Safe switching from a pdFIX (Immunine®) to a rFIX (Bax326).

The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma-derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine® to a recently developed rFIX Bax326 product. Patients (aged <65 years) who completed a pretreatment study which prospectively documented the exposure to Immunine® and monitored FIX inhibitors while receiving prophylactic treatment were transitioned into pivotal (patients aged 12-65 years) and paediatric (patients aged <12 years) clinical studies investigating prophylaxis and treatment of bleeding episodes with Bax326. None of the 44 patients developed inhibitory or specific binding anti-FIX antibodies during the course of the studies. A total of 38 unrelated adverse events (AEs) were occurred in 20/44 (45.5%) subjects during the Immunine® study. Following a switch to Bax326, 51 AEs were reported in 25/44 (56.8%) subjects. The incidence of AEs related to Bax326 treatment (two episodes of dysgeusia in one patient) was low (2.3%); there were no serious adverse reactions. The comparison between Immunine® and Bax326 demonstrated analogous haemostatic characteristics and annualized bleeding rates. Overall, there is direct evidence indicating a safe and clinically effective transition from a pdFIX (Immunine®) to a newly developed rFIX (Bax326(1) ) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.

Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B.

BAX326 is a recombinant factor IX (rFIX; nonacog gamma) manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps (solvent/detergent treatment and 15 nm nanofiltration). The aim of this prospective trial was to investigate the pharmacokinetics, haemostatic efficacy and safety of BAX326 in previously treated patients aged 12-65 years with severe or moderately severe haemophilia B. BAX326 was safe and well tolerated in all 73 treated subjects; adverse events considered related to treatment (2.7% incidence, all non-serious) were transient and mild, and no hypersensitivity reactions, inhibitor formation or thrombotic events were observed. Pharmacokinetic (PK) equivalence (n = 28) between BAX326 and a licensed rFIX was confirmed in terms of the ratio of geometric mean AUC(0-72) h per dose. Twice-weekly prophylaxis [mean duration 6.2 (±0.7) months; 1.8 (±0.1) infusions per week, 49.5 (±4.8) IU kg(-1) per infusion] was effective in preventing bleeding episodes, with a significantly lower (79%, P < 0.001) annualized bleed rate (4.2) compared to an on-demand treatment in a historical control group (20.0); 24 of 56 subjects on prophylaxis (43%) did not bleed throughout the study observation period. Of 249 total acute bleeds, 211 (84.7%) were controlled with one to two infusions of BAX326. Haemostatic efficacy at resolution of bleed was rated excellent or good in 96.0% of all treated bleeding episodes. The results of this study indicate that BAX326 is safe and efficacious in treating bleeds and routine prophylaxis in patients aged 12 years and older with haemophilia B.

Estudio de concordancia en el grado de fibrosis hepáticaestimada mediante los índices bioquímicos APRI y FORNS, y la elastografía de transición (Fibroscan®) en pacientes coinfectados por VIH-VHC / Grade of consistency existing in the grade of hepatic fibrosis calculated with the APRI and FORNS biochemistry indexes and transient elastography (Fibroscan®) in patients coinfected with HIV-HCV

Introducción. Existen métodos diagnósticos no invasivos de fibrosis hepática que se basan en determinaciones bioquímicas (como APRI o Forns) o en elastografía de transición. Este estudio se propone comparar la concordancia entre ellos en pacientes coinfectados por los virus de inmunodeficiencia humana y el de la hepatitis C. Pacientes y métodos. Se realizó elastografía, APRI y Forns a 331 pacientes para valorar la concordancia entre grados avanzados y bajos de fibrosis. Se estimaron los grados de concordancia existentes entre ellos mediante el coeficiente kappa. Resultados. Los pacientes que presentaron grados intermedios de fibrosis estimados por APRI y Forns (51 y 54% respectivamente) no fueron incluidos en el estudio. La concordancia de la elastografía en el grado avanzado frente al índice APRI fue del 65% y del 76% frente al Forns. Cuando la elastografía obtuvo estimaciones de grado bajo de fibrosis la concordancia con APRI fue del 89 y del 82,2% con Forns. La concordancia global fue del 85,5%, y con al menos un índice bioquímico del 72,1%. Conclusión. En los pacientes coinfectados por VIH y VHC la utilización de los índices bioquímicos APRI y Forns para estimar el grado de fibrosis hepática no logra clasificar adecuadamente a al menos la mitad de los pacientes. Sin embargo, en los pacientes clasificados como con fibrosis alta ó baja, la concordancia entre las estimaciones obtenidas mediante la elastografía y las derrivadas de los índices de APRI y de Forns es moderada-alta(AU)

