Microbiological findings in febrile neutropenia.

BACKGROUND: This study was carried out to assess the isolation rate of bacterial and fungal causative agents in Mexican neutropenic adults with hematological neoplasia. METHODS: A prospective observational survey involving 120 consecutive episodes of febrile neutropenia during 1 year was carried out. These episodes were observed in 630 patients discharged with diagnoses of leukemia or lymphoma, or after bone-marrow transplantation. RESULTS: At least one pathogen was isolated in 42 of 120 episodes (35%), and was present in 39 patients with acute myeloid leukemia (AML) (43%), acute lymphoblastic leukemia (ALL) (23%), and in patients who underwent bone-marrow transplantation (20%). Primary bacteremia was the most frequent cause of fever (24 episodes, 57%), followed by intravascular device-related infections (5 episodes, 17%), and soft-tissue infections (5 episodes, 15%). Escherichia coli (33%) was the most frequently isolated agent of primary bacteremia, followed by coagulase-negative Staphylococcus (29%), and Klebsiella oxytoca (16%). Fungal infection was responsible for five events (4%): two episodes of pneumonia (Penicillium marneffei and Aspergillus fumigatus, one event each); two cases of fungemia, one due to Candida tropicalis and one to Rhodotorula gluttinis, and one cryptococcal meningitis event. CONCLUSIONS: The isolation rate, approximately 30%, was in accordance with previous reports; similar percentages of Gram-positive and Gram-negative isolates were found. A remarkably low rate of viridans group streptococci and fungal agents was observed, despite the fact that neutropenia is the main risk factor for infection due to these agents. Studies reporting local microbiological findings are necessary because they support an antibiotic choice for prophylaxis or therapy more accurately than reports from other areas.

Allogeneic bone marrow transplantation for chronic myeloid leukemia: a single center experience.

BACKGROUND: Bone marrow transplantation (BMT) is the therapy of choice for patients with chronic myeloid leukemia (CML) who have a human leukocyte antigen (HLA)-identical donor and are under 50 years of age. METHODS: Here, 45 patients with CML were treated with busulfan (Bu) 16 mg/kg and cyclophosphamide (Cy) 120 mg/kg before allogeneic BMT from an HLA-identical sibling 27 (60%) or a 1-antigen mismatch donor 18 (40%). Eighteen patients (40%) were in the early chronic phase (CP) and 27 (60%) in late CP. We used cyclosporin-A (CsA) in 20 patients and cyclosporin-A-methotrexate (CsA-MTX) in 25 for graft-vs.-host disease (GVHD) prophylaxis. RESULTS: We observed a high incidence of acute and chronic GVHD (69% and 67%, respectively). A multivariate analysis identified differences in the sex of the donor and the recipient (p = 0.03) and grade III-IV acute GVHD (p = 0.0001) as significant adverse influences on disease-free survival. Age, sex, chronic GVHD, disease phase, one antigen-mismatch and use of CsA or CsA-MTX had no statistical significance. The 3-year probabilities of relapse, disease-free survival, and overall survival were 11%, 55%, and 60%, respectively. Transplant-related mortality occurred in 31% of the cases. The high frequency of GVHD is explained by HLA determination by serological typing, differences in sex between the donor and recipient, and a high proportion (40%) of 1 antigen-mismatch donors. CONCLUSIONS: BMT is a procedure feasible for patients with CML in early and late chronic phase and even in those with an HLA non-identical donor. Strategies directed to decrease acute GVHD could improve the outcome of these patients.

Prospective randomized clinical trial comparing high-dose ifosfamide + GM-CSF vs high-dose cyclophosphamide + GM-CSF for blood progenitor cell mobilization.

