Fatih Demirkan

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

Background Blinatumomab, a bispecific monoclonal antibody construct that enables CD3‐positive T cells to recognize and eliminate CD19‐positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B‐cell precursor ALL on the basis of single‐group trials that showed efficacy and manageable toxic effects. Methods In this multi‐institutional phase 3 trial, we randomly assigned adults with heavily pretreated B‐cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard‐of‐care chemotherapy. The primary end point was overall survival. Results Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event‐free survival than that with chemotherapy (6‐month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem‐cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Conclusions Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B‐cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167.)

Circulated Activated Platelets and Increased Platelet Reactivity in Patients With Behçet’s Disease:

Behçet’s disease (BD) is a multisystem disorder. Venous as well as arterial thrombosis is a common complication of BD but exact pathogenetic mechanism of the thrombotic tendency is not well known. This study aimed to evaluate circulating activated platelets and platelet reactivity in Behçet’s patients. Twenty-two Behçet’s patients (4 female, 18 male; mean age 38.6 ± 10.9 years) and 20 control subjects (8 female, 12 male; mean age 38.8 ± 9.4 years) were included. Those patients who had hypertension, hyperlipidemia, peripheral or coronary artery disease, hepatic or renal function abnormality, and who were using aspirin and other platelet-active drugs were excluded. Platelet activity and reactivity to adenosine diphosphate (ADP) were measured by whole blood flow cytometry. We assessed markers of platelet degranulation (P-selectin; CD62P) and the activated glycoprotein IIb/IIIa receptor (PAC1 binding to fibrinogen binding site) before and after stimulation with ADP. Platelet P-selectin expression was not significantly different between patients and control subjects both at baseline (p=0.420) and after stimulation (p=0.56). Baseline (p=0.001) and ADP-stimulated (p=0.003) PAC1 binding was significantly higher in Behçet’s patients than in the control group. Clinical activity has no effect on P-selectin expression and PAC1 binding. There is evidence of platelet activity and hyperreactivity in patients with BD and this may contribute to a prothrombotic state. In addition to aspirin, other antiplatelet drugs may be useful in the prevention and treatment of thrombosis in Behçet’s patients.

Plasma levels of free tissue factor pathway inhibitor in patients with various thyroid disorders

Various coagulation abnormalities occur in thyroid disorders and its range may vary from subclinical laboratory abnormalities to clinically significant disorders of coagulation. Tissue factor pathway inhibitor (TFPI), which inhibits the initial reaction of tissue factor mediated coagulation pathway, is reported to be increased in patients with Graves disease (GD) in one study. Hyperthyroid (n=10), hypothyroid (n=10) and subclinical hypothyroid (n=10) patients and control cases (n=16) were evaluated for free and total tissue factor pathway inhibitor (tTFPI), plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) levels in disease and euthyroid states. Free TFPI levels were significantly higher in hyperthyroid patients compared with the control group and subclinic hypothyroid patients (p<0.001), but not with hypothyroid patients (p>0.05). After the euthyroid state was obtained in the hyperthyroid group, the levels of total TFPI (p<0.05), free TFPI (fTFPI) (p<0.005), t-PA (p<0.005) and PAI-1 (p<0.02) decreased significantly. In hyperthyroid patients, there was a strong correlation between thyroid functions and free TFPI levels. In conclusion, we hypothesize that coagulation abnormalities seen in thyroid disorders cannot be explained directly with the impaired fibrinolytic activity but also with the elevated fTFPI levels. Both increased plasma fTFPI and PAI-1 levels could be markers of the peripheral activity of thyroid hormones.

Prognostic significance of immunohistochemical classification of diffuse large B-cell lymphoma

Abstract Aim: To evaluate the clinical significance of immunoperoxidase staining for CD10, bcl-6, mum-1 and bcl-2 to subdivide DLBCL into prognostic subgroups, we analysed 50 DLBCL cases using immunohistochemical methods. Methods and results: Fifty DLBCL patients were evaluated retrospectively. The expression of CD10 was associated with better OS (p=0·04) whereas expression of mum-1 was associated with worse OS (p=0·009). There were no significance of OS in case of expression of bcl-6 (p=0·05) and bcl-2 (p=0·3). They were subclassified using CD10, mum-1, bcl-6 as germinal center B-cell like (GCB) lymphoma (30%) and non-GCB lymphoma (70%). The OS and EFS (event free survival) were longer in GCB group (p=0·002) and 5-year OS for GCB group was 92% compared with only 44% for the non-GCB group (p=0·02). The OS of the GCB group also was longer compared to that of the non-GCB group in low IPI subgroup (p=0·01). Conclusion: The existance of survival differences between GCB a non-GCB group also in the patients with low IPI score, showed the importance of prognostic classification in the risk-adaptive treatment approaches. The classification as GCB and non-GCB based immunostains may enable to define more accurate prognostic groups in DLBCL.

Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase III study.

LBA7005 Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR (BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study. METHODS Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded. Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival (OS) and overall response rate (ORR) per IRC. RESULTS 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of pts in the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P< 0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs 54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia (53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and 1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb. CONCLUSIONS The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL. CLINICAL TRIAL INFORMATION EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745.

Hemophagocytic syndrome associated with inappropiate secretion of antidiuretic hormone in lymphoma and acute myeloblastic leukemia: Report of two cases

Hemophagocytic syndrome (HPS) is a rare clinicopathological disorder characterized by systemic proliferation of phagocytizing histiocytes associated with fever, cytopenias, lymphadenopathy, hepatosplenomegaly, and disseminated intravascular coagulopathy. We present the association of hemophagocytic syndrome associated with inappropriate secretion of antidiuretic hormone (SIADH) in two cases of hematological malignancies; anaplastic large cell lymphoma (ALCL) and acute myeloblastic leukemia (AML M4) In the patient with lymphoma, the diagnosis of lymphoma, HPS and SIADH were concurrent. In the patient with AML, HPS and SIADH were observed while the patient was in hematological remission. Thus it seems that patients with HPS may also carry a risk for the development of SIADH; the relationship with HPS and SIADH should be further investigated.

Gingival involvement in a patient with CD56+ chronic myelomonocytic leukemia

Leukemic infiltration of the gingiva is most commonly reported to be associated with monocytic subtypes of acute myeloblastic leukemia (AML) but rarely with myelodysplastic syndromes (MDS). Here we report a case of CD56 +  chronic myelomonocytic leukemia (CMML) who developed gingival involvement simultaneously when the leukocyte count elevated. At that time no increase in peripheral or bone marrow blasts were observed. Gingival hypertrophy regressed with the treatment of hydroxyurea. Three months later, bone marrow blast count elevated and the patient was treated with two courses of AML-like regimen and then one course of consolidation therapy. The patient is in complete hematological remission for one and a half years. Similar to other extramedullary involvements, gingival hypertrophy in CMML can be a harbinger of the disease entering a more aggressive phase requiring systemic chemotherapy.

Serum sickness‐like reactions associated with type III insulin allergy responding to plasmapheresis

A 26-year-old woman with Type 1 diabetes for 8 years developed subdermal, small, tender and mildly erythematous nodules at her insulin pump injection sites, occurring 4–8 h after changing pump sets. Her blood glucose levels increased after the nodules became prominent. Simultaneously, she began to experience unpredictable hypoglycaemic episodes. Previous glycaemic control had been good, with HbA1c 5.6%. She had no diabetes complications. She had used insulin aspart via continuous subcutaneous insulin infusion (MMT Paradigm 712; Minimed Technologies, Sylmar, CA, USA) for 3 years, having taken multiple daily injections of human regular insulin and neutral protamine Hagedorn (NPH) insulin previously. Her only other complaint was of asthma for 24 years, well-controlled by inhaled steroids. Her body mass index was 23.0 kg ⁄ m. Her insulin was changed initially to insulin lispro and subsequently to regular insulin, but the skin reactions persisted. Skin-prick test was positive for all available insulin preparations (regular, aspart, lispro, NPH, glargine and detemir). Her IgE and IgG levels were 91.7 IU ⁄ ml (normal 0–87) and 7.31 g ⁄ l (normal 7–16), respectively. Serum complement C3 and C4 levels were normal. Antinuclear antibody was negative. In view of typical Arthus’ reaction, type III allergy to insulin was diagnosed, and treatment with antihistamines was initiated. Methylprednisolone was administered locally by injection and via pump and later given orally at a dose of 40 mg ⁄ day when no response was observed with antihistamines and local steroids. She recovered dramatically and her insulin requirement decreased. She was discharged on an oral steroid tapering scheme. One month later, she presented as an emergency with diabetic ketosis, while she was using 28 mg ⁄ day methylprednisolone orally. She was pyrexial (38.3 C), with polyarthralgia affecting her wrists, elbows, ankles and knees bilaterally, myalgia of the extremities, and oedema on the dorsal part of her hands and distal lower extremities. Infection was excluded by examination, blood cultures, chest X-ray and abdominal ultrasound. Intravenous human regular insulin was given to treat the diabetic ketosis. She required a minimum of 1000 U ⁄ day. Her serum total insulin level was > 400 lIU ⁄ ml (normal 6.0–28.4). Serum sickness-like reaction was diagnosed, and methylprednisolone dose was increased to 48 mg ⁄ day. However, the clinical findings did not resolve. Treatment with methotrexate and azathioprine was also unsuccessful. Plasmapheresis with fresh frozen plasma was started, by continuous flow centrifugation using a Fresenius Comtec-S5L cell separator (Fresenius Medical Care, Hamburg, Germany). Saline with sodium citrate was used as anticoagulant. The plasma removed was substituted mainly by blood donor plasma, partly freshfrozen, and saline. She responded dramatically within hours. All clinical findings resolved and the daily insulin requirement decreased to 40–50 U. However, she needed repeated plasmapheresis every 1–3 days. Pancreas transplantation was planned. While she was being prepared for transplantation, she developed an anaphylactic reaction during plasmapheresis. Despite resuscitation, she died. The frequency of insulin allergy is reduced with the use of humaninsulin;however, it isstillamajorproblemthatmaybelifethreatening in some cases. In a Type III allergy, insulin–antibody complexes cause basophile degranulation and local release of histamine and other mediators of hypersensitivity. Complement fixation, leucocyte attraction and an inflammatory response to antigen–antibody complex formation are involved [1]. Plasmapheresis has been used in the treatment of type B insulin resistance, which is caused by polyclonal IgG antibodies directed against the insulin receptor [2]. However, our paper is the first report of plasmapheresis in the treatment of type III insulin allergy and serum sickness-like reactions. The effect of plasmapheresis is temporary, as de novo synthesis of antibodies is ongoing since cellular components of the immune system are not directly affected by plasmapheresis. The most serious possible reaction of plasmapheresis is an allergic reaction to the plasma replacement fluids or the sterilizing agents used in the tubes [3]. The anaphylactic reaction in our patient might be considered a complication of plasmapheresis [3,4]. However, the anaphylactic reaction, which caused her death, might also be related to the widespread immune-mediated reactions due to unidentified antigen stimulants or insulin. Although rare, insulin allergy is still a major problem in the management of diabetes. Despite the unfortunate outcome in our patient, we suggest that plasmapheresis is a temporarily effective treatment for type III allergy to insulin.

