Lipoprotein Lp(a) excess and coronary heart disease

A pharmacokinetic study of all-trans retinoic acid (ATRA) was performed in 8 patients with various types of leukemia and MDS. After oral administration at a dose of 30 mg/m2, the mean peak plasma concentration was 430 ng/ml and was reached at 150 min. In one patient who failed to respond a very low plasma ATRA level was seen. Though the plasma ATRA exposure decreased significantly with daily drug administration, an intermittent schedule of ATRA administration would yield higher plasma drug concentrations. We treated 2 patients with refractory acute promyelocytic leukemia (APL) in a pilot study of ATRA followed by intensive chemotherapy (APL-ATRA protocol). Two patients successfully achieved complete remission with ATRA after failing under conventional chemotherapy. Based on the pharmacokinetic study of ATRA, an intermittent schedule of ATRA in addition to chemotherapy suggests an effective regimen for children with APL. Phase II trials to evaluate the role of intermittent schedules of ATRA are planned in Children's Cancer and Leukemia Study Group.     

Results of the CCLSG high risk ALL 874 protocol in childhood acute lymphoblastic leukemia. Children's Cancer and Leukemia Study Group

One hundred and eighty eight children with acute lymphoblastic leukemia (ALL) were treated in a Children's Cancer and Leukemia Study Group high-risk ALL 874 study from April, 1987 to September, 1991. These patients received a four-drug induction regimen followed by the early consolidation regimen, cranial irradiation at 6 months of remission and three years of continuation therapy with rotational administration of four drugs. The patients were randomized into two regimens. In regimen A, the consolidation chemotherapy consisted of the intermediate dose cytosine arabinoside (Ara-C), cyclophosphamide (CPM) plus 6MP, and in regimen B, it consisted of high-dose Ara-C plus CPM. Regimen A was given to 106 patients and 82 patients received regimen B. The complete remission induction rate for regimen A and B was 89.4% (93/104) and 98.7% (78/79), respectively. The 3-year event-free-survival (EFS) rate was 70.6% for regimen A, which was higher than the 56.7% for regimen B. The 3-year EFS rate was 44.4% for the 53 patients with an initial leukocyte count > or = 10 x 10(4)/microliters and 72.2% for 132 patients with a leukocyte count < 10 x 10(4)/microliter. We considered that Ara-C plus L-asp, added to the conventional high-risk ALL 811 protocol, improved the prognosis of the high risk ALL patients. However, further intensive chemotherapy was required for improvement of the outcome of the patients with hyperleukocytosis (> or = 10 x 10(4)/microliters).     

Treatment of newly diagnosed acute promyelocytic leukemia (APL) by all transretinoic acid (ATRA) combined with chemotherapy: The European experience. European APL Group

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbacks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.     

三氧化二砷联合全反式维甲酸治疗初发急性早幼粒细胞白血病50例疗效观察

目的 观察三氧化二砷(ATO)联合全反式维甲酸(ATRA)治疗初发急性早幼粒细胞白血病(APL)的疗效.方法 98例初发APL患者分为对照组和治疗组,对照组48例,治疗组50例.对照组采用常规ATRA+DA双诱导方案治疗;治疗组采用ATRA每天25 mg/m2,ATO每天0.15 mg/kg(ATRA后第10天开始)联合治疗,直至完全缓解(CR),CR后接受ATO和ATRA联合巩固治疗.比较两组CR率、PML-RAR α融合基因转阴时间及5年无病生存率.结果 对照组和治疗组CR率分别为89.5%(43/48)和90.0%(45/50),获得CR时间分别为(30.0±5.1)d和(28.1±4.4)d,两组CR率(x2=-0.068,P=0.946)及获得CR时间(t=1.757,P=0.083)相比差异均无统计学意义.在所有获得CR的患者中,3例分别在CR后第276、385和394天复发.所有患者发病时PML-RAR α融合基因均阳性,对照组和治疗组CR时分别有25.0%(5/20)和29.4%(5/17)转阴,巩固后分别有92.5%(37/40)和97.6%(41/42)转阴.对照组和治疗组5年无病生存率分别为(85.3±5.9)%和(87.6±5.6)%,差异无统计学意义(x2=0.232,P=0.630).结论 ATO联合ATRA能有效治疗初发APL患者,可以作为常规化疗方案外的另一选择.     

