Improved Survival from Transfusion Dependence in Lower-Risk MDS Receiving Iron Chelation, Adjusting for MDS and Patient Characteristics: An MDS-Can Analysis

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Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167

the clonogenic assays carried out before treatment point to impairment in patients MNCs-derived CFU growth compared with controls (Figure 3a). This capacity trends to improve after DFX treatment, when the ratio cluster/CFU approximates to control values (Figure 3-b).

Conclusion: We can conclude that BM cells in pre-treated MDS patients showed a higher oxidative stress conditions and poor hematopoietic differentiation in vitro. These adverse features seem to be restored after DFX treatment in vitro.

283 IMPROVED SURVIVAL FROM TRANSFUSION DEPENDENCE IN LOWER-RISK MDS RECEIVING IRON CHELATION, ADJUSTING FOR MDS AND PATIENT CHARACTERISTICS: AN MDS-CAN ANALYSIS H.A. Leitch1, R.A. Wells2, L. Chodirker2, N. Zhu3, T.J. Nevill4, K.W.L. Yee5, B. Leber6, M.M. Keating7, M. Sabloff8, E. St. Hilaire9, R. Kumar10, R. Delage11, M. Geddes12, J.M. Storring13, A. Shamy14, M. Elemary15, M. Lenis2, J. Francis2, L. Zhang2, R. Buckstein2 1 Hematology, St. Paul’s Hospital- University of British Columbia, Vancouver, British Columbia, Canada; 2Hematology, Odette Cancer Centre- Sunnybrook Health Sciences Centre, Toronto- Ontario, Canada; 3Hematology/Oncology, University of Alberta, EdmontonAlberta, Canada; 4Hematology, Leukemia/BMT Program of British Columbia, Vancouver, British Columbia, Canada; 5Hematology, Princess Margaret Cancer Centre- University Health Network, Toronto- Ontario, Canada; 6Hematology, McMaster University, Hamilton, Ontario, Canada; 7Hematology, Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada; 8Hematology, Ottawa General Hospital, Ottawa, Ontario, Canada; 9Hematology, Centre d’Oncologie- Dr-Leon-Richard, Moncton, New Brunswick, Canada; 10 Hematology/Oncology, CancerCare Manitoba, Winnipeg, Manitoba, Canada; 11Hematology, Centre Hospitalier Universitaire- Laval University, Quebec City, Quebec, Canada; 12Medicine/Hematology, Foothills Medical Centre, Calgary, Alberta, Canada; 13Hematology, McGill University Health Centre, Montreal, Quebec, Canada; 14 Hematology, Sir Mortimer B Davis Hospital- McGill University, Montreal, Quebec, Canada; 15Hematology, Saskatoon Cancer CenterUniversity of Saskatchewan, Saskatoon, Saskatchewan, Canada Background: Iron overload (IOL) is a common complication of red blood cell (RBC) transfusion dependence (TD) in MDS patients. Previous analyses suggest IOL adversely impacts overall survival (OS) and case control studies have demonstrated that iron chelation therapy (ICT) attenuates this survival impact, but these data are possibly biased by unbalanced yet impactful patient-related factors. The Canadian MDS registry prospectively measures patient frailty, comorbidity and disability. We analyzed the impact of ICT on OS, adjusting for both MDS- and patient-related factors. As time to RBC TD may introduce lead-time bias, we performed the survival analyses from TD rather than from MDS diagnosis. Methods: TD MDS patients with low and intermediate-1 IPSS risk scores (at the time of RBC TD) were included. Patient and disease characteristics at MDS diagnosis and RBC TD were compared according to the receipt of ICT. Univariate and multivariate (MVA) Cox proportional hazard models determined predictive factors for OS. With the possibility that there may be differences between ICT and non-ICT patients in age, IPSS-R scores, number of RBC units/ month received and time from MDS diagnosis to RBC TD favoring ICT patients, a matched pair analysis considering these factors was conducted. Results: 83 of 239 patients with adequate data for this analysis received ICT. The median duration of ICT was 12.4 (interquartile range 4.4, 24.6) months. The clinical frailty score, Charlson Comorbidity Index (CI), MDS-CI and Lawton-Brody Disability Score did not differ between ICT and non-ICT patients ( p = NS for all). Median OS from TD was superior in ICT versus non-ICT patients (5.2 vs. 2.1 years, respectively; p < 0.0001). By MVA, not receiving ICT independently predicted inferior OS, (HR 1.9 [95% CI 1.1–3.7], p = 0.0334). In a matched pair analysis the superior survival of ICT patients was still observed (5.2 vs 2.2 years, respectively; p = 0.015; see Figure). Leukemia-free survival did not differ significantly between ICT and non-ICT patients either in the whole group or in the matched pair analysis ( p = NS for both).

Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167

Conclusion: Receiving ICT remained an independent predictor of superior OS, both from RBC TD, even adjusting for age, frailty, comorbidity, disability, IPSS-R, TD severity and time to TD. These data provide the strongest evidence to date that ICT may confer significant benefit in lower IPSS risk MDS.

284 A REAL-LIFE STUDY OF DEFERASIROX IN PATIENTS WITH HIGHER RISK MYELODYSPLASTIC SYNDROMES P. Musto1, L. Maurillo2, V. Simeon3, A. Poloni4, C. Finelli5, E. Balleari6, A. Ricco7, F. Rivellini8, A. Cortelezzi9, G. Tarantini10, O. Villani11, M. Breccia12, P. Niscola13, A. Sanna14, C. Clissa15, M.T. Voso2, S. Fenu16, A. Venditti2, V. Santini14, E. Angelucci6 1 IRCCS CROB, Scientific Direction, Rionero in Vulture PZ, Italy; 2 Department of Biomedicine and Prevention, Tor Vergata University, Haematology, Rome, Italy; 3IRCCS CROB, Laboratory of Pre-clinical and Translational Research, Rionero in Vulture PZ, Italy; 4Department of Clinic and Molecular Sciences, Università Politecnica delle Marche, Haematology Clinic, Ancora, Italy; 5University School of Medicine, Seràgnoli Institute of Haematology, Bologna, Italy; 6Department of Haematology and Oncology, IRCCS AOU San Martino – IST, Genova, Italy; 7Department of Emergency and Organ TransplantationHaematology Section, University of Bari, Bari, Italy; 8A. Tortora Hospital, Onco-Haematology, Pagani SA, Italy; 9DepartmentUniversity of Milan and Fondazione IRCCS Ca” Granda- Ospedale Maggiore Policlinico, Department of Oncology and Haemato-Oncology and Haematology Unit, Milan, Italy; 10Di Miccoli Hospital, Haematology Unit, Barletta, Italy; 11Department of Onco-Haematology, IRCCS CROB, Rionero in Vulture PZ, Italy; 12Department of Cellular Biotechnologies and Haematology, La Sapienza University, Rome, Italy; 13Haematology Unit, S. Eugenio Hospital, Rome, Italy; 14Haematolog, University of Florence- AOU Careggi, Florence, Italy; 15AORMN, Haematology and Haematopoietic Stem Cell Transplant Center, Pesaro, Italy; 16 Haematology, San Giovanni Hospital, Rome, Italy Limited data are currently available about the use of iron-chelating therapies in higher risk myelodysplastic syndromes (HR-MDS). We evaluated use, efficacy and safety of the oral chelator deferasirox (DFX) in a real-life, retrospective study of 51 patients with transfusion-dependent, intermediate-to-very high R-IPSS risk MDS conducted across 14 italian haematology centers belonging to the two major national registries (FISM and GROM) and to GIMEMA MDS Working Party. The patients represented 14% of all HR-MDS cases observed in the participating Centres during the study period. The reasons why the investigators chose to treat their

