- Email: [email protected]
Hypomethylating Agents-associated Infections—Systematic Review and Meta-analysis of Randomized Controlled Trials
Original Study
Hypomethylating Agents-associated Infections—Systematic Review and Meta-analysis of Randomized Controlled Trials Liat Shargian-Alon,1,2 Ronit Gurion,1,2 Pia Raanani,1,2 Dafna Yahav,2,3 Anat Gafter-Gvili1,2,4 Abstract Data regarding the effects of hypomethylating agents on the risk of infections are lacking. Therefore, we conducted a systematic review and meta-analysis of all randomized controlled trials comparing hypomethylating agent-containing regimens with any other regimen for patients with myeloid neoplasms. Treatment with hypomethylating agents was associated with an increase in the grade 3/4 infection rate compared with the comparator. Background: The reported data regarding the effects of hypomethylating agents (HMAs) on the risk of infections seem to be poorly documented and heterogeneous. We conducted a systematic review and meta-analysis of all randomized controlled trials comparing HMA-containing regimens with any other regimen administered to patients with myeloid neoplasms. Materials and Methods: A comprehensive search was conducted until February 2018. Two reviewers appraised the quality of the trials and the extracted data. The primary outcome was grade 3/4 infections. The secondary outcomes included febrile neutropenia, fever of unknown origin, grade 3/4 neutropenia, infection-related mortality, and all-cause mortality. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool the data unless significant heterogeneity was present, in which case a random-effects model was used. Results: We identified 9 trials reported from 2002 to 2016 and randomizing 2184 patients. HMAs were associated with an increase in grade 3/4 infections compared with the comparator (RR, 1.30; 95% CI, 1.02-1.66). This was true for the subgroup of patients aged >60 years (RR, 1.19; 95% CI, 1.01-1.39). In addition, HMAs resulted in an increase in the rate of fever of unknown origin and neutropenia (RR, 1.48; 95% CI, 1.151.92; RR, 1.48; 95% CI, 1.22-1.78, respectively). Although no difference was found in the incidence of fatal infections (RR, 1.44; 95% CI, 0.72 to 2.89), treatment with HMA reduced the incidence of all-cause mortality (RR, 0.74; 95% CI, 0.66-0.88). Conclusion: Treatment with HMAs was associated with an increase in the grade 3/4 infection rate. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2018 Elsevier Inc. All rights reserved. Keywords: Azacitidine, Decitabine, HMAs, Infection, Neutropenia
Introduction 1
Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, PetahTikva, Israel 2 Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 3 Infectious Disease Unit 4 Department of Internal Medicine A, Rabin Medical Center, Petah-Tikva, Israel Submitted: Apr 5, 2018; Revised: May 12, 2018; Accepted: May 21, 2018 Address for correspondence: Liat Shargian-Alon, MD, Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah-Tikva 49100, Israel E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2018.05.017
The hypomethylating agents (HMAs), 5-aza-20 -deoxycytidine (decitabine) and 5-azacitidine (azacitidine) are pyrimidine analogues, that target aberrant DNA methylation and restore the expression of tumor suppressor genes by inhibiting DNA methyltransferase.1 At present, HMAs are considered the standard of care for elderly patients with high-risk myelodysplastic syndrome (MDS) who are not candidates for allogeneic stem cell transplantation2 and an emerging treatment option for those with acute myeloid leukemia (AML).3,4 Treatment with HMAs has demonstrated a survival benefit for patients with high-risk MDS and a borderline survival
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Hypomethylating Agents and Infections benefit for patients with AML.4 Although HMAs are considered to be safe and are usually administered within an outpatient setting, infectious complications remain a main concern.5-7 Data regarding the effects of HMAs on the risk of infection seem poorly documented and heterogeneous. Although early pivotal randomized controlled trials (RCTs) of HMAs demonstrated a low risk of infection,2,8 later retrospective studies reported a more substantial infection rate. For example, in a retrospective study of 173 patients, Merkel et al9 showed that 54% of high-risk MDS and AML patients treated with azacitidine developed infectious events. A significant proportion of these patients required hospitalization. In addition, the death rate was 16%.9 More recently, Schuck et al10 described a similar infectious rate, with 71% of high-risk MDS patients treated with azacitidine developing infectious complications, 6% of which culminated in death. Several risk factors for infections in patients treated with HMAs have been reported in retrospective studies, including early treatment cycles, poor cytogenetics, a high revised International Prognostic Scoring System (R-IPSS) score, previous intensive chemotherapy, higher HMA dose, and peripheral blood cytopenias.9,11-14 We conducted a systematic review and meta-analysis to assess the risk of infectious episodes in patients with high-risk MDS and AML treated with HMAs.
