Teoman Soysal

The Frequency of Tuberculosis in Adult Allogeneic Stem Cell Transplant Recipients in Turkey

In general, tuberculosis (Tb) is rarely seen in allogeneic stem cell transplant (alloSCT) recipients, but this observation has been challenged in developing countries such as Turkey, where Tb infection is more prevalent than in Europe and the US. In this retrospective study, we report on the incidence of Tb infections in 351 alloSCT recipients at 4 bone marrow transplantation units in Turkey over the last 10 years. The frequency of Tb in alloSCT recipients after allografting (5 of 351) was far greater than that in the general population (35.4 per 100,000). Of the 351 patients who underwent alloSCT, 77 who received isoniazid (INH) chemoprophylaxis for 6 months did not develop posttransplantation Tb. However, 5 of the remaining 274 patients who received no chemoprophylaxis developed Tb a median of 12 months (range, 10-47 months) after allografting. Antituberculosis therapy resulted in complete recovery in all cases. In 2 additional patients who were found to have active pulmonary Tb at the time of transplantation, alloSCT was delayed until the infections were treated. Infections of mycobacteria other than Mycobacterium tuberculosis were not observed. The number of patients who received and tolerated INH may not be sufficient for firm conclusions, but the data suggest that, in countries where Tb is prevalent, pre- and posttransplantation follow-up for Tb and the use of INH prophylaxis should be considered.

T-cell-rich B-cell lymphoma: a clinicopathologic study of 21 cases and comparison with 43 cases of diffuse large B-cell lymphoma

Clinicopathologic features of 21 patients with T-cell-rich B-cell lymphoma (TCRBCL) were reviewed and compared to 43 patients with diffuse large B-cell lymphoma (DLBCL) to determine if there were distinguishing clinical characteristics and differences in response or survival to CHOP therapy. For the diagnosis of TCRBCL, the current WHO criteria was used. In all of our cases, the majority of cells are non-neoplastic T cells and <10% large neoplastic B cells are present. The initial pathologic diagnosis was nodular lymphocyte predominant Hodgkins lymphoma (NLPHL) in two cases. Patients with TCRBCL were significantly younger (median: 46 years) and had a significantly higher incidence of B symptoms (62%), hepatomegaly (33%) and marrow infiltration (33%) at presentation when compared to DLBCL (P<0.03). The CR rate after treatment was 48% for TCRBCL patients versus 79% for the DLBCL (P<0.003). Although the CR rates in between the two groups are significant, the difference in 3 years survival rates in each CR groups was insignificant (80% versus 77%). The overall survival time in the two groups was 17 months. Event-free survival time in TCRBCL was 12 months, compared with 17 months in the DLBCL (P>0.05). The frequency of patients with TCRBCL achieving CR was 52.6% whereas that of patients with DLBCL was 79% (P<0.003). The TCRBCL 3 years event-free survival 48% and overall survival 64% were 63 and 72% for DLBCL, respectively.

17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis

We explored the relationship between the cytogenetic/biologic characteristics of B-chronic lymphocytic leukemia (B-CLL) cells and their tendency to undergo spontaneous or fludarabine-induced apoptosis in vitro. B cells from 36 B-CLL patients were incubated with or without fludarabine for 48 h. Apoptosis was determined by two assays: annexin V staining and DNA staining. Fluorescence in situ hybridization was used for detection of trisomy 12, 11q deletion, and 17p deletion. Bcl-2 and CD38 expressions were determined by flow cytometry. Five patients had 17p deletion, 6 had trisomy 12, and another 6 had 11q deletion. B-CLL cells with 17p deletion had significant resistance to apoptosis induced by fludarabine and a slight spontaneous resistance to apoptosis. Bcl-2 and CD38 were not associated with in vitro spontaneous and fludarabine-induced apoptosis. In conclusion, 17p deletion, which causes loss of p53 gene, is associated with resistance to fludarabine-induced apoptosis in vitro. New treatment modalities should be tried in B-CLL patients with 17p deletion.

