Gyula Reményi

One hundred fifty autologous peripheral haemopoietic stem cell transplantations and their lessons

UNLABELLED Five years ago (in September, 2003), the activity of the 5th Haemopoietic Stem Cell Transplantation Centre of Hungary has begun. This centre has been registered as No 648. by the European Group for Blood and Marrow Transplantation-Centres. AIMS To supply the needs of stem cell transplantation regions in north-east Hungary and to develop an active co-operation with the Hungarian and international centres. METHODS Transplantations were made according to international criteria. RESULTS 150 autologous stem cell transplantations has been performed so far, including 74 patients with myeloma multiplex, 43 patients with non-Hodgkin lymphoma, 27 patients with Hodgkins disease, 4 patients with autoimmune disease, and one patient with leiomyosarcoma. The survival rates were similar to the previous Hungarian and international data. The centre played a role in other activities using stem cell therapy at the University of Debrecen (dendritic cell vaccine program, stem cell therapy in myocardial infarction, stem cell therapy in peripheral arterial- and autoimmune diseases). This centre performed the largest quantity of the conditioning protocol Zevalin, Bischloronitrosourea, Etoposide, cytosine-Arabinoside, Melphalan in non-Hodgkin lymphoma in Hungary; ten patients were treated with this protocol.

Comparison of coated-platelet levels in patients with essential thrombocythemia with and without hydroxyurea treatment.

Essential thrombocythemia (ET) is an acquired myeloproliferative disorder with sustained increase of platelet count. This disease may be associated with thrombotic or bleeding complications due to the altered number and function of platelets. Coated-platelets produced by a simultaneous activation of collagen and thrombin represent a subpopulation of activated platelets with high prothombinase activity and the retention of several α-granule-derived coagulation factors on their surface. There is a growing body of evidence for a relationship between variable levels of coated-platelets and different hemostatic alterations. However, no data are available on coated-platelet formation in the pathogenesis of ET in the presence or absence of treatment. The levels of coated-platelets in 43 ET patients (15 non-treated and 28 hydroxyurea-treated) without known thrombotic or hemorrhagic complications were analyzed using flow cytometry. These results were compared with data of 31 healthy individuals. In addition, platelet function was analyzed with PFA-100 analysis, and P-selectin (CD62) positivity was also measured by flow cytometry. Increased P-selectin expression was detected with prolonged PFA-100 closure times in the ET group; however, significantly lower levels of coated-platelets were found in non-treated ET patients compared to controls (23.1 ± 8.8% vs. 37.6 ± 12.7%, p = 0.0008). This tendency was more evident in patients with JAK2-V617F mutation. Patients on hydroxyurea treatment had elevated coated-platelet levels (34.1 ± 12.3%) close to the normal value. In conclusion, lower than normal levels of coated-platelets were generated in ET, which were significantly (p = 0.0008) increased by hydroxyurea treatment. We suppose that abnormal coated-platelet level may also contribute to platelet dysfunction in ET.

Treatment of mantle cell lymphoma with autologous stem-cell transplantation in a patient with severe congenital haemophilia-A and chronic (B and C virus) hepatitis

