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Low-risk patients with myelodysplastic syndromes (MDS) are inclined to long-term accumulation of iron in the organs due mostly to red blood cell transfusion and ineffective erythropoiesis. The effect of free toxic iron species in the liver and heart sites is well known, but recent knowledge assumes that oxidant-mediated tissue injury is also effective in the bone marrow. We aimed to investigate the predictive value of bone marrow iron accumulation as demonstrated by Perls staining on the overall survival (OS) of MDS patients. We retrospectively analyzed 114 low and intermediate-I IPSS risk MDS patients who were diagnosed at our institution in the last 20 years. The median age was 70 years (range 32–93). Two different experienced hematologists analyzed all samples. Perls Prussian blue stain was used to stain the bone marrow, which was assessed by modified Gale’s grading and then correlated with the outcome. Twenty-seven patients had grade 1 (+), 31 grade 2 (++), and 56 grade 3 (+++). The 20-year OS was significantly lower in patients with a higher Perls score (6.8 ± 6.1%, median 80 ± 7 months in grade 3; 18.7 ± 9.4%, median 70 ± 17 months in grade 2; 33.2 ± 16.4%, median 144 ± 18 months in grade 1; p = 0.011); bone marrow iron overload (p = 0.003; HR 1.7) and transfusion dependency (0.001; HR 2.6) negatively impacted on survival. We suggest that a higher grade of iron storage at diagnosis can impact on the outcome in MDS patients. Perls stain, together with ferritin and the blood transfusional burden, could be another marker at diagnosis of iron-related toxicity that predicts survival.

Background Erythropoiesis‐stimulating agents effectively improve the hemoglobin levels in a fraction of anemic patients with myelodysplastic syndromes (MDS). Higher doses (HD) of recombinant human erythropoietin (rhEPO) have been proposed to overcome suboptimal response rates observed in MDS patients treated with lower “standard doses” (SD) of rhEPO. However, a direct comparison between the different doses of rhEPO is lacking. Methods A cohort of 104 MDS patients treated with HD was retrospectively compared to 208 patients treated with SD in a propensity score‐matched analysis to evaluate hematological improvement‐erythroid (HI‐E) rate induced by the different doses of rhEPO. The impact of rhEPO doses on survival and progression to leukemia was also investigated. Results Overall HI‐E rate was 52.6%. No difference was observed between different rhEPO doses (P = .28) in matched cohorts; in a subgroup analysis, transfusion‐dependent patients and patients with higher IPSS‐R score obtained a higher HI‐E rate with HD, although without significant impact on overall survival (OS). Achievement of HI‐E resulted in superior OS. At univariate analysis, a higher HI‐E rate was observed in transfusion‐independent patients (P, When compared in a propensity‐score matched analysis, standard doses of rhEPO showed similar effects to those of higher doses in anemic MDS patients. Achievement of favorable response with hematologic improvement in this clinical scenario is possible by reducing drug doses and costs.

Iron is essential in cellular life, however, when in excess, it favors the production of reactive oxygen species (ROS) that, when overwhelm the physiological cellular antioxidant system, produce an oxidative stress state leading to cellular damages and organ failure. What is not yet completely clear is whether the damage is related more to the amount of iron or to the duration of exposure to ROS. Various cellular pathways are sensitive to the detrimental action of ROS in a non-dose-dependent manner. In addition, different organs have a different capacity to respond to iron-mediated toxicity, suggesting that the toxicity thresholds are disease-specific and patient-dependent. The aim of this article is to review the recent understanding of the concept of exposure to free iron-mediated damage, comprehending the need to design protocols in which reducing organ exposure to ROS is the primary objective in order to prevent or delay the development of organ damage.

Excess iron can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Preclinical studies on the role of free iron on bone marrow function have shown that iron toxicity leads to the accumulation of reactive oxygen species, affects the expression of genes coding for proteins that regulate hematopoiesis, and disrupts hematopoiesis. These effects could be partially attenuated by iron-chelation treatment with deferasirox, suggesting iron toxicity may have a negative impact on the hematopoietic microenvironment. Iron toxicity is of concern in transfusion-dependent patients. Importantly, iron chelation with deferasirox can cause the loss of transfusion dependency and may induce hematological responses, although the mechanisms through which deferasirox exerts this action are currently unknown. This review will focus on the possible mechanisms of toxicity of free iron at the bone marrow level and in the bone marrow microenvironment.

