Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients




Standard therapy for older patients with acute myeloid leukemia (AML) has a poor outcome. The authors have designed a combination of clofarabine plus low-dose cytarabine followed by a prolonged consolidation alternating with decitabine.


Sixty patients with a median age of 70 years (range, 60-81 years) with newly diagnosed AML were included. They received clofarabine 20 mg/m2 intravenously daily for 5 days plus cytarabine 20 mg subcutaneously twice daily for 10 days. Responding patients continued for up to 17 courses of consolidation therapy including decitabine.


Forty of 59 evaluable patients responded (66%). Complete remission rate was 58%. Median relapse-free survival (RFS) was 14.1 (95% confidence interval [CI], 6.9 to not estimable), and median overall survival (OS) was 12.7 months (95% CI, 8.8 to not estimable). Median OS of responding patients (complete response [CR]/CR with platelet count <100 × 109/L) was 24.2 months (95% CI, 17 to not estimable). Compared with a historical group of patients who received clofarabine plus low-dose cytarabine with a shorter consolidation, RFS was not statistically different. Induction mortality was low (7% at 8 weeks) and toxicities manageable.


Clofarabine plus low-dose cytarabine alternating with decitabine in consolidation is active in older patients with newly diagnosed AML. The benefits of a prolonged consolidation remain unproven. Cancer 2012. © 2012 American Cancer Society.


Therapy for newly diagnosed patients ≥60 years with acute myeloid leukemia (AML) remains challenging, with low response rates, short durability of responses, and a high risk of treatment-related toxicities after standard dose-intensive therapy.1, 2 Recent years have therefore seen a heightened level of activity in the exploration of new drugs and lower-intensity approaches.

Clofarabine is a deoxyadenosine nucleoside analog with US Food and Drug Administration approval for children with relapsed acute lymphoblastic leukemia. The recommended phase 2 dose of clofarabine for adults with acute leukemias was 40 mg/m2 intravenously daily for 5 days.3 However, 2 large multicenter studies, from the United States and Europe, respectively, have since shown that lower doses of clofarabine can improve the toxicity profile while still demonstrating activity in the up-front treatment of newly diagnosed older patients with AML.4, 5

We have shown in a randomized trial that the combination of lower-dose clofarabine with low-dose cytarabine produced higher response rates with a comparable safety profile compared with single-agent clofarabine.6 However, beyond achieving high remission rates, the ultimate goal is to improve survival. The current study was therefore designed with the following rationale: 1) to deliver lower doses of clofarabine than in the previous study; 2) to expand the duration of therapy; and 3) to provide multiple drugs with different mechanisms of action to prevent cross-resistance. As an additional drug to be administered during consolidation, we chose the DNA methyltransferase inhibitor decitabine. It can be delivered at low doses with acceptable toxicity and with activity in AML.7, 8 We also compared survival and relapse-free survival (RFS) between patients on the current study and a group of patients who received the combination therapy in a previous protocol where the number of consolidation cycles was shorter and DNA methyltransferase inhibitors were not used.6



Sixty patients were enrolled between October 2008 and January 2010, of whom 59 were evaluable for response. Patients were eligible if they were ≥60 years of age with a diagnosis of previously untreated AML (based on World Health Organization [WHO] criteria) or high-risk myelodysplastic syndrome (MDS; ≥10% blasts or ≥intermediate-2 by the International Prognostic Scoring System). Prior therapy with hydroxyurea and biological or targeted therapy were allowed. No patients received prior clofarabine or decitabine, although previous use of azacitidine was permissible. Additional requirements included an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 and adequate organ function (serum total bilirubin ≤2 mg/dL, alanine aminotransferase or aspartate aminotransferase ≤4 × the upper limit of normal, serum creatinine ≤2 mg/dL, and cardiac ejection fraction [by either echocardiography or multigated acquisition scan] of >40%). The study was approved by the institutional review board of The University of Texas MD Anderson Cancer Center and was conducted in accordance with the basic principles of the Declaration of Helsinki. All patients provided written informed consent according to institutional guidelines.

