ALBERT

Description: Introduction: Recent studies indicate an increased risk for developing low bone mineral density (BMD) in patients with haemophilia. This has been suggested to result from less physical activity, and impaired vitamin D metabolism due to viral liver disease. Here we present the preliminary results of an ongoing study aiming to identify the risk factors for impaired bone health in adult haemophilia patients. Material and Method: Twenty-nine severe and 7 moderate haemophilia A and B patients were included in the study. Patient characteristics were given in Table-1. All patients had haemophilic arthropathy in ≥1 joints and were on prophylactic factor replacement therapy except 2 on demand patients. None of the patients had decompensated chronic liver disease. Eleven patients had a history of joint intervention (RAS or joint replacement). None of the patients had received on vitamin D supplementation. DEXA scans to screen BMD, blood chemical analysis including liver and kidney function tests, vit. D (25 hydroxy vitamin D) calcium, parathormone, alkaline phosphatase were obtained from all patients at study entry. Results: Osteoporosis and/or osteopenia according to WHO criteria were detected by DEXA scans in 2/3 of the patients. Twenty-six patients (72%) had vit. D levels below 20ng/mL, with half of them having levels less than 10ng/mL. Median lumbar and femur T scores were in the osteopenia range, being -1.2 and -2.2, respectively. Osteoporosis/penia rates and vit. D levels did not significantly differ between patients with severe and moderate haemophilia. However, patients with severe haemophilia had lower lumbar T scores (p=0.048) and seemed to acquire low BMD 2 times more likely than moderate haemophiliacs. Patients with a history of joint intervention had significantly lower vit. D levels (p=0.005) and 1.4 times more risk for low BMD. Conclusion: Preliminary results of our study are in line with the recent literature indicating an increased frequency for osteopenia and osteoporosis in patients with haemophilia. Despite their young age our cohort of patients had lower BMD and vitamin D levels than the age-matched healthy population. This is an interesting finding in a country like Turkey where the average yearly total number of hours of bright sunshine is over 3000. Data at hand suggest increased risk for reduced BMD especially in severe haemophiliacs with impaired joint mobility. The most probable underlying cause for reduced BMD seems to be haemophilic arthropathy related inactivity. Furthermore, impaired bone health seems to be partially associated with less sunlight exposure, which is probably a result of increased home confinement of patients with haemophilia due to joint disease. The study is still recruiting. We hope to clarify other questions regarding factors influencing bone health in haemophiliacs when the study is completed and additional data on radiological and physical examination as well as on quality of life are obtained. Table. Patient Characteristics (n=36) Age, years (median [range]) 35 [20 - 55] Type of haemophilia ( A/B), n 32/4 Genotype (severe/moderate), n 29/7 Factor activity level, % (median [range]) 0.4 [0.1 - 4.2] Type of treatment (prophylaxis/on demand) 34/2 Annual bleeding rate (median [range]) 4 [1 - 12] Joint replacement, number of patients (%) 7 (19) Radioactive synoviectomy, number of patients (%) 7 (19) Any joint intervention, number of patients (%) 11 (30.5) Lumbar T scores (median [range]) -1.2 [-5.2 - 1] Femur T scores (median [range]) -2.2 [-3.9 - 0.6] Vit. D, ng/mL (median [range]) 10.5 [1.3 - 45] Calcium, mg/dL (median [range]) 9.6 [8.9 - 10.2] Alkaline phosphatase, U/L (median [range]) 91.5 [53 - 177] Parathormon, pg/mL (median [range]) 39 [20 - 179] Haemoglobin, g/dL (median [range]) 14.75 [8.9 - 16] Osteopenia, number of patients (%) 12 (33) Osteoporosis, number of patients (%) 12 (33) HBV/HCV/HIV, n 1/11/0 Disclosures No relevant conflicts of interest to declare.

