Thrombosis and hemostatic abnormalities in hematological malignancies.

There is a paucity of data that pertain to thrombosis in patients with hematological malignancies. Recent studies showed that patients with lymphoma, multiple myeloma, and acute leukemia have an increased thrombotic risk, particularly at the time of diagnosis and during chemotherapy. We searched the PubMed database for articles on thromboembolic complications in patients with hematological malignancies published between 1996 and 2013. The incidence of thrombotic events is variable, and is influenced by the type and the stage of hematological malignancy, the antitumor therapy, and the use of central venous devices. The pathogenesis of thromboembolic disease in hematological malignancies is multifactorial. Tumor cell-derived procoagulant, fibrinolytic, or proteolytic factors, and inflammatory cytokines affect clotting activation, and chemotherapy and immunomodulatory drugs increase the thrombotic risk in patients with lymphoma, acute leukemia, and multiple myeloma. Infections might also contribute to the pathogenesis of the thromboembolic complications: endotoxins from gram-negative bacteria induce the release of tissue factor, tumor necrosis factor and interleukin-1b, and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII. In the setting of plasma cell dyscrasias, hyperviscosity, decreased fibrinolysis, procoagulant autoantibody production, inflammatory cytokines, acquired activated protein C resistance, and the prothrombotic effects of antimyeloma agents might be the cause of thromboembolic complications. Anticoagulant therapy is very complicated because of high risk of hemorrhage. Therefore, an accurate estimate of a patient's thrombotic risk is essential to allow physicians to target thromboprophylaxis in high-risk patients.

Hematopoietic growth factors: personalization of risks and benefits.

A common side effect of cancer treatment is bone marrow suppression. The resulting myelosuppression and anemia can cause significant morbidity and mortality for patients. Agents such as granulocyte colony stimulating factors (GCSF) and erythropoietin stimulating agents (ESAs) may be helpful to ameliorate this depression of blood counts; however these agents have risks which also need to be carefully weighed.

Haematopoietic growth factors and their therapeutic use.

Haematopoietic growth factors constitute an important group of proteins that predominantly regulate the process of haematopoiesis. While some of these proteins have a very broad array of action on very early haematopoietic progenitors leading to multi-lineage increases in haematopoietic cell production and differentiation, others act in a restricted manner on specific committed terminally differentiated cell types. On the basis of their unique spectrum of activities, several factors are approved for clinical use in various indications while others are under investigation in the clinic either alone or as combination therapy. In this review, we have described factors which directly and in some cases indirectly influence haematopoiesis with particular focus on those factors which are either approved or show potential for clinical use. A brief description of the products that are currently available for clinical use is also provided. At present, several new products which include fusion proteins, peptide mimetics are either at the pre-clinical stage or in clinical development for various indications and these are also briefly described.

Hematopoietic growth factors for the treatment of inherited cytopenias.

The clinical availability of recombinant hematopoietic growth factors was initially thought to be breakthrough in the treatment of bone marrow failure syndromes. However, in most disorders of hematopoeisis, the clinical use was rather disappointing. Only in congenital neutropenias (CNs) has the long-term administration of granulocyte colony-stimulating factor (G-CSF) led to a maintained increase in absolute neutrophil count (ANC) and a reduction of severe bacterial infections. In other disorders of hematopoiesis, the use of lineage-specific growth factors is either not possible due to mutations in the growth factor receptor or leads to a transient benefit only. Initial clinical trials with multilineage hematopoietic growth factors, such as stem cell factor (SCF; c-kit ligand) were discontinued due to adverse events. It is well known that bone marrow failure syndromes are pre-leukemic disorders. So far, there is no evidence for induction of leukemia by hematopoietic growth factors. However, it has been shown in patients with CN and Fanconi anemia that hematopoietic growth factors might induce preferential outgrowth of already transformed cells. Thus, it is strongly recommended to monitor patients for clonal aberrations prior to and during long-term treatment with hematopoietic growth factors.

A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C.

UNLABELLED: We conducted a national retrospective survey on hospital practitioners to evaluate the magnitude of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF) prescriptions in patients treated for chronic hepatitis C. Four hundred seventy-one questionnaires were sent, and 274 practitioners (58.2%) responded. Forty-six percent of practitioners used EPO, and 31% used G-CSF. The total number of HCV-infected patients receiving antiviral therapy per year was estimated at 6,630 patients, of whom 8.8% and 4% received EPO and G-CSF, respectively. EPO-beta was the main EPO molecule prescribed at a median dose of 30,000 IU/wk (range: 2,000-80,000). The indications for prescribing EPO varied greatly, including "fragile patients" (34%), "low" Hb level (8-11 g/dL) (19%), "rapid decline" in Hb level (2-5 g/dL during the first month of therapy) (12%), and symptomatic anemic patients (7%). G-CSF was mainly prescribed for a "low" level of neutrophils ranging from 400 to 750 neutrophils/mm3. In multivariate analysis, independent predictors of EPO and G-CSF prescription were age of practitioner less than 45 years (EPO: OR = 1.96, P = 0.03; G-CSF: OR = 2.27, P = 0.004), practice in university hospital (EPO: OR = 5.89, P < 0.0001; G-CSF: OR = 2.39, P = 0.003), and the high number of CHC treated/year (EPO: OR = 6.18, P < 0.0001; G-CSF: OR = 2.58, P = 0.002). CONCLUSION: Our survey reveals an important rate of EPO and G-CSF prescriptions but with considerable disparity in the schedule of injections, the molecules used, and above all the indications. The suitable role of EPO and G-CSF as complements to HCV therapy urgently needs to be clarified.

Haematological malignancies developing in previously healthy individuals who received haematopoietic growth factors: report from the Research on Adverse Drug Events and Reports (RADAR) project.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1-5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed.

