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ROMEI, a prospective, observational study in patients with myelofibrosis receiving the oral JAK1/2 inhibitor ruxolitinib in real-world practice, assesses treatment adherence based on the 8-item Morisky Medication Adherence Scale (MMAS-8). Here, we present MMAS-8 results at week 24. Overall, 101 of 188 evaluable patients completed the questionnaire at every visit (full completers). Mean (±standard deviation) total MMAS-8 scores remained stable from week 4 to week 24 in the overall population (7.54 ± 0.77 and 7.67 ± 0.70, respectively) and full completers (7.53 ± 0.79 and 7.67 ± 0.73, respectively). Rates of low (MMAS-8 ˂6) or medium (MMAS-8 ≥ 6 to ˂8) adherence were 25–40% and 26–36%, respectively. Fifty-five full completers (54%) reported ≥1 change in adherence category (improvement and/or worsening), most of which were associated with unintentional behavior. The data suggest that one-third of patients receiving ruxolitinib may be undertreated due to non-adherence, potentially undermining disease control, and indicate a need for better interventions addressing noncompliance to oral therapies.

Background. Ponatinib is a third-generation tyrosine kinase inhibitor indicated for adults with resistant or intolerant chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia, or those carrying the T315I mutation. Ponatinib has been commercially available since January 2015, yet there is a paucity of data on its use in the real-world setting. The goal of the Observational study of Iclusig ® (ponatinib) Treatment in patients with CML in Italy (OITI) was to evaluate treatment patterns and outcomes, including safety and efficacy, in patients with CML treated in Italy since the approval of ponatinib. Methods. This noninterventional study included patients aged ≥18 years with CP, AP, or BP CML who initiated ponatinib treatment in routine clinical practice across 26 Italian centers (academic and hospital settings). The study population comprised a prospective cohort, including patients who started treatment with ponatinib after site activation during the 12-month enrollment period; a retrospective cohort, including patients who started treatment with ponatinib but died or were lost to follow-up prior to site activation; and a retrospective/prospective cohort, including patients who started treatment with ponatinib prior to site activation and were still on treatment or in follow-up at the end of the study. Demographic, efficacy, and safety data were collected from patient medical charts at study entry and routine visits. The primary endpoint was the complete cytogenetic response (CCyR) rate in CP CML patients 6 months after starting ponatinib. In the absence of cytogenetic evaluation, molecular assessment was used, considering patients in MR2 or better to be in CCyR. Here, the primary analysis of all evaluable patients for the primary endpoint (median follow-up, 23.7 months [range, 1.3-70.8]) is presented. Results. A total of 119 patients (110 CP, 6 AP, and 3 BP CML) were analyzed. Fifty-nine (49.6%) received ponatinib in second-line (2L), 41 (34.4%) in 3L, and 19 (16.0%) in ≥4L. Prior cardiovascular disease/hypertension was recorded in 56 (47.1%) patients. Median age at ponatinib start was 60 years (range, 19-93). Of 68 evaluated patients, 24 (35.3%) had a confirmed ABL1 mutation, including 7 (10.3%) with the T315I mutation. Starting doses of ponatinib were 45 mg (37.0%), 30 mg (41.2%), or 15 mg (21.8%). Median treatment duration was 22.8 months (range, 1.4-73.6). At baseline, 56 patients with CP CML had less than CCyR and 53 were in CCyR. For 1 patient, assessment was not available. At 6 months, 80/107 evaluable patients with CP CML were in CCyR; 29/56 (51.8%) achieved and 50/50 (100%) maintained CCyR compared to baseline, respectively. For 1 patient, baseline data were unavailable. Additionally, 37 (34.6%) and 19 (17.8%) patients with CP CML achieved a major molecular response (MMR; MR3) and a deep molecular response (MR4-MR5), respectively (Table 1). Progression-free survival rates estimated for patients with CP CML at 12 and 24 months were 92.6% (95% CI, 87.8-97.7%) and 84.6% (95% CI, 77.2-92.6%), respectively. Corresponding overall survival rates were 95.4% (95% CI, 91.6-99.4%), and 88.4% (95% CI, 81.7-95.7%). Seventy-one (59.7%) patients had treatment-related adverse events (AEs), most commonly rash, hypertension (Grade 1-2), and thrombocytopenia (Grade 3). Treatment-related arterial occlusive events occurred in 2 (1.7%) patients. Dose modifications occurred in 77 patients: 37.1% were due to AEs, 13.5% were reductions after at least major cytogenetic response, 10.6% were increases due to lack of efficacy, 1.7% were medical decisions, and 37.1% were for other reasons. Thirty-three patients discontinued ponatinib due to AEs (33.3%), medical decisions (24.2%), and other reasons (42.4%), such as death, progression, and hematopoietic stem cell transplantation. Conclusions. This observational study demonstrates that ponatinib has a favorable efficacy and safety profile in patients with CML treated in standard clinical practice. By 6 months, 74.8% of evaluable patients were in CCyR and 52.3% achieved at least MMR. Further, the probability of survival at 2 years was >88%. No new safety signals emerged with ponatinib treatment compared to prior studies. The early use of ponatinib and careful dose selection appear key to the safety and efficacy outcomes observed in this real-world study. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Bonifacio: Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria. Castagnetti: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Inctye Bioscience Italy Srl: Current Employment. Iurlo: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

A reduction in BCR-ABL1/ABL1IS transcript levels to &lt, 10% after 3 months or &lt, 1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (&ge, MR4, 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values &gt, 10% at 3 months but &lt, 1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS &lt, 10% at 3 months but &gt, 1% at 6 months (event-free survival 68.2% vs. 32.7%, p &lt, 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months &gt, 10% but &lt, 1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS &lt, 1% at 6 months (75% vs. 18.2%, 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values &lt, 1% at 6 months (p &lt, 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.

Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. © 2016 Wiley Periodicals, Inc.

Here we describe the case of a 61-year-old woman who developed chronic myeloid leukaemia in chronic phase under treatment with antiaritmic-therapy (amiodarone) for Parossistic Sopraventricular Tachycardia (PSVT). Initially the patient started with imatinib at standard dose of 400 mg/day but after 6 months of treatment she reached only a Minor Cytogenetic Response (“sub-optimal response”, according to European LeukaemiaNet criteria 2006). After 9 months, she was still in a Minor Cytogenetic Response. We therefore performed a mutation screening analysis that highlighted T240S, N322S, T406A, Y435N mutations. The patient switched to nilotinib at the dose of 800 mg day: Complete Cytogenetic Response and Major Molecular Response were reached after 3 months. Nilotinib was safely administered without further QTc prolongation or haematologic and extrahaematologic adverse side effects.

Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses. Experimental Design: We correlated BCR–ABL/GUSIS and BCR–ABL/ABL transcripts at diagnosis with the outcome—defined by the 2013 European LeukemiaNet recommendations—of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR–ABL/GUSIS and BCR–ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS). Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as “warnings,” 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher BCR–ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (P < 0.001), FFS (P < 0.001), and EFS (P < 0.001). Elevated BCR–ABL/GUSIS levels were also associated with lower rates of TFS (P = 0.029) but not with OS (P = 0.132). Similarly, high BCR–ABL/ABL levels at diagnosis were associated with inferior rates of OR (P = 0.03), FFS (P = 0.001), and EFS (P = 0.005), but not with TFS (P = 0.167) or OS (P = 0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates. Conclusions: Our data suggest that high BCR–ABL transcripts at diagnosis measured using GUS as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. Clin Cancer Res; 23(23); 7189–98. ©2017 AACR.

Background: In myelodysplastic syndromes (MDS), thrombocytopenia is associated with mortality and treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, be effective in improving outcomes in lower-risk MDS with severe thrombocytopenia within a multicentre clinical trial (EQoL-MDS). Initial interim results of short-term efficacy and safety have been published (Oliva et al. Lancet Hem 2017) in the first 90 subjects. We present interim results of the second phase for long-term results in the initial 90 of 174 subjects. Methods: In a single-blind, randomised, controlled, phase 2 trial of adult patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS and severe thrombocytopenia. Adult patients with a stable platelet (PLT) count Results: The first 90 subjects were enrolled between 2011 and 2016. Characteristics of patients have been previously published (Lancet Hem 2017). PLT responses occurred in 28 (47.5%) of 59 patients in the eltrombopag group versus 1 (3.2%) of 31 patients in the placebo group (odds ratio 27.1 [95% CI 3.5-211.9], p=0.002) in median time 14 days (95% CI 7-40 days). Severe bleeding (WHO bleeding score ≥2) occurred in 19 patients, with a significantly higher incidence in the placebo (11 [35.3%] of 31 patients) than in the eltrombopag arm (8 [13.6%] of 59 patients; p=0.015). Sixty-eight grade 3-4 adverse events occurred in 30 of 59 (50.8%) eltrombopag patients versus 10 events in 6 of 31 placebo cases (19.4%;χ2=8,4, p=0.004, stopping rule not reached). The outcomes acute myeloid leukemia (AML) evolution, progression and death occurred in 5 (8.5%), 4 (6.8%), and 5 (8.5%), respectively of 59 eltrombopag cases versus 2 (6.5%), 3 (9.7%), 2 (6.5%), respectively of 31 placebo cases (P ranging from 0.69 to 1.00). Median LFS, combined outcome (AML, disease progression and death) and OS were not reached in the whole group. Differences in LFS, combined outcome and OS at 2 and 5 years by study arms were adjusted for baseline bone marrow blasts since the proportion of patients with >2% blasts (i.e. the median value of the whole study cohort) tended to be higher (P=0.06) in Eltrombopag (59.3%) than in placebo treated (38.7%) patients and resulted to be a strong predictor of study outcomes at both 2 and 5 years (P Conclusion. Eltrombopag is well-tolerated in patients with lower-risk MDS and severe thrombocytopenia and is clinically effective in raising PLT count and reducing bleeding events. QoL improves with response to treatment. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. Disclosures Oliva: Novartis: Consultancy, Speakers Bureau; Apellis: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Alati:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Giai:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Balleari:Celgene: Membership on an entity's Board of Directors or advisory committees. Ferrero:Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Fenaux:Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Palumbo:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Hospira: Honoraria. Liberati:Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Buccisano:Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Candoni:Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Martino:Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Latagliata:Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Eltrombopag is indicated for: 1. the treatment of patients aged 1 year and above with primary immunethrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments; 2. in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy; 3. in adult patients with acquired severe aplastic anaemia who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplantation

Background: Non-adherence to medications is recognized as one of the most important and costly worldwide healthcare problems in the 21st century; according to an EU report, non-adherence to therapies is responsible for 194,500 deaths and costs €125 billion annually. Taking into account those data, the use of adherence measurements in clinical trials could be extremely useful, in order to better understand patients (pts) behaviours and outcomes. The 8-item Morisky Medication Adherence Scale (MMAS-8, Morisky DE et al, J Clin Hypertens,2008 - Krousel-Wood MA et al, Am J Manag Care 2009- Morisky DE et al, J Clin Epidemiol. 2011) is a widely used questionnaire to asses indirectly pts adherence to medications. The first seven items are yes/no questions, and the last item is a five point Likert-scale. Ruxolitinib (RUX) is an oral JAK1/2 inhibitor approved for the treatment of symptoms and/or splenomegaly in myelofibrosis (MF) pts. ROMEI (CINC424AIT04-Ruxolitinib Observational study in Myelofibrosis treated patients in Italy) is a prospective observational study focused on real life management of MF pts with RUX; the trial enrolled 215 pts and included a prospective evaluation of MMAS-8 as a secondary endpoint. To date, no data regarding MMAS-8 and RUX are available and here we show a descriptive analysis of MMAS-8 after 24 weeks (wks) of RUX treatment. Methods: After informed consent signature, pts started RUX according to Summary of Product Characteristics; MMAS-8 questionnaire was administered at wks 4, 8, 12 and 24 after RUX initiation. MMAS-8 were analysed only if pts provided all responses to the questionnaire; a score ˂ 6 indicates low adherence, a score between 6 and 8 indicates medium adherence, and a score = 8 suggests high adherence. As per protocol, only adherence classes (low-medium-high) assessment was scheduled and in case of low or medium adherence (ie suboptimal adherence), no action in term of target education or psychological interventions was planned. Results: Out of 215 enrolled pts, 188 were evaluable for MMAS-8. The MMAS-8 was completed by 163 pts (87%) at week (wk) 4, 156 pts (83%) at wk 8, 146 pts (78%) at wk 12 and 134 pts (71%) at wk 24. A total of 101 out of 188 eligible pts (54%) completed all 4 scheduled questionnaires. MMAS-8 total score seems to remain stable over the time. Mean MMAS-8 total score was 7.54±0.77 (min; max: 4.75; 8.00) at wk 4 and 7.67±0.70 (min; max: 4.25; 8.00) at wk 24, resulting in a mean change from wk 4 of 0.14±0.79 (min; max: -2.25; 2.25). Regarding adherence classes, the distribution between low, medium and high adherence over time is shown in table 1. Likewise, if we consider pts who completed all scheduled questionnaires, MMSA-8 total score remains stable over the wks, with total score of 7.53±0.79 (min; max: 4.75; 8.00) at wk 4, 7.60±0.71 (min; max: 4.75; 8.00) at wk 8, 7.69±0.69 (min; max 4.50; 8.00) at wk 12 and 7.67±0.73 (min; max: 4.25; 8.00) at wk 24, as well as adherence classes distribution (Fig 1). Regarding adherence classes in this subgroup of pts, seems that pts with high adherence at wk 4 are more prone to maintain the same class during time. Finally, we tried to perform an exploratory analysis relating spleen response according to IWG-MRT criteria with adherence classes at each time points: considering the small number of evaluable pts with complete information regarding both available parameters, no correlation between spleen responses and adherence classes was demonstrated (data available at the meeting). Conclusion: This is the first time of MMAS-8 applied in MF pts as well as those treated with RUX. Our analysis showed a not irrelevant percentage of pts (ranging from 25% to 40%) belonging to a low-intermediate adherence classes during treatment. Surprisingly overall approximately one third of patients could be exposed to a suboptimal treatment over time and probably clinicians underestimate the number of those pts in clinical practice. Although we did not find in our cohort a correlation between adherence classes and spleen responses, probably due to low number of evaluable pts for both variables, the knowledge regarding pts attitude to therapy, especially for long-term and chronic treatments, remains crucial from clinical and pharmacoeconomic perspectives. Standardized methods to assess pts adherence such as MMAS-8 should be implemented in prospective well-designed clinical trials and could be a precious tool guiding clinicians in the everyday practice. Disclosures Palandri: Novartis: Consultancy, Honoraria. Cilloni:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morelli:Novartis: Employment. Passamonti:Celgene Corporation: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Breccia:Bristol-Myers Squibb, Celgene, Incyte, Novartis, Pfizer: Honoraria.

Summary Background In myelodysplastic syndromes, thrombocytopenia is associated with mortality, but treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, might be effective in improving thrombocytopenia in lower-risk myelodysplastic syndromes and severe thrombocytopenia. Methods EQoL-MDS was a single-blind, randomised, controlled, phase 2 superiority trial of adult patients with low-risk or International Prognostic Scoring System intermediate-1-risk myelodysplastic syndromes and severe thrombocytopenia. Patients with a stable platelet count of lower than 30 × 10 9 platelets per L, aged at least 18 years, with refractoriness, ineligibility to receive treatment with alternative medications, or relapse while receiving treatment with alternative medications were included in this trial. Patients were randomly assigned (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression and were masked to treatment allocation. Here, we report the results in the intention-to-treat population of the first phase of the trial, for which the primary endpoints were the proportion of patients achieving a platelet response within 24 weeks and safety. The interim analysis presented here was protocol-specified and used a two-sided significance level of 0·001 and a p value at or below this limit for both primary endpoints to indicate the need for early trial termination. Duration of platelet transfusion independence, duration of response, overall survival, leukaemia-free survival, and pharmacokinetics will be reported at the end of the phase 2 portion of the trial. This trial is registered with EudraCT, number 2010-022890-33. Findings Between June 13, 2011, and June 17, 2016, we enrolled 90 participants for the first phase of the trial. The median follow-up time to assess platelet responses was 11 weeks (IQR 4–24). Platelet responses occurred in 28 (47%) of 59 patients in the eltrombopag group versus one (3%) of 31 patients in the placebo group (odds ratio 27·1 [95% CI 3·5–211·9], p=0·0017). During the follow-up, 21 patients had at least one severe bleeding event (WHO bleeding score ≥2). There were a higher number of bleeders in the placebo (13 [42%] of 31 patients) than in the eltrombopag arm (eight [14%] of 59 patients; p=0·0025). 52 grade 3–4 adverse events occurred in 27 (46%) of 59 patients in the eltrombopag group versus nine events in five (16%) of 31 patients in the placebo group (χ 2 =7·8, p=0·0053, stopping rule not reached). The outcome acute myeloid leukaemia evolution or disease progression occurred in seven (12%) of 59 patients in the eltrombopag group versus five (16%) of 31 patients in the placebo group (χ 2 =0·06, p=0·81). Interpretation Eltrombopag is well-tolerated in patients with lower-risk myelodysplastic syndromes and severe thrombocytopenia and is clinically effective in raising platelet counts and reducing bleeding events. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. Funding Associazione QOL-ONE.