Materials and Methods Meta-analyses are exempt from institutional or national ethical committee approval, because they do not include individual participants.
Data Sources The following data sources were searched: the Cochrane Central Register of Controlled Trials (CENTRAL) reported in the Cochrane Library (issue 12, December 2017), PubMed (1966 to December 2017), and conference proceedings of the American Society of Hematology (2005-2017), the American Society of Clinical Oncology (2005-2017), and the European Hematology Association (20052017), and the databases of ongoing and unpublished trials (available at: http://www.controlled-trials.com/; http://www.clinicaltrials.gov/ ct; and http://clinicaltrials.nci.nih.gov/). We cross-searched the terms: hypomethylating, azacitidine, and decitabine. The results were limited to RCTs using a highly sensitive filter.15 We scanned the references of all included trials and reviews identified to find additional studies.
Study Selection
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Eligible studies included all RCTs assessing adult patients aged >18 years with a morphologically proven diagnosis of AML or MDS. According to the current World Health Organization classification system, AML is defined as the presence of > 20% blasts in the marrow or blood.16 Previously, using the French-American-British (FAB) classification system, patients with 20% to 29% blasts in the blood or marrow were classified in the MDS subgroup of refractory anemia with an excess of blasts in transformation.17 We thus also included earlier studies in which MDS was defined as 30% of blasts. We included trials comparing HMA-containing regimens (alone or combined with other chemotherapeutic agents) with any other
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regimens. We included both patients receiving an HMA as first-line therapy and patients receiving an HMA as maintenance therapy. Trials were included regardless of publication status, date of publication, and language. For cases in which several reports were available for the same study, the most relevant data were included. Two of (L.S., A.G.) conducted the search and applied the inclusion criteria independently.
Data Extraction and Quality Assessment Two of us (L.S., A.G.) independently extracted the data from the included trials. In the event of a disagreement between the 2 reviewers, a third reviewer (R.G.) extracted the data, and the results were attained by consensus. Both reviewers (L.S., A.G.) independently assessed the risk of bias in the included trials using the Cochrane Collaboration’s tool for assessing the risk of bias. We individually assessed the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcomes assessment, incomplete outcome data reporting, and selective outcome reporting. We separately assessed each domain and graded it as a low risk of bias, unclear risk, or high risk of bias according to the criteria specified in the Cochrane Handbook, version 5.1.0.15
Definition of Outcomes The primary outcome measure was grade 3/4 infection as defined in the individual trials. When the definition in the trials was unclear, we defined grade 3/4 infection using the Common Terminology Criteria for Adverse Events, version 4.03, as an infection treated with intravenous antibiotic, antiviral, or antifungal agents or a lifethreatening infection associated with septic shock, hypotension, or acidosis.18 The secondary outcomes included febrile neutropenia, fever of unknown origin (FUO), grade 3/4 neutropenia, infectionrelated mortality, and all-cause mortality. In addition, data regarding other infections such as bronchitis, pneumonia, cellulitis, and herpes simplex were collected.
Data Synthesis and Analysis Dichotomous data were analyzed by calculating the risk ratio (RR) for each trial with 95% confidence intervals (CI) (Review Manager [RevMan], version 5.2, for Windows, The Cochrane Collaboration, Oxford, UK). We assessed the heterogeneity of the trial results using a c2 test to calculate the heterogeneity and the I2 measure for inconsistency. We used a fixed-effects model with the Mantel-Haenszel method to pool the trial results throughout the review,19 unless statistically significant heterogeneity was found (P < .10 or I2 > 50%), in which case, we used a random-effects model and the DerSimonian and Laird method.20 The comparisons were subcategorized by the type of drug. The subgroup analyses for grade 3/4 infection were planned for MDS patients and patients aged 60 years.
