Resistance to natural product-derived anti-cancer drugs, such as the anthracyclines and etoposide, contributes to the failure of chemotherapeutic treatment of leukaemia. One biological resistance mechanism of potential importance is the overexpression of the plasma membrane drug transporter proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP). Many studies have reported evidence for a correlation of Pgp/MDR1 expression with unfavourable prognostic features in acute myeloid leukaemia (AML). Failure to achieve complete remission (CR) is correlated with Pgp and the CD34+ phenotype. For MRP fewer data are available, which suggest a basal expression level in most AMLs. Another protein reported to correlate with treatment failure in AML is the lung resistance protein or major vault protein (LRP), a protein with a still unknown function. Co-expression of Pgp and LRP especially seems to define an adverse prognostic population. Further progress towards the understanding of the clinical importance of these proteins is hampered by the lack of validation of methods to determine their expression. A reliable way to measure Pgp seems to be the assessment of the active transport of fluorescent Pgp substrates, such as rhodamine 123 out of AML cells. Such functional Pgp assays can be used to validate mRNA or protein measurements and to quantify the effect of Pgp or the magnitude of the effect of a blocker of the Pgp-mediated drug efflux on the intracellular drug concentration. The prognostic value of such methods has still to be shown.
Iron chelation therapy is essential to prevent death from cardiac toxicity in patients with thalassemia major or other severe refractory anemias who need regular blood transfusions. Iron chelating drugs also have potential for clinical use as antiproliferative agents in neoplastic diseases and to reduce free radical-induced tissue damage in rheumatoid arthritis, anthracycline-induced cardiotoxicity, and reperfusion injury. Experimental data and clinical trials also suggest they may have therapeutic value as adjuncts to antimalarial and anti-Pneumocystis carinii therapy and to reduce aluminum toxicity. There is therefore an urgent need for an orally active, inexpensive iron chelating drug, because desferrioxamine, the only currently widely available iron chelator, must be given parenterally and is expensive, making it unavailable for long-term use in many parts of the world. L1 (also known as deferiprone, 1-2 dimethyl-3-hydroxpyrid-4-one, DMHP, and CP20) has emerged as an orally active iron chelator with comparable efficiency to desferrioxamine in both short- and long-term clinical studies. Adverse side-effects, principally agranulocytosis and arthropathy, have raised doubts about its safety, and further trials are now planned to evaluate the incidence of these and other toxicities. Despite numerous studies, no other orally active agent has been shown in clinical trials to be as effective or as safe as L1.
Diagnosis of von Willebrand's disease (vWD), particularly vWD Type 1, remains a clinical problem for several aspects. Its definitive diagnosis requires documentation of three factors: bleeding, low levels of qualitatively normal von Willebrand factor (vWF), and inheritance. In the absence of any of these factors the diagnosis may be only merely 'possible', or even unacceptable. Laboratory diagnosis of vWD includes screening tests and confirmatory tests. vWD Types 2 and 3 are relatively easy to diagnose and appear to be genetic disease of a single locus, the vWF gene. As new genetic and possibly non-genetic factors are discovered, the diagnosis of vWD Type 1 may become easier.
For all patients with a histocompatibiliy antigen (HLA) identical donor we are actually using two protocols to whom the patient is assigned. This is based on which class the patients belongs to at the time of bone‐marrow transplant and is independent from the patient's age. For 116 patients in Class 1 and for 271 patients in Class 2 prepared for the transplant with bulsulfan 14 mg/kg, cyclophosphamide 200 mg/kg and cyclosporin alone, the probabilities of survival and of event‐free survival are 95% and 90% for Class 1 and 85% and 81% for Class 2. For 125 Class 3 patients prepared for the transplant with busulfan 14 mg/kg, cyclophosphamide reduced to 120–160 mg/kg, cyclosporin and ‘short’ methotrexate, the probabilities of survival and of event‐free survival are 78% and 54%. For 108 adult patients aged between 17 and 35 years, who underwent the transplant after preparation with the same protocol used for the Class 2 or Class 3 patients, the probabilities of survival are 67% and of event‐free survival are 63%. Bone marrow transplantation remains the only form of radical treatment of thalassaemia in those patients with an HLA identical donor.
