Mediterranean Journal of Hematology and Infectious Diseases

Original Article

Treatment with Low-Dose Cytarabine in Elderly Patients (Age 70 Years or Older)

with Acute Myeloid Leukemia: A Single Institution Experience
Maël Heiblig1, Mohamed Elhamri1, Isabelle Tigaud2, Adriana Plesa3, Fiorenza Barraco1, Hélène Labussière1,
Sophie Ducastelle1, Mauricette Michallet1, Franck Nicolini1, Claudiu Plesa4, Eric Wattel1, Gilles Salles1 and Xavier
Thomas1.
1
Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre Bénite, France;
2
Laboratory of Cytogenetics, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre Bénite, France;
3
Laboratory of Cytology and Immunology, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre Bénite, France;
4
Trarieux Clinic, Lyon, France.

Competing interests: The authors have declared that no competing interests exist.

Abstract. Objectives: Low-dose cytarabine (LD-AraC) is still regarded as the standard of care in
elderly patients with acute myeloid leukemia (AML) ‘unfit’ for intensive chemotherapy. In this
study, we reported our experience with LD-AraC in patients ≥ 70 years old and compared the
results to those of intensive chemotherapy, best supportive care (BSC), or hypomethylating
agents in the same age population.
Methods: Between 2000 and 2014, 60 patients received LD-AraC at 20 mg once or twice daily by
subcutaneous injection for 10 consecutive days every 4-6 weeks.
Results: Complete remission rate with LD-AraC was 7% versus 56% with intensive
chemotherapy and 21% with hypomethylating agents. Median overall survival (OS) of patients
treated with LD-AraC was 9.6 months with 3-year OS of 12%. Survival with LD-AraC was
better than with BSC only (P = 0.001). Although not statistically significant, intensive
chemotherapy and hypomethylating agents tended to be better than LD-AraC in terms of OS
(median: 12.4 months and 16.1 months, respectively). There was no clear evidence that a
beneficial effect of LD-AraC was restricted to any particular subtype of patients, except for
cytogenetics. There was a trend for a better OS in LD-AraC treated patients in the setting of
clinical trials as compared with those treated outside of a clinical trial.
Conclusions: Despite a trend in favor of intensive chemotherapy and hypomethylating agents
over LD-AraC, no real significant advantage could be demonstrated, while LD-AraC showed a
significant advantage comparatively to BSC. All this tends to confirm that LD-AraC can still
represent a baseline against which new promising agents may be compared either alone or in
combination.

Citation: Heiblig M., Elhamri M., Tigaud I., Plesa A., Barraco F., Labussière H., Ducastelle S., Michallet M., Nicolini F., Plesa C., Wattel
E., Salles G., Thomas X. Treatment with low-dose cytarabine in elderly patients (age 70 years or older) with acute myeloid leukemia: a
single institution experience. Mediterr J Hematol Infect Dis 2016, 8(1): e2016009, DOI: http://dx.doi.org/10.4084/MJHID.2016.009

Published: January 1, 2016 Received: August 14, 2015 Accepted: November 26, 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Correspondence to: Xavier Thomas, Department of Hematology, Lyon-Sud Hospital, Bat. 1G, 165 chemin du Grand Revoyet,
69495 Pierre Bénite Cedex, France; phone: (33)478862235; fax: (33)472678880; e-mail: [email protected]

Introduction. Despite multiple advances in AML are living longer, the incidence of AML is increasing.
therapy, the treatment outcome for older patients with The treatment outcome for patients aged 70 years or
acute myeloid leukemia (AML) is unsatisfactory, older has not improved significantly over the last two
especially for patients in their latter years. As people decades in spite of improved supportive care. Most of

