Outcomes of Substituting Oral Fludarabine for Intravenous Fludarabine in Combination with Cytarabine and Filgrastim for Treatment of Primary Refractory or Relapsed Acute Leukemias.

BACKGROUND: Treatment of relapsed/refractory acute myeloid or lymphoid leukemia consists of salvage chemotherapy followed by allogeneic hematopoietic stem-cell transplantation. Intravenous fludarabine, cytarabine, and filgrastim is an effective regimen in this setting. In view of the lack of availability of intravenous fludarabine in Mexico from 2009-2013, we substituted an equivalent oral fludarabine dose (40 mg) for the intravenous formulation. OBJECTIVE: This is a retrospective comparison of the toxicity and effectiveness of oral fludarabine, cytarabine, and filgrastim versus intravenous fludarabine, cytarabine and filgrastim. RESULTS: A total of 44 patients with relapsed/refractory acute myeloid leukemia or acute lymphoid leukemia treated in an academic medical center from 2005-2013 with oral fludarabine, cytarabine and filgrastim (21 patients) or intravenous fludarabine, cytarabine and filgrastim (23 patients) were included in the analysis. There was a trend towards a higher complete remission rate and a longer overall survival following intravenous fludarabine, cytarabine, and filgrastim as compared with oral fludarabine, cytarabine, and filgrastim: complete remission rates 39.1 vs. 23.8% (p = 0.342) and overall survival 6.14 vs. 10.78 months (p = 0.363), respectively. A higher incidence of neutropenic fever (100 vs. 76.2%; p = 0.019) and septic shock (34.8 vs. 0%; p = 0.003) and a longer hospitalization (26.8 vs. 19.4 days; p = 0.046) were observed with intravenous fludarabine, cytarabine, and filgrastim. In multivariate analysis, factors associated with a shorter survival were septic shock (HR: 3.93; 95% CI: 1.67-9.25; p = 0.002) and a higher number of previous treatments (HR: 2.5; 95% CI: 1.26-4.99; p = 0.009). Complete remission was associated with better survival (HR: 0.18; 95% CI: 0.08-0.44; p < 0.001). CONCLUSIONS: Further studies are needed to determine the optimal dose and timing of oral fludarabine when given as part of the fludarabine, cytarabine, and filgrastim regimen for relapsed/refractory acute leukemia. Our data suggest that the dose of oral fludarabine used, 40 mg/m² per day for five days, may be a lower bioequivalent dose to the intravenous dose in fludarabine, cytarabine, and filgrastim.

Diagnosing and treating mixed phenotype acute leukemia: a multicenter 10-year experience in México.

Mixed phenotype acute leukemia (MPAL) in adults represents nearly 2 to 5 % of all acute leukemia cases. There are two large studies throughout the world and only case reports and small series have been reported in Latin America. This study retrospectively analyses the clinical characteristics and survival of 27 patients with MPAL evaluated in three medical institutions of Mexico. All cases meet World Health Organization 2008 criteria; 70.3 % of patients had B lymphoid/myeloid lineage MPAL. Induction chemotherapy protocols included 7 + 3 hyper-CVAD, high-density schedules, and pediatric-like regimens such as New York II and total XI. Complete remission was achieved in 23/27 patients (85.2 %). Only one patient died due to chemotherapy-induced aplasia during remission induction (5.2 %). In 68 % of cases, we were able to administer maintenance therapy as a regimen in lymphoblastic leukemia. At the time of analysis, 70.4 % of the patients in the entire cohort had died mainly as result of disease progression (73.6 %). Disease-free survival was 13 months (95 % CI, 9.6-16.3 months) and overall survival was 14.8 months (95 % CI 13.4-16.27). Survival rates are low and standardized therapy for the management of this type of leukemia is still lacking. This is the largest series reported in Mexico and to the best of our knowledge in Latin America.