Results The search yielded 516 potentially relevant titles, 31 of which were considered for further investigation. Of these, 23 trials were excluded for various reasons (Figure 1). We found 9 trials in 11 publications conducted from 1994 to 2014 and reported from 2002 to 2016, randomizing 2184 patients, that fulfilled the inclusion criteria.
Liat Shargian-Alon et al Figure 1 Trial Flow According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Abbreviation: RCTs ¼ randomized controlled trials.
Characteristics of Included Trials The characteristics of the included trials are listed in Table 1.2-4,8,21-26 One of the trials, CALGB (Cancer and Leukemia Group B) 9221, was a crossover trial.8 That trial included 2 arms: azacitidine and best supportive care (BSC). After a minimum interval of 4 months of supportive care, the patients whose disease was worsening were permitted to cross to the azacitidine arm. Therefore, 49 patients crossed to the azacitidine arm. The remaining studies included no crossover options. Because data regarding infections from the AZA (azacitidine)-001 trial were lacking in the original report, data extraction was performed using a more recent report.21 Although the AZA-001 trial
compared 3 treatment arms, data regarding infections were reported only for the BSC arm. Three trials included only MDS patients (FAB classification, 30% blasts).2,22,23 Four trials included AML patients: 2 according to the earlier FAB classification (> 30% blasts)4,26 and 2 using the current World Health Organization classification (>20% blasts).3,25 Two trials8,24 included both AML and MDS patients. The HMA arm consisted of azacitidine in 5 trials2,4,8,25,26 and decitabine in 4 trials.3,22,24 In 6 trials, HMA was administered as a standalone treatment for patients in the first-line setting. The comparator consisted of BSC in 3 trials.8,22,23 In an additional 3
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Study
Myeloid Neoplasm
BM Blasts, %
Treatment Setting
Regimen
Schedule and Dose SC AZA, 75 mg/m2/d for 7 d q28d; BSC, blood products and antibiotics without growth factors IV DEC, 15 mg/m2 over 3 h q8h for 3 d q6wk; BSC, blood products, antibiotics, and growth factors SC AZA, 75 mg/m2/d for 7d q28d; conventional care, blood products, antibiotics, and growth factors; SC LDAC, 20 mg/m2/d for 14 d q28d; intensive chemotherapy (induction 7 þ 3) IV DEC, 15 mg/m2 over 4 h q8h for 3 d q6wk; BSC IV DEC, 20 mg/m2/d over 1 h for 5 d q4wk; supportive care, SC LDAC 20 mg/m2/d for 10 d q4wk SC AZA, 75 mg/m2/d for 7d q28d; SC LDAC 20 mg/m2/d BID for 10 d q4wk; IC (7 þ 3 followed by 2 consolidation cycles) DEC, 20 mg/m2/d for 5 d q35d; tosedostat, 120 mg on D1-21; DEC, 20 mg/m2/d for 5 d q35d; cytarabine 1 g/m2/d for 5 d SC AZA, 75 mg/m2/d for 5 d before each cycle of 7 þ 3 or HIDAC; 7 þ 3/HIDAC SC AZA, 75 mg/m2/d for 7 d (first cycle, 50 mg/m2/d); BSC
Silverman et al,8,21 2002 (CALGB 9221)
MDS
< 20%, 66; 20%-30%, 24; 30%, 10
First line
AZA; BSC
Kantarjian et al,22 2006
MDS
< 20%, 82; 20%-30%, 18; 30%, 0
First line
DEC; BSC
Fenaux et al,2,21 2009 (AZA-OO1)
MDS
< 20%, 65; 20%-30%, 35; 30%, 0
First line
AZA; conventional care
Lübbert et al,23 2011
MDS
First line
DEC; BSC
Kantarjian et al,3 2012
AML
< 20%, 68; 20%-30%, 32; 30%, 0 < 20%, 0; 20%-30%, 25; 30%, 75
First line
DEC; treatment choice
Dombert et al,4 2015
AML
< 20%, 0; 20%-30%, 0; 30%, 100
First line