There are now a number of potential candidates for inherited thrombophilia but a definite causal relationship has been established for only a proportion of these. Accepted causes of familial thrombophilia include the factor V Leiden defect and the prothrombin 20210 G > A variant, as well as deficiencies of antithrombin, protein C and protein S. Together these inherited abnormalities account for 30-50% of individuals presenting with venous thromboembolism. Factor V Leiden, which is present in up to 7% of the European population, is the most common cause of familial thrombophilia. On a worldwide basis its prevalence varies greatly with ethnic origin. In common with other types of familial thrombophilia the frequency of factor V Leiden is highly dependent on the population group studied. Venous thromboembolism, present in approximately 55% of individuals with familial coagulation inhibitor deficiencies, is the predominant clinical manifestation of familial thrombophilia. There are indications that the venous thrombotic risk is somewhat less in those with factor V Leiden. The thrombotic risk is markedly increased in those with combined defects and in those who are homozygous for factor V Leiden. Risk factors for thrombosis include pregnancy, including the puerperium, surgery, oral contraceptive usage and prolonged periods of immobilization. A substantial proportion of venous thrombotic events may occur spontaneously, i.e. without an obvious precipitating event. The management of patients with familial thrombophilia comprises counselling, thromboprophylaxis and thrombosis treatment. Although the immediate treatment of an acute thrombotic event is not significantly different from that of patients without recognised abnormalities, detailed patient management is seriously hampered by a lack of appropriate clinical trials. Prospective clinical studies, designed to ascertain individual thrombotic risk and to evaluate different therapeutic strategies are urgently required.
The objectives of this analysis were an assessment of the feasibility of a more individually tailored approach of empirical antibiotic therapy in febrile neutropenia and an exploration of the reasons to modify the initial regimen.
Gene therapy of haematopoietic stem cells (HSCs) has been under investigation for 15 years. HSCs can be easily transduced with retroviral vectors (Moloney murine leukaemia virus = MMLV) in the mouse and expression of transferred genes can be achieved in long-term reconstituted mice. While human haematopoietic progenitor cells can be transduced with high efficiency using amphotropic MMLV retroviral vectors, and expression of the transferred gene is easily obtained in their progeny cells, it has proven problematic to transfer genes efficiently into the HSCs of humans in clinical trials. Efforts are now under way, in many laboratories, to increase the gene transfer efficiency of retroviral vectors, or alternatively to develop new vectors that can transduce quiescent human HSCs with higher efficiency than is currently possible. This brief review will address the two main research areas that are being explored. Firstly, investigations in human haematopoiesis to gain understanding into the molecular and cellular mechanisms that control HSC behaviour in vitro and in vivo. Secondly development of new vectors that can transfer genes to quiescent human HSCs.
In the last 30 years the treatment of acute lymphoblastic leukaemia has radically changed and intensified and has resulted in improvements in the chances of cure in children to up to 70% but in adults only 30% will achieve long-term disease-free survival. Data from large therapeutic trials have determined good and poor prognostic risk factors which have been of use in planning risk-directed treatment protocols and can influence the chance of cure. However intensification of treatment has also been associated with increased toxicity and significant late effects, particularly in children. In the future it will be necessary for more international collaboration and a more uniform approach to treatment in order to achieve continued improvements in the survival from this disease. In children it will be necessary to focus efforts on improving treatment of relapsed patients: chemotherapy protocols in those with a first remission of > 36 months, or for the high-risk patients with a shorter first remission, new transplantation approaches directed towards enhancing the graft-versus-leukaemia effect are going to be of increasing importance. In adults, continued efforts will be directed towards improving first remission rates with the use of increasingly intensive chemotherapeutic protocols and growth factors. The use of unrelated donor transplantation is also likely to increase, particularly in patients with 'poor-risk' disease.