全反式维甲酸、三氧化二砷、化疗联合治疗急性早幼粒细胞白血病疗效观察

目的 评估全反式维甲酸(ATRA)、三氧化二砷(As2O3)、化疗联合治疗初诊急性早幼粒细胞白血病(APL)的疗效和患者不良反应.方法 对40例采用ATRA、As2O3、化疗三联疗法治疗的APL患者的临床资料进行回顾性分析,观察其疗效及不良反应.结果 总体CR率92.5%(37/40),完全缓解所需中位时间27(22～61)d;白细胞≥10×109/L组CR率72.7%(8/11),白细胞<10×109/L组CR率100%(29/29),差异有统计学意义(x2=8.550,P=0.004);治疗过程中无严重不良反应,仅1例发生维甲酸综合征.结论 ATRA、As2O3、化疗联合应用可作为APL患者的首选治疗方案.     

Treatment of acute promyelocytic leukemia--combined use of all-trans retinoic acid and granulocyte colony-stimulating factor

We evaluated the effect of treatment by all-trans retinoic acid (ATRA) in 9 patients with acute promyelocytic leukemia (APL). Of 6 patients who had circulating leukemic blasts before treatment, 3 initially received ATRA alone but died of respiratory failure due to retinoic acid syndrome (RAS). High dose steroid therapy did not rescue RAS in these patients. Another 3 who were given intensive chemotherapy followed by ATRA and/or granulocyte colony-stimulating factor (G-CSF) achieved complete remission (CR). Of 3 patients without peripheral leukemic blasts before treatment, 1 received intensive chemotherapy followed by G-CSF and reached CR, 1 who had been previously given ATRA did not respond to ATRA, and 1 did not initially respond sufficiently to ATRA alone but responded dramatically to ATRA plus G-CSF. In the treatment of APL, appropriate combination of ATRA, G-CSF and chemotherapy should always be taken into consideration. In addition, RAS have to be carefully avoided when applying ATRA therapy in patients who have circulating leukemic blasts before treatment.     

Acute promyelocytic leukemia: all-trans retinoic acid (ATRA) along with chemotherapy is superior to ATRA alone

This study was conducted to compare the results of treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid alone (ATRA) or a combination therapy of ATRA followed by chemotherapy. Forty-three patients treated between February 1992 and February 1996 were included in this study. Eighteen patients were treated with ATRA alone and 25 patients were treated with ATRA followed by chemotherapy. The cytogenetic analysis was done in 41 patients at presentation, following treatment, and at follow-up. A complete response (CR) was achieved in 13 (72%) patients on ATRA and 19 (76%) on ATRA followed by chemotherapy. Eleven of 13 patients with response to ATRA alone relapsed with median survival of eight months (range, 1 to 28). One patient died of hepatitis in CR and one patient is alive 2 years after diagnosis. In the combination therapy arm, 10 patients are in CR with a median follow-up of 22 months (range, 6 to 56 months). After achieving a CR, four patients died due to infections during chemotherapy therapy, and only 5 of 19 patients have relapsed. Major cytogenetic response was seen in 8 of the 10 patients in whom cytogenetic data was available after treatment with ATRA at the time of remission. Similarly, 13 of 15 for whom data was available showed a major cytogenetic response after treatment with ATRA plus chemotherapy. Prior to relapse, 80% of the patients had an increase in the percentage of t(15;17) cells in the marrow. Patients with a complete hematological response but no cytogenetic response relapsed within six months. Ten patients died prior to response evaluation. Two patients who received ATRA died of retinoic acid syndrome, one of pneumonia, and one of intracranial hemorrhage. Of the six patients on ATRA and chemotherapy, four died of retinoic acid syndrome (RAS), one of intracranial hemorrhage, and one of left ventricular failure. Only one patient is alive at 24 months following treatment with ATRA alone. The relapse-free survival is 42% at four years for patients treated with ATRA followed by chemotherapy. This trial is a historical comparison of ATRA alone and ATRA with subsequent combination chemotherapy. Nonetheless, the trial shows a significant improvement in the event free survival of patients receiving chemotherapy as consolidation following ATRA.     

Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: a report from the Children's Cancer Group

PURPOSE: Compared with previous Children's Cancer Group (CCG) acute lymphoblastic leukemia (ALL) trials, therapy based on the Berlin-Frankfurt-Munster (BFM) 76 trial has effected an improvement in event-free survival (EFS). In an attempt to improve EFS further, CCG investigators formulated an augmented BFM (A-BFM) regimen that provides prolonged, intensified postinduction chemotherapy relative to the CCG-modified BFM regimen. PATIENTS AND METHODS: We tested A-BFM in 101 patients with ALL and unfavorable presenting features that showed slow early response (SER) to induction therapy who attained remission on day 28. Their outcome was compared with that of 251 concurrent patients with unfavorable presenting features, a rapid early response to therapy (RER), and remission by day 28, treated with CCG-BFM with or without cranial radiation (CRT). RESULTS: The 4-year EFS rate from the end of induction for SER patients treated with A-BFM was 70.8% +/- 4.6%. Seventeen patients remain in continuous remission beyond 5 years. Vincristine (VCR) neurotoxicity developed in 50% of patients, but was rarely debilitating. Allergies to Escherichia coli L-asparaginase (L-ASP) occurred in 35% of patients. Avascular necrosis of bone (AVN) developed in 9% of patients. In comparison, a concurrent RER group treated with standard BFM +/- CRT had a 4-year EFS rate of 73.1% +/- 4.6%. CONCLUSION: The toxicity of A-BFM is significant, but acceptable. Compared with historical control SER patients treated with CCG-modified BFM, A-BFM therapy appears to produce a significant improvement in EFS. This is the first study to show that intensive chemotherapy, as given in the A-BFM regimen, can abrogate the adverse prognostic significance of SER.     

