ALBERT

Description: Background: Severe thrombocytopenia is an uncommon event in lower risk MDS patients, but it may significantly influence the prognosis. In fact, when it occurs, major bleeding may be a life-threatening complication. No licensed pharmacologic approach is nowadays available yet for these patients. Eltrombopag seems to be a very interesting product, but its efficacy and safeness are still to be better demonstrated. Romiplostim could be suitable too, but, at present, its safety is uncertain in MDS patients. Also danazol, an attenuated androgen, seems to have some ability to increase the platelet count in this context. Patients and methods: We retrospectively reviewed 17 thrombocytopenic patients affected by MDS, treated with danazol and observed for at least 6 months. Three patients of these had a therapy-related MDS. At the starting time of danazol therapy, the IPSS was “low” or “intermediate-1” in 16 cases; “intermediate-2” in 1 case. The IPSS-R was “very low”, “low” or “intermediate” in 16 cases; “very high” in 1 case. In 14 patients the platelet count was lower than 25x109/L, in the other 3 lower than 40x109/L, but with spontaneous bleeding. The initial dose was 600 mg/day for all the patients. The IWG criteria of response (Cheson 2006) were adopted. The outcomes were observed after 3 and 6 months from the beginning of therapy. Only descriptive statistical analysis was used. Results: At the beginning of therapy, the average platelet count of the 17 patients was 22.6 x109/L (S.D. 8.8, range 6-38). After 3 months, the therapy with danazol was ongoing in 16 patients (in 1 case the drug was discontinued due to renal failure). Platelet improvement, according to IWG criteria, was observed in 8 cases (47%). The average platelet count was 45.3x109/L (S.D. 32.9, range 4-133). The only one “high risk” patient did not show response. After 6 months danazol was still ongoing in 11 patients (in 5 cases the drug was stopped for inefficacy). The response according to IWG criteria was evident in 9 patients (52% of the initial 17 patients). The average platelet count was 66x109/L (S.D. 63.9, range 11-218). Adverse events recorded were as follows: increase in transaminases in 3 cases (in 2 of these the dose was reduced to 400 mg/day); severe but reversible renal failure in 1 case (the drug was stopped); moderate increasing of serum creatinine in 1 case (the drug was reduced to 400 mg/day); reversible cutaneous rush (the drug was reduced to 400mg/day); amenorrhea in 1 case (the only fertile woman in the series); weight loss and loss of appetite in 1 case, weight gain in 1 case. Conclusions This series confirms the efficacy of danazol to improve platelet count in approximately half of patients with severe thrombocytopenia due to “low-risk” MDS. In all patients with increased platelet count, the response was clinically significant. The response may not be immediate. Actually, there was an improvement of platelet count even after three months of therapy. The toxicity profile of this drug is low. The mechanism of action of danazol in MDS patients remains unclear. Waiting for more information on the efficacy and safety of eltrombopag from the clinical trials in progress, danazol may be a good therapeutic option for these patients. Disclosures Off Label Use: Danazol in MDS patients with severe trhombocytopenia.