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these patients do not receive intensive chemotherapy Patients and Methods.
either because they decline or because they are not Patients: In total, 234 patients (aged 70 years or older)
considered fit enough for such therapy. The basis on with newly diagnosed AML have been seen in the
which patients are not considered fit enough for Department of Hematology at Lyon-University
intensive chemotherapy remains not clear and varies Hospital from 2000 to 2014. From 2000 to 2006,
considerably from one investigator to another. Clearly patients with PS  2 were considered ‘fit’ by the local
performance status remains an important factor in physician and received an intensive treatment approach
therapy planning. However, evaluation of ‘fitness’ systematically. No specific criteria for defining
remains unclear. Recent reports have shown that ‘fitness’ were used. After 2006, a more ‘personalized’
geriatric assessment methods, with a focus on cognitive treatment using either intensive chemotherapy or
and physical function, improve risk stratification and lower-intensity therapies (including LD-AraC,
may inform interventions to improve outcomes for decitabine or azacitidine) based on the clinical
older AML patients.1 Others showed that candidacy for judgment of the treating physician and the availability
intensive therapy should be based on biological of clinical trials were proposed.20 Most patients older
features of disease rather than on age.2 than 70 years received, therefore, a non-intensive
Although low-dose cytarabine (LD-AraC) has not option. Any type of AML (de novo or secondary) was
been adopted universally, it still represents a treatment considered. Acute promyelocytic leukemia and blast
reference (at least in Europe) for patients considered transformation of chronic myeloid leukemia were
‘unfit’ for intensive chemotherapy. LD-AraC was excluded. Among the 234 patients (aged 70 years or
investigated extensively more than 20 years ago. LD- older) with newly diagnosed AML, 60 patients (16%)
AraC has been used in various schedules showing received LD-AraC. They were compared to 85 patients
responses that included complete remission (CR).3-9 Its treated with intensive therapy (anthracycline- and
mechanism of action is still not completely clear, cytarabine-based chemotherapy), 34 patients treated
acting potentially through cytotoxic action and/or with hypomethylating agents (12 by decitabine and 22
through induction of apoptosis by differentiation by azacitidine), and 43 patients receiving only BSC.
induction.10,11 LD-AraC is relatively well tolerated and The 12 remaining patients received other treatments in
can be given in an outpatient care setting. However, it the setting of investigational trials and were not
can induce excess cytopenia although this may be a considered for the study.
prerequisite for efficacy. In the literature, 10% to 20%
of patients have been reported to achieve CR.3-9,12 Treatment: On entry, patients received LD-AraC 20
Randomized studies between intensive and non- mg once or twice daily (according to physician’s
intensive treatments showed better responses in choice) by subcutaneous (sc) injection for 10
intensively treated patients, but no significant consecutive days. Subsequent courses of LD-AraC
differences in terms of survival.13,14 LD-AraC has been were administered at intervals of 4 to 6 weeks.
demonstrated to be more beneficial than best Regarding the control groups, intensive chemotherapy
supportive care and hydroxyurea among patients not fit consisted of a combination of intermediate-dose
for intensive therapy, although fitness was not defined cytarabine with an anthracycline. Azacitidine was
for patients’ age > 70 years.12 LD-AraC therapy still given at the dose of 75 mg/m2/day for 7 consecutive
represents a baseline against which novel drugs may be days by sc injection, and decitabine was administered
compared either alone or in addition to LD-AraC. by intravenous route once daily at 20 mg/m2 for 5
Currently, the role of lower-intensity regimens is under consecutive days. Subsequent courses of these low-
active investigations.12,15-19 Recent randomized trials intensity treatments were administered at intervals of 4
comparing DNA hypomethylating agents, azacitidine to 6 weeks until disease progression. All clinical trials
or decitabine, with LD-AraC found improved CR rates received approval from the institutional review board
and better survival with hypomethylating agents.15,19 and were conducted in accordance with the Declaration
These studies urged us on analyzing our series of of Helsinki. All participants gave their written
elderly patients treated with LD-AraC with the aim to informed consent. Policies with regard to blood
evaluate whether this treatment could still represent a product support, antibiotic and anti-fungal prophylaxis,
standard therapy in this patient population to which and treatment of febrile neutropenia were determined
new treatments should be compared. We, therefore, by established local practice. BSC consisted only in the
evaluated the efficacy of LD-AraC, in a single application of these policies plus eventually the
institution experience, in patients aged 70 years or administration of hydroxyurea in order to control white
older, and compared it to that of other treatments blood cell (WBC) count in case of the proliferative
received by patients of the same age (intensive disease. Patients receiving intensive chemotherapy
chemotherapy, best supportive care (BSC), and lower were systematically hospitalized for induction
intensity therapy based on hypomethylating agents). chemotherapy (median hospitalization duration: 36
days) and consolidation chemotherapy courses. Blood