The author presents a brief overview of current therapy in adults of various ages with acute myelogenous leukemia, including remission induction and post-remission treatment and the use of haematopoietic growth factors.
Re-activation of the fetal globin genes is the most realistic approach to correct the deranged pathophysiology of the haemoglobinopathies because the presence of gamma-chains can neutralize the toxic effects of the unbound alpha-globin chains in the beta-thalassaemias and inhibit the polymerization of Hb S in the sickle cell syndromes. Re-induction of fetal haemoglobin synthesis can be brought about either by direct activation of the respective promoter genes and possibly other positively acting elements, or by recruitment into proliferation and differentiation of a population of erythroid precursors which retain the gamma-chain synthesis programme but remain dormant in the bone marrow of the adult unless called up in cases of acute erythroid expansion. Examples of the first group include the butyric acid and derivatives and 5' azacytidine. The second group comprises erythropoietin and a series of cytostatics, with hydroxyurea as the main representative. The activity of most of the above agents has already been studied in cell cultures and animals and confirmed in several patients, both at the haematological and biochemical level as well as through their frank clinical improvement. However, application of these drugs at large is not yet justified because a series of questions concerning their long-term efficacy, the correct dosage and timing, their tolerance and toxicity, and the potential long-term dangers. including mutagenicity are still unresolved.
The haematopoietic stem cells in the bone marrow have long been considered, at least in theory, as an ideal target for gene therapy. Of the more than 250 clinical gene transfer protocols reported from around the world up to December 1996, almost one in three involves manipulation of haematopoietic cells. This includes both marketing trials and trials with a therapeutic intent. The human gene transfer trials targeting haematopoietic cells, the knowledge gained from them and their limitations are briefly summarized.
Follicle centre lymphomas (FCLs) comprise the predominant subtype of indolent nodal lymphomas. Therapy is based on the stage of the disease and consists of extended field or total nodal irradiation in stages I and II. Patients with advanced stages III and IV may initially remain untreated and be watched until the occurrence of disease‐related symptoms such as B‐symptoms, haematopoetic insufficiency, lymphoma progression or bulky disease. On the occurrence of these signs a cytoreductive chemotherapy of mild to moderate intensity such as cyclophosphamide, vincristine, prednisone (COP) or mitoxantrone, chlorambucil, prednisone (MCP) should be initiated. In responding cases maintenance with interferon‐alpha (IFNα) leads to a significant prolongation of the progression‐free interval. Modifications of this approach include the upfront combination of IFNα with anthracycline containing combinations such as cyclophosphamide, doxorubicin, teniposide, prednisone (CHVP). New perspectives arise from the introduction of myeloablative radio‐chemotherapy with subsequent stem‐cell transplantation and antibody‐based immuno‐biological therapies.
Antimicrobial prophylaxis in neutropenic patients has been practised in one form or another for several decades but the goal is no longer clear. From being initially solely an attempt at decontamination, drugs such as co-trimoxazole and later the fluoroquinolones were preferred to non-absorbable regimens because they achieve reliable protection against bacteraemia due to Gram-negative bacilli. Nevertheless, fever still invariably occurs during neutropenia leading to the initiation of traditional empirical therapy. Not only is this approach illogical but it also ignores the flexibility afforded the oral and parenteral formulations of the fluoroquinolones. Instead, it might be as effective and less costly if these agents were given orally until the end of neutropenia unless there was evidence of malabsorption or poor oral intake, in which case treatment would be continued parenterally. Should patients develop fever, an attempt would be made to complement treatment with another anti-microbial agent for microbiologically or clinically defined infection. This would be carried out at diagnosis, before any changes in the prophylactic regimen could be made. Otherwise, treatment with the prophylactic regimen would continue without modification. There is a less compelling need for prophylaxis against candidosis, herpes simplex and cytomegalovirus disease as these would be better managed pre-emptively when there is evidence of yeast carriage or re-activation of viral infection. Similarly, prophylaxis of aspergillosis is a forlorn hope and again a pre-emptive approach might serve us better once there is a screening test available and a safe and effective drug.
