[Clinical outcome of allogeneic hematopoietic stem cell transplantation with FLAG sequential busulfan/cyclophosphamide conditioning regimen for refractory/relapsed acute myeloid leukemia].

Objective: To investigate the therapeutic effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with FLAG sequential busulfan/cyclophosphamide(Bu/Cy) conditioning regimen for refractory/relapsed acute myeloid leukemia. Methods: From February 2012 to June 2017, 21 patients with refractory/relapsed acute myeloid leukemia underwent allo-HSCT with FLAG sequential Bu/Cy conditioning regimen. Transplantation-related complications and clinical outcome were retrospectively analyzed. Results: After conditioning, no hepatic veno-occlusive disease (VOD) and grade Ⅲ hemorrhagic cystitis occurred. 76.2% (16/21) patients had fever with 4 septicemia. One patient died of septic shock before engraftment. Twenty patients achieved neutrophil engraftment with a median time of 13 days (range, 10 to 21 days). Seventeen patients achieved platelet engraftment with a median time of 18 days (range, 9 to 25 days). The cumulative incidence of acute graft-versus-host disease (aGVHD) was 39.5%, and 3 patients developed grade Ⅲ-Ⅳ aGVHD. Of 19 patients who survived more than 100 days after transplantation, 4 had local chronic graft-versus-host disease (cGVHD). Of 21 patients, the median survival time was 15 months (range, 0.5 to 67 months) post-transplantation. Transplantation-related mortality rate was 28.7%. Leukemia relapse occurred in 4 patients with a median time of 4 months (range, 3 to 8 months) after transplantation. The cumulative relapse rate at 1 year was 21.4%. The 1-year and 3-year overall survival (OS) rates were 60.7% and 54.9% respectively. Log-rank analysis revealed that bone marrow blasts ≥ 20% or extramedullary leukemia before transplantation, poor platelet engraftment and grade Ⅲ-Ⅳ aGVHD were significantly related to shortened OS (P<0.05). Conclusions: Allo-HSCT with FLAG sequential Bu/Cy conditioning regimen in patients with refractory/relapsed myeloid leukemia has acceptable transplantation-related risk and relapse rate. The 1-year and 3-year OS rates are comparable with those in remission patients.

Clinical outcome of allogeneic hematopoietic stem cell transplantation with FLAG sequential busulfan/cyclophosphamide conditioning regimen for refractory/relapsed acute myeloid leukemia / 中华内科杂志

Objective@#To investigate the therapeutic effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with FLAG sequential busulfan/cyclophosphamide(Bu/Cy) conditioning regimen for refractory/relapsed acute myeloid leukemia.@*Methods@#From February 2012 to June 2017, 21 patients with refractory/relapsed acute myeloid leukemia underwent allo-HSCT with FLAG sequential Bu/Cy conditioning regimen. Transplantation-related complications and clinical outcome were retrospectively analyzed.@*Results@#After conditioning, no hepatic veno-occlusive disease (VOD) and grade Ⅲ hemorrhagic cystitis occurred. 76.2% (16/21) patients had fever with 4 septicemia. One patient died of septic shock before engraftment. Twenty patients achieved neutrophil engraftment with a median time of 13 days (range, 10 to 21 days). Seventeen patients achieved platelet engraftment with a median time of 18 days (range, 9 to 25 days). The cumulative incidence of acute graft-versus-host disease (aGVHD) was 39.5%, and 3 patients developed grade Ⅲ-Ⅳ aGVHD. Of 19 patients who survived more than 100 days after transplantation, 4 had local chronic graft-versus-host disease (cGVHD). Of 21 patients, the median survival time was 15 months (range, 0.5 to 67 months) post-transplantation. Transplantation-related mortality rate was 28.7%. Leukemia relapse occurred in 4 patients with a median time of 4 months (range, 3 to 8 months) after transplantation. The cumulative relapse rate at 1 year was 21.4%. The 1-year and 3-year overall survival (OS) rates were 60.7% and 54.9% respectively. Log-rank analysis revealed that bone marrow blasts ≥ 20% or extramedullary leukemia before transplantation, poor platelet engraftment and grade Ⅲ-Ⅳ aGVHD were significantly related to shortened OS (P<0.05).@*Conclusions@#Allo-HSCT with FLAG sequential Bu/Cy conditioning regimen in patients with refractory/relapsed myeloid leukemia has acceptable transplantation-related risk and relapse rate. The 1-year and 3-year OS rates are comparable with those in remission patients.