Background. Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapies. However these clinical trials included patients selected according to different inclusion and exclusion criteria, particularly age and comorbidities, and with specific treatment obligations. In daily clinical practice (real life), no inclusion and exclusion criteria do exist, and treatment outcomes depend not only on choice of the first-line TKI, but also on doctor- and patient-choice of second- and third-line TKIs. Aims. To investigate the response and the outcome on first-line imatinib, with switch to 2nd generation TKIs in case of failure or toxicity, in BCR-ABL1+ CML patients enrolled in a population-based registry (real-life setting). Methods. We report here the results from a prospective study, enrolling all newly diagnosed patients (N = 236, median age 60 years) living in two Italian regions, that were registered according to population-based criteria and treated front-line with imatinib. The decision to switch to second-line treatment was up to the Local Investigator (no predefined criteria) Definitions: major molecular response (MMR or MR3.0): BCR-ABL1IS ratio 10,000 ABL1 copies; failure and suboptimal response: according to 2009 European LeukemiaNet (ELN) criteria; progression: transformation to advanced phases according to ELN criteria; leukemia-related death (LRD): death after progression. Results. Median age was 60 years at diagnosis and 64 years at last contact, with a median follow up of 48 months (range 2-86 months). High risk patients according to Sokal score and new EUTOS long-term survival (ELTS) score were 23% and 18%, respectively. A switch from imatinib to a second generation TKI was reported in 14% of patients for side-effects, and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The median time to switch was 8 months for toxicity and 20 months for failure. At 12 months, 55% of all evaluable patients were in MR3.0 or better. At last contact, 75% of all evaluable patients were in MR3.0 or better and 48% were in MR4.0 or better. The molecular response of patients switching for failure or suboptimal response was evaluable in 61/63 patients: improved in 57%, not modified in 38%, worsened by at least 1 log in 5% of patients. Overall, the treatment switch was associated with a remarkable increase of MR3.0 rate: from 10% at the time of switching to 52% at last qPCR. Overall, 33% achieved a stable MR4.0, of whom 22% with imatinib alone, and 11% after switching to a second generation TKI (Table 1). The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively. Twenty-seven patients (11%) died, of whom 13 (6%) of leukemia, after disease progression and 14 (6%) of "other" causes, without any evidence of progression. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients who received nilotinib in second-line. OS was not affected by age in the interval between 18 and 69 years (5-year OS 92%, ranging from 89% to 95 % in the different decades), but 5-year OS probabilities of elderly (70-79 years) and very elderly patients (≥ 80 years) were significantly lower (78%, P = 0.003, and 34%, P < 0.0001, respectively). The probability of LRS was not affected by age. The Sokal score predicted OS, but not LRS. The ELTS score clearly separated low, intermediate, and high risk patients for OS and also for LRS. Conclusions. The results of this prospective population-based study emphasize the importance of second-line treatment in the clinical practice: the CML management with the 3 available TKIs in the period 2008-2012, according to current treatment recommendations for switching and without any predefined obligation, resulted in response rates and outcomes, that are in the high range of prospective interventional studies investigating the efficacy and the safety of a single TKI in selected patients. This study provides a robust dataset on the results of CML treatment with TKI in clinical practice, that will be important for interpreting and evaluating the results of the next prospective studies, arguably limited to selected patients. Disclosures Castagnetti: Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Marasca:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy. Martinelli:Genentech: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy. Cavo:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Ariad: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.

To evaluate efficacy, safety, changes in biological features, and quality of life (QoL) in low-risk anemic patients with MDS treated with darbepoetin alfa (DPO), 41 patients received DPO 150 microg weekly for 24 weeks. The dose was increased to 300 microg weekly in non-responsive patients. During treatment, 10/17 (59%) transfusion-dependent (TD) and 13/23 (56%) transfusion-free (TF) patients responded. In TF patients, Hb increased from 9.2 +/- 0.9 g/dL to 10.3 +/- 1.4 g/dL by 24 weeks (p = 0.004). The mean response duration was 22 weeks (95% CI: 19.7-24.0) in TF patients compared with 15.1 weeks (95% CI: 13.3-17.5) in TD patients. Response to treatment was associated with increases in QoL. Decreases in the percentage of apoptotic progenitor cells (p = 0.007) and CD34+ cells (p = 0.005) were observed. These results confirm previous studies demonstrating the safety and efficacy of DPO in anemic patients with MDS. Biological changes and improvement in QoL were associated with response. Adequate dosing is to be determined.

