ALBERT

Description: Background: Gene expression profiles have been associated with prognosis in myelodysplastic syndromes. WT1 is a tumor-suppressor gene coding for a transcription factor located on chromosome 11p13, which was originally identified for its involvement in the pathogenesis of the Wilms’ tumor. In normal bone marrow, WT1 expression is low or undetectable, whereas it is aberrantly expressed in hematological malignancies. Evidence indicates that WT1 is important in the lineage-specific differentiation of hematopoietic cells and leukemogenesis. In myelodysplastic syndromes (MDS), WT1 expression has prognostic significance: it is directly correlated with the type of MDS, with IPSS score and with disease progression. Recent data demonstrate that WT1 is a potent activator of the EPO gene under normoxia and it is suggested that WT1 may regulate paracrine EPO synthesis in a tissue-specific manner. Bmi-1 is a transcriptional repressor gene which may be expressed restrictedly in stem cells and progenitors and is required to regulate the adult self-renewing hematopoietic and leukemic stem cells. It appears that it also plays an important role in providing cells the potential for proliferation. A number of reports on Bmi-1 provide perspectives on the close association of its expression with the progression of hematopoietic malignancies. Furthermore, flow cytometry has shown that Bmi-1 positivity in CD34+ cells is positively correlated with IPSS score. Introduction: We have designed a study to evaluate changes in gene expression profiles of bone marrow mononuclear cells of primary low and intermediate-1 IPSS risk MDS patients receiving erythropoetic growth factors (darbepoetin or high-dose rHuEpo alpha). Associations with response, changes in Hb, in percentage of CD34+ and apoptotic cells are evaluated. We present preliminary results in 6 patients. Methods: Bone marrow samples were obtained before and after 12 weeks of treatment. Mononucleated cells were cryopreserved and later thawed for total RNA extraction and cDNA synthesis. Gene expression profiling and the expressions of WT1 and Bmi-1 by RT-PCR were evaluated. Results: Baseline median Hb was 9,5 g/dL (interquartile range 8,7 10,1). Baseline mean Bmi-1 was 14011 (± SD 3927). All patients had a major erythroid response to treatment. Preliminary results demonstrate a significant decrease in WT1 from baseline median 1635 (interquartile range 1251–2150) to 1192 (interquartile range 1005–1365, P=0.046). Fig. 1. Changes in WT1 expression during therapy. Fig. 1. Changes in WT1 expression during therapy. Discussion: Though few patients have yet been studied, it is suggested that WT1 decreases in patients responding to erythropoetic growth factors. Further evaluation with stratification for erythropoetic response in the extended study may furnish novel associations between gene expression, erythropoetic growth factors and prognosis in MDS patients.

Description: According to the World Health Organization (WHO) 2008/2016 criteria for classification of myeloid neoplasms, a platelet (PLT) count ≥ 450X109/l, thus reduced from the previous WHO 2001 level ≥ 600 x 109/l, was considered the new PLT threshold for the diagnosis of Essential Thrombocythemia (ET). Aim of the study was to validate in a setting of current clinical practice this important diagnostic change and compare clinical and hematological features at diagnosis and during follow-up of patients with PLT ≥600 x 109/l versus patients with PLT 〈 600 x 109/l. We retrospectively analyzed data from 264 patients with ET according to WHO 2008/2016 criteria, enrolled in our center from 1/2008 to 12/2017. Patients were divided into Group A (G-A) (PLT ≥600 x 109/l at diagnosis) (199 patients - 75.4%) and Group B (G-B) (PLT ≥ 450 x 109/l 〈 600 x 109/l at diagnosis) (65 patients - 24.6%) and compared for clinical features at the onset, clinical course and follow-up. Main features and commonly recognized pro-thrombotic risk factors at diagnosis of the entire cohort as well as of G-A and G-B are reported in the Table 1. Among clinical features, only the median value of leukocytes was significantly higher in G- A [9.1 x 109/l, interquartile range (IQR) 7.8-10.3 vs 7.4 x 109/l, IQR 6.0-9.6; p = 0.001]. Among pro-thrombotic risk factors, only the median cholesterol value was significantly lower in the G-A [187 mg/dl (IQR 164-220) vs 204 mg/dl (RIQ 177-238); p = 0.048]. Cytostatic treatment was administered in 175 patients (71.1%) of entire cohort at different intervals from diagnosis, with a significantly higher rate in patients of G-A (76.9% versus 49.2%, p 1.000 x 109/l, highlights how thrombotic risk is unrelated to PLT value and leads to consider the administration of adequate cytostatic therapy even in patients with relatively lower PLT count at diagnosis. Disclosures Breccia: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Foà:INCYTE: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau.