AZA; conventional care
Mawad et al,24 2016
MDS þ AML
< 20%, 19; 20%, 81
First line
DEC plus tosedostat; cytarabine plus tosedostat
Müller-Tidow et al,25 2016
AML
< 20%, 0; 20%-30%, 19; 30%, 81
Priming
AZA þ 7 þ 3/HIDAC; 7 þ 3/HIDAC
Oliva et al,26 2013
AML
< 20%, 0; 20%-30%, 0; 30%, 100
Maintenance
AZA; BSC
Study Design
Patients Randomized, n
Median Age, y (Range)
Crossover
92; 99
69 (31-92); 67 (35-88)
Parallel
89; 81
70 (65-76); 70 (62-74)
Parallel
179; 179
69 (42-83); 70 (38-87)
Parallel
119; 114
Parallel
242; 243
69 (60-90); 70 (60-86) 73 (64-89); 73 (64-91)
Parallel
241; 247
75 (64-91); 75 (65-89)
Parallel
13; 13
70; 72
Parallel
105; 109
69.6; 69.4
Parallel
8; 11
72.5 6.2; 72.5 6.2
Abbreviations: AML ¼ acute myeloid leukemia; AZA ¼ azacitidine; BM ¼ bone marrow; BSC ¼ best supportive care; CALGB ¼ Cancer and Leukemia Group B; DEC ¼ decitabine; HIDAC ¼ high-dose cytarabine; IV ¼ intravenous; LDAC ¼ low-dose cytarabine; MDS ¼ myelodysplastic syndrome; SC ¼ subcutaneous.
Hypomethylating Agents and Infections
Clinical Lymphoma, Myeloma & Leukemia Month 2018
Table 1 Characteristics of Included Randomized Controlled Trials
Liat Shargian-Alon et al trials, the comparator arm was decided by physician preference from several options: BSC, low-dose cytarabine, and intensive chemotherapy.2-4 Of the remaining 3 trials, 1 trial24 compared the combination of tosedostat, an oral aminopeptidase inhibitor, with either decitabine or cytarabine as first-line treatment. Another trial25 compared chemotherapy and chemotherapy with azacitidine, added as an epigenetic priming agent applied before each cycle of intensive chemotherapy. The last trial evaluated azacitidine as a maintenance postremission treatment versus BSC.26 The median age of the patients in the different trials ranged from 67 to 75 years. The incidence of infections was highly variable among the trials. The infection rate in the HMA arm versus the comparator arm in each of the trials is listed in Table 2. None of the trials included antibacterial or antifungal prophylaxis. Two trials were assessed as having a low risk of selection bias (adequate allocation concealment and sequence generation). Seven trials did not report the methods of allocation concealment or sequence generation, or both, and were judged to have an unclear risk of selection bias. The other parameters of the risk of bias assessment are shown in Supplemental Table 1 (available in the online version).
Primary Outcome Four trials with 894 patients reported relevant data for the analysis of grade 3/4 infections.2,8,23,25 Treatment with HMA was associated with a statistically significant greater rate of grade 3/4 infections compared with the comparator arm (RR, 1.30; 95% CI, 1.02-1.66), with significant heterogeneity (I2 ¼ 57%) found with the random-effects model (Figure 2). The subgroup analysis of the patients aged > 60 years included 2 trials that included only patients aged > 60 years and a trial that was a subgroup of that AZA001 study that included patients > 75 years.27 That analysis showed similar results, with a greater rate of infections among the HMA arm patients (RR, 1.19; 95% CI, 1.011.39; 3 trials; Figure 3). The subgroup analysis of only MDS patients revealed a trend toward an increase in grade 3/4 infections among MDS patients treated with HMA compared with the comparator arm (RR, 1.38; 95% CI, 0.93-2.05; 3 trials, 686 patients; Figure 4).
