ida-flag regimen for the therapy of primary refractory and relapse acute leukemia - a single-center...

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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 efficacy and toxicity profiles of fludarabine, Ara-C, idarubicin, and G-CSF (Ida-FLAG)combination chemotherapy in 56 refractory and/or relapsed acute leukemia patients. Patientswere treated with fludarabine phosphate 25 mg/m2/d (d1-5), Ara-C 2 g/m2/d (d1-5), idarubicin12 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 lympho-

blastic 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 moderatenausea, vomiting, and mucositis and could be controlled by routine measures. Stem cell trans-plantation was performed in 5 patients and all achieved CR, 2 autologous and 3 allogeneic. In ALLpatients, CR and PR were obtained in 8 (42.2%) and 2 (10.5%) of 22 cases; disease was resistant toIda-FLAG in 9 (47.3%) cases. Grade IV hematologic toxicity occurred in all ALL cases. Leukocyterecovery time was 17 days. Nonhematologic toxicity consisted of nausea, vomiting, and mucositisand could be controlled by supportive therapy. Autologous transplantation was performed in1 patient, but relapse disease occurred after 5 weeks. There was no correlation between response rateand leukemia subtype (AML versus ALL), leukocyte count, age, sex, disease status (de novo versussecondary), 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 incontinuous remission. The rest of the patients died. In conclusion, Ida-FLAG is a good choice in caseswith refractory/relapsing acute leukemia for salvage chemotherapy. High efficacy and a low-toxicityprofile are preferable properties of this regimen, and this regimen has been found to be useful forcytoreduction, especially in candidates for allo-SCT.

Keywords:IDA-FLAG, FLAG, relapse, acute leukemia, refractory acute leukemia

INTRODUCTION

Conventional chemotherapy is highly effective in thetreatment of acute leukemias. However, relapse devel-ops in 50% to 70% of the cases. Ten percent to 40% of

the cases with acute leukemias have primary refractorydisease. The management of cases with primary refrac-tory and/or relapse disease is very difficult. In thesecases, complete remission rates are low and remission

duration is very short.1 For this reason, clinical studieswith different alternatives are ongoing in cases withrelapse and/or refractory acute leukemias.

Ara-C is an effective chemotherapeutic agent used inacute myeloblastic leukemia (AML). High-dose Ara-C(HiDAC) regimens have been found to be effective inthese refractory/relapse cases. The rationale of HiDACis to increase the intracellular Ara-C triphosphate

Division of Oncology, Department of Internal Medicine, School ofMedicine, Cukurova University, Balcali-Adana, Turkey.*Address for correspondence: Division of Oncology, Departmentof Internal Medicine, Cukurova University, School of Medicine,01330 Balcali-Adana, Turkey. E-mail: [email protected]

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(Ara-CTP) concentration and to augment the cytotox-icity of the drug. One of the chemoresistance mecha-nisms is the P-glycoprotein (P-gp)-dependent effluxand HiDAC down-regulates the P-gp efflux.16 It has

been shown that there is a positive correlation betweencomplete response and high intracellular Ara-Ccontent. The combination of Ara-C with fludarabinephosphate increases the Ara-C content two- to seven-fold in leukemic cell. This synergistic effect has beenshown in various studies. Ara-CTP content and cyto-toxicity increase when HiDAC is given after fludarabineinfusion. Besides, granulocyte-colony stimulating factor(G-CSF) given in this schema augments the incorpora-tion of Ara-CTP to leukemic cell DNA and causes anincrease in blastic cell death with G-CSF, especially asAML blasts enter the S phase of the cell cycle andcytotoxicity increases.2,4,79 For this reason, fludarabinephosphate, Ara-C, and G-CSF regimen (FLAG) is animportant choice in cases with refractory/relapsingacute leukemias. In recent years, idarubicin has been

added to FLAG to increase the efficiency of therapy andis named as Ida-FLAG.10 The Ida-FLAG combination isan effective regimen in cases with refractory/relapsingacute leukemias that have poor prognosis and lowresponse rates. We report here the efficacy of Ida-FLAGin 56 cases with refractory/relapsing acute leukemia(34 AML and 22 ALL).