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patients with DFX were: (a) candidates for allogeneic transplant (16%); (b) high transfusion burden (33%); (c) stable/responsive disease under life-extending therapies (47%); (d) unspecified (4%). Thirty-four patients were males and 17 females; median age was 65 years (range 36–83). R-IPSS was intermediate in 7 patients, high in 29 patients and very high in 15 patients. Median time from diagnosis to DFX treatment was 11.1 months (range 0–84.9). The median number of transfusions received before starting DFX was 23 (range 2–60). Thirty-five patients had been previously treated with r-HuEPO, azacitidine, or both. DFX was given at a median dose of 1,000 mg per-day (range 375–2,500 mg) for a median of 11 months (range 0.4–75). The initial daily dose/kg was 5 mg in 8%, 10 mg in 42%, 20 mg in 48%, and 30 mg in 2% of patients, respectively. Thirty-nine patients continued or started concomitant treatments during DFX therapy (mostly azacitidine, 71%). Eight patients (16%) showed grade 2–3 toxicities (renal or gastrointestinal) and 4 of them (8%) required drug interruption. In evaluable patients, median ferritin levels decreased from 1,709 ng/mL at baseline (range 460–7,293) to 1,100 /mL after 12 months of treatment (range 198–4,282) ( p = 0.02). Eight out of 17 patients (47%) with initially abnormal ALT/AST levels improved or normalized transaminase levels under DFX treatment. One patient achieved a complete and durable haematological response, without receiving any other active therapy when this response occurred. At a median follow up of 35.3 months from diagnosis and 21.4 months after the start of DFX, median overall survival was 37.5 and 24.4 months, respectively, with 19 (37%) leukemic evolutions. The results of this first survey focused on DFX in HR-MDS are comparable with those observed in lower-risk cases and suggess that DFX is feasible and might be considered in selected HR-MDS patients, particularly in those who concomitantly receive azacitidine.

285 FULL DOSE OF DANAZOL IS A HIGHLY EFFECTIVE TREATMENT OF CYTOPENIA IN LOWER RISK MYELODYSPLASTIC SYNDROMES F. Schieppati1, A.M. Pelizzari1, E. Borlenghi1, A. Passi1, M. Farina1, V. Orlando1, G. Rossi1 1 Hematology Department, ASST Spedali Civili di Brescia, Brescia, Italy Introduction: Recent discovery of danazol potential activity on telomere elongation in bone marrow failure has elicited renewed interest in this drug. Here we report on the efficacy of danazol in cytopenic MDS patients at a single institution, classified by IPSS and IPSS-R. Methods: From Jun-’11 to May-’15, danazol was administered to 20 consecutive MDS cytopenic patients. Criteria for treatment were: transfusion dependency (TD) despite erythropoietin (ESA) therapy, isolated thrombocytopenia, or bicytopenia including ANC < 1 × 109/ L. OR was assessed by IWG 2006 criteria. Results: Median age was 70 (53–86), male 11/20. Twelve patients were TD, 15 had thrombocytopenia (<50 × 109/L), and 7 were bicytopenic. Twelve patients received the full dose of 600 mg daily. A 400 mg daily dosing was given to 8 patients, due to toxicity (4) and comorbidities (4). Median duration of treatment was 6 months (1–60). ORR was 50%. Hematological improvement on platelets, hemoglobin and ANC was seen in 9 (90%), 4 (40%) and 2 (20%) patients, respectively. All patients had a lower-risk disease according to IPSS and IPSS-R, except 2 and 3 patients respectively; non-responders had a higher rate of TD, were more thrombocytopenic and neutropenic than responders (Table). Interestingly, duration of response was significantly higher in the 600 mg arm compared to the 400 mg ( p = 0.001, Figure). Adverse events were: hepatotoxicity (3 G1, 1 G3), muscle pain/CPK elevation (2 G1), transient renal impairment (1 G1), hyporexia (1 G1). Drug