Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.

CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.

Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS.

Lenalidomide is the approved treatment for patients with red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)). We report the long-term outcomes (median follow-up 3.2 years) in patients treated with lenalidomide in the MDS-003 trial. RBC transfusion independence (TI) ≥ 8 weeks was achieved in 97 of 148 treated patients (65.5%), with a median response duration of 2.2 years. Partial or complete cytogenetic response was achieved by 63 of 88 evaluable patients (71.6%). Median overall survival (OS) was longer in patients achieving RBC-TI ≥ 8 weeks (4.3 vs 2.0 years in non-responders; P<0.0001) or cytogenetic response (4.9 vs 3.1 years in non-responders; P=0.010). Time to acute myeloid leukemia (AML) progression was longer in patients achieving RBC-TI ≥ 8 weeks or any cytogenetic response versus non-responders (P=0.001 and P=0.0002, respectively). In a landmark multivariate analysis, RBC-TI ≥ 8 weeks was associated with prolonged OS (P<0.001) and a trend toward reduced relative risk of AML progression (P=0.080). Among these lower-risk MDS patients with del(5q), lenalidomide was associated with prolonged RBC-TI and cytogenetic responses, which were linked to improved OS and reduced risk of AML progression.

Mechanism of thrombocytopenia in chronic hepatitis C as evaluated by the immature platelet fraction.

INTRODUCTION: Thrombocytopenia occurs frequently in chronic hepatitis C. The mechanism of this association was investigated utilizing the immature platelet fraction (IPF%) as an index of platelet production together with assay of thrombopoietin (TPO). METHODS: In a cross-sectional study, 47 patients with chronic hepatitis C were studied, 29 with thrombocytopenia and 18 without thrombocytopenia (six patients in each group were on interferon therapy). RESULTS: IPF% was elevated in the thrombocytopenic compared with the nonthrombocytopenic group (9.0 ± 4.8% vs. 4.7 ± 2.4%, P < 0.001), and an increase in IPF% was significantly associated with thrombocytopenia on multivariable analysis (P < 0.05). Splenomegaly was more common in thrombocytopenic than in nonthrombocytopenic subjects (66% vs. 6%, P < 0.001), and on multivariable analysis, splenomegaly was the factor associated with the highest relative risk of thrombocytopenia (RR = 1.9, P < 0.05). IPF% values were elevated in a similar proportion of thrombocytopenic patients with and without splenomegaly (58% and 60%, respectively). There was no difference in TPO levels between thrombocytopenic and nonthrombocytopenic patients, and TPO levels were not related to the risk of thrombocytopenia on multivariable analysis. Significantly more thrombocytopenic than nonthrombocytopenic subjects had abnormal liver function tests, cirrhosis, and portal hypertension, and a decrease in serum albumin was significantly associated with thrombocytopenia (P < 0.005) on multivariable analysis. CONCLUSIONS: Factors associated with liver disease in general are associated with thrombocytopenia in chronic hepatitis C. Peripheral platelet destruction or sequestration is the major mechanism for thrombocytopenia, with hypersplenism being an important cause. Low TPO levels were not related to the occurrence of thrombocytopenia in this study.

Giant anal condylomatosis after allogeneic bone marrow transplantation: a rare complication of human papilloma virus infection.

Condyloma acuminata or genital warts are caused by human papilloma virus (HPV). Ongoing proliferation of HPV in patients with congenital or acquired immunodeficiency states leads to the development of rapidly progressive and sometimes locally invasive tumor with or without dysplasia. Aggressive treatment, diagnostic immuno-typing, and follow-up are necessary in patients with ongoing immunosuppression. We report a case of giant ano-genital condylomatosis due to HPV types 6 and 11 in a patient with chronic myeloid leukemia after allogeneic bone marrow transplantation. The tumor was successfully treated with surgical excision and local application of 5% imiquimod cream.

Fatal chemotherapy-induced encephalopathy following high-dose therapy for metastatic breast cancer: a case report and review of the literature.

