal margin) splenomegaly in patients with an International Prognostic Scoring System (IPSS)/dynamic IPSS risk intermediate 2 or high. Ruxolitinib was also strongly recommended for improving systemic symptoms in patients with an MPN10 score >44, refractory severe itching, unintended weight loss not attributable to other causes or unexplained fever. Because of weak evidence, the panel does not recommend ruxolitinib therapy for improving survival. Also, the recommendations given above do not necessarily apply to patients who are candidates for allogeneic stem cell transplant.

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome.

SummaryEvidence of distinct disease propagating stem cells in myelodysplastic syndrome (MDS) has emerged in recent years. However, immunophenotypic characterization of these cancer stem cells remains sparse. In acute myeloid leukaemia (AML), we have previously described aberrant expression of the C‐type lectin domain family 12, member A (CLEC12A) as a stable and reliable marker of leukaemia blasts and as a tool for assessing minimal residual disease. Furthermore, CLEC12A has been proposed as a promising marker of leukaemic stem cells in AML. The role of CLEC12A in MDS, however, remains to be elucidated. In this study, we found CLEC12A aberrantly expressed on the CD34+ CD38− cell compartment in 71% (22/31) of MDS patients, distributed across all Revised International Prognostic Scoring System risk groups. We showed that the CD34+ CD38− CLEC12A+ cells were indeed malignant and possessed functional stem cell properties in the long‐term colony‐initiating cell assay. As opposed to reported findings in AML, we showed that cancer stem cells from MDS samples derived from both CLEC12A positive and negative CD34+ CD38− subpopulations. Due to the absence of CLEC12A on normal haematopoietic stem cells, CLEC12A stem cell immunophenotyping may contribute to diagnosing and monitoring MDS patients and could furthermore add knowledge about disease propagating cells in MDS.

Comparison of Myelodysplastic Syndrome Prognostic Scoring Systems.

Objective:Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease. Patients are at risk of developing cytopenias or progression to acute myeloid leukemia. Different classifications and prognostic scoring systems have been developed. The aim of this study was to compare the different prognostic scoring systems.Materials and Methods:One hundred and one patients who were diagnosed with primary MDS in 2003-2011 in a tertiary care university hospital’s hematology department were included in the study.Results:As the International Prognostic Scoring System (IPSS), World Health Organization Classification-Based Prognostic Scoring System (WPSS), MD Anderson Prognostic Scoring System (MPSS), and revised IPSS (IPSS-R) risk categories increased, leukemia-free survival and overall survival decreased (p<0.001). When the IPSS, WPSS, MPSS, and IPSS-R prognostic systems were compared by Cox regression analysis, the WPSS was the best in predicting leukemia-free survival (p<0.001), and the WPSS (p<0.001) and IPSS-R (p=0.037) were better in predicting overall survival.Conclusion:All 4 prognostic systems were successful in predicting overall survival and leukemia-free survival (p<0.001). The WPSS was found to be the best predictor for leukemia-free survival, while the WPSS and IPSS-R were found to be the best predictors for overall survival.