Dysplastic peripheral blood polymorphs link acute myeloblastic leukaemia in elderly to the myelodysplastic syndromes.

We studied dysplastic features in peripheral blood polymorphs from 80 patients with acute leukaemia. Thirty-seven patients with de novo acute myeloblastic leukaemia (AML) were compared to 26 patients with AML that had developed after a myelodysplastic phase (MDS-AML), and 17 cases of acute lymphoblastic leukaemia (ALL). Cytoplasmic hypogranulation in neutrophils, measured as a score value (G-score; normal range: 255-300), and the percentage of pelgeroid polymorphs (ppp; normal range: 0.5%) were studied retrospectively by reviewing the diagnostic peripheral blood smears. The mean G-score was decreased in MDS-AML (178 +/- 67.9), and in de novo AML (212 +/- 65.1), but not in ALL (275 +/- 24.3). When de novo AML patients were divided by age, the elderly (greater than 60 yr) had significantly (p = 0.0001) lower mean G-score than the younger (less than 45 yr) ones; 156 +/- 64.8 v 243 +/- 41.4. This age-related difference became accentuated when only patients with extreme hypogranulation (G-score less than 150) were studied. Elderly de novo AML patients also had significantly (p = 0.0057) higher mean ppp. By studying the degree of polymorph dysplasia in the peripheral blood, it seems possible to identify a subset of dysplastic elderly AML patients, who might have passed a (preleukaemic) MDS phase unnoticed.     

Myelodysplastic relapse of de novo acute myeloid leukaemia with trilineage myelodysplasia: a previously unrecognized correlation

We describe the occurrence of an unusual mode of relapse in six of 24 patients who presented with de novo acute myeloid leukaemia (AML) associated with trilineage myelodysplasia (TMDS). After the induction of complete remission (CR) by intensive chemotherapy in five patients and following bone marrow transplantation (BMT) in one, the myelodysplastic state, but not overt AML, recurred. Relapse of myelodysplasia occurred at a median of 147 weeks (50-520) from presentation and in two instances was followed a year later by AML. In five cases, myelodysplastic relapse was treated with low-dose cytosine arabinoside given alone or with other chemotherapeutic agents. Three patients remain in CR after 1, 2 and 5 years. The reappearance of myelodysplastic features in these six patients was strongly correlated with the presence of TMDS at presentation of the AML. It was not observed once in the 136 AML patients, treated similarly, who did not have associated TMDS at presentation (P less than 0.001). Thus, relapse with myelodysplasia is not an effect of chemotherapy as has been previously postulated.     

Significance of trilineage myelodysplasia in de novo acute myeloid leukaemia during remission rather than at diagnosis

Patients with trilineage myelodysplasia (TMDS) in de novo acute myeloid leukaemia (AML) at diagnosis and remission were clinically evaluated between 1983 and 1996. AML with TMDS (AML/TMDS) was observed in 20 (12%) of 162 patients with de novo AML at diagnosis. Complete remission (CR) was achieved with combination chemotherapy in 12 (67%) of 18 AML/TMDS cases. This CR rate was relatively worse than the rate of 78% (106/136 cases) of AML without TMDS, but this difference was not significant. Disease-free survival curves also showed no difference between AML/TMDS and AML without TMDS. During remission, eight (67%) of 12 AML/TMDS cases had myelodysplastic remission marrow (AML/MRM). AML/MRM was also seen in seven (7%) of 106 AML cases without TMDS. The actuarial disease-free survival was significantly lower in AML/MRM than in AML without MRM ( P  = 0.0003). All of the AML/MRM cases exhibited early leukaemic relapse; median remission duration was only 9 months. Clonal changes occurred in two cases of AML/TMDS and five cases of AML/MRM at the time of relapse. These findings suggest that TMDS during remission predicts a poorer prognosis and early leukaemic relapse when compared with the absence of TMDS.     

