Cost-effectiveness analysis of treating transplant-eligible multiple myeloma patients in Macedonia.

PURPOSE: A decision-analytic model was developed to study the impact of induction regimens vincristine, adriamycin, dexamethasone (VAD); thalidomide, dexamethasone (TD); and bortezomib, dexamethasone (BorD), followed by autologous stem cell transplantation (ASCT) for treating multiple myeloma (MM) patients in Macedonia. Additionally, a cost-effectiveness analysis (CEA) of treatment sequences to predict health effects and costs of different treatment sequences was performed. METHODS: Model strategies were based on a previously published study for treating patients with MM in Macedonia. The data on disease progression and treatment effectiveness were obtained from the published reports of randomized clinical trials (GIMEMA M-B02005, IFM 2005-01). Utility parameters were extracted from the literature. To compare treatment combinations, a decision tree model was developed. Additionally, a cost analysis for one-time per-protocol costs was performed from a Macedonian national health care perspective. The incremental cost-effectiveness ratios (ICERs)/quality-adjusted life years (QALYs) gained for 1-, 10-, and 20-year time horizons were determined. Costs and health outcomes were discounted to evaluate the effects of time in the model. RESULTS: The one-time costs of BorD (EUR 5,656) were higher compared to VAD (EUR 303) and TD (EUR 329), increasing the overall costs for BorD. Thus, the BorD combination dominated in the baseline results (1 and 10 years) and the ICER for TD vs. VAD was EUR 7,564/QALY (20 years, undiscounted model). However, in the discounted 20-year model, BorD showed an ICER of EUR 138,747/QALY gained for BorD vs. TD. CONCLUSION: The CEA performed indicated that considering 1-year time horizon costs, VAD may be a cost-effective alternative vs. TD or BorD. However, for the longer period (10 or 20 years) including the discounting of future costs and outcomes, the TD and BorD combinations showed higher health benefits in terms of QALYs and more cost-effective vs. VAD. These results should be considered as supportive evidence by decision-makers and providers when deciding on the most cost-effective induction treatment strategy prior to ASCT in MM patients.

Analysis of Factors that Influence Hematopoietic Recovery in Autologous Transplanted Patients with Hematopoietic Stem Cells from Peripheral Blood.

BACKGROUND: Successful hematopoietic stem cell transplantation (HSCT) requires a rapid and durable hematopoietic recovery. AIM: The aim of our study was to analyse factors that influence hematopoietic recovery after autologous HSCT. MATERIALS AND METHODS: Multiple regression analysis was used to analyse factors affecting neutrophil and platelet engraftment in 90 autologous transplanted patients - 30 with acute myeloid leukaemia (AML), 30 with lymphoma and 30 with multiple myeloma (MM) from 2008 till 2016. RESULTS: The neutrophil recovery in AML patients was significantly influenced by transfusion support with random-donor platelets, sex and number of transplanted mononuclear cells (MNC) and CD34+ cells; and in lymphoma patients, it was influenced by sex, age, mobilisation strategy and some transplanted MNC. The influence of investigated factors on neutrophil engraftment in MM patients was not statistically significant. The platelet recovery in AML patients was influenced by transfusion support with random-donor platelets; in lymphoma patients, it was influenced by sex, age, time from diagnosis to harvesting and time from diagnosis to HSCT; and in MM patients it was influenced by transfusion support with random-donor platelets. CONCLUSION: Additional studies are necessary to better understanding of engraftment kinetic to improve the safety of HSCT and to minimise potential complications and expenses related to HSCT.

How is patient care for multiple myeloma advancing?

INTRODUCTION: Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment options. New drugs and effective approaches are currently available for the treatment of multiple myeloma, including immunomodulatory agents, proteasome inhibitors and autologous stem cell transplantation. Areas covered: We have described the recent updated criteria to start treatment in multiple myeloma and summarized clinical data from major studies including most recent agents. Particularly, results with pomalidomide, carfilzomib, ixazomib, monoclonal antibodies such as elotuzumab, daratumumab, and checkpoint inhibitors have been reported. Both transplant and non-transplant settings have been covered. Expert commentary: Despite the successful improvement in overall survival and time to relapse, multiple myeloma still remains incurable. Therefore, there is still an unmet need for new treatment strategies with novel mechanisms of action, like monoclonal antibodies, novel immunomodulators, and novel proteasome inhibitors. Implementation of these novel drugs in rationally designed therapies with a good balance of efficacy and safety should be carefully considered in order to improve outcome.

Molecular Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib - Single Centre Experience.

