Abdullah Katgi

Nilotinib Does Not Alter the Secretory Functions of Carotid Artery Endothelial Cells in a Prothrombotic or Antithrombotic Fashion

Background: There have been concerns about the possible prothrombotic effects of nilotinib, especially in patients having cardiovascular risk factors. The potential mechanism behind the increased risk of thromboembolic events is still not clear. Objectives: In this study, we aimed to evaluate possible harmful effects of nilotinib on endothelial cells. To this aim, we examined proliferative capacity and secretory functions of healthy human carotid artery endothelial cells (HCtAECs) in response to nilotinib. Methods: 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation method was used to determine antiproliferative effects of nilotinib on HCtAECs. The HCtAECs were incubated with 5, 10, and 100 nmol/L doses of nilotinib for 72 hours. Then, in order to assess the endothelial function, levels of nitric oxide (NO), von Willebrand factor (vWF), tissue plasminogen activator, plasminogen activator inhibitor 1 (PAI-1), and endothelin 1 (ET-1) were evaluated using enzyme-linked immunosorbent assay from tissue culture supernatants. Results: There were slight but statistically significant decreases in cell proliferation in response to nilotinib. Nilotinib increased the secretion of t-PA, PAI-1, and vWF in a dose-dependent manner when compared with the untreated control group. The ET-1 secretion was lower in 5 nmol/L and higher in 10 and 100 nmol/L nilotinib-treated cells as compared to untreated cells. Regarding NO secretion, lower levels were observed in 5 and 10 nmol/L, and higher levels were detected in 100 nmol/L nilotinib-treated cells as compared to untreated control group cells. Conclusion: Considering the results obtained in our study, nilotinib does not affect the functions of endothelial cells either in a prothrombotic or an antithrombotic fashion, despite a dose-dependent decline in cell viability.

Is the BFM Regimen Feasible for the Treatment of Adult Acute Lymphoblastic Leukemia? A Retrospective Analysis of the Outcomes of BFM and Hyper-CVAD Chemotherapy in Two Centers

Multiple induction regimens have been developed for adult patients with acute lymphoblastic leukemia (ALL). However, there have been no prospective randomized trials that directly compare these regimens. In this study, we wanted to evaluate the outcome of 50 adult ALL patients treated with BFM (i.e. Berlin-Frankfurt-Munster, n = 20) and hyper-CVAD (n = 30) protocols between March 2006 and October 2012. The median age was 25 years in the BFM group and 30.5 years in the hyper-CVAD group with a male/female ratio of 15:5 and 17:13, respectively. Forty-five percent of the patients in the BFM group and 30.3% in the hyper-CVAD group were <25 years old. The majority of cases were B cell in origin (80% in the BFM group and 70% in the hyper-CVAD group). Complete remission after induction therapy was achieved in 95 and 96% of the patients, respectively. The median follow-up time was 37 months. The 5-year survival rate was higher in the BFM group than in the hyper-CVAD group (59 vs. 34%). There were also no complications which could cause a delay during the hyper-CVAD regimen. Both chemotherapies were well tolerated. None of the patients died from drug-related toxicity. Only mild liver enzyme elevations were seen as toxicity in the BFM group; these did not cause any delay in therapy. The BFM regimen seems to be feasible for adult patients with ALL in terms of tolerability and efficacy, especially in young adults.

Renal and neurological response with eculizumab in a patient with transplant associated thrombotic microangiopathy after allogeneic hematopoietic progenitor cell transplantation.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenge after allogeneic hematopoietic progenitor cell transplantation, considering the diagnostic uncertainties and lack of established treatment. We report a 43-year-old male patient who was diagnosed as TA-TMA after allogeneic progenitor cell transplantation for a progressive ALK negative anaplastic large cell lymphoma and responded to eculizumab with dramatically improving neurological status and renal function. Rapid neurological and renal recovery achieved after eculizumab could support a possible relationship between complement activation and TA-TMA. Eculizumab should be a reasonable treatment approach in patients with TA-TMA after allogeneic hematopoietic progenitor cell transplantation.

Ischemic stroke after recombinant factor VIIa treatment in acquired hemophilia A patient.

Acquired hemophilia is a rare, life-threatening coagulopathy in adults caused by the development of autoantibodies against factor VIII. Bypass agents such as recombinant factor VIIa (rFVIIa) are usually preferred for bleeding control; however, thromboembolic complications may occur. We report here a case that presented with extensive cutaneous and mucosal bleedings due to factor VIII inhibitors and was treated successfully with rFVIIa and steroid therapy, but was complicated with a life-threatening thromboembolic attack during follow-up.

Hypoalbuminemia is a surrogate biomarker of poor prognosis in myelodysplastic syndrome even when adjusting for comorbidities.

The serum albumin (SA) level has been reported to be an independent prognostic biomarker that may serve as a surrogate representative of disease biology in patients diagnosed with myelodysplastic syndrome (MDS). However, its prognostic ability has not been tested in a model adjusting for comorbidities. We analyzed 200 patients who were diagnosed as having de novo MDS. Median overall survival (OS) of all patients was 25 months and median leukemia-free survival (LFS) was 24 months. Median OS according to the SA level groups of ≤ 3.5, 3.6–4.0 and > 4.0 mg/dL were 24, 39 and 77 months, respectively. SA level remained an independent predictor of both LFS and OS even when adjusting for the hematopoietic cell transplant comorbidity index (HCT-CI) and the International Prognostic Scoring System (IPSS) or World Health Organization classification-based Prognostic Scoring System (WPSS). Our findings indicate that SA level at the time of diagnosis is a significant and independent predictor of LFS and OS even when adjusting for commonly used prognostic systems and comorbidities.