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product transfusions were systematically administered analyzes used the Cox proportional hazard method for
when hemoglobin was  80 g/l and platelets  20 x survival. Hazard ratios (HRs) with 95% confidence
109/l. Requirements for transfusions were the same for intervals (CIs) were calculated for the main endpoint.
patients treated with lower intensity therapies (LD- An HR < 1 indicated a benefit for one factor over
AraC or hypomethylating agents) while platelets were another. All P values are two-tailed, with a P value ≤
only transfused to patients with bleedings in the case of 0.05 considered statistically significant. Computations
treatment by BSC alone. Hospitalization was reserved were performed using BMDP PC-90 statistical
for patients with infectious complications or other program (BMDP Statistical Software, Los Angeles,
severe complications for patients belonging to two last CA, USA).
groups of treatment.
Results. Between 2000 and 2014, 60 patients (aged 70
Endpoints: CR was defined by bone marrow aspiration, years or older) with newly diagnosed AML, including
which was required to consist of more than 50% 35 de novo AML and 25 secondary AML, were treated
normal cellularity with evidence of trilineage in our Institution by LD-AraC. Characteristics and
maturation and less than 5% bone marrow blasts, no outcome of these patients were compared to those of
evidence of extramedullary disease, and regeneration patients treated during the same period of time by
of the peripheral neutrophil count to 1.0 x 109/l and the intensive chemotherapy (85 patients), hypomethylating
platelet count to 100 x 109/l. The persistence of agents (34 patients), or only BSC (43 patients). The
myelodysplastic features did not exclude the diagnosis characteristics of patients, split by the treatment type at
of CR. Response to therapy was evaluated after one or onset, are provided in Table 1, which shows, as
two courses for patients treated with intensive expected, differences according to the distinct
chemotherapy, and after 4 to 6 courses for those treated therapeutic approaches.
by lower-intensity treatments. Overall survival (OS) The median number of treatment courses given was
was the primary endpoint. It defines the time from 5 for LD-AraC (range: 1 – 20+) with a median length of
starting treatment to death from any cause. For treatment of 5.1 months (range: 0.9 – 28+ months). The
remitters, disease-free survival (DFS) is the time from overall CR rate of patients treated with LD-AraC was
CR to first event (recurrence or death in CR). 7% (4 of the 60 patients). The median number of
courses to achieve CR was 4 (range, 3-9 courses). The
Statistical analyses: Surviving patients were censored CR rate was significantly better in patients treated by
at the end of September 2014 when follow-up was up intensive chemotherapy (48/85 patients; 56%) (P <
to date for 95% of patients. Descriptive statistics was 0.0001) and in patients treated by hypomethylating
used to characterize patients and their disease. agents (7/34 patients; 21%) (P = 0.09). Median OS of
Categorical variables were compared between patients treated with LD-AraC was 9.6 months (95%
treatment options by Fischer exact tests. Continuous CI, 5.8-13.5 months) with 3-year OS of 12%.
variables were analyzed by parametric tests (t tests) or Survival with LD-AraC was better than that with BSC
nonparametric tests (Wilcoxon) as appropriate. only (median OS: 9.6 months vs. 3.4 months; P =
Estimated probabilities of survival were calculated 0.001) (Figure 1). Although not statistically
using the Kaplan-Meier method, and the log-rank test significant, intensive chemotherapy tended to be better
evaluated differences between survival distributions. than LD-AraC in terms of OS (median OS: 12.4
All variables tested by univariate analyzes were months vs. 9.6 months; 3-year OS: 27% vs. 12%; P =
included in the multivariate analysis. Multivariate
Figure 2. Overall survival: LD-AraC versus intensive
Figure 1. Overall survival: LD-AraC versus best supportive care. chemotherapy.

