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FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies
Leukemia Research 26 (2002) 725–730
FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies Javier de la Rubia, Ana I. Regadera, Guillermo Mart´ın, José Cervera, Guillermo F. Sanz, Jesús A. Mart´ınez, Isidro Jarque, Inmaculada Garc´ıa, Rafael Andreu, Federico Moscardó, Carmen Jiménez, Susana Mollá, Luis Benlloch, Miguel A. Sanz∗ Hematology Service, University Hospital La Fe, Valencia, Spain Received 24 May 2001; received in revised form 16 November 2001; accepted 4 December 2001
Abstract Forty-five patients with high-risk myeloid malignancies (32 acute myeloid leukemia and 13 high-risk myelodysplastic syndromes) were treated with fludarabine, cytarabine, idarubicin, and G-CSF (FLAG-IDA). Twenty-four (53%) patients achieved complete remission (CR), and five (11%) partial remission. Infection predominantly with pulmonary involvement was the most common regimen-related toxicity. Mucositis (15 patients) and pulmonary toxicity (19 patients) were the most frequently observed non-hematologic side effects. There were four early deaths and 12 patients presented with resistant disease. Overall survival (OS) at 12 months was 40%. The FLAG-IDA regimen shows evident antileukemic activity in patients with high-risk myeloid malignancies with acceptable toxicity. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Myeloid malignancies; High-risk; Fludarabine; Toxicity
1. Introduction About 50–80% of adult patients with de novo acute myeloblastic leukemia (AML) achieve complete remission (CR) with the currently available chemotherapy regimens consisting of anthracyclines and cytarabine [1–6]. However, 15–25% of patients fail to achieve CR because of resistance to treatment or death, and >40% of CR patients will relapse within two years [1–6]. Although several different chemotherapy combinations have been administered to patients with refractory AML or those in relapse, the prognosis in this subset of patients is still poor, with a CR rate ranging from 33 to 41%, and a median duration of CR ranging from 6 to 24 months [7–10]. Similarly, the CR rate in patients with high-risk myelodysplastic synAbbreviations: FLAG-IDA, fludarabine, cytarabine, idarubicin and GCSF; G-CSF, granulocyte colony-stimulating factor; AML, acute myeloid leukaemia; MDS, myelodysplastic syndromes; CR, complete remission; PR, partial remission; HSCT, hematopoietic stem cell transplantation; OS, overall survival ∗ Corresponding author. Tel.: +34-96-386-8757; fax: +34-96-386-8757. E-mail address: [email protected] (M.A. Sanz).
dromes (MDS) and secondary AML is low, under standard AML-type chemotherapy regimens [11–14]. The poor prognosis of these patients has prompted a search for novel drugs or drugs combinations with which to improve the initial response rate and prolong survival. Preliminary results with the combination of fludarabine and cytarabine (Ara-C), with or without idarubicin, reported response rates of 47–95% in patients with relapsed or refractory AML and high-risk MDS, with acceptable toxicity [15–18]. These encouraging results have been confirmed in recent reports [19–25]. At our institution, several chemotherapy regimens have been employed in patients with refractory or relapsed AML with a response rate of 29–44% [26–28]. In an attempt to improve these results, we have administered the combination of fludarabine, Ara-C, and idarubicin, with granulocyte colony-stimulating factor (G-CSF) (FLAG-IDA) to patients with refractory, relapsed, and secondary AML, as well as to those with high-risk MDS, since December 1997. In this report, we present the toxicity and response to FLAG-IDA treatment in a series of 45 patients with high-risk myeloid malignancies treated at our institution. Our results confirm
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the acceptable toxicity and high response rate observed with this regimen in this very high-risk subgroup of patients.
