Ann Hematol (2005) 84: 557–564

DOI 10.1007/s00277-005-1046-0

ORIGINA L ARTI CLE

A. Wrzesień-Kuś . T. Robak . A. Wierzbowska . E. Lech-Marańda . A. Pluta .

E.Wawrzyniak . A. Krawczyńska . K. Kuliczkowski . G. Mazur . M. Kiebiński .
A. Dmoszyńska . M. Wach . A. Hellmann . W. Baran . J. Hołowiecki .
S. Kyrcz-Krzemień . S. Grosicki

A multicenter, open, noncomparative, phase II study

of the combination of cladribine (2-chlorodeoxyadenosine),
cytarabine, granulocyte colony-stimulating factor
and mitoxantrone as induction therapy in refractory acute
myeloid leukemia: a report of the Polish Adult Leukemia Group
Received: 8 January 2005 / Accepted: 2 April 2005 / Published online: 27 April 2005
# Springer-Verlag 2005

Abstract Purine nucleoside analogues, cladribine (2-chlo- toxicity of induction treatment consisting of 2-CdA (5 mg/
rodeoxyadenosine, 2-CdA) and fludarabine (FAMP) are m2), Ara-C (2 g/m2), mitoxantrone (MIT, 10 mg/m2) and
active agents in acute myeloid leukemias (AMLs). Syner- granulocyte colony-stimulating factor (G-CSF) (CLAG-M)
gistic interaction between FAMP or 2-CdA with cytarabine in refractory AML. In case of partial remission, a second
(cytosine arabinoside, Ara-C) has been demonstrated in CLAG-M was administered. Patients in complete remission
preclinical and clinical studies. The current multicenter (CR) received consolidation courses based on high-dose
phase II study was initiated to evaluate the efficacy and Ara-C and MIT with or without 2-CdA. Forty-three patients
from five centers were registered: 25 primary resistant and
18 relapsed. CR was achieved in 21 (49%) patients, 20
(47%) were refractory and 2 (5%) died early. Hematologic
A. Wrzesień-Kuś . T. Robak (*) . A. Wierzbowska . toxicity was the most prominent toxicity of this regimen.
E. Lech-Marańda . A. Pluta . E. Wawrzyniak . The overall survival (OS; 1 year) for the 42 patients as a
A. Krawczyńska
Department of Hematology, whole and the 20 patients in CR were 43% and 73%,
Medical University of Lódz, respectively. Disease-free survival (1 year) was 68.6%.
ul. Pabianicka 62, None of the analyzed prognostic factors influenced the CR
93-513 Lódz, Poland and OS probability significantly. We conclude that CLAG-
e-mail: robaktad@csk.am.lodz.pl
Tel.: +48-426-895191 M regimen has significant antileukemia activity in refrac-
Fax: +48-426-895192 tory AML, which seems to be better than the activity of
many other regimens. The toxicity of the treatment is
K. Kuliczkowski . G. Mazur . acceptable.
M. Kiebiński
Department of Hematology,
Medical University, Keywords Cladribine . 2-Chlorodeoxyadenosine . Purine
Wrocław, Poland nucleoside analogs . Mitoxantrone . Refractory AML .
Induction treatment
A. Dmoszyńska . M. Wach
Department of Hematology,
Medical University,
Lublin, Poland Introduction

