Piotr Rzepecki

The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant

In this multicenter study, we assessed the use of palifermin (recombinant human–keratinocyte growth factor 1) in the prevention of oral mucositis (OM) and acute GvHD (aGvHD) induced by a hematopoietic stem cell transplant (HSCT). Fifty-three patients with hematological diseases received three doses of palifermin (60 μg/kg once daily i.v.) pre- and post-conditioning regimens (total six doses). A retrospective control group of 53 transplant patients received no palifermin. There was a significant reduction in the incidence of OM of WHO (World Health Organization) grades 1–4 (58 vs 94%, P<0.001), 3–4 (13 vs 43%, P<0.001) and the median duration of OM (4 vs 9 days, P<0.001) in the palifermin group compared to the control group. The incidence of analgesics (32 vs 75.5%, P<0.001), opioid analgesics (24 vs 64%, P<0.001) and total parenteral nutrition (11 vs 45%, P<0.001) was also significantly reduced. The analysis of distribution of affected organs revealed that aGvHD was less prevalent in the palifermin group (P=0.036). There was no significant difference in the onset of any OM after HSCT, time to engraftment and length of hospitalization between groups. The drug was generally well tolerated and safe. Our results suggest that the use of palifermin reduces OM and probably aGvHD after HSCT, but a randomized trial is needed.

Outcome of HLA-matched related allogeneic hematopoietic stem cell transplantation for patients with acute leukemia in first complete remission treated in Eastern European centers. Better results in recent years

The goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemia transplanted in first complete remission in Eastern European countries. Six hundred forty HSCT were performed between 1990 and 2006 for adults with acute myeloid (n = 459) and lymphoblastic (n = 181) leukemia. Two-year leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse incidence were 58 ± 2%, 19 ± 2%, and 23 ± 2%, respectively. The cumulative incidence of NRM decreased from 22 ± 2% for patients treated between 1990 and 2002 to 15 ± 3% for transplantations performed between 2003 and 2006 (p = 0.02), despite increasing recipient age. In a multivariate analysis, time of HSCT affected both NRM and LFS. Among other prognostic factors, the use of TBI decreased relapse incidence and increased the LFS rate. We conclude that results of MRD-HSCT for acute leukemia in Eastern Europe improved over time as a consequence of decreased NRM. The use of TBI containing regimens appears advantagous.

Biochemical indices for the assessment of nutritional status during hematopoietic stem cell transplantation : are they worth using? A single center experience

Hematopoietic stem cell transplantation (HSCT) is being used increasingly in an attempt to cure many hematological disorders, solid tumors and autoimmune diseases. One of the major challenges in the post-transplant period is nutrition. The purpose of this investigation was to assess changes in the biochemical indices of nutritional status during HSCT and compare them with acute-phase protein levels to find the best parameters for nutritional support qualification. Nutritional status was assessed in 54 patients during autologous (30 cases) and allogeneic (24 cases) transplantation. Fifteen patients had to be treated with total parenteral nutrition (TPN), eight of them needing prolonged hospitalization. All nutritional indices and acute-phase protein levels were evaluated during the day before the beginning of conditioning regimen, after chemotherapy completion and every 7 days until engraftment, at least three times after stem cells infusion. Wilcoxon test and canonical analysis were used for statistical analyses. The measurement of retinol-binding protein and transferrin can be useful for nutritional assessment during autologous and allogeneic HSCT, respectively. Prealbumin level, measured 8 days after the end of conditioning regimen, is helpful in making a decision about starting TPN.

Development of chronic myeloid leukaemia in patients treated with anti-VEGF therapies for clear cell renal cell cancer

Tyrosine kinase inhibitors are novel therapies targeting specific cellular signalling pathways. Sunitinib and sorafenib primarily block tyrosine kinase receptors involved in the progression of many tumours, including clear cell renal cell cancer (ccRCC). Although developed to target selected receptors, it is becoming apparent that they inhibit other kinases; this may result in the development of unexpected side effects. This is potentially dangerous as kinases on noncancerous cells are also inhibited. TKI off-target effects contributing to cardiotoxicity, hypothyroidism, hypertension, fatigue, hair depigmentation, hand-foot syndrome and gastrointestinal perforation have been described. We report three patients (3/412) treated with sunitinib and sorafenib who developed chronic myeloid leukaemia (CML) during treatment for ccRCC, proposing a molecular mechanism of tyrosine kinase inhibitors action on bone marrow cells that might be co-responsible for CML development.

New approach for amino acid profiling in human plasma by selective fluorescence derivatization

A new approach for the separation of 6-aminoquinolyl-carbamyl (AQC)-derivatized amino acids has been proposed. The chromatography used ion-pairing mechanism to increase the method selectivity. Mobile phase was based on triethylamine buffer containing N,N-dimethyloctylamine as a modifier. A number of factors, buffer composition and pH, counterion concentration, temperature and acetonitrile gradient profile, were optimized to achieve final chromatographic conditions. With the presented analytical method, the separation and identification of 34 AQC-amino acids and amino compounds present in human plasma is possible. The results of validation proved the applicability of the method for quantification of 27 amino acids in biological samples. The ultrafiltration proposed as deproteinization procedure gave repeatable and reliable results for the amino acids under investigation. This method introduced in routine testing can be a suitable tool for amino acid profiling in plasma including all aspects of clinical application.