Description: Gemtuzumab Ozogamycin (GO) is a drug conjugated monoclonal antibody which targets CD33 an antigen highly expressed on the surface of AML blasts. GO is approved for the treatment of both newly-diagnosed and relapsed AML. Despite growing evidence regarding its efficacy and safety among AML patients there is limited data about the use of GO in isolated extra-medullary relapsed AML. Extramedullary AML remains as an unmet clinical need regarding the poor prognosis and lack of a standard therapeutic approach. Our cases demonstrated a rapid and long lasting response with a favorable toxicity profile, in patients who were treated with GO as a single agent after an isolated extramedullary relapsing disease. Our first case was a 40-years-old woman admitted to our outpatient clinic with pain in her joints and redness in her back and stomach. She was diagnosed with CD33-positive Acute Myeloid Leukemia according to the immunophenotyping of bone marrow blasts. Idarubicin and ARA-C (7+3) combination initiated as a frontline induction therapy and morphological remission was achieved after the first cycle of induction. After the first cycle of consolidation chemotherapy with high dose ARA-C she has relapsed with skin myeloid sarcomas and diffuse bone marrow infiltration. Soon after the relapsing disease she was put on to ida-flag salvage chemotherapy and she responded well with the disappearance of skin lesions and morphological complete remission of bone marrow. After achieving response, an allogeneic stem cell transplantation (HSCT) was applied from her sibling donor with a myeloablative conditioning. Unfortunately patient had a relapsing extramedullary disease with reappearance of skin lesions even with an ongoing acute skin gvhd (Figure) soon after allogeneic HSCT. Bone marrow biopsy revealed no increase in blast count. We have decided to initiate a novel targetted therapy to control the extramedullary disease. As her blasts infiltrating the skin were universally CD 33 positive we considered to put her on GO therapy with the approval obtained from health authority. GO was applied according to the dosage approved by FDA for relapsing disease. After the first cycle of GO she had a rapid disappearance of all skin lesions just complicated with a febrile neutropenic episode and re-activation of CMV infection which was controlled with Gancyclovir. She has retained a complete remission regarding extramedullary disease throughout the repeated courses of GO for 3 times, and she is still in remission for 4 months after the first appearance of skin lesions (Figure). Our second case was a 24-years-old boy who admitted to our outpatient clinic with a worsening fatigue and shortness of breath. He was also diagnosed with CD33-positive Acute Myeloid Leukemia according to the immunophenotyping of bone marrow blasts and was able to achieve a morphological CR after frontline induction therapy with 7+3 protocol. After two cycles of high dose ARA-C consolidation he was transplanted from a matched unrelated donor because of an intermediate cytogenetic risk profile. At the 14th month of allogeneic transplantation he had relapsed with a bone marrow blast count of 90% and harboring a monosomy on the 10th chromosome. After the first salvage chemotherapy with IDA-FLAG protocol he has achieved a morphological CR and we have decided to proceed with an alternative donor transplantation. But unfortunately soon after discharge, he has admitted to the emergency clinic with a new onset headache and nausea and vomiting. A cranial CT revealed multiple foci of solid masses with peripheral edema. We have performed a lumbar puncture and CSF fluid revealed a high number of CD33 positive blastic cells (over 100 cells per HPF). At the time of central nervous system (CNS) relapse his bone marrow was free of blastic infiltration. We decided to initiate GO treatment with the diagnosis of isolated central nervous system relapse of AML, accompanying intra-thecal chemotherapy via an Omaya Reservoir. He has received two cycles of GO which was complicated with neutropenic fever and grade 4 leukopenia and thrombocytopenia, and his CNS lesions also responded well and clinically he had no CNS related signs or symptoms. The patient received additional GO with continued response but unfortunately after a severe pneumonia he passed away at intensive care unit. Our case series documented a clinically relevant therapeutic field for GO in isolated extramedullary relapse of AML. Disclosures No relevant conflicts of interest to declare.