Ex vivo evaluation of the effect of regulatory T cells on the anti-tumor activity of bortezomib in multiple myeloma

Multiple myeloma (MM) is a hematologic cancer characterized by malignant proliferation of plasma cells and their precursors. Immunosuppressive CD4+CD25+Foxp3+ regulatory T (Treg) cells are increased in the peripheral blood of patients with MM. On the basis of this finding, we sought to evaluate the ex vivo effect of CD4+CD25+Foxp3+ Treg cells on the anti-tumor effect of the proteosome inhibitor bortezomib on MM cells. We collected peripheral blood and bone marrow aspiration samples from 20 patients with newly diagnosed MM and isolated CD4+CD25+Foxp3+ Treg cells from peripheral blood mononuclear cells. The bone marrow mononuclear cells were cultivated in RPMI at 37°C and 5% CO2 for 72 hours. The LD50 doses of bortezomib, isolated Treg cells, and their combination were added. After 24 hours, the viability of CD138+ myeloma cells was evaluated by WST-1. We compared the anti-tumor effect of bortezomib alone and in combination with Treg expansion and statistically analyzed the measured differences with respect to the clinical parameters of the patients. Treg cells had varied effects on bortezomib, increasing, decreasing, or not changing its anti-tumor effect. The increased in vitro anti-tumor effect of bortezomib after Treg cell expansion was correlated in patients who did not develop bortezomib resistance in vivo (p = 0.022). These patients with in vivo non-bortezomib-resistant MM also responded to Treg expansion with decreased cell viability (p = 0.024). Our data indicate that the ex vivo expansion of Treg cells increased the cytotoxic effect of bortezomib in clinically sensitive cases.

Successful hematopoietic engraftment with gray platelets after allogeneic hematopoietic stem cell transplantation from gray platelet syndrome donor.

Gray platelet syndrome (GPS) is a rare inherited disorder characterized by the absence of &agr;-granules and their constituents. It may be present with thrombocytopenia and bleeding tendency. Platelets have a large and gray appearance under light and electron microscope. A 19-year old female patient with her second relapse acute lymphoblastic leukemia had to be consolidated with allo-hematopoietic stem cell transplantation (HSCT) after achieving remission with induction chemotherapy. The only available and one mismatch compatible donor was her brother, who was previously diagnosed as GPS. Allogeneic HSCT was performed from her brother in spite of GPS, and successful neutrophil and platelet engraftment achieved at the 12th and 42nd day of reinfusion, consecutively. The engrafted and circulating thrombocytes were large and gray and had little or no &agr;-granules under electron microscope. The patient was well with no major bleeding event and increased need for thrombocyte replacement until developing bronchiolitis obliterans organizing pneumonia and respiratory distress syndrome. Thereafter death occurred. This is the first case of successful thrombocyte engraftment with documented gray thrombocyte megakaryopoiesis after allogeneic HSCT from a GPS donor. The only noteworthy issue was the slight prolongation of engraftment.

Periferik Hematopoietik Kök Hücre Nakli Yapılan Lenfoma Hastalarımız: Tek Merkez Deneyimi

Amac: Birinci sira tedaviye yeterli yanit vermeyen yada relaps olan Hodgkin ve Non-Hodgkin lenfomali hastalarda ikinci sira tedavi sonrasi otolog periferik kok hucre (OKIT) destekli yuksek doz kemoterapi yaygin olarak kullanilmaktadir. Biz bu calismada Dokuz Eylul Universitesi Tip Fakultesi Hematoloji Bilim dali tarafindan 2005-2009 yillari arasinda izlenen ve periferik kok hucre nakli yapilan 45 lenfoma hastasini sunmayi amacladik. Gerec ve yontemler: Hastalarin yaslari 19-67 arasinda ve yas ortalamalari 38,87 idi. Tanilarina bakildiginda %24,4’u Diffuz Buyuk B hucreli NHL, %35,6’si Noduler Sklerozan Hodgkin Lenfoma, %17,8’i miks selluler Hodgkin lenfoma, %8,9’u lenfoblastik lenfoma idi. Bulgular: Hastalarin %90’ina OKIT destekli yuksek doz tedavi, %10’una ise allogeneik kok hucre nakli uygulandi. Nakil sonrasi hastalarin son yapilan degerlendirmelerinde 45 hastanin 13’unun komplet remisyonda, 2’sinin progresif hastalik, 2’sinin parsiyel yanitli, 3’unun stabil hastalik oldugu goruldu. 12 hasta hastalik iliskili, 2’si hastalik disi nedenlerle ve 11 hastada sepsis nedeni ile kaybedildi. Sonuc: Otolog periferik kok hucre destekli yuksek doz tedavi ile ozellikle platin bazli tedaviye yanit veren lenfoma hasta gurubunda yuz guldurucu sonuclar alinmaktadir.