Despite the significant progress made in the treatment of

A. Hellmann . W. Baran
Department of Hematology, acute myeloid leukemia (AML) in the last decade, 20–
Medical University, 40% of patients still do not achieve complete remission
Gdańsk, Poland (CR) with standard induction chemotherapy and 50–70%
of patients in first CR (CR1) may be expected to relapse
J. Hołowiecki . S. Kyrcz-Krzemień . S. Grosicki
Department of Hematology and Bone Marrow Transplantation, [8, 33]. Patients with primary refractory disease and with
Silesian Medical University, early relapses following a CR1 of less than 6 months in
Katowice, Poland duration have a significantly poorer response to therapy
558
and overall outcomes when compared with patients in re-
lapse after a CR1 of more than 6 months in duration (CR
rate 28% vs. 59%) [23]. Most salvage therapies that have
been studied in patients with refractory or relapsed AML
are combination regimens using various doses of cytosine
arabinoside (Ara-C) with a variety of other agents. The
number of patients achieving CR with these regimens is
low (16–44%), with usually short disease-free survival
(DFS) and overall survival (OS) [1, 2, 6, 12, 20, 23, 27,
32, 38].
The purine analogs, cladribine (2-chlorodeoxyadeno-
sine, 2-CdA) and fludarabine (FAMP), represent a relative-
ly novel group of cytotoxic agents with activity against
AML refractory to conventional treatment [9, 14, 24, 26,
34]. Estey et al. developed chemotherapy consisting of
FAMP, Ara-C and granulocyte colony-stimulating factor
(G-CSF) (FLAG) [10]. Since its original description, the
FLAG regimen has been used in a large number of pri-
marily single-center studies of relapsed or refractory AML,
with CR rates of 30–81% reported [2, 13, 19, 20, 28, 29,
38]. The addition of mitoxantrone (MIT) or idarubicine
(IDA) to the FLAG regimen may result in antileukemic
synergism of this combination [4, 7, 16, 30, review in 34].
However, no prospective studies comparing the FLAG
regimen with FLAG+ anthracycline have been reported to
date.
Both in vitro and ex vivo pharmacological studies dem-
onstrated a 50–65% increase in the rate of Ara-CTP ac-
cumulation after pretreatment with 2-CdA [15, 24]. In
the pilot study of the combination of 2-CdA with high
doses of Ara-C and G-CSF (CLAG), the CR rate was 50%
in primary refractory and relapsed AML patients with CR1
of less than 12 months in duration [32]. These prelimi-
nary results have been recently confirmed in a phase II
multicenter study. In the group of 58 patients, where the
majority of cases had been diagnosed as primary resistant
AML, the CR rate after CLAG regimen was 50%, which
is better than the CR rate achieved with many other reg-
imens in this very poor risk group of patients [39].
However, less is known about possible synergistic anti-
leukemic activity of MIT and Ara-C in combination with
2-CdA. So far, 2-CdA with Ara-C and IDA or daunoru-
bicin (DNR) has been used in the treatment of de novo
AML or AML in the elderly [18, 21]. No increase in the
toxicity has been observed and the CR rate after one in-
duction course has been higher in the treatment arm with
2-CdA, in both the de novo AML group and the elderly
AML patients.
These results and the results of our multicenter phase II
study of CLAG regimen were the rationales for a mul-
ticenter phase II study assessing the efficacy and toxicity
of the combination of CLAG regimen with MIT (CLAG-
M) in patients with refractory AML. To the best of our
knowledge, these are the first results of a multicenter
analysis of the efficacy of 2-CdA in combination with
Ara-C, G-CSF and MIT in this poor risk group of AML
patients.
Patients and methods
Patient selection
Patients were considered eligible if they (1) had been di-
agnosed as having refractory AML, (2) were in perfor-
mance status ≤2 according to the WHO scale and (3) had a
life expectancy of ≥6 weeks. Ineligibility criteria were (1)
AML subtype M3 according to the French–American–
British (FAB) classification, (2) uncontrolled infection, (3)
hepatic or renal insufficiency and (4) refusal to participate
in the study.
Refractory AML was defined according to the follow-
ing criteria: (1) primary resistance to initial induction ther-
apy, (2) first early relapse with a remission duration of less
than 6 months, (3) second or subsequent relapse and (4)
recurrence, after either allogeneic or autologous stem cell
transplantation (SCT) [23, 37]. Written informed consent
was obtained from all patients before registration. The
study was approved by a local ethics committee at each
center.
Treatment protocol
The treatment protocol scheme is described in Fig. 1. Pa-
tients received induction chemotherapy consisting of 2-
CdA 5 mg/m2, in 2-h i.v. infusions daily, for 5 consecutive
days; Ara-C 2 g/m2, in 4 h infusions, started 2 h after 2-CdA,
for 5 consecutive days; MIT 10 mg/m2 i.v. for 3 days and G-
CSF at a dose of 300 μg s.c., for 6 days, started 24 h before
chemotherapy. In cases of white blood cells (WBC) >20
G/l, G-CSF and 2-CdA were commenced simultaneously.
No dose modification was permitted. All other concurrent
treatment and supportive care were administered in ac-
cordance with local practice at the participating centers. In
cases of partial remission (PR), the second induction
course was recommended. Patients not in CR (NR) after
two induction courses were withdrawn from the study. If
CR had been achieved, the patient was given two consol-
idation courses. In the group of primary refractory patients
the first consolidation course consisted of MIT 10 mg/m2
(days 3–5) and Ara-C 1.5 g/m2 (days 1–3) (HAM). (Fig. 1)
[18]. In the group of patients with relapsed AML, the first
consolidation course, HAM or another CLAG-M was given
according to the treatment center choice. The second con-
solidation course based on high doses (HD) of Ara C with
or without 2-CdA in all patients.
Patients in CR were qualified for stem cell transplan-
tation or maintenance therapy.
Diagnosis and response criteria
Patients were considered relapsed when they had >5%
blasts in the bone marrow (BM) examination and primary
refractory (resistant) if they had >25% blasts or >5% in the
 559
CLAG-M without either a del(9q), or being part of a complex kar-
2-CdA 5mg/m2 iv d 1-5
Ara-C 2g/m2 iv d 1-5 yotype. The intermediate risk category included patients
NR
MIT 10 mg/m2 iv d 1-3 characterized by +8, −Y, +6, del(12p) or normal karyo-
G-CSF 300 µg sc d 0-5 Off protocol type. The unfavorable risk category was defined by the
presence of one or more of −5/del(5q), −7/del(7q), inv(3q),
abn11q, 20q, 21q, del(9q), t(6;9), t(9;22), abn 17p and
PR complex karyotype defined as three or more abnormalities.
In the fourth group, patients with cytogenetic aberrations
of unknown prognostic significance were classified.

