International Journal of Hematology

, Volume 87, Issue 2, pp 118–125

The value of oral cytarabine ocfosfate and etoposide in the treatment of refractory and elderly AML patients

Authors

    • Department of Internal MedicineNihon University, Nerima-Hikarigaoka Hospital
  • Kazuhiro Takei
    • Department of Internal MedicineNihon University, Nerima-Hikarigaoka Hospital
  • Yoshifumi Hosokawa
    • Department of Internal MedicineNihon University, Nerima-Hikarigaoka Hospital
  • Shigemasa Sawada
    • Department of Internal MedicineNihon University, Nerima-Hikarigaoka Hospital
Original Article

DOI: 10.1007/s12185-007-0019-6

Cite this article as:
Horikoshi, A., Takei, K., Hosokawa, Y. et al. Int J Hematol (2008) 87: 118. doi:10.1007/s12185-007-0019-6

Abstract

Twenty-one acute myeloid leukemia (AML) patients were enrolled and received oral induction therapy with cytarabine ocfosfate (SPAC) and etoposide (EP). The median age was 69 years (range: 33–86). There were 11 patients with de novo AML and 10 AML cases that had evolved from myelodysplastic syndromes. Seventeen patients had abnormal karyotypes including eight complex abnormalities, various complications, and 7 of 21 had a poor performance status (PS) with Eastern Cooperative Oncology Group (ECOG) scores of 3–4. All patients completed induction therapy without severe adverse events. Seven achieved complete remission (CR), and two achieved partial remission (PR). Uni- and multivariate analyses demonstrated a positive and significant correlation between the results of therapy (CR ± PR) and overall survival. The plasma concentrations of cytosine arabinoside (ara-C) in some cases were higher than those previously reported, indicating the accumulation of ara-C with increasing numbers of days of SPAC administration. We conclude that this therapy is well tolerated and useful for refractory and elderly AML patients.

Keywords

Cytarabine ocfosfateAra-CEtoposideRefractory acute myeloid leukemiaInduction therapy

1 Introduction

Acute myeloid leukemia (AML) patients who fail to achieve complete remission (CR) or relapse after first-line therapy have a very poor prognosis [1, 2]. Furthermore, elderly AML patients, and those cases where the AML has evolved from myelodysplastic syndrome (MDS) have many factors indicating a poor prognosis. These include a poor performance status (PS), being immunocompromised, having a higher proportion of unfavorable karyotypes, and aging itself. These patients have low remission rates and short periods of disease-free survival despite intensive chemotherapy [35]. Drug-resistant clones that express the multi-drug resistance (MDR-1) gene [6] may be a cause of the poor prognosis.

Since the number of high-risk patients with AML is increasing, novel therapeutic approaches are needed. Though induction therapy for AML is based on the combination of cytarabine (ara-C) and an anthracycline, anthracyclines sometimes induce severe marrow hypoplasia and cardiac toxicity. On the other hand, low-dose ara-C has been used for some time in the treatment of MDS and provides effective antileukemic therapy [7]. Furthermore, recently, etoposide (EP) was found to be a highly active agent in de novo relapsed AML [8].

Cytarabine ocfosfate (SPAC: 1-β-d-arabinofuranosylcytosine-5′-stearylphosphate) is rapidly transformed into ara-C after oral administration [9]. Oral administration of SPAC at 150–300 mg/m2/day was pharmacokinetically comparable to the continuous infusion of ara-C at 20 mg/m2/day [10]. We attempted to use SPAC combined with oral EP in refractory and elderly AML patients to evaluate the toxicity and antileukemic efficacy of these agents.

2 Patients and methods

Patients over 65 years of age with AML, patients with AML following MDS, AML resistant to primary chemotherapy, and relapsing AML were eligible. Also eligible were patients with newly diagnosed AML, not eligible for standard protocols because of their physical or psychological conditions such as severe thrombocytopenia, leukopenia, coexistence of cancer, poor PS (>2), depressive state, and patients’ refusal to receive standard protocols. AML was classified according to the revised FAB criteria [11]. Between 1996 and 2004, we enrolled 21 AML patients (12 women and 9 men).

