To investigate the efficacy of the FLAG regimen for refractory and relapsed acute myeloid leukemia. In this study, 27 patients with refractory and/or relapsed acute myeloid leukemia were treated with the FLAG regimen (fludarabine 50 mg IV (30 min drip) for days 1-5; cytarabine 1000 mg/m2 IV for days 1-5; G-CSF 150-300 μg subcutaneously for days 0-5), including 10 cases of refractory (AML) and 17 cases of relapsed AML. Among the 27 patients, 13 patients with refractory and relapsed AML achieved complete remission (CR rate 48.2%) and 4 patients achieved partial remission (PR rate 14.8%), with an overall effective rate of 63.0%. 3 of the patients with CR had undergone allogeneic HSCT, and all 3 are currently in disease-free survival, with the longest survival of 20 months, still in CR phase. The main toxic side effects were bone marrow suppression, gastrointestinal symptoms, and mild liver function abnormalities. CONCLUSION: FLAG regimen is still effective in some refractory and relapsed AML, and the toxic side effects are tolerable. It can be used to treat refractory and relapsed AML that is not effective with other chemotherapy regimens, and to create opportunities for patients to undergo hematopoietic stem cell transplantation.
Acute myeloid leukemia (AML) is a relatively common life-threatening hematologic malignancy that accounts for 80% to 90% of adult leukemia. Although the use of combination chemotherapy has significantly improved the efficacy of AML, about 15-30% of patients do not achieve complete remission (CR), and more than 40-50% of patients who have achieved CR eventually relapse [1]. Therefore, the treatment of refractory and relapsed AML becomes one of the challenges to be solved in leukemia treatment. In this paper, 27 cases of refractory and/or relapsed AML were treated with the FLAG regimen to understand the efficacy of this regimen in refractory and/or relapsed AML and its toxic effects.
Materials and methods
Clinical data
Twenty-seven cases of AML, observed by clinical and cytomorphological tests and treatment effects, met the diagnostic criteria for refractory and relapsed AML [2,3]. Among them, there were 10 cases of primary refractory AML and 17 cases of relapsed AML. There were 18 males and 9 females; the average age was 43.8 (15-59) years; typing: 3 cases of M1 type, 9 cases of M2 type (including 1 case transformed by MDS), 4 cases of M4 type (including 1 case of M4E0), 10 cases of M5 type (1 case of slow-granular acute monomorphism), and 1 case of mixed cell leukemia. The regimens that the patients had used before the current application of FLAG regimen included MAE regimen, H(D)A regimen, IA(E) regimen, ACG regimen, and high/medium dose Ara-C regimen.
Chemotherapy regimens
FLAG regimen: fludarabine 50 mg IV (30 min drip completion) Day 1~5; application of cytarabine 1000 mg/ m2 IV after 2~3 hours interval, Day 1~5; G-CSF 150~300 μg subcutaneous injection Day 0~5. Efficacy was judged after two courses of chemotherapy. Routine blood, liver and kidney function, bone marrow aspiration, electrocardiogram, X-ray (or CT), ultrasound and other examinations were performed before and after chemotherapy.
Supportive treatment
When chemotherapy was administered, hydration and alkalinization were given, and endoxifen or vomitobi was routinely applied to stop vomiting; heart and other organ functions were monitored; infection prevention measures were taken when white blood cells decreased, including room disinfection and alternate gargling with furacilin and mycophenolate mouthwash; G-CSF was applied when WBC was <1×109/L, and red blood cells and platelets were transfused when severe anemia and platelets were below 30×109/L.
Judgment of therapeutic efficacy [2]
According to the efficacy criteria established by the National Leukemia Symposium in Suzhou in 1987. According to the patients’ clinical manifestations, peripheral blood and bone marrow images were classified into three levels: complete remission (CR), partial remission (PR) and non-remission (NR), and CR+PR was the total effective rate.
Results
Clinical efficacy
The results of this study showed that among 27 patients, 13 patients with refractory and/or relapsed AML achieved complete remission (CR rate 48.2%) and 4 patients achieved partial remission (PR rate 14.8%), with an overall effective rate of 63.0%. 3 of the patients with CR had allogeneic HSCT and were currently in disease-free survival, with the longest survival of 20 months still in CR. Five patients relapsed within 6 months; three patients remained in remission after intensive treatment with high-dose Ara-C and other regimens; and two patients were lost to contact.