The effect of the acute submaximal exercise on thrombin activatable fibrinolysis inhibitor levels in young sedentary males.

Depending on type, duration, and intensity of the exercise, changes occur in hemostasis. In this study, we evaluated the changes in the parameters of coagulation and fibrinolytic systems that happened after the submaximal aerobic exercises by bicycle ergomater. Twelve healthy male participants whose ages were between 21 and 28 have been included. The venous samples have been drawn before the exercise as well as at the 0th, 15th, and 60th minutes after the submaximal exercise. The values of prothrombin time (PT), active partial thromboplastin time (aPTT), D-dimer, fibrinogen, plasminogen activator inhibitor 1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) have been measured. Plasminogen activator inhibitor 1 values have shown an insignificant increase after exercise (P = .328), whereas, it has decreased significantly during the resting period (P = .033) Postexercise 15th and 60th minutes TAFI values have decreased significantly comparing to basal and postexercise (0th minute) values (P = .001). Fibrinolytic system activation is observed after acute submaximal aerobic exercise of sedentary healthy participants.

The clinical, haematological and morphological profile of patients with myelodysplastic syndromes : A single institution experience from Turkey

In a retrospective analysis of 113 patients with primary myelodysplastic syndromes (MDS) diagnosed according to French-American-British (FAB) classification, we evaluated the prognostic impact of FAB and World Health Organisation (WHO) classifications, International Prognostic Scoring System (IPSS), and other clinical and laboratory variables. The median age was 69. IPSS could be applied to 75 patients classified according to the FAB criteria and to 50 patients reclassified according to the WHO criteria. At a median follow-up of 24 months, 22 patients (19.5 %) transformed to acute myelogenous leukaemia (AML). Overall survival (OS) of patients differed significantly between the FAB and WHO subgroups (p < 0.0001). In WHO classification, significant differences were observed in both OS and leukaemia free survival (LFS) between patients with RA/RARS and refractory cytopenia with multi-lineage dysplasia/refractory cytopenia with multi-lineage dysplasia and ringed sideroblasts (RCMD/RS-RCMD) (p = 0.0001). High-risk according to IPSS score and blood transfusion need were significantly predictive for a shorter survival and higher risk of transformation. Hemoglobin <10 g/dl, neutrophil count <0.5 × 109/L, platelet count <50 × 109/L had an unfavourable prognostic impact on survival in multi-variate analysis. Our conclusions support the previous findings on the value of WHO classification for prediction of prognosis in MDS.