CLAG-M PR, NR Statistics

Off protocol
Sample size was calculated using the 0.05 level of sig-
nificance and assuming the power of the study at 80%.
The objective was to increase the CR of 20%, after other
historical salvage regimens, to 50% following CLAG-M.
At least 40 patients were to be included. Disease-free
survival (DFS) was defined as the time from the docu-
CR mentation of a CR to the date of relapse or death from any
Consolidation
cause or the last survival and relapse-free date. The du-
ration of overall survival (OS) was measured from the date
of entry into the study to the date of death from any cause.
or Patients surviving at the time of the analysis were censored
HAM
Ara-C 1,5 g/m2 iv d 1-3 CLAG-M on the date they were last known to be alive. The rela-
Mitox 10 mg/m2 iv d 3-5
tionships between qualitative and discrete parameters were
analyzed by use of the chi-square and Mann–Whitney
tests. Survival curves of patients were prepared using the
Kaplan–Meier method, and differences between the groups
in the OS were assessed using the log-rank test. Ninety-five
HiDAC
Ara-C 4 g/m2 iv d 1,3,5 percent confidence intervals (CI) were calculated for DFS
±2-CdA 5 mg/m2 iv d 1,3,5 and OS.

Fig. 1 Treatment schedule with CLAG-M regimen in patients with

refractory AML Results

A total of 43 patients from five centers were registered

BM examination, after the first and second standard in-
duction treatment, respectively. Response criteria were es-
tablished according to those developed by the National
Cancer Institute-sponsored workshop [3]. CR was defined
as less than 5% blasts in BM and normal peripheral count.
PR was defined as BM blasts with percentage between 5
and 25%. NR was defined when these criteria were not
satisfied. Early death (ED) was defined as death from any
cause during the first 30 days from the commencement of
the induction treatment. Hematological and extra hemato-
logical toxicity were assessed according to the WHO cri-
teria. The number of nights spent in hospital and days of
i.v. antibiotic therapy during CLAG-M induction course
were also recorded.
Cytogenetic analysis
Four cytogenetic categories were defined according to the
Southwest Oncology Group (SWOG) criteria [35]. The
favorable risk category included patients with inv(16)/del
(16q)/t(16;16) with any additional abnormalities, t(8;21)
between November 2000 and September 2004. The clin-
ical and hematological characteristics of the patients are
listed in Table 1. There were 21 women and 22 men in the
study group, with the median age of 44 years (range, 20–
66 years). Twenty-five patients suffered from primary
refractory AML and 18 patients relapsed; 17 of these
subjects were in first relapse, with 1 in second, and among
relapsed patients 6 relapsed 5–24 months after auto-SCT.
In 2 patients, myelodysplastic syndrome (MDS) preceding
the diagnosis of AML had been documented. The median
number of WBC count at diagnosis was 25.0 g/l (range
1.4–500.0 g/l), WBC before CLAG-M was 3.9 (range,
0.8–131.7) and the median percentage of blasts in BM
before CLAG-M was 39.8 (range, 6–97). Twenty-seven
patients were in the WHO performance status 0–1, and 16
patients in performance status 2. According to the karyo-
type analysis performed at diagnosis of AML, 21 patients
were assigned to the intermediate and 11 to the unfavor-
able group; 1 patient had nonclassified abnormalities of
unknown prognostic significance. None of the patients
was assigned to the favorable risk group. In the group of
10 patients, cytogenetics was not available.
560
Table 1 Characteristics of patients Table 2 Treatment outcome after CLAG-M regimen
No. of patients (%) Treatment No. of patients DFS, median OS, median
(n=43) outcome (%) (n=43) (range), weeks (range), weeks

Median age (range), years 44 (20–66) CR 21 (49) 26.2 (0.5–138+) 43 (3–174+)

Sex, F/M 21/22 (n=20) (n=20)