Mild chronic graft-versus-host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study

Internal tandem duplication (ITD) of the FLT3 gene (Fms‐like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3‐ITD at diagnosis was retrospectively estimated for allo‐HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo‐HSCT after myeloablative conditioning in first complete remission of AML. FLT3‐ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo‐HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3‐ITD positive than FLT3‐ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft‐versus‐host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3‐ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo‐HSCT. It appears that allo‐HSCT does not cure patients with FLT3‐ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI.

Case-adjusted bortezomib-based strategy in routine therapy of relapsed/refractory multiple myeloma shown to be highly effective—A report by Polish Myeloma Study Group

The observational study was aimed at evaluating response, survival and toxicity of bortezomib-based, case-adjusted regimens in real-life therapy of 708 relapsed/refractory MM patients. Bortezomib was combined with anthracyclines, steroids, thalidomide, alkylators or given in monotherapy. The ORR was 67.9% for refractory and 69.9% for relapsed MM. The median PFS was 14 months and OS 57 months. Patients responding to the therapy had the probability of a 4-year OS at 67.0%. No toxicity was noted in 33.1% of patients. Severe events (grade 3/4) were reported in 35.9% of patients: neurotoxicity (16.7%), neutropenia (9.2%), thrombocytopenia (8.5%), and infections (6.5%). Bortezomib-based, case-adjusted regimens are in real-life practice effective in salvage therapy offering reliable survival with acceptable toxicity for relapsed/refractory MM patients.

Seeking new prognostic and predictive factors in patients with metastatic renal cell carcinoma - hypoxia-induced factors

Malignant tumours of the kidneys are relatively rare tumours that occur in adults, although there has been a constant increase in the incidence of this cancer type in recent years. It occupies the 10th place in terms of the number of new cases of cancer in men and 14th place in women. Considerable progress in the treatment of renal cell carcinoma over the last years has forced researchers to look for new factors of potential prognostic or predictive value in this tumour type in order to clarify the selection of patients for optimal treatment. The drugs from the group of tyrosine kinase inhibitors have played a decisive role. So far, the Motzer model, grouping the prognostic factors, has been most commonly used in clinical practice. Based on the current research looking for new markers of prognostic or predictive value, these factors can be divided into cellular hypoxia-induced proteins and proteins regulating the cell cycle and the apoptosis process. In the second part of this study, hypoxia-inducible factors will be discussed.

Sources of Hematopoietic Stem Cells

Hematopoietic stem cell transplantation (HSCT) has the potential to cure a variety of malignant and nonmalignant diseases. Sources of hematopoietic stem cells for transplantation have expanded progressively since the beginning of the modern era of transplantation in the late 1960s. Although bone marrow was the main source of stem cells in the early years of transplantation, in the past 10 to 15 years peripheral blood has assumed increasing importance. The initial impetus for the use of PBSCs for transplantation was to be able to offer transplantation to patients who were not candidates for the use of bone marrow cells (tumor contamination of the marrow or those with hypocellular marrows). Subsequent studies demonstrated that PBSCs could be mobilized from the bone marrow with either hematopoietic growth factors (GM-CSF, G-CSF) or a combination of chemotherapy and growth factors, which increased the number of hematopoietic progenitors collected from the blood by 10to 1000fold compared with steady-state conditions. Umbilical cord blood represents the newest source of stem cells for transplantation. At now peripheral blood is the main source in the autologous setting. Within the allogeneic setting, multiple sources of stem cells are possible and include those derived from individuals related or unrelated to the patient. Hematopoietic progenitor cell (HPC) products contain hematopoietic stem and lineagecommitted progenitor cells capable of providing hematopoietic and immune reconstitution after myeloablative or reduced-intensity preparative regimens. HPCs administered intravenously migrate to the marrow, where they adhere, expand, selfrenew (stem cells only), and differentiate. The differentiated cells are released into the blood, restoring blood counts and immunity. The time from administration of HPCs to recovery of adequate or normal blood counts is variable. Recipients of peripheral blood stem cells recover counts faster than recipients of bone marrow. Cord blood tends to be the slowest to engraft. The minimum number of HPCs necessary for engraftment in a myeloablated recipient has not been established. Different products have widely different numbers of progenitors and stem cells. However, eligibility criteria for some protocols usually dictate a minimum number of cells to be collected and infused. Several methods are used to measure the number of cells in an HPC collection. Simple cell count may be adequate for many marrow collections. Most centers use flow cytometric enumeration of CD34+ cells for the majority of cellular products. The discovery of the CD34 antigen in the early 1980s revolutionized our understanding of hematopoiesis. Cells expressing CD34 are capable of reconstituting hematopoiesis in lethally irradiated animals and humans, indicating that the putative hematopoietic stem cell expresses CD34.

Consolidation in multiple myeloma – current status and perspectives

Although multiple myeloma (MM) is still considered an incurable disease, the treatment philosophy is changing due to the introduction of novel agents. Standard treatment consists of an induction phase and autologous stem cell transplantation in patients under 65–70 years. Prolonged treatment (consolidation and/or maintenance) is being introduced in many countries. We present a review of clinical trials dedicated to consolidation treatment in multiple myeloma. Bortezomib, lenalidomide and carfilzomib in different combinations were tested in the trials mentioned below. Although they did not prolong overall survival, the data are very promising. Three very important large clinical trials are still in progress. The results might help to establish the actual value of consolidation treatment.