Recently, after years of research often characterized by disappointments and frustrations, finally a new drug impacting on pathological human erythropoiesis has been developed and approved. This drug, luspatercept-aamt (Reblozyl), proved to be effective in both malignant and nonmalignant disease characterized by ineffective erythropoiesis with consequent life-threatening severe anemia. Moreover, for the first time, a medication demonstrated efficacy and effectiveness in β-thalassemia where no other drug, including recombinant human erythropoietin, showed effectiveness in improving anemia. Despite recent impressive advances in understanding human normal and abnormal erythropoiesis, there are few new drugs and limited pharma research focusing on ineffective erythropoiesis. This review will discuss recent advances in understanding normal and pathological erythropoiesis that represent the background to discuss pharmacology, toxicology, efficacy, safety and effectiveness of this new drug for the treatment of human β-thalassemia.

Iron, although essential, is harmful in high amounts. Oxidative stress as a result of excess reactive oxygen species (ROS) and a prooxidative/antioxidative imbalance between ROS production and elimination, play a key role in cellular damage. There is evidence to support the role of ROS in the pathogenesis of a range of diseases including the myelodysplastic syndromes (MDS) and leukaemia. Oxidative stress seems to affect the self-renewal, proliferation and differentiation of haematopoietic stem cells and impair cell growth. Three aspects of these defective haemopoietic mechanisms may be associated with the activities of ROS: clonal evolution, haematological improvement and recovery of haemopoiesis after haematopoietic stem cell transplantation (HSCT). This review aims to provide haematologists with an overview of results from in vitro and murine models and preliminary clinical evidence on the diagnostic, prognostic and therapeutic implications of the complex interactions between the haemopoietic niche, iron, oxidative stress and inadequate haemopoiesis.

The issue of iron overload in hemopoietic cell transplantation has been first discussed in the field of transplantation for thalassemia. Thalassemia major is characterized by ineffective erythropoiesis and hemolysis leading to anemia in the majority of patients. Patients require regular blood transfusion therefore they develop iron overload causing organ damage and hematopoietic cell transplantation (HCT) is a consolidated reliably curative option. In this category of patients an important issue for transplant outcome is the iron burden before transplant and in the long-life post-transplant. Nevertheless, today the concept of the impact of iron overload / toxicity on the outcome of HCT) has been extended to other diseases characterized by periods of variable duration of transfusion dependence Recent preclinical data has shown how increased production of reactive oxygen species (ROS) resulting under iron overload condition, could impair the stem cells clonality capacity, proliferation and maturation. Also, microenvironment cells could be affected through this mechanism. For this reason, iron overload is becoming an important issue also in the engraftment period post-transplantThe aim of this review is to update consolidated knowledge about the role of iron overload/iron toxicity in the HCT setting in non-malignant and in malignant diseases introducing the concept of exposition of free toxic iron forms and related cellular damage in the different stage of transplant.

Solid evidence has established the negative impact of high iron burden and related tissue damage on the outcome of hemopoietic stem cell transplantation for thalassemia major. Recent improvements in our knowledge of iron metabolism have been focused on elevated non-transferrin-bound iron and labile plasma iron levels in the peritransplantation period as potential contributors to tissue toxicity and subsequent adverse transplant outcome. As mouse models have shown, iron overload can injure bone marrow hematopoiesis by increasing reactive oxygen species. The Pesaro experience, conducted in the deferoxamine-only era, clearly defined three iron-related factors (liver fibrosis, hepatomegaly, and quality of lifelong chelation) as significantly affecting transplant outcome. The detrimental effect of iron has only been clarified in recent years. Active interventional strategies are ongoing. Although successful hematopoietic stem cell transplantation clinically resolves the thalassemia marrow defect, patients still remain carriers of iron overload and of all the clinical complications acquired during prior years of transfusion therapy. Therefore, adequate "iron diagnosis" and management is mandatory after hemopoietic stem cell transplantation. In transplanted thalassemia patients, body iron should be returned to within the normal range. Phlebotomy is the gold standard to reduce iron burden; though deferoxamine is a proven, acceptable alternative, clinical investigations on deferasirox are ongoing.

