FLAG方案治疗成人难治复发急性白血病20例临床观察

目的 探讨FLAG方案(氟达拉宾、阿糖胞苷和非格司亭联合应用)治疗成人难治复发急性白血病(acute leukemia,AL)的疗效及不良反应.方法 对20例成人难治复发AL患者采用FLAG方案化疗,观察疗效及其不良反应.氟达拉宾50mg/d,静脉滴注,持续30 min,第1～5天;阿糖胞苷0.5～1.0 g/(m2·...     

CAG与FLAG方案治疗难治或复发急性髓系白血病的疗效初步研究

目的比较分析CAG方案与FLAG方案治疗难治AML的疗效和不良反应。方法 28例患者应用CAG方案,另15例患者采用FLAG方案治疗。所有病例经过1个疗程化疗后评估疗效和不良反应,获得完全缓解(CR)或部分缓解(PR)的有效者均重复原方案化疗;无效者改用其他方案。结果 CAG组28例中13例获得CR,5例获得PR,总有效率64.29%,早期病死率10.71%;FLAG组15例中4例获得CR,5例获得PR,总有效率60%,早期病死率13.33%。2组方案主要不良反应为骨髓抑制。FLAG组在感染、胃肠道反应及肝损等不良反应发生率显著高于CAG组。结论 CAG方案和FLAG方案均为复发难治AML治疗的有效方案,其中CAG方案非血液学不良反应低。     

Relationship between deoxycytidine kinase (DCK) genotypic variants and fludarabine toxicity in patients with follicular lymphoma

DCK catalyzes the intracellular phosphorylation of fludarabine. The promoter and coding region of the DCK gene were analyzed in 74 follicular lymphoma (FL) patients receiving a therapeutic regimen that included fludarabine. DCK mRNA expression was quantified in a cohort of healthy donors. Four previously described genotypic variants, −360C>G, −201C>T (rs2306744), C28624T (rs11544786) and c.91+37G>C (rs9997790), as well as the new variant, −12C>G, were identified. Variant C28624T showed a lower risk of lymphopenia (P = 0.04), but a higher risk of neutropenia (P = 0.04). Statistical significance was found in bivariate logistic regression between lymphopenia and infectious episodes in the induction period (odds ratio 3.85, P = 0.04).     

氟达拉滨联合吡柔比星治疗复发难治性惰性非霍奇金淋巴瘤

 目的　探讨FT（氟达拉滨及吡柔比星）方案治疗复发难治惰性非霍奇金淋巴瘤（NHL）的有效性和安全性。方法　复发难治惰性NHL40例,采用FT方案化疗,28 d为1个周期,共6个周期。FND（氟达拉滨、米托蒽醌及地塞米松）方案治疗惰性NHL的数据为对照。结果　FT组40例共治疗228个周期,有效率62.5 %,中位无进展生存期超过20个月,2年总生存率70.0 %,与对照组相似（P＞0.05）;不良反应以中性粒细胞减少（80.0 %）最为常见,但Ⅲ～Ⅳ度中性粒细胞减少症和肺炎的发生率均低于对照组,分别为12.5 %、29.0 %和2.5 %、23.0 %（P＜0.05）。结论　FT方案治疗复发难治惰性NHL安全有效,骨髓抑制轻,感染发生率低。     

Fludarabine and melphalan conditioning with tacrolimus as GVHD prophylaxis for allogeneic stem cell transplant recipients is an effective reduced-intensity combination regimen compared to the conventional regimen

Background  As a reduced-intensity stem-cell transplantation (RIST) regimen, the combination of fludarabine and melphalan (FM) with an appropriate immunosuppressant reduces nonrelapse mortality (NRM). Methods  We retrospectively compared the efficacy of a RIST regimen with FM with that of a conventional stem cell transplantation (CST) regimen. Eighty-two consecutive hematological patients who underwent allogeneic stem-cell transplantation (SCT) at our hospital were enrolled. Preparation for RIST consisted of 25 mg/m² fludarabine and melphalan 70 mg/m². The conventional regimen employed high-dose cyclophosphamide and total-body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis for RIST consisted of tacrolimus alone or in conjunction with short-term methotrexate for unrelated donors. Results  Of the 82 patients, 42 received the conventional CST regimen (median age, 35 years) and 40 received the RIST regimen (median age, 51 years). The probability of NRM was 17% (7/42) in the CST group and 8% (3/40) in the RIST group. Grade II to IV GVHD occurred in significantly more CST patients (38%) than RIST patients (28%). However, the overall survival was the same in the two groups (43%). Conclusion  The RIST regimen with FM incorporating tacrolimus and methotrexate demonstrated low TRM incidence and moderate control of GVHD and had efficacy comparable to that of the CST regimen, despite the advanced age of the RIST patient group.     

