Incorporación de las altas dosis de antraciclina en el tratamiento de la leucemia mieloide aguda del adulto / Incorporation of the high dose of anthracycline in the treatment of adult acute myeloid leukemia

Introducción: La leucemia mieloide aguda representa el 80 por ciento de las leucemias agudas entre los adultos; el tratamiento de inducción a la remisión, para los pacientes menores de 60 años, está basado en la combinación de antraciclinas y arabinósido de citosina. Objetivo: incorporar las altas dosis de antraciclinas al tratamiento de inducción de la leucemia mieloide aguda no promielocítica en pacientes adultos menores de 60 años. Método: Se realizó un estudio cuasiexperimental en 41 pacientes con este diagnóstico, atendidos en el servicio de Adultos del Instituto de Hematología e Inmunología, desde septiembre del 2013 hasta diciembre del 2016. A todos los pacientes se les realizó estudios morfológicos, inmunológicos, citogenéticos y moleculares al inicio de la enfermedad y ecocardiografía para determinar la fracción de eyección y de acortamiento del ventrículo izquierdo al año de finalizado el tratamiento, para determinar la cardiotoxicidad por el uso de las altas dosis de antraciclinas. Resultados: La distribución por edad fue mayor en el grupo de 46 a 52 años representado por el 26,8 por ciento de los casos y predominó el sexo masculino 60,9 por ciento. En el 85 por ciento de los casos la enfermedad apareció de novo. Según los criterios morfológicos de la clasificación Franco Británico Americana el 31,7 por ciento correspondió a la variante M1, en estrecha relación con las determinaciones por citometría de flujo, para esta variedad. Los genes más comúnmente involucrados fueron el NPM1 y el AML/ETO, para el 24 por ciento y 22 por ciento, respectivamente. El 56,1 por ciento de los pacientes alcanzó la remisión hematológica con un solo ciclo de tratamiento y el 14,6 por ciento, necesitó realizar un segundo esquema de inducción. No se reportaron eventos de cardiotoxocidad por antraciclina durante el tratamiento, ni al año de culminado este. Conclusiones: Con el uso de las altas dosis de antraciclina se lograron remisiones hematológicas, sin toxicidad cardiovascular demostrada(AU)

Introduction: Acute myeloid leukemia represents 80 percent of acute leukemias among adults; the induction treatment to obtain remission in patients under 60 years old is based on the combination of anthracyclines and cytosine arabinoside. Objective: to incorporate the high doses of anthracyclines to the treatment of induction of non-promyelocytic acute myeloid leukemia in adult patients under 60 years of age. Method: We conducted a quasi-experimental study in 41 patients with this diagnosis, at the adult clinic service of the Institute of Hematology and Immunology, from september 2013 to december 2016. Morphological, immunological, cytogenetic and molecular studies were carried out at the beginning of the disease and also echocardiography was performed to determine the ejection fraction and shortening of the left ventricle a year after the end of treatment, to determine cardiotoxicity due to the use of high doses of anthracyclines. Results: The distribution by age was higher in the group of 46 to 52 years represented by 26.8 percent of the cases and the male sex predominated 60.9 percent. In 85 percent of the cases the disease appeared de novo. According to the morphological criteria of the French American British classification, 31.7 percent corresponded to the M1 variant, in close relation with the determinations by flow cytometry, for this variety. The genes most commonly involved were NPM1 and AML / ETO, for 24 percent and 22 percent respectively. 56.1 percent of patients achieved hematological remission with a single treatment cycle and 14.6 percent of patients needed a second induction scheme. No anthracycline cardiotoxicity events were reported during the treatment, nor a year after the treatment, in the patients evaluated. Conclusions: With the use of high doses of anthracycline, have been hematological remissions, without demonstrated cardiovascular toxicity(AU)

Progress of the study on cytosine arabinoside in the treatment of acute leukemia in children / 中华实用儿科临床杂志

Cytosine arabinoside (Ara-C) is one of the key chemotherapy drugs comprising all stages combined protocols during long-term chemotherapy for children with acute leukemias,which demonstrated its efficacy and safety.Along with the progress of basic and clinical researches,in Ara-C clinical dose and treatment,prevention of adverse reactions,relationship between the drug metabolism and long-term clinical results,and new nucleoside drugs have achieved remarkable results.This paper on the above fields of research,progress and trends,briefly summarized as follows.

