Progress in the therapy of myelodysplastic syndromes

The progress in the therapy of the myelodysplastic syndromes has been far from spectacular during recent years. No currently available treatment has been shown to be consistently effective in producing sustained improvement in hematopoiesis or in delaying leukemic evolution. With regard to both quantity and quality of life, no other treatment has been proven superior to classical supportive treatment, with the possible exception of bone marrow transplantation in younger patients. While in selected cases anecdotal successes have been noted with the use of hormonal therapy, some differentiation inducers, e.g. vitamin A- en D-analogues, have not hold their promises in placebo controlled trials. Attempts to induce complete remissions in MDS with antileukemic treatment have usually been unsuccessful. Toxicity is substantial and a considerable proportion of patients fare worse with chemotherapy than with standard supportive care. Recently, a flood of reports has appeared on the use of biological response modifiers e.g. cytokines and growth factors in the treatment of MDS. Perhaps some of these hold promises for a new era in MDS, but the data are preliminary and no follow-up on long term survival is at hand.     

Updates and advances in pyruvate kinase deficiency

Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for maintenance of the red cell membrane and function. Heterogeneous clinical manifestations can result in significant morbidity and reduced health-related quality of life. Treatment options have historically been limited to supportive care, including red cell transfusions and splenectomy. Current disease-modifying treatment considerations include an oral allosteric PK activator, mitapivat, which was recently approved for adults with PK deficiency, and gene therapy, which is currently undergoing clinical trials. Studies evaluating the role of PK activators in other congenital hemolytic anemias are ongoing. The long-term effect of treatment with disease-modifying therapy in PK deficiency will require continued evaluation.     

Erythropoietin for oncology supportive care

Recombinant human erythropoietin (rhEPO), the prototype erythropoiesis-stimulating agent developed in the 1980s, was among the first recombinant human proteins to be marketed for clinical use in the oncology setting. Anemia is a frequent concern in patients with cancer receiving myelosuppressive chemotherapy and the availability of rhEPO as an alternative to red blood cell transfusions to treat symptomatic anemia created excitement among clinicians, particularly during an era of mounting concern for transfusion-transmissible infections. Early studies of rhEPO for chemotherapy-induced anemia in patients with non-myeloid malignancies showed these agents improved hemoglobin levels and reduced transfusion rates. rhEPO therapy was reported to decrease fatigue and improve quality of life, although the magnitude and clinical meaningfulness of these effects have been debated. More recent clinical trials since 2003 linking rhEPO therapy to increased risk of tumor progression, thrombo-vascular events and mortality prompted implementation of use restrictions to minimize potential for harm. Scientific research to understand the basic mechanisms of the biologic effects of erythropoietin at the cellular receptor and signaling level has revealed pleiotropic cytokine effects extending beyond erythropoiesis regulation. The importance of erythropoietin receptor signaling in normal, non-erythroid tissues and in pre-clinical tumor models has been under intense investigation and scrutiny, as potential mechanisms of the adverse outcomes associated with rhEPO therapy have been debated. Further research will be required to clarify the complex interplay between the diverse hematopoietic and non-hematopoietic effects of erythropoietin in normal and malignant tissues and to optimize the clinical use of rhEPO in the supportive care of cancer patients.     

Improvement of iron-mediated oxidative DNA damage in patients with transfusion-dependent myelodysplastic syndrome by treatment with deferasirox