patients) or two courses (one patient) of first line chemotherapy including idarubicin and standard dose Ara-C. 2.3. Therapeutic protocol
2. Materials and methods 2.1. Patient characteristics Between December 1997 and August 2000, 45 adult patients with refractory, relapsed, or secondary AML, or with high-risk MDS, were eligible for the study. MDS was defined as high-risk when a patient scored 3 on the Spanish scoring system, and/or intermediate-1 on the International Prognostic Score System [29,30]. Thirty-one patients were male and 14 female, with a median age of 59 years (range, 18–79). Karyotypic findings were classified according to Grimwade et al. for AML patients [31], and according to Greenberg et al. for patients with MDS [30]. Main patient characteristics are shown in Table 1. 2.2. Previous therapy At the time of inclusion in this study, 24 patients (13 MDS and 11 AML) received FLAG-IDA as front-line chemotherapy. Fifteen patients with AML were in relapse after either autologous stem cell transplantation (eight patients), or conventional chemotherapy (seven patients). The median duration of first CR for patients in relapse was 13 months (range, 6–22 months). Finally, the disease was considered refractory in the six remaining AML patients, after one (five
No. of patients/CR
%
45/24
53
Diagnosis Relapsed AML First relapse Second relapse MDS RAEB RAEB-T Secondary AML MDS Other malignancies Refractory AML
13/4 9/3 4/1 13/8 9/5 4/3 13/8 9/4 4/4 6/4
31
Karyotype Not available Good prognosis Intermediate prognosis Poor prognosis
13/5 3/2 14/10 15/7
Patients Sex Male Female Age (median and range)
2.3.2. Post-induction therapy Consolidation chemotherapy consisted of 1 cycle of idarubicin (10 mg/m2 per day for 3 days), Ara-C (200 mg/m2 per day for 5 days), and glycosylated G-CSF (263 g per day from day 7 after chemotherapy until the ANC was >1×109 /l). For patients <60 years, autologous or allogeneic hematopoietic stem cell transplantation (HSCT) was considered after consolidation. For elderly patients, 1 cycle of carboplatin (300 mg/m2 per day for 4 days, as a 24 h continuous infusion) was administered as intensification treatment. 2.4. Supportive care
Table 1 Base-line characteristics and remission induction results Median (range)
2.3.1. Remission induction Fludarabine, 30 mg/m2 per day intravenously (iv), was administered over 30 min on four consecutive days. Four hours after the fludarabine treatment, Ara-C (2 g/m2 per day, iv) was administered over 4 h, on days 1–4. When the creatinine clearance was between 30 and 70 ml/min, the dose of fludarabine was halved. Idarubicin (10 mg/m2 per day, iv) was given for the first 3 days of chemotherapy, and glycosylated G-CSF (lenograstim; Granocyte® , Aventis, Paris, France) was administered subcutaneously, at a daily dose of 300 g/m2 , beginning one day before chemotherapy and continuing until day 5. G-CSF was administered again at a daily dose of 263 g per day, 7 days after chemotherapy, until the absolute neutrophil count (ANC) was >1×109 /l for three consecutive days.
31 14 59 (18–79)
62
62
67
A Hickman catheter was placed in every patient. Oral antimicrobial prophylaxis with cotrimoxazole, ciprofloxacin, fluconazole, and inhaled amphotericin B was administered in all patients. In cases of fever, intravenous antibiotics were administered according to local protocols. All patients received filtered and irradiated blood products. 2.5. Definitions The primary objective of this study was to determine the CR rate achieved with the FLAG-IDA regimen. CR was defined according to the criteria established by the Cancer and Leukemia Group B [32]. Partial remission (PR) was defined as either <5% blast in the marrow, but incomplete recovery of blood cell counts, or 5−25% blast in the bone marrow with normalisation of platelet and granulocyte counts in peripheral blood. Failures were classified as early death or resistant disease. Early death was defined as death during induction therapy or during the period of post-chemotherapy aplasia. A further secondary objective was to investigate toxicity. Toxicity was graded according
J. de la Rubia et al. / Leukemia Research 26 (2002) 725–730