One patient had been treated with a medium dose of cytarabine (14g), which did not achieve remission, and after the current treatment with the FLAG regimen (in which the Ara-C dose was 6g), the patient achieved CR.
Toxic side effects
1. Effects on hematopoietic system
WBC <1×109/L and PLT <30×109/L in 27/27 patients (100%). 27 patients had a minimum decrease in WBC to 0.21×109/L (0.05~0.7×109/L); the minimum decrease in PLT to 6.7 (0~.20×109/L). In patients in remission, the time for PMN to rebound >0.5×109/L was 15.2 (10~29 days), and the time for PLT to rebound >20×109/L was 14.1 days (9~26 days).
2.Infection status
After treatment, 27/27 patients (100%) developed infectious fever (T≥37.5℃), including 3 cases of oral infection, 4 cases of upper respiratory tract infection, 3 cases of pulmonary infection, 3 cases of perianal infection, 7 cases of multi-site infection (more than two sites) (2 cases diagnosed sepsis), and 7 cases of fever with unclear site of infection.
3. Effects on non-hematopoietic organs
In 27 cases, 22 patients (81.5%) had loss of appetite, nausea and vomiting, which were relieved after symptomatic treatment; 4/27 cases (14.8%) had constipation; 1/27 cases (3.7%) had diarrhea; 3/27 cases (11.1%) had abnormal liver function (GTP50~200, GOP50~200); 2/27 cases (7.4%) had drug fever; 2/27 cases (7.4%) had fever. One patient (3.7%) died of pulmonary infection and gastrointestinal bleeding.
Discussion
Although some progress has been made in the treatment of adult AML, some patients are still ineffective or partially effective against first-line chemotherapeutic agents, and most of those who have achieved CR eventually relapse. Treatment of refractory and relapsed AML is difficult, and switching to multiple chemotherapy regimens is ineffective; moreover, patients with AML have poor results with hematopoietic stem cell transplantation when they have not achieved CR, which directly affects the outcome of AML and the prognosis of patients. Cytarabine is one of the most effective drugs for the treatment of refractory and/or relapsed AML. It is a drug precursor that must be converted intracellularly to cytidine 5′-triphosphate (ara-CTP) in order to exert its antitumor biological effects. The higher the dose, the higher the intracellular formation of Ara-CTP and the greater the leukemic cell-killing effect, but Ara-C is susceptible to degradation by adenosine deaminase, thus diminishing its tumor-killing activity. Fludarabine (FDR) is a fluorinated purine immunosuppressant, which is not easily degraded by adenosine deaminase, so it can maintain its activity in vivo. FDR has a synergistic effect with Ara-C, and its application 4 hours before Ara-C administration increases the concentration of Ara-CTP in leukemia cells, thus enhancing its tumor suppressive effect [4,5]. In the present study, 27 patients with refractory and/or relapsed AML were treated with the FLAG regimen, and the results showed that of the 27 patients, 13 patients with refractory and/or relapsed AML achieved complete remission (CR rate 48.2%) and 4 patients achieved partial remission (PR rate 14.8%), with an overall effective rate of 63.0%, which was similar to that reported by Jackson et al [6-9].
In the present study, one patient who had been treated with a medium dose of cytarabine (14 g) and did not achieve remission, achieved CR after the present treatment with FLAG (Ara-C dose 6 g) regimen, suggesting a significant increase in the leukemic killing effect of fludarabine (FDR) in combination with Ara-C. Three of the patients in CR had undergone allogeneic HSCT and all are currently in a disease-free survival status, with the longest survival of 20 months still in CR. The main toxicities were bone marrow suppression, gastrointestinal symptoms, mild liver function abnormalities, rash, and fever. Only one patient (3.7%) died due to complete cytopenia, pulmonary infection, and gastrointestinal bleeding. It is suggested that the toxic side effects of this regimen are tolerated by the patients.
In this study, patients had been on other regimens before applying the FLAG regimen without remission. Application of the FLAG regimen still led to complete remission in 13 cases (48.2%), indicating that there was no complete cross-resistance between the FLAG regimen and other chemotherapy regimens. Some of the refractory and relapsed AML that were ineffective to other chemotherapy regimens (e.g. MAE, IAE, /high to medium dose Ara-C, etc.) were still effective with FLAG regimen and could achieve complete remission, which could significantly increase the CR rate and prolong the survival of patients. It can also create conditions for stem cell transplantation therapy, so that more patients can have a chance of long-term survival or even cure.