Phase-II trial of idarubicin, fludarabine, cytosine arabinoside, and filgrastim (Ida-FLAG) for treatment of refractory, relapsed, and secondary AML

 The current phase-II trial was initiated to assess the efficacy and toxicity of the Ida-FLAG regimen in patients with poor-risk acute myeloid leukemia (AML). Three subgroups of patients with AML were eligible for the study: (a) refractory, (b) first relapse, or (c) secondary AML (i.e., signs of trilineage myelodysplasia at diagnosis or the history of a myelodysplasia or myeloproliferative disorder). Fifty-seven fully evaluable patients were included in the study. Twenty patients received a second course of Ida-FLAG. Complete remission was achieved by 1/14 patients with refractory AML, 12/15 patients with relapsed AML, and 17/28 patients with secondary AML. The median duration of ANC <1000/μl was 17 days (10–36); of platelets <30,000/μl 23 days (9–65); of days with fever >38.0  °C 6 days (1–33). Thirteen patients (22.8%) died within 42 days of severe infection or hemorrhage. Overall survival at 20 weeks in the subgroups was 24% for patients with refractory, 78% for patients with relapsed, and 55% for patients with secondary AML. The toxicity of the first cycle of Ida-FLAG is moderate. The feasibility and subjective tolerance of the Ida-FLAG regimen are acceptable. There is no evidence for an increase of atypical infections. The efficacy for patients with secondary AML and especially those with first relapse of AML is good, with a high rate of complete remissions. Remission duration seems to be short. Therefore, an intensified post-remission therapy seems necessary. Received: August 28, 1998 / Accepted: April 9, 1999     

FLAG (Fludarabine,Cytarabine, G-CSF) as a second line therapy for acute lymphoblastic leukemia with myeloid antigen expression: in vitro and in vivo effects

Abstract: Thirteen consecutive adult patients with primary refractory (n = 5) or relapsed (n = 8) acute lymphoblastic leukemia (ALL) were treated by an induction schedule (FLAG) consisting of Fludarabine (30 mg/sqm/d) plus high dose Cytarabine (HD-ara-C: 2 g/sqm/d) (d 1–5) and G-CSF (from d 0 to polymorphonuclear recovery). Patients achieving complete remission (CR) were administered a second FLAG course as consolidation and were then submitted to an individualized program of post-remission therapy, depending on the patient's age and performance status. CR was achieved in 8/12 evaluable cases (67%). The median CR duration was 22.5 w. CR attainment was significantly related to the co-expression of lymphoid and myeloid antigens. ALL/My+ patients achieved CR in 6/6 evaluable cases vs. 2/6 for ALL/My^-. In vitro ³H ara-C incorporation into cellular DNA resulted significantly increased by Fludarabine (in 7/9 tested cases) and, furthermore, by the association of Fludarabine-G-CSF in 5 evaluable ALL/My+ cases; in contrast, no effect of G-CSF addition to Fludarabine was observed in 4 ALL/My^–. Myelosuppression was observed in all patients: the median time to neutrophils >0.5 × 10⁹/l was 16.3 d (range 13–22) and 16.2 d (range 9–29) to platelets>20 × 10⁹/l. Nonhematological toxicity was minimal. In conclusion, FLAG is an active and tolerable combination in refractory ALL, particularly in cases with myeloid antigen expression where G-CSF appears to improve efficacy, probably increasing ara-C incorporation into the DNA of leukemic cells.     

Phase II Clinical Trial of Fludarabine in Chronic Lymphocytic Leukemia on a Weekly Low-Dose Schedule

The major complication during therapy of chronic lymphocytic leukemia (CLL) with the purine nucleotide analogue fludarabine is infection, which is also the main cause of morbidity and mortality in the disease. As the incidence of infectious episodes during therapy correlated with severity of neutropenia, stage of disease, and response to therapy, an effort was made to reduce therapy-related myelosuppression and improve response by altering the conventional therapy regimen. The protocol which yielded a response rate of 57% in previously treated patients with CLL consisted of five consecutive daily doses of 25-30 mg/m^z fludarabine given every three to four weeks. Based on observations from intracellular pharmacology studies it was hypothesized that repetitive single weekly doses of fludarabine would allow normal bone marrow cells to recover while maintaining cytotoxic levels in the leukemic cells. The cumulative four-week dose of the once-weekly regimen was approximately 80% of the original protocol.

Eleven out of 46 evaluable patients (24%) responded to the therapy. Seven patients (15%) achieved a complete remission, and four (9%) a partial remission. While myelosuppression was reduced by about 30% compared with the original protocol, the incidence of febrile episodes was increased by 17%. Pretreatment serum IgG levels below the normal range correlated significantly with a high incidence of infectious episodes and with a short median survival time. These observations suggest that in addition to myelosuppressive therapy, disease related depressed immune function causes morbidity and mortality due to infections. The results further show that changes in the scheduling of the therapy regimen, associated with a slightly lower dose, resulted in reduced efficacy as measured by the response rate.     

Sequential Cis-Platinum and Fludarabine with or without Arabinosyl Cytosine in Patients Failing Prior Fludarabine Therapy for Chronic Lymphocytic Leukemia: A Phase II Study

Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100mg/m² continuous intravenous (IV) infusion over 4 days, fluda 30 m/m² IV over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m IV over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage 1-11 patients had a median survival of 7 months and stage 111-IV patients had a median survival of 3 months. Major toxici-ties (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent.

In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-plfluda combination in this study group.