Myelodysplastic syndrome (MDS) is characterized by dysplastic and ineffective hematopoiesis, peripheral blood cytopenias, and a risk of leukemic transformation. Most MDS patients eventually require red blood cell (RBC) transfusions for anemia and consequently develop iron overload. Excess free iron in cells catalyzes generation of reactive oxygen species that cause oxidative stress, including oxidative DNA damage. However, it is uncertain how iron-mediated oxidative stress affects the pathophysiology of MDS. This study included MDS patients who visited our university hospital and affiliated hospitals (n=43). Among them, 13 patients received iron chelation therapy when their serum ferritin (SF) level was greater than 1000ng/mL or they required more than 20 RBC transfusions (or 100mL/kg of RBC). We prospectively analyzed 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in peripheral blood mononuclear cells (PBMC) obtained from MDS patients before and after iron chelator, deferasirox, administration. We showed that the 8-OHdG levels in MDS patients were significantly higher than those in healthy volunteers and were positively correlated with SF and chromosomal abnormalities. Importantly, the 8-OHdG levels in PBMC of MDS patients significantly decreased after deferasirox administration, suggesting that iron chelation reduced oxidative DNA damage. Thus, excess iron could contribute to the pathophysiology of MDS and iron chelation therapy could improve the oxidative DNA damage in MDS patients.     

Blood transfusion effects in kidney transplantation

Within the three decades since the beginnings of the field of clinical renal transplantation there have been four phases in blood transfusion policies, swinging from liberal transfusions to avoidance of transfusions, followed by a repeat cycle of deliberate transfusions and at present turning back to abstinence again. Because of improving skills at the prevention and treatment of rejections, the beneficial effects of random transfusions in the transplant population as a whole is marginal. This comes at a time when community fears of blood-borne infections and the prospects of supporting red cell production by the use of EPO have emerged as new factors in blood banking. Observations on patients at risk for graft loss, namely those having rejection episodes, indicate that a beneficial blood transfusion effect still exists, however. Future application of deliberate HLA antigen exposure in conjunction with novel immunological manipulations may provide a more effective avenue to tolerance induction. The use of blood transfusions matched for one HLA-DR antigen with the recipient has produced major benefits in preliminary trials and represents one starting point in this direction.     

Current status in iron chelation in hemoglobinopathies

Although blood transfusions are important for patients with hemoglobinopathies, chronic transfusions inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. Desferrioxamine (DFO) is the reference-standard iron chelator whose safety and efficacy profile has been established through many years of clinical use. DFO side effects are acceptable and manageable however the prolonged subcutaneous infusion regimen of 5-7 days per week is very demanding and results in poor adherence to therapy. Deferiprone (Ferriprox, L1) is a bidentate molecule, orally administrable three-times/day, licensed in Europe and in other regions but in the USA and Canada, for the treatment of iron overload in patients for whom DFO therapy is contraindicated or inadequate. Preliminary evidences suggest that Deferiprone may be more effective than DFO in chelating cardiac iron. The side effects include gastrointestinal symptoms, liver dysfunction, joint pain, neutropenia and agranulocytosis. A weekly assessment of white blood cell counts is recommended because of the risk of agranulocytosis. Deferasirox is a new, convenient, once-daily oral iron chelator that has demonstrated in various clinical trials good efficacy and acceptable safety profile in adult and pediatric patients affected by transfusion-dependent thalassemia major and by different chronic anemias (SCD, BDA, MDS). The long half-life of Deferasirox (16-18 hours) provides sustained 24 hr iron chelation coverage. The efficacy and safety profile have been evaluated in more than 1000 patients in clinical trials allowing FDA registration. Patient satisfaction with Deferasirox was superior than with DFO therapy.     

Supportive therapy of lung cancer patients

The effectiveness of cancer treatment given to lung cancer patients is indicated by the asymptomatic and non-toxic survival time. The goal is not to prolong the patients' suffering, but to lengthen the duration of the best quality of life lived (Time Without Symptoms and Toxicity-TWIST). Supportive care is the prevention and management of side effects which occur during therapy (chemotherapy, radiotherapy, surgery) given to patients suffering from cancer. Supportive care is the widespread activity of doctors, nurses and social workers, including psychosocial assistance and rehabilitation through the various stages of illness till death. Though palliative therapy is understood to be the high level and professional treatment of terminally ill patients in those cases where curative measures are not possible anymore, supportive and palliative treatment often overlap (e.g. pain control, cachexia, obstructive syndromes). Palliative care is part of supportive therapy. The goal of supportive care is to reduce the patients' subjective symptoms to the minimum ("well being") during therapy, follow up and consequently until death. The essence of supportive care is to keep the patients' quality of life on the highest possible level. This article summarizes the pathophysiology, prevention and therapy of the most frequently occuring side effects observed during the management of lung cancer patients.     