PATIENTS AND METHODS

Fifty-six cases with refractory/relapsing acute leuke-

mia treated at the Oncology Department of Cx

ukurovaUniversity, Faculty of Medicine are included in thisstudy. Peripheral blood and bone marrow sampleswere evaluated by morphology, histochemistry, andimmunophenotyping. Inclusion criteria included se-rum creatinine level ,2 mg/dL, bilirubin ,2 mg/dL,and left ventricle ejection fraction .50%. Patients notresponding to remission induction therapy were ac-cepted as primary refractory. Relapsing disease wasdefined as a response to remission induction and blastincrease in peripheral blood and/or bone marrow.5%during follow-up. dA relapse developing in patients infirst 6 months after complete remission was accepted as

early relapse.

Treatment protocol

Fludarabine 25 mg/m2/d (d1-5) i.v. as a 30-minuteinfusion, 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

subcutaneously from sixth day to until absolute neu-trophil count (ANC) .500/mL.

Response criteria are as follows:

1. Complete remission (CR): Peripheral blood countswithin normal limits plus bone marrow blastpercentage ,5%.

2. Partial remission (PR): Peripheral blood counts

within normal limits plus bone marrow blastpercentage between 5% and 20%.

3. Refractory disease (RD): No improvement in pe-ripheral blood and/or bone marrow blastic cells.

4. Early death (ED): Death within 6 weeks ofchemotherapy.

Overall survival (OS)

1. Duration of first day of chemotherapy to death orlast control visit.

2. Relapse-free survival (RFS): Duration from theday detected CR to relapse and/or last control

visit.3. WHO classification was used to determine thechemotherapy associated hematologic and non-hematologic toxicity.

Statistical analysis

SPSS 11.5 pocket program has been used for statisticalanalysis. For comparisons t test, x2 test, multivariatelogistic regression, and Cox regression analyses wereused.P value .0.05 has been accepted as meaningful.

RESULTSFifty-six patients with refractory/relapsing acuteleukemia were included in this study. Thirty-four ofthem had AML and 22 had ALL. Mean age was 37(range 1559) and 25 (range 1548) in cases with AMLand ALL, respectively. Female/male ratio was 1.1/1 inAML and 1.2/1 in ALL cases. One third of the AMLcases and 45% of ALL cases were primary refractorydisease and rest of them had relapse disease. Thirty-one of AML cases had de novo disease and 3 had AMLsecondary to myelodysplastic syndrome (Table 1).

AML casesIda-FLAG was given 1 cycle to 21 cases, 2 cycles to 8cases, and only 3 cases received 3 cycles (Table 2). CRwas achieved in 15 cases (53.6%). One case showed PR(3.6%) and 12 cases (42.8%) had RD. ED developed in 6cases (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

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not different in cases with relapse and primaryrefractory disease (P= 0.57). PR was obtained in only1 case with primary refractory disease. ED developed

in 3 of 12 (25%) and 3 of 23 (13%) cases with primaryrefractory and relapse AML, respectively (Table 3).

Grade IV hematologic toxicity occurred in all caseswith AML; leukocyte nadir was 43/mL (range 5231/mL) and febrile neutropenia developed in all cases.Leukocyte recovery time was 16 days (range 1434days). Among 34 cases, nonspecific pneumonia de-veloped in 9 cases, mucormycosis in 1, and invasivepulmonary aspergillosis (IPA) in 1. ED was seen in 6cases; 3 due to hemorrhagic complications, 1 due tomucormycosis, 1 due to IPA, and 1 due to septic shock.Nonhematologic complications were mild to moderatenausea, vomiting, and mucositis and could be con-

trolled 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 6weeks due to relapse disease. Two of 3 patients withallogeneic transplantation are in CR at 14 and 18 monthspost-transplantation; extramedullary relapse developedin 1 case at 11 months post-transplantation (Table 4).

ALL cases

Ida-FLAG was given 1, 2, and 3 cycles in 14, 6, and 2cases, respectively. CR and PR were obtained in 8

(42.2%) and 2 (10.5%) of 22 cases, respectively. Disease

was resistant to Ida-FLAG in 9 (47.3%) cases and EDoccurred in 3 (13.7%) cases. According to the diseasestatus, in cases with primary RD, CR, PR, resistantdisease (RD), and early death (ED) were detected in 3 of9 (33.3%), 1 of 9 (11.1%), 5 of 9 (55.5%) and 1 of 10(10%), respectively. In relapse cases CR, PR, RD, andED were detected 5 of 10 (50%), 1 of 10 (10%), 4 of 10(40%), and 2 of 12 (16.7%), respectively. CR rate in caseswith ALL was higher in relapse cases as compared withprimary refractory cases (33.3% versus 50% but non-significant,P .0.05) (Table 3).

