American Journal of Therapeutics 13, 389393 (2006)

IDA-FLAG Regimen for the Therapy of Primary Refractory and Relapse Acute Leukemia: A Single-Center Experience
Sinan Yavuz,* Semra Paydas, Umut Disel, and Berksoy Sahin

We evaluated efcacy and toxicity proles of udarabine, Ara-C, idarubicin, and G-CSF (Ida-FLAG) combination chemotherapy in 56 refractory and/or relapsed acute leukemia patients. Patients were treated with udarabine phosphate 25 mg/m2/d (d1-5), Ara-C 2 g/m2/d (d1-5), idarubicin 12 mg/m2/d (d1-3), G-CSF was given subcutaneously from sixth day until absolute neutrophil count (ANC) .500/mL. One third of the acute myeloblastic leukemia (AML) and 45% of acute lymphoblastic leukemia (ALL) cases were primary refractory disease. In AML patients, complete remission (CR) was achieved in 15 cases (53.6%). One case showed partial remission (PR) (3.6%) and 12 cases (42.8%) had resistant to this regimen (RD). Grade IV hematologic toxicity occurred in all AML cases. Leukocyte recovery time was 16 days. Nonhematologic complications were mild to moderate nausea, vomiting, and mucositis and could be controlled by routine measures. Stem cell transplantation was performed in 5 patients and all achieved CR, 2 autologous and 3 allogeneic. In ALL patients, CR and PR were obtained in 8 (42.2%) and 2 (10.5%) of 22 cases; disease was resistant to Ida-FLAG in 9 (47.3%) cases. Grade IV hematologic toxicity occurred in all ALL cases. Leukocyte recovery time was 17 days. Nonhematologic toxicity consisted of nausea, vomiting, and mucositis and could be controlled by supportive therapy. Autologous transplantation was performed in 1 patient, but relapse disease occurred after 5 weeks. There was no correlation between response rate and leukemia subtype (AML versus ALL), leukocyte count, age, sex, disease status (de novo versus secondary), and RFS (early versus late relapse) (P . 0.05). Median survival was 16 weeks in all cases (22 weeks in AML versus 13 weeks). At present, only 3 patients are alive and 2 of these are in continuous remission. The rest of the patients died. In conclusion, Ida-FLAG is a good choice in cases with refractory/relapsing acute leukemia for salvage chemotherapy. High efcacy and a low-toxicity prole are preferable properties of this regimen, and this regimen has been found to be useful for cytoreduction, especially in candidates for allo-SCT. Keywords: IDA-FLAG, FLAG, relapse, acute leukemia, refractory acute leukemia

INTRODUCTION
Conventional chemotherapy is highly effective in the treatment of acute leukemias. However, relapse develops in 50% to 70% of the cases. Ten percent to 40% of
Division of Oncology, Department of Internal Medicine, School of Medicine, Cukurova University, Balcali-Adana, Turkey. *Address for correspondence: Division of Oncology, Department of Internal Medicine, Cukurova University, School of Medicine, 01330 Balcali-Adana, Turkey. E-mail: siyav@cu.edu.tr 10752765 2006 Lippincott Williams & Wilkins

the cases with acute leukemias have primary refractory disease. The management of cases with primary refractory and/or relapse disease is very difcult. In these cases, complete remission rates are low and remission duration is very short.1 For this reason, clinical studies with different alternatives are ongoing in cases with relapse and/or refractory acute leukemias. Ara-C is an effective chemotherapeutic agent used in acute myeloblastic leukemia (AML). High-dose Ara-C (HiDAC) regimens have been found to be effective in these refractory/relapse cases. The rationale of HiDAC is to increase the intracellular Ara-C triphosphate

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(Ara-CTP) concentration and to augment the cytotoxicity of the drug. One of the chemoresistance mechanisms is the P-glycoprotein (P-gp)-dependent efux and HiDAC down-regulates the P-gp efux.16 It has been shown that there is a positive correlation between complete response and high intracellular Ara-C content. The combination of Ara-C with udarabine phosphate increases the Ara-C content two- to sevenfold in leukemic cell. This synergistic effect has been shown in various studies. Ara-CTP content and cytotoxicity increase when HiDAC is given after udarabine infusion. Besides, granulocyte-colony stimulating factor (G-CSF) given in this schema augments the incorporation of Ara-CTP to leukemic cell DNA and causes an increase in blastic cell death with G-CSF, especially as AML blasts enter the S phase of the cell cycle and cytotoxicity increases.2,4,79 For this reason, udarabine phosphate, Ara-C, and G-CSF regimen (FLAG) is an important choice in cases with refractory/relapsing acute leukemias. In recent years, idarubicin has been added to FLAG to increase the efciency of therapy and is named as Ida-FLAG.10 The Ida-FLAG combination is an effective regimen in cases with refractory/relapsing acute leukemias that have poor prognosis and low response rates. We report here the efcacy of Ida-FLAG in 56 cases with refractory/relapsing acute leukemia (34 AML and 22 ALL).