Between August 1994 and June 1999, 56 patients were prospectively randomized to receive ifosfamide 10 g/m2 + GM-CSF 5 microg/kg/day (IFO+GM-CSF n = 28) and cyclophosphamide 4 g/m2 + GM-CSF 5 microg/kg/day (CY+GM-CSF n = 28). Both groups were comparable for age, gender, diagnosis, disease stage and previous chemotherapy. The IFO+GM-CSF group demonstrated a shorter median interval between therapy and apheresis (10 days (8-14) vs 13 days (8-25) P = 0.002), median number of doses of GM-CSF (9 (7-13) vs 15 (9-31) P = 0.001), median of days with aplasia (0.5 (0-10) vs 6 (0-21) P = 0.001), median days with fever (0 (0-6) vs 3 (0-9) P = 0.006) and median of days using i.v. antibiotics (0 (0-11) vs 7.5 (0-19) P = 0.002). The median MNC yield was similar in both groups. The CD34+ cell yield was better in the CY+GM-CSF group (3.14 (0.9-11.8) vs 5.33 (0. 08-32)) but not at significant levels (P = 0.1). White blood cell hematopoietic recovery was more rapid in the CY+GM-CSF group (16 (10-22) vs 13 (10-24) P = 0.02). Platelet engraftment was similar in both groups. Costs of mobilization and transplantation were almost the same: $28 570 ($18 527-$47 028) and $30 020 ($17 281-$67 591), respectively (P = 0.9). There were no differences in disease-free survival and overall survival between both groups. Mild and transient non-hematological toxicity (hemorrhagic cystitis, decrease in serum creatinine clearance and CNS dysfunction) was seen most frequently in the IFO+GM-CSF group.

Comparative bioavailability evaluation of two cyclosporine oral formulations in healthy Mexican volunteers.

BACKGROUND: The use of conventional cyclosporine (Sandimmune) requires great care, as this drug exhibits a narrow therapeutic index and wide interindividual variability in its pharmacokinetics. Recently, a new microemulsion formulation (Neoral) was developed. With this formulation, cyclosporine is absorbed at the small intestine without the presence of bile. Therefore, the objective of this study was to compare the bioavailability of cyclosporine after the administration of conventional and microemulsion formulations in healthy Mexican volunteers in order to approach the optimal dosage regimen of microemulsion in the Mexican population. METHODS: The trial was conducted using 23 healthy volunteers according to a randomized crossover design. Volunteers received one 7.5-mg/kg dose as each formulation, with a 1-week washout period between treatments. Blood samples of 0.5 mL were obtained according to the following schedule: 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after medication. RESULTS: These indicated that Cmax and AUC0-24 values were higher with the microemulsion than with the conventional formulation. CONCLUSIONS: The microemulsion had a better absorption profile than the conventional formulation, because plasma levels with the conventional formulation demonstrated oscillations rather than reflecting an erratic absorption. Lower doses of the microemulsion are required to obtain Cmax values similar to those obtained with conventional cyclosporine.

Malignant fibrous histiocytoma after allogeneic bone marrow transplantation.

A 24-year-old woman with CML underwent allogeneic BMT in August 1995 from a one-antigen HLA mismatched brother. Conditioning included BuCy2 and CsA and MTX were used to prevent GVHD. In July 1997 she developed right leg pain, lytic bone lesions of distal femur and a solid mass of soft tissue. Histological diagnosis of malignant fibrous histiocytoma was made. Despite treatment with surgery and chemotherapy (doxorubicin and ifosfamide), the patient died 1 year later with local recurrence of the tumor and liver, lung and brain metastases. The CML was in CR.

Intravesical rhGM-CSF for the treatment of late onset hemorrhagic cystitis after bone marrow transplant.

In the present study, we assessed the clinical effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in the treatment of refractory, grade III-IV hemorrhagic cystitis (HC) in six patients who underwent bone marrow transplantation (BMT). These were four males and two females, aged 24-40 years (median age 30.5 years). All received allogeneic BMT from HLA-identical siblings after preparation with busulfan-cyclophosphamide. HC was evident 24. 5 days (range 15-33 days) after BMT. Median duration of HC before treatment was 5 days (range 4-9 days). Treatment consisted of intravesical instillation of rhGM-CSF (400 microg) for 3 consecutive days. A complete response was observed in three patients, the other three showed a partial response. Median time to achieve response was 36 h (range 0.2-72 h). Hematuria was controlled after the first (two patients), second (two patients) or third (two patients) dose of intravesical rhGM-CSF. Patients were discharged from the hospital 10. 5 days (range 3-41 days) after treatment. All patients have been followed for up to 10 months and none have required further treatment. No systemic or bladder side-effects have been observed. Although our results indicate that intravesical instillation of rhGM-CSF is effective in the treatment of HC, a phase II clinical trial, including a larger series of patients, is needed.