Poor response to intensive chemotherapy in de novo acute myeloid leukaemia with trilineage myelodysplasia

Summary. The findings of morphologically dysplastic features in haemopoietic cells in de novo acute myeloid leukaemia (AML) has been named AML with trilineage myelodysplasia (AML/TMDS). We analysed the clinical data, karyotypes, and treatment outcomes of 230 de novo AML patients treated with the Japan Adult Leukaemia Study Group AML-87 protocol. 40 (17%) patients had AML/TMDS. Platelet count was significantly higher ( F =0·006) and bone marrow blasts were fewer ( P =0·01) in the AML/TMDS group than in the AML without TMDS. Abnormal karyotype was shown in 12/30 patients (40%) analysed.
The complete remission (CR) rate for AML/TMDS was significantly lower than AML without TMDS (63% v 81%) ( P =0·01). The overall survival curves showed that the 40 patients with TMDS had a significantly worse survival than the 190 without TMDS ( P =0·0005). AML/TMDS also showed significantly worse disease-free survival (DFS) ( P =0·0001).
Multivariate analysis revealed that the absence of TMDS in AML was the most significant factor in obtaining CR ( P =0·01) and a significant factor in predicting longer DFS ( P =0·04). Our data suggest that AML/TMDS responds poorly to intensive chemotherapy. Further study is required to determine the best treatment strategy for AML/TMDS and the biological differences between AML/TMDS and other types of AML.     

The relationship between bcl-2 expression and response to chemotherapy in acute leukaemia

Summary. Immunocytochemistry was used to assess bcl-2 expression in blasts obtained from the bone marrow of 28 patients with acute lymphoblastic leukaemia (ALL) (16 children and six adults at presentation and three children and three adults on relapse) and 20 with acute myeloid leukaemia (AML) (19 adults and one child, 13 with de novo AML, 11 at presentation and two on relapse, and seven secondary to myelodysplasia or chronic myeloid leukaemia). Slides were examined both for the percentage of positive cells and for the intensity of staining using a five-point scale. There was a statistically significant increase in both the percentage of positive cells seen (P < 0.002) and the intensity of staining (P < 0.01) between samples obtained at relapse and those at presentation in ALL. There was a significantly greater intensity of staining in cells from patients with ALL (P < 0.05) and AML (P < 0.05) who failed to achieve remission after chemotherapy than in those who responded. The intensity of staining in cases of secondary AML was lower than that in de novo disease (P < 0.01). These results suggest that expression of bcl-2 may be an important prognostic feature in both de novo AML and in ALL, but not in secondary AML.     

Cytogenetic clonality analysis: typical patterns in myelodysplastic syndrome and acute myeloid leukaemia

The cell morphology and karyotype of bone marrow samples from 24 patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) were studied simultaneously with a combined technique of May-Grünwald-Giemsa (MGG) staining and fluorescence in situ hybridization (FISH) with chromosome-specific DNA probes. This enabled us to investigate cell lineage involvement in three malignant conditions: MDS ( n  = 12), leukaemia-transformed MDS (LT-MDS) ( n  = 5) and de novo AML ( n =7). In MDS we found blasts and often significant proportions of mature granulocytic and erythroid cells to be cytogenetically abnormal. Percentages of granulocytic and erythroid cells with cytogenetic aberrations were generally less than those of blasts. These data support the involvement of a transformed pluripotent stem cell that has retained maturation abilities. In two patients with chronic myelomonocytic leukaemia (CMMoL) the clonal involvement of monocytes was predominant. Results in the five patients with LT-MDS were similar to those in MDS. In the bone marrow of five of the seven de novo AML patients the cytogenetic abnormalities were restricted to the blasts and did not include the more mature granulocytic or erythroid populations. In the other two patients with AML, both with a t(8;21) and a loss of the Y chromosome, high percentages of mature neutrophils were cytogenetically abnormal. These patterns of clonal lineage involvement in MDS, LT-MDS, t(8;21) AML and AML appear typical and may be of clinical use, for example, for distinguishing LT-MDS from de novo AML in newly presenting patients.     

AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC''s 9th AML trial

The outcome of treatment with standard first line therapy of 66 patients with acute myeloid leukaemia (AML) secondary to preceding chemotherapy (Group 1), a myelodysplastic state (Group 2) or a myeloproliferative disorder (Group 3) was analysed in relation to the preceding disorder, the cytogenetic pattern where available, and the cytology and cytochemistry of blood and bone marrow. The complete remission (CR) rate for the secondary AMLs was 36% (24/66), with 24% (16/66) dying in the induction period and 39% (26/66) having resistant disease. The CR rate was 25% (5/20) for Group 1, 42% (15/36) for Group 2, and 40% (4/10) for Group 3. Even after allowance for the generally older age of the secondary AML patients, they still had a significantly poorer CR rate than the de novo AMLs (P = 0.0004). The lower CR rate was chiefly due to resistant disease. Despite this, overall survival was not significantly worse for the secondary AML patients (P = 0.15). For the 36% that achieved remission, remission duration appeared similar to that of de novo cases. Of 62 cases with adequate cytology, 38 (61%) had evidence of erythroid and/or megakaryocytic dysplasia with a CR rate of 32% (12/38). The CR rate of these multineage leukaemias was not significantly different from that of the 24 (39%) who showed granulocyte/monocyte precursor involvement only, 42% (10) of whom achieved CR. The presence of features of differentiation within blast cells such as Auer rods or sudanophilia (greater than 50% positive blasts) was associated with a higher remission rate 47% (18/38) than that of poorly differentiated cases 17% (3/18) (P = 0.04) and thus appeared to be a more important determinant of CR achievement than was lineage involvement. Cases with a normal karyotype had a 33% (7/21) CR rate, while those with chromosomal abnormalities had a 37% (9/24) CR rate. Only 12 of the 45 cases with adequate cytogenetic analysis showed deletions or monosomies involving chromosomes 5 or 7, and seven of these were in Group 1.     

Normal membrane function of abnormal β-related erythrocyte sialoglycoproteins

Megakaryocytopoiesis was morphologically investigated in 129 adults with de novo acute leukaemia. Three types were identified: type I (84 cases), no detectable megakaryocytes; type II (32 cases), quantitatively preserved megakaryocytes with normal morphology; type III (13 cases); quantitatively preserved megakaryocytes but with distinct dysplastic changes such as micromegakaryocytes and megakaryocytes with multiple small separated nuclei. Type III was found in M1 (one out of 21 cases), M2 (one out of 20 cases). M4 (eight out of 24 cases), M6 (two out of four cases) and hypoplastic leukaemia (one out of 13 cases). M3 cases were all classified into type I. Most of acute lymphoid leukaemia cases (21 cases) belonged to type II. Among AML cases, the complete remission (CR) rate by intensive chemotherapy with daunorubicin and cytosine arabinoside was significantly lower in type III (11%) than in types I (87%) and II (71%). Among M4 cases, CR rates in type III (14%) was also significantly lower than those in type I (75%) and II (100%). Thus, the present study indicates the importance of recognizing dysmegakaryocytopoiesis in AML for clarification of the heterogeneous biology or pathophysiology of acute leukaemias and formulation of an appropriate therapeutic strategy.     

Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia

To investigate the regulatory mechanisms of angiogenesis in the development of myelodysplastic syndromes (MDS) and its progression to overt leukaemia (OL), bone marrow samples from control, paired samples from MDS patients before and after transformation to OL (MDS --> OL) and de novo acute myeloid leukaemia (AML) were analysed. Immunohistochemical staining showed a significant increase of bone marrow microvascular density (MVD) in MDS and de novo AML compared with controls. Surprisingly, in MDS, MVD significantly decreased upon transformation to OL, which was also significantly lower than the MVD of de novo AML. This evidence was strengthened by the pattern of angiogenic mediator gene expression, confirming the importance of various angiogenic mediators including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumour necrosis factor alpha (TNFalpha), hepatocyte growth factor (HGF) and the angiopoietin family of mediators (Ang-1 and Ang-2) as well as the receptors for angiogenic mediators, such as VEGF receptor 2 (VEGFR2) and the tyrosine kinase receptor, TIE2. By contrast, the anti-angiogenic mediator, transforming growth factor-beta (TGFbeta) exhibited significantly higher expression in the bone marrow of MDS --> OL, indicating the importance of this cytokine as the suppressive factor of angiogenesis in MDS. These findings indicate that the bone marrow microenvironment in MDS --> OL and de novo AML differs remarkably, suggesting the different efficacy of anti-angiogenic therapy between de novo AML and leukaemia secondary to MDS.     