to WHO criteria [33]. Pyrexial episodes (i.e. all episodes of pyrexia 38 ◦ C equivalent to a WHO toxicity 2, and any other symptoms or signs of infection) were recorded separately. Overall survival (OS) was calculated from the start of chemotherapy until death or last follow-up. 2.6. Statistical analysis All data were analysed as of 1 January 2001. Actuarial curve for OS was plotted according to the Kaplan–Meier method [34]. A Mann–Whitney test was used to analyse the difference between two independent means. Comparisons between proportions were performed with Fisher’s exact test. All calculations were performed using the BMDP statistical software [35]. 3. Results 3.1. Induction response The results of remission induction are summarised in Table 1. Overall, 29 patients (64%) responded to FLAG-IDA, 24 (53%) achieving CR, and 5 (11%) PR. Treatment was considered to have failed in 16 patients (36%), due either to resistance (12 patients) or to early death (4 patients). CR was observed in four of six refractory patients with AML (67%), in 8 of 13 patients with secondary AML (62%), in 8 of 13 patients with high-risk MDS (62%), and in 4 of 13 patients with relapsed AML (31%). In the latter subgroup of patients, 4 of 7 patients with a first CR duration >12 months achieved remission after FLAG-IDA therapy, whereas no CR was observed among the six patients with a first CR <12 months. On the other hand, response was not associated with younger age, with 13 of 23 (56%) patients aged <60 years entering CR compared with 11 of 22 (50%) patients aged >60 years. In our series, the three patients with good prognostic karyotypic findings responded to chemotherapy (two CR and one PR). However, a poor-prognosis karyotype was not associated with a worse outcome. In fact, 9 of 15 patients responded to chemotherapy (seven CR and two PR), five patients were resistant to treatment, and the remaining patient died during induction. 3.2. Hematopoietic reconstitution
727
Table 2 Time to hematopoietic recovery Previously untreated (days)
Previously treated (days)
P-value
ANCa 0.5 × 109 1 × 109
16 (4) 17 (4)
21 (6) 23 (6)
0.019 0.031
Platelets 20 × 109 50 × 109
19 (5) 24 (7)
28 (13) 28 (13)
a
ANC: absolute neutrophil count. Values are expressed as means ±
S.D.
3.3. Non-hematological toxicity Non-hematologic toxicity data for induction were tabulated for all patients. Forty-four patients (98%) developed fever. Infections were clinically documented in 17 patients, microbiologically documented in 12 patients (bacteremia in six patients, and fungemia in three), and of unknown origin in 15 patients. Toxicity was graded according to WHO criteria (Table 3). Ten patients developed severe pulmonary toxicity (grade 3 or 4). No patient developed congestive heart failure that could be attributed to anthracycline administration and the documented severe cardiac complications were associated with septic or pulmonary infections. Grade IV mucositis was observed in five cases, severe neurological toxicity was observed in two patients (encephalitis and ischemic cerebrovascular attack) and one patient developed renal failure without requiring dialysis. Transient laboratory evidence of self-limiting hepatic dysfunction was observed in 22 patients (49%). Ten patients had bleeding, which was severe in four patients (gastrointestinal hemorrhage in two, pulmonary bleeding in one, and both subdural hematoma and pulmonary bleeding in one). The median red blood cells concentrates transfused per patient was 14 (range, 0–26). Median number of platelet concentrates transfused per patient was nine (range, 1–42). Overall, there were five toxic deaths (11%). Four patients died of respiratory insufficiency secondary to pulmonary infection, three of them during post-induction chemotherapy Table 3 Non-hematological toxicity WHO grade
After excluding those patients who did not reach CR, 24 of 45 patients were evaluated for hematological toxicity. The mean time to reach an absolute neutrophil count (ANC) >0.5 × 109 and 1 × 109 /l was 18 ± 5 and 19 ± 6 days, respectively. The mean times to achieve a platelet count >20 × 109 and 50 × 109 /l were 22 ± 10 and 25 ± 9 days, respectively. Neutrophil recovery was significantly faster in patients receiving FLAG-IDA as front-line treatment (18 patients), when compared with previously-treated patients (P < 0.05) (Table 2).