Introduction. There are non-invasive diagnostic methods of liver fibrosis that are based on biochemical measurements (such as APRI or Forns) or on transient elastography. This study aims to compare the consistency between them in patients coinfected by the human immunodeficiency virus and the hepatitis C virus. Patients and methods. An elastography, APRI and Forns were performed for 331 patients to evaluate the consistency between the advanced and low grades of fibrosis. The grades of consistency existing between them were calculated with the kappa coefficient. Results. The grades of fibrosis calculated by APRI and by Forns provided intermediate results (51.1% and 54.7%, respectively), and these patients were not enrolled in the study. The consistency of the elastography in the advanced grade versus the APRI index was 65% and 75% for the Forns index. Results. When the elastography obtained low grade calculations of fibrosis, the consistency with APRI was 80% and 82.2% with Forns Global consistency was 85.5% and with at least one biochemistry index of 72.1%. Conclusion. In the HIV and HCV coinfected patients, the use of the APRI and Forns biochemistry indexes to calculate grade of liver fibrosis does not successfully classify at least half of the patients. However, in the patients classified as having high or low fibrosis, the consistency between the calculations obtained by elastography and those derived from the APRI and Forns indexes is moderate to high(AU)

[Grade of consistency existing in the grade of hepatic fibrosis calculated with the APRI and FORNS biochemistry indexes and transient elastography (Fibroscan in patients coinfected with HIV-HCV]. / Estudio de concordancia en el grado de fibrosis hepáticaestimada mediante los índices bioquímicos APRI y FORNS, y la elastografía de transición (Fibroscan((R))) en pacientes coinfectados por VIH-VHC.

INTRODUCTION: There are non-invasive diagnostic methods of liver fibrosis that are based on biochemical measurements (such as APRI or Forns) or on transient elastography. This study aims to compare the consistency between them in patients coinfected by the human immunodeficiency virus and the hepatitis C virus. PATIENTS AND METHODS: An elastography, APRI and Forns were performed for 331 patients to evaluate the consistency between the advanced and low grades of fibrosis. The grades of consistency existing between them were calculated with the kappa coefficient. RESULTS: The grades of fibrosis calculated by APRI and by Forns provided intermediate results (51.1% and 54.7%, respectively), and these patients were not enrolled in the study. The consistency of the elastography in the advanced grade versus the APRI index was 65% and 75% for the Forns index. When the elastography obtained low grade calculations of fibrosis, the consistency with APRI was 80% and 82.2% with Forns Global consistency was 85.5% and with at least one biochemistry index of 72.1%. CONCLUSION: In the HIV and HCV coinfected patients, the use of the APRI and Forns biochemistry indexes to calculate grade of liver fibrosis does not successfully classify at least half of the patients. However, in the patients classified as having high or low fibrosis, the consistency between the calculations obtained by elastography and those derived from the APRI and Forns indexes is moderate to high.

Distribution of CYP1A1*2A polymorphism in adult patients with acute lymphoblastic leukemia in a Mexican population.

The effects of the CYP1A1*2A genotype on susceptibility to leukemia have received particular attention in recent years because this enzyme plays a central role in the activation of carcinogens. Several polymorphisms at the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. We evaluated the role of the CYP1A1*2A genotype in adults with acute lymphoblastic leukemia (ALL) by genotyping 210 patients and 228 healthy controls from the Mexican population. The frequency of the CC genotype was 8% (18/228) in the control group and 42% (88/210) in ALL patients; the frequency of the CT genotype was 39% (89/228) and 29.5% (62/210), respectively; and that of the TT genotype was 53% (121/228) and 28.5% (60/210), respectively. The odds ratio was 8.4 (95% CI, 4.7-15.5; P < 0.001). These data indicate that the CYP1A1*2A genotype contributes significantly to susceptibility to adult ALL in a sample of the Mexican population.

Autologous peripheral blood stem cell transplantation in multiple myeloma using oral versus I.V. melphalan.

