The role of interleukin-2 as maintenance therapy in children and adults with acute myeloid leukaemia in first complete remission

Background

Acute myeloid leukaemia (AML) is a malignant cancer of blood cells. Most people with AML are subjected to chemotherapy or bone marrow transplantation to eliminate cancer cells. In response to these treatments, people might achieve complete remission (CR), the status without cancer cells in blood and signs of blood cancer. Although the disease is well controlled at the beginning of the treatment, AML may return, progress again, and result in unsatisfactory life expectancy. People in CR still need to receive further treatment. Interleukin-2 (IL-2) is an alternative as maintenance therapy to maintain the curative effect and deter disease progression. Clinical results have been published comparing the use of IL-2 and no maintenance therapy in people who had achieved CR, but the effect of IL-2 remains unclear.

Review question

The aim of this review is to assess and summarise any scientific studies that focus on the efficacy and harmful effect of IL-2 as maintenance therapy for children and adults with AML who have achieved first CR and have not relapsed.

Study characteristics

We searched all databases for relevant studies published between January 1950 and August 2015 and identified 679 citations. We included nine studies involving 1665 participants. These trials enrolled from 24 to 528 participants between 1991 and 2008, with a median follow-up period of 2.4 to 8.3 years. Participants were aged from 0 to more than 60 years old. Six studies included adult participants; the other three included both adults and children. However, the latter three studies did not report data for children, so we were unable to conduct subgroup analysis of children. One Chinese study did not report any outcomes of interest for this review. Funding sources of these trials were mainly national institutes or organisations. Participants in the treatment group received IL-2 maintenance therapy, and participants in the control group received no further treatment. We did not identify studies comparing IL-2 with maintenance chemotherapy or comparing IL-2 plus maintenance chemotherapy with maintenance chemotherapy alone. The evidence is current to August 2015.

Key results

We analysed the data with respect to the effect of IL-2 on disease-free survival (the time interval from the date of remission to leukaemic relapse or death from any cause) and overall survival (the time between when participants entered the study and when they died) compared with no treatment. We found no evidence for difference in disease-free survival or overall survival between the IL-2 group and the control group. Another outcome we considered was event-free survival (the time interval from the date of randomisation or entry into study to treatment failure, first relapse, or death from any cause), and found that IL-2 did not extend the event-free survival. None of the included studies analysed treatment-related mortality or quality of life. We also looked at whether IL-2 treatment resulted in any adverse events. We found that very low quality evidence that adverse events were more common in participants receiving IL-2 than in those receiving no treatment. Reported adverse events included reduction in blood platelet count or neutrocyte count, malaise, fatigue, fever, and infection. No death related to adverse effect was reported.

Quality of evidence

We considered the quality of the evidence as low with respect to disease-free survival and event-free survival. The quality of evidence was moderate for overall survival and very low for adverse events.

Conclusion

We found no evidence for a difference between IL-2 maintenance therapy and no treatment with respect to disease-free survival or overall survival of people with AML in first CR; however, the quality of the evidence is moderate or low, and further research is likely or very likely to have an important impact on the estimate or our confidence in the estimate. Adverse events seem to be more frequent in people treated with IL-2, but the quality of the evidence is very low and our confidence in the estimates is very uncertain. Thus, further prospective randomised trials are needed before definitive conclusions can be drawn on these issues.

Authors' conclusions: 

There is no evidence for a difference between IL-2 maintenance therapy and no treatment with respect to disease-free survival or overall survival of people with AML in first CR; however, the quality of the evidence is moderate or low, and further research is likely or very likely to have an important impact on the estimate or our confidence in the estimate. Adverse events seem to be more frequent in participants treated with IL-2, but the quality of the evidence is very low and our confidence in the estimates is very uncertain. Thus, further prospective randomised trials are needed before definitive conclusions can be drawn on these issues.

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Background: 

Acute myeloid leukaemia (AML) is a malignant cancer of hematopoietic stem cells. The treatment of AML consists of two treatment phases: the remission induction phase to achieve a rapid, complete remission (CR) and the consolidation phase to achieve a durable molecular remission. People in CR are at risk of AML relapse, and people with relapsed AML have poor survival prospects. Thus, there is a continuous need for treatments to further improve prognosis. Interleukin-2 (IL-2), an immune-stimulatory cytokine, is an alternative to standard treatment for people with AML to maintain the efficacy after consolidation therapy. Maintenance therapy is not an integral part of the standard treatment for AML. Studies have been conducted to evaluate the efficacy of IL-2 as maintenance therapy for people with AML in first CR, but the effect of IL-2 is not yet fully established.

Objectives: 

To evaluate the efficacy and safety of IL-2 as maintenance therapy for children and adults with AML who have achieved first CR and have not relapsed.

Search strategy: 

We systematically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 8), MEDLINE (1950 to August 2015), EMBASE (1950 to August 2015), LILACS (1982 to August 2015), CBM (1978 to August 2015), relevant conference proceedings (2000 to 2015), and metaRegister of Controlled Trials (since inception to August 2015) of ongoing and unpublished trials. In addition, we screened the reference lists of relevant trials and reviews.

Selection criteria: 

Eligible studies were randomised controlled trials (RCTs) comparing IL-2 with no treatment in people with AML who had achieved first CR and had not relapsed. We did not identify studies comparing IL-2 versus best supportive care or maintenance chemotherapy or studies comparing IL-2 plus maintenance chemotherapy versus maintenance chemotherapy alone.

Data collection and analysis: 

Two review authors independently screened studies, extracted data with a predefined extraction form, and assessed risk of bias of included studies. We extracted data on the following outcomes: disease-free survival, overall survival, event-free survival, treatment-related mortality, adverse events, and quality of life. We measured the treatment effect on time-to-event outcomes and dichotomous outcomes with hazard ratio (HR) and risk ratio, respectively. We used inverse-variance method to combine HRs with fixed-effect model unless there was significant between-study heterogeneity.

Main results: 

We included nine RCTs with a total of 1665 participants, comparing IL-2 with no treatment. Six studies included adult participants, and three studies included both adults and children. However, the latter three studies did not report data for children, thus we were unable to conduct subgroup analysis of children. One Chinese study did not report any outcomes of interest for this review. We included six trials involving 1426 participants in the meta-analysis on disease-free survival, and included five trials involving 1355 participants in the meta-analysis on overall survival. There is no evidence for difference between IL-2 group and no-treatment group regarding disease-free survival (HR 0.95; 95% CI 0.86 to 1.06, P = 0.37; quality of evidence: low) or overall survival (HR 1.05; 95% CI 0.95 to 1.16, P = 0.35; quality of evidence: moderate). Based on one trial of 161 participants, IL-2 exerted no effect on event-free survival (HR 1.02; 95% CI 0.79 to 1.32, P = 0.88; quality of evidence: low). Adverse events (including thrombocytopenia, neutropenia, malaise/fatigue, and infection/fever) were more frequent in participants receiving IL-2, according to one trial of 308 participants. No mortality due to adverse events was reported. None of the included studies reported treatment-related mortality or quality of life.

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