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Table 1. Patient characteristics and outcome split by initial treatment type.

LD-AraC Intensive chemotherapy Hypomethylating agents Best supportive care

Characteristics
(60 patients) (85 patients) (34 patients) (43 patients)

Age (years) 76 (70-84)a 72 (70-79) 76 (70-86) 76 (71-89)

Gender (M/F) 39/21 45/40 20/14 27/16
WHO PS > 2 4 (7%) 1 (1%) 0 10 (23%)
FAB criteria:
M0/M1/M2/M4 4/10/21/8 2/19/24/8 2/2/12/3 3/5/14/4
M5/M6/M7/ND 8/1/0/8 27/1/3/1 4/4/1/6 5/1/0/11
Antecedents:
Oncology 18 (30%)b 14 (16%) 9 (26%) 11 (26%)
MDS 8 (13%) 20 (24%) 10 (29%) 9 (21%)
Cytogenetics:c
Favorable 1 (2%) 2 (2%) 0 1 (2%)
Intermediate 38 (63%) 48 (56%) 15 (44%) 9 (21%)
Unfavorable 13 (22%) 16 (19%) 16 (47%) 16 (37%)
Failure 8 (13%) 19 (23%) 3 (9%) 17 (40%)
LDH (UI/l) 317 (149-2998) 466 (124-2909) 394 (164-17773) 412 (149-6825)
Peripheral blood:
Hb (g/l) 97 (53-136) 93 (62-152) 93 (39-126) 83 (41-131)
WBC (x109/l) 4.4 (0.4-117.9) 3.4 (0.5-223) 2.2 (0.3-45.3) 2.3 (0.6-62.3)
Platelets (x109/l) 75 (5-261) 52 (6-285) 60 (15-214) 66 (3-598)
PMN (%) 24 (1-67) 15 (0-97) 26 (1-67) 19 (0-72)
Blasts (%) 12 (0-90) 15 (0-97) 3 (0-63) 10 (0-95)
Bone Marrow:
Blasts (%) 50 (20-95) 62 (20-100) 30 (20-90) 53 (20-95)
Outcome:
CR 4/60 (7%) 48/85 (56%) 7/34 (21%) 1/43 (2%)
OS (median) 9.6 months 12.4 months 16.1 months 3.4 months
a
Median (range); b Number of cases (percentage); c The favorable risk category included patients with inv(16)/t(16;16)/del(16q), or t(8;21),
with or without other chromosome abnormalities; the intermediate risk category included patients characterized by +8, Y, +6, del(9q),
del(12p) or normal karyotype; the unfavorable risk category was defined by the presence of one or more of 5/del(5q), 7/del(7q),
inv(3q)/t(3;3), abnormal 20q or 21q, translocation involving 11q23, t(6;9), t(9;22), abnormal 17p or complex karyotype, defined as 3 or more
chromosomal abnormalities.
Abbreviations: Hb, hemoglobin; LDH, lactate dehydrogenase; MDS, myelodysplastic syndromes; M/F, male/female; ND, not determined;
PMN, polymorphonuclear; WBC, white blood cell; WHO PS, World Health Organization performance status.