Description: Background Anemia is a common symptom in patients with Myelodysplastic Syndromes (MDS) and although erythropoietic agents are often active, it is frequently treated with red blood cell (RBC) transfusions. A substantial proportion of patients might also eventually become transfusion-dependent and, Iron-chelating therapies might be important to minimize complications of iron overload. Objectives To investigate the impact of deferasirox therapy on health-related quality of life (HRQOL) of lower risk transfusion-dependent MDS patients over a one year period. Secondary objectives were to investigate relationships between HRQOL and ferritin levels and to explore the prognostic value of baseline HRQOL on the probability of achieving transfusion independence. Patients and Methods This was a prospective study whose clinical findings (i.e., primary endpoint was safety and tolerability) were previously reported. HRQOL was a secondary endpoint of the study and we herein report, for the first time, HRQOL prospective findings. Eligible patients included: MDS patients 18 years or older, International Prognostic Scoring System (IPSS) low or intermediate-1 risk and diagnosed with transfusional siderosis following a minimum of 20 blood transfusions. Patients received daily oral deferasirox at a dose between 10 and 30 mg/kg of body weight for a period of 1 year. HRQOL was assessed with the EORTC QLQ-C30. HRQOL at baseline and at 3, 6, 9 and 12 months after treatment start. The EORTC QLQ-C30 consists of 30 items and includes five functional scales (physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and vomiting and pain) and a global health status/QOL scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). The mean trend of HRQOL over time was estimated via a linear mixed model with a one-step autoregressive covariance structure. Such covariance structure provided the best model fit among those investigated. Results Overall, 159 patients were screened at 37 centers. The median duration of disease at enrollment was 32 months and median number of units of packed RBC received was 37. Seven patients did not start treatment at all and thus there were 152 expected HRQOL forms at baseline assessment. Out of these, 146 patients returned the questionnaire yielding a baseline compliance of 96%. No statistically significant differences over time were found for any scale of the EORTC QLQ-C30. Figure 1 depicts mean scores over time for selected scales of: fatigue, physical functioning, pain and global HRQOL. No HRQOL differences were found between patients with serum ferritin levels lower or higher than 2000 μg/L (pretreatment median value) at baseline. Also, the possible impact of ferritin level on HRQoL over time was estimated via a linear mixed model with a one-step autoregressive covariance structure. Coefficients and p values are reported in table 1. The prognostic impact of baseline HRQOL on the probability of achieving transfusion independence (i.e., defined as freedom from transfusion for 3 consecutive months) was investigated. Higher severity of pain (P=0.007) was associated with a greater likelihood of achieving transfusion independence. Multivariate analysis, controlling for age, IPSS risk score, time from diagnosis, number of previous blood transfusions and baseline ferritin level confirmed the independent value of pain (P=0.003). Conclusion Current findings suggest that Deferasirox therapy does not decrease HRQOL in lower risk transfusion-dependent MDS patients. Patients with higher baseline pain severity seems more likely to achieve transfusion independence and further analysis is needed to understand underlying reasons. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4959 Few epidemiological data about IFI in chronic lymphoid malignancies are available in literature. Our aim is to describe epidemiology, clinical manifestations and outcome of IFI in these patients (pts). We reviewed the records of pts with lymphoproliferative disorders, treated between 2004 and 2010 for probable/proven IFI, according to the revised criteria of EORTC/MSG. We registered 40 probable/proven IFI. Twenty-five pts were affected by lymphoma, 9 by CLL, 3 by Waldenström macroglobulinemia, 2 by multiple myeloma and 1 by hairy cell leukemia. The median age was 57 years (r: 17–71). Twenty-nine pts (75%) had progressive/relapsed hematological disease, and 75% were treated with multiple lines of chemotherapy. Risk factors for IFI were: neutropenia (11 pts), previous solid organ transplant (3) or allogeneic HSCT (3), treatment with high dose steroids (3), monoclonal antibodies (MABs) such as rituximab (9) and alemtuzumab (3), nucleosidic analogues (3) or multiple of these factors (8). Regarding mortality the following factors were evaluated: deep and prolonged neutropenia, multiple lines chemotherapy, MABs and purine analogues administration, diagnosis and status of the underlying disease. Incidence of IFI was 2,7%; (moulds 2%, yeasts 0,4%, mixed infections 0,3%). We recorded 7 yeast infections: 6 were documented by cultures (3 