Introduction of tyrosine kinase inhibitors (TKI) dramatically improves the treatment and survival of the patients with chronic myeloid leukemia (CML) in the last decade. Imatinib (IM) and other TKI induce larger percentage of complete cytogenetic response (CCyR) and major molecular response (MMR). Treatment resistance to TKIs still remains an important problem in the treatment of CML. The aim of our study was to analyze the molecular response (MR) in CML patients treated with Imatinib in our institution. We have analyzed 53 CML patients (pts), 28 females and 25 males, treated with IM as a front or second line treatment. Only 15 pts were treated with IM as a front-line therapy, while 38 pts were pretreated with hydroxyurea or/and interferon. Median duration of CML was 6 years (range: 1 year- 17 years). Median duration of IM treatment was 3 years (range: 1 year-10 years). MR was analyzed in one up to 8 time points with Real Time Quantitative RT-PCR method. Forty six pts (87%) had complete hematological response and 55% of pts had MMR, 13/53(24.5%) pts had MMR at 4.0-4.5 log and 16/53(30.2%) pts had MMR at 3.0-4.0 log. MMR was not achieved in 24/53(45.3%). Our results have shown smaller percentage of patients (55%) with MMR, mostly due to the fact that larger proportion of patients (38/53) were heavily pretreated with HU or/and Interferon for a prolonged period of time, before the IM treatment. This is a major risk factor for acquisition of additional molecular and cytogenetic abnormalities responsible for IM resistance and poor treatment response.

New approaches to management of multiple myeloma.

Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. New antimyeloma drugs such as thalidomide, lenalidomide, and bortezomib have dramatically changed treatment paradigm leading to both tumor reduction and tumor suppression. Much progress has been made, but still many unsolved questions remain. In the mode of sequencing treatment for patients with multiple myeloma, we are still using old drugs such as the alkylating agent melphalan, which continues to play a central role in the transplantation setting. Newer drugs are now emerging and are being tested: monoclonal antibodies, histone deacetylase (romidespsin), MLN9708 (ixazomib) a new oral proteasome inhibitor, carfilzomib, signal transduction modulator perifosine. Many advances have been made, but there is still a long way to go.

Influence of Prognostic Factors on OverallSurvival in Myelodysplastic Syndromes.

BACKGROUND: Accurate prediction of a patient's prognosis is useful to define the risk posed by the disease. Age, gender, peripheral blood cytopenia, proportion of bone marrow (BM) blasts, performance status, comorbidities, transfusion dependence, specific karyotype abnormalities and molecular biomarkers can refine the prediction of prognosis in MDS. AIM: to assess the influence of the some prognostic factors like age, gender, cytopenia, BM blast percentage, transfusion dependence, ferritin, hemoglobin (Hb), lactate dehydrogenase (LDH), albumin and specific karyotype abnormalities in myelodysplastic syndromes on overall survival (OS). PATIENTS AND METHODS: we retrospectively analyzed the cohort of 108 patients diagnosed between 1.1.2011 and 31.12.2013 at the University Clinic of Hematology, Ss Cyril and Methodius University, Skopje, Macedonia. They were evaluated for clinical and hematologic features at diagnosis and at leukemic transformation. RESULTS: in the study group 62 were man and 46 women. Male to female ratio was 1.35 to 1. The differences in OS between men and women were significant (p = .03015). The mean age at diagnosis was 66,6 years. According to the age OS was 16,4 months. FAB subtypes influenced OS significantly (p = .03015). OS inversely correlated with BM blast percentage (p= .02327). Cytopenia had no impact on OS (p=.33755). Hb as a whole and groups with different levels of Hb had no influence on OS (p = .12142) and (p= .07535), respectively. The group with ferritin <500 µg/L had better OS (p=.04720). Transfusion dependence, LDH and albumin had no impact on OS. Leukemic transformation was noticed in 10 (9,3%) patients. Mortality was 36,1%. CONCLUSION: gender, FAB subtypes, BM blast percentage and the serum levels of ferritin had an influence on OS, while age, hemoglobin level, transfusion dependence, LDH and albumin had no impact on OS.

Tretatment approach of nontransplant patients with multiple myeloma.