Chemotherapy-induced encephalopathies occur in a variety of clinical settings and the most detailed accounts have been described following combination methotrexate and radiation therapy. The case described herein developed severe encephalopathy following a high-dose chemotherapy protocol used in the treatment of metastatic carcinoma of the breast. Visual symptoms developed 3 weeks after completing high-dose chemotherapy and peripheral blood hematopoietic stem cell transplantation. Over the next several weeks, additional neurologic deficits developed and continued to progress despite various treatment interventions. Diffuse deep gray matter damage was identified on MR imaging and a brain biopsy revealed pathological findings similar in many respects to those described for methotrexate/radiation, cisplatin, BCNU and/or 5 FU/levamisole-related leukoencephalopathy. The patient succumbed to complications resulting from the CNS disorder, 8 weeks after the onset of symptoms. This case is unusual for two reasons. First, the patient developed severe encephalopathy following a high-dose chemotherapy protocol commonly used in the treatment of metastatic breast carcinoma and second, the encephalopathy involved primarily deep gray matter structures rather than white matter.

Erythropoietin, iron, and erythropoiesis.

Recent knowledge gained regarding the relationship between erythropoietin, iron, and erythropoiesis in patients with blood loss anemia, with or without recombinant human erythropoietin therapy, has implications for patient management. Under conditions of significant blood loss, erythropoietin therapy, or both, iron-restricted erythropoiesis is evident, even in the presence of storage iron and iron oral supplementation. Intravenous iron therapy in renal dialysis patients undergoing erythropoietin therapy can produce hematologic responses with serum ferritin levels up to 400 microg/L, indicating that traditional biochemical markers of storage iron in patients with anemia caused by chronic disease are unhelpful in the assessment of iron status. Newer measurements of erythrocyte and reticulocyte indices using automated counters show promise in the evaluation of iron-restricted erythropoiesis. Assays for serum erythropoietin and the transferrin receptor are valuable tools for clinical research, but their roles in routine clinical practice remain undefined. The availability of safer intravenous iron preparations allows for carefully controlled studies of their value in patients undergoing erythropoietin therapy or experiencing blood loss, or both.

Effects of erythropoietin therapy on iron absorption in chronic renal failure.

The effect of erythropoietin administration on the absorption of dietary and therapeutic iron was examined in patients with anemia of chronic renal failure on maintenance hemodialysis. Absorption from test meals tagged extrinsically with iron 55, iron 59, or both was determined 2 weeks later by using incorporated red blood cell radioactivity and whole body counting. In an initial study of food iron absorption, the effect of initiating erythropoietin therapy was determined by measuring the absorption of heme and nonheme iron before and 2 weeks after the administration of 64 U/kg body weight erythropoietin (range, 46-85 U/kg body weight) three times weekly. Absorption of heme iron increased 1.6-fold from 18.6% to 30.1% (P < .05), and nonheme iron increased 3.7-fold from 1.3% to 4.9% (P < .01) after erythropoietin therapy. In a second study therapeutic iron absorption was evaluated at baseline and after erythropoietin administration (63 U/kg body weight (range, 48-74 U/kg body weight) three times weekly). The absorption of 50 mg of iron as ferrous sulfate increased 2.4-fold from 3.8% to 9.4% (P < .05) when given without food and 4.2-fold from 1.4% to 5.9% (P < .05) when given with food after erythropoietin administration. After adjusting for changes in iron stores with serum ferritin after erythropoietin therapy, the enhanced erythropoiesis associated with erythropoietin therapy increased absorption about 2-fold, which was similar to the response observed previously in normal subjects. In a final study we examined the absorption of therapeutic iron during the steadystate phase of erythropoietin therapy after an erythroid response to erythropoietin had occurred. The absorption of 50 mg of iron was lower than that occurring with the initiation of erythropoietin therapy at 2.2% when given alone and 1.3% when taken with food. We conclude that iron absorption with or without erythropoietin stimulation is unimpaired in patients with chronic renal failure.

Reversible methotrexate associated lymphoproliferative disease evolving into Hodgkin's disease.

We describe a case of nodular sclerosing Hodgkin's disease (NSHD) developing in a 61-year-old woman with seropositive rheumatoid arthritis treated with oral methotrexate (MTX) 5 to 15 mg/week for 5 years. Computed tomography (CT) of the abdomen revealed splenomegaly and marked abdominal and retroperitoneal lymphadenopathy. MTX was discontinued; several weeks later prednisone 10 mg/day was added to control worsening polyarthralgia. Repeat CT at 3 months showed almost complete regression of the splenomegaly and lymphadenopathy. However, CT studies at 10 months showed asymptomatic progression of lymphadenopathy, which on biopsy revealed NSHD. Patients with apparently reversible MTX associated lymphoproliferative disorder require periodic monitoring for asymptomatic development of malignant lymphoma.

Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study.