Autologous peripheral blood stem cell transplantation is the therapy of choice for the treatment of multiple myeloma (MM) patients younger than 70 years old. Between August 1993 and November 2004, 54 patients with MM were autografted after conditioning with high-dose oral melphalan 140 mg/m(2) in combination with etoposide and carmustine (28 patients) or with high-dose melphalan 200 mg/m(2) I.V. (26 patients). The oral and IV melphalan groups were comparable. There were no significant differences in disease-free survival (DFS) and overall survival (OS) between the groups; however, in patients transplanted in remission, OS and DFS were better in the I.V. melphalan group. Four good-prognostic factors were identified: interval between diagnosis and transplant <18 months, number of prior chemotherapy lines < or =2, remission status (complete or partial), and the use of I.V. melphalan. In conclusion, I.V. melphalan is the therapy of choice for conditioning patients with MM who are in remission.

Allogeneic peripheral blood stem cell transplantation using reduced intensity versus myeloablative conditioning regimens for the treatment of leukemia.

Reduced intensity conditioning (RIC) have allowed the application of transplantation to older patients and to patients with underlying medical problems. Between October, 1999, and June, 2003, 61 patients with acute leukemia or chronic myeloid leukemia received allogeneic peripheral blood hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings. Thirty-four were conditioned with myeloablative protocols and twenty-seven with RIC regimens. The patients in the myeloablative group were younger (29 vs. 37 years; p < 0.0003), most of them were transplanted in complete remission (74% vs. 59%; p < 0.03), had a shorter interval between diagnosis and HSCT (12 vs. 21 months; p < 0.02) and a greater proportion belonged to standard-risk prognosis (68% vs. 48%; p < 0.1). The median times to neutrophil, platelet and red blood cell engraftment for the myeloablative and RIC groups were 14 versus 11 days (p < 0.009), 17 versus 9 days (p < 0.0001), and 19 versus 12 days (p < 0.007), respectively. Transfusion requirements were lower in the RIC group. Severe mucositis was present in 32% and 7%, respectively (p < 0.01). The proportion of patients having acute graft versus-disease (GVHD), chronic GVHD, and infections was the same, as well as early and late mortality, disease-free survival, and overall survival. Analyzing all the patients together, three factors significantly influenced overall survival: standard risk patients, complete remission at transplant, and the absence of severe acute GVHD. In conclusion, our data suggest that even in high-risk patients, RIC transplantation seems to be as useful as ablative HSCT.

Cytochrome P4501A1 polymorphism is associated with susceptibility to acute lymphoblastic leukemia in adult Mexican patients.

We studied the role of cytochrome P4501A1 (CYP1A1 Val/Val) genotypes in the etiology of acute lymphoblastic leukemia (ALL) in adult Mexican patients. Distributions of CYP1A1 Val/Val genotypes in peripheral blood DNA samples from 136 healthy controls and 136 adult patients with ALL were evaluated. There was an increased frequency of the CYP1A1 Val/Val genotype among ALL patients, showing a significant association between this genotype and the risk of developing ALL.

[Hematopoietic cell transplantation. Experience at the Western National Medical Center]. / Trasplante de células hematopoyéticas. Experiencia del Centro Médico Nacional de Occidente.

UNLABELLED: Bone marrow transplantation has recently reached an special place as a therapeutic tool, which was not available ten years ago. AIM AND SETTING: Descriptive information about the first fifteen cases transplanted at Centro Médico Nacional de Occidente, on a third level attention in Guadalajara, Jalisco, Mexico. MATERIAL AND METHODS: Fifteen patients were transplanted, were carried out autologous transplantation in ten patients and five have received allogeneic transplant; one allogeneic transplant was performed with bone marrow aspiration donor, all next donation were taken off from peripheral blood stem cell through apheresis procedures. From autologous transplant 3 with chronic myelogenous leukemia (CML), 3 with Hodgkin's disease, 2 with solid tumor, 1 with high risk acute myelogenous leukemia and 1 large and small cell lymphoma III-B stage. Received allogeneic transplant 4 patients with CML in chronic phase and one with acute lymphoblastic leukemia Ph+. RESULTS: All patients grafted, the median time to achieve > 0.5 x 10(9)/L granulocytes was 14 days (range: 11-18) from autologous and 16 (range: 14-18) days from allogeneic transplant, whereas the median time to achieve > 20 x 10(9)/L platelets was 18 days (range: 15-35) from autologous and 22 days from allogeneic, three patients died into 100 days postprocedure, two allogeneic, from graft versus host disease III-IV degree, and one autologous from interstitial pneumonia, surviving patients have showed +30 days to +1000 days survival. CONCLUSION: With these data we show that this procedure is inexpensive, is factible and possible if it does coexist with multidisciplinary and on time support, interest, dedication on care, and enough information and desire to do it, including official decisions to perform and sponsor its continuity to the people who participate in it.