Oral treatment of acute myeloid leukaemia with etoposide, thioguanine, and idarubicin (ETI) in elderly patients: a prospective randomised comparison with intravenous cytarabine, idarubicin, and thioguanine in the second and third treatment cycle

A randomised multicentre study was conducted among patients over 65 yr of age with newly diagnosed acute myeloid leukaemia (AML) to compare oral treatment with etoposide 80 mg/m(2) and thioguanine 100 mg/m(2) twice daily on 5 d and idarubicin 15 mg/m(2) on 3 d (ETI) to a mainly i.v. combination of cytarabine 100 mg/m(2) twice daily on 5 d, idarubicin 12 mg/m(2) x 1, and thioguanine (TAI). Ninety-two patients were enrolled. Their median age was 72 yr, range 65-84 yr. Sixty-five patients had de novo AML, 21 AML subsequent to myelodysplastic syndrome, and six treatment-related AML. They received at first a 6-d i.v. treatment with cytarabine and idarubicin. After the first treatment, 68 patients were randomised to receive two cycles of ETI (n = 36) or TAI (n = 32) and thereafter maintenance with mercaptopurine and methotrexate. Of the 92 patients, 52 (57%) achieved remission at some stage. The median survival was 10 months. There were no significant differences between the patients randomised to ETI or TAI in the remission rate (67% vs. 72%), survival (12 months from randomisation in both arms), event-free survival or relapse rate. The patients randomised to receive ETI spent significantly fewer days at hospital during the two randomised cycles (20 vs. 41 d, P = 0.010), and they had fewer days with infusions, shorter neutropenias and thrombocytopenias and fewer and less severe infections. In conclusion, treatment with oral ETI resulted in a similar antileukaemic effect as obtained with mainly i.v. TAI, with less toxicity and reduced need for hospitalisation.     

Emergence of karyotypically unrelated clone in remission of de novo acute myeloblastic leukaemias

Serial cytogenetic analysis revealed karyotypically unrelated clones in four patients with acute myeloblastic leukaemia (AML) in remission. At diagnosis, three patients had t(8;21)(q22;q22) and one had an inv(16)(p13q22). After 18-22 months in remission, different clones emerged in each patient with myelodysplastic features of the bone marrow cells. The emergence of clones with abnormalities of chromosome 7 in remission seems to be an unfavourable factor for prognosis.     

Clonal evolutions during long-term cultures of bone marrow from de novo acute myeloid leukaemia with trilineage myelodysplasia and with myelodysplastic remission marrow

Summary. We previously established a long-term bone marrow culture (LTBMC) system in which novel abnormal karyotypes could emerge in vitro prior to the appearance of the same karyotypes in vivo in patients with myelodysplastic syndrome (MDS). We extended our study to examine whether acute myeloid leukaemia (AML) transformed from MDS (MDS/AML) and de novo AML with trilineage myelodysplasia (AML/TMDS) show clonal evolution in LTBMC similar to that of typical AML or MDS. We also analysed the cytogenetic changes in cultures with bone marrows from AML with myelodysplastic remission marrow (AML/MRM) as well as chronic myeloid leukaemia (CML) to compare them with typical AML with respect to the liability of clonal evolution. Among the 34 AML cases, abnormal karyotypes were newly detected in four of seven MDS/AML, three of six AML/TMDS and three of three AML/MRM. Novel abnormal karyotypes were also observed in nine out of 13 CML cases after culture. In contrast, no other abnormal karyotypes were found after culture in 18 typical AML without myelodysplasia. These findings suggest that AML/TMDS and AML/MRM are different from typical AML and are similar to MDS/AML and CML in view of their potential for disease progression from latent multiple clones. Typical AML may develop from a single abnormal clone without any subclones.     