FAB ED 2 (5)
0 4 (10) NR 20 (47) 21.5 (6–79)
1 9 (21) DFS Disease-free survival, OS overall survival, CR complete
2 18 (42) remission, ED early death, NR no remission
4 10 (23)
5 1 (2)
6 1 (2)
Antecedent history CR was achieved in 40% and 61% in each group, re-
MDS/AML 2 (5) spectively (p=NS).
De novo 41 (95) Thirty-five patients had received DNR and Ara-C as the
WHO performance status first-line induction therapy (DA-7); 8 patients had received
0–1 27 (63) additional 2-CdA (DAC-7) during the first-line treatment.
2 16 (37)
The CR rates after CLAG-M regimen were 49% and 50%
WBC (g/l), range
in each group, respectively. CLAG-M regimen was ad-
ministered as a first salvage treatment in 19 out of 25
At diagnosis 25.0 (1.4–500.0)
primary resistant patients, and in 6 patients at least one
Before CLAG-M 3.9 (0.8–131.7)
other salvage regimen was used before CLAG-M. CR rate
Percent of blasts in BM before CLAG-M 39.8 (6–97)
was 42% vs 33% in both groups, respectively (p=NS).
(range)
Cytogenetics at diagnosis
Favorable 0/33 Toxicity associated with CLAG-M regimen
Intermediate 21/33
Unfavorable 11/33 Two patients (5%) died early, both from infections, one of
UN [46,XX t(4;17), t(8;16)] 1/33 them from fungal sepsis. Hematological toxicity and in-
NA 10 fections were the most prominent toxicities of the CLAG-M
Primary resistant (%) 25 (58) induction treatment (Table 4). For patients, who achieved
Relapse (%) 18 (42) CR, the median duration of neutrophils <0.5 g/l and plate-
Second relapse (%) 1/18 lets <20 g/l was 20 days (range, 13–35) and 24 days (range,
Preceding auto-SCT 6/18 12–104), respectively. Patients received a median of 6 units
F Females, M males, MDS myelodysplastic syndrome, WBC white of packed red cells (range, 10–16) and 24 units (range, 3–
blood cells, BM bone marrow, UN karyotype abnormalities of 72) of platelets. The median time of hospitalization was 33
unknown prognostic significance, NA not available days (range, 19–54). All but one patient in the whole group
had fever during the period of aplasia, in 21 (49%) of them
infection grade 3/40 according to the WHO toxicity scale
had been diagnosed (Table 5). The median duration of anti-
Response to CLAG-M induction therapy biotic therapy was 20 days (range, 11–34 days). WHO >2
extrahematological toxicity is summarized in Table 5.
After one induction with CLAG-M regimen, 20 (47%) and
5 (12%) achieved CR and PR, respectively. Three patients
with PR received a second CLAG-M regimen, 1 was Follow-up
withdrawn from the study because of poor performance
status after the first cycle, and 1 patient did not agree for Consolidation therapy
further intensive treatment. Finally CR was achieved in
21 (49%) patients, 20 (47%) were resistant and 2 pa- At the time of analysis 16 of 21 patients in CR received
tients (5%) died early (Table 2). Twelve of 21 patients consolidation therapy, 2 patients received maintenance
(57%) with intermediate karyotype achieved CR; 4 of 11 treatment or allo-SCT directly after CLAG-M regimen, 2
(36%) from the unfavorable prognostic group according to patients are awaiting allo-SCT or first consolidation course
karyotype (p=NS) and 1 patient with karyotype abnor- and 1 patient in CR has been lost from observation. Eleven
malities of unknown prognostic significance achieved CR patients received HAM and 5 CLAG-M as the first con-
(Table 3). In the analyzed group, 25 patients were primary solidation course. All but one patient stayed in CR; 1
resistant to first-line induction therapy and 18 relapsed. patient relapsed after HAM regimen. Nine patients of 15 in
 561
Table 3 The efficacy of Risk groups No. of CR (no. of DFS, range OS, range No. of patients (%) treated
CLAG-M regimen according to
karyotype at diagnosis (accord- according to patients patients/%) (weeks) (weeks) with SCT after CLAG-M
ing to SWOG criteria) karyotype