Grade IV hematologic toxicity occurred in all caseswith ALL, leukocyte nadir was 41/mL (range 6138)and febrile neutropenia developed in all cases as seenin cases with AML. Leukocyte recovery time was 17days (range 1327). Pneumonia developed in 7 cases;nonspecific pneumonia in 5, IPA in 1, and mucormy-cosis in 1. Early death was detected in 3 cases: 1 due tohemorrhagic complication, 1 due to mucormycosis,and 1 due to IPA. Nonhematologic toxicity consisted ofnausea, vomiting, and mucositis and could be con-trolled by supportive therapy.

Allogeneic transplantation could not be performeddue to the lack of a donor in none of the cases obtainedCR. Autologous transplantation was performed in 1case, but relapse disease occurred after 5 weeks.

There was no correlation between response rate andleukemia subtype (AML versus ALL), leukocyte count,age, sex, disease status (de novo versus secondary),and RFS (early versus late relapse) (P . 0.05). Mediansurvival was 16 weeks (range 2100 weeks) in all cases(22 weeks in AML versus 13 weeks). At present, only3 patients are alive and 2 of these are in continuousremission. The rest of the patients died.

Table 1. Clinical characteristics of patients.

Parameter Number

AML 34

Relapse 23

Primary refractory 11

Male 18

Female 16

Median age 37 (1559)ALL 22

Relapse 12

Primary refractory 10

Male 12

Female 10

Median age 25 (1548)

Total 56 patients

Table 2. Number of FLAG-Ida course in patients.

1st course 2nd course 3rd course

ALL (22 patients) 14 6 2

AML (34 patients) 23 8 3

Table 3. Clinical response rates in all patients.

Patients CR (%) PR (%) NR (%) ED (%)

AML 53.6 3.6 42.8 17,6

Primary refractory pts. 62.5 12.5 25 26

Relapse pts. 50 50 13

ALL 42.2 10.5 47.3 13,7

Primary refractory pts. 33.3 11.1 55.5 10

Relapse pts. 50 10 40 16,7

Table 4. Transplantation status in patients (HSCT).

Autologous Allogeneic

ALL 1 (died after 5 wks)

AML 2 (died after 4 and

6 wks)

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 chemo-therapy regimens. However, relapse occurs in themajority of these cases. Relapse disease is a poorcondition because of the limited therapeutic choices,low response rates, and short remission duration. The

only curative approach in cases with relapse disease isallogeneic stem cell transplantation (SCT), and CRstatus predicts good survival after allo-SCT. For thisreason, effective and safe salvage chemotherapyregimen is highly useful in these cases before trans-plantation. The other important problem is the lowprobability of an HLA-matched donor. Autologoustransplantation is another choice in cases withouta donor. However, autologous transplantation resultsare not good enough and the relapse rate is high inthese cases, as seen in the cases in our study.

HiDAC has been used and found to be effective inrefractory/relapse acute leukemias.3,5 On the other

hand Ara-C + fludarabine phosphate combinationshave been given to chronic lymphocytic leukemia(CLL) patients first and high response rates have beenobtained.7 Synergistic activity of these 2 agents has

been shown by in vitro studies. In experimentalstudies, it has been shown that intracellular Ara-CTPconcentration has been found to be increased afterfludarabine therapy and, as a result, Ara-C cytotoxicityhas been found to be increased. Antieukemic efficacyhas been found to be increased after G-CSF addition tothis combination.2,3,7 Complete remission rates of

between 40% and 60% have found been with the

FLAG regimen; this combination has mostly been usedin cases of AML; and also CR rates up to 50% have beendetected in cases of ALL.2,7,11 The most importantlimitation of the studies published so far is the lownumber of patients. The common results observed inthese studies are high response rates and also relativelya low toxicity profile with the FLAG regimen.Idarubicin has been added to the FLAG regimen toincrease the therapeutic efficacy; results have not beenseen to have changed as much as seen in in vitroexperiments. However, toxicity profile is not worse inthe Ida-FLAG as compared with FLAG.5,10 We pre-ferred the Ida-FLAG regimen due to the low toxicity

and theoretically higher response rate. Our results arenot different from those in the literature; CR status wasfound to be 53.6% and 42.2% in AML and ALL,respectively. However, the results of previous studieshave not been published in detail according to therefractory or relapse disease, early or late relapsestatus, and de novo or MDS-related disease, which areparameters affecting the response in acute leukemia.