Determination of active metabolites of cytosine arabinoside in HL-60 cells / 临床儿科杂志

10.3969/j.issn.1000-3606.2013.06.007

Algunas variables clínicas y de laboratorio en pacientes adultos con leucemia mieloide crónica tratados con interferón alfa recombinante + citosina arabinósido / Some clinical and laboratory variables in adult patients with chronic myeloid leukemia treated with recombinant alpha interferon + cytosine arabinoside

La leucemia mieloide crónica del adulto es la hemopatía maligna más frecuente dentro de los síndromes mieloproliferativos. En un estudio retrospectivo longitudinal realizado entre enero de 1985 y diciembre de 2009, se evaluaron 46 pacientes en fase crónica atendidos en el Instituto de Hematología e Inmunología. Todos recibieron tratamiento inicial citorreductor y posteriormente interferón ? recombinante (INF?r) + citosina arabinósido. El 41,0 por ciento de los enfermos presentó un índice pronóstico de Sokal de alto riesgo. Las manifestaciones clínicas más frecuentes al diagnóstico fueron astenia (37 por ciento), esplenomegalia (31 por ciento) y pérdida de peso (28,3 por ciento). La respuesta hematológica parcial y completa fue del 26,8 por ciento y 65,9 por ciento a los 6 meses; la respuesta citogenética y molecular completa de 9,1 por ciento y 16,3 por ciento, respectivamente. Las reacciones adversas más frecuentes fueron fiebre (34,9 por ciento), trombocitopenia (26,2 por ciento) y síndrome general (23,8 por ciento). El 47,8 por ciento de los casos mostraron resistencia o intolerancia al INF?r y el 90,9 por ciento falleció por progresión de la enfermedad. La sobrevida global a los 5 años fue del 63,8 por ciento y la sobrevida libre de eventos a los 3 años fue del 68,9 por ciento. Según el índice pronóstico de Sokal, la sobrevida global mostró diferencia significativa entre los 3 grupos (p= 0,005), no así para la sobrevida libre de eventos (p= 0,165). El tratamiento con INF?r mostró resultados superiores a los de algunos países desarrollados y constituye una opción terapéutica eficaz en Cuba

Chronic myeloid leukemia is the most frequent myeloproliferative syndrome in adults. In a longitudinal retrospective study performed between January 1985 - December 2009, 46 patients in chronic phase diagnosed at the Institute of Hematology and Immunology were evaluated. They received cytoreductor agent as first treatment followed by interferon ?2 + cytosar. Forty one percent showed high risk Sokal prognosis score. The most frequent clinical manifestations at diagnosis were asthenia (37 percent), splenomegaly (31 percent) and weigh lost (28.3 percent). The partial and complete hematological response was of 26,8 percent and 65.9 percent after 6 months and the complete cytogenetic and molecular response was of 9.1 percent and 16.3 percent. The most frequent adverse reactions were: fever (34.9 percent), thrombocytopenia (26.3 percent) and general syndrome (23.8 percent). Resistance or intolerance to INF?2 was found in 47.8 percent of the patients and 90.0 percent died due to progression of the disease. The 5 year overall survival was of 63.8 percent and the 3 years free event survival was of 68.9 percent. According to Sokal prognosis score the overall survival showed significant difference between groups (p= 0.005) but there was no significant difference for free event survival (p= 0.165). The INF?2 treatment in our patients showed better results than those obtained in different developed countries and is an effective therapeutic option in Cuba

Long-term Complete Remission in a 71-year-old Patient with AML-M7 after Low-dose Cytarabine Induction and Intermediate-dose Cytarabine Consolidation Treatment

The authors describe the case of a 71-year-old patient with acute megakaryocytic leukemia (AML-M7) who was successfully treated with low-dose cytarabine induction followed by intermediate-dose cytarabine consolidation therapy. The patient presented with infection and rapidly increasing blood blasts. The diagnosis was consistent with AML-M7 with a normal karyotype. Peripheral blood blasts decreased rapidly upon low-dose cytarabine administration, and the patient achieved complete remission after two courses of low-dose cytarabine (10 mg/m2 bid for 12 days). Consolidation therapy with intermediate-dose cytarabine (1.0 g/m2 bid on day 1, 3 and 5) was then instituted without serious complication. He remained in complete remission at the time of writing 47 month after diagnosis. In spite of multiple poor prognostic factors, this patient showed excellent treatment outcome through low-dose cytarabine induction and intermediate- dose cytarabine consolidation. It needs to be validated whether acute leukemia with a megakaryocytic morphology is exceptionally sensitive to cytarabine.