Background Most MDS patients require regular packed red blood cells (RBC) transfusions and finally most become transfusion dependent. One of the unavoidable consequences of transfusion therapy is iron overload which has been found to be deleterious for different categories of patients including MDS patients. So far tissue and organ damage have been directly and strictly connected to the amount of tissue iron deposition (i.e. a "bulky" disease). All the studies performed in the last years have linked survival to markers of iron accumulation (mainly indirect markers) such as serum ferritin (PLoS One 2017;12: e0179016 17). Recent data support the notion that iron disease is not only a "bulky" disease exclusively secondary to iron accumulation but rather it is a toxic disease in which tissue damage is due to toxic iron forms (Non-Transferrin-Bound-Iron, NTBI, and Labile Plasma Iron, LPI) (Free Radic Biol Med 2014; 72: 23-40). These tissue reactive iron species are present in plasma since early phase of transfusion therapy or even before (Hematology 2017; 22: 9-15. Clin Biochem 2017 Nov;50: 911-7). NTBI and LPI emerge in the serum only once iron binding capacity is saturated in a rate over 60-70% (Haematologica 2016; 101: 38-45). Notably these iron fractions are chelatable and can be removed from circulation by a chelator (Blood. 2003; 102: 2670-7). The scientific rationale for this study (ClinicalTrials.gov: NCT03920657; CICL670AIT17T) is the notion that iron-induced tissue damage is not only a process of progressive organs bulking through high-volumes iron deposition, but also a reactive iron species related "toxic" damage. Therefore, a timely early initiation of iron chelation may be of benefit before overt iron overload is seen. Our hypothesis is that early and low dose Deferasirox film coated tablets (DFX-FCT) is well tolerated and is able to prevent iron accumulation, oxidative stress and related tissue damage, by consistently suppressing iron reactive oxygen species (NTBI and LPI). Study design and Methods. For inclusion, patients must be affected by Myelodysplastic Syndrome (MDS), aged ≥ 18 years, with very low, low and intermediate revised IPSS stage. They must have a limited history of transfusions (5-20 RBC units) and be chelation naïve. Additional inclusion criteria are serum ferritin levels >350 ng/mL and transferrin saturation >60%. In a recruitment period of 1 years, 60 patients from 10 Italian centers will be included in the study. DFX-FCT will be administered at the fixed dose of 3.5 mg/kg/day for the entire study year. The primary efficacy objective and end point is to evaluate impact on of iron burden in one-year treatment in early phase of transfusion requirement by low dose DFX-FCT acting as prevention of iron accumulation as demonstrated by hepatic iron concentration determined by liver MRI (end of study versus baseline). Most relevant secondary objectives and endpoints are 1) Definition of iron overload and oxidative stress in MDS at beginning of transfusion history. 2) demonstrating presence and quantitative changes of toxic serum iron forms and oxidative stress under low dose DFX-FCT therapy by regular NTBI, LPI and serum Malonildialdehyde (MDA) monitoring. 3) Verify if regular suppression of the "free iron forms" prevent tissue iron accumulation by absolute change in hepatic iron concentration end of study versus baseline 4) Evaluate the overall safety of low DFX-FCT dose in patients with lower risk MDS at the beginning of their transfusion history 5) hemopoietic response Conclusions This prospective multicenter study has been designed to investigate the clinical benefit and safety of early chelation therapy with DFX-FCT in patients with MDS at the beginning of their transfusion history to verify the possibility to continually suppress tissue NTBI, LPI and Oxidative stress thus preventing iron accumulation and tissue damage. Disclosures Angelucci: Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; Jazz Pharmaceuticals: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC; BlueBirdBio: Other: Local advisory board. Forni:Novartis, Iron chelation: Research Funding; Roche, Erithropoiesis Stimulation: Research Funding; BlueBirdBio: Consultancy; Celgene, Erithropoiesis Stimulation: Research Funding. Girelli:Vifor Pharma: Other: honoraria for lectures; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; La Jolla Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Oliva:Novartis: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy. Pilo:Novartis: Other: Advisory board. 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. Crisà:Jannsen: Honoraria. Santini:Menarini: Membership on an entity's Board of Directors or advisory committees; 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.