Journal of Internal MedicineVolume 242, Issue S740 p. 53-54 ArticleFree Access Malignant lymphoma: current aspects in biology and classification H. STEIN, H. STEIN Institute of Pathology, Benjamin Franklin University Hospital, Free University of Berlin, Berlin, GermanySearch for more papers by this author H. STEIN, H. STEIN Institute of Pathology, Benjamin Franklin University Hospital, Free University of Berlin, Berlin, GermanySearch for more papers by this author First published: 17 September 2018 https://doi.org/10.1111/joim.1997.242.s740.53 Correspondence: Professor Harald Stein, Benjamin Franklin University Hospital, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Harris NL, Jaffe ES, Stein H. et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994: 84: 1361– 92. 2Rosenberg SA. Classification of lymphoid neoplasms. Blood 1994: 84: 1359– 60. 3Harris NL, Jaffe ES, Stein H. et al. Lymphoma classification proposal: clarification. Blood 1995: 85: 857– 60. 4Stein H. Critique of the critique: response to the editorial entitled ‘Classification of lymphoid neoplasms’ by Dr Saul Rosenberg which accompanied the publication of the ‘Revised European-American Lymphoma Classification Proposal’ in the September 1994 issue of Blood. Ann Oncol 1995: 6: 109. 5 National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project. Cancer 1982: 49: 2112– 35. 6Weisenburger DD, Armitage JO. Mantle cell lymphoma — an entity comes of age. Blood 1996: 87: 4483– 94. 7Pulford K, Lamant L, Morris SW. et al. Blood 1997: 89: 1394– 405. Volume242, IssueS740July 1997Pages 53-54 ReferencesRelatedInformation
Inherent or acquired drug resistance is a major obstacle for the successful treatment of cancers. Many mechanisms of drug resistance have been described including a decreased drug uptake, an increase in DNA damage repair, enhanced drug detoxification, an altered level or mutation of the intracellular drug target or an increased drug efflux from the cell. Most of these mechanisms impinge upon the interaction of a drug with its cellular target or immediate consequences of such as interaction. For example, a decrease in the cellular levels of topoisomerase II thwarts the efficacy of certain topoisomerase II inhibitors, and enhanced levels of glutathione increase resistance to DNA alkylating agents. However, some tumours are inherently resistant to all chemotherapeutic agents, i.e. with different mechanisms of action. What is the mechanism(s) underlying this pleiotropic drug resistance? One possibility is that such drug-resistant tumour cells have an abnormally high threshold for the engagement of apoptosis (programmed cell death). The suppression of apoptosis as a mechanism for drug resistance is discussed in this article.
The ability to transfer novel genes into mammalian cells has allowed us to conceive of novel strategies towards cancer therapy. Since the initial gene-transfer clinical trial in 1989, over 300 cancer patients have been enrolled in gene therapy trials. Despite this, an NIH-sponsored panel concluded that 'clinical efficacy has not been definitively demonstrated at this time in any gene therapy protocol'. However, the first 8 years of gene therapy research have provided us with insights regarding the areas that require further scientific progress. For example, it is now clear that while in vitro assays of gene-modified haemotopoietic progenitor cells suggest high transduction efficiencies, once these cells are infused in vivo, only a small percentage of circulating transduced cells can be detected. While the initial clinical studies have demonstrated that gene transfer in patients can be safe and feasible, they have also indicated that future research is necessary towards the development of improved gene transfer techniques for these approaches to be successful.
