Serdar Sivgin

Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study

BACKGROUND In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. METHODS RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients. FINDINGS Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43-15·45]; p<0·0001). The most frequent haematological adverse events of any grade were anaemia (ten [14%] of 74 in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3-4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3-4 anaemia and three patients (4%) reported grade 3-4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3-4 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group. INTERPRETATION RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population. FUNDING Novartis.

Neutrophil-to-Lymphocyte Ratio is Associated With Severity of Coronary Artery Ectasia

We investigated the association between coronary artery ectasia (CAE) and Neutrophil-to-lymphocyte ratio (NLR), an indicator of the inflammatory state. The study population included 434 patients (247 males, mean age 62 ± 10 years) including 230 patients with isolated CAE and 104 patients with coronary artery disease and 100 patientss with normal coronary arteries. The NLR was measured at admission and 30 days after coronary angiography in all the patients. The NLR was significantly higher in patients with CAE than those with normal coronary arteries (2.2 ± 0.6-1.3 ± 0.6, P < .001). Linear regression analyses revealed that NLR (coefficient β = −.61, P < .001) was significantly associated with severity of CAE. The NLR is significantly higher in patients with CAE compared to controls with normal coronary arteries, and NLR is associated with severity of CAE.

The management of iron overload in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients: Where do we stand?

Iron overload (IO), primarily related to multiple red blood cell transfusions, is a relatively common complication in hematopoietic stem cell transplant (HSCT) recipients. Elevated pretransplant ferritin levels have been reported to increase the risk of non-relapse mortality following HSCT and might influence the risk of acute and chronic graft versus host disease. IO has been shown to be an important cause of mortality and morbidity in patients who have undergone alloHSCT (Armand et al., Blood 109:4586–4588, 2007; Kim et al., Acta Haematol 120:182–189, 2008; Kataoka et al., Biol Blood Marrow Transplant 15:195–204, 2009). We know that excessive iron accumulation results in tissue damage and organ failure, mainly as a result of the generation of free radicals that cause oxidative damage and organ dysfunction (e.g., hepatotoxicity, cardiotoxicity, and endocrine dysfunction) (Altes et al., Bone Marrow Transplantation 29: 987–989, 2002; Papanikolaou et al., Toxicol Appl Pharmac 202:199–211, 2005). In the last decade, efforts have been directed toward identifying alternative treatment for IO in alloHSCT recipients to maintain improved transplant outcomes.

Mean platelet volume is associated with poor postinterventional myocardial blush grade in patients with ST-segment elevation myocardial infarction.

ObjectiveIn a significant proportion of patients with ST-elevation myocardial infarction (STEMI), microvascular and myocardial reperfusion cannot be regained despite successfully restored thrombolysis in myocardial infarction (TIMI) grade 3 epicardial blood flow. Myocardial blush grade (MBG) is a reliable marker for microvascular patency and predicts short-term and long-term mortality after primary percutaneous coronary intervention (PCI) in patients with acute STEMI, independent of other variables. Mean platelet volume (MPV), a unique measure of platelet size, is an indicator of platelet reactivity. In this study, we aimed to investigate the relation of admission MPV with postinterventional MBG in patients with STEMI and TIMI grade 3 flow at infarct artery after primary PCI. Materials and methodsThree hundred and ten patients were selected as a study group among patients with STEMI and TIMI grade 3 epicardial blood flow after primary PCI. Blood samples for analysis were obtained during the initial evaluation of patients at the emergency department. MBGs of patients were classified at the end of angioplasty. Patients with MBG 0 and 1 were defined as having poor myocardial blush and patients with MBG 2 and 3 were defined as having normal myocardial blush. ResultsPatients with poor myocardial blush had higher admission MPV (10.5±1.3 to 9.1±1 fl, P<0.001), higher peak creatine kinase myocardial band isoenzyme levels (260±53 to 190±38 U/l, P<0.001), higher white blood cell count (11.3±4 to 10.3±3×103/&mgr;l, P=0.012), and lower left ventricular ejection fraction (42±7 to 51±8%, P<0.001) compared with patients with normal myocardial blush. Linear regression analysis showed that admission MPV was significantly associated with postinterventional MBG (coefficient=0.598, P<0.001). Cardiovascular mortality (13–5%, P=0.013) and acute–subacute stent thrombosis at 3 months (12–8%, P=0.028) were significantly higher in patients with poor postinterventional myocardial blush compared with those with normal myocardial blush. ConclusionThe MPV measured at admission is significantly associated with poor postinterventional MBG in patients with STEMI and TIMI grade 3 flow at infarct artery after primary PCI.

