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Leukemia Research 38 (2014) 425–427

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Leukemia Research
journal homepage: www.elsevier.com/locate/leukres

Commentary

Cladribine in the treatment of acute myeloid leukemia

Keywords: part by the study population. The relapsed patients had very short
2-CdA first CR duration, more than 36% had refractory leukemia and all
AML
the patients were previously treated with anthracyclines. Another
Cladribine
Clofarabine Phase 2 study of 2-CdA in adult patients with relapsed or refrac-
Induction tory AML (median 60 years) performed by ECOG [8] recorded no
Refractory examples of CR, though bone marrow aplasia was observed in eight
Relapsed
patients. The results presented above indicate that 2-CdA used as
a single agent is more active in children with AML and has little
activity in adult patients with relapsed or refractory disease. How-
The standard treatment for acute myeloid leukemia (AML) ever, 2-CdA in combination with other drugs has demonstrated
is remission induction chemotherapy with an anthracy- significant antileukemic activity both in children and in adults
cline/cytarabine (Ara-C) combination (‘3 + 7’), followed by either [5,9].
consolidation chemotherapy or allogeneic stem cell transplan- Several in vitro and in vivo pharmacological studies have
tation [1]. Despite improvements in therapy, the vast majority demonstrated that 2-CdA can increase Ara-C triphosphate (Ara-
of patients cannot be cured with current treatment strategies. CTP) in leukemic blasts by 50–65% [10,11]. Based on these
Cladribine (2-CdA) is a deoxyadenosine analog that is rapidly phos- observations, combined regimens of 2-CdA together with Ara-C
phorylated to the triphosphate form, which resists degradation by and/or other agents were investigated in previously treated and
adenosine deaminase and thus accumulates to cytotoxic levels in untreated AML patients. In a study performed by the Polish Adult
the intracellular space. The drug inhibits DNA synthesis, causes Leukemia Group (PALG), a CLAG regimen consisting of a combi-
cell death and induces apoptosis [2,3]. nation of 2-CdA with high dose Ara-C and G-CSF, was used in 58
Cladribine is the drug of choice in the treatment of hairy cell patients with refractory or relapsed AML. A 50% CR rate and 29%
leukemia but is also highly active in other indolent lymphoid malig- progression free survival (PFS) after 1 year was reported [12]. More
nancies [4]. Cladribine as a single agent has also been investigated recently, a study by Price et al., published in this journal detailed
in both children and adults with AML, with a better outcome being the results of a retrospective comparison of CLAG with an MEC reg-
achieved in the former group [5,6]. Krance et al. treated 72 chil- imen (etoposide, cytarabine, and mitoxantrone) in 167 relapsed or
dren with newly diagnosed primary AML with 2-CdA alone and refractory AML patients [13]. The overall CR rate for CLAG was 37.9%
achieved 24% of complete remission (CR) after one course of 2-CdA and for MEC 23.8% (P = 0.048), with median overall survival (OS) val-
and 40% after two courses [5]. The agent was well tolerated and ues of 7.3 and 4.5 months, respectively (P = 0.05). In patients with
its toxicity was acceptable. Unfortunately the encouraging results first-relapse, CR rates were also higher with CLAG (36.8%) than with
with 2-CdA seen in childhood AML have not been confirmed in MEC (25.9%). In addition, the median relapse free survival (RFS) was
adults. Vahdat et al. report the preliminary results of treatment better in the CLAG group. CLAG was approved by the FDA for the
with 2-CdA in 30 adult patients with relapsed AML [6]. Cladrib- treatment of AML.
ine was administered at a dose of 5–21 mg/m2 /day in continuous Even better results were noted when CLAG was combined with
infusion for 5 days. CR was achieved only in one patient who mitoxantrone (CLAG-M) in patients with refractory and relapsed
received a dose of 15 mg/m2 /day. The most significant adverse AML [14]. In the PALG study, sixty-six out of 118 heavily pretreated
event was the development of a progressive sensorimotor periph- patients (58%) achieved a CR after one or two courses of CLAG-M.
eral neuropathy. In a study performed by Van den Neste et al., The probability of 4 year disease free survival (DFS) was 30% for all
2-CdA was given intravenously at a dose of 0.1 mg/kg/day for 7 66 patients in CR and the probability of OS was 14%. In this study,
days with or without daunorubicin (DNR) in relapsed or refractory OS was influenced by age and poor karyotype in both univariate
adult AML [7]. No CR was achieved and only one patient had par- and multivariate analyses. Moreover, poor karyotype was the only
tial remission (PR). All the patients experienced peripheral blood factor associated with decreased probability of DFS. These results
cytopenia and the median time to reach the leukocyte nadir was suggest that CLAG-M seems to be more effective in refractory AML
12 days. These unsatisfactory results can be explained at least in than many other regimens. These observations were confirmed
by Martin et al. at Washington University [15]. In their study,
24 high-risk, previously untreated or relapsed/refractory patients
DOI of original article: http://dx.doi.org/10.1016/j.leukres.2013.12.010. were treated with CLAG or CLAM (CLAG + M). CR was achieved in