Adult biphenotypic acute leukaemia: an entity with poor prognosis which is related to unfavourable cytogenetics and P-glycoprotein over-expression

Biphenotypic acute leukaemia (BAL) patients represented 8% of the 287 de novo consecutive adult acute leukaemias (23 BAL, 230 acute myeloid leukaemia (AML) and 34 acute lymphoblastic leukaemia (ALL)) referred to our department during the last 4-year period. Of these 23 BAL patients, 14 patients showed myeloid morphology and nine cases lymphoid morphology according to FAB criteria. There were no differences between lymphoid and myeloid BAL according to clinical and biological presentation and treatment outcome. We confirm the poor prognosis of BAL when compared to AML or ALL seen during the same period of time, in terms of complete remission (47%, 62% and 82% respectively, BAL v AML, NS and BAL v ALL, P  = 0.006) and 4-year overall survival (8.1%, 25.8% and 23.8% respectively, BAL v AML, P  = 0.05 and BAL v ALL, P  = 0.003). Comparing adult BAL patients with AML patients, we found an increase in poor prognostic factors: CD34⁺ phenotype (82% v 60% respectively, P  = 0.03), unfavourable karyotype (60% v 20%, P  < 0.0001) and Pgp over-expression by RT-PCR (0.705 v 0.107, P  < 0.0001) and flow cytometry (0.824 v 0.391, P  = 0.0001). MRP and LRP were not found to be poor prognostic factors. Comparing BAL patients with ALL patients, we found also an increase in poor prognostic factors: age (51 v 39, P  = 0.003) and CD34⁺ phenotype (82% v 50%, P  = 0.02). We conclude that BAL patients need a more aggressive treatment procedure, including high-dose AraC or the use of Pgp modulators for first-line therapy.     

Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome

Wnt signaling activates the canonical pathway and induces the accumulation of non-phosphorylated beta-catenin (NPBC) in the nucleus. Although this pathway plays an important role in the maintenance of haematopoietic stem cells as well as in oncogenesis, the significance of nuclear NPBC remains unclear in malignant haematopoiesis. This study examined the expression of nuclear NPBC in bone marrow specimens from 54 and 44 patients with de novo acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), respectively. On immunohistochemistry with an anti-NPBC antibody, the nuclei were positively stained in 22 and 18 of AML and MDS specimens, respectively. Staining of nuclear NPBC was associated with AML subtypes (M6 and M7), low complete remission (CR) rate, and poor prognosis. Nuclear NPBC was also associated with a high score when using the International Prognostic Scoring System (IPSS) for MDS and with −7/−7q and complex karyotypes. These findings suggest that in situ detection of nuclear NPBC by immunohistochemistry could provide new insights into the pathogenesis and prognosis of AML and MDS.     

Marked dysmyelopoiesis after induction chemotherapy in a case of acute myelomonocytic leukemia (M 4) with t(6; 11)

A case of AML (M 4) with t(6; 11) showed recovery to myelodysplastic syndrome (MDS)-like bone marrow after one course of DCMP regimen. Dysplastic changes of three cell-lineages were observed and micromegakaryocytes were markedly increased in number. Recovering hematopoiesis was incomplete. During MDS-like phase, t(6; 11) disappeared, reverting to normal karyotypes. Low dose ara-C regimen did not show any effect. AML soon relapsed with reappearance of t(6; 11). MDS-like abnormal hematopoiesis has recently been reported to occur after remission induction therapy or at the time of relapse. G-6PD isozyme study revealed in a remission case of AML that hematopoiesis still consisted of abnormal clone in spite of karyotypic normalization. The abnormal hematopoiesis observed in our case can be referred to such a clonal disorder predominating after disappearance of blastic component of AML. It seems important to reveal what proportion of de novo AMLs shows such an abnormal hematopoiesis and to establish suitable therapeutic approach.     

Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simultaneously determined by flow cytometry

To evaluate the clinical relevance of multidrug resistance (MDR) phenotype, the intracellular daunorubicin accumulation (IDA) and P- glycoprotein (P-gp) expression were investigated in 87 adult patients with acute leukemia: 69 patients with de novo acute myeloid leukemia (AML), 10 with AML at relapse, and eight with secondary leukemia to myelodysplastic syndromes (MDS-AML). IDA and P-gp expression were determined by double-labeling flow cytometry analysis. Of 87 patients, 36 expressed P-gp (41%). P-gp expression was more frequently observed in AML at relapse and MDS-AML as compared with de novo AML (P = .0001). P-gp expression was significantly associated with CD34 expression (P = .0003) and chromosome 7 abnormalities (P = .027). A significantly reduced IDA was observed in P-gp+ as compared with P-gp- patients (P = .0007). Of the 87 patients, 51 achieved complete remission (CR). A reduced IDA was observed in patients in failure as compared with patients in CR (22% +/- 17% v 42% +/- 21%; P = 10(-4). Twelve of 36 P- gp+ patients as compared with 40 of 51 P-gp- patients achieved CR (33% v 78%; P = 10(-4). The prognostic value of IDA and P-gp expression was confirmed in multivariate analysis. These data suggest that the determination of IDA and P-gp expression may be useful in designing therapy for patients with AML.     