Clinical use of rHuEPO in bone marrow transplantation

Recipients of bone marrow (BMT) or peripheral blood progenitor stem cells (PBSCT) transplant have in the period following transplantation a frequent need for red blood cell transfusions and therefore an increased risk of blood-transmitted infections. The anaemia is caused mainly by myelosuppression after high-dose chemotherapy, but an impaired erythropoietin (EPO) production and an inappropriate EPO response may also contribute. Since recombinant human erythropoietin (rHuEPO) has been established as a treatment for renal anaemia it has been of interest whether treatment may be of benefit in the transplant setting. This paper gives an overview of the studies conducted to date with rHuEPO treatment in patients receiving bone marrow transplants. Current data donot support any transfusional benefits when rHuEPO is used in patients receiving autologous transplants. However, in patients receiving allogeneic transplants several studies clearly indicate a therapeutic role for rHuEPO with patients showing accelerated erythroid engraftment, increased haemoglobin levels, a reduced requirement for red blood cell transfusions, and a shortened time to transfusion independence. Especially patients with immune haemolysis after transplantation seems to benefit from the treatment. In addition, rHuEPO treatment has been used for lateonset anaemia after BMT and to prevent the need for homologous red blood cell transfusions to the BMT donor. To reduce costs, it is important in future studies to identify not only the optimal dose and route of administration of rHuEPO but also the most effective combination with other haematopoietic growth factors and cytokines that are used before and after transplantation.     

Prophylaxis and treatment of bacterial infections: do we need new strategies?

Bacterial infections in patients with hematologic malignancies still represent a severe and life-treating problem. Several observational studies during the last decade have revealed that neutropenic patients with fever are a heterogeneous population with various differences regarding response to initial therapy, development of serious complications and mortality. The role of neutropenia as main risk factor for infections in hematologic patients and the definition of different level of risk related to neutrophils count and duration of neutropenia have been extensively studied and different categories of patients based on the risk of infection, mostly the condition of neutropenia, have been clearly defined. The strategies on antimicrobial therapy and supportive care in hematologic patients need to be continuously assessed, in fact new conditions favouring the occurrence of infectious complications in patients with hematologic malignancies have progressively emerged. The use of oral prophylactic antibiotics in neutropenic cancer patients is still a matter of debate. Before 2005, several trials showed how the prevention of infection can be extremely important in this setting of patients but none was conclusive. In 2005 two meta-analysis and two large randomized clinical trials gave new evidence that antibacterial prophylaxis can reduce in neutropenic patients several important outcomes including mortality. The use of the empiric antibacterial therapy represents the cornerstone of the antimicrobial strategies in the febrile neutropenic patients leading, over the span of 20 years, to a dramatic decrease of deaths: Actually beta-lactam monotherapy is commonly used for the empiric treatment of febrile neutropenia. Recently, large randomized clinical trials and meta-analysis showed that the addition of an aminoglycoside and/or a glycopeptides results in a more favourable outcome only in selected severe infections. The use of antibiotics should be prudent and safe also in neutropenic hematologic patients to prevent emergence of microbial resistance, to save costs, to reduce toxicity. For this reasons, according to the evidence, antibacterial prophylaxis should be restricted to high risk hematologic patients and empiric parenteral antibiotic monotherapy should be recommended in case of febrile neutropenia limiting the use of amynoglicosides and glycopeptides. In the next future, a major effort should be made to state in hematologic patients new risk factors which could more accurately define subgroups for targeted anti-infective strategies.     