Small MAF genes variants and chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is one of the most frequent hematological neoplasia worldwide. The abnormal accumulation of reactive oxygen species may be an important factor in CML development. The transcription factor NRF2 can regulate the transcription of a battery of antioxidant and detoxificant genes after heterodimerizing with small-Maf proteins. Although the participation of NRF2 in the development of chronic degenerative diseases has been thoroughly studied, the role of small-Maf genes has not been documented. We have identified polymorphisms in the three MAF genes (F, G and K) and assessed their association with CML. Over 266 subjects with CML and 399 unrelated healthy donors have been studied. After sequencing each MAF gene by Sanger technology, we found 17 variants in MAFF gene, eight in MAFG and seven in MAFK. In the case-control study, the homozygote genotype CC for the rs9610915 SNP of MAFF was significantly associated with CML. The frequency of the ACC haplotype from MAFK was significantly lower than controls. After stratification by gender, the ACC and GTG haplotypes were associated only with males with CML. These novel data suggest an association between MAFF and MAFG and the development of CML.

Incidence of thrombosis in adults with acute leukemia: a single center experience in Mexico.

BACKGROUND: Acute leukemias are hematopoietic malignancies that may be accompanied by hemostatic abnormalities. In general, information on the frequency of thrombotic events, their clinical characteristics and survival in adult patients with acute leukemia is still scarce and controversial. OBJECTIVES: To describe the frequency of thrombotic events, their clinical characteristics and survival of adult patients with acute leukemia at the Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City. MATERIAL AND METHODS: A patient cohort, diagnosed and treated between October 2003 and December 2009, was retrospectively analyzed in terms of thrombotic events, frequencies and survival curves. RESULTS: We analyzed 181 patients with a median age of 33 years, 80 were female (44.2%). Fifteen cases with thrombosis (8.3%) were documented and in 53.3% of cases, they were related to the use of a central venous catheter. The median time to development of thrombosis was 92 days; 33.3% of events occurred during the first 30 days after diagnosis. The incidence of thrombosis in patients receiving L-asparaginase was 15%. Of the 15 patients with thrombosis, 27% were alive and without evidence of disease at last follow-up, and 73% had died; disease progression was the most common cause of death (81.8%). None of the thrombotic events had an impact on mortality. Median overall survival (OS) was 349 days. CONCLUSIONS: The incidence of thrombosis in this adult acute leukemia population is comparable to that reported in the literature. Only a third of cases occurred during the first month after diagnosis; however, 93.3% of patients developed a thrombotic event during the first year after the diagnosis of acute leukemia. All cases were symptomatic and central venous catheter-related thrombosis was the most frequent presentation in this group. Survival curves comparing patients with and without thrombosis were similar. Prospective studies are necessary in order to assess the risk factors fostering thrombosis in adult patients with acute leukemia.

Circulating HMGB1 is increased in myelodysplastic syndrome but not in other bone marrow failure syndromes: proof-of-concept cross-sectional study.

Background: Myelodysplastic syndrome (MDS) is associated with persistent immune activation. High mobility group box-1 (HMGB1) is a ubiquitous, functionally diverse, non-histone intranuclear protein. During acute and chronic inflammatory states, HMGB1 is actively released by inflammatory cells, further amplifying the inflammatory response. A role in MDS and other hypoplastic bone marrow (BM) disorders is incompletely understood. Objectives: The objective of the study is to evaluate whether circulating HMGB1 is elevated in patients with MDS and other BM failure syndromes [namely, aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH)]. Design: This is a observational, cross-sectional, single-center, exploratory study. Methods: We evaluated circulating concentrations of HMGB1, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in patients with MDS and age-matched hematologically healthy controls as well as patients with AA and PNH. Results: We included 66 patients with MDS and 65 age-matched controls as well as 44 patients with other BM failures (AA = 27, PNH = 17). Circulating levels of HMGB1 were higher in patients with MDS [median, 4.9 ng/ml; interquartile range (IQR): 2.3-8.1] than in AA (median, 2.6 ng/ml; IQR: 1.7-3.7), PNH (median, 1.7 ng/ml; IQR: 0.9-2.5), and age-matched healthy individuals (median, 1.9 ng/ml; IQR: 0.9-2.5) (p = 0.0001). We observed higher concentrations of HMGB1 in the very low/low-risk MDS patients than in the intermediate/high/very high-risk ones (p = 0.046). Finally, in comparison with patients with AA, those with hypocellular MDS (h-MDS) had significantly higher levels of circulating HMGB1 (n = 14; median concentration, 5.6 ng/ml, IQR: 2.8-7.3; p = 0.006). We determined a circulating HMGB1 value of 4.095 ng/ml as a diagnostic cutoff differentiator between h-MDS and AA. Conclusion: These observations indicate that circulating HMGB1 is increased in patients with MDS. HMGB1 (but not IL-1ß or TNF-α) differentiated between MDS and other BM failures, suggesting that HMGB1 may be mechanistically involved in MDS and a druggable target to decrease inflammation in MDS.