von Willebrand's disease (vWD) is caused by qualitative (type 2) and quantitative (types 1 and 3) abnormalities of von Willebrand factor (vWF). vWD type 3, a severe form of the disease with nearly complete deficiency of the protein in plasma, are found to be homozygous or compound heterozygous for null mutations in the vWF gene. Null mutations in both alleles of the vWF gene completely disrupt the protein synthesis resulting in a nearly complete deficiency of the vWF in the type 3 patients. The vWD type 1 patients (mild form with partial deficiency of the protein) could be heterozygous for null mutations or compound heterozygous for the mutations (null mutation + missense mutation) in the gene. The vWD type 2, divided into four variants: types 2A, 2B, 2M and 2N, are caused exclusively by missense mutations within three different domains of the protein (gain or loss of function). The majority of type 2A mutations are located in the A2 domain and the types 2B and 2M mutations are in the A1 domain, while the type 2N mutation is in the FVIII binding domain.
The protein C system is an important natural anticoagulant pathway. Protein C is the key component of the system and it is activated by thrombin bound to thrombomodulin on the surface of endothelial cells. Activated protein C (APC) inhibits coagulation by cleaving and inactivating coagulation factors factor Va and factor VIIIa. Until recently, the major genetic causes of familial venous thrombophilia were inherited deficiencies of protein C, protein S or antithrombin, but together they were found in less than 5-10% of patients with thrombosis. In 1993, the situation changed drastically with the description of inherited APC-resistance as a novel risk factor for venous thrombosis. APC-resistance is characterized by a poor anticoagulant response to APC. Inherited APC-resistance is the most common genetic risk factor for this disease and it is found in 20-60% of patients. The condition is caused by a single point mutation in the gene for factor V which predicts substitution of arginine (R) at position 506 with a glutamine (Q). Mutated factor V (FVR506Q, FV:Q506 or FV Leiden) expresses normal procoagulant properties but is partially resistant to APC. The resulting hypercoagulable state confers a life long increased risk of venous but not arterial thrombosis. The FVR 506Q mutation is common in Caucasians with a prevalence of 1-15%, whereas it is not found in other human races. The FVR 506Q mutation may, due to its high prevalence, be an additional risk factor in individuals carrying other inherited defects such as deficiency of protein S, protein C or antithrombin. Such individuals have a high incidence of thrombosis and severe thrombophilia is a multigenetic disease. The high prevalence of inherited APC-resistance and the availability of easy functional and genetic tests will stimulate the development of prophylactic regimens and hopefully result in a decreased incidence of thrombosis.
Acute promyelocytic leukaemia (APL) is a distinct entity of acute myeloid leukaemia characterized by blast cell morphology, severe coagulopathy and t(15;17) translocation that fuses the PML gene on chromosome 15 to the retinoic acid receptor alpha (RAR alpha) gene on chromosome 17. Past experience indicated that APL is highly sensitive to anthracycline-based chemotherapy. GIMEMA experience reported a similar complete remission (CR) rate (77% versus 69%) in APL patients treated with idarubicin alone or idarubicin plus Ara-C, respectively. At present all-trans-retinoic-acid (ATRA) represents the mainstay of APL treatment. Current available clinical trials show that combination of ATRA and anthracycline induction therapy produces approximately 90% CR rate and seems to significantly improve disease-free survival. Furthermore ATRA combined therapy reduces induction death rate since ATRA syndrome has been managed with high-dose corticosteroids. However the development of ATRA resistance could limit the use of ATRA as post-remission treatment and therefore future efforts should be addressed to the search of new retinoids with comparable clinical activity, which can overcome ATRA resistance.
At least two transport proteins, P-glycoprotein (Pgp) and the multidrug resistance associated protein (MRP), are believed to play a significant role in clinical resistance to cytotoxic therapy. These proteins are expressed at relatively high levels in a number of malignant diseases including various types of leukaemias. They are variably expressed on both the plasma membrane and intracellular vesicular membranes resulting in cellular drug efflux or vesicular drug sequestration, respectively. The action of MRP as a drug transporter depends on intracellular levels of glutathione. A number of strategies for circumvention of these drug resistance mechanisms have been developed and some of these are now in clinical trial.