Description: Background: Management of surgical procedures in people with hemophilia (PwH) has always been a major concern. Insufficient hemostatic control might be an important cause of morbidity and mortality. However, the success of surgical procedures does not only depend on appropriate replacement of the missing factor. Pre- and post-operative interventions, laboratory monitoring, care and rehabilitation of the patient are important. Therefore, surgical procedures in hemophilia patients should be performed in full-fledged hospitals capable of providing a multidisciplinary approach as a "Comprehensive Hemophilia Treatment Center". The aim of our study is to evaluate the outcomes of major surgical procedures (MSPs) among PwH who were followed at Cerrahpasa Medical Faculty. Methods: All MSPs performed on PwH between 2004 and 2017 were included. Baseline activated partial thromboplastin time (aPTT)and factor levels prior to MSP, inhibitor screening and (if any) the inhibitor titration results together with complete blood count, blood group and liver function tests were retrospectively obtained from patient files. The type of MSP, amount of factor concentrates given prior to, during and after the operation, the factor levels and aPTT results following factor replacement; complications developing during or after surgery, and information on the type of treatment modality prior to surgery (on demand vs. prophylaxis) were noted. The amount of factor concentrates administered to patients was determined in units per kilogram. Results: Of the 39 patients included in the study (37 hemophilia A and two hemophilia B) 20 were severe, 7 were moderate and 12 were mild hemophilia (Table 1). The median age at the time of MSP was 37 (20-61) years. A total of 49 MSPs were performed, two patients had 3 surgeries, six patients had 2 surgeries, and 30 patients had one surgery. Fifteen surgical procedures were performed in two, one surgical procedure was performed in three, and 33 operation procedures were performed in one operation area. There were no significant differences in complication rates between hemophilia types (A vs. B), severities (severe vs. moderate vs. mild) and number of operated regions (1 vs. 〉1). In our study, general surgery (n=15) and orthopedic (n=10) operations were the most frequently performed MSPs (Table 2). There was no significant difference in complication rates among surgical branches. Complications were observed in a total of 6 (12%) MSPs, and one patient was deceased due to sepsis. Complication rates were 16% and 11% for MSPs done in PwH with and without inhibitors, respectively (p=non-significant). Factor consumption (U/kg) was highest in patients undergoing orthopedic surgery, followed by cardiovascular and neurosurgical operations. Factor utilization was significantly less for operations done in general surgery, urology and ear, nose and throat departments (p

Description: Background: Although it may vary between different registries, the median age of chronic myeloid leukemia (CML) at diagnosis is between 50-60 years, and approximately 40% of the patients (pts) are diagnosed after age 60 [Hoffmann et al. Leukemia. 2015;29(6):1336-43]. Tyrosinekinase inhibitors (TKIs) have revolutionized the treatment of CML and currently pts with CML may expect to live close to normal lifespan. So the number of elderly CML pts with various potentialcomorbidities started to increase, which then brings out the issues regarding TKI toxicities, medication adherence and responses to TKI treatment. Aim: The aim of this study was to evaluate the efficacy and safety ofimatinib treatment in the elderly population (pts equal to or older than 60 years) with CML and to compare these data with younger pts (pts 〈 60 years). Patients and Methods: Pts diagnosed and followed in our clinic with CML were enrolled in the study. Patient demographics, dose and duration ofimatinib therapy, disease risk scores, cytogenetic and molecular responses,comorbidities, adverse events (AEs), follow-up durations and outcomes were evaluated from files of the pts, retrospectively. TheCharlsoncomorbidity index (CCI) of each patient was calculated as stated before [Breccia et al.Haematologica. 2011;96(10):1457-61]. Results: The patient cohort was consisted of 158 pts with a median age of 44 years (range, 18 - 83 years). Group A consisted of thirty-three pts who were equal to or older than 60 years (Fig. 1), and there were 125 pts (Group B) who were 〈 60 years of age (Table 1). The two groups were balanced regarding gender, disease stage, treatments prior to TKI therapy, and the starting dose ofimatinib. There were more pts with intermediate and highSokal risk scores in Group A than that of Group B (p