Bioavailability of oral cyclosporine in healthy Mexican volunteers: evidence for interethnic variability.

The existence of population variations in cyclosporine pharmacokinetics could be expected, as this drug, similar to nifedipine, is biotransformed by cytochrome P-450 subfamily 3A4, and the existence of interethnic variability in nifedipine disposition has been demonstrated previously. The bioavailability of oral cyclosporine was studied in 23 healthy Mexican volunteers receiving 7.5-mg/kg doses of cyclosporine. Blood samples were drawn over 24 hours, and concentration of cyclosporine in whole blood was determined by a radioimmunoassay using monoclonal antibodies specific for the unchanged drug. The bioavailability of cyclosporine exhibited wide interindividual variability. Maximum concentration (Cmax) ranged from 528 ng/mL to 2,689 ng/mL, area under the concentration-time curve (AUC) ranged from 6,550 ng.hr/mL to 18,562 ng.hr/mL, and time to reach Cmax (tmax) ranged from 1 to 8 hours. Half-life (t1/2) exhibited less important variations, ranging from 4.4 to 9.1 hours. The bioavailability of oral cyclosporine in Mexicans was higher than that reported for white populations under similar conditions. The present results suggest the existence of interethnic variability in the pharmacokinetics of cyclosporine, as is the case with nifedipine.

Cytogenetic findings in 303 Mexican patients with de novo acute myeloblastic leukemia.

In this report we show the chromosomal changes seen in a group of 303 Mexican patients with de novo Acute Myeloblastic Leukemia (AML). Two hundred forty-two patients were diagnosed and treated at two hospitals affiliated with the Instituto Mexicano del Seguro Social (IMSS). These are the Centro Medico Nacional Siglo XXI and Centro Medico La Raza Hospitals; the remaining 61 patients were diagnosed and treated at the Hospital General de Mexico (HGM). Clonal abnormalities were detected in 75.6% of the patients; this result agrees with what has been reported in other large series of AML studies. The incidence of changes per hospital was similar in patients from the IMSS hospitals (72-75%), while an increase was seen in patients from the HGM (85.2%). The chromosomal changes seen in this study in order of frequency were: t(15;17)[18.8%], t(9;22)[9.2%], miscellaneous chromosomal changes (mainly rearrangements of chromosomes 1,2,3,12y17)[8.2%], abnormalities of 16q22 [7.3%], t(8;21)[6.3%], -7/del(7q)[5.6%], t(6;9)[5.3%], and abnormalities of 11q23 [4.6%]. We reported an increase in the incidence of certain types of chromosomal changes seen in cases of AML, in comparison with reports from other countries. These differences could be due to methodological variations, although ethnic, socioeconomic and nutritional differences must not be disregarded. We support this finding when comparing distribution of changes in the population of patients seen in the IMSS hospitals with those from the HGM; the main difference lies in the socioeconomic level.

[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.

[Interferon in the eradication of the Philadelphia chromosome in chronic myeloid leukemia]. / El interferón en la erradicación del cromosoma Filadelfia de la leucemia mieloide crónica.

OBJECTIVE: To evaluate if human recombinant interferon alpha (IFN) combined with chemotherapy is able to suppress the Philadelphia chromosome clone in patients with chronic myeloid leukemia (CML). MATERIAL AND METHODS: The cytogenetic evolution in 53 patients with CML in chronic phase de novo was studied. They received one of three treatment schemes: a) induction of remission with daunorubicin, vincristine, cytosine arabinose and prednisone (DOAP) and maintenance with IFN (n = 12); b) induction with busulfan (BUS) or hydroxyurea (HYDX) and maintenance with IFN (n = 26); c) induction with DOAP and maintenance with BUS (n = 15). RESULTS: The remission was seen two to six months after the start of treatment: 10 had complete remission, six a partial one, 14 a minor remission and 23 none. The 16 with complete or partial response received treatment with IFN. None of the 15 cases maintained with BUS had complete or partial response. The proportion of cases with complete response (3/12) was slightly lower in patients treated with intensive chemotherapy (BUS/HIDX/IFN) than in those receiving conventional treatment (7/26). CONCLUSIONS: Our results showed that: a) IFN in combination with chemotherapy induced partial or complete response in 30% of our cases; and b) intensive chemotherapy combined with IFN was not superior in terms of a cytogenetic response to treatment with monodrugs (BUS/HIDX) and IFN.