The role of aggressive chemotherapy in the treatment of the myelodysplastic syndromes

Fifteen patients with the initial diagnosis of myelodysplastic syndrome (MDS) received aggressive chemotherapy with high dose cytarabine or with a standard acute myeloid leukaemia (AML) regime. Cases treated with aggressive chemotherapy were either younger individuals with refractory anaemia with excess of blasts (RAEB) or patients, irrespective of age in advanced stages of MDS (RAEB in transformation or after evolution to frank AML), who did not have a major infection at the time of presentation. Age seemed to be the most important factor in determining the outcome of aggressive remission induction chemotherapy in MDS: 86% of the patients less than 50 years entered complete remission, compared to only 25% in the older age group. In spite of intensive consolidation therapy the duration of complete remission was short. We conclude that young patients (less than 50 years) with excess of bone marrow blasts should be treated with aggressive chemotherapy even in the early stages of the disease. Elderly patients in advanced stages of MDS should be treated with less aggressive chemotherapy.     

Prognostic value of dysmyelopoietic features in de novo acute myeloid leukaemia: a report on 132 patients

The prognostic value of cytological features was assessed in 132 patients with de novo acute myeloid leukaemia (AML) treated by anthracycline-cytosine-arabinoside combination chemotherapy. Of these patients, 98 (75%) achieved complete remission (CR). A significantly lower CR rate was seen in patients with trilineage dysmyelopoiesis (TDMP) (P = 0.003), but not in patients with dyserythropoiesis and/or dysgranulopoiesis without abnormal megakaryocytes. Other unfavourable factors were age greater than 50 years (P = 0.042), leucocyte count greater than 100 x 10(9)/l (P = 0.006), M5 FAB subtype (P = 0.013), presence of complex cytogenetic rearrangement or abnormalities of chromosome 5 and/or 7 (P = 0.001). Bone marrow eosinophilia greater than 3% was significantly associated with a higher CR rate (P = 0.04). In a multivariate analysis, a low CR rate was best predicted by the presence of a complex karyotype or abnormalities of chromosome 5 and/or 7 (P = 0.0001) and by the TDMP (P = 0.0036). Median actuarial disease-free survival (DFS) was 24 months. Actuarial DFS was significantly shorter in patients with TDMP (P = 0.0001) and an elevated leucocyte count (P = 0.02). Age, FAB subtype and karyotype had no significant incidence on DFS. Presence of TDMP appears to be an important prognostic factor in de novo AML. This could be used as one of the guidelines to therapy.     

Impaired granulocytic function in patients with acute leukaemia: only partial normalisation after successful remission-inducing treatment

In vivo chemotaxis and phagocytic activity of polymorphonuclear neutrophils (PMN) were evaluated in 20 patients with acute myeloid leukaemia (AML), and in 10 patients with acute lymphoblastic leukaemia (ALL). For comparison, 20 healthy individuals were investigated. A skin-chamber technique and a phagocytosis test were used to quantify the neutrophil functions. The local leucocyte mobilisation in the skin- chamber was significantly lower in untreated patients with AML and ALL than in healthy individuals (P<0.05). Patients with acute leukaemia in remission showed an increase in chemotactic parameters though they remained below normal levels. The phagocytosis index (PI) of peripheral blood PMN was lower than 30% (normal individuals: 60%) in untreated AML and ALL; this difference was significant (P<0.05). The PI of peripheral blood PMN in patients with acute leukaemia in remission returned to the normal level. Investigation of granulocytic function in patients with acute leukaemia in remission may reveal evidence for reduced protection by these cells against infections and lead to adequate therapy. Received: 20 November 1997 / Accepted: 9 December 1997     

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

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.