Mantle cell lymphoma (MCL) is a highly malignant disease with a median survival of 3–5 years. Most of the patients have advanced stage disease at the time of diagnosis. Combined chemo-immunotherapy, mainly rituximab and cyclophosphamide, vincristine, doxorubicin, dexamethasone altering with methotrexate and cytarabine [hyper-CVAD (cyclophosphamide, vincristine, doxorubicine, dexamethasone altering with methotrexate and cytarabine) programme], autologous stem-cell transplantation (ASCT) in first remission and allogeneic stem-cell transplantation (in patients with relapsed or refractory MCL) improved the outcome, resulting in longterm disease control [1]. We present a case of MCL associated with severe congenital haemophilia A as well as chronic B and C virus infection. It is the first report of ASCT in such a patient. The first (and so far only) ASCT in a patient with severe haemophilia A and AIDS-related lymphoma was described in 2007 [2]. Our patient was not infected with HIV. A 38-year-old man, with severe congenital haemophilia A [factor VIII (FVIII) <1%, inhibitor was not detectable] and chronic (B and C virus) hepatitis, presented with generalized lymphadenopathy. Viral infections were acquired via factor substitutions. Lymph node biopsy revealed MCL (blastoid variant) with bone marrow involvement (stage IV/A). Viral loads were not investigated at this time. Eight cycles of CEOP (cyclophophamide, etoposide, oncovin and prednisone) therapy were administered in a county hospital. Follow-up PET-CT revealed only slight response. Treatment was continued with two cycles of dexamethasone, high-dose Ara-C and cisplatin (DHAP) with poor response. Hyper-CVAD programme was started at our department with good partial response. As a result of chronic viral infection and absence of appropriate virological investigation, rituximab was not added. Stem-cell collection was performed after the third cycle of therapy; however, some weeks later, rapid enlargement of abdominal lymph nodes was detected. Despite the lymph node progression, he proceeded to ASCT. At this time, a detailed virological investigation was carried out: HBV DNA, determined by RT-PCR method, was negative. Other HBV assays were performed as follows: HBeAg: negative, anti-HBe: positive, antiHBc IgM: negative. HCV RNA was positive at high titre (5 650 000 IU mL), measured by HCV Amplicor (TaqMan Roche, Rotkreutz, Switzerland) assay. Transaminase levels were normal. The therapy was supplemented with rituximab. The conditioning regimen included total body irradiation (TBI) (4 · 3 Gy, on days )7 to )4), cyclophosphamide (2 · 60 mg kg, on days )3 to )2) and rituximab (375 mg m on day )1), where treatment was supplemented with bortezomib (1.3 mg m on day )3), followed by infusion of 8.25 · 10 CD34+ cells bwkg (day 0). Recovery of neutrophils (‡1.0 · 10 L) occurred on day 9. As abdominal lymphadenopathy was still observed subsequent to transplantation, steroid therapy (32 mg methylprednisolone daily), alfa-2b interferon (1.5 MU three times weekly) and rituximab treatment (375 mg m once a month) were initiated. Before stem-cell transplantation, he was on prophylactic therapy (3.000 IU octanate/octapharma/ twice weekly). He had no bleeding complication during the year before transplantation. Once platelet count dropped below 50 · 10 L because of chemotherapy, 1 · 40 IU bwkg FVIII concentrate was administered daily to achieve 17–35% plasma FVIII levels (12 h after the FVIII substitution). There was Correspondence: Laszlo Rejto, 2nd Dept. of Medicine, Health Sciences Center, University of Debrecen, Nagyerdei 98, Debrecen 4012, Hungary. Tel.: +36 52 314 410; fax: +36 52 255 152; e-mail: lrejto@dote.hu

Dasatinib inhibits coated-platelet generation in patients with chronic myeloid leukemia

Abstract Since the introduction of tyrosine kinase inhibitors, the overall survival of patients with chronic myeloid leukemia has markedly improved. However long term use of these drugs results in various adverse events. Treatment with second generation dasatinib is often complicated by hemorrhagic events. Previous lumi-aggregometry studies have shown impaired platelet function in patients on dasatinib therapy. Dual agonist activated platelets (coated-platelets) are also sensitive indicators of platelet function. We hypothesized that dual activation with convulxin and thrombin of platelets in a flow cytometric assay could be a more sensitive method for detecting platelet dysfunction as compared to single agonist studies used in lumi-aggregometer. Platelets of healthy volunteers incubated with dasatinib as well as platelets from patients on dasatinib therapy were investigated. Low therapeutic plasma level dasatinib concentrations at which a considerable reduction in coated-platelet generation was observed in vitro, did not cause detectable change in platelet aggregation response. Coated-platelet assay and lumi-aggregometry were also investigated at 0, 1 and 4 hours after drug administration in dasatinib treated CML patients. Significant decrease was observed at 1 hour in maximal aggregation by collagen. Although the aggregation curves became normalized by 4 hours, coated-platelet generation was still inhibited in dasatinib treated patients. Nilotinib, another second generation tyrosine kinase inhibitor, had no effect on aggregation and on coated-platelet formation neither in vitro nor in ex vivo samples. At therapeutic plasma levels coated-platelet assay is more sensitive than lumi-aggregometry studies for the demonstration of the inhibitory effect of dasatinib on platelet function.

[Treatment of acute myeloid leukemia -- a single center experience (2007-2013)].

INTRODUCTION Mortality of acute myeloid leukemia is still 60-70% in young (<60 years) adults and 90% in elderly (≥60 years) patients. AIM The aim of the authors was to analyse the outcome of treatment in their patients with acute myeloid leukemia. METHOD From 2007 to 2013, 173 patients with acute myeloid leukemia were treated. Patients were classified according to the European LeukemiaNet prognostic guideline. Association between mortality and the type of acute myeloid leukemia (secondary or primary), dose of daunoblastin at induction of treatment, and the rate of minimal residual disease were investigated. RESULTS The 5-year survival probability was 25% in young adults and 2% in the elderly. The survival was significantly influenced by these prognostic factors. The 5-year survival rate was 50% in the young, favorable prognostic group. The 90 mg/m2 daunoblastin dose was found to be beneficial. Addition of bortezomib to the standard induction protocol had an additional beneficial effect. CONCLUSIONS The speed and depth of the response to induction therapy, and the initial white blood cell count had an apparent effect on survival.

