Fludarabine, cytarabine, G‐CSF and idarubicin (FLAG‐IDA) for the treatment of poor‐risk myelodysplastic syndromes and acute myeloid leukaemia

Abstract

Nineteen patients with high‐risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte‐colony stimulating factor (G‐CSF), and idarubicin chemotherapy (de novo MDS/MDS‐AML, nine; relapsed/refractory MDS/AML, seven; therapy‐related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG‐idarubicin with 12 (63%) achieving complete remission (CR) (<5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS‐AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow‐up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG‐idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.

Early allogeneic transplantation for refractory or relapsed acute leukaemia following remission induction with FLAG

“…1 Several recent studies have shown that a high CR rate of 50-80%, can be reproducibly achieved using the FLAG/FLAGIda regimens in these poor risk AML patients. [8][9][10][11][12][13] These results compare favourably with the use of other Ara-C containing reinduction regimens which have reported CR rates of 43% and 47% in similar groups of high risk patients. 16,17 However, the response rate to FLAG/FLAG-Ida may be reduced in elderly patients Ͼ50 years and in those with unfavourable chromosomal abnormalities, 12,13 particularly monosomy 7.…”

“…[8][9][10][11][12][13] However, remission duration appears to be short, with a median of about 3 months in most series in which it has been studied, 8,12 suggesting that additional therapy is required to achieve longterm survival in these patients. Our approach has therefore been to use the FLAG regimen or its derivative FLAG-Ida to achieve complete remission in these difficult patients followed by early allogeneic transplantation from either a sibling or an unrelated donor if no suitable sibling donor was available.…”

In vitro cytotoxic effects of fludarabine (2-F-ara-A) in combination with commonly used antileukemic agents by isobologram analysis

“…Clinical studies of fludarabine phosphate with topo-II inhibitors have been carried out against leukemia and lymphoma. [19][20][21][22] In our study, 2-F-ara-A in combination with doxorubicin showed additive effects for three cell lines and Leukemia synergistic/additive effects for one cell line, while 2-F-ara-A in combination with etoposide showed additive effects in all four cell lines. These findings suggest that the simultaneous administration of fludarabine phosphate with doxorubicin or etoposide would have the expected activity.…”

“…[9][10][11][12][13][14] Most clinical regimens incorporate two or more drugs in combination, and fludarabine phosphate has been combined with a variety of agents. [15][16][17][18][19][20][21][22][23][24][25] Although 2-F-ara-A has been reported to show synergistic effects with cytarabine and cisplatin, there are few experimental data available about the combination of 2-F-ara-A and other anticancer agents which are active against leukemia and lymphoma. [26][27][28][29][30][31][32][33] In the present study, we investigated the in vitro effects of 2-F-ara-A in combination with cytarabine, doxorubicin, etoposide, 4-hydroperoxy-cyclophosphamide, hydroxyurea, methotrexate, and vincristine against four human leukemia cell lines.…”

The presence of an HLA-identical sibling donor has no impact on outcome of patients with high-risk MDS or secondary AML (sAML) treated with intensive chemotherapy followed by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and GIMEMA Leukemia Groups (EORTC study 06921)

“…[13][14][15][16][17] The median remission duration is usually short because of a high incidence of early relapses. Therefore, the role of autologous stem cell transplantation (SCT) after remission-induction and consolidation chemotherapy has been investigated.…”