[Dermatoses in patients with acute myeloid and lymphoid leukemia. Cohort follow-up in a tertiary care hospital]. / Dermatosis en pacientes con leucemia aguda mieloide y linfoide. Seguimiento de una cohorte en un hospital de tercer nivel.

INTRODUCTION: Cutaneous manifestations in patients with acute leukemia (AL) cover a broad spectrum, including those due to leukemia per se, to chemotherapy and other drugs and those inherent to hospital care. MATERIAL AND METHODS: This is a cohort study in a tertiary hospital setting where the development of dermatoses was followed for 2 years in 22 patients with the diagnosis of AL. RESULTS: During the study, all patients developed some type of dermatosis, mostly due to chemotherapy.

[Acute myeloid leukemia in adults: experience at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán from 2003 to 2008]. / Experiencia del INCMNSZ en pacientes adultos con leucemia mieloide aguda. Cohorte 2003-2008.

INTRODUCTION: Acute myeloid leukemia (AML) comprises a group of diseases with different biologic characteristics; despite knowledge improvements, these are not reflected in long term survival. OBJECTIVE: To describe characteristics of adults with AML in a hospital of Mexico City, their treatment response, complications and to evaluate survival related factors. MATERIAL AND METHODS: Cohort study. Between January 2003 and July 2008, patients with AML diagnosis were included (except promyelocitic). Treatment protocols used: 3 + 7, high doses of cytarabine and autologous bone marrow transplant as consolidation therapy. RESULTS: 53 patients were included. Median age: 44 years (15-79). At diagnosis: tumor lysis syndrome in 4/ 53 (7.5%), 3/51 (5.9%) with altered liver function test and hyperleukocytosis in 8/53 (15.1%). 46 patients had available cytogenetic and this was successful in 28/46 (60.8%), 12/28 (42.8%) had adverse cytogenetic; 16/28 (57.1%) intermediate risk and none was favorable. There were 2 losses during follow up, 7 patients did not receive chemotherapy with curative intent and 1 died at diagnosis. 43 patients received 3 + 7, 13.9% died during aplasia, complete remission was achieved in 27/43 (62.7%) and 10/43 (23.2%) were refractory to treatment. A second induction attempt was required in 39.5% (17/43). Median disease free survival (DFS) was 491 days (366-615), with a median follow up of 993 days (105-1744). The median overall survival (OS) was 531 days (312-749). Aplasia related mortality decreased (p = 0.09) between the actual cohort (13.9%) and the historical cohort (37%). CONCLUSIONS: Long term survival in AML patients remains poor despite improvements in diagnosis, classification, and treatment. In our institution, it is required to improve induction protocols and cytogenetic analysis in order to adequately choose the group of patients that could be benefit from stem cell transplant.

[Acute lymphoblastic leukemia: experience in adult patients treated with hyperCVAD and 0195 Protocol, at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Cohort 2003-2007]. / Experiencia del INCMNSZ en pacientes adultos con leucemia linfoide aguda. Cohorte 2003-2007 con esquemas de tratamiento Hiper-CVAD y Protocolo 0195.