Description: INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for malignant and nonmalignant diseases. Improved long-term survival after HSCT translates into coming across secondary neoplasms. Contributory factors include primary disease, male sex, young age, prior therapies, conditioning regimens. The secondary neoplasms are particularly solid tumors, as well as lymphoproliferative disorders. Chronic graft-versus-host disease (GvHD) and immunosupressive therapy have also been reported to contribute to neoplasia risk. OBJECTIVE: The purpose of this study was to evaluate the frequency and distribution of the posttransplant secondary neoplasms in our center, to determine the possible contributory factors and relative effect of GvHD. METHODS: From 457 patients who received a HSCT between 1994-2014 clinical records of 312 patients were available to review retrospectively. 21 patients diagnosed with a secondary neoplasia in the posttransplant period are included in the study. Age, sex, primary diagnosis and treatment, time of HSCT, GvHD and immunosupressive treatments, localisation of neoplasms and outcomes were reported. RESULTS: Twenty-one cases of secondary neoplasms were observed (%6,7). The median age at diagnosis and transplantation were 44 and 47, respectively. The median follow-up time was 122 months (32-304). The most common primary diagnosis was Hodgkin's disease (HD). The most commonly used pretransplant conditioning regimen was BEAM. There were no cases of acute GvHD, chronic GvHD was observed in 3 cases. The most common secondary neoplasm was skin cancer followed by urogenital system cancers. The secondary malignancies seen in cases with chronic GvHD are concordant with GvHD sites. Three patients had benign neoplasms comprising fibroadenoma, mol hydatiforme and hibernoma; 2 patients developed preinvasive lesions of vulva (VIN 3) and oral cavity (squamous papilloma). For 20 patients the median time interval between the date of HSCT and diagnosis of a secondary neoplasia is 62 months (5-118); data is missing for 1 case. Two deaths were observed, 1 due to disease progression, 1 due to secondary colorectal malignancy. %90,4 of the study group are alive and in remission. Details are listed in Table 1 and 2. CONCLUSION: Patients undergoing HSCT have an increased risk of secondary cancers later in life. Known risk factors are primary disease, age at transplantation, pretransplant therapies, pretransplant conditioning regimens like total body irradiation, chronic GvHD and immunosuppressive therapies. Our study group is small to comment on these risk factors. Coherent with the literature skin cancer was the most common secondary cancer in our cohort as well. Interestingly we observed a trend towards increased urogenital cancers in comparison to reported data. This finding can be incidental because of the small number of study population or needs to be clarified yet. The increased risk of secondary neoplasms over time after transplantation and the greater risk among younger patients indicate the need for lifelong surveillance. Table 1 Characteristics of patients with secondary neoplasms after HSCT Characteristic n (%) Sex Female 10 (%47) Male 11 (%53) Primary diagnosis Acute myeloid leukemia 1 (%4,7) Acute lymphoblastic leukemia 3 (%14,3) Chronic myelogeneous leukemia 3 (%14,3) Multiple Myeloma 5 (%23,8) Hodgkin’s disease 6 (%28,6) Non-Hodgkin’s lymphoma 3 (%14,3) Prior therapy Chemotherapy 9 (%42,7) Chemoimmunotherapy 3 (%14,3) Chemoradiotherapy 5 (%23,7) Combination treatment* 3 (%14,3) Type of HSCT Allogeneic 5 (%23,8) Related 5 Unrelated 1 Autologous 15(%71,5) Both 1(%4,7) Conditioning regimens TBI+Cy 3 (%14,3) BEAM 8 (% 38,1) MEL 6 (% 28,6) BU+Cy 2 (% 9,5) Unknown 2 (%9,5) Acute GvHD 0 Chronic GvHD 3 (%14,3) Skin 3 Oral cavity 2 Eye 2 Pulmonary 1 Hepatic 1 Acute GvHD prophylaxis 7 (%33,3)  CsA 1 MTX+CsA 6 Chronic GvHD treatment 3 (14,3) Steroid+CsA 2 CsA 1 Table 2 Characteristics and risk factors of patients who had secondary malignancy undergoing HSCT Breast Skin GIS Urogenital Lung Lymphoma Risk factors (n:2) (n:6) (n:2) (n:3) (n:2) (n:1) Prior therapy Chemotherapy 0 4 0 2 1 0 Chemoimmunotherapy 1 1 1 1 0 0 Chemoradiotherapy 1 0 0 0 1 1 Combination 0 1 1 0 0 0 Allogeneic Related 1 3 0 1 0 0 Unrelated 0 1 0 0 0 0 Autologous 1 3 2 2 2 1 TBI+Cy 0 1 0 0 0 0 BEAM 1 2 1 0 1 1 MEL 0 1 1 2 1 0 BU+Cy 0 1 0 1 0 0 Unknown 1 1 0 0 0 0 Chronic GvHD 0 2 0 0 0 0 Sex Female 2 2 2 1 0 0 Male 0 4 0 2 2 1 Disclosures No relevant conflicts of interest to declare.