Clinical characteristics and treatment results of acute promyelocytic leukemia in children (Children's Cancer and Leukemia Study Group)

The clinical characteristics and treatment outcome in 40 children with acute promyelocytic leukemia (APL) treated at institutions participating in the Children's Cancer and Leukemia Study Group (CCLSG) were studied retrospectively. The median age at diagnosis was 8 years old. Bleeding diathesis was the predominant presenting symptom (90%), associated with laboratory findings of disseminated intravascular coagulation. Hepatomegaly, splenomegaly and lymphadenopathy were observed in 35%, 10%, and 15% of the cases, respectively. The median WBC count was 4.25 x 10(9)/l. Anemia (hemoglobin < 8 g/dl) and thrombocytopenia (< 30 x 10(9)/l) were present in more than half of the patients. Cytogenetic studies demonstrated the characteristic 15; 17 translocation in about 90% of the patients analyzed. Induction therapy consisted of cytosine arabinoside and an anthracycline, with or without other agents. Twenty-nine patients (73%) achieved complete remission (CR) while early fatal hemorrhage was the predominant cause of induction failure. The survival rates continued to decrease (28% at 3 years, 24% at 5 years, and 7.9% at 10 years) due to late marrow relapses. Anthracycline cardiotoxicity was fatal in three patients in remission. These clinical features of childhood APL should be taken into account in the development of new protocols.     

Gq-protein alpha subunit expression and distribution in pregnant rat myometrial tissues

Coagulation patterns of 19 newly-diagnosed acute promyelocytic leukemia (APL) patients with disseminated intravascular coagulation (DIC) at presentation were studied. Seventeen patients had hemorrhagic complications, of which four were fatal. Fatal hemorrhages were related with lower fibrinogen level and lower platelet count. DIC of the APL patients without infection was characterized by low fibrinogen and normal antithrombin III (ATIII) level. Thrombin-ATIII complex level was elevated in all patients examined. Patients with infection had higher fibrinogen levels than those without infection and some patients had reduced ATIII level. Ten remission inductions were tried with multidrug chemotherapy and seven with all-trans retinoic acid (ATRA). Complete remission was achieved in seven of ten inductions with chemotherapy and in all seven inductions with ATRA. Two patients treated with chemotherapy had fatal hemorrhage after starting therapy but none treated with ATRA.     

Differentiating therapy in acute myeloid leukemia

Differentiating therapy is a new antineoplastic strategy which has received increasing attention due to the remarkable activity of the vitamin A derivative, all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). Although it has been known for years that a variety of agents, including retinoids, could induce leukemic cells to differentiate in vitro, it was not until the initial report from Shanghai in 1988 that laboratory studies translated into clinical activity and benefit in patients. Since this initial report, a number of studies have confirmed that the majority of patients with both newly diagnosed and previously chemotherapy-treated patients with APL achieve complete remission (CR) with ATRA. In addition, the characteristic life-threatening coagulopathy resolves quickly. Several limitations to this approach have emerged, including the development of retinoid resistance, hyperleukocytosis and the retinoic acid syndrome, a constellation of findings including unexplained fever, fluid retention, pleuropericardial effusions and pulmonary infiltrates. Although ATRA is very effective in inducing CR, its benefits compared to conventional chemotherapy are only now being addressed. The first prospective randomized trial comparing ATRA plus chemotherapy to chemotherapy alone was terminated early because of an improved event-free survival for patients receiving ATRA. The benefit was attributable to a difference in relapse rate. A large, intergroup, prospective, randomized trial comparing conventional chemotherapy to ATRA for induction and ATRA to observation for maintenance has recently completed accrual and will provide insight into the emerging role of ATRA in patients with APL. ATRA represents the first example of a specific form of antileukemic therapy targeting a specific genetic abnormality and may serve as a paradigm for the development of differentiating therapy for patients with other hematologic malignancies.     