Intermediate 21 12/57 53.8 61 (3–174+) 5 (42)

(2–135+) (n=12)
Unfavorable 11 4/36 7 14.5 (4–90) 1 (25)
CR Complete remission, DFS (0.5–86.5) (n=4)
disease-free survival, OS overall Unknown [46,XX 1 1 16.5 23.5 0
survival, SCT stem cell t(4;17), t (8;16)]
transplantation

CR received HD Ara-C as the second consolidation course
(3 of them with 2-CdA); 3 patients received allo-SCT di-
rectly after consolidation 1. Three patients with AML with
relapse after auto-SCT performed in CR1 received main-
tenance therapy after consolidation cycle 1 because of
poor tolerance of intensive treatment; 1 of them died in
CR2.
Disease-free and overall survival
One patient was lost from observation after achievement
of CR with CLAG-M. The median OS for the group of 42
patients was 23.7 weeks (range, 3–174+weeks) and 43
weeks (range, 3–174+weeks) for patients who achieved
CR. The probability of 1-year OS for the group as a whole
(42 patients) and the group of 20 patients in CR was 43%
(95% CI, 28–58%) and 73% (95% CI, 53.5–92%), re-
spectively (Fig. 2). Median time of DFS was 26.2 weeks
(range, 0.5–138+weeks). The probability of 1-year DFS
was 68.6% for all 20 patients in CR (95% CI, 49–89%).
Stem cell transplantation
Seven out of 21 patients in CR received SCT, 6 of them as
the postconsolidation treatment: 5 allogeneic and 2 au-
tologous. Median time from CR achievement to SCT was
17.3 weeks (range, 7–27 weeks). All patients after allo-
SCT are alive and in CR. Both patients treated with auto-
SCT relapsed after 14 and 30 months; 1 died. Median DFS
in the group of patients treated with SCT, when compared
with the group treated with chemotherapy alone, was 86.5
weeks (range, 62–138+) and 16.5 weeks (range, 0.5–74+),
respectively. Median OS was 90 weeks (range, 69–174+)
in group 1 and 23.5 weeks (range, 3–116+) in group 2.
Prognostic factors for response to remission
induction therapy
The following factors were analyzed for prognostic value
for CR probability: age, WHO performance status, WBC
at diagnosis, WBC and percent of blasts in BM before
CLAG-M, karyotype abnormalities at diagnosis (interme-
diate vs unfavorable) and number of preceding CLAG-M
salvage regimens. None of these factors significantly in-
fluenced the probability of CR after salvage treatment with
CLAG-M (p>0.05 for all comparisons in the chi-square
with Yate’s correction and the Mann–Whitney tests).
Prognostic factors for DFS and OS
The following factors were analyzed according to their in-
fluence on OS and DFS probability: age, the WHO per-
formance status, WBC at diagnosis and WBC and percent
of blasts in BM before CLAG-M and number of preceding
CLAG-M salvage regimens. Karyotype at diagnosis (inter-
mediate vs unfavorable) was not included in the analysis as
five patients in the group with karyotype of intermediate
prognostic significance had SCT early after induction
treatment (Table 3). None of the analyzed factors influ-
enced the OS probability significantly (p>0.05 for all
comparisons in the log-rank test).
Discussion
The prognosis of adult patients with AML resistant to first-
line, standard induction therapy or relapsed after CR1 of
Table 5 Nonhematologic toxicity (WHO >2)
Toxicity (WHO 3/4) No. of patients (%) (n=43)