Irreversible Paraplegia Following One Time Prophylactic Intrathecal Chemotherapy in an Adult Patient with Acute Lymphoblastic Leukemia

We present an adult female patient who developed irreversible paraplegia and areflexia four days post intrathecal chemotherapy with methotrexate, cytosine arabinoside and hydrocortisone. On magnetic resonance imaging (MRI) of the lumbar spine, diffuse gadolinium enhancement of the anterior spinal nerve roots (ventral roots) was detected. Methylprednisolone was intravenously administered at a daily dose of 30mg/kg for three days. Despite this treatment, flaccid weakness in the lower extremities and urinary retention persisted. Following consolidation chemotherapy, no improvement in neurologic status was noted. Six months later, a follow-up MRI revealed severe atrophy of the thoracic spinal cord.

A Case of High Dose Cytosine Arabinoside Induced Stevens-Johnson Syndrome in a Patient with Malignant Lymphoma

Many chemotherapeutic agents induce variable cutaneous adverse reactions. Among the side effects, Stevens-Johnson syndrome is rare, but a fatal complication. There are two prior reports of cytosine arabinoside (ARA-C) induced toxic epidermal necrolysis, which is considered in the continuum of Stevens- Johnson syndrome. The prior cases were female patients under 16 years old with acute lymphocytic leukemia. We treated a 77-year-old man with recurrent mantle cell lymphoma who developed Stevens- Johnson syndrome after high dose ARA-C therapy. This is the first case of ARA-C induced Stevens- Johnson syndrome in Korea.

Selective Removal of Fibroblast with Using Proline Analogue and Cytosine Arabinoside in Myoblast Culture

OBJECTIVE: The phenomenon of fibroblast overgrowth is one of the major problems encountered during long-term culture such as myoblast culture. The first goal of the study is to determine the effects of proline analogue and cytosine arabinoside to reduce fibroblasts in myoblast culture. The second goal is to investigate whether the chemicals influence the growth and differentiation of myoblast. METHOD: Muscle tissues were obtained from legs of healthy men, and then fibroblasts and myoblasts were isolated and cultured. Those mixed cells were divided into three groups; control group, proline analogue (cis-hydroxyproline) treated group and cytosine arabinoside (araC) treated group. We evaluated the effectiveness of cis-hydroxyproline and araC on selective removal of fibroblasts in culture. We have also determined if cis-hydroxyproline and araC could alter differentiation of myoblast in each group. RESULTS: The treatment with araC was effective to eliminate fibroblasts comparing to the control group (p0.05). Myoblasts of all three groups were differentiated into myotube. CONCLUSION: Using araC, we could reduce a number of fibroblasts in myoblast culture where contamination and subsequent overgrowth with fibroblasts remained a problem.

Inhibition of activation of NF-?B enhanced apoptosis induced by cytosine arabinoside in leukemic cells / 中国癌症杂志

Purpose:To explore effects of dexamethasone and vincristine on apoptosis and activation of NF ?B of HL60 n cells induced by cytosine arabinoside (Ara C). Methods:Apoptosis induced by Ara C in HL60 n cells was analysed by Tunel and DNA electrophoresis. The DNA binding activation of NF ?B of HL60 n cells was determined by electrophoretic mobility shift assay(EMSA).Results:The apoptosis and activation of NF ?B of HL60 n cells could be induced by Ara C. Dexamethasone 1?mol/L and vincristine 0.1?mol/L increased significantly the apoptosis induced by Ara C (increased by 39.1% and 59.2%, P

Effects of Low-Dose Cytosine Arabinoside Plus Granulocyte-Macrophage Colony-Stimulating Factor and the Changes of Peripheral Blood Lymphocytes and Bone Marrow Clonogenic Assay in Myelodysplastic Syndrome / 대한혈액학회지