BACKGROUND: Total parenteral nutrition (TPN) supplemented with glutamine (GLN) has been reported to be effective for patients with bone marrow transplantation (BMT). Our aim was to evaluate enteral and parenteral glutamine in patients undergoing BMT. METHODS: For evaluation of GLN in BMT, 66 patients with 43 hematologic and 23 solid malignancies (21 breast carcinomas), were randomized, double-blinded, to either oral GLN (n = 35) or glycine-control (GLY) (n = 31), 10 g three times daily. When TPN became necessary, patients who received GLN orally were given TPN with GLN (0.57 g/kg). Those who received GLY received standard TPN, isocaloric and isonitrogenous. Patients with hematologic malignancies received high-dose chemotherapy, total body irradiation, and either allogeneic (ALLO) BMT (n = 18) or autologous (AUTO) stem cell transplantation (n = 25). Patients with solid malignancies (n = 23) received AUTO. RESULTS: There were 14 in-hospital deaths without relationship to GLN administration. For respective comparisons of ALLO and AUTO transplants in the GLN and GLY hematologic groups and AUTO in the solid tumor groups, there were no significant differences in hospital stay, duration of stay after BMT, TPN days, neutrophil recovery >500/mm3, incidence of positive blood cultures, sepsis, mucositis, and diarrhea. Acute graft us host disease occurred in 1 of 10 hematologic patients receiving GLN and in 3 of 8 patients receiving GLY placebo (p > .05). Possible reduction in need for TPN and a suggestion of improved long-term survival were associated with GLN. CONCLUSIONS: Oral and parenteral GLN seemed to be of limited benefit for patients having AUTO or ALLO BMT for hematologic or solid malignancies. Further study of long-term effects of GLN in BMT seems warranted.

An assessment of dried blood-spot technology for identifying iron deficiency.

The present study was undertaken to assess the feasibility of using ferritin and transferrin receptor measurements on dried capillary blood spots to identify iron deficiency (ID) in public health surveys. Measurements on serum and blood spots prepared from venous blood were performed in 71 healthy subjects, 41 of whom were iron-replete and 30 who had ID, either without (n = 20) or with (n = 10) anemia. Parallel measurements were performed on hemolyzed whole blood and washed hemolyzed red blood cells to assess the erythrocyte contribution of ferritin and transferrin receptor to dried blood samples. The concentration of ferritin in dried blood samples was threefold higher than serum assays due to the release of ferritin from hemolyzed erythrocytes, which diminished the usefulness of ferritin measurements for detecting ID. On the other hand, there was negligible erythrocyte contribution to the measurement of transferrin receptor in dried blood spots. The most sensitive parameter in dried blood spots was the ratio of receptor/ferritin, which was suitable for identifying iron-deficiency anemia (IDA), but less reliable than serum assays for detecting milder ID without anemia. We conclude that tandem measurements of serum ferritin and transferrin receptor in dried blood spots can be used to facilitate the identification of IDA in epidemiologic studies.

Markers of masked iron deficiency and effectiveness of EPO therapy in chronic renal failure.

Recombinant erythropoietin (rHuEPO) is well established in the management of anemia of chronic renal disease. However, a number of clinical issues, including the best laboratory indicators of an imminent marrow response to rHuEPO replacement, the ideal measurements to detect masked iron deficiency, and optimal methods of iron replacement, remain unanswered. To investigate these issues, studies were performed in anemic chronic hemodialysis patients. A number of standard hematologic measurements in addition to automated reticulocyte counts (Sysmex R-1000) and serum transferrin receptors (TfR) were obtained in these patients. A response to initiation of rHuEPO administration could be predicted if the serum TfR concentration was less than 6 mg/L (normal, 3.8 to 8.5 mg/L). In patients on rHuEPO, an imminent hemoglobin response to an increased rHuEPO dose could be predicted after 1 week based on a greater than 20% increase from baseline in the serum TfR or absolute reticulocyte count, with a sensitivity of 92%. In patients on rHuEPO replacement with serum ferritin levels greater than 30 microg/L, none of the panel of tests, including serum TfR, reliably detected masked iron deficiency. In a long-term study over 5 months in patients on a stable maintenance dose of EPO, a gradual decline in total body iron occurred, even in subjects with initial adequate iron stores, and despite taking 50 mg elemental iron daily as oral ferrous sulphate. The serum TfR is useful for predicting a hemoglobin response when initiating rHuEPO therapy, and combined with automated reticulocyte counting it is valuable for predicting a hemoglobin response when increasing the dose of rHuEPO. The serum TfR loses its specificity for detecting tissue iron deficiency in patients on maintenance rHuEPO therapy because of increased erythropoiesis, which itself raises serum TfR levels.