0.07) (Figure 2). However, differences in favor of years) (median OS: 9.2 months vs 9.6 months; P =
intensive chemotherapy were only confirmed for 0.92), WHO PS (0-2 vs > 2) (median OS: 9.6 months
patients aged less than 75 years (median: 12.7 months vs 9.2 months; P = 0.63), bone marrow blastic
vs. 9.2 months; 3-year OS: 28% vs. 10%). In patients
aged  75 years, median OS was better with LD-AraC Figure 3. Overall survival: LD-AraC versus hypomethylating
agents.
(9.6 months vs. 2.8 months). Although there was a
trend for better results with hypomethylating agents, no
significant differences were observed when compared
with LD-AraC (median OS: 16.1 months with
hypomethylating agents vs. 9.6 months with LD-AraC;
3-year OS: 22% vs. 12%; P = 0.1) (Figure 3). In a
multivariate analysis including cytogenetics
(unfavorable vs. intermediate/favorable risk), age (< 75
years vs.  75 years), de novo or secondary AML, and
the type of treatment, only cytogenetics was of
prognostic value (HR, 1.93; 95% CI, 1.50-2.47; P <
0.001).
There was no clear evidence that a beneficial effect
of LD-AraC was restricted to any particular subtype of
patients. In the univariate analysis, similar treatment
effects were observed for all ages (< 75 years vs  75

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Table 2. Multivariate analysis: Factors associated with overall survival in patients treated with LD-AraC.
Factor HR 95% CI P value
Initial cytogenetics
1.95 1.05 – 4.03 0.04
(Unfavorable vs Favorable/Intermediate)
Secondary AML
0.46 0.22 – 0.96 0.05
(no antecedents vs prior malignant history)
Age, WHO performance status, bone marrow blast cells, cytogenetics, secondary AML, WBC count were factors included in the model.
A HR < 1 indicated a benefit for one factor over another.

infiltration at diagnosis ( 30% vs > 30%) (median OS: combination of 6-mercaptopurine with oral
17.7 months vs 9.2 months; P = 0.15), initial WBC methotrexate. Five patients received a second line
count ( 10 x 109/l vs > 10 x 109/l) (median OS: 11.5 therapy: one with azacitidine and 4 with a new drug
months vs 4.7 months; P = 0.35), and secondary AML inside a phase 1 investigational trial.
(prior history of MDS or cancer vs no antecedents)
(median OS: 5.8 months vs 13.5 months; P = 0.08). Discussion. Overall, despite a trend in favor of
There was only a significant difference regarding initial intensive chemotherapy and hypomethylating agents
cytogenetics (favorable and intermediate-risk vs over LD-AraC, no real significant advantage could be
unfavorable-risk) (median OS: 11.4 months vs 4.3 demonstrated in terms of OS, while LD-AraC showed a
months; P = 0.03). In the multivariate analysis in a significant advantage comparatively to BSC. CR rates
model taking into account all these factors, only initial were higher with intensive chemotherapy or treatment
cytogenetics and secondary AML appeared of by hypomethylating agents than with LD-AraC, but
prognostic value (Table 2). this did not translate into a significant benefit in terms
Of the patients who received LD-AraC, 24 patients of OS. The old principle of achieving a CR with
were treated inside clinical trials, while 36 patients intensive chemotherapy to convey a favorable outcome
were not. There were no substantial differences might not apply to this patient population, for which
between those patients with respect to blood product OS and quality of life represent the most relevant
support, hospitalization, and days on antibiotics. endpoints. However, one recent study regarding the
However, the clinical trials required significantly more quality of life beyond 6 months after diagnosis in this
day care visits for patients. Median OS was 13.2 patient population showed that achievement of CR is
months (95% CI, 8.6-15.1 months) for patients associated with improvements in global health,
included in clinical trials vs 7.8 months (95% CI, 4.3- physical function, and role function without negatively
11.5 months) for those not included, with 3-year OS of affecting other health domains.21 In our series, the
18% and 9%, respectively (P = 0.21) (Figure 4). There prolonged OS contrasting with the low CR rate after
were no significant differences in terms of survival treatment by LD-AraC could be explained by the
between patients receiving LD-AraC at 20 mg per day pursuit of treatment as long as the disease was
and those receiving 20 mg twice a day. controlled and that the treatment was considered
Most of the patients (92%) upon failure after LD- beneficial for the patient and the selection of patients
AraC therapy received only BSC with eventually a with the orientation of frailer patients directly to BSC
alone. This approach explained the higher median
Figure 4. Overall survival: LD-AraC: Comparison between patients number of treatment courses given in our study
included into clinical trials and those not included into clinical comparatively to the median number of courses given
trials.
in previous studies.15,19,22 The same therapeutic
behavior applied to hypomethylating agents can also
explain the differences between our findings and the
recently published studies of decitabine and azacitidine
in elderly AML patients.15,19
Our results with LD-AraC showed lower CR rates
but a median OS better than those observed in previous
studies.4,12,23 Differences in terms of CR rates could be
explained by the different schedules used. The
response to LD-AraC appears dose dependent. Burnett
et al., who reported 18% to 21% of CR rate, used AraC
at 20 mg twice daily for 10 consecutive days,12,22 while
Rodriguez and Tilly, who observed 28%2 to 32%4 of
CR, used LD-AraC for a longer period of time (cycles
of 21 days). Theoretically, patients who achieved CR
have a better median survival compared with those