All trans-retinoic acid decreases early mortality in patients with promyelocytic leukemia and can be given entirely on an outpatient basis.

The results of the treatment of 43 patients with acute promyelocytic leukemia (PML) are reported: 27 were treated initially with all-trans-retinoic acid (ATRA), whereas 16 were treated with conventional chemotherapy. All patients received myelosuppressive chemotherapy after the initial treatment. Respectively, the complete remission rate was 92% and 37% (P < 0.01), the 5-day mortality rate was 0% and 44% (P < 0.001), and the 28-day mortality rate was 4% and 44% (P < 0.001). The median disease-free survival was 12 and 1 months (P < 0.01), whereas the 12-month disease-free survival was 50% and 13% (P < 0.01) and the 36-month disease-free survival was 41% and 9% (P < 0.01). Thirteen of the patients treated with ATRA were given the treatment fully as outpatients. ATRA given as initial therapy decreased significantly early mortality in promyelocytic leukemia patients; because some promyelocytic leukemia patients given ATRA as initial therapy can be treated as outpatients, the costs of this treatment modality may be diminished.

Acute Promyelocytic Leukemia in Late Pregnancy. Successful Treatment with All-Trans-Retinoic Acid (ATRA) and Chemotherapy.

The use of all-transretinoic acid (ATRA) in APL is a great advance in the treatment of acute leukemia, driving the maturation steps until adult form. The effect of this medication in pregnant women with APL is being a safe and effective treatment only after the first trimester of pregnancy. If used in the first three months, it can cause fetus malformations due to its potent teratogenicity. The two patients we reported here, gave birth to normal children, yet they received ATRA. After a week with ATRA treatment, fibrinogen level improved and "D" dimers decreased, so as observed slowly maturation of leukemic leucocytes. ATRA used at the same time with chemotherapy; such as Cytarabine and Idarrubicine seems highly useful for induction and long term control of disease. One short discussion about the findings and compare with those found in the literature are presented.

Non-cryopreserved peripheral blood stem cells autotransplants for hematological malignancies can be performed entirely on an outpatient basis.

We have prospectively performed peripheral blood stem cell autotransplants in six patients with hematological malignancies on an entirely outpatient basis. Patients were conditioned with high-dose melphalan and received a median of 4.2 x 10(8)/kg non-cryopreserved, non-purged mononuclear cells, containing a median of 3.9 x 10(6)/kg CD34 + cells. The median time to achieve > 500 granulocytes/microl was 21 days, with a range of 16 to 40, whereas the median time to achieve > 20,000 platelets/microl was 38 days, with a range of 21 to 48. Only three patients were transfused with platelets whereas packed red blood cells were transfused in two. All patients survived 60 days after the autograft and three are alive at 450, 690, and 1,950 days after the autotransplant. One patient was given an allogeneic bone marrow transplant when relapsing after the autotransplant. One patient had to be admitted to the hospital on day +10 because of fever. A median of 6,500.00 USD per patient was calculated as the total cost of each outpatient autotransplant. Since outpatient autologous transplants with non-frozen PBSC are feasible, restrictions to PBSC autotransplant programs may be overcome and costs may be diminished.

Two different Philadelphia chromosomes in a cell line from an AML-M0 patient.

A second Philadelphia (Ph) chromosome is one of the most common nonrandom secondary chromosome changes in leukemias with 9;22 translocations. It has been suggested, and observed in two studies of masked t(9;22), that the second Ph chromosome is an exact duplication of the entire derivative chromosome 22. In a cytogenetic study of bone marrow cells from an acute myelogenous leukemia patient, a cell line carrying two different Ph chromosomes evidenced by a chromosome 22 centromeric heteromorphism was found. From this observation arose the question whether the second der(22) was a true Ph chromosome or whether it was a deleted chromosome derived from the normal chromosome 22 that did not contain the bcr-abl rearrangement. A fluorescent in situ hybridization (FISH) study with the t(9;22) probe revealed two bcr-abl positive signals on 60 of 100 interphase nuclei. The second Ph could have resulted from a mitotic crossing over; or, analogously to late-appearing Philadelphia chromosomes, it may be derived from a new chromatid translocation between the chromosomes 9 and 22 not involved in the initial t(9;22).