BACKGROUND: In vitro data indicate that granulocyte-macrophage colony-stimulating factor (GM-CSF) induces leukemic clonogenic cells to proliferate, thereby enhancing preferentially the cytotoxicity of the cell cycle-specific drug cytosine arabinoside (Ara-C) when compared with normal hematopoietic progenitor cells. We evaluated the therapeutic outcomes of low-dose Ara-C (LD Ara-C) plus GM-CSF for the patients with high-risk myelodysplastic syndrome (MDS). At the same time we evaluated the lymphocyte subset of peripheral blood and the bone marrow clonogenic assay of those patients. METHODS: Thirteen patients of MDS were treated with combination therapy composed of LD Ara-C and GM-CSF. The proportion of peripheral blood CD4, CD8 T-lymphocytes and natural killer (NK) cells were enumerated by flow cytometric direct immunofluorescence method. Clonogenic assays were done by methylcellulose culture system. Those laboratory parameters were analyzed with regard to the therapeutic responses. RESULTS: The subtypes according to the FAB classification included 8 patients of refractory anemia with excess of blasts (RAEB), 4 RAEB-transformation (RAEBT) and 1 chronic myelomonocytic leukemia (CMML). Five cases (38.5%) achieved complete remission after this type of treatment, two (15.4%) had a partial remisison and six (46.2%) had no response. The treatment was generally tolerable. There was no early toxic death. The median disease-free survival of the complete responders was 6 months. Three cases had a progression to acute leukemia. The proportion of pre-treatment CD4-positive T-lymphocytes in non-responders was significantly lower than that of complete responders (P<0.05). Eight cases (61.5%) showed "leukemic" growth pattern in clonogenic assay. The proportion of the "nonleukemic" growth in the complete responders was higher than that of nonresponders. CONCLUSION: The combined treatment of LD Ara-C and GM-CSF was tolerable for the patients with high-risk MDS. The immunologic parameters and in vitro growth pattern were thought to be associated with therapeutic responses. Further studies for the large number of patients will be required.

Clinical Features of Pancreatitis in Children with Leukemia and Lymphoma / 대한소아혈액종양학회지

PURPOSE: The aim of this study was to review the clinical characteristics and treatment outcome of pancreatitis developed in 19 children with leukemia and lymphoma in Asan Medical Center. METHODS: Hospital and outpatient records of 19 children either with leukemia or lymphoma who developed acute pancreatitis were reviewed. Clinical characteristics of these patients along with serologic data were analysed. RESULTS: 1. Median age at diagnosis of pancreatitis in 19 patients was 11 years of age. 2. Patients had acute lymphocytic leukemia (12 cases; 53%), acute myelocytic leukemia (4 cases; 21%), non-Hodgkins lymphoma (3 cases; 16%). 3. The etiologies of pancreatitis were L-asparaginase (16 cases) therapy, continuous Ara-C therapy (2 cases) and gallbladder stone (1 case). 5. L-asparaginase realated pancreatitis developed during the course of CCG 1882 induction (7 cases), CCG 1901 onsolidation (4 cases), CCG 1901 induction (1 case), and ADCOMP induction (1 case). 6. All patients experienced abdomial pain. Nausea, fever, vomiting, abdominal distention and diarrhea were also manifested clinically. 7. Hypocalcemia, sepsis, ascites, hyperglycemia, diabetic ketoacidosis, pancreatic pseudocysts and fistula were complicating events. 8. 6 patients were dead. The causes of death were from progression of lymphoma/ leukemia itself in 5 cases. One patient died of regimen related toxicity. The period of follow-up ranged from 2 months to 6.6 years with median follow-up of 28 months. CONCLUSION: 1. It is neccessary to monitor the level of serum amylase and lipase or to perform radiologic evaluation in patients who develop abdominal pain during L-asparaginase and Ara-C therapy especially in the course of CCG 1882 induction and CCG 1901 consolidation. 2. The outcome of chemotherapy induced pancreatitis is favorable in most instances but in some patients chronic pancreatitis may remain. The delay of chemotherapy due to pancreatitis may be responsible for the relapse of cancer. Therefore, prompt diagnosis and aggressive supportive therapy are important.