Description: Abstract 3783 The achievement of Complete Cytogenetic Response (CCyR, Ph+ cells 0%) with Imatinib (IM) treatment still remains a crucial objective in Chronic Myelogenous Leukemia (CML) patients. According to The European Leukemia NET guidelines, CCyR should be achieved within the 12th month of treatment. To address the incidence and prognostic role of a very early achievement of CCyR, we revised 150 chronic phase CML patients [M/F 75/75, median age 56.6 years, interquartile range (IR) 41.8 – 68.4] treated with front-line IM at our Institution from June 2002 to December 2010 who had evaluable karyotype after 3 months of treatment. At onset, median WBC and PLT counts were 75.9 × 109/l (IR 35.3 – 125.5) and 402 × 109/l (IR 281 – 592), respectively. Sokal risk score was low in 72 patients (48.2%), intermediate in 68 (44.8%) and high in 10 (7.0%); a short pre-treatment phase (〈 3 months) with Hydroxyurea (HU) was administered to 132/150 patients (88.0%). Starting daily dose of IM was 400 mg in 133 patients (88.6%), 800 mg in 12 (8.0%) and 300 mg in 5 (3.4%). After 3 months of IM treatment, 118 patients (78.6%) achieved CCyR while 32 patients (21.4%) still presented Ph+ metaphases (〈 33% 14 patients and ≥ 33% 18 patients) at cytogenetic analysis. At univariate analysis, factors with a negative prognostic impact on achievement of CCyR at 3 months were palpable spleen enlargement (p 100.0 × 109/l at onset (p 65 years, Sokal risk score, PLT count 〉 500 × 109/l at onset and pre-treatment with HU did not appear to affect early CCyR achievement. Among the 118 patients in CCyR after 3 months, there were 12 failures (10.1%) during subsequent follow-up (2 suboptimal responses for molecular resistance, 7 cytogenetic relapses, 2 molecular relapses and 1 evolution to blastic phase); among the 32 patients who did not achieve early CCyR, there were 18 failures (56.2%) during subsequent follow-up (12 primary cytogenetic resistances and 6 cytogenetic relapses). The difference in the incidence of failures during follow-up in the 2 groups was highly significant (p