Multiple myeloma is still an incurable disease with pattern of regression and remission followed by multiple relapses raising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. In recent years there is a huge improvement in treatment of patients with multiple myeloma. The milestones of these improvement are: autologous transplantation and high-dose melphalan, imunomodulating drugs (thalidomide, lenalidomide), proteosom inhibitors (bortesomib, carfilzomib). The most significant improvement in overall survival has been achieved in the patients younger than 65 years. So, the major challenge for hematologist is to translate this improvement in the elderly patients with multiple myeloma. Today, physicians are able to offer wider variety of treatment options for elderly patients with multiple myeloma. Therapeutic options should be tailored and personalized according to patient's characteristics by balancing efficacy and toxicity of each drug which is especially important for elderly patients. In the mode of sequencing treatment for elderly patients with multiple myeloma, our goal is to achieve and maintain maximal response while limiting treatment -related toxicities as much as possible. Second-generation novel agent, such as carfilzomib, pomalidomide, elotuzumab, bendamustine are currently being evaluated as an option to improve treatment outcome in elderly patients.

Acute graft versus host disease in hematopoietic stem cell alotransplant recipients.

INTRODUCTION: The transplantation of hematopoietic stem cells (HSCT) is a therapeutic intervention where the hematopoietic stem cells and the cells originating from them are being removed and replaced by the normal stem cells of donor or the patient him/her-self. HSCT today represent standardized biological manipulation for treating malignant, genetic and autoimmune diseases. The application of allogeneic hematopoietic stem cell transplantation (HSCT) is limited by life-threatening complications such as severe or acute graft-versus-host disease (GVHD). Despite intensive prophylaxis with immunosuppressive agents, the incidence of GVHD occurs in 9-50% of patients undergoing transplant with an identical HLA sibling matched donor and 75% of patients undergoing unrelated HLA donors. AIM OF STUDY: To evaluate our experiences in GVHD prophylaxis and treatment after alloHSCT, GVHD incidence and prognostic factors and administration of new immunosuppressive regiments. Can we recognize clinical parameters which are associated with occurrence and severity of graft-versus-host disease? PATIENTS AND METHODS: Starting from September 2000 till September 2010, 63 patients (36 males and 27 females) at the age of 16-56 (median range 33 years) with hematological malignancies were treated with alloHSCT on Department of Hematology, Clinical Centre, Skopje. In 10 patients bone marrow was used as source of stem cells and in 53 patients stem cells were obtained from peripheral blood. From the group of 63 patients, 26 patients had active disease at the time of transplantation. GVHD prophylaxis was accomplished with combination of cyclosporine and methotrexate (Seattle regimen) or more intensive immunosuppression regiments. RESULTS: GVHD was noticed in 30 patients (47.6%) and in 33 patients (52.4%) a manifestation of GVHD was noticed. Acute GVHD was noticed in 24 patients (38%) and chronic GVHD in 20 patients (31.7%) The remaining 32 patients (45%) achieved complete clinical and hematological remission. Lethal outcome was confirmed in 31(49%) patients (9 from chrGVHD, 6 from acute GVHD, 16 from disease relapse). CONCLUSION: The incidence of acute GVHD in our study was 38% and 31% for chronic GVHD. The most common GVHD reaction was registered in female donors and male recipients, with higher GVHD incidence in elderly patients. In all patients stem cells were obtained from peripheral blood. Active disease, sex, source of hematopoietic cells, age and conditional regiments are the most significant predictive factors with the high incidence of GVHD.

Hairy cell leukemia treatment: where we are now?

Hairy cell leukemia (HCL) is a very rare type of leukemia, in which abnormal B lymphocytes, present in the bone marrow, spleen, and peripheral blood stream, get worse slowly or do not get worse at all. HCL is the disease where patients have pancytopenia with splenomegalia over 90% percent, palpable lymphadenopathy occur in 35% of patients, some form of serious infection eventually developed in over 50% of patients and was the most common cause of death in patients. HCL is dominantly a male disease, with the male-female ratio, ranging from 4:1 to 7:1. Treatment and prognosis of HCL depends on: the number of HC in the peripheral blood or bone marrow, if the spleen is enlarged and on the existence of the visible leukemia infection symptoms. Prognostic factors are similar to the above mentioned and also if the basic disease HCL is aggressive or the number of HC grow slowly and there is no need for treatment. Starting from September 1985 till September 2010, we observed a group with total number of 28 patients (22 males and 6 females) at the age of 30-76 (median range 46 years), all with HCL disease. From the total number of participants, 20 patients (71,43%) received hemotherapy, Cladribine and 8 patients (28,57%) received different type of therapy, such as immunomodulator therapy, surgery or combination of both, without Cladribine. Most effective therapy for HCL, from all of the above mentioned was definitely Cladribine which is dominant with a resulting response rates of 80-100%, where 70-90% of patients were achieving a complete remission, as defined by a complete disappearance of hairy cells in the bone marrow.