Matjaž Sever

CD34 + Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Patients

Recent trends indicate that patients with nonischemic dilated cardiomyopathy represent the largest subpopulation of heart failure patients with a significant need for alternative treatment modalities. Similar to patients with ischemic cardiomyopathy, patients with nonischemic dilated cardiomyopathy have been found to have myocardial regions with flow abnormalities, which may represent targets for neoangiogenic therapies. CD34+ stem cells might contribute to the formation of new blood vessels from existing vascular structures in ischemic tissues by the direct incorporation of injected cells into the newly developing vasculature or by the production and secretion of angiogenic cytokines. This review summarizes the long‐term clinical effects and potential underlying mechanisms of CD34+ cell therapy in patients with nonischemic dilated cardiomyopathy.

Increased red cell distribution width is associated with poor stem cell mobilization in patients with advanced chronic heart failure.

Abstract Parameters associated with poor CD34+ stem cell mobilization in advanced chronic heart failure (CHF) patients were investigated. Forty-four CHF patients underwent bone marrow stimulation with granulocyte colony stimulating factor. Poor cell mobilization presents in 32% of patients. Poor and good mobilizers did not differ significantly regarding age, gender, left ventricular ejection fraction, kidney or liver function and exercise capacity. Significant differences were found regarding NT-proBNP levels and red cell distribution width (RDW). Increased RDW was the only independent predictor of poor CD34+ stem cell mobilization on multivariable analysis and may serve as a biomarker of poor stem cell mobilization in CHF patients.

Stem Cell Therapy in Patients with Chronic Nonischemic Heart Failure

Aim of the Review The aim of this review is to discuss recent advances in clinical aspects of stem cell therapy in chronic nonischemic heart failure (DCMP) with emphasis on patient selection, stem cell types, and delivery methods. Recent Findings Several stem cell types have been considered for the treatment of DCMP patients. Bone marrow-derived cells and CD34+ cells have been demonstrated to improve myocardial performance, functional capacity, and neurohumoral activation. Furthermore, allogeneic mesenchymal stem cells were also shown to be effective in improving heart function in this patient population; this may represent an important step towards the development of a standardized stem cell product for widespread clinical use in patients with DCMP. Summary The trials of stem cell therapy in DCMP patients have shown some promising results, thus making DCMP apparently more inviting target for stem cell therapy than chronic ischemic heart failure, where studies to date failed to demonstrate a consistent effect of stem cells on myocardial performance. Future stem cell strategies should aim for more personalized therapeutic approach by establishing the optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patients age and stage of the disease.

Unrelated allogeneic stem-cell transplantation in adult patients – 10-year experience

Objectives: Allogeneic stem-cell transplantation is an efficient treatment modality for adult patients with various leukemias. Due to the lack of family donors, stem-cell transplantation with unrelated HLA identical donors is on the increase. In the past, such transplantation was mostly performed for chronic myeloic leukemia. Today it is rarely used in this type of leukemia because of tyrosine kinase inhibitors, but it is becoming more popular for acute leukemias with unfavorable prognostic factors. Methods: Between the years 2002 and 2011, eighty-six patients mostly with acute leukemias were transplanted. The survival curves were calculated and both the impact of the type of disease on the treatment outcome and the change in indications after the introduction of new target drugs were estimated. Results: Estimated 10-year survival for patients with acute myeloblastic leukemia is around 35 %, and for patients with acute lymphoblastic leukemia around 25 %. Unrelated transplantation for chronic myeloic leukemia is now only rarely performed but the number of transplants for multiple myeloma and lymphomas is increasing. Conclusion: Unrelated allogeneic stem-cell transplantation is suitable for acute myeloblastic leukemias with unfavorable risk factors. However, results in acute lymphoblastic leukemia are worse. Unrelated transplantation is not efficient as salvage treatment for patients with recurrent disease after autologous transplantation or chemotherapy- resistant relapse.