Background The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has generated a need for early molecular parameters associated with inadequate responses to Imatinib Mesylate (IM). Objective We correlated quantitative determination of BCR-ABL transcripts at diagnosis with the outcome (defined according to the 2013 European Leukemia Net recommendations) of 272 newly diagnosed CML patients receiving IM 400 mg/die. Methods BCR-ABL transcripts were measured from peripheral blood samples drawn at diagnosis before patients received any pharmacological treatment using Real-Time Quantitative PCR (RQ-PCR). All molecular determinations were performed twice (in triplicates) on the same sample using either ABL or glucuronidase-beta (GUS) as reference genes. BCR-ABL values were then reported on the international scale (IS). Results With a median follow-up of 60 months, 65.4% of patients achieved an optimal response, 5.6% presented a response currently defined as "warning", 22.4% failed IM treatment and 6.6% switched to a different tyrosine kinase inhibitor because of intolerance to the drug. We recorded 19 deaths (6.9%), 7 (2.5%) attributable to disease progression. We applied Receiver Operating Characteristic (ROC) curves to define BCR-ABL/GUSIS expression levels that would separate patients likely (i.e. below the threshold) or unlikely (i.e. above the threshold) to achieve multiple endpoints, namely: optimal response (OR), failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS). Employing the specific threshold calculated for each endpoint we found that high BCR-ABL/GUSIS levels at diagnosis were associated with inferior probabilities of OR (p Conclusions High BCR-ABL transcripts at diagnosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from standard dose IM that should be considered for alternative forms of treatment. Disclosures Hochhaus: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

BACKGROUND: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage. PATIENTS AND METHODS: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period. RESULTS: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011). CONCLUSIONS: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome. CLINICAL TRIAL NUMBERS: NCT00510926, NCT00514488, NCT00769327, NCT00481052. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

In the hemopoietic system, interactions between stem cells and components of the bone marrow microenvironment play a pivotal role in blood cell proliferation and differentiation. Among the adhesion molecules, the integrins of the beta 1-subfamily are known to direct cell-cell and cell-matrix interactions and evidence has been provided that CD34-positive stem cells bind either to the bone marrow stroma or to the extracellular matrix proteins through the beta 1-integrins. It seems that changes in their expression pattern or signalling function are likely to reflect disturbances at the hemopoietic bone marrow microenvironmental level. Any alteration of their biological functions makes them attractive candidates for playing decisive roles in the leukemic processes. In this view, beta 1-integrins have been recognized to mediate those cellular interactions and migrations that are important in the biology of leukemia. In this paper we review some aspects of the role played by beta 1-integrins, especially VLA-4 and VLA-5, in adult acute lymphoblastic leukemia in relation with the expression rate of the stem cell antigen CD34.

The approval of three tyrosine kinase inhibitors (TKIs) for the first line treatment of Chronic Myeloid Leukemia (CML) has generated an urgent need for molecular parameters predictive of unfavorable therapeutic outcomes. Recent evidence suggests that failure to achieve early molecular responses (i.e. BCR-ABL/ABLIS levels With the current study, we wanted to establish if high BCR-ABL transcripts at diagnosis would be associated with unfavorable responses to Imatinib Mesylate (IM). Thus, we correlated quantitative determinations of BCR-ABL levels at diagnosis with the outcome of 230 newly diagnosed CML patients that were assigned to receive IM 400 mg/die. BCR-ABL transcripts were measured from peripheral blood samples drawn before exposure to any form of treatment. Real-Time Quantitative PCR (RQ-PCR) determinations were subsequently performed in triplicates using glucuronidase-beta (GUS) as the reference gene, since previous evidence has demonstrated that ABL is not a reliable control gene in samples collected at diagnosis. Values were then reported on the International Scale employing a conversion factor obtained from the laboratory of the University of Heidelberg in Mannheim, Germany. Median follow-up of the study population was 50 months. Estimated 5-year cumulative incidences of complete hematologic response, complete cytogenetic response (CCyR) and major molecular response were 97.9%, 89.5% and 64.7%. Five-year probabilities of overall survival (OS), transformation-free survival (TFS: survival without disease transformation to the accelerated phase or blast crisis) and failure-free survival (FFS: survival without IM failure as defined by the 2009 European Leukemia Net recommendations) were 93.8%, 97.8% and 76%. Elevated BCR-ABL/GUSIS correlated with inferior probabilities of optimal response (p15.96%) probabilities of obtaining an Optimal Response and found that 69% of patients displaying We conclude that high BCR-ABL transcripts at diagnosis measured by RQ-PCR employing GUS as a reference gene allow the identification of CML patients unlikely to benefit from IM that should receive alternative forms of treatment. Disclosures: Muller: Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria.