Treatment Design and Monitoring

Induction therapy consisted of clofarabine 20 mg/m2 by intravenous infusion daily for 5 days on days 1 to 5 plus cytarabine 20 mg subcutaneously twice daily for 10 days on days 1 to 10. On days 1 through 5, clofarabine preceded the cytarabine injections by about 3 to 4 hours.6 Patients who did not achieve a complete remission (CR) could receive 1 reinduction cycle at the same dose and schedule but not before at least 28 days had passed after the start of cycle 1. In the case of persistent disease after reinduction, patients could proceed with decitabine 20 mg/m2 as a 1- to 2-hour intravenous infusion daily for 5 days on days 1 to 5 as an alternative attempt to achieve a remission. Once in remission, patients would receive up to 17 cycles of consolidation therapy. Consolidation was administered in blocks of 3 cycles where clofarabine plus cytarabine at an abbreviated schedule alternated with decitabine (Fig. 1). Consolidation cycles were repeated every 4 to 7 weeks depending on hematopoietic recovery (absolute neutrophil count [ANC] ≥1 × 109/L and platelet count ≥50 × 109/L) and resolution of toxicities (any nonhematologic toxicity had to return at least to grade 1).

Figure 1.

Treatment flow diagram is shown. BID, twice daily; CR, complete remission; iv, intravenous; sc, subcutaneous.

It was recommended that all patients receive cycle 1 of the induction in a laminar air flow room, where they stayed hospitalized for the duration of the induction (on average 30 days). Patients received anti-infectious prophylaxis consisting of levofloxacin, valacyclovir, and voriconazole (or equivalent). To avoid hepatotoxicity, the latter was withheld on the first 5 days while clofarabine was administered. Hematopoietic growth factors (eg, erythropoietin, filgrastim, pegfilgrastim, sargramostim) were used at the discretion of the treating physician. Antiemetic therapy was routinely provided as appropriate. The patients' fluid status and hepatic and renal function were carefully monitored daily during the drug administration period.

Patients were monitored with complete blood count (CBC), differential and platelet count, and chemistry profile daily during induction and then at least weekly (CBC) or every 2 to 4 weeks (chemistry) as long as they were receiving drug therapy. Repeat marrow aspirates were performed starting on day 21 and then at least every 2 weeks until confirmation of remission or nonresponse. For most patients, this occurred within 42 days.

Response Criteria

Response was assessed based on criteria by the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia.9 CR required an ANC of ≥1 × 109/L, platelet count of ≥100 × 109/L, and marrow blasts ≤5%. CRp was defined as CR but with platelet counts <100 × 109/L. Any other response was considered treatment failure.

Statistical Considerations

The primary objective of this phase 2 trial was to determine RFS and overall survival (OS). Stopping boundaries were developed for monitoring efficacy and safety. Patient characteristics were summarized using frequency (percentage) for categorical variables and median (range) for continuous variables. Fisher exact test was used to assess the differences in categorical variables between patients accrued on the historical and current trials, respectively. Wilcoxon rank sum test was used to compare continuous variables. OS was defined as the time interval between the date of treatment and the date of death from any cause or last follow-up date, whichever occurred first. Among patients who achieved CR or CRp, RFS was defined as the time interval between the date of response (ie, CR or CRp) and the date of relapse or date of death, whichever occurred first. CR or CRp patients who were alive and relapse-free were censored at the off-study date. OS and RFS were estimated using the method of Kaplan and Meier.10 Log-rank test was used to compare OS or RFS between patients treated in the 2 trials.11 Univariate and multivariate Cox proportional hazards models were fit to compare OS or RFS between patients treated in these 2 studies, after adjusting for other patient characteristics or clinical factors. All statistical analyses were performed using SAS and Splus.12


Study Group

Characteristics for all patients (current and historical) are summarized in Table 1. Among the current group of patients, all had a diagnosis of AML (WHO).9 Patients with unfavorable pretreatment characteristics included those with age ≥75 years (29%), those with an ECOG performance status of 2 (18%), those with secondary AML with an antecedent hematologic disorder (23%), and those with complex cytogenetic abnormalities (33%). Of the 14 patients with antecedent hematologic disorder, 11 had a diagnosis of MDS. Four of these patients received prior azacitidine (1 in combination with an investigational histone deacetylase inhibitor). Other treatments for MDS that preceded enrollment into the study included hematopoietic growth factors (erythropoietin, darbepoietin, filgrastim), lenalidomide, cyclosporine and prednisone (in 1 patient with hypoplastic MDS), and the PR-1 vaccine. Two patients had a preceding diagnosis of chronic myelomonocytic leukemia and 1 of a myeloproliferative neoplasm, not otherwise specified. The latter 3 patients received hydroxyurea at some point prior. The other 18 patients with nonhematologic pre-existing malignancies received either chemotherapy, radiation, or both. Patients who were treated with surgery only were not included in this group.