A cytogenetic study was successfully performed at diagnosis on bone marrow or peripheral blood cells in all patients using standard G-banding with trypsin-Giemsa staining; a minimum of 20 metaphases were examined for each patient.

Complete remission (CR) was defined by a normocellular bone marrow that contained less than 5% blast cells, and recovery of peripheral-blood values to platelet counts of at least 10 × 104/μL and neutrophils of at least 1,000/μL. Partial remission (PR) was defined by bone marrow smears that contained between 5 and 25% blasts and less than 5% circulating blast cells.

Subjects received oral induction therapy with SPAC at 300 mg/day and EP at 50 mg/day after meals, two times daily, for 14 days.

Ara-C and EP concentrations in the plasma at the baseline and 3 h after drug administration were detected in seven patients using a modified radioimmunoassay and a modified HPLC assay with fluorescence detection [12, 13].

The relationship between the initial, categorized, ordered variables (age, chromosomal abnormality, WBC count, AML from MDS, and dose of SPAC) and the CR + PR rate after induction was statistically tested using the χ2 test and a logistic model for multivariate analysis. Clinical features of patients and outcomes of therapy were analyzed for their prognostic value on overall survival using the Kaplan-Meier technique for univariate analysis and an extended Cox model for multivariate analysis. Survival curves were compared using the log-rank test and the generalized Wilcoxon test.

3 Results

3.1 Clinical and biological findings

As shown in Tables 1 and 2, we enrolled a total of 21 high-risk cases (10 men/11 women, median age: 69 years; range: 33–86 years). Eleven had de novo AML and 10 had AML evolving from MDS. Eight had been previously treated with cytotoxic chemotherapy or ubenimex (Bes), a specific inhibitor of CD13 (aminopeptidase N) [14]. Thirteen patients had previously been untreated. Seventeen patients had abnormal karyotypes including eight complex abnormalities (Table 3). Patients had various complications and 7 of 21 had poor PS scores (3–4) using Eastern Cooperative Oncology Group (ECOG) criteria.
Table 1

Clinical and laboratory characteristics of AML patients (NR)

Patient

Age

Sex

Diagnosis

Previous treatment

PS

Complications

Hb (g/dL)

WBC (/μL) (blast%)

Plt (×104/μL)

B.M. blasts (%)

Abnormal karyotype

1

70

M

Hypo-L*1

(−)

1

(−)

6.8

2000 (0)

2.5

32.0

(−)

2

66

M

RAEB-T →M2

Bes*2

2

HT*7, HL*8

6.3

2100 (9.0)

2.3

30.0

Complex

3

83

M

RAEB-T →M2

HU*3 DNR ×1*4

2

HT, DM*9

5.5

114000 (69.0)

23.5

N.D.

47, XY, + 8

4

86

M

CMML →M4

(−)

3

Aneurysm Scabies

8.5

14700 (1.0)

5.2

31.0

Complex

5

54

M

M6

(−)

1

(−)

9.7

11200 (4.0)

3.2

7.8

Complex

6

67

F

M0

LVP*5 CHOP*6

0

NHL*10

11.0

11800 (95.0)

5.2

79.6

Complex

7

69

F

RAEB→M2

(−)

1

Depression

7.5

9200 (7.5)

3.5

26.8

Complex

8

49

M

M7

(−)

1

Gastric ca

7.3

7000 (5.5)

8.9

22.6

Complex

9

58

F

RAEB-T→M2

(−)

0

(−)

6.0

1700 (18.0)

12.1

24.2

Complex

10

68

F

CMML→M2

Bes*2

1

(−)

10.4

45100 (13.5)

3.2

37.8

47, XX, + 8

11

64

F

M1

(−)

4

Pneumonia

7.6

60300 (99.0)

6.0

95.0

47, XX, + 8

12

69

M

RAEB →M2

(−)

0

AF*11

8.7

4100 (2.0)

8.4

62.0

(−)

*1: hypoplastic leukemia, *2: ubenimex, *3: hydroxyurea, *4: daunorubicin, one injection, *5-: L-asparaginase + vincristine + prednisolone, *6: cyclophosphamide + doxorubicin + vincristine + prednisolone, *7: hypertension, *8: hyperlipidemia, *9: diabetes mellitus, *10: non-Hodgkin’s lymphoma, *11: atrial fibrillation