Description: INTRODUCTION: Quality-of-life (QOL) is a patient-related outcome of increasing interest in onco-haematological setting. However, there are very few reports on QOL in elderly patients with Acute Myeloid Leukemia (AML). Prognosis of AML in elderly patients is still poor with a median survival of 9–12 months and less than 20% survival at 5 years. This is due to age-related factors and also to a higher incidence of poor-risk cytogenetics, multi-drug resistance and treatment-related mortality. The measurement of QOL at diagnosis may provide useful information regarding patient preferences and prognosis while followup measurements may indicate acceptance, adaptation and adverse effects of disease and therapy. METHODS: From 2/2003 and 2/2007, we included 113 elderly AML patients in a multicenter Italian 12-month observational study to evaluate the association of baseline QOL scores and their changes with disease factors, therapy and survival. Patients aged 〉 60 years (M/F 58/55, mean age 71.7 ± 5.9 yrs) from 4 Institutions with “de novo” AML according to WHO classification were evaluated from diagnosis prospectively up to 12 months. Two different questionnaires were employed: the EORTC QLQ-C30 and the QOL-E v.2. Therapeutic choice was not restricted by protocol and was given freely by the individual center. RESULTS: Forty-eight patients (43%) received intensive chemotherapy and 65 (57%) lowdose therapy or supportive care. Both age 〉 70 years (p=0.007) and concomitant diseases (p=0.031) had a significative impact on medical decision for palliative approaches. At diagnosis, general QOL was affected (median QOL-E standardized score 54, IQ range 47– 68, median EORTC global score 50, IQ range 42–67), loss of appetite was perceived by 75% of patients and QOL-E fatigue scores were low, indicating poorer QOL (median 45, IQ range 32–53). There was a significant correlation between fatigue and age, Hb levels and the duration of fever. In a multivariate regression model, both Hb and age indipendently predicted fatigue (linear R2 0.114, p=0.001, and linear R2 0.066, p=0,010). Most patients were given a good ECOG Performance Status (〈 2) that, interestingly, did not correlate with the perception of QOL, in particular physical and functional scores. QOL scores worsened after 1 month from diagnosis but patients surviving thereafter perceived an improvement in the following months. When correcting for the effects of age, concomitant diseases and changes in Hb values, fatigue improved in patients undergoing aggressive chemotherapy while it worsened in those on standard or supportive-care (p=0.004). Median overall survival was 49 weeks (95% CI 35–63). Patients receiving aggressive therapy had a longer survival with the median not reached at 60 weeks and 72% of patients surviving versus patients receiving palliative care (median 39 weeks, 95% CI 16–63, p 70 yrs (HR 2.4, 95%CI 1.2 – 5.0, p=0.02) and concomitant diseases (HR 2.0, 95% CI 1.1 – 3.8, p=0.044) had an independent negative prognostic impact on survival, as previously reported in many other studies. However, in order to evaluate the predictive value of QOL at diagnosis for survival, in a multivariate model corrected for age, concomitant diseases and treatment option, QOL measures that independently predicted survival were fatigue (p=0.003), global QOL (p = 0.004), physical QOL (p = 0.006) and functional QOL (p = 0.002). CONCLUSION, QOL seems to have an important role also in the elderly AML setting: though QOL is a highly subjective measurable value, we outline the role of QOL measures at diagnosis as a prognostic factor for overall survival and, thus, as a potential factor for treatment decision.

Description: Dasatinib is a 2nd generation tyrosine-kinase inhibitor active in CML patients resistant or intolerant to Imatinib; at present there is no data on its toxicity and efficacy in elderly patients. To highlight this issue, 37 patients treated with Dasatinib when aged 〉 60 years were retrospectively evaluated. There were 21 males and 16 females, median age at Dasatinb was 69.3 years (IR 64.9–73.0), Sokal Risk at diagnosis was low in 13 patients, intermediate in 14, high in 5 and not valuable in 5. Twenty-two patients (59.4%) were primary resistant, 4 (10.8%) intolerant and 11 (29.8%) secondary resistant to Imatinib; all but 2 patients were in CP when Dasatinib was started. Median time from diagnosis to Dasatinib treatment was 99.2 months (IR 56.8–124.5); 25/37 patients (67.5%) have been pretreated with IFN ± Ara-C before Imatinib, all patients received Imatinib at standard dose (400 mg/day) followed in 20/37 (54%) by Imatinib at increased dose (600–800 mg/day) with an overall median period of Imatinib treatment of 52.8 months (IR 26.2–60.9). In addition, 7/37 patients (18.9%) received other 2nd line treatment (3 with Nilotinib, 2 with Imatinib + HU and 2 with other drugs) before Dasatinib. Starting dose of Dasatinib was 140 mg/day in 18 patients and 100 mg/day in 19 patients, respectively. After a median period of treatment of 9.4 months (IR 3.0–19.1) all patients were evaluable for toxicity; among 18 patients receiving 140 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 14 (77.7%) and 6 (33.3%) patients, respectively; among 19 patients receiving 100 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 4 (21.0%) and 1 (5.2%) patients, respectively. Pleuro-pericardial effusions occurred in 3 patients, all treated with 140 mg as starting dose. Overall, 3/37 patients (all treated with 140 mg) discontinued permanently Dasatinib due to early toxicity; a dose reduction was needed in 17/37 patients [16/18 (88.8%) treated with 140 mg and 1/19 (5.2%) with 100 mg]. As to response, 28 patients were considered evaluable (≥ 6 months of treatment) and 9 considered as too early; five patients (17.9%) did not have any response (including 3 patients with early Dasatinib discontinuation for toxicity) and 23 (82.1%) achieved Complete Haematological Response (CHR). Furthermore, 11/28 patients (39.2%) achieved a Cytogenetic Response (CyR) (Major CyR in 4 and Complete CyR in 7) and 4/28 patients (14.2%) achieved a molecular response. In conclusion, Dasatinib, when employed at the current recommended starting dose of 100 mg/day; seems effective and very well tolerated also in heavily pretreated elderly subjects; these results are encouraging also for a future use of this drug in early chronic phase elderly patients.