subcutaneously from sixth day to until absolute neutrophil count (ANC) .500/mL. Response criteria are as follows: 1. Complete remission (CR): Peripheral blood counts within normal limits plus bone marrow blast percentage ,5%. 2. Partial remission (PR): Peripheral blood counts within normal limits plus bone marrow blast percentage between 5% and 20%. 3. Refractory disease (RD): No improvement in peripheral blood and/or bone marrow blastic cells. 4. Early death (ED): Death within 6 weeks of chemotherapy. Overall survival (OS) 1. Duration of rst day of chemotherapy to death or last control visit. 2. Relapse-free survival (RFS): Duration from the day detected CR to relapse and/or last control visit. 3. WHO classication was used to determine the chemotherapy associated hematologic and nonhematologic toxicity. Statistical analysis SPSS 11.5 pocket program has been used for statistical analysis. For comparisons t test, x2 test, multivariate logistic regression, and Cox regression analyses were used. P value .0.05 has been accepted as meaningful.

PATIENTS AND METHODS

Fifty-six cases with refractory/relapsing acute leukemia treated at the Oncology Department of C xukurova University, Faculty of Medicine are included in this study. Peripheral blood and bone marrow samples were evaluated by morphology, histochemistry, and immunophenotyping. Inclusion criteria included serum creatinine level ,2 mg/dL, bilirubin ,2 mg/dL, and left ventricle ejection fraction .50%. Patients not responding to remission induction therapy were accepted as primary refractory. Relapsing disease was dened as a response to remission induction and blast increase in peripheral blood and/or bone marrow .5% during follow-up. dA relapse developing in patients in rst 6 months after complete remission was accepted as early relapse. Treatment protocol Fludarabine 25 mg/m2/d (d1-5) i.v. as a 30-minute infusion, then 4 hours later Ara-C 2 g/m2/d (d1-5) i.v. as a 4-hour infusion and idarubicin 12 mg/m2/d (d1-3) i.v. as a 30-minute infusion; G-CSF was given
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RESULTS
Fifty-six patients with refractory/relapsing acute leukemia were included in this study. Thirty-four of them had AML and 22 had ALL. Mean age was 37 (range 1559) and 25 (range 1548) in cases with AML and ALL, respectively. Female/male ratio was 1.1/1 in AML and 1.2/1 in ALL cases. One third of the AML cases and 45% of ALL cases were primary refractory disease and rest of them had relapse disease. Thirtyone of AML cases had de novo disease and 3 had AML secondary to myelodysplastic syndrome (Table 1). AML cases Ida-FLAG was given 1 cycle to 21 cases, 2 cycles to 8 cases, and only 3 cases received 3 cycles (Table 2). CR was achieved in 15 cases (53.6%). One case showed PR (3.6%) and 12 cases (42.8%) had RD. ED developed in 6 cases (17.6%). CR was obtained in 5 of 11 cases (62.5%) with primary refractory disease and 10 of 20 (50%) cases with relapse disease. CR rates to Ida-FLAG was

IDA-FLAG Regimen for Acute Leukemia Table 1. Clinical characteristics of patients. Parameter AML Relapse Primary refractory Male Female Median age ALL Relapse Primary refractory Male Female Median age Total Number 34 23 11 18 16 37 (1559) 22 12 10 12 10 25 (1548) 56 patients Table 3. Clinical response rates in all patients. Patients AML Primary Relapse ALL Primary Relapse refractory pts. pts. refractory pts. pts.

