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IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: Experiences of a phase II trial

Department of Paediatric Haematology/Oncology of University Bonn, Germany.
British Journal of Haematology (Impact Factor: 4.96). 09/1998; 102(3):647-55. DOI: 10.1046/j.1365-2141.1998.00836.x
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ABSTRACT A phase II trial was designed to explore the potential feasibility and efficacy of a reinduction therapy consisting of fludarabine, cytarabine, idarubicin and granulocyte colony stimulating factor (G-CSF) for acute myelogenous leukaemia (AML) patients with poor prognosis. Twenty-three patients aged 1 2-17.5 years with refractory (n=3), relapsed (n=19) or secondary (n=11) AML were treated with the IDA-FLAG regimen, a combination therapy of idarubicin (days 2-4, 12 mg/m2/d), fludarabine (days 1-4, 30 mg/m2/d), cytarabine (days 1-4, 2000mg/ m2/d) and G-CSF (day 0 up to ANC > 1 x 10(9)/l, 400 microg/m2/ d). They received a total of 3 7 courses of IDA-FLAG and/or FLAG (IDA-FLAG without idarubicin). 17/23 patients achieved a complete remission (CR) with a median duration of 13.5 months (1-39 months), one patient showed a partial remission, and five were nonresponders while in CR, 11 patients underwent bone marrow or PBSC (peripheral blood stem cells) transplantation. Overall, nine patients remain in continuous complete remission with a median duration of 17.5 months (9.5-39 months). The toxicity of the IDA-FLAG courses was more severe than for the FLAG courses with marked neutropenia and thrombocytopenia (for IDA-FLAG: median 22.5 and 25 d respectively; for FLAG: median 10.5 and 14 d respectively). Pulmonary infections were the main nonhaematological toxicity. One patient died in CR from invasive aspergillosis. The IDA-FLAG regimen produced a CR of >12 months in more than half of the patients and can be recommended as a therapeutic option prior to allogeneic or autologous bone marrow transplantation.

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    • "The purine analogue fludarabine is highly immunosuppressive and has been shown to be effective in nonmyeloablative regimens in conjunction with antithymocyte globulin (ATG) (Slavin et al, 1998a,b), busulphan (Slavin et al, 1998a,b), melphalan (Giralt et al, 1997, 1998; Wasch et al, 2000), cyclophosphamide (Childs et al, 1998a,b), carmustine (Wasch et al, 2000) and cytosine arabinoside (Khouri et al, 1998). Fludarabine in combination with highdose cytosine arabinoside, granulocyte colony-stimulating factor (G-CSF) with or without idarubicin (FLAG ^ Ida) has been shown to be active against a variety of haematological malignancies including high-risk acute leukaemias (Estey et al, 1994; Parker et al, 1997; Fleischhack et al, 1998). Recently, Giralt et al (1997) reported the use of FLAG±Ida as non-myeloablative conditioning before allogeneic peripheral blood stem cell transplantation (PBSCT) in seven patients with acute leukaemia who were not considered fit for standard conditioning regimens. "
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    ABSTRACT: Acute leukaemias in relapse after allogeneic stem cell transplantation (SCT) respond poorly to donor leucocyte infusions (DLI) compared with chronic myeloid leukaemia (CML), at least in part because of faster disease kinetics. Fludarabine-containing 'non-myeloablative' chemotherapy followed by further allo SCT may offer more rapid and effective disease control. We report 14 patients with relapse after allo SCT for acute leukaemia [seven acute myeloid leukaemia (AML), five acute lymphoblastic leukaemia (ALL)] or refractory anaemia with excess blasts in transformation (RAEB-t, n = 2) treated with fludarabine, high-dose cytosine arabinoside (ara-C) and granulocyte colony-simulating factor (G-CSF) with (n = 10) or without (n = 2) idarubicin (FLAG +/- Ida) or DaunoXome (FLAG-X) (n = 2) and second allo SCT from the original donor. Donors were fully human leucocyte antigen (HLA) -matched in 13 cases with a single class A mismatch in one. Actuarial overall survival was 60% and disease-free survival was 26% at 58 months. Remissions after the second SCT were longer than those after the first bone marrow transplantation (BMT) in eight of the 13 assessable patients to date. Haematopoietic recovery was rapid. Transplants were well tolerated with no treatment-related deaths. The major complication was graft-versus-host disease (GvHD, acute >/= grade II-2 cases, chronic - eight cases, two limited, six extensive) although there have been no deaths attributable to this. FLAG +/- Ida and second allo SCT is a safe and useful approach and may be more effective than DLI in the treatment of acute leukaemias relapsing after conventional allo SCT.