A randomized study of mitoxantrone plus cytarabine versus daunomycin plus cytarabine in the treatment of previously untreated adult patients with acute nonlymphocytic leukemia.

Between May 1985 and November 1988, 143 adult patients with previously untreated acute nonlymphocytic leukemia were randomized to receive mitoxantrone and cytarabine (MTT+Ara-C) or daunomycin and cytarabine (DNM+Ara-C) in order to compare the efficacy and acute and chronic toxicities. Therapy consisted of 3 days of MTT 12 mg/m2/i.v. or DNM 45 mg/m2/i.v.; both groups received Ara-C 100 mg/m2 daily by continuous infusion (CI) for 7 days. Those who failed to achieve a complete remission after one induction course received a second induction course for 2 and 5 days at the same doses. All the patients who achieved complete remission received two consolidations of 2 days of MTT or DNM and 5 days of Ara-C in CI at the same dose as for induction. Of the 72 patients on MTT+Ara-C, 38 (53%) achieved complete remission, compared with 29 (43%) of 67 treated with DNM+Ara-C. Three and 5 patients had partial remission, 7 and 18 failed to respond, 24 and 15 died in the first 21 days of induction, of those treated with MTT+Ara-C or DNM+Ara-C, respectively (p = 0.34). Median duration of complete remission and survival was 185 and 103 days or 165 and 160 days, respectively (p = 0.85). More early deaths were observed with MTT+Ara-C due to greater myelosuppression, and a higher incidence of failure with DNM+Ara-C. No significant differences between treatment groups were observed in 21 categories of adverse events. The results demonstrate similar incidence of complete response, length of duration of complete remission, overall survival, and toxicity with MTT+Ara-C and DNM+Ara-C.

Randomized study of danazol vs. placebo in myelodysplastic syndromes.

A double-blind, placebo-controlled randomized study of danazol was performed to determine if the drug has a therapeutic effect in patients with myelodysplastic syndromes (MDS). Fifty evaluable patients with MDS were randomized to receive, a single daily oral dose of either danazol (600 mg/day) or matching placebo. Treatment was continued, when possible, for a period of 6 months. Response was based on clinical course, peripheral blood counts with white blood cells differential, platelet, reticulocyte at specified intervals. Repeat bone marrow aspirates and biopsy were also done. Significant differences was observed between the treatment groups in response to test drug. Increase in hemoglobin, granulocytes, platelets and improvement in survival was noted in danazol group. Side effects were minimal. Our study suggests that danazol exerts a beneficial therapeutic effect in patients with MDS.

[Treatment of acute lymphoblastic leukemia in low risk adults]. / Tratamiento de la leucemia aguda linfoblástica del adulto de riesgo bajo.

Forty five adult patients with low risk acute lymphoblastic leukemia were treated with prednisone, vincristine and adriamycin. 91 per cent (41 patients) obtained complete remission with a mean survival was of 39 months. The side effects of treatment were minimal and less patient had to delay his chemotherapy. This regimen of treatment is a good option for adults patients with low risk acute lymphoblastic leukemia, in consequence of: a) high value of complete remission and its duration. b) the mean survival obtained and the probability of cure. c) the absence of severe side effects and without necessity of support therapy or hospitalization.

Prognostic factors in myelodysplasic syndromes: a multivariante analysis in 138 patients.

A multivariate analysis of clinical, biochemical and hematologic data was performed in 138 patients with myelodysplastic syndromes (MDS) in order to evaluate their prognostic significance. The most important individual variables, isolated in a previous univariate analysis, were placed in a multiple regression modeling procedure to identify major prognostic factors. Multivariate analysis tends to identify prognostic variables containing significant predictive information. Characteristics were examined on both continuous and binary bases. The FAB classification was the first parameter entered in regression equations of both models, followed by platelet count, systemic symptoms, bone marrow blast and infection. Our analysis confirms FAB classification as the best prognostic factor in MDS. It supports the previously predictive value of platelet count, hemoglobin level and bone marrow blast and recognizes the importance of systemic symptoms and infection as prognostic characteristics in MDS.