Nausea/vomiting Skin Mucositis Diarrhoea Renal Liver Pulmonary Cardiac Neurological
1
2
3
4
8 11 5 3 7 12 3 4 0
2 4 5 6 3 9 6 1 0
2 0 0 2 1 1 5 2 1
1 0 5 0 0 0 5 0 1
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J. de la Rubia et al. / Leukemia Research 26 (2002) 725–730
Fig. 1. Overall group survival.
aplasia and one patient in CR before consolidation. Finally, the remaining patient presented with post-chemotherapy regenerative failure and died 64 days later. 3.4. Follow-up Nineteen of the 24 patients achieving CR received consolidation chemotherapy. The remaining five patients did not receive any post-induction treatment for various reasons: early relapse, severe renal failure, advanced age, diagnosis of solid tumour, and death due to bronchopneumonia. After consolidation, nine patients underwent HSCT (allogeneic from an unrelated donor in five cases and autologous in four), five patients received intensification chemotherapy with carboplatin, and two are awaiting HSCT. The remaining three patients did not receive further therapy because of relapse (two patients) or poor performance status. Among the five patients in PR, three of them did no received further therapy due to advanced age (two cases) or bad performance status (one case). The remaining two patients received consolidation therapy (one achieved CR and the other patient died due to bacterial infection after consolidation). The median follow-up period for the whole series was eight months (range, 0.5–29 months), and the actuarial OS at 12 months was 40% (Fig. 1).
4. Discussion The combination of fludarabine, Ara-C, and G-CSF, with or without idarubicin, has recently been employed as an induction treatment for patients with poor-prognosis hematological malignancies [16–25]. In this study, we evaluated the efficacy and toxicity of the FLAG-IDA regimen as induction chemotherapy in a group of adult patients with high-risk myeloid malignancies. In our series, the CR rate was 53%, similar to that reported by different groups [16–20], and higher than that observed with other second-line chemotherapy protocols [2,9,10,26,27], confirming the high antileukemic efficacy of this regimen. Although no direct comparisons have been reported to
date, the CR rate observed in patients receiving FLAG chemotherapy (without idarubicin) has ranged from 49 to 74% [16–18,20,21,25]. However, in some of these studies, patients required two courses of induction chemotherapy to achieve CR, and some series included patients with de novo AML [17,20,25]. Therefore, no definitive conclusions can be drawn about the impact that the addition of idarubicin has on the CR rate in patients with high-risk AML or MDS. Recapitulating previously reported results, the worst outcome in our series was observed among AML patients with early relapse (time from initial remission <12 months) [18,20,25]. The low CR rate and high incidence of resistant disease in patients with a short initial CR suggest a common mechanism of resistance operating for a wide variety of chemotherapy regimens, such as an increased expression of the multidrug resistance-1 protein [36]. In our series, there were no differences in CR rate according to cytogenetic findings, and a poor-prognosis karyotype was not associated with a worse outcome. Other authors have reported that the presence of monosomy or deletions of 7q was associated with an adverse effect on outcome [19,21], a finding not confirmed by us. Unfortunately, the small number of patients in this group precludes any conclusion in this regard. Likewise, in our study patient’s age did not affected the CR rate, and we did not observe significant differences in terms of CR between patients above or below 60 years. This suggests that this scheme can be considered a useful alternative for elderly patients considered candidates for intensive chemotherapy. Confirming previously reported data from other studies, the toxicity of this combination was acceptable, with a treatment-related mortality of 11%, due mainly to infection associated with bone marrow suppression, a finding commonly described with this scheme [16,18,21]. Severe infection was observed in 29 patients and involved predominantly the lung. The high rate of pulmonary infections could have been caused by a toxic injury of the lung epithelial cells by the cytostatic drugs and the long-term neutropenia involving a high risk for severe infection. Likewise, the high immunosuppressive effect of fludarabine could have also contributed to the high incidence of severe pulmonary infections observed in our series. Of the two patients with severe neurological toxicity, one of them could have been secondary to treatment with fludarabine [37]. Overall, the toxicity profile of the FLAG-IDA combination in patients of advanced age suggests that this regimen provides a useful alternative to other more toxic regimens [27]. The faster neutrophil recovery in patients receiving FLAG-IDA as front-line therapy probably reflects the higher repopulation capacity of the bone marrow in previously untreated patients. In summary, the FLAG-IDA regimen is associated with a high rate of CR and an acceptable toxicity profile in patients with high-risk myeloid malignancies. However, results among AML patients in early relapse suggest the need of
J. de la Rubia et al. / Leukemia Research 26 (2002) 725–730
developing new therapeutic approaches in this subset of patients.
