Lower-intensity Regimen Shows Promise for Older Patients with AML

Combining cladribine and low-dose cytarabine alternating with decitabine (Dacogen) resulted in high response rates and improved survival compared with currently established low-intensity therapies for patients with acute myeloid leukemia who are older than 60, according to results newly published in <em>Lancet Haematology.</em>

Tapan M. Kadia, MD

Combining cladribine and low-dose cytarabine (Cytosar-U) alternating with decitabine (Dacogen) resulted in high response rates and improved survival compared with currently established low-intensity therapies for patients with acute myeloid leukemia (AML) who are older than 60, according to results newly published inLancet Haematology.

The median disease-free survival (DFS) in this single-arm, single-center, open-label, phase II study (N = 118) was 10.8 months (IQR, 5.4-25.9). The median overall survival (OS) was 13.8 months (6.9-28.6). The 1-year OS was 64% (95% CI, 52-71) and the 2-year OS was 28% (95% CI, 20-38).1

Eighty (68%) patients achieved objective response, including 69 (58%) complete responses (CR) and 11 (9%) patients had CR with incomplete count recovery.

Previous studies of elderly patients with AML have shown that lower-intensity regimens, such as low-dose cytarabine or hypomethylating agents, can induce a remission rate of 18%-28% and a median OS of 8-10 months.

Investigators led by first author Tapan M. Kadia, MD, department of Leukemia, University of Texas MD Anderson Cancer Center, added that the combination was well tolerated. The 4-week mortality rate was 1% and the 8-week rate was 7%.

“To our knowledge, this is the first report of this combination tested in older patients (aged ≥60 years) with AML,” Kadia and colleagues wrote. “Our findings suggest that the combination of cladribine and low-dose cytarabine alternating with decitabine is a highly active and well tolerated regimen for older patients with AML.

“Confirmation of these data in a randomized phase 3 trial might provide an alternative to hypomethylating agents as the de-facto standard low-intensity backbone for AML, providing more effective therapy and improved outcomes.”

Lower-intensity regimens have shown promise in previous studies. Hervé Dombret, MD, of Hôpital Saint Louis, Institut Universitaire d'Hématologie, University Paris Diderot, and co-investigators evaluated azacitidine (Vidaza) versus conventional care regimens in a multicenter, randomized, open-label, phase III trial. Conventional care included standard induction chemotherapy, low-dose ara-c (LDAC), or best supportive care (BSC) only.

Patients were assigned to 75 mg/m2of daily azacitidine for 7 consecutive days during a 28-day treatment cycle for at least 6 cycles. BSC included blood product transfusions and antibiotics, plus G-CSF for neutropenic infection. LDAC was administered subcutaneously at 20 mg twice daily for 10 days during at least four 28-day treatment cycles. Chemotherapy consisted of 100 mg/m2to 200 mg/m2of daily cytarabine for 7 days, plus 3 days of either 45 mg/m2to 60 mg/m2of daily daunorubicin or 9 mg/m2to 12 mg/m2of daily idarubicin for 1 cycle, followed by up to 2 consolidation cycles for patients who achieved CR or partial response. Reinduction was not allowed.2

The trial included 488 patients aged ≥65 years with newly diagnosed AML with >30% bone marrow blasts. Azacitidine induced superior OS (10.4 vs 6.5 months; HR, 0.85; 95% CI, 0.69-1.03; stratified log-rankP= .1009) and 1-year OS rate (46.5% vs 34.2%; 95% CI, 3.5-21.0).

Nausea was the most frequent drug-related treatment-emergent adverse event (AEs) in the azacitidine (27.1%), LDAC (22.2%), and chemotherapy (42.9%) groups, followed by neutropenia (19.9%, 22.9%, and 31.0%, respectively), and thrombocytopenia (17.4%, 22.2%, and 21.4%, respectively). Investigators determined that rates of anemia, neutropenia, febrile neutropenia, and thrombocytopenia were “substantially lower” in the azacitidine arm after adjusting for patient-years of treatment exposure.

In results from a multicenter, randomized, open-label, phase III trial published in 2012, investigators evaluated 20 mg/m2of daily decitabine versus treatment choice (TC) of supportive care or 20 mg/m2of daily cytarabine in 485 patients aged ≥65 years. Patients in the decitabine arm were treated for 5 consecutive days every 4 weeks for 4 cycles while those assigned to cytarabine were treated for 10 consecutive days every 4 weeks for 2 cycles.3

After 396 deaths, investigators observed a median OS of 7.7 months with decitabine compared with 5.0 months with TC (HR, 0.85; 95% CI, 0.69-1.04;P= .108). Treatment-related AEs with decitabine were similar to those found in the cytarabine arm. Investigators found that the incidence and severity of AEs leading to discontinuation or death were similar between arms despite a longer decitabine treatment duration and AE reporting period.

In the results reported by Kadia et al, patients were treated from February 2012 to July 2017 and the median time on study was 37.2 months. Fifty-two (44%) patients were aged ≥70 years.

Investigators observed some delayed responses with continued therapy, but most patients (n = 57; 48%) responded after a median of 1 cycle (IQR, 1-2). Seventy-three (62%) patients had an objective response after cycle 2, 77 (65%) after cycle 3, and 80 (68%) after cycle 4.

The median OS among responders was 16.2 months (IQR, 11.7-33.7). The 1-year OS was 72% (95% CI, 63-83) and 2-year OS was 36% (95% CI, 26-49). Eighteen of 80 (23%) responders subsequently received allogeneic stem cell transplant, but transplant had no effect on median OS.

Myelosuppression was present in all patients. There were 88 (74.5%) grade ≥3 infections, including 9 deaths. Investigators observed 2 incidents of central nervous system bleed, including 1 fatality, a grade 4 gastrointestinal bleed, and a grade 3 vaginal bleed.

Writing in an accompanying editorial, Norbert Vey, MD, professor in hematology and head of the leukemias treatment unit at Institut Paoli-Calmettes in Marseille, France, noted that the patient population in this study is not comparable to a traditional unfit population, which typically has a median age of roughly 75 years and does not include patients who have undergone transplant. However, Vey noted that the findings for OS and DFS were comparable to outcomes of intensive regimens in fit, elderly patients.4

“The time might have come to change old thinking that divides the elderly patient population into fit and unfit, and to compare this regimen with intensive therapies in fit, elderly patients,” he wrote. “Whatever the strategy followed, there is a need for the development of active backbones and more complex, but tolerable, multiagent combinations using new targeted agents.”


  1. Kadia TM, Cortes J, Ravandi F, et al. Cladribine and low-dose cytarabine alternating with decitabine as front-line therapy for elderly patients with acute myeloid leukaemia: a phase 2 single-arm trial [published online August 13, 2018].Lancet Haematol. doi: 10.1016/ S2352-3026(18)30132-7.
  2. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts.Blood. 2015;126(3):291-9. doi: 10.1182/blood-2015-01-621664.
  3. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.J Clin Oncol. 2012;30(21):2670-2677. doi: 10.1200/JCO.2011.38.9429.
  4. Vey N. Blurring lines between treatment intensity and patient fitness in elderly people with AML [published online August 13, 2018].Lancet Haematol.doi: 10.1016/ S2352-3026(18)30136-4.