Does G6PD-deficiency related oxidative stress and hemolysis affect erythroid response to erythropoietic stimulating agents (ESA) in Myelodysplastic patients? Federica Pilo1, Valeria Santini2, Anna Angela DiTucci1, Valentina Serreli1 and Giorgio La Nasa11 Hematology and Bone marrow Transplant Unit, A. Businco Hospital, Cagliari, Italy 2 MDS Unit, Hematology, AOU Careggi, Firenze, ItalyKeywords : G6PD deficiency, Myelodysplasia, erythropoietic stimulating agentsContextAnemia is the most frequent cytopenia in Myelodysplastic Syndrome (MDS) . ESA have been investigated in several studies as useful to treat anemia in this category of patients. Available pre-clinical data support oxidative stress and hemolysis contributing to ESA resistance but not clinical data is today available.G6PD deficiency is an X-linked condition characterized by a markedly reduced capability to protect red blood cells from oxidative stress. In the island of Sardinia the prevalence of G6PD deficiency is reported to be as high as 12%. DesignWe retrospectively analyzed all MDS patients who had received ESA in our Center in the last 10 years. Diagnosis of MDS was made according to WHO criteria. Patients were stratified based on International Prognostic Scoring System (IPSS). At diagnosis baseline EPO level and G6PD quantitative estimation were detected. G6PD deficiency was defined as an enzyme dosage of less than 0.96 UI/g of Hb in the peripheral blood. Erythroid hematologic improvement (HI-E) was evaluated according to the International Working Group (IWG) response criteria ( Cheson JCO 2006).PatientsForty-two patients met the above specified criteria. Of them 13 were G6PD-defiecient and 29 had normal G6PD level values. Median age was 71 years (range 51-96). Thirty-four patients were IPSS low- risk and 8 Intermediate I. At baseline serum EPO level was less then 200 IU/L in all patients before starting ESA treatments. ResultsTwenty-eight (80%) achieved an HI-E (16 major and 12 minor). In the G6PD-deficient group HI-E was observed in 13 over 13 patients ( major in 7 and minor in 6). In the control group HI-E was observed in 23 over 29 patients (major in 13 minor in 10). ( P= 0.29). ConclusionsWe evaluated 42 MDS low- risk and Intermediate I IPSS patients who received ESA in the last 10 years in our centre. Despite the common belief that oxidative stress and hemolysis may contribute to ESA resistance, no statistically significant difference to potentially resistance to ESA treatment in G6PD deficiency have been observed. We conclude that G6PD-deficiency does not contraindicate the use of ESA in this setting of patients.

Background Myelodysplastic syndromes (MDS) are heterogeneous group of acquired clonal hematopoietic stem cell disorders characterized by atypical stem cells maturation and genetic instability leading to an enhanced risk of progression to acute myeloid leukemia. Low risk MDS patients have a lower probability to evolve in leukemia but are commonly characterized by dyseritropoiesis. These patient are incline to long term accumulation of iron in the organs due mostly to red blood cell transfusion (RBC) but iron overload may also occur in MDS patients who do not receive RBC transfusions due to the ineffective erythropoiesis. It is well known the effect of oxidant-mediated tissue's injury through the formation of free toxic iron species in the liver and heart site, but recent knowledges assumes that this mechanism is effective also in the bone marrow nice, where oxidative stress seems to impaired the haematopoietic stem cells growth. At this moment microscopic examination of the stainable iron in the bone marrow is considered the gold standard for determining the iron stores. The effect of bone marrow's iron overload on overall survival in the low risk MDS has been a matter of unresolved debate. We aimed to investigate the predictive value of bone marrow iron accumulation as demonstrated by Perl's staining on outcome in such patients. Design We retrospectively analyzed all low risk,intermediate-I MDS patients who had diagnosed in our institution in the last 20 years (since 1998). Diagnosis of MDS was made according to WHO criteria. Patients were stratified based on International Prognostic Scoring System (IPSS). Patients had undergone bone marrow aspiration as part of the diagnostic work up for their MDS. Two different experienced hematologist analyzed all samples. Bone marrow aspiration slides with at least seven fragments were considered suitable. Perl's Prussian blue stain was used to stain bone marrow, assessed by modified Gale's grading (Tab. 1) and then correlated with outcome. Patients and methods Marrow staining of one hundred and fourteen consecutive MDS patients were revised and analyzed. Median age was 70 years (range 32-93). Eighty three patients were IPSS low- risk and 30 Intermediate I. All patients were evaluated for bone marrow iron stores with Perl's stain. Twenty-seven patients had grade 1 (+), 31 grade 2 (++) and 56 grade 3 (+++). Patients had never or minimally received RBC . None of these patient had received iron chelation before marrow examination. Probability of overall survival (OS) was estimated by the Kaplan-Meier method and the significance was assessed by the log-rank test. Results 20-year OS was significantly lower in patients with higher Perl's score (median = 80 ±7 months in grade 3; median = 70 ±17 months in grade 2; median = 144 ±18 months in grade 1 , P=0.011); Fig. 1 Conclusions We evaluated retrospectively the bone marrow aspirate from 114 consecutive new MDS low-risk, Intermediate-I IPSS patients with Perl's stain for iron detection. Although Perl's grading is a qualitative method, it is still the gold standard to detect iron storage in the bone marrow. Our results correlate Perl's stain at diagnosis with long term outcome in MDS patients. We show how higher grade of iron storage at diagnosis can impact on outcome in these patients. We conclude that Perl's stain, together with Ferritin and blood transfusional burden could be another marker at diagnosis of iron-related toxicity that predict overall survival. Disclosures Pilo: Novartis Italy: Honoraria. Angelucci:Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC.