Interestingly, we did not find a significant difference inresponse in primary refractory and also early and laterelapsing disease. For this reason, we can suggest thatthe Ida-FLAG regimen can be effectively used in casesof refractory disease as in relapsing disease.

Grade IV hematologic toxicity occurred in all cases,and early death occurred in 6 cases due to hemorrhagiccomplications and severe opportunistic fungal infec-tions. Although it has not been advised routinely,prophylactic antifungal drugs and higher plateletsupport may be useful in these cases. Although weused G-CSF + 6-day, neutrophil recovery was similar tothat 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 sufficient to control the signsand symptoms.

Ida-FLAG is a useful choice in cases with refrac-tory/relapsing acute leukemias to prepare the patientsfor allo-SCT, which is the only curative treatment in

these cases. Autologous transplantation has been foundto be useful in a limited number of the cases. This isdue to the resistant leukemic clones, and the lack ofgraft versus leukemia effect of autologous transplan-tation necessitates the allo-SCT approach. We couldperform allo-SCT to only 3 cases, 2 of which are incomplete remission for 14 and 18 months and 1 inrelapse. The low rate of allo-SCT (5.4%) in our cases isdue to the lack of HLA-matched family donor and lowsocioeconomic status of the patients.

In conclusion, Ida-FLAG is a good choice in caseswith refractory/relapse acute leukemia for salvagechemotherapy. High efficacy and a low toxicity profile

are preferable properties of this regimen, and thisregimen has been found to be useful for cytoreduction,especially in candidates for allo-SCT.

REFERENCES

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2. Visani G, Tosi P, Zinzani PL, et al. FLAG (fludarabine,cytarabine, G-CSF) as a second line therapy for acute

lymphoblastic leukemia with myeloid antigen expression:in vitro and in vivo effects. Eur J Haematol. 1996;56:308312.3. Huhmann IM, Watzke HH, Geissler K, et al. FLAG

(fludarabine, cytosine arabinoside, G-CSF) for refractoryand relapse acute myeloid leukemia. Ann Hematol. 1996;73:265271.

4. Montillo M, Mirto S, Petti MC, et al. Fludarabine,cytarabine, and G-CSF (FLAG) for the treatment of poorrisk acute myeloidleukemia.Am J Hematol. 1998;58:105109.


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5. Steinmetz HT, Schulz A, Staib P, et al. Phase-II trial ofidarubicin, fludarabine, cytosine arabinoside, and filgras-tim (Ida-FLAG) for treatment of refractory, relapsed, andsecondary AML. Ann Hematol. 1999;78:418425.

6. Higashi Y, Turzanski J, Pallis M, et al. Contrasting in vitroeffects for the combination of fludarabine, cytosinearabinoside (Ara-C) and granulocyte colony-stimulatingfactor (FLAG) compared with daunorubicin and Ara-C

in P-glycoprotein-positive and P-glycoprotein-negativeacute myeloblastic leukemia.Br J Haematol. 2000;111:565569.

7. Visani G, Tosi P, Zinzani PL, et al. FLAG (fludarabine +high-dose cytarabine + G-CSF): an effective and tolerableprotocol for the treatment of poor risk acute myeloidleukemias.Leukemia. 1994;11:18421846.

8. Tedeschi A, Montillo M, Ferrara F, et al. Treatment ofchronic myeloid leukemia in the blastic phase with

fludarabine, 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 treat-ment of high risk myelodysplastic syndromes. Cancer.1999;86:20062013.

10. Pastore D, Specchia G, Carluccio P, et al. FLAG-IDAin 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 fluda-rabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acutemyeloid leukemia and de novo refractory anaemia withexcess of blasts in transformation.Br J Haematol. 2001;112:127137.


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