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http://dx.doi.org/10.1016/j.leukres.2014.01.005
426 Commentary / Leukemia Research 38 (2014) 425–427

53% of previously untreated patients and 44% of relapsed/refractory P = 0.002). Toxicity was comparable in both groups. The probability
patients. of 3-year leukemia-free survival (LFS) for the DAC and DA groups
In this issue of Leukemia Research, Jaglal et al. report the was 43 and 34%, respectively (P = NS) and there was a trend toward
results of a case control comparison of the efficacy of CLAG-M a higher LFS rate for patients aged >40 years receiving DAC com-
induction vs. standard ‘3 + 7’ induction chemotherapy in patients pared with the DA regimen (44 vs. 28%, P = 0.05). This study proved
with AML arising from myelodysplastic syndrome (MDS) who that addition of 2-CdA increases the antileukemic potency of the
had previously failed an azanucleoside analog [16]. In this study, 3 + 7 regimen. Subsequently, the same group compared the efficacy
CLAG-M has encouraging activity in these poor prognosis patients. and toxicity of DA, DAC and DA combined with fludarabine (DAF) in
Response rates were 64% in the CLAG-M group vs. 29% in the 652 previously untreated adult AML patients [22]. While the CR rate
‘3 + 7’ group (P = 0.014). Median OS values were 202 vs. 86 days, was 62% in the DAC group and 51% in the DA group (P = 0.02), there
respectively (P = 0.025). Taken together, these reports demonstrate was no significant difference in early outcome between the two
that 2-CdA has an important role in the treatment of very high- groups. However, the 3-year values were significantly improved
risk relapsed/refractory AML, especially when used in combination for the DAC (45%, median 24 months) compared to the DA group
with Ara-C and mitoxantrone, and suggest that 2-CdA-based regi- (33%, median 14 months, P = 0.02). The OS rate for the DAF and DA
mens should be the preferred therapy for these patient populations. arms did not differ significantly. In our opinion, the DAC regimen
National Comprehensive Cancer Network (NCCN) Acute Myeloid should be considered a new standard of care as remission induc-
Leukemia Panel Members recommend CLAG ± M for the treatment tion in adult AML patients. In 2013, the NCCN AML panel included
of relapsed or refractory AML [17]. DAC regimen as another category 1 treatment option for previously
In patients with AML, 2-CdA was also combined with other untreated AML patients younger than 60 years [23]. Recently, a
drugs. Inaba et al. evaluated a 5-day course of 2-CdA followed Phase 2 study of 2-CdA combined with low dose Ara-C induction
by topotecan in pediatric patients with recurrent/refractory dis- followed by consolidation with 2-CdA and low-dose Ara-C alter-
ease [18]. This combination was safe and well tolerated in patients nating with decitabine in previously untreated patients with either
previously treated with anthracycline-containing regimens and AML or high-risk MDS was initiated at the M.D. Anderson Cancer
very drug-resistant pediatric patients. The response rate was also Center (ClinicalTrials.gov Identifier: NCT01515527).
encouraging, as 9 (34.6%) of 26 patients achieved a CR, and 7 (30.4%) It should be remembered, however, that a newer purine nucleo-
achieved a PR. Recently, CLAG induction therapy in combination side analog, clofarabine, has also demonstrated promising activity
with all-trans retinoic acid and midostaurin, a FLT3 inhibitor, is a in pediatric and adult patients with AML. Clofarabine is a next-
subject of an ongoing Phase 1 clinical trial in relapsed/refractory generation nucleoside analog that has been designed to combine
AML (CLAG ATRA AML) performed at the Washington University the most favorable activity and pharmacokinetic properties of flu-