Description: Median age of patients with CML is about 65 years, according to SEER 2000–2005 data. However, the treatment with Imatinib in elderly has been seldom specifically addressed: in particular, there is a lack of data regarding very elderly CML patients. To highlight peculiar aspects of toxicity and efficacy of Imatinib in this subset which accounts for at least 10–15% of all CML cases, we revised retrospectively 28 CML patients treated with Imatinib when aged 〉 75 years from 4 haematological Institution in Rome; there were 12 males and 16 females, median age at Imatinib was 78.7 years (IR 75.8 – 82.9), Sokal Risk at diagnosis was intermediate in 20 patients, high in 6 and not valuable in 2. One or more concomitant diseases requiring specific treatments were present in 26/28 patients (92.8%), with 15 patients (53.5%) assuming 3 or more concomitant drugs. Nine patients (32.1%) have been pretreated ≥ 6 months with HU before starting Imatinib; on the whole, median time from diagnosis to Imatinib was 1.8 months (IR 0.7 – 25.1). Starting dose of Imatinib was 400 mg/day in 23 patients (82.1%) and 300 mg/day in 5 patients (17.9%); overall, 15 patients (53.5%) (14/23 at 400 mg starting dose and 1/5 at 300 mg starting dose) needed a dose reduction and 6 (21.4 %) discontinued Imatinib for toxicity (early toxicity in 4 and late toxicity in 2). Excluding the 4 patients who discontinued Imatinib due to early toxicity, maximum tolerated daily dose during treatment was 400 mg in 8 patients, 300 mg in 13 patients and 200 mg in 3 patients. According to CTC-AE, grade 3 – 4 haematological and extra-haematological toxicities were observed in 7 (25%) and 12 (42.8%) patients, respectively; 2 patients (7.1%) presented a pleural effusion during Imatinib treatment. All patients were fully evaluable for response to Imatinib, with a median treatment period of 30.6 months (IR 15.7 – 49.2); six patients (21.4%) failed any response, (including 4 patients who discontinued Imatinib due to early toxicity) and 22 (78.6%) achieved a complete haematological response (CHR). Among these 22 patients in CHR, 4 refused any other karyotipic or molecular evaluation (3 are still alive in CHR, 1 died in CHR from unrelated cause after 44,5 months) and 17/18 (60.7% of all 28 patients) achieved a cytogenetic response (CyR), major in 1 patient and complete in 16 patients. In addition, 7 patients (25% of all 28 patients) achieved a complete molecular remission, with an undetectable BCR/ABL hybrid gene at qualitative nested PCR. In conclusion, Imatinib at reduced daily dose of 300 mg seems a relatively safe and quite effective treatment for very elderly CML patients; from our data, no upper age limit should be given for TKinhibitors treatment but also very elderly (and with concomitant severe diseases) patients should have this chance of cure.

Description: Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

Description: There is a high prevalence of thromboembolic events in myeloproliferative syndromes (MPS) ranging from 20% to 40% as compared to the general elderly Italian population (males 2.4–3.6%, females 1.1–1.9%, data from Progetto Cuore). In particular, in Polycythemia Vera (PV), cardiovascular events (CVE) represent a major cause of mortality. In MPS, in addition to common cardiovascular (CV) risk factors (RF), the role of disease-related hemostatic abnormalities are far from being elucidated. A retrospective chart review in 463 patients in 3 Italian hematology centers was performed to evaluate the prevalence of CVE and to identify RF in patients with MPS diagnosed between 1977 and 2006. Mean age was 59 (range 17–89) years, 237 M/ 226 F. CVE were recorded in 164 patients.One hundred (21.6%) patients had a CVE before diagnosis: Essential Thrombocytemia (ET) 41/173 (24%); Myelofibrosis (MF) 13/43 (30%); PV 36/142 (25%); other MPS 2/12; Hypereosinophilic Syndrome 1/6; Hypoplasia 1/7; Myelodysplastic Syndromes (MDS) 4/28 (14%); CML 1/51 (2%) and the only patient with CMMoL. Comparing to CML, the risk (OR) of CVE in patients with ET was 12.1 (p=0.001, 95% CI: 1.7–85.7), with PV 12.8 (p=0.006, 95% CI: 1.8–91.3), and with MF 15.4 (p=0.004, 95% CI: 2.1–113.1). However, after adjusting for age, sex, dyslipidemia, diabetes, arterial hypertension, chronic renal failure, and tobacco use, there was no significant difference in CV risk between these MPD. In a logistic regression analysis, the overall independent factors associated with a history of CVE were hypertension (p