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FLAG-IDA regimen (fludarabine, cytarabine, idarubicin and G-CSF) in the treatment of patients with high-risk myeloid malignancies Javier de la Rubia, Ana I. Regadera, Guillermo Mart´ın, José Cervera, Guillermo F. Sanz, Jesús A. Mart´ınez, Isidro Jarque, Inmaculada Garc´ıa, Rafael Andreu, Federico Moscardó, Carmen Jiménez, Susana Mollá, Luis Benlloch, Miguel A. Sanz∗ Hematology Service, University Hospital La Fe, Valencia, Spain Received 24 May 2001; received in revised form 16 November 2001; accepted 4 December 2001
Abstract Forty-five patients with high-risk myeloid malignancies (32 acute myeloid leukemia and 13 high-risk myelodysplastic syndromes) were treated with fludarabine, cytarabine, idarubicin, and G-CSF (FLAG-IDA). Twenty-four (53%) patients achieved complete remission (CR), and five (11%) partial remission. Infection predominantly with pulmonary involvement was the most common regimen-related toxicity. Mucositis (15 patients) and pulmonary toxicity (19 patients) were the most frequently observed non-hematologic side effects. There were four early deaths and 12 patients presented with resistant disease. Overall survival (OS) at 12 months was 40%. The FLAG-IDA regimen shows evident antileukemic activity in patients with high-risk myeloid malignancies with acceptable toxicity. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Myeloid malignancies; High-risk; Fludarabine; Toxicity
1. Introduction About 50–80% of adult patients with de novo acute myeloblastic leukemia (AML) achieve complete remission (CR) with the currently available chemotherapy regimens consisting of anthracyclines and cytarabine [1–6]. However, 15–25% of patients fail to achieve CR because of resistance to treatment or death, and >40% of CR patients will relapse within two years [1–6]. Although several different chemotherapy combinations have been administered to patients with refractory AML or those in relapse, the prognosis in this subset of patients is still poor, with a CR rate ranging from 33 to 41%, and a median duration of CR ranging from 6 to 24 months [7–10]. Similarly, the CR rate in patients with high-risk myelodysplastic synAbbreviations: FLAG-IDA, fludarabine, cytarabine, idarubicin and GCSF; G-CSF, granulocyte colony-stimulating factor; AML, acute myeloid leukaemia; MDS, myelodysplastic syndromes; CR, complete remission; PR, partial remission; HSCT, hematopoietic stem cell transplantation; OS, overall survival ∗ Corresponding author. Tel.: +34-96-386-8757; fax: +34-96-386-8757. E-mail address: [email protected] (M.A. Sanz).
dromes (MDS) and secondary AML is low, under standard AML-type chemotherapy regimens [11–14]. The poor prognosis of these patients has prompted a search for novel drugs or drugs combinations with which to improve the initial response rate and prolong survival. Preliminary results with the combination of fludarabine and cytarabine (Ara-C), with or without idarubicin, reported response rates of 47–95% in patients with relapsed or refractory AML and high-risk MDS, with acceptable toxicity [15–18]. These encouraging results have been confirmed in recent reports [19–25]. At our institution, several chemotherapy regimens have been employed in patients with refractory or relapsed AML with a response rate of 29–44% [26–28]. In an attempt to improve these results, we have administered the combination of fludarabine, Ara-C, and idarubicin, with granulocyte colony-stimulating factor (G-CSF) (FLAG-IDA) to patients with refractory, relapsed, and secondary AML, as well as to those with high-risk MDS, since December 1997. In this report, we present the toxicity and response to FLAG-IDA treatment in a series of 45 patients with high-risk myeloid malignancies treated at our institution. Our results confirm
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J. de la Rubia et al. / Leukemia Research 26 (2002) 725–730
the acceptable toxicity and high response rate observed with this regimen in this very high-risk subgroup of patients.