INTRODUCTION: Despite therapeutic advances, acute lymphoblastic leukemia (ALL) in adults remains a disease with poor long term outcome and survival rates. Developing countries lack of information about this disease. On the other hand, infections are frequent complications related to mortality and some research studies do not show accurate rates of septic shock or other related factors. OBJECTIVE: To describe characteristics of adults with acute lymphoblastic leukemia, response to treatment, complications and to evaluate further survival related factors and to compare our experience with other reports of literature. MATERIAL AND METHODS: Between September 2003 to November 2007, the entire cohort of patients with diagnosis of ALL was included. The treatment regimens used were MDACC HyperCVAD (HCVAD) and 0195 (institutional regimen). RESULTS: Of 40 patients included with the diagnosis of ALL, 92% was B phenotype and 8%, T phenotype, with a median age of 27 years. The median follow up was 28.5 months. Initially, 14% showed central nervous system infiltration; of 51% with available cytogenetics, 16.7% was Philadelphia chromosome positive. There were 36 patients who received treatment: 13 received HCVAD and 23 the 0195 protocol; 78% achieved global complete remission, 85% for the patients with HCVAD and 74% with 0195. The induction death rate was 2.8%. The median disease-free survival was 11.6 months (IC 95%, 2.5-20.8 months) and overall survival was 15 months (IC 95%, 10.6-19.4 months). In 95% of patients, no prophylactic antibiotic therapy was used and treatment related death was 8.4% (2.8% during induction and 5.6% during the rest of treatment). Factors associated with worse survival rate were hyperleukocytosis, T phenotype and lack of early complete remission. During induction, grade 3 to 4 non hematopoietic toxicity was 17%. Incidence of neutropenic febrile episodes was 61% and septic shock was 11%. CONCLUSIONS: With HCVAD, we observed worse complete remission, disease-free survival and overall survival rates compared with the original MDACC reports. Chemotherapy related death rates are similar to other early reports, despite prophylactic antibiotic was not used during myelosuppression.

Survival and treatment response in adults with acute promyelocytic leukemia treated with a modified International Consortium on Acute Promyelocytic Leukemia protocol.

Acute promyelocytic leukemia has good prognosis in view of the high complete remission and survival rates achieved with therapies containing all-trans retinoic acid or arsenic trioxide. However, there is a significant risk of death during induction due to hemorrhage secondary to disseminated intravascular coagulation. This has contributed to a gap in the prognosis of patients between developed and developing countries. The International Consortium on Acute Promyelocytic Leukemia was created in 2005 and proposed a treatment protocol based on daunorubicin and all-trans retinoic acid stratified by risk geared toward developing countries. Herein are presented the results from the first patient cohort treated in a single developing country hospital employing a slightly modified version of the International Consortium protocol in a real life setting. Twenty patients with acute promyelocytic leukemia were enrolled: 27.8% had low-risk, 55.6% intermediate risk and 16.7% high-risk. The complete remission rate was 94.4% after a median of 42 days. Both relapse rates and death rates were one patient (5.5%) each. No deaths were observed during consolidation. After a median follow-up of 29 months, the overall survival rate was 89.1%. Efficacy and safety of the International Consortium on Acute Promyelocytic Leukemia protocol has been reproduced in acute promyelocytic leukemia patients from a developing country.