Effect of G-CSF on Myeloid Leukemic Cell Lines after Treatment with Ara-C / 대한임상병리학회지

BACKGROUND: G-CSF or GM-CSF was frequently used in treatment of acute myeloid leukemia patients. But it has been argued whether this increases the apoptosis of tumor cells in synergy with chemotherapeutic agent, or decreases apoptosis of leukemic cells. We attempted to determine the effect of granulocyte colony-stimulating factor (G-CSF) on leukemic cell line after cytosine arabinoside (Ara-C) treatment. METHODS: KG-1 and HL60 cell lines were incubated with Ara-C for 48 hours, and then washed with media, divided into two groups, one being with the addition of G-CSF and the other being without G-CSF and incubated for another 48 hours. The controls were the same cell lines incubated without Ara-C. The absolute cell counts and apoptotic percentage measured by flowcytometry after stained with 7-aminoactinomycin D (7-AAD) were compared among three groups at 0, 48, and 96 hours. RESULTS: KG-1 cell line showed decreased cell count and increased apoptotic percent in Ara-C/G-CSF and Ara-C group compared with the control group at 48 and 96 hours, and did not showed significant difference between G-CSF group and nonG-CSF group. In HL60, control group showed higher cell count at 48 hours, and G-CSF/Ara-C group showed lower cell count and higher apoptosis than Ara-C group in all trials. CONCLUSIONS: The treatment of G-CSF after Ara-C did not protect apoptosis nor increase the tumor cells in KG-1 and HL60 cell lines. We concluded it would be safe to use G-CSF after administration of chemotherapeutic drug.

The use of cytosine arabinoside in glaucoma filtering surgery

Posterior lip sclerectomies were performed in rabbits and cytosine arabinoside (Ara-C) was applied by topical instillation or subconjunctival injection. In both groups, the mean intraocular pressure (IOP) of the treated eyes was significantly lowered at postoperative week 1 and 2, but there was no significant difference between the mean IOP of the control eyes and that of the treated eyes at postoperative week 3 and 4. In both groups, at postoperative week 2, the sclerectomy sites of the control eyes were totally occluded by granulation tissue, but those of the treated eyes were partially replaced by granulation tissue. At postoperative week 4, the sclerectomy sites of the treated eyes were totally occluded by the granulation tissue ultimately in both groups. There were no differences in the mean IOP and the histologic finding of the treated eyes between the topical instillation group and the subconjunctival injection group. We concluded that either topical instillation or subconjunctival injection of Ara-C can delay wound healing at the surgical site after glaucoma filtering surgery in rabbits.

The Effect of Cytosine Arabinoside on Wound Healing after Glaucoma Filtering Surgery in the Rabbit

Posterior lip sclerectomies were performed in rabbits and cytosine arabinoside (Ara-C) was applied by topical instillation or subconjunctival injection. In both groups, the mean intraocular pressure (lOP) of the treated eyes was significantly lower at postoperative week 1 and 2, but there was no significant difference between the mean lOP of the control eyes and that of the treated eyes at postoperative week 3 and 4. In both groups, at postoperative week 2, the sclerectomy sites of the control eyes were totally occluded by granulation tissue, but those of the treated eyes partially replaced by granulation tissue At postoperative week 4, the sclerectomy sites of the treated eyes were totally occluded by the granulation tissue ultimately in both groups. There were no differences in the mean lOP and the histologic finding of the treated eyes between the topical instillation group and the subconjuctival injection gorup. We concluded that either topical instillation or subconjunctival injection of Ara-C can delay wound healing at the surgical site after glaucoma filtering surgery in rabbits.

The Effect of Cytosine Arabinoside on Wound Healing after Glaucoma Filtering Surgery in the Rabbit

Posterior lip sclerectomies were performed in rabbits and cytosine arabinoside (Ara-C) was applied by topical instillation or subconjunctival injection. In both groups, the mean intraocular pressure (lOP) of the treated eyes was significantly lower at postoperative week 1 and 2, but there was no significant difference between the mean lOP of the control eyes and that of the treated eyes at postoperative week 3 and 4. In both groups, at postoperative week 2, the sclerectomy sites of the control eyes were totally occluded by granulation tissue, but those of the treated eyes partially replaced by granulation tissue At postoperative week 4, the sclerectomy sites of the treated eyes were totally occluded by the granulation tissue ultimately in both groups. There were no differences in the mean lOP and the histologic finding of the treated eyes between the topical instillation group and the subconjuctival injection gorup. We concluded that either topical instillation or subconjunctival injection of Ara-C can delay wound healing at the surgical site after glaucoma filtering surgery in rabbits.