C. albicans, 2 C. glabrata and 1 Blastoschyzomices capitatus), and 1 by the microscopic observation of Candida spp in the vitreum. Thirty pts developed an invasive mould infection (IMI); 3 of them had a proven pulmonary IMI diagnosed by histology (2 Aspergillus spp, 1 Mucor). Twenty-seven pts had a probable IMI: 24 had lung involvement, 2 a sinusal localization, and 1 a pulmonary infection disseminated to brain. Mycological criteria were more often provided by the positivity of the galactomannan antigen (GM, 14 pts) in serum and/or BAL fluid. Cultures resulted positive in 12 cases (5 A. fumigatus, 2 Aspergillus spp, 2 A. flavus, 1 A. niger, 1 Fusarium and 1 for both Scedosporium and Aspergillus); in 4 of them, both GM and culture positivity from the BAL fluid were present. Finally, we observed 3 mixed infections by both moulds and yeasts: in 2 pts a proven yeast infection with isolation in the blood culture (1 C. albicans, 1 C. glabrata) was associated to a probable IMI with the positivity of CT scan and GM; in 1 pt autopsy revealed a pneumonia by Candida spp and a disseminated infection by Aspergillus spp. Eight of 40 pts died due to infection, but only in one pt IFI was the unique cause of death. IFI attributable mortality rate was 20%. At the univariate analysis, the only risk factor related to mortality was the administration of multiple lines of chemotherapies (p 0.04). Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 923 Introduction: The increased risk of bleeding in myelodysplastic syndromes (MDS) is due to low platelet (PLT) counts and abnormalities of PLT morphology and function. Severe thrombocytopenia occurs in about 10% of low and Int-1 International Prognostic Scoring System (IPSS) risk MDS patients in whom PLT transfusions are indicated mainly in the presence of bleeding. Short therapeutic effect and the development of refractoriness to PLT transfusions motivate research in novel treatments. Eltrombopag is an oral, non peptide, non-competitive agonist of the thrombopoetin-receptor (TPOR) which interacts selectively with the TPOR transmembrane domain to initiate TPO signaling. Eltrombopag is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura. Its potential in increasing PLT count in lower risk MDS has not been evaluated. Study Design and Methods: We present preliminary results of a Phase II, multicentre, prospective, placebo-controlled, single blind study to evaluate the safety and efficacy of eltrombopag in low and intermediate-1 risk adult MDS patients with PLT count 200 Gi/L or adverse events. PLT response is defined as Response (R) if: 1) baseline 〉 20 Gi/L: absence of bleeding and absolute increase in PLT ≥ 30 Gi/L/mm3; 2) baseline 〈 20 Gi/L: PLT

Description: Abstract 4945 Background: bone marrow blast count is a crucial parameter to determinate the prognostic score according to IPSS in myelodysplastic syndromes. However even among the major experts the agreement about detection of a blast cells by optical microscopy is less than 90% (Mufti et al: Haematologica 2008). The aim of this study is to evaluate prognostic significance of immunocytometric count of medullar blasts compared to cytological count. Method: in a retrospective analysis of 104 patients with a minimum follow-up of three years, IPSS was calculated replacing cytological count of blasts with the flow cytometry one. Blasts were expressed as percentages of total cellularity, and identified by the combination of CD45/SSC with/without CD33, CD34 and CD117 antigens. The monoclonal antibodies used were CD34 FITC, CD117 PE, CD45 PerCp, CD33 APC. Acquisition of information on 1×105 stained cells corresponding to the whole bone marrow cellularity was assessed on a dual-laser FACSCalibur flow cytometer using the CellQUEST software (Becton Dickinson, San José CA USA). Survival of “low + intermediate-1 risk” (“IPSS1+2”) patients was compared to “intermediate-2 + high risk” ones (“IPSS3+4”) using Kaplan Meier method followed by logrank test. The comparison of ability among all blast count models to distinguish the probability of survival of the two groups (“IPSS 1+2” vs “IPSS3+4”) was based on χ2 value obtained by the logrank test. Results: considering IPSS obtained from any of the immunocytometric markers considered (CD33, CD34, CD117 and CD45dim/SSC), “IPSS1+2” group had always an extremely better survival than “IPSS 3+4” group with a level of statistical significance similar to survival study of “standard IPSS”. Of all markers, CD45dim/SSC was the most capable to distinguish survival of “IPSS1+2” group versus “IPSS3+4” group (χ2 = 42. 5). Among others, CD117 and CD33 had a better discriminating power than cytological count (respectively χ2 = 38, 1 and χ2 = 22, 3 versus χ2 18, 2); only CD34 was worse than cytological count (χ2 =14, 2). Conclusion: the immunocytometric markers considered are demonstrated to be even better than cytological count as parameter in IPSS score. Their use has to be encouraged, especially where there is little experience in optical microscopy. Disclosures: No relevant conflicts of interest to declare.