Table 2

Clinical and laboratory characteristics of AML patients (PR and CR)

Patient

Age

Sex

Diagnosis

Previous treatment

PS

Complications

Hb (g/dL)

WBC (/μL) (blast%)

Plt (×104/μL)

B.M. blasts (%)

Abnormal karyotype

13

36

F

M1

DCMP*1,MEC*2 SPAC + EP

4

Pneumonia

7.3

1400 (56.0)

2.3

38.2

46,XX,del(5)(q?), add(7)(q22)

14

33

F

M0 Relapse

LVP*3,DCMP*1

ACMP*4,MEC*2

IDA*5,VCR*6

BUS*7 + EP + EX*8

 + PBSCT*9

2

(−)

9.2

1000 (50.0)

4.8

88.6

46,XX,add(1)(p3?)

15

78

F

RAEB-T→M2

(−)

4

CHF*10

7.8

28700 (29.0)

47.6

20.4

47, XX,   + 11

16

74

M

RAEB-T →M2

SPAC + EP

0

DM*11,HT*12

8.0

1500 (0)

2.7

24.8

(−)

17

67

M

M2

(−)

3

DIC*13 Pneumonia

4.6

2400 (7.0)

10.1

44.8

45,XY,-7 45,idem,del(2)(q?), add(3)(q21)

18

50

F

M2

(−)

1

Phlegmon Depression

8.3

1000 (18.0)

3.7

45.4

47,XX, + 11

19

70

F

M2

(−)

1

DM*11

5.7

13000 (6.5)

5.7

Drytap

Complex

20

78

F

M5a

(−)

4

HT,HL*14 OMI*15

8.2

186000 (93.5)

5.8

93.0

(−)

21

79

F

RAEB-T →M1

SPAC + EP

3

OA*16

11.2

73100 (93.5)

2.0

92.0

(−)

*1: daunorubicin + ara-C + 6MP + prednisolone, *2: mitoxantrone + etoposide + ara-C, *3: L-asparaginase + vincristine + prednisolone, *4: aclarubicin + ara-C + 6MP + prednisolone, *5: idarubicin, *6: vincristine, *7: busulfan, *8: cyclophosphamide, *9: peripheral blood stem cell transplantation, *10: congestive heart failure, *11: diabetes mellitus, *12: hypertension, *13: disseminated intravascular coagulation, *14: hyperlipidemia, *15: old myocardial infarction, *16:osteoarthritis

Table 3

Complex abnormal karyotypes

Patient 2

A:42,XY,−5,−7,inv(9)(p11 q13),del(12)(q2?),−17, −18,−19,−20,−21,−22,−22,−22,+ 5mar

B:43,idem,+ mar

C:42,idem,add(4)(p1?),−15,−16,−17,+ 3mar

D:46,XY,inv(9)(p11q13)

Patient 4

A:45,XY,−7

B:45,idem,−2,−4,add(7)(p22),−21, + mar1,+ mar2 + mar3

Patient 5

A:44,XY,−5,add(7)(q22),−18,−19,+ mar1

B:44,idem,add(6)(p21),del(13)(q?),−21,+ mar2

C:44,idem,add(6)(p21),add(8)(q24),del(13)(q?),−21, + mar3

D:44,idem,add(12)(p1?),del(13)(q?)

Patient 6

A:46,XX,add(2)(q31),add(8)(p11),add(16)(q13)

B:46,idem,?t(X;7)(q22;p15)

C:46,XX,add(2)(q31),+ 8,dic(8;16)(p11;q13)×2, + 16,add(19)(p13)

Patient 7

A:48,XX,+ X, add(3)(p21),del(5)(q?)×2, del(6)(q13), del(7)(q?),der(8)(8qter→8q11::8p21→8qter), add(11)(q13),+ 13,add(16)(q24),add(17)(p11),−18,del(20)(q11q13.3),+ mar1

