This protocol has been superseded due to the availability of superior alternatives. The preferred regimen is ID 4285 Acute myeloid leukaemia consolidation cytarabine (age under 60 years) or ID 4354 Acute myeloid leukaemia consolidation cytarabine (age 60 years and over).
A search of the literature found limited evidence to support the use of IDAC in the consolidation treatment of AML. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the Sperr et al. study.r
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Sperr et al 2004r |
Yes |
Yes |
1 g/m2/day bd, days 1,3,5 |
Observational studies |
N/A |
N/A |
N/A |
- |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
3.2021 |
Yes |
Yes |
- |
BCCA |
N/A |
N/A |
N/A |
- |
High-dose cytarabine is not recommended for patients over 60 years of age due to the high rate of neurologic toxicity.r The AML NCCN guidelines suggest the use of cytarabine at a dose of 1-2 g/m2 as a consolidation option for the elderly patients with AML.r The ideal number of consolidation cycles with this cytarabine dose has not been studied. In patients who are candidates for allogenic stem cell transplant, it is recommended that patients proceed to transplant once morphologic remission is attained.
Sperr et al. studied 47 patients who were consolidated with cytarabine 1 g/m2 every 12 hours on days 1, 3 and 5 (total 6 doses) for four cycles of consolidation. 25 of 47 patients (53%) completed the scheduled 4 cycles whereas, 32% discontinued due to severe infection and 33% relapsed during consolidation. The probability of remaining free of leukaemia was 22% at 5 years. The median overall survival (OS) of patients receiving IDAC was 31.8 months. Importantly, patients with an adverse AML karyotype had a median OS of only 5 months.r
This was a non-randomised trial but was well conducted with the dropout and loss to follow-up rate being low. The majority (70%) of patients completed 3-4 consolidation cycles indicating that the therapy was well tolerated. Supportive care strategies are well described and can be applied in our setting. Outcomes and toxicities are well described.
There are several cytarabine based consolidation protocols which have been studied in elderly AML patients and are worth comparing to IDAC. Most have little in common with one another and it is not possible to compare the outcomes objectively. The trials used various combinations of chemotherapeutic agents with cytarabine, various doses, and methods of administration (bolus, infusion and oral).
Table 1: List of cytarabine-based AML consolidation protocols for patients aged over 60 years.
Source |
Study and Year Published |
Consolidation option 1 |
Consolidation option 2 |
Overall Survival (OS) |
Progression-free survival (PFS) |
Comments |
Prospective phase II |
Sperr et al. 2004r |
ARA-C 1 g/m2 bd (D1, 3 and 5) x 4 cycles |
No comparison arm |
Median OS 10.6 months |
Median DFS 15.5 months |
N=47
Age >60 |
Prospective randomised controlled trial |
Huang et al. 2014r |
DNR 45 mg/m2 day 1-3 ARA-C 100 mg/m2 D1-7 x 2 cycles followed by ARA-C 1.5 g/m2 daily (D1-4) x 4 cycles N= 141 |
DNR 30 mg/m2 D1-3 ARA-C 75 mg/m2 D1-7 x 2 cycles followed by ARA-C 1 g/m2 daily (D1-3) x 4 cycles (n=156) |
5 year median OS 24 vs 39 months (p<0.001) |
Median PFS 23 vs 35 months (p<0.001) |
Age >65 |
Prospective randomised controlled trial |
Gardin et al. 2007r |
“Ambulatory”: DNR 45 mg/m2 D1 (or IDA 9 mg/m2 D1) with SC ARA-C 60 mg/m2 bd D1-5 (n=81) |
“Intensive”: DNR 45 mg/m2 D1- 4 or IDA 9 mg/m2 D1-4 with infusion ARA-C 200 mg/m2 D1- 7 (n=68) |
2-year OS 56% vs. 37% in favour of ambulatory consolidation |
2-year DFS 28% vs 17% in favour of ambulatory consolidation |
Ambulatory consolidation in outpatient setting compared with intensive consolidation
Age ≥65 |
Prospective randomised controlled trial |
Jehn et al. 2006r |
IV: IDA 8 mg/m2 D1, 3, 5, etop 100 mg/m2 D1-3, ARA-C infusion 100 mg/m2 D1-5 (n=166) |
Oral: IDA 20 mg/m2 D1, 3, 5 etop 100 mg/m2 bd D1-3 ARA-C 50 mg/m2 SC BD D1-5 (n=165) |
Median OS 15.7 months (oral) vs. 17.8 months (IV) (p=0.19) |
Median DFS 9 months (oral) vs. 10.4 months (IV) (p=0.15) |
Infusional versus non-infusional consolidation
Age 61-80 |
Prospective randomised controlled trial |
Mayer et al. 1994r |
ARA-C infusion 100 mg/m2 D1-5 |
ARA-C infusion 400 mg/m2 D1-5 |
Median DFS was 12 months (equal between groups) |
OS at 4 years was 9% (equal between groups) |
Age >60 |
Retrospective phase II |
Prebet et al. 2009r |
ARA-C SC + oral MTX and 6MP |
IV bolus ARA-C doses higher than 500 mg/m2 for “at least 2 days” (n=48) |
No difference in survival between |
LFS 26 months (IV ARA-C) vs. 14 months (SC ARA-C) |
Core binding factor (CBF) AML only
Age >60 |
NB: ARA-C: Cytarabine, DNR: Daunorubicin, IDA: Idarubicin, Etop: Etoposide, MTX: Methotrexate, 6MP: 6 Mercaptopurine, DFS: Disease-free survival, LFS: leukaemia-free survival, D:day, vs:versus, SC:subcutaneous, IV:intravenous.