Evaluation of prognostic factors in patients with relapsed AML: Clonal evolution versus residual disease.

BACKGROUND: It is widely known that the prognosis of acute myeloid leukemia (AML) depends on chromosomal abnormalities. The majority of AML patients relapse and experience a dismal disease course despite initial remission. METHODS: We reviewed the medical records and laboratory findings of 55 AML patients who had relapsed between 2004 and 2013 and who had been treated at the Division of Hematology of the Pusan National University Hospital. RESULTS: The event-free survival (EFS) was related to prognostic karyotype classification at the time of diagnosis and relapse (unfavorable vs. favorable or intermediate karyotypes at diagnosis, 8.2 vs. 11.9 mo, P=0.003; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.2 vs. 11.9 mo, P=0.009). The overall survival (OS) was significantly correlated with karyotype classification only at diagnosis (unfavorable vs. favorable or intermediate vs. karyotypes at diagnosis, 8.5 vs. 21.8 mo, P=0.001; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.5 vs. 21.2 mo, P=0.136). A change in karyotype between diagnosis and relapse, which is regarded as a factor of resistance against treatment, was not a significant prognostic factor for OS, EFS, and post-relapse survival (PRS). A Cox proportional hazards model showed that the combined use of fludarabine, cytosine arabinoside, and granulocyte colony-stimulating factor (FLAG) as a salvage regimen, was a significant prognostic factor for OS (hazard ratio=0.399, P=0.010) and the PRS (hazard ratio=0.447, P=0.031). CONCLUSION: The karyotype classification at diagnosis predicts survival including PRS in relapsed AML patients as well as in treatment-naïve patients. We suggest that presently, administration of salvage FLAG could be a better treatment option.

Evaluation of prognostic factors in patients with relapsed AML: Clonal evolution versus residual disease

BACKGROUND: It is widely known that the prognosis of acute myeloid leukemia (AML) depends on chromosomal abnormalities. The majority of AML patients relapse and experience a dismal disease course despite initial remission. METHODS: We reviewed the medical records and laboratory findings of 55 AML patients who had relapsed between 2004 and 2013 and who had been treated at the Division of Hematology of the Pusan National University Hospital. RESULTS: The event-free survival (EFS) was related to prognostic karyotype classification at the time of diagnosis and relapse (unfavorable vs. favorable or intermediate karyotypes at diagnosis, 8.2 vs. 11.9 mo, P=0.003; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.2 vs. 11.9 mo, P=0.009). The overall survival (OS) was significantly correlated with karyotype classification only at diagnosis (unfavorable vs. favorable or intermediate vs. karyotypes at diagnosis, 8.5 vs. 21.8 mo, P=0.001; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.5 vs. 21.2 mo, P=0.136). A change in karyotype between diagnosis and relapse, which is regarded as a factor of resistance against treatment, was not a significant prognostic factor for OS, EFS, and post-relapse survival (PRS). A Cox proportional hazards model showed that the combined use of fludarabine, cytosine arabinoside, and granulocyte colony-stimulating factor (FLAG) as a salvage regimen, was a significant prognostic factor for OS (hazard ratio=0.399, P=0.010) and the PRS (hazard ratio=0.447, P=0.031). CONCLUSION: The karyotype classification at diagnosis predicts survival including PRS in relapsed AML patients as well as in treatment-naïve patients. We suggest that presently, administration of salvage FLAG could be a better treatment option.

Efficacy of cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG) regimen compared to FLAG regimen for adult patients with relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia.