Therapeutic plasma exchange in patients with thrombotic thrombocytopenic purpura: A retrospective multicenter study

UNLABELLED Thrombotic thrombocytopenic purpura (TTP) is a particular form of thrombotic microangiopathy typically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological abnormalities, and renal dysfunction. TTP requires a rapid diagnosis and an adapted management in emergency. Daily sessions of therapeutic plasma exchange (TPE) remain the basis of management of TTP. Also, TTP is a rare disease that is fatal if it is not treated. TPE has resulted in excellent remission and survival rates in TTP patients. AIM We aimed to present our experience in 163 patients with TTP treated with TPE during the past 5years from 10 centers of Turkey. PATIENTS AND METHODS One hundered and sixty-three patients with TTP treated with TPE during the past 5years from 10 centers of Turkey were retrospectively evaluated. TPE was carried out 1-1.5times plasma volume. Fresh frozen plasma (FFP) was used as the replacement fluid. TPE was performed daily until normalization of serum lactate dehydrogenase (LDH) and recovery of the platelet count to >150×10(9)/dL. TPE was then slowly tapered. Clinical data, the number of TPE, other given therapy modalities, treatment outcomes, and TPE complications were recorded. RESULTS Fifty-eight percent (95/163) of the patients were females. The median age of the patients was 42years (range; 16-82). The median age of male patients was significantly higher than female (53 vs. 34years; p<0.001). All patients had thrombocytopenia and microangiopathic hemolytic anemia. At the same time, 82.8% (135/163) of patients had neurological abnormalities, 78.5% (128/163) of patients had renal dysfunction, and 89% (145/163) of patients had fever. Also, 10.4% (17/163) of patients had three of the five criteria, 10.4% (17/163) of patients had four of the five criteria, and 6.1% (10/163) of patients had all of the five criteria. Primary TTP comprised of 85.9% (140/163) of the patients and secondary TTP comprised of 14.1% (23/163) of the patients. Malignancy was the most common cause in secondary TTP. The median number of TPE was 13 (range; 1-80). The number of TPE was significantly higher in complete response (CR) patients (median 15.0 vs. 3.5; p<0.001). CR was achieved in 85.3% (139/163) of the patients. Similar results were achieved with TPE in both primary and secondary TTP (85% vs. 87%, respectively; p=0.806). There was no advantage of TPE+prednisolone compared to TPE alone in terms of CR rates (82.1% vs. 76.7%; p=0.746). CR was not achieved in 14.7% (24/163) of the patients and these patients died of TTP related causes. There were no statistical differences in terms of mortality rate between patients with secondary and primary TTP [15% (21/140) vs. 13% (3/23); p=0.806]. But, we obtained significant statistical differences in terms of mortality rate between patients on TPE alone and TPE+prednisolone [14% (12/86) vs. 3% (2/67), p<0.001]. CONCLUSIONS TPE is an effective treatment for TTP and is associated with high CR rate in both primary and secondary TTP. Thrombocytopenia together with microangiopathic hemolytic anemia is mandatory for the diagnosis of TTP and if these two criteria met in a patient, TPE should be performed immediately.

The results of therapeutic plasma exchange in patients with severe hyperthyroidism: a retrospective multicenter study.

Hyperthyroidism characterized by elevated serum levels of circulating thyroid hormones. The aim of hyperthyroidism treatment is to achieve a euthyroid state as soon as possible and to maintain euthyroid status. However, drug withdrawal and utilization of alternative therapies are needed in cases in which leucopenia or impairment in liver functions is observed during medical therapy. In the present study, we aimed to present our cases which underwent therapeutic plasma exchange (TPE) due to severe hyperthyroidism. The results of 22 patients who underwent therapeutic plasma exchange due to hyperthyroidism in Apheresis Units of Erciyes University and Gaziantep University, between 2006 and 2012, were retrospectively reviewed. These cases had severe thyrotoxic values despite anti-thyroid drug use. After TPE, we observed a significant decrease in free thyroxin (FT4) (p<0.001) and free triiodotyhronin (FT3) (p<0.004) levels. There was statistically significant increase in the mean values of TSH levels after TPE (p<0.001). Clinical improvement was achieved in hyperthyroidism by TPE in 20 cases (91%). Both FT3 and FT4 levels remained above the normal limits in two of 22 patients. TPE should be considered as an effective and safe therapeutic option to achieve euthyroid state before surgery or radioactive iodine treatment. TPE is a useful option in cases with severe hyperthyroidism unresponsive to anti-thyroid agents and in those with clinical manifestations of cardiac failure and in patients with severe adverse events during anti-thyroid therapy.