Bovine ferritin iron bioavailability in man.

The bioavailability of ferritin iron was evaluated in human subjects using radiolabelled [55Fe]ferritin isolated from bovine spleen and liver. Preliminary studies with bovine spleen ferritin labelled in vitro demonstrated an inappropriately high absorption compared with ferritin labelled in vivo, and the latter was therefore used in all subsequent absorption studies. In 10 subjects, geometric mean absorption from 5 mg of ferritin iron was 3.8% when taken without and 3.2% when taken with food (P > 0.05). These values were significantly lower than absorption from the same dose of iron given as ferrous sulphate, which averaged 24.1% without and 8.2% with food. When the iron dose was increased 10-fold, absorption of ferritin iron averaged only 0.6-0.7% with or without food as compared with 7.9% without and 2.6% with food when the iron was given as ferrous sulphate. In a further study, mean absorption from bovine spleen ferritin of 4.0% did not differ significantly from the mean of 2.7% observed with bovine liver ferritin. These findings confirm previous studies indicating that ferritin iron is poorly absorbed. Furthermore, its use as a pharmaceutical iron preparation cannot be advocated.

Alveolar macrophages accumulate iron and ferritin after in vivo exposure to iron or tungsten dusts.

Extracellular iron present in alveolar structures may contribute to oxidative lung injury induced by toxic mineral dusts by enhancing dust-induced generation of hydroxyl radicals. Alveolar macrophages (AMs) can sequester iron within ferritin and limit generation of hydroxyl radicals. In the current study we sought to assess whether AMs accumulate iron and ferritin after in vivo exposure to a dust with high iron content, to iron oxide, or to an inflammatory dust, calcium tungstate. We performed lung lavage 1, 7, 14, 28, 42, and 56 days after intratracheal instillation of mineral dust in saline solution or instillation of saline solution alone and quantitated cell recovery and AM content of iron and ferritin. Instillation of iron oxide increased neutrophil recovery only on a day 1 when compared with results in controls, whereas calcium tungstate increased neutrophil recovery through day 14. AMs recovered after instillation of iron oxide contained increased amounts of iron and ferritin, beginning on day 1 and progressing through day 56 after treatment (7.57 +/- 0.38 microgram iron per 10(6) AMs vs 1.54 +/- 0.28 microgram iron per 10(6) AMs for controls, p < 0.001; and 5908 +/- 768 ng ferritin per 10(6) AMs vs 395 +/- 20 ng ferritin per 10(6) AMs, p < 0.001). AMs recovered after calcium tungstate instillation also contained increased amounts of iron and ferritin beginning 14 days after treatment, with greatest content 42 days after treatment (4.85 +/- 0.68 microgram iron per 10(6) AMs, p < 0.001, and 2274 +/- 736 ng ferritin per 10(6) AMs, p < 0.001). Tumor necrosis factor, which can enhance iron accumulation by macrophages, was spontaneously released by AMs recovered from tungsten-treated rats. These studies indicate that AMs accumulate iron and ferritin in response to both iron loading of the lungs with iron oxide exposure and lung inflammation induced by calcium tungstate exposure.

Ferritin excretion and iron balance in humans.

Under normal circumstances, most of the lumenal iron taken into the intestinal mucosal cell is stored within the cell as ferritin and subsequently is lost in the faeces when the cell exfoliates at the end of its lifespan. To evaluate whether faecal iron proteins reflect mucosal cell iron as well as whole body iron and to examine further the kinetics of gastrointestinal iron transport, faecal H-rich and L-rich ferritin were measured in normal subjects and patients with iron deficiency and genetic haemochromatosis. In normal and iron-deficient subjects, the concentration of L-rich but not H-rich faecal ferritin correlated closely with body iron status. In genetic haemochromatosis, the faecal L-rich and H-rich ferritin concentrations were lower than expected for their body iron status. The administration of oral iron to normal subjects led to a rise in L-rich ferritin. Administration of oral or parenteral iron to patients with iron deficiency led to a prompt rise in both forms of faecal ferritin, although the relative increase of L-rich ferritin was greater than that of H-rich ferritin with oral iron administration. Faecal ferritin correlated closely with iron stores in normals and patients with iron deficiency but faecal ferritin levels were lower than expected in genetic haemochromatosis, similar to that previously noted in the duodenal mucosal cells of these patients.

