General AML

Cladribine in combination with standard chemotherapy in elderly AML patients – results from the PALG phase II trial

Standard induction therapy for fit elderly Acute Myeloid Leukemia (AML) patients consist of daunorubicin and cytarabine (DA). However, outcomes in this subgroup of patients remain unsatisfactory. 

In an article in the American Journal of Hematology, Agnieszka Pluta from the Medical University of Lodz, Poland, and colleagues published results from their randomized phase II study conducted by the Polish Adult Leukemia Group (PALG). In this study, the efficacy and safety of DA combined with cladribine (DAC), a purine analogue, was compared with DA alone in newly diagnosed elderly AML patients eligible for intensive chemotherapy.

A total of 171 AML patients (median age = 66 years, range 60–79) were randomly assigned to receive either DAC (n = 86) or DA (n = 85). 

The key results of the study were:
  • Complete Remission (CR) after first induction in all evaluable patients (n = 64) in the DAC (n = 35) and DA arm (n = 29); 44% vs 34%, P = 0.19
  • CR in patients aged 60–65 years in the DAC (n = 23) and DA (n = 10) arm; 51% vs 29%, P = 0.02
  • CR in patients aged 60–65 years with good and intermediate karyotype in the DAC (n = 13) and DA (n = 4) arm; 69% vs 21%, P = 0.0032
  • Median Overall survival (OS) in all patients in the DAC and DA arms; 8.6 vs 9.1 months, P = 0.64
  • OS was longer in patients aged 60–65 years with good and intermediate karyotype in DAC arm compared to DA arm; P = 0.02
  • Non-hematological and hematological toxicities were similar in the DA and DAC arms
  • Death occurred in 17% and 23% of patients in the DA (n = 14) and DAC (n = 18) arms respectively; P = 0.19

In summation, DAC improved the outcomes of elderly AML patients aged 60–65 years with good and intermediate risk karyotype.


Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

  1. Pluta A. et al., Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial. Am J Hematol. 2017 Apr; 92(4): 359–366. DOI: 1002/ajh.24654. Epub 2017 Feb 13.

Expert Opinion

The development of strategies to improve outcomes for older patients with Acute Myeloid Leukemia (AML) is a critical unmet need. For over four decades, standard induction therapy of adult with AML has been a combination of two drugs daunorubicin and cytarabine (DA). Numerous trials tested the addition of a third agent to the standard DA regimen in an effort to make the therapy more effective. The Polish Adult Leukemia Group (PALG) has studied the addition of purine analogue, cladribine in relapsed/refractory and newly diagnosed AML patients ≤ 60 years with encouraging results.1,2 Cladribine increases cellular uptake of cytarabine and its accumulation in leukemic blasts. Cladribine also has hypomethylating activity.3,4 Results from retrospective analysis of PALG trials, showed that cladribine added to DA induction prolongs survival of FLT3-ITD+ normal karyotype AML patients.5

Pluta et al., on behalf of PALG reported the results of randomized phase II study, which compared efficacy and toxicity of the standard DA regimen (DNR 45mg/m2, i.v, days 1-3, AraC 100mg/m2, 24-hours i.v infusion) with DAC regimen (DA plus 2-CdA 5mg/m2, 2-hours i.v infusion, days 1-5) in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study. A trend towards higher Complete Remission (CR) was observed in the DAC arm compared to the DA arm, which did not lead to improve median Overall Survival (OS). DAC appeared to be superior in the group of patients aged 60–65 (CR rate: DAC 51% vs. DA 29%; p=0.02) especially those <65 years of age without a poor-risk karyotype, who benefited from addition of cladribine also in terms of OS. It should be noted that both hematologic and non-hematologic toxicity was comparable among the treatment arms, indicating that addition of purine analogs did not impair tolerance of the treatment. Results of the study indicate that a three-drug combination including cladribine is more effective in selected elderly AML patients.

However, the median OS time for the whole group was 8.6 months, which is still unsatisfactory. Further improvement of long term results could be achieved with using higher doses of daunorubicin (60 or 90 mg/mper day for 3 days), an early bone marrow evaluation 7–10 days after induction with prompt second induction applied for patients with persistent leukemia as well as post-remission intensification with allogeneic stem cell transplantation with a reduced-intensity conditioning. This new policy is currently realized within the new PALG protocols in the hope to further improve outcome of elderly AML patients in Poland.


  1. Wierzbowska A. et al. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, 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 of the Polish Adult Leukemia Group. Eur J Haematol. 2008 Feb; 80(2): 115–26. DOI: 10.1111/j.1600-0609.2007.00988.x. Epub 2007 Dec 11.
  2. Holowiecki J. et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012 Jul 10; 30(20): 2441–8. DOI: 10.1200/JCO.2011.37. Epub 2012 Apr 16.
  3. Freyer C.W. et al. Revisiting the role of cladribine in acute myeloid leukemia: an improvement on past accomplishments or more old news?  Am J Hematol. 2015 Jan; 90(1): 62–72. DOI: 10.1002/ajh.23862. Epub 2014 Oct 25.
  4. Robak T & Wierzbowska A. Cladribine in the treatment of acute myeloid leukemia . Leuk Res. 2014 Apr; 38(4): 425–7. DOI: 10.1016/j,leukres.2014.01.005.  
  5. Libura M. et al. Cladribine added to daunorubicin-cytarabine induction prolongs survival of FLT3-ITD+ normal karyotype AML patients. Blood. 2016 Jan 21;127(3):360-2. DOI: 10.1182/blood-2015-08-662130. Epub 2015 Nov 13.


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