B:48,idem,−18,+ mar

C:48,idem,-add(11),+ add(11)(q23),+ 18,−22

Patient 8

A:44,XY,del(5)(q?),−7,−9,−14,add(17)(p11),−21,+ mar1,+ mar2

B:43,idem,−1,der(16)t(1;16)(q12;q11)

C:43,idem,−10,−mar2,+ mar

Patient 9

46,XX,add(8)(q24),add(10)(q22),add(18)(q11)

Patient 19

48,XX,−1,add(1)(p11),−2,−3,−4,−4,−5,−8, add(10)(q22),−13,−14,−17, dic(19;?)(q13;?),+ 12mar

3.2 Response and toxicity

As shown in Tables 4 and 5, seven patients achieved CR, and two achieved PR. The rate of CR + PR was the same for the older group (42.9%, 6/14; (65 years) and the younger group (42.9%, 3/7) making the overall rate 42.9% (9/21).
Table 4

Results of chemotherapy with SPAC and ET (NR)

Patient

Duration of therapy (days)

Nadir (day)*1

Duration of cytopenia (days)

Response

Side effects

Post-therapy

Response

Survival after start of therapy (mon)

WBC (/μL)

PL (×104/μL)

WBC <1000

Plt <2×104

1*2

12

31 (1200)

18 (0.8)

0

Not clear

NR*3

(−)

Bes*4 Methenolon

(−)

9

2*2

14

4 (1800)

8 (1.2)

0

Not clear

NR*3

(−)

(−)

(−)

4

3*2

14

19 (4500)

19 (2.0)

0

0

NR*3

(−)

SPAC

(−)

2

4*2

14

23 (1200)

16 (1.3)

0

1

NR*3

(−)

Bes*4

(−)

5

5*2

16

13 (7700)

5 (1.1)

0

9

NR*3

(−)

DCMP*5

(−)

3

6

14

18 (600)

18 (4.4)

10

0

NR*3

(−)

SPAC + EP DCMP*5

(−)

6

7

14

13 (3000)

8 (1.8)

0

1

NR*3

(−)

(−)

(−)

1.5

8

14

23 (2700)

14 (3.6)

0

0

NR*3

(−)

Mini-DCMP*6 SPAC + EP, LVP*7

(−)

6

9

14

25 (700)

15 (0.8)

19

26

NR*3

(−)

Mini-DCMP*6

PR

9

10

7

9 (4900)

9 (2.6)

0

0

NR*3

(−)

SPAC + EP DCMP*5

CR

16

11

14

24 (500)

22 (1.4)

15

15

NR*3

(−)

Mini-DCMP*6 CAG*8

(−)

4

12

14

16 (1500)

20 (1.7)

0

1

NR*3

(−)

(−)

(−)

4

*1: number of days from the start of therapy till the day showing the lowest counts of WBC and PL, *2: SPAC:200 mg/day, *3: no remission, *4: ubenimex, *5: daunorubicin + ara-C + 6MP + prednisolone, *6: short duration of DCMP therapy, *7: L-asparaginase + vincristine + prednisolone, *8: ara-C + aclarubicin + G-CSF

Table 5

Results of chemotherapy with SPAC and EP (PR and CR)

Patient

Duration of therapy (days)

Nadir (day)*1

Duration of cytopenia (day)

Response

Side effects

Post-therapy

Duration of remission (mon)

Relapse

Survival*2 after start of therapy (mon)

WBC (/μL)

PL (×104/μL)

WBC <1000

Plt <2×104

13

14

20 (400)

15 (1.7)

23

Not clear

CR*4

Nausea GOT& GPT↑

HD-Ara-C*6 BMT*7

7

(−)

9

14*3

14

3 (1200)

10 (0.8)

0

1

CR*4

(−)

SPAC + EP CAG*8 AtripleV*9 HD-Ara-C*6

1.5

(+)

16

15*3

14

25 (400)

25 (7.0)

24

0

PR*5

(−)

Bes*10 Methenolon SPAC + EP

9

(+)

12

16

14

15 (900)

13 (1.2)

1

1

PR*5

(−)

Mini-DCMP*11 SPAC + EP

7

(+)

14

17

14

25 (300)

35 (1.6)