Treatment of cancer-related anemia

Anemia with consequent tissue hypoxia is common problem in cancer patients. Developed via various patophysiological mechanisms, it has deleterious effect on quality of life and survival of patients with cancer. Recognition of symptoms and timely initiation of treatment improve patients' quality of life, as well as efficacy of oncological treatment. Red blood cells transfusions are well known and efficient way of anemia correction. They are "golden standard" in treatment of cancer-related anemia today, and are unavoidable in almost all patients with hemoglobin concentration below 80 g/L. Newest therapy guidelines in developed countries, supported by recent literature, encourage use of recombinant human erythropoietin (rHu-EPO), although detailed meta-analyses and prospective randomized clinical trials have shown that rHu-EPO decreases the need for transfusions in only 9-45% patients with cancer, only if they have mild anemia, rHu-EPO increases incidence of thromboembolic events, and suspicion arises that it supports tumor cells growth and multiplication. Therefore, it is necessary to define subgroups of patients which are best candidates for rHu-EPO therapy, to accomplish lower intensity of transfusion therapy.     

Occurrence of hepatitis and hepatitis B surface antigen in adult patients with acute leukemia.

Fifty-eight adult patients with acute leukemia were screened at the onset of the disease for hepatitis B antigen (HBSAg) in the serum, and during the course of the disease for the development of hepatitis B. One patient had a positive test for HBSAg by the radioimmunoassay technique only at the time leukemia was diagnosed; this patient had received transfusions some years before. In six patients icteric hepatitis B developed; five recovered completely and one died of leukemia during the course of hepatitis. All patients in whom hepatitis developed had received transfusions as a part of supportive therapy for leukemia. The hepatitis risk for patients who received transfusions of blood found to be negative for HBSAg by counterimmunoelectrophoresis was 0.26 percent per unit of blood administered.     

Music therapy in supportive cancer care

The purpose of this paper is to show some aspects of music therapy application in cancer care and to present the integration of music therapy program into a continuous supportive cancer care for inpatients. A cancer diagnosis is one of the most feared and serious life events that causes stress in individuals and families. Cancer disrupts social, physical and emotional well-being and results in a range of emotions, including anger, fear, sadness, guilt, embarrassment and shame. Music therapy is a part of a complementary medicine program in supportive cancer care which accompanies medical treatment. There are many benefits of music therapy for cancer patients—interactive music therapy techniques (instrumental improvisation, singing) as well as receptive music therapy techniques (listening to recorded or live music, music and imaginary) can be used to improve mood, decrease stress, pain, anxiety level and enhance relaxation. Music therapy is an effective form of supporting cancer care for patients during the treatment process. It may be also basic for planning effective programs of rehabilitation to promote wellness, improve physical and emotional well-being and the quality of life.     

Improvement of anemia by recombinant erythropoietin in patients with myelodysplastic syndromes and aplastic anemia

Eight patients with myelodysplastic syndromes (MDS) and four patients with aplastic anemia (AA) were treated with recombinant erythropoietin (rEpo) to investigate its effect on the anemia of these patients. rEpo was administered by i.v. injection three times a week for at least four weeks. The doses were 3,000, 6,000, or 12,000 U/day. Despite an elevated "endogenous" Epo level, a greater than 1.5 g/dl increase in hemoglobin (Hb) concentration was observed in one patient with refractory anemia (RA), one patient with refractory anemia with excess of blasts (RAEB), and one patient with AA. A greater than 50% decrease in red cell transfusion requirement was observed in one patient with RA and one patient with AA. One RA patient and one AA patient have received rEpo as maintenance therapy for more than 64 and 100 weeks, respectively. They no longer need red cell transfusions and have had a normal Hb concentration and normal ferrokinetics. No side effect was seen. These results indicate that rEpo may benefit some patients with MDS and AA who are dependent on red cell transfusions while further studies will be necessary to elucidate the mechanism by which rEpo stimulates erythropoiesis and improves anemia in patients with these diseases.     