Secondary Outcomes The rate of FUO events and neutropenia was greater in the HMA arm compared with the other treatment options, and the difference was statistically significant (RR, 1.48; 95% CI, 1.15-1.92 [5 trials]; RR, 1.48; 95% CI 1.22-1.78 [5 trials], respectively). When assessing febrile neutropenia, no statistically significant difference was found between the 2 study arms (RR, 1.65; 95% CI, 0.60-4.52; 5 trials). However, subcategorizing according to the disease revealed that patients with MDS who were treated with an HMA had a significantly greater rate of febrile neutropenia (RR, 2.84; 95% CI, 1.2-6.73; 3 trials) compared with the AML patients. An increase of borderline significance in grade 3/4 pneumonia was found in the HMA arm compared with the comparator arm (RR, 1.25; 95% CI, 0.99-1.59; 6 trials). No significant difference between the study arms was noted regarding sepsis (RR, 1.03; 95% CI, 0.65-1.62; 5 trials), cellulitis (RR, 1.04; 95% CI, 0.53-2.05; 3 trials), and acute bronchitis grade 3/4 (RR, 0.79; 95% CI, 0.4-1.58; 4 trials). No difference was found in infection-related mortality between patients treated with HMA and those treated in the comparator arm (RR, 1.44; 95% CI, 0.72-2.89; 3 trials). However, the all-cause mortality at 6 months was significantly decreased among patients treated with HMAs compared with those treated in the comparator arm (RR, 0.74; 95% CI, 0.66-0.88; 8 trials). Subcategorizing the data according to the type of drug revealed similar results for each agent with respect to the infection rate. Although decitabine was significantly associated with lower mortality rates (RR, 0.75; 95% CI, 0.64-0.88; 4 trials), azacitidine trials displayed only a nonsignificant trend for decreased mortality (RR, 0.76; 95% CI, 0.57-1.02; 4 trials). Data on hospitalization rates, hospital duration (in days), quality of life, and transfusion requirements were not available from the included trials; therefore, we could not analyze these outcomes in our meta-analysis.
Discussion Our systematic review compiled all RCTs comparing HMAcontaining regimens with other treatment regimens in patients with myeloid lineage malignancies. Our results have demonstrated that HMAs are associated with an increase in grade 3/4 infections compared with the comparator treatment. This was true for the whole
Table 2 Infection Rates in Included Randomized Controlled Trials Grade 3/4 Infection, % Study Silverman et al,8 2002 (CALGB 9221) Kantarjian et al,22 2006 Fenaux, et al2 2009 (AZA-OO1) Lübbert et al,23 2011 Kantarjian et al,3 2012 Dombert et al,4 2015 Mawad et al,24 2016 Müller-Tidow et al,25 2016 Oliva et al,26 2013
Regimen
HMA Arm
Comparator Arm
AZA versus BSC DEC versus BSC AZA versus conventional care DEC versus BSC DEC versus treatment choice AZA versus conventional care DEC plus tosedostat versus cytarabine plus tosedostat AZA plus 7 þ 3/HIDAC versus 7 þ 3/HIDAC AZA versus BSC
19 NR 24 58 NR NR NR
17 NR 48 50 NR NR NR
66
56
NR
NR
Abbreviations: AZA ¼ azacitidine; BSC ¼ best supportive care; CALGB ¼ Cancer and Leukemia Group B; DEC ¼ decitabine; HIDAC ¼ high-dose cytarabine; HMA ¼ hypomethylating agent; NR ¼ not reported.
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Hypomethylating Agents and Infections Figure 2 Incidence of Grade 3/4 Infections Between Hypomethylating-containing Regimens Compared With Other Regimens
Abbreviations: AZA ¼ azacitidine; CALGB ¼ Cancer and Leukemia Group B; CI ¼ confidence interval; M-H ¼ Mantel-Haenszel method.