patients) or two courses (one patient) of first line chemotherapy including idarubicin and standard dose Ara-C. 2.3. Therapeutic protocol
2. Materials and methods 2.1. Patient characteristics Between December 1997 and August 2000, 45 adult patients with refractory, relapsed, or secondary AML, or with high-risk MDS, were eligible for the study. MDS was defined as high-risk when a patient scored 3 on the Spanish scoring system, and/or intermediate-1 on the International Prognostic Score System [29,30]. Thirty-one patients were male and 14 female, with a median age of 59 years (range, 18–79). Karyotypic findings were classified according to Grimwade et al. for AML patients [31], and according to Greenberg et al. for patients with MDS [30]. Main patient characteristics are shown in Table 1. 2.2. Previous therapy At the time of inclusion in this study, 24 patients (13 MDS and 11 AML) received FLAG-IDA as front-line chemotherapy. Fifteen patients with AML were in relapse after either autologous stem cell transplantation (eight patients), or conventional chemotherapy (seven patients). The median duration of first CR for patients in relapse was 13 months (range, 6–22 months). Finally, the disease was considered refractory in the six remaining AML patients, after one (five
No. of patients/CR
%
45/24
53
Diagnosis Relapsed AML First relapse Second relapse MDS RAEB RAEB-T Secondary AML MDS Other malignancies Refractory AML
13/4 9/3 4/1 13/8 9/5 4/3 13/8 9/4 4/4 6/4
31
Karyotype Not available Good prognosis Intermediate prognosis Poor prognosis
13/5 3/2 14/10 15/7
Patients Sex Male Female Age (median and range)
2.3.2. Post-induction therapy Consolidation chemotherapy consisted of 1 cycle of idarubicin (10 mg/m2 per day for 3 days), Ara-C (200 mg/m2 per day for 5 days), and glycosylated G-CSF (263 g per day from day 7 after chemotherapy until the ANC was >1×109 /l). For patients <60 years, autologous or allogeneic hematopoietic stem cell transplantation (HSCT) was considered after consolidation. For elderly patients, 1 cycle of carboplatin (300 mg/m2 per day for 4 days, as a 24 h continuous infusion) was administered as intensification treatment. 2.4. Supportive care
Table 1 Base-line characteristics and remission induction results Median (range)
2.3.1. Remission induction Fludarabine, 30 mg/m2 per day intravenously (iv), was administered over 30 min on four consecutive days. Four hours after the fludarabine treatment, Ara-C (2 g/m2 per day, iv) was administered over 4 h, on days 1–4. When the creatinine clearance was between 30 and 70 ml/min, the dose of fludarabine was halved. Idarubicin (10 mg/m2 per day, iv) was given for the first 3 days of chemotherapy, and glycosylated G-CSF (lenograstim; Granocyte® , Aventis, Paris, France) was administered subcutaneously, at a daily dose of 300 g/m2 , beginning one day before chemotherapy and continuing until day 5. G-CSF was administered again at a daily dose of 263 g per day, 7 days after chemotherapy, until the absolute neutrophil count (ANC) was >1×109 /l for three consecutive days.
31 14 59 (18–79)
62
62
67
A Hickman catheter was placed in every patient. Oral antimicrobial prophylaxis with cotrimoxazole, ciprofloxacin, fluconazole, and inhaled amphotericin B was administered in all patients. In cases of fever, intravenous antibiotics were administered according to local protocols. All patients received filtered and irradiated blood products. 2.5. Definitions The primary objective of this study was to determine the CR rate achieved with the FLAG-IDA regimen. CR was defined according to the criteria established by the Cancer and Leukemia Group B [32]. Partial remission (PR) was defined as either <5% blast in the marrow, but incomplete recovery of blood cell counts, or 5−25% blast in the bone marrow with normalisation of platelet and granulocyte counts in peripheral blood. Failures were classified as early death or resistant disease. Early death was defined as death during induction therapy or during the period of post-chemotherapy aplasia. A further secondary objective was to investigate toxicity. Toxicity was graded according
J. de la Rubia et al. / Leukemia Research 26 (2002) 725–730