Chronic myeloid leukemia patients who develop grade I/II pleural effusion under second-line dasatinib have better responses and outcomes than patients without pleural effusion

Dasatinib is a potent second generation TKI, and it is widely used in patients with CML, both in the up-front setting and failure after imatinib. Lymphocytosis in cases receiving dasatinib therapy has been shown to be associated with pleural effusion (PE) and better outcome. Although patients who gather lymphocytosis during dasatinib have superior responses, there is only little data about the correlation between PE, response rates, and survival. In order to answer this question, the aim of our study was to determine the frequency of PE and lymphocytosis among our CML patients receiving second-line dasatinib, and to compare the responses and outcomes between patients with or without PE. There were 18 patients (44%) who developed PE, in a total of 41 patients, with a median time of 15 months. Lymphocytosis was observed in nine patients (9/41, 22%) with a median duration of 6.5 months of dasatinib treatment. There were fourteen patients with at least one comorbidity that may play a role in the generation of PE. The cumulative MMR and CCyR rates were greater in PE+ patients (p<0.05). The PFS was significantly higher in PE+ group than PE- patients (p=0.013), also the OS was higher among PE+ patients than PE- group (p=0.042). In patients with a grade I/II PE, and durable responses under dasatinib, performing the management strategies for the recovery of effusion, together with continuing dasatinib can be a reasonable choice mainly in countries where third generation TKIs are not available. But alternative treatment strategies such as nilotinib or third generation TKIs can be chosen in patients with grade III/IV PE especially if the quality of life is severely affected.

Successful management of cryoglobulinemia-induced leukocytoclastic vasculitis with thalidomide in a patient with multiple myeloma

Leukocytoclastic vasculitis (LV) is a systemic inflammatory disorder involving mostly the small vessels. It is characterised by segmental angiocentric neutrophilic inflammation, endothelial cell damage and fibrinoid necrosis. LV is related to a variety of clinical disorders including cryoglobulinemia and, very rarely, multiple myeloma (MM), among many others. The development of LV in patients with MM has been linked to cryoglobulinemia, infections, drugs and paraneoplasia. It has been speculated that myeloma patients with a poorer prognosis and progressive disease are more prone to develop LV. Thalidomide is a rediscovered old drug with anti-angiogenic, immunomodulatory and anti-inflammatory properties. It is highly effective in the treatment of MM and other clinical disorders such as leprosy, various cancers, graft-versus-host disease and autoimmune diseases. We report here a female patient with Durie–Salmon stage IIA MM who initially presented with cryoglobulinemia and LV. LV in this patient was primarily considered to be the result of progressive cryoglobulinemia, which was closely associated with MM. She was successfully managed with thalidomide and dexamethasone.

The efficacy of generic formulations of imatinib mesylate in the treatment of chronic myeloid leukemia.

Th e treatment of chronic myeloid leukemia (CML) has changed greatly, and the outlook of patients with CML has improved dramatically, with the introduction of tyrosine kinase inhibitors (TKIs) [1]. Th e fi rst TKI developed for CML was imatinib mesylate (IM) (Glivec; Novartis, Basel, Switzerland) [2], and thereafter many other TKIs became available on the market [3]. Th e high cost of new cancer drugs including those developed for CML is a major concern for healthcare payers, especially in countries with restricted resources. Reimbursement policies worldwide, therefore, encourage generic drug use to lower the prices. It is true that generics lead to considerable cost savings, but they also give rise to questions associated with their effi cacy, safety and quality. In Turkey, there are three commercially available generics of IM (Imatis; Deva, Imatenil; Logus and Imavec; Ko c ak Farma), which have been licensed for the treatment of CML for more than a year. Th ere is a price diff erence between Glivec and the generics, and due to the reimbursement policy, patients who prefer to receive the original molecule must pay the price diff erence; the price diff erence was the only reason for switching from Glivec to any generic among our cohort. Th e fi rst issue that physicians caring for patients with CML encounter is whether the effi cacy of these generics is comparable to that of the original molecule; the second issue is what the potential adverse events (AEs) are, other than those with use of Glivec, if any. To answer these questions, we retrospectively reviewed our data.

Pleural and pericardial effusions in chronic myeloid leukemia patients receiving low-dose dasatinib therapy