Nausea/vomiting 5 (12)
Table 4 Hematopoietic recovery and supportive treatment in Diarrhoea 7 (16)
patients who achieved CR after CLAG-M regimen (n=21)
Mucositis/stomatitis 8 (19)
Days for neutrophils <0.5 g/l 20 (13–35) Hepatotoxicity 1 (2)
Days for platelets <20 g/l 24 (12–104) Alopecia 15 (35)
Packed red cells units (range) 6 (10–16) Cardiotoxicity 2 (4)
Platelets units (range) 24 (3–72) Haemorrhages 2 (4)
Days of hospitalization (range) 33 (19–54) Allergy 1 (2)
Days of antibiotic therapy 20 (11–34) Infection/fever of unknown origin 21 (49)
562
Fig. 2 Overall survival (OS)
probability in the group of 42
refractory AML patients after
CLAG-M induction treatment
Proportion surviving
less than 6 months’ duration is very poor. The average CR
rates in this group of patients are estimated for 10–20%
with less than 10% probability for OS of 52 weeks [11].
AML relapsed after SCT or AML in second or subsequent
relapse has similar poor prognosis [23, 37]. There is no
consensus on how to manage this poor-risk refractory
AML. Most salvage therapies are based on the combina-
tion regimens, using various doses of Ara-C, the most
active drug in AML, with a variety of other agents [1, 6,
12, 15, 17, 23, 25, 27, 37].
Our group has recently reported the results of a phase II
study of the use of 2-CdA, Ara-C and G-CSF (CLAG
regimen) in poor-prognosis refractory AML. The results of
that study indicated that the CLAG regimen is an effective
and well-tolerated induction treatment. CR was achieved
in 29 (50%) patients, 19 (33%) were refractory and 10
(17%) died early [39].
The only studies so far assessing the toxicity and ef-
ficacy of the combination of 2-CdA, Ara-C and IDA or
DNR have been performed by Juliusson et al. [21] in the
group of elderly AML and by Hołowiecki et al. [18] in
patients below 60 years of age with de novo AML. No
increase in the toxicity has been observed and the CR rate
after one induction course has been higher in the treatment
arm with 2-CdA, both in de novo AML group and in the
elderly AML patients. However, there are no existing data
so far concerning the efficacy and toxicity of similar treat-
ment combination in refractory AML. With the obser-
vations in mind concerning CLAG regimen, we had the
possibility to evaluate specifically the relative safety and
efficacy of the CLAG-M protocol in the similar group of
refractory AML patients. The association of CLAG with
MIT did not increase the CR rate, when retrospectively
compared to the CLAG regimen (49% vs 50%, respec-
tively). However, the CR rate of 49% in this very poor risk
group of patients deserves further attention and is still better
than the CR rate achieved with many other regimens. In
some studies, MIT or IDA has been added to the FLAG
regimen [4, 20, 22, 28, 30]. De la Rubia [7] et al. reported
Overall survival
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
0 50 100 150 200
Weeks
the results of the FLAG–Ida regimen in the group of 12
patients with resistant AML or AML relapsed after CR of
less than 12 months’ duration. The CR rate was only 33%.
Steinmetz et al. [36] reported the results of the treatment of
refractory, relapsed and secondary AML with the FLAG–
Ida regimen. CR was achieved by 1 of 14 patients with
refractory AML, defined as primary resistant or relapsed
within 6 months of CR1. Clavio et al. [4] treated with FLAG
or FLAG with MIT (FLANG) protocols 8 patients with
refractory AML and 9 with AML relapsed within 12 months
from diagnosis or in second relapse. The CR rate was 33%
in the refractory group and 75% in the group with relapsed
AML.
In our group of 43 patients, 8 received 2-CdA in com-
bination with DNR and Ara-C (DAC-7) as the first-line
induction chemotherapy. They were primary refractory to
this induction regimen and were subsequently enrolled to
the CLAG-M therapy as the salvage, second-line treat-
ment. Four (50%) of 8 patients achieved CR. This obser-
vation is different from our former study, where 2-CdA in
the first-line treatment was the only one adverse prognos-
tic factor for the CR probability after CLAG [39]. It cannot
be excluded that the addition of MIT to the CLAG reg-
imen significantly improved treatment results in this group
of patients.
Karyotype abnormalities did not significantly influence
the treatment results. This is similar to the observation
made by others [4, 7, 36]. However, it is worth mentioning
that none of our patients with known karyotype at diag-
nosis belonged to the group of favorable prognosis and
30% of patients belonged to the group of poor prognosis
according to the SWOG criteria. This is different from our
former study with CLAG, in which only 16% of patients
belonged to the poor-prognosis group according to the
karyotype and 15% of patients had favorable cytogenetic
abnormalities [39]. Although the small number of patients
precludes any conclusion in this regard, the 50% CR rate
after salvage treatment with CLAG-M in the group of
patients with intermediate and unfavorable prognosis ac-