Background: About 10% of low risk patients with myelodysplastic syndromes (MDS) experience severe thrombocytopenia. Bleeding and the scarce efficacy of platelet (PLT) transfusions drive research in novel treatments. Eltrombopag is an oral agonist of the thrombopoetin-receptor (TPO-R). Its potential in increasing platelet (PLT) counts in low risk MDS has not been evaluated. We present interim results on the efficacy and safety of eltrombopag in inducing PLT responses in patients with low and intermediate-1 International Prognostic Scoring System (IPSS) risk MDS with severe thrombocytopenia in a Phase II, multicentre, prospective, placebo-controlled, single-blind study (EQoL-MDS). Methods: Primary endpoints are safety and efficacy of eltrombopag. Secondary endpoints include changes in quality of life (QoL), PLT transfusion requirement, incidence and severity of bleeding, and survival. Inclusion criteria are adult age; PLT200 Gi/L or adverse events. Study design is shown in the figure. PLT response, assessed at each visit, is defined as Response if: 1) baseline PLT>20 Gi/L: absence of bleeding and increase by at least 30 Gi/L from baseline; 2) baseline PLT20 Gi/L and increase by at least 100%, not due to PLT transfusions; and Complete Response if PLT≥100 Gi/L and absence of bleeding. QoL scores are analysed by MDS-specific instrument, QOL-E v. 3. Results: Seventy patients (46 on eltrombopag - Arm A, 24 on placebo -Arm B) have been randomized at the time of this report. Mean age is 68.3 (SD 13.0) years, M/F 38/32. ECOG performance status was 0 in 47 cases, 1 in 16 cases, 2 in 7 cases. Ten patients had comorbidities. According to the WHO 2008 classification, 22 patients had refractory cytopenia with unilineage dysplasia, 9 had refractory anemia with ringed sideroblasts, 31 had refractory cytopenia with multilineage dysplasia (of which 15 with ringed sideroblasts), 6 had refractory anemia with excess blasts-1 and 2 were unclassified. IPSS score was low in 48 cases. Mean baseline platelet (PLT) count was 17.1 (SD 8.2) Gi/L, mean hemoglobin level 10.8 (SD 2.5) g/dL and mean white blood cell count was 5.0 (SD 3.8) Gi/L. Twenty-five (36%) patients were red blood cell transfusion-dependent. Thirty-three had a WHO bleeding scale of 1, 2 experienced mild blood loss, 4 a gross blood loss and 1 a debilitating blood loss. Fourteen patients in Arm A and 8 in Arm B had required PLT transfusions in the 8 weeks prior to randomization. Twenty-three cases (50%) in Arm A have responded versus 2 (8%) in Arm B (p=0.001). Thirty-three patients have completed at least 24 weeks of study. Median time to response was 14 days (IQR 7-46 days) at a median daily dose of 75 (IQR 50-162.5 mg). PLT count increased by mean 53.2 (SD 68.1) Gi/L (p=0.001) in Arm A versus no significant changes in Arm B by week 24. QOL-E scores at baseline and 12 weeks in 47 cases in both arms are shown in the table. There was an increase in treatment outcome index,mainly experienced in the first 3 weeks (p=0.034). Fatigue improved from baseline to 12 weeks associated with response (p=0.016). Related Grade III-IV adverse events (AE) occurred in 10 patients (22%) in Arm A and consisted in: nausea (4), hypertransaminasemia (3), hyperbilirubinemia (1), sepsis (1), pruritis (1), heart failure (1), asthenia (1), vomit (1), while in Arm B 1 patient (4 %) experienced grade 3 bone marrow fibrosis. MDS disease progression occurred in 5 (11%) in Arm A versus 2 (8%) in Arm B, p=ns. Conclusions: Preliminary data indicate that lower risk MDS patients with severe thrombocytopenia undergoing treatment with eltrombopag experience significant improvements in PLT counts accompanied by improvements in fatigue. The drug appears to be well-tolerated and not associated with MDS progression. Further follow-up is required to evaluate the impact on survival. Figure 1. Study design Figure 1. Study design Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Disclosures Oliva: Novartis: Speakers Bureau; Celgene: Other: Advisory Board, Speakers Bureau; Amgen: Consultancy. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Palumbo:Novartis: Honoraria, Other: Advisory Board. Fenaux:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

Background The aim of this study was to evaluate changes in quality of life scores and their association with therapy and survival in unselected elderly patients with acute myeloid leukemia.Design and Methods From February 2003 to February 2007, 113 patients aged more than 60 years with de novo acute myeloid leukemia were enrolled in a prospective observational study. Two different quality of life instruments were employed: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – C30 (EORTC QLQ-C30) and a health-related quality of life questionnaire for patients with hematologic diseases (QOL-E).Results Forty-eight patients (42.4%) received intensive chemotherapy and 65 (57.6%) were given palliative treatments. Age greater than 70 years (P=0.007) and concomitant diseases (P=0.019) had a significant impact on treatment allocation. At diagnosis, general quality of life was affected [median QOL-E standardized score 54, interquartile range 46–70; median EORTC global score 50, interquartile range 41–66]. Most patients were given a good ECOG Performance Status (< 2), which did not correlate with the patients’ perception of quality of life. At multivariate analysis, palliative approaches (P=0.016), age more than 70 years (P=0.013) and concomitant diseases (P=0.035) each had an independent negative impact on survival. In a multivariate model corrected for age, concomitant diseases and treatment option, survival was independently predicted by QOL-E functional (P=0.002) and EORTC QLQ-C30 physical function (P=0.030) scores.Conclusions Quality of life could have an important role in elderly acute myeloid leukemia patients at diagnosis as a prognostic factor for survival and a potential factor for treatment decisions.