to WHO criteria [33]. Pyrexial episodes (i.e. all episodes of pyrexia 38 ◦ C equivalent to a WHO toxicity 2, and any other symptoms or signs of infection) were recorded separately. Overall survival (OS) was calculated from the start of chemotherapy until death or last follow-up. 2.6. Statistical analysis All data were analysed as of 1 January 2001. Actuarial curve for OS was plotted according to the Kaplan–Meier method [34]. A Mann–Whitney test was used to analyse the difference between two independent means. Comparisons between proportions were performed with Fisher’s exact test. All calculations were performed using the BMDP statistical software [35]. 3. Results 3.1. Induction response The results of remission induction are summarised in Table 1. Overall, 29 patients (64%) responded to FLAG-IDA, 24 (53%) achieving CR, and 5 (11%) PR. Treatment was considered to have failed in 16 patients (36%), due either to resistance (12 patients) or to early death (4 patients). CR was observed in four of six refractory patients with AML (67%), in 8 of 13 patients with secondary AML (62%), in 8 of 13 patients with high-risk MDS (62%), and in 4 of 13 patients with relapsed AML (31%). In the latter subgroup of patients, 4 of 7 patients with a first CR duration >12 months achieved remission after FLAG-IDA therapy, whereas no CR was observed among the six patients with a first CR <12 months. On the other hand, response was not associated with younger age, with 13 of 23 (56%) patients aged <60 years entering CR compared with 11 of 22 (50%) patients aged >60 years. In our series, the three patients with good prognostic karyotypic findings responded to chemotherapy (two CR and one PR). However, a poor-prognosis karyotype was not associated with a worse outcome. In fact, 9 of 15 patients responded to chemotherapy (seven CR and two PR), five patients were resistant to treatment, and the remaining patient died during induction. 3.2. Hematopoietic reconstitution
727
Table 2 Time to hematopoietic recovery Previously untreated (days)
Previously treated (days)
P-value
ANCa 0.5 × 109 1 × 109
16 (4) 17 (4)
21 (6) 23 (6)
0.019 0.031
Platelets 20 × 109 50 × 109
19 (5) 24 (7)
28 (13) 28 (13)
a
ANC: absolute neutrophil count. Values are expressed as means ±
S.D.
3.3. Non-hematological toxicity Non-hematologic toxicity data for induction were tabulated for all patients. Forty-four patients (98%) developed fever. Infections were clinically documented in 17 patients, microbiologically documented in 12 patients (bacteremia in six patients, and fungemia in three), and of unknown origin in 15 patients. Toxicity was graded according to WHO criteria (Table 3). Ten patients developed severe pulmonary toxicity (grade 3 or 4). No patient developed congestive heart failure that could be attributed to anthracycline administration and the documented severe cardiac complications were associated with septic or pulmonary infections. Grade IV mucositis was observed in five cases, severe neurological toxicity was observed in two patients (encephalitis and ischemic cerebrovascular attack) and one patient developed renal failure without requiring dialysis. Transient laboratory evidence of self-limiting hepatic dysfunction was observed in 22 patients (49%). Ten patients had bleeding, which was severe in four patients (gastrointestinal hemorrhage in two, pulmonary bleeding in one, and both subdural hematoma and pulmonary bleeding in one). The median red blood cells concentrates transfused per patient was 14 (range, 0–26). Median number of platelet concentrates transfused per patient was nine (range, 1–42). Overall, there were five toxic deaths (11%). Four patients died of respiratory insufficiency secondary to pulmonary infection, three of them during post-induction chemotherapy Table 3 Non-hematological toxicity WHO grade
After excluding those patients who did not reach CR, 24 of 45 patients were evaluated for hematological toxicity. The mean time to reach an absolute neutrophil count (ANC) >0.5 × 109 and 1 × 109 /l was 18 ± 5 and 19 ± 6 days, respectively. The mean times to achieve a platelet count >20 × 109 and 50 × 109 /l were 22 ± 10 and 25 ± 9 days, respectively. Neutrophil recovery was significantly faster in patients receiving FLAG-IDA as front-line treatment (18 patients), when compared with previously-treated patients (P < 0.05) (Table 2).