Increased release of ferritin and iron by iron-loaded alveolar macrophages in cigarette smokers.

The lower respiratory tract of cigarette smokers contains an increased amount of iron that is predominantly sequestered within alveolar macrophages (AM), but is also present in alveolar epithelial fluid. Extracellular ferritin-bound iron could potentially be released by reductants present in cigarette smoke and catalyze generation of highly reactive hydroxyl radicals capable of causing oxidant injury. To determine whether AM are a source of alveolar extracellular ferritin and iron, we assessed in vitro release of iron, ferritin, and transferrin by AM recovered by bronchoalveolar lavage (BAL) of 27 healthy subjects including nine nonsmokers (NS), nine light smokers (LS), and nine heavy smokers (HS). Release of iron in vitro over 20 h was increased in AM recovered from LS (2.24 +/- 0.21 nmol/10(6) AM/20 h, p < 0.001) and HS (3.11 +/- 0.32 nmol/10(6) AM, p < 0.001) compared with NS (1.28 +/- 0.08 nmol/10(6) AM). Release of ferritin in vitro over 20 h was also increased in AM recovered from LS (71 +/- 24 ng/10(6) AM, p < 0.05) and HS (176 +/- 35 ng/10(6), p < 0.001) compared with NS (18 +/- 3 ng/10(6) AM). AM recovered from 12 smokers (8 HS, 4 LS) contained greater than 10 nmol of iron per 10(6) cells. These iron-loaded AM released a greater percentage of cell ferritin stores in vitro over 4 h (8.4% +/- 1.1, p < 0.01) than did AM from NS (3.2% +/- 0.6). Release of lactate dehydrogenase (LDH) over 4 h was substantially less (2.9% +/- 0.3, p < 0.001) than ferritin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Iron deficiency: the global perspective.

The prevelance of IDA in industrialized countries has declined in recent decades, but there has been little change in the worldwide prevalence. IDA is currently estimated to affect more than 500 million people. Recent studies have indicated that anemia per se, the most common manifestation of iron deficiency, is less important from a public health standpoint than liabilities associated with tissue iron deficiency. The most important of the latter are an impairment in psychomotor development and cognitive function in infants and preschoolers, a deficit in work performance in adults, and an increase in the frequency of low birth weight, prematurity, and perinatal mortality in pregnancy. There have been several recent advances in combatting nutritional iron deficiency. One of the major problems has been in distinguishing iron deficiency from other causes of anemia seen epidemiologically such as malaria, HIV infection, chronic inflammation, hemoglobinopathies, and protein energy malnutrition. When combined with serum ferritin and hemoglobin determinations, the serum transferrin receptor assay is a valuable addition in epidemiologic surveys because it provides a quantitative measure of functional iron deficiency and it distinguishes true IDA from the anemia of chronic disease. The most difficult challenge is to develop effective methods of supplying iron to large segments of a population. Supplementation with iron tablets is suitable for only brief periods of need such as during pregnancy. The poor compliance with existing supplementation programs is believed to be due mainly to the gastrointestinal side effects of oral iron which can be eliminated by the use of a gastric delivery system. The most effective long-term strategy is to increase the intake of bioavailable iron in the diet. The customary approach has been to fortify a food staple such as wheat, rice, sugar, or salt, and thereby increase the iron intake of the entire population. However, because of concerns about the risk of cancer and heart disease in individuals with high iron stores, there is an increasing reluctance to supply iron to individuals who do not require it. A more effective strategy is to fortify food vehicles that are targeted to segments of the population at greatest risk of iron deficiency such as infants and school children. Because of the strong inhibitory properties of diets in regions of the world where iron deficiency is most prevalent, the use of NaFeEDTA has important advantages for food fortification.

The physiological significance of circulating transferrin receptors.

A soluble truncated form of the tissue transferrin receptor has been recently identified in human serum. The concentration of this serum receptor appears to reflect the total mass of tissue receptor and is consequently elevated with tissue iron deficiency and enhanced red cell production. When coupled with the serum ferritin, the serum transferrin receptor concentration provides a sensitive, quantitative index of iron status over a wide spectrum. While the physiological significance of the circulating receptor is still unknown, this new laboratory measurement will play an important role in the clinical and epidemiological detection of iron deficiency anemia.