INTRODUCTION: Patients with myelodysplastic syndromes (MDS) are at continuous risk of complications and must face the reality of a relatively low survival while still mainly depending on supportive care. The chronic nature of MDS, the risk of progressive evolution, advanced age, anemia and the rapid changes in physical status make the MDS patient unique within the cancer population. Quality of Life (QoL) in MDS is undoubtedly compromised by functional, psychological, and disease-specific components. Treatment options are still scarce in this elderly population and hematologists must select candidates for experimental therapy. Patients’ preferences are requisites for therapeutic choice so that it is essential that clinicians understand patients’ perceptions. STUDY DESIGN: We designed a multicenter Italian 18-month prospective observational study in 150 MDS patients from diagnosis to evaluate the correlation between QoL changes and changes in Hb and other MDS-related variables. Comparison between the patients’ and the physicians’ perception of QoL, QoL changes related to adaptation, progression and treatment response, and feasibility, consistency and validity of the QoL instruments were evaluated. Selection criteria included adult age, MDS at diagnosis with IPSS score < 2, at least 1 cytopenia, ability to complete the QoL questionnaires and ECOG PS < 3. METHODS: The QoL instruments (QOL-E v.2, LASA scale, and EQ-5D) were completed by patients and physicians (both blind to each other’s responses) at baseline, months 1, 3, 6, 12, and 18. Clinical and laboratory data were collected throughout the study. RESULTS: Median age was 74 (IQ range 67–79); 85 were males (57%). Patients were classified according to WHO: 48 RA (32%), 30 RCMD (20%), 21 RAEB-1 (14%), 7 RAEB-2 (5%), 6 5q-syndrome (4%), 4 RARS (3%), 3 CMML (2%), 1 RCMD/RS (1%), 30 MDS-U (20%). Fifty-six patients (37%) had IPSS low risk, 62 (41%) Int-1 and 14 (9%) Int-2. In 18 (12%) patients IPSS was not evaluable due to karyotype. Thirty-nine patients (26%) were transfusion-dependent (TD) and 28 (72%) had at least 1 additional cytopenia. In the transfusion-free (TF) patients, median Hb was 10.5 g/dL (IQ range 9.2–12.6); 77 patients (69%) were anemic (Hb < 12.0 g/dL) and 48 (43%) had at least 1 additional cytopenia. ECOG PS was significantly better in TF patients (p=0.0061). Charlson’s comorbidity index was 0 in 78 patients (52%), 1 in 38 patients (25%), 2 in 20 patients (13%) and ≥ 3 in 14 patients (9%). Median serum epo was 50.4 U/L (N=94). Of the 29 QOL-E items, 25 items had a response rate > 90%. Though 26 of the 29 QOL-E items showed significant correlations between patients’ and physicians’ scores, there were significant score differences in 9 (31%) of the items with a general trend of physicians to overestimate patients’ problems. Several QoL scores correlated with Hb levels and were significantly lower in TD patients than in TF patients (Table). Table. Patient QoL scores in transfusion-dependent (TD) and transfusion-free (TF) patients and correlations with Hb values. QOL domain Whole group Correlation with Hb r (p) TD patients (n = 39) TF patients (n = 111) p QOL-E, scores Q1 33 (33–67) 0.186 (0.023) 33 (0–33) 33 (33–67) 0.036 Q2 67 (67–100) −0.032 (0.70) 67 (33–100) 67 (67–67) 0.11 Physical 63 (38–75) 0.286 (0.0004) 50 (38–63) 63 (50–75) 0.0072 Social 50 (25–63) 0.197 (0.017) 44 (17–63) 50 (38–63) 0.064 Sexual 100 (50–100) 0.250 (0.011) 50 (0–100) 100 (75–100) 0.0011 Fatigue 81 (71–86) 0.236 (0.0038) 78 (67–86) 81 (71–90) 0.14 MDS-specific 81 (71–90) 0.287 (0.0005) 74 (63–83) 83 (74–93) 0.0005 LASA, scores Energy 48 ± 25 0.285 (0.0004) 42 ± 25 50 ± 25 0.081 Activity 54 ± 27 0.226 (0.0055) 50 ± 29 56 ± 26 0.24 General 53 ± 27 0.304 (0.0002) 44 ± 25 57 ± 27 0.0093 EQ-5D, scores Mobility 50 (50–100) 0.119 (0.15) 50 (50–100) 75 (50–100) 0.45 Self-Care 100 (100–100) 0.148 (0.074) 100 (100–100) 100 (100–100) 0.14 Usual Activity 100 (50–100) 0.129 (0.12) 50 (50–100) 100 (50–100) 0.0050 Pain/Discomfort 50 (50–100) −0.027 (0.75) 100 (50–100) 50 (50–100) 0.48 Anxiety/Depression 50 (50–100) 0.010 (0.90) 50 (50–100) 50 (50–100) 0.88 VAS Health State 60 ± 20 0.212 (0.010) 52 ± 19 63 ± 19 0.0020 Data are reported as mean ± standard deviation or median and interquartile range as appropriate. CONCLUSIONS: QoL is compromised in MDS and is associated with Hb values and transfusion-dependence. Patient preferences must be evaluated when considering treatment options since hematologists seem to overestimate patients’ perception of healthrelated problems. The disease-specific questionnaire, QOL-E, and the LASA scale are valid tools for the evaluation of QoL in MDS patients.

Up to 40% of patients with myelodysplastic syndromes (MDS) respond to pharmacological doses of epoetin. Darbepoetin alfa (DPO) has a longer half-life and greater biological activity. Recent data suggest a 60% response rate in patients receiving DPO. We report preliminary results of a Phase II study in 41 patients with low and intermediate-1 risk MDS and Hb < 11 g/dL. The primary endpoint is to evaluate the efficacy of DPO for the treatment of anemia of MDS. Secondary endpoints are the evaluation of the safety of DPO and of the variations in Hb, the number of monthly transfusions and quality of life (QoL) in treated patients. Patients receive DPO 150 mcg s.c weekly to be doubled in non-responders. Treatment target is Hb =12.0 g/dL. Treatment is to be temporarily interrupted for Hb >12 g/dL and re-initiated when Hb Results: The 33 patients who received at least 8 weeks of DPO included 19M/14F of median age 74 (range 49–84) years. Morphology was: 31 RA, 1 RARS and 1 CMML. IPSS score was low in 75%, and Int-1 in 25%. Serum epoetin levels were < 200 mU/ml. Meduab Hb level at baseline was 9.5 (range 7.0–10.8) g/dL. Six patients had previously received epoetin alfa or beta without success. Thirteen patients (39%) were transfusion-dependent. At the initial dosage, 6 transfusion-free patients (30%) responded at 4 weeks (3 reached the endpoint of Hb=12.0 g/dL). Total number of cases responding at 8 weeks were 17, including 7 (53%) transfusion-dependent patients. Ten responses were minor (30%) and 7 major (21%). After dosage doubling, there were 56% responders of the 16 patients that have completed the study at 24 weeks: 7 of 12 transfusion-free patients (2 at a dosage of 150 mcg/wk, 2 at 300 mcg/wk and 3 at 300 mcg every 3 weeks) and 2 of 4 transfusion-dependent patients at a dosage of 300 mcg/wk. Five patients reached Hb > 12g/dl during the study period. Finally, 3 of the 6 patients previously unresponsive to epoetin responded to DPO. At univariate ANOVA analysis, response to treatment was associated with increases in QOL-E treatment outcome index (p=0.033), specific (p=0.009), fatigue (p= 0.013), physical (p=0.001), functional (p=0.042), social (0.001), general (p=0.001), and total (p=0.004) scores. There were significant reductions in CD34+ cells (p=0.025) and apoptotic cells (p=0.008) and these were associated with treatment response (p=0.045 and p=0.065, respectively). No adverse events were reported. Conclusions: DPO is safe and well-tolerated in patients with MDS. A reduction in apoptotic cells is observed during treatment. Therapeutic response is associated with improvements in QoL. Our study suggests that DPO is effective for the treatment of anemia of MDS.