School of Medicine (ClinicalTrials.gov Identifier: NCT01161550). darabine and 2-CdA [24]. Clofarabine demonstrates efficacy alone
Cladribine combination regimens were also investigated in AML or in combination with other cytotoxic drugs in patients with AML
as induction therapy [19,20]. Rubnitz et al. tested a combination [24,25]. Whether clofarabine is more active and/or less toxic than
of 2-CdA and Ara-C administered before standard chemotherapy 2-CdA in AML patients needs to be determined in well designed,
to 96 children with previously untreated AML or MDS [19]. The randomized clinical trials.
patients received a 5-day course of 2-CdA (9 mg/m/m2 per dose) In conclusion, the results of the case control study reported in
and Ara-C (500 mg/m2 per day) as daily 2-h infusions or a continu- this issue of Leukemia Research and previously published Phase
ous infusion. For all patients, 5-year event-free survival (EFS) was 2 trials indicate that CLAG-M combination therapy has encour-
44% and OS was 50%. Encouraging results with combination of 2- aging efficacy in poor prognosis patients with relapsed/refractory
CdA, Ara-C and idarubicin (CCI) have been also obtained in elderly AML. This regimen should be welcomed by physicians involved
patients by Juliusson et al. In this randomized Phase II trial, pre- in the treatment of patients with AML. In addition, the previously
viously untreated elderly AML patients with a median age of 71 reported results of a Phase 3 randomized trial confirm that 2-CdA
years were randomized to receive either a CCI regimen of 2-CdA added to ‘3 + 7’ induction therapy has an advantage over ‘3 + 7’ alone
5 mg/m2 , given before intermediate-dose Ara-C (1 g/m2 /2 h) b.i.d. in previously untreated AML. Taken together, 2-CdA combined with
for 4 days with idarubicin 10 mg/m2 /day for 2 days, or a two-drug standard drugs should be more widely used in the first and subse-
regimen of Ara-C and idarubicin without 2-CdA [20]. The CR rate quent lines of treatment in AML.
was 62%, with 51% CR from one course of CCI in comparison with
35% for the two-drug combination (P = 0.014). The median survival Conflict of interest statement
with a 2-year follow-up was 14 months, and the 2-year survival
was over 30%, and was similar in both groups. It should be noted The authors have no conflict of interest to declare.
that 2-CdA did not increase early death rates, time of granulocyte
and platelet regeneration, median time with fever >38 ◦ C, or intra- Acknowledgement
venous antibiotics.
The efficacy and safety of 2-CdA combined with Ara-C and This work was supported in part by grants from the Medical
daunorubicin (DAC) was compared with standard ‘3 + 7’ (DA) University of Lodz (No. 503/1-093-01/503-1).
chemotherapy in previously untreated AML patients in a random- Contributions. TR drafted the report and AW substantially
ized multicenter trial by the PALG cooperative group [21]. The revised it.
DAC protocol consisted of 60 mg/m2 /day daunorubicin on days
1–3, 200 mg/m2 /day Ara-C on days 1–7 and 5 mg/m2 2-CdA in 2-h References
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Lodz, 93-510 Lodz, Ciołkowskiego 2, Poland
and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with
refractory and relapsed acute myeloid leukemia of the poor risk: a final report ∗ Corresponding author. Tel.: +48 42 689 51 91;
of the Polish Adult Leukemia Group. Eur J Haematol 2008;80:115–26.
fax: +48 42 689 51 92.
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Clin Lymphoma Myeloma 2009;9:298–301. (T. Robak)
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induction in acute myeloid leukemia from myelodysplastic syndrome after 31 December 2013
azanucleoside failure. Leuk Res 2014;38:443–6. Available online 14 January 2014

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