Description: Treatment of acute myeloid leukemia (AML) in elderly patients is generally tailored on the basis of age, performance status, concomitant diseases and patient consent. Toxicity and low-response rates are major constraints and therapeutic options are most likely conditioned by clinicians’ opinions rather than patient preferences. Health-related quality of life (HRQoL) may be useful in this setting. We designed a prospective multicenter study to evaluate the predictive potentials of HRQoL measures on prognosis in AML patients aged over 60 years. We present results in 95 patients of median age 72 (range 61–90) years. HRQoL was measured by the QOL-E and the EORTC QLQ-C30 questionnaires. Demographic and disease-related factors were also evaluated. The questionnaires showed good internal consistencies. Scores were low at baseline (reflecting poor HRQoL), particularly in the QOL-E fatigue (41.8), disease-specific (33.2) and treatment-related index (S_TOI=53.1) scales. Increasing age was correlated with concomitant diseases (r=0.256, p=0.012) and with EORTC global health (r=−0.217, p=0.041), QOL-E general/total (r=−0.239, p=0.022 / r=−0.247, p=0.019), physical function (QLQ-C30 r=−0.304, p=0.003; QOL-E r=−0.249, p=0.016), role function (QLQ-C30 r=−0.347, p=0.001), functional and fatigue (QLQ-C30 r=0.329, p=0.001; QOL-E r=−0.301, p=0.003) and QOL-E S_TOI (r=−0.281, p=0.007) scores. The presence of concomitant diseases was associated with poorer general health (p=0.019), physical well-being (p=0.011), role (p=0.026) and emotional function (=0.036). Baseline Hb levels correlated with fatigue, pain, dyspnea, insomnia, appetite loss and role function (QLQ-C30 p

Description: Introduction: Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by excessive red cell production and release of pro-inflammatory cytokines resulting in increased thrombotic risk, presence of systemic symptoms and reduced overall survival (OS). Abnormal body mass index (BMI) and comorbidities, as categorized by the Charlson Comorbidity Index (CCI), were found to influence treatment success and survival in several hematological malignancies, including myelofibrosis (MF). We evaluated the impact of CCI and BMI on the outcome of PV pts on the basis of real-world data. Methods: A network called "PV-NET" started in January 2019 including clinical/laboratory data of 2016 WHO-defined PV pts diagnosed and followed in 16 European Hematology Centers. Data cut-off was June 2019. OS was calculated from PV diagnosis to last contact or death (log-rank p). Cumulative incidences of events (thromboses, hemorrhages, infections, second neoplasia, and evolution into blast phase [BP] or MF) were conducted with Fine & Gray model with death as competing risk. Therapies were treated as time-to-event variables. Results: A total of 530 PV pts were collected. Median follow-up was 5.4 yrs (0.5-34) (total observation: 3633 pt-yrs). Main characteristics at diagnosis were: median age: 62.4 yrs (18.3-89.5); males: 53.4%; median (range) leukocyte/platelet count, x109/l: 9.8 (1.1-33)/448 (143-1386); median hemoglobin (g/dl)/hematocrit (%): 18.6/56 (males); 17.6/54.4 (females). Sixty-four (12.1%) and 34 (6.4%) pts had a thrombosis prior to or at diagnosis, respectively. At least one cardiovascular risk factor (CVRF) among smoke, diabetes, and hypertension was present in 343 pts (64.7%). Age-adjusted CCI was 0 (15.9%), 1 (18.9%), 2 (23.8%), and ≥3 (41.5%). Median BMI was 24 (17.4-37.3); 3.3%, 51.2%, 35.9% and 9.6% were underweight (BMI