36

1

CR*4

(−)

DCMP*12 ACMP*13 HD-Ara-C*6

4

(+)

8

18

14

19 (500)

27 (0.8)

33

16

CR*4

(−)

(−)

2

(+)

9

19

14

24 (1700)

13 (1.8)

0

1

CR*4

(−)

SPAC + EP Bes*10

14

(+)

34 +

20

14

7 (500)

10 (1.3)

51

10

CR*4

Eruption

SPAC + EP + G-CSF

2

(+)

11

21

14

14 (800)

14 (2.7)

13

0

CR*4

(−)

Mini-DCMP*11

4

(+)

10

*1: number of days from the start of therapy till the day showing the lowest counts of WBC and PL, *2: 8,31,2006, *3: SPAC:200 mg/day, *4: complete remission, *5: partial remission, 6: high-dose ara-C, *7: bone marrow transplantation, *8: ara-C + aclarubicin + G-CSF, *9: ara-C + etoposide + vincristine + vinblastine, *10: ubenimex, *11: short duration of DCMP therapy, *12: daunorubicin + ara-C + 6MP + prednisolone,*13: aclarubicin + ara-C + 6MP + prednisolone

We reduced the dose of SPAC (300 mg to 200 mg) for seven patients, and shortened the duration of drug therapy for two. These treatment changes were not due to toxicity but of PS, severe cytopenia, and complications. It is noteworthy that SPAC + EP therapy induced CR in two patients (patients 13 and 14) who had failed to achieve CR from intensive chemotherapies including ara-C and EP (DCMP, ACMP, and MEC therapies). Two (patients 16 and 21) of the CR + PR patients had received SPAC + EP in the previous MDS period. At that time, both patients also reached CR. The nadir of leukocyte and platelet counts occurred 3–31 days from the start of therapy (median; leukocytes: 19 days, platelets: 15 days). Leukocytopenia (<1,000 leukocytes) and thrombocytopenia (<20,000 platelets) were not prolonged, but some CR and PR patients showed a long duration of leukopenia (23–51 days). G-CSF was used for patients 11 and 17 for supportive therapy, and induction therapy combined with G-CSF was given to patient 20. No serious adverse events were observed from any patients. Only two patients developed nausea, eruption, and slight hepatic toxicity. Two of 12 patients in the no-remission group achieved CR and PR after additional induction therapy. The duration of survival was 1.5–34 + months (as of the end of August 2006).

3.3 Prognostic factors for achieving remission and surviving

Prognostic factors for survival are presented in Table 6. Not only uni- but also multivariate analysis identified therapy effects (CR + PR) as a prognostic factor for overall survival. There was a clear survival advantage for patients achieving CR or PR (Fig. 1). Uni- and multivariate analyses failed to identify any prognostic factors that significantly increased the rate of remission.
Table 6

Uni- and multivariate analyses of prognostic factors for overall survival

Factor

P-values

Univariate analysisa

Multivariate analysis

Age

65/≥65

0.5126

0.4093

Chromosomal abnormality

Normal/abnormal

0.7870

n.c.b

Chromosomal abnormality

Not complex/complex

0.4144

0.7200

Dose of SPAC

200 mg/300 mg

0.5250

0.4461

WBC counts

<3,000/≥3,000

0.8170

0.7302

WBC counts

<10,000/≥10,000

0.4065

n.c.b

AML

MDS→overt/de novo

0.6456

0.9359

Response

NR/CR + PR

0.0137

0.0344

aLog-rank test bnot calculated

https://static-content.springer.com/image/art%3A10.1007%2Fs12185-007-0019-6/MediaObjects/12185_2007_19_Fig1_HTML.gif
Fig. 1

Kaplan Meier curves for overall survival among patients with CR&PR and NR

3.4 Plasma concentrations of ara-C and EP

Plasma ara-C and EP concentrations of seven patients before and 3 h after taking drugs in the morning are shown in Table 7. The ara-C concentrations ranged between 4.60 and 21.62 ng/mL at 2–3 days, and 6.84 and 42.82 ng/mL at 7 days after SPAC administration. Very high concentrations were observed in patients 11 who did not achieve remission, although the plasma was analyzed only on day 14. It is clear that the ara-C concentration was little influenced by SPAC administration over the course of any day, although ara-C accumulation over the duration of SPAC administration was considerable. EP concentrations ranged between 0.15 and 1.28 μg/mL at 2–3 days and 0.20 and 1.82 μg/mL at 7 days after administration of EP. The accumulation of EP in plasma over the duration of EP administration was not observed.
Table 7