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CR (%) PR (%) NR (%) ED (%) 53.6 62.5 50 42.2 33.3 50 3.6 12.5 10.5 11.1 10 42.8 25 50 47.3 55.5 40 17,6 26 13 13,7 10 16,7

not different in cases with relapse and primary refractory disease (P = 0.57). PR was obtained in only 1 case with primary refractory disease. ED developed in 3 of 12 (25%) and 3 of 23 (13%) cases with primary refractory and relapse AML, respectively (Table 3). Grade IV hematologic toxicity occurred in all cases with AML; leukocyte nadir was 43/mL (range 5 231/mL) and febrile neutropenia developed in all cases. Leukocyte recovery time was 16 days (range 1434 days). Among 34 cases, nonspecic pneumonia developed in 9 cases, mucormycosis in 1, and invasive pulmonary aspergillosis (IPA) in 1. ED was seen in 6 cases; 3 due to hemorrhagic complications, 1 due to mucormycosis, 1 due to IPA, and 1 due to septic shock. Nonhematologic complications were mild to moderate nausea, vomiting, and mucositis and could be controlled by routine measures. Stem cell transplantation was performed in 5 cases achieving CR; 2 autologous, and 3 allogeneic. However, autologous transplantation patients were lost within 6 weeks due to relapse disease. Two of 3 patients with allogeneic transplantation are in CR at 14 and 18 months post-transplantation; extramedullary relapse developed in 1 case at 11 months post-transplantation (Table 4). ALL cases Ida-FLAG was given 1, 2, and 3 cycles in 14, 6, and 2 cases, respectively. CR and PR were obtained in 8 (42.2%) and 2 (10.5%) of 22 cases, respectively. Disease
Table 2. Number of FLAG-Ida course in patients. 1st course ALL (22 patients) AML (34 patients) 14 23 2nd course 6 8 3rd course 2 3

was resistant to Ida-FLAG in 9 (47.3%) cases and ED occurred in 3 (13.7%) cases. According to the disease status, in cases with primary RD, CR, PR, resistant disease (RD), and early death (ED) were detected in 3 of 9 (33.3%), 1 of 9 (11.1%), 5 of 9 (55.5%) and 1 of 10 (10%), respectively. In relapse cases CR, PR, RD, and ED were detected 5 of 10 (50%), 1 of 10 (10%), 4 of 10 (40%), and 2 of 12 (16.7%), respectively. CR rate in cases with ALL was higher in relapse cases as compared with primary refractory cases (33.3% versus 50% but nonsignicant, P . 0.05) (Table 3). Grade IV hematologic toxicity occurred in all cases with ALL, leukocyte nadir was 41/mL (range 6138) and febrile neutropenia developed in all cases as seen in cases with AML. Leukocyte recovery time was 17 days (range 1327). Pneumonia developed in 7 cases; nonspecic pneumonia in 5, IPA in 1, and mucormycosis in 1. Early death was detected in 3 cases: 1 due to hemorrhagic complication, 1 due to mucormycosis, and 1 due to IPA. Nonhematologic toxicity consisted of nausea, vomiting, and mucositis and could be controlled by supportive therapy. Allogeneic transplantation could not be performed due to the lack of a donor in none of the cases obtained CR. Autologous transplantation was performed in 1 case, but relapse disease occurred after 5 weeks. There was no correlation between response rate and leukemia subtype (AML versus ALL), leukocyte count, age, sex, disease status (de novo versus secondary), and RFS (early versus late relapse) (P . 0.05). Median survival was 16 weeks (range 2100 weeks) in all cases (22 weeks in AML versus 13 weeks). At present, only 3 patients are alive and 2 of these are in continuous remission. The rest of the patients died.
Table 4. Transplantation status in patients (HSCT). Autologous ALL AML 1 (died after 5 wks) 2 (died after 4 and 6 wks) Allogeneic 3 (two pts in CR at 14 and 18 months, other patient in relapse at 11 months)