Autologous bone marrow transplantation with monoclonal antibody purged marrow for children with acute lymphoblastic leukemia in second remission. Spanish Working Party for BMT in Children

The purpose of this study was to evaluate the outcome of children with acute lymphoid leukemia (ALL) in second remission who have undergone high-dose chemotherapy and radiotherapy and autologous bone marrow transplantation (ABMT) with monoclonal antibody purged marrow, and to determine the main prognostic factors. From 1987 to 1992, 55 children with ALL in second remission underwent ABMT. The conditioning regimen consisted of total body irradiation (TBI) plus cyclophosphamide in 21 patients and TBI plus cyclophosphamide plus cytarabine or VP-16 in 28 patients; the remaining six patients were treated with chemotherapy alone (cyclophosphamide and busulfan, and/or VP-16). The marrow was purged using monoclonal antibodies and complement or magnetic microspheres in all cases. All patients engrafted. Three patients (5%) died early post transplant from infections. Twenty-six patients (47%) relapsed (median 150 days); 26 patients (47%) are alive and in complete remission (CR) at a median of 36 months. The Kaplan-Meier estimation showed a probability of event-free survival (EFS) of 46 +/- 0.007%. In the univariate analysis, first CR length and conditioning with TBI plus two or more cytotoxic drugs were found to be the most significant predictors of EFS. ABMT with purged marrow is a treatment modality which offers a chance of cure in children with ALL after relapse, including children who relapse early.     

Long-term results after caval filter implantation]

The aim of the present study was to better understand the possibility of utilizing growth factors of the myelomonocytic line in acute leukemias. The study is an examination of morphological changes and marker behavior in peripheral and bone marrow cells in AML and APL during treatment both with all-transretinoic acid (ATRA) alone and in association with chemotherapy and G-CSF. The same treatment was carried out in a patient who had been diagnosed with Vaquez's disease 15 years earlier and currently presented a bone marrow and peripheral picture of AML (80% myeloblasts) with thrombocytopenia. We observed that treatment with ATRA, alone or in association with chemotherapy, was followed by a remission of AML and especially of APL, with amelioration of the general condition of the patients. The addition of G-CSF to ATRA at the end of chemotherapy, during consequent pancytopenia, produced a rapid increase in mature peripheral granulocytes and an apparent medullary complete remission, which was more prolonged in APL than in AML; there was no increase in peripheral blasts. Discontinuation of G-CSF was followed by a relapse in the patient with AML. A patient with Vaquez's disease, in remission for 15 years and presenting a progressive increase in bone marrow and peripheral myeloblasts, did not have a positive response to the administration of ATRA; however, the association of G-CSF to ATRA was followed by a complete remission. The morphological changes observed in bone marrow and peripheral granulocytes (with changes in the main cellular markers: CD11b, CD13, CD14, CD15, CD34) seemed to express progressive modification of the single elements towards differentiation, with progressive bone marrow reduction and peripheral disappearance of blasts. The data agree with the changes observed in in vitro blasts cultured in the presence of ATRA and G-CSF.     

ALL R-87 protocol in the treatment of children with acute lymphoblastic leukaemia in early bone marrow relapse

Seventy-three children with acute lymphoblastic leukaemia (ALL) in first bone marrow (BM) relapse, occurring within 30 months from complete remission (CR), were enrolled in an Italian cooperative study (ALL R-87 protocol). This treatment programme consisted of an induction phase with intermediate-dose cytarabine (IDARA-C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction. The response rate was significantly higher for children with a first CR duration > or = 12 months (P=0.0005) and for those with a white blood cell (WBC) count at relapse < 20 x 10(9)/l (P=0.004). The estimated disease-free survival (DFS +/- SE) at 82 months was 0.18 +/- 0.05 for all responders, and 0.70 +/- 0.14 for allotransplanted patients versus 0.05 +/- 0.05 for those autografted (P=0.001). The estimated probabilities of survival +/- SE and event-free survival (EFS +/- SE) at 83 months were 0.16 +/- 0.07 and 0.13 +/- 0.04, respectively. for all enrolled children. Univariate analysis showed that age < 10 years at initial diagnosis and B-lineage immunophenotype favourably influenced both DFS (P=0.001) and EFS probabilities (P=0.0014 and P=0.012, respectively), whereas a first CR duration > or = 12 months and a WBC count at relapse < 20 x 10(9)/l were associated only with a better EFS rate (P=0.026 and P=0.004, respectively). Our results show the efficacy of the IDA plus IDARA-C schedule used in the ALL R-87 protocol in high-risk relapsed ALL children. Allogeneic BMT proved effective for patients with an HLA sibling donor. In a multivariate analysis, age > or = 10 years at initial diagnosis (P=0.016) and WBC count at relapse > or = 20 x 10(9)/l (P=0.048) were independently associated with a worse disease outcome.