In this study, we retrospectively assess the results in comparing the efficacies and toxicities of the three chemotherapy regimens: CAG (cytarabine, aclarubicin and granulocyte colony-stimulating factor (G-CSF), n=87), HD-CAG (increasing the dose of aclarubicin in CAG regimen, n=73), and FLAG (fludarabine, cytarabine and G-CSF, n=41) regimens in patients with relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph--ALL). Our study indicated that after one therapy course, the overall response (OR, complete reimssion (CR)+partial remission (PR)) rate was higher in CAG than that in FLAG regimen (55.2% vs. 31.7%, P=0.013), while the CR (50.7% vs. 26.8%, P =0.013) and OR (64.4% vs. 31.7%, P=0.001) rates in HD-CAG regimen were both higher than that in FLAG regimen. Furthermore, the results were more pronounced in the subgroup of patients with T cell and refractory Ph--ALL. There were no significant differences in CR and OR rates between the CAG and HD-CAG regimens. Meanwhile, the adverse effects of CAG regimen were less toxic than the FLAG and HD-CAG regimens. There were no statistically significant differences in overall survival rates at two years among the three groups (FLAG: 9.8%±4.6%, CAG: 11.8%±4.5%, HD-CAG: 11.1%±4.0%; P>0.05). Our preliminary results indicated that CAG and HD-CAG regimens could be more effective and safer than FLAG regimen for relapsed/refractory Ph--ALL.

Clinical study on FLAG and MEA regimen for refractory or relapsed adult acute myeloid leukemia / 白血病·淋巴瘤

Objective To investigate the therapeutic effects and side effects of FLAG and MEA regimen in the treatment of relapsed and refractory adult acute myeloid leukemia.Methods Use retrospective analysis to Observe the therapeutic effects and side effects of the 51 cases of relapsed and refractory adult acute myeloid leukemia (M3 except) from January 2009 to June 2012 in our hospital,which are divided into FLAG group (23 cases) and MEA group (28 cases) according to chemotherapy.Results In FLAG group,the rate of complete remission was 30.4 ％ (7/23),the rate of partial remission was 17.4 ％ (4/23),the effective rate was 47.8 ％ (11/23).In MEA group,the rate of complete remission was 35.7 ％ (10/28),the rate of partial remission was 21.4 ％ (6/28),the effective rate was 57.1％ (16/28),difference between two groups was not statistically significant. Both groups appeared Ⅳ degrees myelosupression,and there were no significant differences between them on incidences of secondary infection [95.7 ％ (22/23) vs 89.3 ％ (25/28)] and haemorrhagia [82.6 ％ (19/23) vs 85.7 ％ (24/28)].Difference on cardiac toxicity was statistically significant.Conclusions Compared with MEA regimen, FLAG regimen are similar effective and can be well tolerated,which has lower cardiac toxicity. Thus, FLAG regimen can be used as first-line treatment for relapsed and refractory adult acute myeloid leukemia.

Effects of FLAG regimen and IA regimen for acute myeloblastic leukaemia cells on P-glycoprotein-positive and P-glycoprotein-negative / 白血病·淋巴瘤

Objective To explore in vitro effects and the mechanism for FLAG regimen compared with IA regimen in P-glycoprotein-positive and -negative acute myeloblastic leukemia(AML) cell lines. Methods The expression of P-glycoprotein in K562 and K562/A02 cells were analyzed by flow cytometry. The effects of FLAG and IA on the proliferation of K562 and K562/A02 cells were detected by MTT assay. The Ara-CTP and Ara-C levels in those cells were measured by HPLC,the gene expression of hENT1 in K562 and K562/A02 cells was detected by real-time PCR. Results The positive rates of P- glycoprotein were (1.32±0.24)% in K562 cell and (97.66±3.77)% in K562/A02 cell, respectively. The expression of P- glycoprotein had no change after treated with FLAG or IA. The cytotoxicity to K562 of IA was better than FLAG [(84.41±9.33) % v.s (73.17±13.20)%, P<0.05], and the cytotoxicity to K562/A02 of FLAG was better than IA [(70.55±11.32)% v.s (48.46±12.81)%, P<0.01]. Ara-C and Ara-CTP accumulation and hENT1 expression in AML cells treated with FLAG were higher than that treated with IA. Conclusion P-glycoprotein-positive AML cells are more sensitive to FLAG regimen than IA regimen. The biochemical modulation of Ara-CTP and Ara-C may be the major mechanism.