Plasma concentrations of Ara-C and etoposide

Case (Response)

Day*1

Ara-C (ng/mL)

EP (μg/mL)

Pre*2

Post*3(3h)

Pre*2

Post*3(3h)

7 (NR)

7

9.79

10.71

0.46

1.24

8 (NR)

2

4.79

4.60

0.23

0.48

7

7.69

9.51

0.29

0.70

9 (NR)

2

16.88

13.52

0.15

0.48

7

42.82

39.39

0.20

0.59

10 (NR)

3

7.29

8.63

ND*4

ND*4

7

6.84

11.81

0.48

ND*4

11 (NR)

14

64.55

61.31

0.10

0.16

16 (PR)

3

5.52

5.70

0.84

1.28

7

9.66

12.01

1.04

1.82

17 (CR)

3

21.62

15.47

ND*4

ND*4

7

35.11

39.55

ND*4

0.40

*1:number of days of drug administration, *2:before taking drugs in the morning, *3:3 h after taking drugs in the morning, *4: not done

4 Discussion

Standard induction therapies for elderly AML patients and refractory leukemia cases have, due to the poor condition of these patients, generally been associated with low CR rates, and short relapse-free and overall survival [15]. Although efforts to treat AML in elderly and refractory cases have been made [15, 16], clear improvements have not been observed. This led us to study the effects of mild induction therapy consisting of SPAC and oral EP in such patients.

In a phase 1 clinical and pharmacokinetic study, during a 5-day oral administration regimen of SPAC at a dose of 300 mg/day, the ara-C concentration in the blood changed from 2.3 to 4.1 ng/mL, and remained at almost the same concentration as during the administration period, until the second day after the completion of drug administration [17]. These concentrations are similar to the blood levels of ara-C administered at a low dose (20 mg/m2/day) intravenously [18].

As for clinical trials of SPAC for acute leukemia and MDS, two phase II studies [19, 20] and one multi-institutional study combined with G-CSF [21] showed the effectiveness of this regimen at a dose of 100–400 mg/day for more than 14 days. All patients with acute leukemia who achieved CR in these studies had received more than 300 mg/day of SPAC.

EP has a broad spectrum of antitumor activity and was shown to induce the differentiation of human leukemic cell lines at low concentrations in vitro [22]. Edick et al. [23] showed that plasma concentrations of EP with oral EP administration (50 mg/m2/day) were suitable for once- or twice-daily administration in children with relapsed or refractory acute lymphoblastic leukemia (ALL), even though prolonged higher concentrations (>1.7 μM:1 μg/mL) were associated with toxicity in some cases. Ogata et al. [24] reported that low-dose EP (50 mg/body, i.v. 2-h infusion) was effective for patients with MDS.

The therapeutic efficacy of SPAC and EP in our study was comparatively satisfactory: CR + PR was achieved in 42.9% of patients. This contrasts with previous reports which found lower rates of CR + PR [15]. Although the PS was poor (scores of 3–4), 5 of 7 patients achieved CR or PR. Because of the low toxicity, no enrolled patients required the cessation of SPAC and EP. However, severe cytoreduction seems to be essential for the achievement of hematological remission, as shown in Table 4. This finding suggests that the SPAC-EP combination acts as a cytoreductive agent, like the LDAC-VP-16 infusion therapy reported by Kuriya et al. [25].