cohort and for the subgroup of patients aged > 60 years. In addition, we found an increase in the rate of FUO events and neutropenia. A trend toward an increased rate of grade 3/4 pneumonia was also noted. In addition, treatment with HMAs reduced the rate of all-cause mortality, despite more grade 3/4 infections in this treatment arm. Our findings have confirmed previous retrospective reports that HMAs are associated with a greater risk of infective complications compared with other conventional regimens.9-11 An important finding from our systematic review is that although treatment with HMAs was associated with an increase in the grade 3/4 infection rate compared with BSC and other common comparators, we found no difference in infection-related mortality. Moreover, all-cause mortality at 6 months was significantly lower among the patients treated with HMAs, as previously shown.28 It is possible that the detrimental rate of infectious complications during the treatment period is counterbalanced by the favorable effect of HMAs on
disease-related mortality. Thus, the overall survival advantage of HMAs is achieved despite the greater toxicity profile of these drugs. Our systematic review and meta-analysis demonstrated similar results for decitabine and azacitidine. A previous propensity scorematched retrospective cohort from Korea that included MDS patients reported significantly greater infection rates with decitabine.29 A RCT comparing low-dose decitabine with low-dose azacitidine in low-risk MDS patients reported similarly low rates of infections and neutropenic fever between the 2 study arms.30 However, because the population enrolled and the dosage tested were not common, their randomized comparison does not contribute much to the understanding of the differences in the safety profile between the 2 drugs when used for high-risk MDS and AML, such as in our meta-analysis. A subgroup analysis in our systematic review, according to type of drug, showed that the point estimates were in the same direction.
Figure 3 Incidence of Grade 3/4 Infections Between Hypomethylating-containing Regimens Compared With Other Regimens for Patients Aged > 60 Years
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Abbreviations: AZA ¼ azacitidine; CALGB ¼ Cancer and Leukemia Group B; CI ¼ confidence interval; M-H ¼ Mantel-Haenszel method.
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Liat Shargian-Alon et al Figure 4 Incidence of Grade 3/4 Infections Between Hypomethylating-containing Regimens Compared With Other Regimens for Myelodysplastic Syndrome Patients
Abbreviations: AZA ¼ azacitidine; CALGB ¼ Cancer and Leukemia Group B; CI ¼ confidence interval; M-H ¼ Mantel-Haenszel method.
The propensity for infections raises the issue of antibacterial prophylaxis. However, whether antibacterial prophylaxis might benefit patients with MDS and AML receiving HMAs has not been established. Antibacterial prophylaxis was shown to significantly reduce the risk of death from all causes in neutropenic patients with hematologic malignancies who are receiving chemotherapy, including AML, according to a meta-analysis of 109 RCTs.31 Nevertheless, trials of patients treated with HMAs were not included in that meta-analysis, because no RCTs have assessed antibacterial prophylaxis in this setting. Moreover, the latest Infectious Diseases Society of America guidelines for neutropenic fever in patients with cancer did not address the issue in MDS patients.32 Approaches to infection prevention during and after HMA therapy vary and rely only on data derived from retrospective studies, some of which have demonstrated a significant decrease in infectious complications with antibiotic prophylaxis among patients treated with HMAs,33,34 especially among neutropenic patients.35 However, the conclusions drawn from these studies should be interpreted with caution, because different antibacterial drugs were used, and the administration of these agents was not randomly assigned but was left to the discretion of the physicians. The RCTs included in our study did not administer antibiotic prophylaxis routinely; thus, this parameter could not be assessed. Data regarding fungal infections and antifungal prophylaxis were reported even less. In a meta-analysis of 67 RCTs, antifungal prophylaxis administered to allogeneic hematopoietic stem cell transplantation and acute leukemia patients decreased all-cause mortality compared with that in the comparator arm.36 Nevertheless, trials of patients treated with HMAs were also not included in that meta-analysis. Retrospective studies of patients treated with HMAs have reported nonsubstantial numbers of invasive fungal infections and reported that these numbers do not justify the use of antifungal prophylaxis.11,37 Future randomized prospective trials, specifically addressing the issue of infections, will be important in resolving the question of prophylaxis and might also provide data regarding the role of further improvement in supportive care techniques, including antibacterial prophylaxis as a method to further improve the substantial survival advantage of HMA administration in these patients. To the best of our knowledge, ours is the first systematic review and meta-analysis performed with the primary aim of evaluating the
incidence and severity of infectious complications in MDS and AML patients treated with HMAs. Several limitations of our analysis merit consideration. The included trials were highly heterogeneous regarding the definitions of MDS and AML according to the blast percentage cutoff, with different agents and regimens in the HMA arm, different chemotherapy regimens in the comparator arm, and different treatment lines (ie, first-line, maintenance). Consequently, we could not perform a highly informative subgroup analysis to assess MDS and AML patients separately. In addition, data regarding some types of infections in the individual trials were too scarce to analyze. Although we could assess important specific types of bacterial infections, such as sepsis, pneumonia, cellulitis, and bronchitis, data regarding bacterial pathogens were scarce and data regarding fungal and viral infections per se were not sufficient. As previously stated, no data were available regarding antibacterial or antifungal prophylaxis in the trials that could contribute to our understanding of their role in this setting. Using data from RCTs to report severe adverse events, such as infections, might be debatable, because severe events might be too rare to be captured by a design such as a RCT. Moreover, the recording of adverse events might be less rigorous and more biased than that of the primary efficacy outcomes in such studies. However, the infections in the included trials were not rare and were reported by all the trials.