On the basis of these trials several general conclusions can be made regarding consolidation chemotherapy in elderly patients with AML:
1. In elderly AML patients with adverse risk cytogenetics there did not appear to be a benefit with using higher doses of cytarabine than 1 g/m2.r
2. Patients who were palliated and did not receive any consolidation had a worse OS than those who had consolidation.r
3. Similarly, patients who received low dose subcutaneous cytarabine or hydroxyurea has a poorer OS and progression-free survival (PFS) than those who received intravenous cytarabine doses over 500 mg/m2 for at least 2 days.r
4. Treatment with azacitidine results in worse OS than with age appropriate intensive chemotherapy based on treatment.r
5. In the core binding factor AML population there was no difference in the outcome of the patients treated with one cycle of intermediate dose cytarabine compared to those who received more than one cycle although this was based on a small population of patients and the authors explained that the study was underpowered to detect a significant difference.r
6. There was no difference between the disease-free survival (DFS) and OS in patients over 60 who were randomised to HiDAC compared to 100 mg/m2 or 400 mg/m2 infusional cytarabine consolidation.r
7. Infusional cytarabine has not been compared to bolus cytarabine in a randomised format in adults over the age of 60.
Efficacy
The use of IDAC consolidation in elderly patients with AML results in acceptable long term outcomes. There are no trials directly comparing this regimen with the others tabulated above. In the study by Sperr et al. overall disease-free surviva (DFS) was 22% at 5 years and median DFS was 15 months. Patients with poor risk cytogenetics had a median DFS of only 6 months and median OS of 6 months. Patients who attained a complete remission (CR) and received consolidation had a median DFS of 31 months. The authors state that elderly patients with de novo AML who receive IDAC consolidation while in remission post induction had long-term outcomes similar to that of younger patients with AML.r
Overall survival, influence of age and karyotype on OS and continuos complete remission in patients receiving post-remission cytarabine consolidation.r
© Clinical Cancer Research 2004
Toxicity
Quality of life (QOL) data was not presented, however authors detailed the haematologic and non-haematologic toxicity of the protocol. Overall, IDAC was well tolerated and the toxicity was acceptable. There were no neurologic toxicities and no deaths due to sepsis. This is compared to the 30% of the 60 year olds who experienced neurotoxicity with high-dose cytarabine (HiDAC). Neurologic recovery was seen in 40% of these patients only. Median duration of neutropenia was short (9 days) and neutropenic sepsis occurred in 49% with IDAC; rash was seen in 17% and grade 3 hepatotoxicity in 0.7% of patients. G-CSF was not used routinely unless patients had severe sepsis. Prophylaxis with trimethoprim/sulfamethoxazole and ciprofloxacin was recommended.r
Toxicity profile based on data from Sperr et al.r
Causes |
Number of events (total patients=47 and total IDAC cycles=145) |
Febrile neutropenia |
55% of all cycles
Specifically: 49% cycle 1, 60% cycle 2, 44% cycle 3 and 72% cycle 4
|
Prolonged aplasia |
4 |
Treatment related death |
2 |
Non treatment related death |
2 |
Median duration of neutropenia |
9 days |
Use of G-CSF |
41% IDAC cycles |
Grade 3 or 4 neurotoxicity |
0% |
Drug fever |
32% IDAC cycles |
Hepatotoxicity |
less than 1% |
Nephrotoxicity |
0% |