Allogeneic hemopoietic stem cell transplantation (HSCT) is the only method currently available to cure transfusion-dependent thalassemia major that has been widely used worldwide. To verify transplantation distribution, demography, activity, policies and outcomes inside the European Group for Blood and Marrow Transplantation (EBMT), we performed a retrospective non-interventional study, extracting data from the EBMT hemoglobinopathy prospective registry database. We included 1493 consecutive patients with thalassemia major transplanted between 1 January 2000 and 31 December 2010. In total, 1359 (91%) transplants were performed on patients

Solid evidence has established the negative impact of high iron burden and related tissue damage on the outcome of hemopoietic stem cell transplantation for thalassemia major. Recent improvements in our knowledge of iron metabolism have been focused on elevated non-transferrin-bound iron and labile plasma iron levels in the peritransplantation period as potential contributors to tissue toxicity and subsequent adverse transplant outcome. As mouse models have shown, iron overload can injure bone marrow hematopoiesis by increasing reactive oxygen species. The Pesaro experience, conducted in the deferoxamine-only era, clearly defined three iron-related factors (liver fibrosis, hepatomegaly, and quality of lifelong chelation) as significantly affecting transplant outcome. The detrimental effect of iron has only been clarified in recent years. Active interventional strategies are ongoing. Although successful hematopoietic stem cell transplantation clinically resolves the thalassemia marrow defect, patients still remain carriers of iron overload and of all the clinical complications acquired during prior years of transfusion therapy. Therefore, adequate "iron diagnosis" and management is mandatory after hemopoietic stem cell transplantation. In transplanted thalassemia patients, body iron should be returned to within the normal range. Phlebotomy is the gold standard to reduce iron burden; though deferoxamine is a proven, acceptable alternative, clinical investigations on deferasirox are ongoing.

Until the beginning of the current millennium, few concrete therapeutic possibilities were available for myelodysplastic syndrome (MDS) patients. This situation has dramatically changed in the last decade when new knowledge, new drugs and new opportunities have become available for physicians and their MDS patients. A correct diagnostic and prognostic assessment of all MDS patients wherever they are first seen in a hematology or internal medicine department is mandatory to identify the best therapeutic option and the most appropriate resources allocation. This article will review modern diagnostic criteria and classification together with correlated new therapeutic opportunities.

Background: Anemia is the most frequent cytopenia in Myelodysplastic Syndrome (MDS). Epoetin alfa, Epoetin beta and Darbepoetin alfa (ESA) have been investigated in several studies as useful to treat anemia in this category of patients. Available preclinical data support oxidative stress and hemolysis contributing to ESA resistance but not clinical data is today available. G6PD deficiency is an X-linked condition characterized by a markedly reduced capability to protect red blood cells from oxidative stresses. In the island of Sardinia the prevalence is reported to be as high as 12%. Patients and Methods: We retrospectively analyzed all MDS patients who had received ESA in our centre. Diagnosis of MDS was made according to WHO criteria. Patients were stratified based on International Prognostic Scoring System (IPSS). At diagnosis baseline EPO level and G6PD quantitative estimation were detected. G6PD deficiency was defined as an enzyme dosage of less than 0.96 UI/g of Hb in the peripheral blood. Red blood cell (RBC) transfusions requirement before starting treatment was evaluated. Erythroid hematologic improvement (HI-E) was evaluated according to the International Working Group (IWG) response criteria ( Cheson et al JCO 2006). Results: Thirty patients met the above specified criteria. Table 1 showed patients’ characteristics. Of them 7 were G6PD-defiecient and 23 had normal G6PD level values. Twenty four patients (80%) achieved an HI-E (14 major and 10 minor). In the G6PD-deficient group HI-E was observed in 7 over 7 patients ( major in 4 and minor in 3). In the control group HI-E was observed in 17 over 23 patients (major in 10 minor in 7). (P= 0.29). Conclusions: We evaluated 30 MDS lowrisk and Int I IPSS patients who received ESA in the last 20 years in our centre. Despite the common belief that oxidative stress and hemolysis may contribute to ESA resistance, no statistically significant difference to potentially resistance to ESA treatment in G6PD deficiency have been observed. We conclude that G6PD-deficiency does not contraindicate the use of ESA in this setting of patients.