    British Journal of Haematology 12/2001; 115(3):622-9. DOI:10.1046/j.1365-2141.2001.03150.x · 4.96 Impact Factor
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    ABSTRACT: ZET Primer tedaviye dirençli veya relaps yapm›ş akut lösemi vakalar›nda kurtarma rejimleri ile komplet remisyon sağla-nabilmekle birlikte, bu genellikle k›sa süreli olup, nadiren tam kür sağlanmaktad›r. Kurtarma tedavilerine refrakter vakalarda tedavi yaklaş›m›n›n nas›l olacağ› konusu halen belirsizliğini sürdürmektedir. Çoklu ilaç direncinin gelişimi kullan›lan tedavi protokollerini etkisiz k›lmaktad›r. Siklosporin çoklu ilaç direncini yenmek için kullan›lan ajanlardan biridir. Bu çal›şmada FLAG tedavi rejimine dirençli olgularda hibrid bir rejim olarak geliştirdiğimiz FLAG-İda-Sik-losporin etkinliğini test etmeyi planlad›k. FLAG kurtarma protokolüne cevaps›z, primer tedaviye refrakter veya relaps, 5 AML, 3 ALL ve 1 T-lenfoblastik lenfoma olmak üzere toplam 9 hastaya FLAG-İda-Siklosporin tedavisi uygulad›k. 5 AML vakas›n›n 3'ünde komplet remisyon gözlenirken, ALL ve T-lenfoblastik lenfoma vakalar›n›n remisyona girmediği gözlendi. Bu bulgular bize FLAG kurtarma tedavisine yan›ts›z, primer tedaviye refrakter veya erken relaps AML vakalar›nda FLAG-İda-Siklosporin tedavisinin alternatif bir tedavi seçeneği olabileceğini, buna karş›n ALL vakalar›nda etkili olmad›ğ›n› telkin etmektedir. Anahtar Kelimeler: Relaps/refrakter AML, ALL, FLAG-İda-Siklosporin ABSTRACT Results of Treatment Regime of FLAG-Ida-Cyclosporine in Acute Leukemia Patients Refractory to FLAG Salvage Regime Although the salvage regimens can induce complete remission in refractory acute leukemia patients, it is generally short and rarely cure is achieved. The plan for refractory patients with respect to salvage regimens is problematic. The emergence of multidrug resistance cause the inefficiency of chemotherapy protocols. Cyclosporine is one of the agents to overcome the drug resistance. In this study, we planned to test the efficiency of hybrid regime FLAG-Ida-Cyclosporine in the refractory cases to FLAG. 9 patients who were primary refractory or relapsed to FLAG salvage regime comprising 5 AML, 3 ALL and 1 T-lymphoblastic lymphoma were enrolled. In 3 out of 5 AML patients, complete remission was observed, however none of ALL and T-lymphoblastic lymphoma patients entered remission. These results suggested that FLAG-Ida-Cyclosporine therapy can be an alternative in the AML patients primary refractory or early relapsed to FLAG salvage regimen, in contrast to the inefficiency in ALL cases.
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    ABSTRACT: Background: Patients with Refractory/Relapsed (R/R) acute leukemia (AL) have a poor prognosis. Objective: We aimed to evaluate the chemotherapy regimen fludara-bine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) in patients with R/R AL. Patients: We studied 33 patients with R/R AL. Distribu-tion of the AL subtype was: myeloblastic n=17 (52%), lymphoblastic n=14 (42%),) and biphenotypic n=2 (6%). Results: Complete remission (CR) was achieved in 15 cases (45.5%) and seven patients dead resulting in a mortality of 21.1%. In patients with hematological recov-ery the median time to neutrophils recovery (> 0.5 x 10 9 / l) was 24 days (range 10-38); platelet levels of more than 20 x 10 9 /l and 50 x 10 9 /l were reached in a median time of 24 (range 17-44) and 27 days (range 18-51), respectively. After CR, five patients underwent allogeneic transplan-tation and 10 patients received a second course of FLAG-IDA. Ten out of 15 patients who achieved CR with FLAG-IDA relapsed at a median of 7.7 months (95% CI 1.8 to 13.6 months). Overall survival (OS) after FLAG-IDA in the surviving cohort had a median of 4 months. We found a significantly better OS in patients who received allo-geneic transplantation post-FLAG-IDA than those who did not (median 11.4 months vs. 2.7 months; HR 0.29; 95% CI 0.1 to 0.6; p=0.017). Conclusions: In our series, FLAG-IDA demonstrated to be an effective salvage chemo-therapy regimen, however, the benefit in survival of this rescue treatment was restrained to patients who under-went allogeneic transplantation.
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