Description: Background: Drug-induced pulmonary arterial hypertension (PAH) can be observed as an adverse event (AE) during the administration of dasatinib (DAS), which is a second generation tyrosine kinase inhibitor (TKI), used in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The occurence of DAS-induced PAH at a late onset in most of the cases suggests a chronic pathological mechanism rather than an acute inflammatory or cardiac etiology. The treatment strategies of DAS-induced PAH include the cessation of the drug and PAH-specific therapies. Aim: The aim of the study was to evaluate the frequency, clinical features, management strategies and outcomes of patients with DAS-induced PAH among a cohort consisted of CML and Ph+ ALL patients who had received DAS as a salvage treatment after imatinib (IM) failure or intolerance. Patients and Methods: Forty patients with Ph+ leukemias who received second-line DAS were enrolled. Patients' demographics, Sokal risk scores, molecular and cytogenetic responses, comorbidities [including preexisting cardiac disease, renal insufficiency, hypertension and chronic obstructive pulmonary disease (COPD)], DAS dose, dosing intervals and treatment durations, durations of IM therapy prior to DAS, and if any, treatments prior to IM (interferon (IFN), cytarabine (Ara-C), and hydroxyurea (HU)) and follow-up periods were noted retrospectively. TKI response criteria were based on the recommendations of European LeukemiaNet, and the definitions of the CML phases and responses were as described elsewhere. Results: Twenty-four patients were male, and the median age was 45 years (range, 18-81 years). There were 39 patients with CML and one with Ph+ ALL. Among the thirty-nine CML patients, 3 were in accelerated phase (CML-AP), two with blast crisis (CML-BC), and the rest were in chronic phase (CML-CP). The percentanges of low, intermediate, and high Sokal risk scores were 46%, 33%, and 21%, respectively. Thirteen patients received only IM prior to DAS, whereas the others had used HU, IFN and Ara-C prior to IM. After a median duration of 41.5 months (range, 1-93 months) of IM, the reason for switching to DAS were IM failure and intolerance in 37 and 3 patients, respectively. DAS was administered with a median of 50 months (range, 2-78 months). During DAS treatment hematological AEs were observed in 6 patients, whereas in twenty-one pulmonary complications including exacerbation of COPD and pneumonia (n=1), pleuro/pericaridal effusions (n=19), PAH (n=5) and gastrointestinal bleeding (n=1) were detected. DAS therapy was ceased in 13 patients, of which ten were switched to nilotinib (NIL) due to AEs (n=7) and failure (n=3). Also, two patients received cytotoxic treatment due to BC and one had allogeneic hematopoietic stem cell transplantation (allo-HSCT). Five patients (12.5%) had DAS-induced PAH (Table 1). Four of them were in CML-CP at diagnosis, and one was in CML-AP. All cases received DAS due to IM failure. At the time of DAS initiation, 4 cases were in CML-CP and one in CML-BC. PAH was diagnosed by transthoracic echocardiography (TTE) in 3 patients, and by right heart catheterization (RHC) in 2, and it was observed after a median of 8 months (range, 2-25 months) of DAS. Three patients had accompanying pleuro/pericardial effusions. All patients with DAS-induced PAH were alive at the time of the analysis, and the management of PAH included dose reduction in two, and DAS was switched to NIL in 2 cases and allo-HSCT was performed in one. Conclusion: DAS-induced PAH seems to be reversible with the cessation and/or modification of DAS ± PAH-specific treatments. As pulmonary vascular toxicity related to DAS is thought to be molecule-related rather than class-related, it seems reasonable to switch to another TKI. The patients in our cohort had good responses to dose modification and drug cessation and none received PAH-specific therapy. Although DAS-induced PAH is mainly defined as a late complication, we detected that PAH can be observed even after 2 months of drug exposure. PAH can be observed during DAS treatment and physicians should be aware of this AE. Routine cardiopulmonary evaluation prior to and/or during DAS may be beneficial. Mechanisms under this pathological condition, preceding and prognostic factors, and treatment strategies are needed to be evaluated with prospective trials. Disclosures No relevant conflicts of interest to declare.