Over recent decades we have been fortunate to witness the advent of new technologies and of an expanded knowledge and application of chelation therapies to the benefit of patients with iron overload. However, extrapolation of learnings from thalassemia to the myelodysplastic syndromes (MDS) has resulted in a fragmented and uncoordinated clinical evidence base. We’re therefore forced to change our understanding of MDS, looking with other eyes to observational studies that inform us about the relationship between iron and tissue damage in these subjects. The available evidence suggests that iron accumulation is prognostically significant in MDS, but levels of accumulation historically associated with organ damage (based on data generated in the thalassemias) are infrequent. Emerging experimental data have provided some insight into this paradox, as our understanding of iron-induced tissue damage has evolved from a process of progressive bulking of organs through high-volumes iron deposition, to one of ‘toxic’ damage inflicted through multiple cellular pathways. Damage from iron may therefore occur prior to reaching reference thresholds, and similarly, chelation may be of benefit before overt iron overload is seen. In this review, we revisit the science and clinical evidence for iron overload in MDS to better characterise the iron overload phenotype in these patients, which is distinct from the classical transfusional and non-transfusional iron overload syndrome. We hope this will provide a conceptual framework to better understand the complex associations between anemia, iron and clinical outcomes, to accelerate progress in this area.

INTRODUCTION:The aim of this report is to evaluate feasibility, safety and activity of a new procedure of computed tomography (CT) - guided percutaneous screw fixation (PSF) plus cementoplasty for treatment of mielomatous osteolytic lesions with refractory pain and fracture or to prevent impending pathological fractures. The association of scew fixation with cementoplasty allows, compared to cementoplasty alone, a better augmentation of the bone and reduces the risk of cement leakage through a selective injection of the of polymethylmethacrylate (especially in case of lytic lesion of vertebral pedicle). METHODS: From September 2014 to May 2016 thirteen (13) consecutive patients (eight men and five women, median age 67 years, range 48-78 years) with Multiple Myeloma who had developed painful and symptomatic bone lytic lesions in the pelvis and vertebrae were submitted to the procedure (three patients underwent multiple interventions). This consisted of PSF followed by percutaneous bone-cement injection with an solution of polymethylmethacrylate (PMMA) in eighteen sessions. The procedures were performed into the thoracic vertebrae (three interventions), lumbar vertebrae (nine interventions), pelvis (five interventions, bilateral in one instance) and into a paravertebral mass which involved the fifth and sixth thoracic vertebrae. For the osteosynthesis we used cannulated screws with lateral holes, that allow to selectively inject the cement through the screw avoiding undesired leakage. After the screw insertion, to obtain a better augmentation of the bone, from 8 to 22 ml of PMMA in all the lesions. In two cases, before the PSF and PMMA injection, in order to reduce the volume of the tumor a radiofrequency ablation was performed. All the procedures were performed using local anesthesia, conscious sedation in all patients and antibiotic prophylaxis with ceftriaxone 2 gr i.v. Pain was measured by visual analogue scale (range 0-10), mobility by functional mobility score system with a range from 1 (normal mobility) to 4 (bedridden). Statistical analysis was performed using the test of Wilcoxon. RESULTS:Technical success was achivied in all patients. The CT scan acquired immediately after the procedure didn't demonstrate any complications such as leakage of cement or incorrect positioning of the screws or undesired burning during thermal ablation. No additional bone fractures occurred during a median follow-up of 19 months (range 3-23 months). Pain relief occurred in all the patients within one month. Median VAS score was 7 (range 4-9), 3 (range1-4) and 1 (range 1-2) before, at one and six months after procedure respectively (p Only three patients needed opioid therapy after the procedure. CONCLUSION:The PSF plus cemetoplasty of the pelvis and vertebrae is safe and effective in patients affected by myelomatous localizzations. The procedure is minimally invasive and allows to stabilize the fracture and prevent pathological fractures with significant pain relief and good recovery of walking ability. Further controlled studies with large series of patients are warranted to confirm these preliminary results. Disclosures No relevant conflicts of interest to declare.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common RBC enzymatic disorder in humans capable of producing hemolytic events. Recently, concern has been raised about using G6PD-deficienct subjects as hemopoietic stem cell (HSC) donors. In a 10-year period, 101 consecutive HSC donors were submitted to donation procedures for transplantation inside their families in our Center. All donors were tested for G6PD and 19 (19%) turned out to be G6PD-deficient. The donors’ safety and the effectiveness of these transplant outcomes were compared with those of the remaining 82 donors. No difference could be observed in any safety parameter between the two groups. No difference was recorded in donors’ complications rates, in HSC production, in quantity of growth factor required, in Hb early drop or in Hb recovery. No difference was found in transplant outcome. From this retrospective analysis, we conclude that a G6PD-deficient but otherwise healthy volunteer can be selected as a HSC donor.