Table 1. Patient Characteristics
  • Abbreviations: AML, acute myeloid leukemia; BM, bone marrow; ECOG, Eastern Cooperative Oncology Group; ITD, internal tandem duplication; PB, peripheral blood; WBC, white blood cell count.

  • P values are not significant for any variable.

  • a

    Two patients with myelodysplastic syndrome/refractory anemia with excess blasts-1 and chronic myelomonocytic leukemia, respectively.

Age, median y (range)69.5 (60-81)70 (60-82)
Age ≥75 years, No. [%]17 [29]20 [25]
ECOG performance status 2, No. [%]11 [18]11 [14]
AML diagnosis, No. [%]60 [100]75 [95]a
Secondary AML, No. [%]14 [23]18 [23]
Cytogenetics, No. [%]  
 Diploid, −Y26 [43]40 [41]
 −5, −719 [32]19 [24]
 Others15 [25]20 [25]
FLT3 ITD positive7 [13]9 [12]
WBC 109/L, median (range)2.2 (0.4-61.2)2.8 (0.8-433)
Hemoglobin, median g/dL (range)8.8 (5-13.4)8.9 (4-12.9)
Platelets, median 109/L, (range)47 (6-416)64 (8-300)
% PB blasts, median (range)7 (0-97)4 (0-93)
% BM blasts, median (range)40 (7-95)43 (9-94)



Fifty-nine patients were evaluable for response. One patient elected not to continue and was taken off study by day 6 before a response assessment was possible. Forty patients (66%) responded; 35 (58%) achieved CR and 5 (8%) CRp. Seven patients (18%; 5 with CR and 2 with CRp) required at least 2 cycles to respond. Median time to CR was 38 days (range, 27-103 days). For patients with CRp, median time to establishing the response was 83 days (range, 25-177 days). Responding patients received a median of 4 consolidation cycles (range, 0-17). Eight (20%) patients received at least 10 consolidation cycles, and consolidation therapy was still ongoing in 14 (35%) patients.

Responses by subgroup are summarized in Table 2. Responses (CR and overall response rate [ORR]) were numerically lower in patients with an antecedent hematologic disorder and complex cytogenetic abnormalities. Conversely, all of the 7 patients with an FLT3 internal tandem duplication abnormality responded, which included CR in 6 (86%).

Table 2. Response Rates (%) by Patient Subgroups
ResponseAgePerformance StatusPrimary vs AHDKaryotypeFLT3 ITD Status
  1. Abbreviations: AHD, antecedent hematologic disorder; Com, complex; CR, complete remission; CRp, CR but with platelet counts <100 × 109/L; Dip, diploid; ITD, internal tandem duplication; N = number of patients; Neg, negative; OR = overall response; Pos, positive.


RFS and OS

The median follow-up is 19.6 months. Among the 40 patients who have achieved CR/CRp, 24 patients (60%) later relapsed or died, and the median RFS was 14.1 months (95% confidence interval [CI], 6.9 to not estimable). Among the 60 patients, 34 (57%) died, and the median OS was 12.7 months (95% CI, 8.8 to not estimable). Median OS of responding patients only (CR/CRp) was 24.2 months (95% CI, 17.0 to not estimable; Fig. 2).

Figure 2.

Kaplan-Meier estimates for overall survival are shown by response status. CR, complete remission; pts, patients.

We compared OS and RFS to a historical group of 79 patients. This group of patients was enrolled on a separate clinical study from August 2004 to June 2006 and received induction therapy with clofarabine 30 mg/m2 intravenously daily for 5 days plus cytarabine 20 mg/m2 subcutaneously daily for 14 days. Consolidation consisted of 3 days of clofarabine and 7 days of cytarabine without inclusion of a hypomethylating agent.6 All other supportive care and monitoring parameters were the same. There were no statistically significant differences in the characteristics between the 2 patient groups (Table 1). Response rates in the historical group were also statistically similar (CR 62%, CRp 5%, ORR 67%).