Regarding the therapeutic efficacy of ara-C and EP combined, the synergistic effect of these two drugs has been demonstrated in clinical [26] as well as in vitro studies [27]. As to the effect of this combination, a sequence-dependent antitumor effect was observed, and administration of EP 6 h before ara-C injection generated the best therapeutic results [28]. Ooi et al. [29] demonstrated that the amount of ara-C incorporation into DNA of L1210 cells was increased to more than 200% of the control by a 3- and 6- h pre-administration of EP. They surmised that the period of repair of DNA damage by EP might be the critical time in which ara-C incorporation into DNA is increased. SPAC was proven to be slowly converted to ara-C in the liver, releasing ara-C into the blood over a prolonged period [9]. Although the time schedules for administering SPAC and EP were the same, the amount of ara-C incorporation into DNA was assumed to be increased by EP and continuous ara-C concentration. As shown in Table 7, plasma concentrations of ara-C not only in CR and PR patients, but also in no-response (NR) patients, were comparatively higher than those reported previously [10]. It is not known why higher concentrations of ara-C were achieved with this combination. The accumulation of ara-C during the days of SPAC administration may be the reason for the higher concentrations. On the other hand, the EP concentrations shown in Table 7 were almost the same as previously reported [23]. It is noteworthy that higher ara-C concentrations caused more marked myelo-suppression, as shown in Tables 4, 5, and 7, even though the number of patients is small. Both concentrations of ara-C and EP in 7 patients showed major differences indicating a different metabolic ability in individual cases. Another possible mechanism for the effects of this combination therapy is induction of the differentiation of malignant cells, as reported previously [22, 30]. In patients 14 and 19, severe neutropenia was not observed and CR was achieved. This mechanism may not be a main contributor to CR because patients 1–5, 7, 8, 10, and 12, who were without severe neutropenia, did not achieve CR. However, it is of note that this oral therapy induced CR in patients who had previously used intensive chemotherapies including ara-C and EP (patients 13 and 14). As shown in Table 2, both patients’ conditions were poor. Leukopenia and thrombocytopenia were severe. So, we chose the SPAC + EP therapy, although usual doses of ara-C and EP had been used. We think that the favorable effects shown by these patients using this therapy may be due to the damage to blasts incurred by recurrent intensive therapies. Some patients under similar conditions who achieved CR by treatment with low doses of ara-C were reported previously [26, 30]. Under these conditions, not only the synergistic effects of DNA damage but also differentiation may be induced.

As reported previously [31], the factors at diagnosis that showed prognostic value for a reduced CR probability and shorter survival times in elderly AML cases include a higher age, poor PS, high WBC count, and unfavorable karyotypes. In this study, complex chromosomal abnormalities were not a significant prognostic variable for a reduced CR, although the value of this factor is supported by a recent chromosomal analysis of AML patients [32]. However, it is noteworthy that despite showing unfavorable karyotypes (patients 13, 17, and 18), CR was available through this oral treatment. Moreover, patients in a poor clinical condition (PS scores of 3 to 4) also achieved CR or PR, indicating the low toxicity and absence of treatment-induced complications with this treatment. For longer survival times, only the achievement of CR or PR was predictive, and the difference between the CR + PR and NR groups was significant (Table 6). However, the major problem with the use of this combination chemotherapy was the short duration of the hematological response. The remission duration was less than 12 months in 7 of 9 patients with CR and PR. Except for patient 13, who expired after bone marrow transplantation without relapse, and patient 17, all other patients received only weak or no post-remission therapy due to their debilitated physical and psychological conditions. Although no significant differences between mitoxantrone and daunorubicin combined with ara-C in induction and consolidation therapies on remission duration and survival time were observed, sequential cycles of low-dose ara-C maintenance therapy led to increased disease free-survival [31]. An attractive feature of low-dose ara-C therapy is that it can be applied to elderly individuals because of its limited toxicity in an outpatient context. This situation fits our SPAC + EP therapy. In future studies, we will try to use SPAC + EP cyclically for post-remission therapy in place of low-dose ara-C. The addition of all-trans retinoic acid to the regimen for induction and consolidation therapy reported by Schlenk et al. [33] may be another option for achieving low toxicity and increased disease-free survival. Although our group of patients was small and follow-up was short, we conclude that SPAC with EP can be administered safely and is a potential treatment of high-risk and elderly AML patients in poor condition.

Acknowledgments

We thank Dr. K. Uenogawa and Dr. M. Inoue for helpful discussions.

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© The Japanese Society of Hematology 2008