The characteristics and treatment of patients with primary myelofibrosis at the University medical centre Ljubljana in the period 2008–2012

Background: Primary myelofibrosis (PMF) is a rare hematologic condition belonging to the group of classical myeloproliferative neoplasms. For the diagnosis of PMF, bone marrow histology examination and fibrosis evaluation is mandatory. No recurrent cytogenetic abnormality has been identified and JAK2 mutation is present only in approximately half of the patients. Treatment is limited mainly to alleviation of B symptoms, splenomegaly and anemia. Only allogeneic hematopoietic stem-cell transplant (HSCT) can offer a cure from the disease. A new drug, JAK2 inhibitor ruxolitinib, that has been available since recently, will change treatment options mainly for patients not eligible for HSCT. Methods: Hipokrat medical database was searched for patients diagnosed with PMF between 2008–2012. Data were collected retrospectively and analysed using basic statistics. Results: PMF was newly diagnosed in 28 patients (18/64.3 % men). Two (7.1 %) patients presented with systemic symptoms and ten (35.7 %) had enlarged spleen. Their median blood counts and lactate dehydrogenase activity (LDH) results were: leukocytes 11.25 x 109/l (3.00–72.00), hemoglobin 117 g/l (68–173), platelets 420 x 109/l (111–1477), LDH 7.45 μkat/l (3.00–20.71). In six (21.4 %) patients only bone marrow cytology examination was performed without histologic examination. Cytogenetics was performed in 11 (39.3 %) patients with three abnormalities detected: complex, +9 and del(13q14). JAK 2 mutation was identified in 12 (60.0 %) of 20 examined cases. Patients were treated with acetylsalicylic acid (n = 12/42.9 %), hydroxyurea (n = 12/42.9 %), blood transfusions or epoetins (n = 12), anagrelide (n = 4/14.3 %), methylprednisolone (n = 4/14.3 %), immunomodulatory drugs (n = 3/10.7 %), interferon (n = 2/7.1 %), spleen irradiation (n = 2/7.1 %) and venipunctures (n = 2/7.1 %). At the end of 2011, first eligible patients were treated with ruxolitinib. Conclusions: PMF is a rare disorder with various presentations and treatment suited specifically to patients’ complaints. The treatment is symptomatic with HSCT being the only curable option available. Ruxolitinib will play an importatnt role in PMF treatment in the future.

Hematopoietic stem cell mobilization using plerixafor – single center experience at the University medical centre Ljubljana

Background: Autologous stem cell transplant is a standard of care for hematologic malignacies. Mobilization and collection of hemopoietic stem cells (HSC) is a prerequisite for its success. Between 5–30 % of healthy donors and up to 60 % of high risk patients for poor mobilization are not able to collect sufficient amount of HSC for the procedure. Bone marrow infiltration, irradiation, age and prior treatment with melphalan, fludarabine, lenalidomide or any high dose chemotherapy are risk factors for poor mobilization. In case of collection failure, a CXCR4 antagonist plerixafor (Mozobil) can be successfuly used with up to 70 % collection rate in this high-risk patient group. Methods: Hipokrat program with its medical database was used to retrospectively analyse data on patients treated with plerixafor at the Department of Hematology, UMC Ljubljana. Basic statistics were applied to the collected data. Results: From 2008 until November 2011 we treated 16 patients with a median age of 57 years (range 21–71). They were diagnosed with multiple myeloma (n = 13/81.3 %), lymphoplasmacytic immunocytoma (6.3 %), mantle cell lymphoma (6.3 %) and Burkitt’s lymphoma (6.3 %). At the time of mobilization three (18.8 %) patients were in complete remission, four (25.0 %) in very good partial remission, six (37.6 %) in partial remisson, two (12.5 %) had stable disease, while in one (6.3 %) the disease status was not assessed. The patients were treated with bortezomib (n = 13/81.3 %), irradiation (n = 7/43.8 %), cyclophosphamide (n = 5/31.8 %), purine analogoues (n = 3/18.8 %), revlimid (n = 3/18.8 %) and thalidomide (n = 1/6.3 %). Ten (62.5 %) patients underwent previous attempt of mobilzation and only one collected > 2x106/kg CD34+ HSC. On the day of plerixafor administration, median CD34+ HSC blood count was 8.7 x106/l (2.0–50.04) and after plerixafor 27.15 x106/l (13.9–307.11). Ten (62.5 %) patients required two administrations of plerixafor. Median collected CD34+ HSC were 2.34 x106/kg (0.98–6,73). Three (18.8 %) patients failed to mobilize. Conclusions: Plerixafor is a new highly successful mobilizing agent in high-risk patients or patients with previously failed mobilization. According to our experience, 13 (81 %) poor mobilizers collected a sufficient amount of HSC on plerixafor to proceed to transplant.