With a median follow-up of 62.9 months, the median RFS of the historical group of patients was 9.3 months (95% CI, 6.2-12). There was no significant difference between the current and historical groups of patients with respect to RFS (P = .24, log-rank test; Fig. 3). Table 3 shows the fitted univariate Cox proportional hazards regression models for RFS, which suggest that older age was significantly associated with an increased risk of relapse or death after achievement of CR/CRp. The fitted multivariate Cox model for RFS suggests that after adjusting for age, there was no significant difference between patients treated on the current protocol and the historical patient group.

Figure 3.

Kaplan-Meier estimates for relapse-free survival are shown.

Table 3. Univariate Cox Proportional Hazards Model for RFS
VariableEstimateSEHRPNo.Relapse or Death, No.
  1. Abbreviations: AHD, antecedent hematologic disorder; AML, acute myeloid leukemia; BM, bone marrow; HR, hazard ratio; PB, peripheral blood; PLT, platelet count; PS, performance status; RFS, relapse-free survival; SE, standard error; WBC, white blood cell count.

log(PB blast)0.1440.0771.154.0629371
BM blast−0.0020.0050.997.6329371
Male vs female0.0450.2431.046.8519371
AHD vs primary AML0.3140.3331.369.3469371
Cytogenetics=diploid vs others−0.1280.2380.879.5919371
FLT3 positive vs negative0.3220.4051.381.4258767
PS=2 vs <20.5080.3191.662.1119371
Current vs historical−0.2960.2550.743.2469371

The median OS of the 79 historical patients was 11.5 months (95% CI, 8.4-18.2 months), with no significant difference between the current and historical groups of patients (P = .4, log-rank; Fig. 4). In a fitted univariate Cox proportional hazards regression model for OS (including age, white blood cell count, hemoglobin, platelet count, circulating blasts, sex, secondary AML, karyotype, FLT3 status, performance status, and current vs historical group of patients), older age, higher white blood cell count, higher numbers of circulating blasts, secondary AML, karyotype other than diploid, and a performance status of 2 were significantly associated with an increased risk of death. Only after adjusting in a fitted multivariate Cox model for older age, higher circulating blast numbers, secondary AML, and a performance status of 2, and after inclusion of baseline cytogenetics (although not statistically significant in the multivariate analysis) in an alternative multivariate Cox model, did the current group of patients demonstrate a better OS (P = .02; Table 4).

Figure 4.

Kaplan-Meier estimates for overall survival are shown.

Table 4. Alternative Multivariate Cox Proportional Hazards Model for Overall Survival (Cytogenetics Added)
  1. Abbreviations: AHD, antecedent hematologic disorder; AML, acute myeloid leukemia; HR, hazard ratio; PB, peripheral blood; PS, performance status; SE, standard error.

Log(PB blast)
AHD vs primary AML1.130.263.09<.0001
PS=2 vs <20.960.282.62.001
Cytogenetics=good vs others−
Current vs historical−0.560.230.57.02

Adverse events

Adverse events are summarized in Table 5, with grade and frequency. Most toxicities did not exceed grade 2. Gastrointestinal-related adverse events including nausea and vomiting, increases of total bilirubin and transaminases, and diarrhea were observed most frequently, followed by skin rashes including palmoplantar dysesthesia in few patients.

Table 5. Adverse Events (Frequency ≥10%)
Adverse EventGrade 1-2, %Grade 3-4, %
  1. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

ALT increase5710
Skin rash58
Bilirubin increase523
AST increase133
Creatinine increase122
Hand-foot syndrome72

Seven patients died while on study. Four of these patients (7%) died within the first 8 weeks of study enrollment. No early deaths within the first 14 days occurred. Only 1 patient died while undergoing consolidation therapies and still in CR. Causes of deaths were infection-related secondary to myelosuppression in all patients.


The combination of clofarabine with low-dose cytarabine followed by a prolonged consolidation with alternating decitabine achieved a response rate of 66% (58% CR), median RFS of 14.1 months, and median OS of 12.7 months. Median OS of responding patients (CR/CRp) was 24.2 months. Eight-week mortality was 7%, and most patients had manageable toxicities of grade ≤2.