Effect of hematopoietic growth factors on severity of experimental autoimmune encephalomyelitis.

We have investigated the influence of different hematopoietic growth factors, including granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), Flt-3 ligand (Flt-3L) and thrombopoietin (TPO), on the course of relapsing experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Disease course and central nervous system histology were evaluated in all groups. When given after immunization but before either disease onset or during remission, Flt-3L, SCF and G-CSF exacerbated disease severity whereas TPO had no effect compared to non-cytokine-treated controls. When compared to controls, TPO did not exacerbate disease. We conclude that autoimmune disease severity may be affected by hematopoietic growth factors currently being employed in hematopoietic stem cell transplantation of patients with autoimmune disease. The mechanism of their effects remains unknown: it may be related to both T helper (Th) 1/Th2 skewing and/or homing of inflammatory cells to the disease-affected organ.

Incidence of Clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma.

Diarrhea is a major cause of morbidity and discomfort for patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT). There are multiple causes of diarrhea in patients undergoing transplantation including antineoplastic chemotherapy, antimicrobials and infection, including Clostridium difficile as the most common pathogen involved. The purpose of this study was to determine the incidence of C. difficile-associated diarrhea (CDAD) 1 week before and 30 days after APBSCT, and to identify risk factors for the development of CDAD including diagnosis. Two hundred and forty-two patients underwent APBSCT for multiple myeloma and lymphoma between October 1996 and October 2001 in two teaching hospitals. Diarrhea was reported in 157 (64.9%) subjects. One hundred and thirty-five out of the 157 subjects were tested for the presence of C. difficile toxin A. These subjects constitute the study group. The incidence of CDAD was 15%. Two thirds of the patients who developed CDAD had multiple myeloma and one third had lymphoma; this difference did not attain statistical significance. The use of cephalosporins (P = 0.03) and the use of intravenous vancomycin (P = 0.02) were the only identified risk factors associated with the development of CDAD. Patients treated with paclitaxel as part of the mobilization regimen had a lower incidence of CDAD than patients who received hematopoietic growth factor only (P = 0.01).

Haemopoietic growth factors for neonates: assessing risks and benefits.

This review summarises the rationale, clinical trial evidence for benefit and potential toxicities of Erythropoietin, Thrombopoietin, Granulocyte Colony Stimulating Factor and Granulocyte-Macrophage Colony Stimulating Factor. Erythropoietin has failed to have a clinical impact on red cell transfusion requirement in very low birth weight infants; it is uncertain whether Thrombopoietin will find a significant clinical role in neonatal thrombocytopenia and there is, as yet, insufficient evidence for the routine use of Granulocyte- or Granulocyte-Macrophage Colony Stimulating Factor to prevent or treat bacterial infection. A number of theoretical risks of haemopoietic growth factor use in neonates have been suggested, but no toxicities have been observed during their clinical use. Exploring the potential for benefit in selected groups of infants should be encouraged.

Therapeutically-induced autoantibodies in patients treated with recombinant hematopoietic growth factors: a brief summary.

Since recombinant gene technology was established to provide rare important regulatory proteins as recombinant molecules, cytokine therapies have widely developed and enormously contributed to the treatment of various diseases; nevertheless, it has been revealed that recombinant therapeutic molecules are not always perfect because of side-effects related to pharmacological functions of cytokines and/or potential antigenicity observed in some clinical cases. Although studies on the antigenicity of recombinant proteins have initiated, and observations in clinical studies have been accumulated over this decade, mechanisms of the autoantibody production are not clarified yet. Among various hematopoietic growth factors introduced into clinical trials, this report summarizes current issues of autoantibodies to primary regulators for terminal hematopoiesis.

Rescue of haemopoiesis by a combination of growth factors including stem-cell factor.

We observed an unexpectedly rapid rise in platelet counts with complete haematological recovery after a BEAM regimen, in a patient who could not be rescued by autologous transplant but who received filgrastim, epoetin alfa, and ancestim. We feel that these results may be attributed to this specific growth factor combination, including ancestim, a cytokine known to act on primitive stem cells. If confirmed, this observation may open new possibilities in intensive chemotherapy for patients for whom haematopoietic progenitors are difficult to harvest. This may also represent an alternative to ex-vivo expansion and deserves further investigation.

Oncology practice patterns in the use of hematopoietic growth factors.

Recombinant hematopoietic growth factors were introduced into clinical practice a decade ago: erythropoietin in 1989, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 1991, and interleukin-11 in 1997. The role of these agents in supportive therapy for children with cancer is still under considerable evaluation. This pediatric-based review summarizes current clinical applications, practice guidelines, and practice patterns for hematopoietic growth factors in the supportive care of children with cancer. It also discusses ongoing controversies and unanswered questions.

Hematopoietic growth factors in the pathogenesis and for the treatment of aplastic anemia.

The production and release of hematopoietic growth factors from bone marrow stromas established in vitro from patients with aplastic anemia is normal or increased. Addition of hematopoietic growth factors to aplastic anemia bone marrow cells results in only modest increases in colony growth, with the exception of granulocyte colony-stimulating factor (G-CSF), which corrects their impaired cloning efficiency to normal. Most clinical data on the use of hematopoietic growth factors in aplastic anemia have derived from uncontrolled and small single-arm studies or case reports. Sustained trilineage hematologic responses have not been observed when hematopoietic growth factors have been used alone or in combination. Serious side effects have been reported for most of the hematopoietic growth factors in patients with aplastic anemia, with the exception of G-CSF. There is a major concern that they may further increase the risk of clonal disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Hematopoietic growth factors should not be used alone in newly diagnosed patients as specific treatment for aplastic anemia, and their use in combination with immunosuppressive therapy should be confined to multicenter, prospective randomized studies.