Treatment with all-trans retinoic acid in addition to chemotherapy for adult patients with acute myeloid leukaemia (non-APL)

What is the aim of this review?

This review aims to determine benefits and harms of all-trans retinoic acid (ATRA) in addition to chemotherapy compared with chemotherapy alone for adults with AML. We did not evaluate participants with acute promyelocytic leukaemia (APL). We collected and analysed all relevant studies to answer this question and found eight studies.

Key messages

The addition of ATRA to chemotherapy did not show relevant differences in terms of overall survival (OS), but the subgroup analyses showed that there is potential benefit for ATRA in combination with a certain chemotherapeutic called decitabine , for older patients (over 60 years) and for patients who already had successful chemotherapy and now receive therapy for maintenance. We assessed the certainty of evidence as moderate for OS, disease-free-survival and on-study mortality.

Rates of toxicities were low, therefore certainty of evidence is 'very low' to 'low' for the adverse events diarrhoea, nausea/vomiting and cardiac toxicity. For the adverse event infection, we judged the certainty of evidence as moderate. Currently, it seems the risk of adverse events with additional ATRA are comparable to chemotherapy only.

Quality of life was not reported by any of the included trials.

What was studied in this review?

Acute myeloid leukaemia is a life-threatening type of cancer that starts in the blood-forming cells of the bone marrow and can cause many different signs and symptoms. It is classified into several subtypes, of which one subtype, acute promyelocytic leukaemia (APL) is treated differently to the other subtypes.

Almost 60% of patients are older than 65 years at the time of diagnosis. Because of advanced age and accompanying diseases an intensive therapy with high-dose chemotherapy and stem cell transplantation often is not possible or is accompanied by high risks for serious adverse events and treatment-related mortality. For these reasons it would be important to know a less intensive and dangerous therapy for older patients.

All-trans retinoic acid (ATRA), an intermediate product of vitamin A, had been integrated into treatment regimens for APL by the end of the 1980s. It is administered orally and is generally well tolerated but can induce a severe, life-threatening complication called differentiation syndrome, which includes breathing difficulties and fever.

The literature provides contradictory data about the benefit of ATRA for patients with AML. It has been reported to increase the sensitivity of AML cell lines to chemotherapy by reducing one protein, which is associated with poor response to chemotherapy and therefore is related to a poor prognosis.These reports have led to the assumption that ATRA added to chemotherapy may improve outcomes and might replace or reduce the intensity of chemotherapy for patients with AML.

What are the main results of this review?

We found eight relevant studies with almost 4000 patients in total, conducted in the UK, Germany and France. These studies compared chemotherapy in combination with ATRA with chemotherapy alone in adult patients (over 18 years) with AML. All the included trials used different chemotherapy schedules, as there are several types of chemotherapy regimens for AML. Only in one trial did participants receive a newer drug, decitabine, which has been licensed for the treatment of AML since 2012.

Adding ATRA to chemotherapy probably makes little or no difference to OS. ATRA may be potentially beneficial in combination with decitabine, for older patients (over 60 years) and for patients who receive therapy for maintenance, but these findings need to be explored by further research.

For disease-free-survival, complete response rate and on-study mortality there was probably no or little difference between treatment groups.

The combination of ATRA probably did not lead to a higher infection rate. Regarding cardiac toxicity and diarrhoea, the certainty of the evidence was assessed as very low, so we are uncertain whether the addition of ATRA is beneficial.

Quality of life was not reported by any of the included trials.

How up-to-date is this review?

We searched for studies that had been published up to July 2018.

Authors' conclusions: 

We found no evidence for a difference between participants receiving ATRA in addition to chemotherapy or chemotherapy only for the outcome OS. Regarding DFS, CRR and on-study mortality, there is probably no evidence for a difference between treatment groups. Currently, it seems the risk of adverse events are comparable to chemotherapy only.

As quality of life has not been evaluated in any of the included trials, further research is needed to clarify the effect of ATRA on quality of life.

Read the full abstract...
Background: 

Acute myeloid leukaemia (AML) is the most common acute leukaemia affecting adults. Most patients diagnosed with AML are at advanced age and present with co-morbidities, so that intensive therapy such as stem cell transplantation (SCT) is impossible to provide or is accompanied by high risks for serious adverse events and treatment-related mortality. Especially for these patients, it is necessary to find out whether all-trans retinoic acid (ATRA), an intermediate of vitamin A inducing terminal differentiation of leukaemic cell lines, added to chemotherapy confers increased benefit or harm when compared with the same chemotherapy alone.

Objectives: 

This review aims to determine benefits and harms of ATRA in addition to chemotherapy compared to chemotherapy alone for adults with AML (not those with acute promyelocytic leukaemia (non-APL)).

Search strategy: 

We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, study registries and relevant conference proceedings up to July 2018 for randomised controlled trials (RCTs). We also contacted experts for unpublished data.

Selection criteria: 

We included RCTs comparing chemotherapy alone with chemotherapy plus ATRA in patients with all stages of AML. We excluded trials if less than 80% of participants were adults or participants with AML, and if no subgroup data were available. Patients with myelodysplastic syndrome (MDS) were included, if they had a refractory anaemia and more than 20% of blasts.

Data collection and analysis: 

Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. We used hazard ratios (HR) for overall survival (OS) and disease-free survival (DFS; instead of the pre-planned event-free survival, as this outcome was not reported), and we calculated risk ratios (RR) for the other outcomes quality of life, on-study mortality and adverse events. We presented all measures with 95% confidence intervals (CIs). We assessed the certainty of evidence using GRADE methods.

Main results: 

Our search resulted in 2192 potentially relevant references, of which we included eight trials with 28 publications assessing 3998 patients. Overall, we judged the potential risk of bias of the eight included trials as moderate. Two of eight trials were published as abstracts only. All the included trials used different chemotherapy schedules and one trial only evaluated the effect of the hypomethylating agent decitabine, a drug know to affect epigenetics, in combination with ATRA.

The addition of ATRA to chemotherapy resulted in probably little or no difference in OS compared to chemotherapy only (2985 participants; HR 0.94 (95% confidence interval (CI) 0.87 to 1.02); moderate-certainty evidence). Based on a mortality rate at 24 months of 70% with chemotherapy alone, the mortality rate with chemotherapy plus ATRA was 68% (95% CI 65% to 71%).

For DFS, complete response rate (CRR) and on-study mortality there was probably little or no difference between treatment groups (DFS: 1258 participants, HR 0.99, 95% CI 0.87 to 1.12; CRR: 3081 participants, RR 1.02, 95% CI 0.96 to 1.09; on-study mortality: 2839 participants, RR 1.02, 95% CI 0.81 to 1.30, all moderate-certainty evidence).

Three trials with 1428 participants reported the adverse events 'infection' and 'cardiac toxicity': There was probably no, or little difference in terms of infection rate between participants receiving ATRA or not (RR 1.05, 95% CI 0.96 to 1.15; moderate-certainty evidence). We are uncertain whether ATRA decreases cardiac toxicity (RR 0.46, 95% CI 0.24 to 0.90; P = 0.02, very low certainty-evidence, however, cardiac toxicity was low).

Rates and severity of diarrhoea and nausea/vomiting were assessed in two trials with 337 patients and we are uncertain whether there is a difference between treatment arms (diarrhoea: RR 2.19, 95% CI 1.07 to 4.47; nausea/vomiting: RR 1.46, 95% CI 0.75 to 2.85; both very low-certainty evidence).

Quality of life was not reported by any of the included trials.

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