In this systematic review, we summarised and analysed the evidence from randomised controlled trials on the efficacy and safety of granulocyte colony stimulating factors (G-CSF) and granulocyte-macrophage colony stimulating factors (GM-CSF) in the treatment of myelodysplastic syndromes (MDS). We searched several important medical databases and found seven randomised controlled trials fulfilling our pre-defined criteria. We included trials which compared G-CSF or GM-CSF in addition to erythropoiesis (production of red blood cells) stimulating agents (ESAs), chemotherapy or no supportive care, in newly diagnosed patients.
Myelodysplastic syndromes are a heterogeneous group of blood cancers which are characterised by the malproduction of one or more lineages of blood stem cells. MDS is described as a rare disease in people under the age of 50 years, but represents a common haematopoietic disorder (a disorder of blood and bone marrow, thus a defect in production and structure of blood cells) in patients older than 70 years. The presented symptoms are dependent on which cell lines are affected and include bleeding, general weakness and bacterial infections.
Standard treatment in older and low-risk patients is restricted to low-dose chemotherapy and supportive care (blood transfusions and haematopoietic growth factors such as ESAs, stimulating red blood cells and G-CSF and GM-CSF, stimulating white blood cells). High-risk patients are curatively treated with blood stem cell transplantation or palliatively with high-dose chemotherapy, always combined with supportive care.
Myeloid growth factors stimulate the production of certain cells. They are released by the human body by nature, but can also be pharmaceutically synthesised and are used for the improvement of blood counts and the avoidance of e.g. infections. The effect of growth factors is under discussion, since their impact on progression to acute myeloid leukaemia (AML), a more aggressive blood cancer, survival and infections is still unclear.
Our review included seven trials investigating the effect of G-CSF or GM-CSF in a randomised design.
Five trials evaluated G-CSF in addition to standard care (N = 337). A meta-analysis of outcomes from this comparison was not conducted, since results were provided in an incomparable and insufficient way across these trials. There was no evidence for a difference between "additional G-CSF" and "standard care only" in terms of overall survival, progression-free survival, time to progression to AML, infections, and incidence of blood product transfusions. Quality of life and serious adverse events were not reported at all.
Two trials assessed GM-CSF in addition to standard care only (N = 149). The meta-analysis on overall survival showed no evidence for a difference between patients receiving supportive care with GM-CSF compared to patients without GM-CSF. All the other pre-defined outcomes were analysed in a non-comparable way or in one trial only and no meta-analysis was possible, without evidence for a difference. Time to progression to acute leukaemia and quality of life were not reported at all.
In summary, we found no evidence for a difference in terms of overall survival, progression-free survival, infection occurrence, quality of life, time to progression to AML, incidence of blood transfusions and adverse events (e.g. infection, bleeding, nausea) for both of the growth factors.
In addition, we identified two trials evaluating 244 patients without publishing results for each trial arm before all patients could receive GM-CSF (cross-over design). Moreover, we identified two trials, of which both have been terminated early, without publishing any results in both cases.
Although we identified seven trials with a total number of 486 patients, two cross-over trials and two unpublished, prematurely finished studies, this systematic review mainly shows that there is a substantial lack of data, which might rectify the use of G-CSF and GM-CSF for the prevention of infections, prolonging of survival or improvement of quality of life.
Quality of the evidence
The evidence is current to 3 December 2015.
Quality of evidence for all the G-CSF analyses is very low, due to very high imprecision and potential publication bias (three trials have not been reported as full-text, although they were published as abstracts several years ago). The quality of the evidence for all GM-CSF analyses was graded as low, due to very high imprecision.
Although we identified seven trials with a total number of 486 patients, and two unpublished, prematurely finished studies, this systematic review mainly shows that there is a substantial lack of data, which might inform the use of G-CSF and GM-CSF for the prevention of infections, prolonging of survival and improvement of quality of life. The impact on progression to AML remains unclear.
Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological diseases which are characterised by a uni- or multilineage dysplasia of haematological stem cells. Standard treatment is supportive care of the arising symptoms including red blood cell transfusions or the administration of erythropoiesis-stimulating agents (ESAs) in the case of anaemia or the treatment with granulocyte (G-CSF) and granulocyte-macrophage colony stimulating factors (GM-CSF) in cases of neutropenia.
The objective of this review is to assess the evidence for the treatment of patients with MDS with G-CSF and GM-CSF in addition to standard therapy in comparison to the same standard therapy or the same standard therapy and placebo.
We searched MEDLINE (from 1950 to 3 December 2015) and CENTRAL (Cochrane Central Register of Controlled Trials until 3 December 2015), as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, European Society of Medical Oncology) for randomised controlled trials (RCTs). Two review authors independently screened search results.
We included RCTs examining G-CSF or GM-CSF in addition to standard therapy in patients with newly diagnosed MDS.
We used hazard ratios (HR) as effect measure for overall survival (OS), progression-free survival (PFS) and time to progression, and risk ratios for response rates, adverse events, antibiotic use and hospitalisation. Two independent review authors extracted data and assessed risk of bias. Investigators of two trials were contacted for subgroup information, however, no further data were provided. G-CSF and GM-CSF were analysed separately.
We screened a total of 566 records. Seven RCTs involving 486 patients were identified, but we could only meta-analyse the two evaluating GM-CSF. We judged the potential risk of bias of these trials as unclear, mostly due to missing information. All trials were randomised and open-label studies. However, three trials were published as abstracts only, therefore we were not able to assess the potential risk of bias for these trials in detail. Overall, data were not reported in a comparable way and patient-related outcomes like survival, time to progression to acute myeloid leukaemia (AML) or the incidence of infections was reported in two trials only.
Five RCTs (N = 337) assessed the efficacy of G-CSF in combination with standard therapy (supportive care, chemotherapy or erythropoietin). We were not able to perform meta-analyses for any of the pre-planned outcomes due to inconsistent and insufficient reporting of data. There is no evidence for a difference for overall survival (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.44 to 1.47), progression-free survival (only P value provided), progression to AML, incidence of infections and number of red blood transfusions (average number of 12 red blood cell transfusions in each arm). We judged the quality of evidence for all these outcomes as very low, due to very high imprecision and potential publication bias, as three trials were published as abstracts only. Data about quality of life and serious adverse events were not reported in any of the included trials.
Two RCTs (N = 149) evaluated GM-CSF in addition to standard therapy (chemotherapy). For mortality (two RCTs; HR 0.88, 95% CI 0.62 to 1.26), we found no evidence for a difference (low-quality evidence). Data for progression-free survival and serious adverse events were not comparable across both studies, without evidence for a difference between both arms (low-quality evidence). For infections, red blood cell and platelet transfusions, we found no evidence for a difference, however, these outcomes were reported by one trial only (low-quality evidence). Time to progression to AML and quality of life were not reported at all.
Moreover, we identified two cross-over trials, including 244 patients and evaluating GM-CSF versus placebo, without publishing results for each arm before crossing over. In addition, we identified two ongoing studies, one of which was discontinued due to withdrawal of pharmaceutical support, the other was terminated early, both without publishing results.