Nausea/vomiting Skin Mucositis Diarrhoea Renal Liver Pulmonary Cardiac Neurological
1
2
3
4
8 11 5 3 7 12 3 4 0
2 4 5 6 3 9 6 1 0
2 0 0 2 1 1 5 2 1
1 0 5 0 0 0 5 0 1
728
J. de la Rubia et al. / Leukemia Research 26 (2002) 725–730
Fig. 1. Overall group survival.
aplasia and one patient in CR before consolidation. Finally, the remaining patient presented with post-chemotherapy regenerative failure and died 64 days later. 3.4. Follow-up Nineteen of the 24 patients achieving CR received consolidation chemotherapy. The remaining five patients did not receive any post-induction treatment for various reasons: early relapse, severe renal failure, advanced age, diagnosis of solid tumour, and death due to bronchopneumonia. After consolidation, nine patients underwent HSCT (allogeneic from an unrelated donor in five cases and autologous in four), five patients received intensification chemotherapy with carboplatin, and two are awaiting HSCT. The remaining three patients did not receive further therapy because of relapse (two patients) or poor performance status. Among the five patients in PR, three of them did no received further therapy due to advanced age (two cases) or bad performance status (one case). The remaining two patients received consolidation therapy (one achieved CR and the other patient died due to bacterial infection after consolidation). The median follow-up period for the whole series was eight months (range, 0.5–29 months), and the actuarial OS at 12 months was 40% (Fig. 1).
4. Discussion The combination of fludarabine, Ara-C, and G-CSF, with or without idarubicin, has recently been employed as an induction treatment for patients with poor-prognosis hematological malignancies [16–25]. In this study, we evaluated the efficacy and toxicity of the FLAG-IDA regimen as induction chemotherapy in a group of adult patients with high-risk myeloid malignancies. In our series, the CR rate was 53%, similar to that reported by different groups [16–20], and higher than that observed with other second-line chemotherapy protocols [2,9,10,26,27], confirming the high antileukemic efficacy of this regimen. Although no direct comparisons have been reported to
date, the CR rate observed in patients receiving FLAG chemotherapy (without idarubicin) has ranged from 49 to 74% [16–18,20,21,25]. However, in some of these studies, patients required two courses of induction chemotherapy to achieve CR, and some series included patients with de novo AML [17,20,25]. Therefore, no definitive conclusions can be drawn about the impact that the addition of idarubicin has on the CR rate in patients with high-risk AML or MDS. Recapitulating previously reported results, the worst outcome in our series was observed among AML patients with early relapse (time from initial remission <12 months) [18,20,25]. The low CR rate and high incidence of resistant disease in patients with a short initial CR suggest a common mechanism of resistance operating for a wide variety of chemotherapy regimens, such as an increased expression of the multidrug resistance-1 protein [36]. In our series, there were no differences in CR rate according to cytogenetic findings, and a poor-prognosis karyotype was not associated with a worse outcome. Other authors have reported that the presence of monosomy or deletions of 7q was associated with an adverse effect on outcome [19,21], a finding not confirmed by us. Unfortunately, the small number of patients in this group precludes any conclusion in this regard. Likewise, in our study patient’s age did not affected the CR rate, and we did not observe significant differences in terms of CR between patients above or below 60 years. This suggests that this scheme can be considered a useful alternative for elderly patients considered candidates for intensive chemotherapy. Confirming previously reported data from other studies, the toxicity of this combination was acceptable, with a treatment-related mortality of 11%, due mainly to infection associated with bone marrow suppression, a finding commonly described with this scheme [16,18,21]. Severe infection was observed in 29 patients and involved predominantly the lung. The high rate of pulmonary infections could have been caused by a toxic injury of the lung epithelial cells by the cytostatic drugs and the long-term neutropenia involving a high risk for severe infection. Likewise, the high immunosuppressive effect of fludarabine could have also contributed to the high incidence of severe pulmonary infections observed in our series. Of the two patients with severe neurological toxicity, one of them could have been secondary to treatment with fludarabine [37]. Overall, the toxicity profile of the FLAG-IDA combination in patients of advanced age suggests that this regimen provides a useful alternative to other more toxic regimens [27]. The faster neutrophil recovery in patients receiving FLAG-IDA as front-line therapy probably reflects the higher repopulation capacity of the bone marrow in previously untreated patients. In summary, the FLAG-IDA regimen is associated with a high rate of CR and an acceptable toxicity profile in patients with high-risk myeloid malignancies. However, results among AML patients in early relapse suggest the need of
J. de la Rubia et al. / Leukemia Research 26 (2002) 725–730
developing new therapeutic approaches in this subset of patients.
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