cording to karyotype abnormalities seems to be the result
worth further attention.
Age was not a significant prognostic factor for CR
probability and survival in this study. However, only two
patients in our group were older than 60 years, and nine
patients were older than 55 years. In this latter group, the
CR rate was 22% as compared with the CR rate of 53% in
younger patients (p=NS; data not shown).
DFS and OS probability of 1 year in this study’s group
of 20 patients in CR was 68.6 and 73%, respectively,
which is much better than the results obtained with other
salvage regimens or CLAG [1, 6, 12, 18, 24, 28, 38].
However, 7 of 20 patients received SCT as consolidation
or postconsolidation phase of treatment, and DFS in the
group of patients not treated with SCT was 48%.
Two (5%) of 43 patients treated with CLAG-M died
early, both from infections. This is an unexpectedly low
mortality rate as compared with other intensive salvage
regimens, among them FLAG–Ida or FLAG–Mito and
CLAG (11%–22,8%) [7, 31, 36, 39]. However, Clavio et al.
described recently the treatment results of FLAD regimen
(daunoXome, FAM and Ara-C) in the group of 62 patients
with high-risk acute leukemias [5]. The treatment-related
mortality was 8%. Improving standards of supportive care
or decisions concerning intensive salvage treatment mak-
ing at earlier stage of the disease may explain these low
mortality rates. The most prominent toxicity of the treat-
ment was hematological toxicity. The median duration of
profound thrombocytopenia and neutropenia, numbers of
platelets transfused and days of hospitalization were longer
after CLAG-M regimen as compared with CLAG. How-
ever, they seem not to be different from hematological
toxicity observed by others after FLAG–Ida or FLAG–Mito
regimens [7, 16].
The nonhematological toxicity was low in most pa-
tients, predominantly reaching the WHO grades 1–2. Se-
vere nonhematological toxicity mainly consisted of loss of
hair, nausea/vomiting, diarrhea and mucositis.
In summary, our results confirm the high antileukemic
efficacy of CLAG-M regimen and an acceptable toxicity
profile in patients with very poor prognosis refractory AML.
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