[Natural history of paroxysmal nocturnal hemoglobinuria in adolescents,adults, and children: the Mexican experience]. / Historia natural de la hemoglobinuria paroxística nocturna en adolescentes, adultos y en la edad pediátrica: la experiencia mexicana.

PURPOSE: To compare the clinical patterns and survival of young and adult (AP) versus paediatric (PP) patients with paroxysmal nocturnal haemoglobinuria (PNH). PATIENTS AND METHODS: The clinical records of 117 patients (82% AP, 18% PP) seen in four cities of the Mexican Republic were analysed, the clinical course and survival of both groups being compared. RESULTS: No sex difference was found in the two patient-groups: 51% and 52% males, 49% and 48% females in AP and PP, respectively. The onset of PNH had similar distribution for the two groups of patients: aplastic form, 45% in AP and 62% in PP; cytopenias, 24% in AP versus 27% in PP; haemolysis, 28% in AP and 9% in PP, and thrombosis, 3% in AP versus 0% in PP. The clinical features with significant difference were: anaemic+haemorrhagic syndrome (39 AP (40%) vs 14 PP (67%), p = 0.02), initial diagnosis of immunologic thrombocytopenic purpura (7 AP (7%) vs 7 PP (33%), p = 0.003), and death rate (17 AP (18%) vs 8 PP (38%), p = 0.04). The actuarial survival curves showed significant differences between both groups (p = 0.045, Cox-Mantel), with estimated 10-year survival of 81% for AP and 55% for PP, and 15-year survivals of 64% for AP and 55% for PP. CONCLUSIONS: Seemingly, PNH in paediatric age has poorer prognosis than in adults, which is associated to higher incidence of fatal haemorrhages due to thrombocytopenia.

Micronucleated erythrocytes in splenectomized patients with and without chemotherapy.

The purpose of the present study was to investigate the range of micronucleated erythrocytes (MNE) in peripheral blood from splenectomized patients with and without genotoxic chemotherapy. The erythrocytes were stained with Wright and Giemsa for microscopic observation. To estimate the number of MNE, two series of 10000 erythrocytes per sample were analyzed and averaged. The results expressed as mean +/- standard deviation were as follows: control patients with genotoxic chemotherapy (n = 6) 2.5 +/- 1.5 (range 1 to 5 MNE); splenectomized patients with genotoxic chemotherapy (n = 7) 65.2 +/- 17.7 (range: 47-108) MNE and splenectomized patients without genotoxic chemotherapy (n = 13) 29.5 +/- 5.8 MNE; (range: 18.5-35.6). The MNE number in the patients treated with genotoxic chemotherapy depended on the type of drugs utilized: cyclophosphamide, mitoxantrone, vincristine, busulphan, cytosine arabinoside and hydroxyurea. Upon these results, it is suggested that splenectomized people could be useful in monitoring exposures, and the baseline MNE level would serve as each person's pre-exposure control when either chronic or acute exposure to environmental mutagens is investigated.

Effect of testosterone on the response of young rat vas deferens to norepinephrine.

1. Following in vitro treatment with 12 microM 6-hydroxy-dopamine, 2 microM B-oestradiol, 0.1 microM propranolol and 10 microM cocaine vasa deferentia isolated from young rats (21-23 days old) showed supersensitivity to norepinephrine (NE) compared to those from adult (3 months old) rats. 2. The pA2 values for prazosin were higher in young (9.6 +/- 0.1) than in adult (8.3 +/- 0.1) rat vas deferens, with the slopes of the Schild plots not different from 1.0 (0.78 +/- 0.26 and 1.14 +/- 0.14, respectively). 3. The treatment of young rats with a single dose of testosterone abolished the supersensitivity to NE and the higher affinity for prazosin. 4. We conclude that there is a reduction of neuronal NE uptake and a decrease in the sensitivity to NE in the vas deferens as the rat matures sexually. 5. Testosterone induces a decrease in the sensitivity to NE, probably via an action on the alpha 1-adrenoceptor population and the sympathetic nerve discharge in this organ.