Management of multiple myeloma

There has been no improvement in the treatment of multiple myeloma (MM) during the last decades and two meta-analyses of randomized trials recorded no significant survival benefit for combination chemotherapy compared to the classic melphalan-prednisone combination. However the past 15 years has seen several innovative strategies which have dramatically modified the management of MM. In younger patients, high-dose therapy with autologous stem cell transplantation is considered to be superior to conventional chemotherapy and is used as part of front-line therapy. A number of issues have been addressed in recent trials in order to improve the results of autologous transplantation (source of stem cells, conditioning regimen, impact of double transplants, maintenance therapy). Bisphosphonates reduce the incidence of skeletal-related events and improve the quality of life. Recombinant erythropoietin reduces red blood cell transfusion need and improves the quality of life. Thalidomide has been introduced more recently. Phase II studies with thalidomide alone or combined with dexamethasone have shown impressive response rates and this drug is currently being evaluated as part of front-line therapy. Finally, analysis of prognostic factors such as beta 2 microglobulin and cytogenetics define subgroups of patients with a completely different outcome and help the process of selecting therapeutics strategies.     

Use of antibiotics in the management of postirradiation wound infection and sepsis

Ionizing gamma irradiation depresses the host defenses and enhances the susceptibility of the immunocompromised host to local and systemic infection due to endogenous or exogenous microorganisms. Trauma and wounding act synergistically and decrease the survival after exposure to irradiation. The current antimicrobial agents suitable for controlling serious infections and their use in post irradiation local and systemic infection with and without trauma are discussed. The experience gained in managing immunocompromised patients following chemotherapy is reviewed. Empiric single agent or combination agent therapy should be directed at the eradication of potential gram-negative as well as gram-positive pathogens. The most important organisms known to cause these infections are Pseudomonas sp. and Enterobacteriaceae. Management of intra-abdominal infections following trauma should include early surgical correlation and antimicrobials directed against the Bacteroides fragilis group and Enterobacteriaceae. Staphylococcus aureus and Streptococcus pyogenes cause most skin and soft tissue infections following trauma. Chemoprophylaxis of enteric sources of systemic infection can be achieved by antimicrobials that selectively inhibit the Enterobacteriaceae sp. and preserve the anaerobic flora. The management of infection in the injured and irradiated host includes supportive and restorative therapy. Supportive therapy includes débridement and cleansing of wounds, fluids, immunoglobulin, and antimicrobials. Restorative therapy includes definite surgery repair and replenishment of the immune system by use of immunomodulators, growth factors, and bone marrow transplantation. Further studies are needed to examine the usefulness of presently available drugs and experimental agents in the irradiated and traumatized host.     

Post-transfusion cytomegalovirus infection in newborn infants

Post-transfusional cytomegalovirus infection (P.T.C.M.V.) represents a minor part (perhaps about 0.2%) when compared with C.M.V. infections or maternal origin (congenital 0.2-0.5% - post-natal first year 20%). However P.T.C.M.V. infections are associated with higher morbidity and mortality because: These infections develop in infants born from uninfected mothers (C.M.V. sero-negative mothers). These newborns have no passively acquired antibodies from maternal origin which probably prevent or limit the spreading of P.T.C.M.V. infection in infants born from C.M.V. seropositive mothers. Transfused newborns are essentially recruited among great premature infants. The transfusional needs of these newborns are great: many of them receive more than ten micro-transfusions of red blood cells during their hospitalisation period. So the risk for developing C.M.V. infection is high (10-20%). The limited immune competence of these newborns and the fact that many already suffer from other developmental defects explain the severity of these P.T.C.M.V. infections. This contrasts with the well-supported C.M.V. infections post-natally acquired in term newborns. Prevention of P.T.C.M.V. infections is possible (A. Yeager, 1981) when using blood from C.M.V. sero-negative donors. Frozen blood appears also effective. It is highly desirable that blood Transfusion Centers permit such a prevention for red blood cells transfusion or exchange-transfusion in newborns less than 1 500 g B.W. and for intra-uterine transfusions.     