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DISCUSSION
CR rates have been increased by combination chemotherapy regimens. However, relapse occurs in the majority of these cases. Relapse disease is a poor condition because of the limited therapeutic choices, low response rates, and short remission duration. The only curative approach in cases with relapse disease is allogeneic stem cell transplantation (SCT), and CR status predicts good survival after allo-SCT. For this reason, effective and safe salvage chemotherapy regimen is highly useful in these cases before transplantation. The other important problem is the low probability of an HLA-matched donor. Autologous transplantation is another choice in cases without a donor. However, autologous transplantation results are not good enough and the relapse rate is high in these cases, as seen in the cases in our study. HiDAC has been used and found to be effective in refractory/relapse acute leukemias.3,5 On the other hand Ara-C + udarabine phosphate combinations have been given to chronic lymphocytic leukemia (CLL) patients rst and high response rates have been obtained.7 Synergistic activity of these 2 agents has been shown by in vitro studies. In experimental studies, it has been shown that intracellular Ara-CTP concentration has been found to be increased after udarabine therapy and, as a result, Ara-C cytotoxicity has been found to be increased. Antieukemic efcacy has been found to be increased after G-CSF addition to this combination.2,3,7 Complete remission rates of between 40% and 60% have found been with the FLAG regimen; this combination has mostly been used in cases of AML; and also CR rates up to 50% have been detected in cases of ALL.2,7,11 The most important limitation of the studies published so far is the low number of patients. The common results observed in these studies are high response rates and also relatively a low toxicity prole with the FLAG regimen. Idarubicin has been added to the FLAG regimen to increase the therapeutic efcacy; results have not been seen to have changed as much as seen in in vitro experiments. However, toxicity prole is not worse in the Ida-FLAG as compared with FLAG.5,10 We preferred the Ida-FLAG regimen due to the low toxicity and theoretically higher response rate. Our results are not different from those in the literature; CR status was found to be 53.6% and 42.2% in AML and ALL, respectively. However, the results of previous studies have not been published in detail according to the refractory or relapse disease, early or late relapse status, and de novo or MDS-related disease, which are parameters affecting the response in acute leukemia.
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Interestingly, we did not nd a signicant difference in response in primary refractory and also early and late relapsing disease. For this reason, we can suggest that the Ida-FLAG regimen can be effectively used in cases of refractory disease as in relapsing disease. Grade IV hematologic toxicity occurred in all cases, and early death occurred in 6 cases due to hemorrhagic complications and severe opportunistic fungal infections. Although it has not been advised routinely, prophylactic antifungal drugs and higher platelet support may be useful in these cases. Although we used G-CSF + 6-day, neutrophil recovery was similar to that reported in the literature for some studies.24,79,12 This is a cost-lowering maneuver. Nonhematologic toxicity was acceptable and routine supportive therapy was sufcient to control the signs and symptoms. Ida-FLAG is a useful choice in cases with refractory/relapsing acute leukemias to prepare the patients for allo-SCT, which is the only curative treatment in these cases. Autologous transplantation has been found to be useful in a limited number of the cases. This is due to the resistant leukemic clones, and the lack of graft versus leukemia effect of autologous transplantation necessitates the allo-SCT approach. We could perform allo-SCT to only 3 cases, 2 of which are in complete remission for 14 and 18 months and 1 in relapse. The low rate of allo-SCT (5.4%) in our cases is due to the lack of HLA-matched family donor and low socioeconomic status of the patients. In conclusion, Ida-FLAG is a good choice in cases with refractory/relapse acute leukemia for salvage chemotherapy. High efcacy and a low toxicity prole are preferable properties of this regimen, and this regimen has been found to be useful for cytoreduction, especially in candidates for allo-SCT.

REFERENCES
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IDA-FLAG Regimen for Acute Leukemia 5. Steinmetz HT, Schulz A, Staib P, et al. Phase-II trial of idarubicin, udarabine, cytosine arabinoside, and lgrastim (Ida-FLAG) for treatment of refractory, relapsed, and secondary AML. Ann Hematol. 1999;78:418425. 6. Higashi Y, Turzanski J, Pallis M, et al. Contrasting in vitro effects for the combination of udarabine, cytosine arabinoside (Ara-C) and granulocyte colony-stimulating factor (FLAG) compared with daunorubicin and Ara-C in P-glycoprotein-positive and P-glycoprotein-negative acute myeloblastic leukemia. Br J Haematol. 2000;111:565 569. 7. Visani G, Tosi P, Zinzani PL, et al. FLAG (udarabine + high-dose cytarabine + G-CSF): an effective and tolerable protocol for the treatment of poor risk acute myeloid leukemias. Leukemia. 1994;11:18421846. 8. Tedeschi A, Montillo M, Ferrara F, et al. Treatment of chronic myeloid leukemia in the blastic phase with

393 udarabine, cytosine arabinoside and G-CSF (FLAG). Eur J Haematol. 2000;64:182187. 9. Ferrara F, Leoni F, Pinto A, et al. Fludarabine, cytarabine, and granulocyte-colony stimulating factor for the treatment of high risk myelodysplastic syndromes. Cancer. 1999;86:20062013. 10. Pastore D, Specchia G, Carluccio P, et al. FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single center experience. Ann Hematol. 2003;82: 231235. 11. Jackson G, Taylor P, Smith GM, et al. A multicenter, open, non-comparative phase II study of a combination of udarabine phosphate, cytarabine and granulocyte colonystimulating factor in relapsed and refractory acute myeloid leukemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol. 2001;112: 127137.

American Journal of Therapeutics (2006) 13(5)