Heveny myeloid leukaemiás betegeink kezelésével szerzett tapasztalataink (2007–2013)@@@Treatment of acute myeloid leukemia – a single center experience (2007–2013)

INTRODUCTION Mortality of acute myeloid leukemia is still 60-70% in young (<60 years) adults and 90% in elderly (≥60 years) patients. AIM The aim of the authors was to analyse the outcome of treatment in their patients with acute myeloid leukemia. METHOD From 2007 to 2013, 173 patients with acute myeloid leukemia were treated. Patients were classified according to the European LeukemiaNet prognostic guideline. Association between mortality and the type of acute myeloid leukemia (secondary or primary), dose of daunoblastin at induction of treatment, and the rate of minimal residual disease were investigated. RESULTS The 5-year survival probability was 25% in young adults and 2% in the elderly. The survival was significantly influenced by these prognostic factors. The 5-year survival rate was 50% in the young, favorable prognostic group. The 90 mg/m2 daunoblastin dose was found to be beneficial. Addition of bortezomib to the standard induction protocol had an additional beneficial effect. CONCLUSIONS The speed and depth of the response to induction therapy, and the initial white blood cell count had an apparent effect on survival.

Heveny myeloid leukaemiás betegeink kezelésével szerzett tapasztalataink (2007-2013)

INTRODUCTION Mortality of acute myeloid leukemia is still 60-70% in young (<60 years) adults and 90% in elderly (≥60 years) patients. AIM The aim of the authors was to analyse the outcome of treatment in their patients with acute myeloid leukemia. METHOD From 2007 to 2013, 173 patients with acute myeloid leukemia were treated. Patients were classified according to the European LeukemiaNet prognostic guideline. Association between mortality and the type of acute myeloid leukemia (secondary or primary), dose of daunoblastin at induction of treatment, and the rate of minimal residual disease were investigated. RESULTS The 5-year survival probability was 25% in young adults and 2% in the elderly. The survival was significantly influenced by these prognostic factors. The 5-year survival rate was 50% in the young, favorable prognostic group. The 90 mg/m2 daunoblastin dose was found to be beneficial. Addition of bortezomib to the standard induction protocol had an additional beneficial effect. CONCLUSIONS The speed and depth of the response to induction therapy, and the initial white blood cell count had an apparent effect on survival.

Current treatment of acute myeloid leukaemia in adults

Recent cytogenetical findings and novel molecular biology results of acute myeloid leukaemia have shed new lights of our understanding in the diagnosis and treatment of the disease. Acute myeloid leukaemia is not only represented by the wide variety of morphological and immunophenotypic diversity but also demonstrates cytogenetical and molecular biological heterogeneity of its own. It has an unfavorable prognosis, especially in the elderly. Overall survival of younger patients (<50-60 years) has increased in the past years due to high dose chemotherapy (daunorubicine, cytarabine). But in case of unfavorable prognostic factors (not only cytogenetical but also molecular biological characters of the disease), allogeneic stem cell transplantation is needed for successful overall outcome. Better understanding the biology of acute myeloid leukaemia could establish novel targeted therapies and help us eventually to cure the disease.

Practical considerations and questions in the treatment of chronic lymphocytic leukemia

Understanding the pathogenesis and refine the treatment of chronic lymphocytic leukemia have been tremendously improved in the past decade. Treatment outcome and estimated prognosis have become more accurate due to the advanced molecular biological techniques and the classical prognostic markers. Incorporation of fludarabine and rituximab into the standard protocols fundamentally improved treatment outcome in chronic lymphocytic leukemia. Chemoimmunotherapy has improved not only the remission rates but had a significant impact on overall survival, as well. Eliminating residual leukemia and achieving complete hematological remissions at such high rates establish potential background for cure. Still, a great deal of dispute has been emerged regarding everyday clinical practice. Authors present their institutional experiences and review the literature.

Gyakorlati szempontok és kérdések a krónikus lymphoid leukaemia kezelésében: Irodalmi és saját tapasztalatok

Understanding the pathogenesis and refine the treatment of chronic lymphocytic leukemia have been tremendously improved in the past decade. Treatment outcome and estimated prognosis have become more accurate due to the advanced molecular biological techniques and the classical prognostic markers. Incorporation of fludarabine and rituximab into the standard protocols fundamentally improved treatment outcome in chronic lymphocytic leukemia. Chemoimmunotherapy has improved not only the remission rates but had a significant impact on overall survival, as well. Eliminating residual leukemia and achieving complete hematological remissions at such high rates establish potential background for cure. Still, a great deal of dispute has been emerged regarding everyday clinical practice. Authors present their institutional experiences and review the literature.