The proliferation index of specific bone marrow cell compartments from myelodysplastic syndromes is associated with the diagnostic and patient outcome

Myelodysplastic syndromes (MDS) are clonal stem cell disorders which frequently show a hypercellular dysplastic bone marrow (BM) associated with inefficient hematopoiesis and peripheral cytopenias due to increased apoptosis and maturation blockades. Currently, little is known about the role of cell proliferation in compensating for the BM failure syndrome and in determining patient outcome. Here, we analyzed the proliferation index (PI) of different compartments of BM hematopoietic cells in 106 MDS patients compared to both normal/reactive BM (n = 94) and acute myeloid leukemia (AML; n = 30 cases) using multiparameter flow cytometry. Our results show abnormally increased overall BM proliferation profiles in MDS which significantly differ between early/low-risk and advanced/high-risk cases. Early/low-risk patients showed increased proliferation of non-lymphoid CD34⁺ precursors, maturing neutrophils and nucleated red blood cells (NRBC), while the PI of these compartments of BM precursors progressively fell below normal values towards AML levels in advanced/high-risk MDS. Decreased proliferation of non-lymphoid CD34⁺ and NRBC precursors was significantly associated with adverse disease features, shorter overall survival (OS) and transformation to AML, both in the whole series and when low- and high-risk MDS patients were separately considered, the PI of NRBC emerging as the most powerful independent predictor for OS and progression to AML. In conclusion, assessment of the PI of NRBC, and potentially also of other compartments of BM precursors (e.g.: myeloid CD34⁺ HPC), could significantly contribute to a better management of MDS.     

Registration of drugs for treating cancer and HIV infection: a plea to carry out phase 3 trials before admission to the market.

Drugs for cancer and HIV infection tend to be admitted to the market on the basis of results from phase 2 trials. Assessing the benefit-risk balance with phase 2 trials often is difficult--the effect of the drug is usually temporary; the correlation between response or improvement of clinical measurements and the patient''s wellbeing is often poor; and the side effects of drugs for these fatal diseases are serious. Therefore, although sometimes difficult to conduct, comparative trials that use standard treatment, placebos, or best supportive care remain the cornerstone for reliably assessing the benefit-risk balance.     

Treatment and prevention of infections in cancer patients with neutropenia

Prognosis of malignant diseases is significantly influenced by infectious morbidity and mortality. Thus, up to date management of cancer patients, in addition to other supportive care modalities, should also incorporate diagnostic methods and therapy of infections. In order to improve outcome, patients developing febrile neutropenia following antitumour treatment should be adequately informed regarding the risk of infections. At the same time, centres responsible for cancer patient care should set up written protocols for basic workup and empirical antibiotic therapy. Here general characteristics of neutropenic infections developing in solid tumour patients are outlined and key points for risk assessment are highlighted. In addition, options and limits of anti-infective therapy as well as prophylaxis of infections are reviewed. Importance of a fully functional institutional infection control system and multidisciplinary patient management is also emphasised.     

Augmentation of innate host defenses against opportunistic fungal pathogens

Development of invasive fungal infection is the result of the complex interaction between fungal and host factors. The outcome of infection, once it has developed, depends upon appropriate use of antifungal therapy, surgical debridement as indicated, and improvement of host defenses. Thus, there have been major efforts for development of new strategies for immunomodulation and augmentation of host defenses in prevention and treatment of invasive mycoses. These modalities include granulocyte and granulocyte-macrophage colony-stimulating factors, interferon-γ, granulocyte transfusions, immunotherapy with infusion of dendritic cells and T cells, anti-heat shock protein 90 monoclonal antibodies, long pentraxin 3, mannose-binding lectin, and deferasirox. Although major strides in our understanding of augmentation of host response to invasive fungal infections are opening up novel avenues of therapy to harness patients’ innate immune systems against these frequently lethal pathogens, well-designed clinical trials are needed to demonstrate safety and efficacy of these new approaches.