Survival and treatment response in adults with acute promyelocytic leukemia treated with a modified International Consortium on Acute Promyelocytic Leukemia protocol

ABSTRACT Acute promyelocytic leukemia has good prognosis in view of the high complete remission and survival rates achieved with therapies containing all-trans retinoic acid or arsenic trioxide. However, there is a significant risk of death during induction due to hemorrhage secondary to disseminated intravascular coagulation. This has contributed to a gap in the prognosis of patients between developed and developing countries. The International Consortium on Acute Promyelocytic Leukemia was created in 2005 and proposed a treatment protocol based on daunorubicin and all-trans retinoic acid stratified by risk geared toward developing countries. Herein are presented the results from the first patient cohort treated in a single developing country hospital employing a slightly modified version of the International Consortium protocol in a real life setting. Twenty patients with acute promyelocytic leukemia were enrolled: 27.8% had low-risk, 55.6% intermediate risk and 16.7% high-risk. The complete remission rate was 94.4% after a median of 42 days. Both relapse rates and death rates were one patient (5.5%) each. No deaths were observed during consolidation. After a median follow-up of 29 months, the overall survival rate was 89.1%. Efficacy and safety of the International Consortium on Acute Promyelocytic Leukemia protocol has been reproduced in acute promyelocytic leukemia patients from a developing country.

Desnutrición en pacientes adultos con leucemia aguda / Malnutrition in adults patients with acute leukemia

El estado nutricio de los pacientes se deteriora principalmente durante el tratamiento intensivo de la enfermedad. Estudios previos sugieren que la desnutrición puede tener efectos negativos en el pronóstico de los enfermos. El objetivo de este estudio fue determinar la frecuencia de desnutrición durante el tratamiento de inducción a la remisión y su impacto en algunas variables clínicas. Se estudiaron durante 18 meses a los pacientes con diagnóstico de leucemia aguda de novo. Se evaluó el estado nutricio a través de la valoración global subjetiva, mediciones antropométricas, albúmina sérica e índice de riesgo nutricio en el diagnóstico y un mes después. Se dio seguimiento a los pacientes durante 2 meses para registrar la estancia intrahospitalaria, remisión completa, mortalidad temprana y toxicidad. Fueron incluidos 32 pacientes. La prevalencia de desnutrición de acuerdo a la valoración global subjetiva fue de 0.61 al diagnóstico e incremento a 0.93 un mes después (p<0.05). Al comparar los indicadores antropométricos se encontraron diferencias significativas en el peso, índice de masa corporal, panículos adiposos, área muscular braquial y porcentaje de masa grasa (p<0.005). 22 pacientes (0.71) alcanzaron la remisión completa y la tasa de mortalidad temprana fue de 0.10. No se demostró asociación entre el estado nutricion y las variables estudiadas. La frecuencia de desnutrición es alta en pacientes con leucemia aguda al diagnóstico y se incrementa significativamente después de la quimioterapia para inducir la remisión. Las tasas de desnutrición registradas en el presente estudio justifican una intervención terapéutica desde el punto de vista nutricional (AU)

The nutritional status of patients is frequently impaired during intensive induction chemotherapy. Previous studies have suggested that malnutrition may have an adverse effect on prognosis. The aim of the study was to determine the prevalence of malnutrition during induction chemotherapy treatment and its impact on the outcome. Acute leukemia patients were prospectively studied during first remission induction chemotherapy. The study was performed over a period of 18 consecutive months. The subjective global assessment, nutrition risk index, anthropometric and laboratory data were determined at diagnosis and on day 30 of the treatment in order to evaluate nutritional status. Patients were prospectively followed until 60 days after diagnosis. An analysis was made including demographic data, nutritional assessment, albumin, complications, rate of complete remission, rate of early mortality and length of hospital stay. 32 patients were included. At diagnosis, the prevalence of malnutrition was 61% according to the subjective global assessment and increased to 93% on day 30(p<0.05). Patients have deterioration of the nutritional status the weight, body mass index, skin folds, arm muscle area and percent body fat were stadistically significant(p<0.005). We obtained initial complete remission in 22 patients (71%), the mortality rate due to post-chemotherapy aplasia (early mortality) in the prospective cohort was 10%. Nutritional status was not associated with complete remission or early mortality rate. The high incidence of malnutrition at the time of diagnosis and during chemotherapy indicate the importance of nutritional status evaluation, during this period intensive supportive care, including nutritional therapy is required (AU)