The study design was based on our previous experience with the combination of clofarabine and low-dose cytarabine alone without the addition of decitabine. The rationale of this study was to attenuate induction doses to minimize early mortality, enable delivery of a more extended postremission therapy, and include a third drug with activity in AML that is non cross-resistant and might circumvent buildup of drug resistance to the 2-drug combination. The first 2 goals have been largely achieved; induction mortality (measured at 8 weeks to incorporate effects of drug-related toxicity and of resistant disease) has been low, and whereas a fifth of the patients received at least 10 consolidation cycles, consolidation is ongoing in another third of the patients. Hence, it is feasible to provide extended therapy with this regimen. As for the third goal, circumvention of drug resistance by adding additional drugs (in this case decitabine), it remains largely speculative. It will also remain difficult to answer in the absence of a direct randomized comparison. We therefore compared the long-term outcome of patients who received clofarabine and low-dose cytarabine in a previous study without decitabine with the current study.6 It needs to be emphasized, however, that there were other differences in the historical group; the induction dose of clofarabine was higher (30 mg/m2 daily × 5 days), the schedule of low-dose cytarabine was different (20 mg/m2 daily × 14 days), and the number of consolidation cycles administered was lower (median of 2). With these caveats in mind, response rates were identical, although induction mortality appeared higher (19%) in the historical group. More importantly, RFS and OS were not different unless an alternative multivariate Cox model was applied that included information from baseline cytogenetics.

Comparisons with induction therapies that use single-agent decitabine only are also limited. The 2 studies by Cashen et al and Blum et al, respectively, differed in the number of days of decitabine per cycle (5 vs 10).7, 8 Whereas the overall response with the 5-day schedule has been only 25% (24% CR), the ORR with the 10-day schedule has been 64% (47% CR). The differences extended to median survival: 7.7 months with the 5-day schedule (14 months for responders only) versus 13 months (no information regarding responders only) with the 10-day schedule.

One of the major issues debated with regard to induction therapy for older patients with AML is the value of standard or intensive therapy. The historical experience based on the 3 + 7 schedule is sobering. CR rates are typically <50%, most patients relapse quickly, and 3-year survival expectations are <10%.13, 14 The value of intensive chemotherapy for older patients has been recently analyzed in a retrospective study by Kantarjian et al.1 Of 446 patients ≥70 years of age treated with cytarabine-based therapy, CR rate was 45%, 8-week mortality 36%, median survival 4.6 months, and 1-year survival probability 28%. Juliusson from the Swedish AML Group argued against the conclusion that intensive therapy benefits few older patients with AML.15 Data from the Swedish Acute Leukemia Registry showed that 55% of 70- to 79-year-olds received intensive therapy, and half of those treated achieved CR. Outcomes were clearly better when compared with patients who opted for or received only palliative care. Conversely, the registry experience does not provide any comparisons of different treatment approaches with each other, and it remains therefore impossible to assess the value of established, intensive therapy vis-à-vis novel therapies.

Despite the conservative doses, this treatment causes myelosuppression, with its accompanying risks of infectious complications, and has several other adverse events typical for chemotherapy regimens (see Table 5). To treat patients with this combination requires meticulous observation and follow-up. We admitted all our patients to a laminar airflow room during their first induction cycle, and all received broad-spectrum antibiotic prophylaxis (antibacterial, antifungal, and antiviral agents). It does, however, provide a different approach based on attenuated induction and consolidation doses (validated by low mortality rates), changing drugs during consolidation, and a prolonged number of consolidation cycles. Both remission and survival rates confirm the activity of this regimen. Where it will be positioned among other approaches and in comparison to conventional therapy (such as 3 + 7) cannot be answered from our study, but requires a more concerted effort of a larger randomized study. These regimens are not mutually exclusive. With better definitions of subsets of patients, there is likely to be a role for conventional therapy in some, whereas investigational therapies are more appropriate for others. In this respect, various prognostic models aid the decision-making process, and investigators should be encouraged to use them.16-18


S.F. designed the research, included patients, collected data, analyzed data, wrote the article, and proofread the protocol; F.R. included patients, collected data, and proofread the protocol; X.H. and X.W. designed the research, analyzed data, and proofread the protocol; E.J., G.G.-M., T.K., A.F., M.K., G.B., and J.B. included patients and collected data; J.F. collected data and proofread the protocol; and H.M.K. designed the research, included patients, and collected data.


The investigators received research funding from Genzyme and Eisai.


S.F. has received research funding from Genzyme and Eisai and has participated in advisory board meetings conducted by Genzyme. J.B. has received research funding from Genzyme. H.M.K. has received research funding from Genzyme and has participated in advisory board meetings conducted by Genzyme.