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who did not achieve CR. However, higher doses or the small size of the cohorts, the absence of data
longer duration schedules are associated with a longer regarding comorbidities (such as diabetes, high blood
period of hypoplasia. Actually our better results in pressure, or cardiac pathology), absence of any quality
terms of median OS could be explained by a higher of life questionnaire, and the under-representation of
rate of severe toxicity in schedules with higher doses patients who received intensive chemotherapy during
and longer treatment4,23 and also by recent the last period of study while the hypomethylation
improvements in terms of supportive care.20 Supportive cohort belongs mainly to this same recent period. The
care improvements over the last decade were also main goal of our study was to report the results of LD-
evidenced by the difference in outcome between our AraC therapy in the real life of one hematology center.
series and that published by the M.D. Anderson Cancer In this setting, comparisons among treatments used in
Center few years ago regarding patients aged  70 this patient population were authorized, although
years receiving intensive chemotherapy.24 They involving unbalanced groups.
reported about patients treated between 1990 and 2008 Although a benefit in OS has been demonstrated
and found 45% of CR and a median OS of only 4.6 with LD-AraC compared with BSC, outcome with LD-
months. This datum is close to the results we AraC remains unsatisfactory. A true step forward in the
previously reported during the same period of time,20 treatment of AML in elderly patients can be expected
while our current series of patients treated with from the development of more effective therapies and
intensive chemotherapy showed a significant the further improvement of supportive measures.
improvement in higher CR rates and longer survival, in Recently, a lower-intensity, prolonged-therapy
relationship with improvements in supportive care. An program testing clofarabine and LD-AraC alternating
important point from our study was a tendency for with decitabine was well tolerated and highly effective
better OS in patients treated inside clinical trials in older patients with AML.25 Hypomethylating agents
comparatively to those who were not. This datum also represent a promising alternative to intensive
stresses one more time on the importance of a regular chemotherapy in this patient population.15,19 On the
follow-up and on supportive care in this patient basis of our findings, LD-AraC did not show sufficient
population, and can explain the better survival with evidence of benefit over hypomethylating agents to be
LD-AraC in our series as compared to previous considered again as the standard treatment for this
ones.4,12,23 patient population, but can still represent a baseline
The strength of our study is that this is a report of against which new promising agents may be compared
treatment with LD-AraC involving only elderly AML either alone or in combination.22
patients aged  70 years and, therefore, reporting on a
relatively homogeneous cohort of patients. Our study, Author contributions. MH interpreted the data, and
however, suffers from limitations. As expected, patient drafted the manuscript; ME collected the data and
characteristics varied significantly among the four provided technical support; IT was responsible for
groups of treatment. Given the nature of clinical coordinating cytogenetics; AP was responsible for
practice, it is conceivable that relatively fit patients coordinating morphological data; FB, HL, SD, MM,
were treated with intensive chemotherapy while less fit FN, CP, and EW included patients; GS gave final
were offered LD-AraC or hypomethylating agents, and approval; XT included patients, collected the data,
frail patients received only BSC. Other limitations conducted the statistical analysis, interpreted the data,
mainly concerned the retrospective profile of the study and wrote the manuscript.
with unbalanced distribution of the treatment options,

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