Local pharmaceutical industry: Total Turkish Pharmaceutical Market is 15 billion TL. (Only IMS value) Oncological drug market constitutes 9% of Turkish drug market. Only 6.8% of Oncological drugs are manufactured locally. Therefore Turkey is still dependent on importation for these drugs. In Oncology and Heamatology not all forms of some molecules are being able to manufactured locally, just in a few facilities some type of molecules could be produced.However these are not enough to increase local manufacturing volumes in Turkey.We need new high tech facitilies to be able to produce high potent and high tech products. Local investments in Turkey: A few companies are involved with new manufacturing investments in Turkey. Local Manufacturerers’ Responsibilities:Production of drugs compliying with GMP and usage of high technology. Closed manufacturing process for cytotoxic products and usage of equipment with isolators (not a legal requirement). Drugs should be represented within ethical rules. Should invest in R&D studies to develop new treatment choicesand decrease the drug cost. Quality and properties of equipment are crucial factors for manufacturing such as clean rooms,water system etc. Biologics, biosimilars and vaccines are target projects in future in Turkey.

Background The management of high dose chemotherapy followed by autologous or allogeneic hemopoietic stem cell transplantation requires an intravenous line for administrations of high-dose chemotherapy, blood and platelet transfusions, antibiotics and parenteral nutrition. In this context a safe central venous access is a basic tool for patients management. The aim of our phase II prospective study is to evaluate feasibility, safety and cost of the use of peripherally inserted central catheters (PICC) for the management of hemopoietic stem cell transplantation. Methods Inclusion criteria included inpatient who needed program of autologous and allogenic hematopoietic stem cell transplantation regardless the underlined hematological disease or white cells and platelets counts. All patients were submitted to a preliminary evaluation of arms vascular anatomy by ultrasonography. All implantation procedures has been done under ultrasound guide with radiographic control after insertion. The PICC cost analysis was performed on the cost of devices, insertion and daily management and compared with a historical cohort of patients with short term central venous catheter (CVC). The study was approved by institutional review board. All patients provided a written informed consent. Results From March 2007 to July 2013 76 consecutive PICC have been implanted in 74 patients for autologous or allogenic stem cell transplantations. There were 37 male and 37 females. Median age was 55 years, range 22-70. With regard to disease, 11 patients (15%) had Hodgkin Lymphoma, 13 (17.5%) non Hodgkin lymphoma, 9 (12%) acute lymphoblastic leukemia, 35 (47%) multiple myeloma, 4 (5.5%) acute myelogenous leukemia, and 2 (3%) other hematological disease. Fifty-five PICC (72%) have been used for single autologous stem cell transplantation, 10 (13%) for double autologous stem cell transplantation and 11 (15%) for allogenic transplantation. Catheter insertion was successful in all instances. PICC median life was 119 days (1-457) for a total of 10877 days of implanted PICC. At the time of this analysis 4 out of 76 PICC (5%) are still “in situ” and in use and 72 (95%) have been removed. Reason for removal was end of therapy in 58 instances (80.5%), accidental withdrawal in 8 (11%), patient death in 1 (1.5%) and catheter related complication in 5 (7%). Catheter related complications were the following: 2 occlusions, 3 suspected PICC-related sepsis. Only 1 episode of confirmed PICC-related septicemia (0.1/1000 days/PICC) was recorded and S.Aureus was isolated. There were only 2 cases (2.6%) of symptomatic PICC-related thrombotic complications which has requested conservative management. Twenty-five of 76 PICC (33%) were power PICC. No patients presented the need for a additional central venous access. Regarding the economic aspect, the actual daily cost of PICC was 1.98 €/day versus 3.40 €/day of the short term CVC (45% lower). Conclusions These data encourage the use of PICC in the autologous and allogenic stem cell transplantation because of insertion easiness, duration of life, cost and low rate complication. Disclosures: Off Label Use: Bendamustine.