They reported 4 patients who developed effusions with 50 or 100 mg daily dasatinib out of a total number of 13 patients. Pleural and pericardial effusions were grade III/IV in 2 of the patients. There were no reports of pre-existing cardiac or pul monary diseases for any of the 4 patients. In 3 cases, dasa tinib had to be discontinued because of the persistence of the pleural fluids despite treatment with diuretics and glu cocorticosteroids. In conclusion, Krauth et al. suggest that all patients should be examined for pre-existing comorbidities and risk factors before the initiation of dasatinib, and they should have repeated chest X-rays during the followup period because of the possibility of pleural or pericardial effusions even under low doses of dasatinib treatment. We report our experience of chronic myeloid leukemia patients receiving low-dose dasatinib who had developed pleural and pericardial effusion. In our institute, a total number of 23 chronic phase chronic myeloid leukemia patients receive dasatinib (50-100 mg daily) due to resist ance or intolerance to imatinib. Among these 23 patients, 10 of them (43%) had pleural and pericardial effusions (9 with pleural effusion and one with pericardial effusion). Eight patients were males and 2 were females. Median age was 61.5 (range 44-69). Nine patients out of 10 were in late chronic phase who were switched to dasatinib because of imatinib resistance. Only one patient was in early chronic phase since she started receiving dasatinib due to intolerance of imatinib. The median duration of dasatinib use was 26 months (range 13-33). All of the patients had grade I/II effusions. In 7 patients dasatinib therapy was interrupted and furosemide plus glucocorti costeroids were initiated; effusions were totally resolved in 4 of the 7. Dasatinib was restarted in those 4 patients and effusions did not reoccur. The remaining 3 patients had just started receiving furosemide and glucocorticosteroids and are under follow up so we were unable to make a comment on the success of the treatment. Dasatinib treatment was not stopped in one patient when he developed pleural effusion; we only added gluco corticosteroids and the effusion improved. No other inter vention was made in the other 2 patients other than inter rupting dasatinib treatment and the pleural effusions improved. After restarting dasatinib in those 2 patients, one of them developed pleural effusion which was then managed with furosemide and glucocorticosteroids, dasa tinib was discontinued and he then fully recovered. Pleural effusion is the most frequent non-hematologic adverse event in dasatinib-treated patients. 2 Although effu sion formation may require some time and the risk of effu sion formation is lower in patients treated with 100 mg dasatinib than patients receiving 140 mg dasatinib daily, patients treated with dasatinib at 100 mg daily dose may also develop pleural effusions.

Generics in chronic myeloid leukemia: current arguments for and against and the established evidence

Tyrosine kinase inhibitors became the mainstay of management in patients with chronic myeloid leukemia. The substantially high treatment cost has unfortunately been a major issue. Recent market entry of the imatinib generics are expected to lower the price and increase the availability of the drug worldwide. However, concerns about their efficacy and safety seem to slacken the approval of the generics in many countries. In this editorial, we discuss the current evidence on imatinib generics based mainly on Turkish experience and other limited data available.

First line treatment of chronic phase chronic myeloid leukaemia patients with the generic formulations of imatinib mesylate

in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America. British Journal of Haematology, 146, 546–556. Vogiatzi, M.G., Macklin, E.A., Fung, E.B., Cheung, A.M., Vichinsky, E., Olivieri, N., Kirby, M., Kwiatkowski, J.L., Cunningham, M., Holm, I.A., Lane, J., Schneider, R., Fleisher, M., Grady, R.W., Peterson, C.C., Giardina, P.J. & Thalassemia Clinical Research Network (2009b) Bone disease in thalassemia: a frequent and still unresolved problem. Journal of Bone and Mineral Research, 24, 543–557.

Bone marrow transplantation for Behçet’s disease: a case report and systematic review of the literature

OBJECTIVES Behçets disease (BD) can be life threatening and may be refractory to corticosteroids and immunosuppressives. There has been some experience with haematopoietic stem cell transplantation (HSCT) in BD either for severe, refractory disease or for a haematological condition. The objectives of this study were to describe a BD patient undergoing HSCT and to evaluate the outcomes of BD patients who underwent HSCT. METHODS We report a BD patient with refractory gastrointestinal (GI) involvement who had HSCT for concomitant myelodysplastic syndrome (MDS). We also performed a systematic literature search regarding HSCT for either refractory disease or concomitant haematological conditions in BD patients. RESULTS A 30-year-old woman with refractory GI BD involvement with trisomy 8 MDS underwent a successful myeloablative allogeneic HSCT resulting in complete resolution of both BD and MDS. Additionally we identified 14 manuscripts providing data on 19 patients with BD who had HSCT. Among these 20 patients, including ours, refractory disease was the indication of transplantation in 9, while 11 patients were transplanted because of accompanying haematological conditions. Transplant indications for the nine patients (four male, five female) with refractory BD were neurological involvement in five, pulmonary artery aneurysm in two, GI disease in one and not reported in one patient. Three patients with neurological disease, both patients with pulmonary artery aneurysm and the patient with intestinal involvement achieved complete remission of their disease. Six patients transplanted for haematological conditions, including the presented case, also had GI involvement of BD. All of these patients achieved complete remission of GI findings after HSCT. CONCLUSION When considering HSCT, the potential adverse events and complications, which can be fatal, need to be kept in mind.