Do thrombophilic gene mutations have a role on thromboembolic events in cancer patients

Aim:  Thromboembolism is common in patients with cancer and may be considered a major cause of morbidity and mortality. We studied the most common genetic polymorphism characteristics that may have roles in the development of thrombosis in patients with cancer.

A rare but severe complication of filgrastim in a healthy donor: Splenic rupture

BACKGROUND Granulocyte-colony stimulating factor (G-CSF) is widely administered to donors who provide peripheral blood stem cells (PBSCs) for individuals who undergo hematopoietic stem cell transplants. G-CSF administration is associated with a small but definite risks of serious adverse events like splenic rupture. CASE STUDY In this case, we report a 40 year old women, a healthy donor for her sister who has aplastic anemia, who had sharp left upper abdominal pain on the forth mobilization day. The diagnosis at CT scan was splenic rupture; irregular intrasplenic low-attenuation areas consistent with ruptured spleen and perisplenic high density fluid. Her bidimensional spleen size was 16×6 cm. RESULTS She was followed conservatively. One month later the CT scan signs of rupture disappeared. CONCLUSION We must pay attention to this rare but serious adverse event during filgrastim use.

Pretransplant iron overload may be associated with increased risk of invasive fungal pneumonia (IFP) in patients that underwent allogeneic hematopoietic stem cell transplantation (alloHSCT)

Invasive fungal pneumonia (IFP) has become increasingly common in patients that previously underwent alloHSCT. The aim of this study was to determine the role of hyperferritinemia, via iron overload in invasive fungal pneumonia in patients that underwent alloHSCT. Medical records of 73 patients with pneumonia that underwent alloHSCT were studied retrospectively, whereby a pre-transplantation serum ferritin level measured up to 100 days prior to transplantation of patients with invasive fungal pneumonia (IFP) and non-fungal pneumonia (non-IFP) was compared. Patient records revealed 35 and 38 cases of IFP and non-IFP, respectively. In risk evaluation for IFP, age, gender, HLA status, conditioning regimen, smoking history, and underlying disease were not significantly different among groups (p>0.05). However, performance status (Karnofsky) was significantly lower in patients with IFP (p<0.05). The median ferritin levels were 1,705 ng/ml (41-7198) in the IFP group and 845 ng/ml (18-7099) in non-IFP group and the difference was found statistically significant (p=0.001). Elevated pretransplant serum ferritin level is associated with IFP in patients that underwent alloHSCT, in particular when values exceed 1550 ng/ml.

Comparison of plateletpheresis on the Fenwal Amicus, Fresenius COM.TEC, and Trima Accel Cell separators

Blood component donations by apheresis have become more common in modern blood transfusion practices. We compared three apheresis instruments (Fenwal Amicus, Fresenius COM.TEC, and Trima Accel) with regard to platelet (PLT) yield, collection efficiency (CE), and collection rate (CR). The single‐needle or double‐needle plateletpheresis procedures of the three instruments were compared in a retrospective, randomized study in 270 donors. The blood volume processed was higher in the COM.TEC compared with the Amicus and Trima. Also there was a significantly higher median volume of ACD used in collections on the COM.TEC compared with the Amicus and Trima. The PLT yield was significantly lower with the COM.TEC compared with the Amicus and Trima. Additionally, the CE was significantly lower with the COM.TEC compared with the Amicus and Trima. There was no significant difference in median separation time and CR between the three groups. When procedures were compared regarding CE by using Amicus device, it was significantly higher in single‐needle than double‐needle plateletpheresis. When double‐needle Amicus system was compared with double‐needle COM.TEC system, CE and PLT yield were significantly higher with Amicus system. When single‐needle Amicus system was compared with single‐needle Trima system, CE and PLT yield were significantly higher with Trima system. All instruments collected PLTs efficiently. However, the CE was lower with the COM.TEC compared with the Amicus and Trima. Also, we found Amicus single‐needle system collected PLTs more efficiently compared with the double‐needle system. CE and PLT yields were significantly higher with the single‐needle Trima instrument compared with the single‐needle Amicus device. J. Clin. Apheresis 30:171–175, 2015.