In this study we evaluated the cytotoxicity of Fludarabine (FAMP) both alone and in combination with alpha and beta interferon (IFN) against B-cells from patients affected by chronic lymphocytic leukemia (CLL). We used an in vitro colorimetric assay based on the bioreduction of the tetrazolium salt XTT by viable cells. Fludarabine concentrations ranging from 0.03 to 30 microM were tested on cells collected from 22 B-CLL patients. For each fludarabine concentration, 800 I.U. of either alpha or beta IFN were added. Interferon alone did not exert any cytotoxic effect, while Fludarabine showed a strong cytotoxicity against B-CLL cells. The concentration of Fludarabine required to induce a 50% cytotoxicity (IC50) was below 3 microM (the achievable serum level after standard dose in vivo administration) for 19 out of 22 patients. After IFNs supplementation to Fludarabine, it was possible to identify three groups of samples. The first in which IFNs addition did not produce almost any significant change in Fludarabine cytotoxicity (13/22), the second in which there was an improvement in FAMP IC50 (6/22), and finally the third group in which IFNs worsened it (3/22). Stage of disease was the only identified factor accounting for these different results. The second group included samples from 5 patients at stage A and one at stage B, while in the third group all three samples were from patients at stage C. Interferon-alpha and -beta induced the same degree of FAMP IC50 variation.(ABSTRACT TRUNCATED AT 250 WORDS)

The therapeutic approach for acute myeloid leukemia (AML) in elderly patients is generally tailored on the basis of age, performance status, comorbidities and patient consent. Toxicity and low-response rates are major constraints and, in general, the therapeutic options are finally conditioned by the clinicians’ views about the patients’ health status and preferences. In this setting, the patients’ perception of their own health (health-related quality of life, or HRQOL) may be useful. With this purpose, we designed a prospective multicenter study to evaluate the predictive potentials of HRQOL measures on prognosis and outcome in elderly AML patients (aged over 60 years). We here present pilot baseline results on data obtained from 25 AML patients of median age 74 (range 60–91) yrs. HRQOL measures were obtained by applying the QOL-E©questionnaire at diagnosis. Reliability of the questionnaire was evaluated and associations with patient and disease-related factors were investigated. We found that the QOL-E© questionnaire as highly reliable in the AML patients (standardized Cronbach alpha coefficients> 0.70). Table 1. Reliability of the QOL-E questionnaire. QOL-E© domains Standardized Cronbach alpha coefficients QOL-E©scores were particularly low (reflecting poor HRQOL) in the fatigue and disease-specific domains. Physical 0.90 Functional 0.80 Social 0.80 Sexual 0.81 Fatigue 0.77 Disease-Specific 0.78 Total 0.70 Table 2. QOL-E scores in the AML patients. QOL-E© domains QOL-E© scores* *Scores are standardized, expressed in percentage ±SEM Physical 60 ± 6 Functional 64 ± 4 Social 56 ± 6 Sexual 50 ± 8 Fatigue 34 ± 4 Disease-specific 26 ± 4 Total 38 ± 5 In this study, male AML patients (15 patients) perceived better well-being in the QOL-E© disease-specific domain than females (33±4 versus 15±7 %, p=0.04). The lack of domestic assistance (reflecting no previous need for help at home) was associated with better functional scores (p=0.037) and a lesser sense of fatigue (p=0.042) at diagnosis. Patients with concomitant diseases had a poorer sense of physical wellbeing (45± %) versus those without (28±8%, p=0.01). Increasing age significantly correlated with decreasing QOL-E© physical (r=−0.414, p=0.04), functional (r=−0.470, p=0.018) and fatigue (r=−0.487, p=0.015) scores. ECOG performance status (objective score of patient’s wellbeing) was not associated with subjective measures of HRQOL in the single domains, but only with the total score (r=−0.570, p=0.04). Noteworthy, the QOL-E© disease-specific scores correlated with the percentage of peripheral blasts (r=−0.302, p=0.078) and bone marrow blasts (r=−0.387, p=0.024). In conclusion, QOL-E© is a very simple and reliable instrument for the assessment of HRQOL in elderly patients with AML. At diagnosis HRQOL is poor, especially with increasing age and in patients with a high blast count. Future prospective results in an adequate number of patients may provide useful information on the implementation of patient-tailored therapy in this particular category of AML patients.