Abstract 905 Background. Hemopoietic allogeneic stem cell transplantation (HSCT) still remains the only available curative option for β-thalassaemia major. At today more than 3000 transplants have been performed worldwide and registered. We analyze transplant activity and outcome after 20 years of the European Hemoglobinopathy Bone Marrow Transplant (EBMT) Registry. Methods. Data have been analyzed from promise MED-A form. Survival data have been reported with the method of Kaplan-Meier in patients with complete survival data. Results. One hundred and 34 centres from 28 different countries reported their data to the registry. Three thousands and 821 (3821) consecutive first HSCT for patients affected by a hemoglobinopathy have been registered. There were only 364 (10.5%) patients aged 18 years or older. Further analyses were restricted to patients with thalassemia major and to transplants performed after January 1st, 2000. In this latter period 1493 transplants have been performed (median age 7.2 years, range 0.3–45.1) with 133 (9.8%) patients aged 18 years or older. During the last decade 70% of the transplants have been performed in Europe and 30% in Asia and Africa with a trend to an increase activity in these countries compared to previous decades. Of the 1493 transplants performed after January 2000, 1061 (71%) have been performed from an HLA identical sibling donors, 129 (8.6%) from a matched other relative, 57 (3.8%) from a mismatched relative, 210 (14%) from an unrelated donor and in 36 (2.4%) cases donor information were missing. Source of stem cells was bone marrow in 1011 patients (67.7%), peripheral blood in 303 patients (20.3%), cord blood in 60 patients (4%), mixed in 82 patients (5.5%). Source of stem cell was missing in 37 (2.5%). In matched sibling donor transplant recipients overall survival (OS) and thalassemia free survival (TFS) plotted at 91 ± 0.01% and 83 ± 0.01%, respectively. Significant differences have been reported in OS and TFS when related to different age groups as reported in Table 1 (P < 0.001). Conclusion. This analysis confirms allogeneic transplantation is a worldwide diffuse high success curative procedure for β-thalassaemia major. Bone marrow still remains the principal source of stem cells. The large majority of transplants have been performed from a matched sibling donor with a marginal role of other donors. In addition these data demonstrate the trend to not transplant adult patients. In the univariate analyses 14 years old appears as threshold age for best transplant strategy. Disclosures: No relevant conflicts of interest to declare.

Allogeneic stem cell transplant (allo HSCT) is a potentially curative approach for patients with hematologic malignancies but it is associated with high treatment related morbidity and mortality. Because transplant related mortality increases with age, advanced disease, and unrelated donors, patients older than 50–55 years may be excluded from this procedure. Reduced intensity conditioning regimens showed a low success rate in long-term follow-up, so new ablative reduced toxicity regimens are of striking interest. The aim of this study was to evaluate toxicity and efficacy of the combination consisting of Treosulfan (Busulphan derivative water soluble alkylating agent) and Fludarabine as a preparative regimen for patients receiving HSCs from matched siblings or unrelated donors for advanced heavily pretreated hematologic malignancies. From July 2005 to June 2006, 21 consecutive patients (10 males, 11 females) were enrolled. Mean age was 45 years (range 17–65). Underlying diseases were: acute leukemia (6 ALL, 5 AML), 1 CML, 3 MM, 5 MDS, 1 hystiocytic sarcoma). All patients were heavily pretreated; only 8 of them were in CR at transplant. Conditioning consisted of Treosulfan (12–14 gr/m2 for 3 days) in combination with Fludarabine (30 mg/m2 for 5 days). Cyclosporine plus short MTX and anti-thymocyte globulin (Thymoglobulin) were used as GVHD prophylaxis. Eleven (11) patients received HSCs from an HLA identical sibling and 10 from a matched unrelated donor. Source of stem cells was bone marrow in 4 patients, and peripheral blood in 17. Twenty (20) patients engrafted; mean time to neutrophil recovery >500 × 109/L was 14 (range 10–24) days, to platelets >20,000 × 109/L was 14 (range 10–21) days. One patient receiving bone marrow did not engraft and died with active disease. Two (2) patients experienced GI toxicity (grade 2), 5 patients had grade 1 liver toxicity and 1 patient grade 1 renal toxicity. Four (4) pts presented acute GVHD (2 grade I, 2 grade II). Eleven (11) patients (52%) are alive in complete remission with a follow-up ranging from 30 to 270 days; 4 died for recurrent disease; 5 patients are alive with active disease. This preliminary report shows that Treosulfan-Fludarabine-ATG conditioning regimen is well tolerated and characterized by reduced toxicity in a cohort of high risk patients with advanced age, who should otherwise be excluded from any other conventional transplant procedure.