Conclusion Although the use of HMAs increased the grade 3/4 infection rates compared with other common regimens, all-cause mortality remained lower owing to a favorable effect on the underlying disease. Most of the trials assessed high-risk MDS and AML patients in the first-line setting. Thus, our results and conclusions mainly apply to this subgroup of patients. Future RCTs should assess not only the mortality rate, an outcome that encompasses both efficacy and safety, but also the rate of adverse events such as infections, in patients treated with HMA. Furthermore, these trials should separately assess targeted populations such as elderly patients, those with recurrent and refractory disease, or patients after allogeneic hematopoietic transplantation, who have a greater risk of infection. In addition, trials should better report specific infectious events. Future RCTs evaluating antibiotic or antiviral prophylaxis, especially during the course of HMA therapy, are warranted.
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Hypomethylating Agents and Infections Clinical Practice Points The reported data regarding the effects of HMAs on the risk of
infections seem to be poorly documented and heterogeneous. We conducted a systematic review and meta-analysis of all RCTs
comparing HMA-containing regimens with any other regimen administered to patients with myeloid neoplasms to assess the risk of infection. Nine trials reported from 2002 to 2016 that had randomized 2184 patients were included; most of the trials assessed high-risk MDS and AML patients in the first-line setting. HMAs were associated with an increase in grade 3/4 infections versus the comparator (RR, 1.30; 95% CI, 1.02-1.66). In addition, the rate of FUO events and neutropenia was increased (RR, 1.48; 95% CI, 1.15-1.92; and RR, 1.48; 95% CI, 1.22-1.78, respectively). HMA usage reduced all-cause mortality (RR, 0.74; 95% CI, 0.66-0.88). Although treatment with HMAs was associated with an increase in grade 3/4 infections compared with best supportive care in mortality, it is possible that the detrimental rate of infectious complications during the treatment period was counterbalanced by the favorable effect of HMAs on disease-related mortality. Thus, the overall survival advantage of HMAs was achieved despite the greater toxicity profile of these drugs. Future RCTs should better document the infections and specific types of infections. By addressing the issue of infections, this could help resolve the question of prophylaxis and might also provide data regarding the role of further improvements in supportive care.
Disclosure The authors have stated that they have no conflicts of interest.
Supplemental Data The supplemental data accompanying this article can be found in the online version at https://doi.org/10.1016/j.clml.2018.05.017.
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10. Schuck A, Goette M, Neukirchen J, et al. A retrospective study evaluating the impact of infectious complications during azacitidine treatment. Ann Hematol 2017; 96:1097-104. 11. Falantes JF, Calderón C, Márquez-Malaver FJ, et al. Patterns of infection in patients with myelodysplastic syndromes and acute myeloid leukemia receiving azacitidine as salvage therapy: implications for primary antifungal prophylaxis. Clin Lymphoma Myeloma Leuk 2014; 14:80-6. 12. Trubiano JA, Dickinson M, Thursky KA, et al. Incidence, etiology and timing of infections following azacitidine therapy for myelodysplastic Syndromes. Leuk Lymphoma 2017; 58:2379-86. 13. Ofran Y, Filanovsky K, Gafter-Gvili A, et al. Higher infection rate after 7compared with 5-day cycle of azacitidine in patients with higher-risk myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk 2015; 15:e95-9. 14. Orero M, Villegas C, Ortiz S, et al. Infection rate and risk factors in patients treated with azacitidine. Clin Lymphoma Myeloma Leuk 2015; 15:e141-2. 15. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions: Version 5.1.0. The Cochrane Collaboration; 2011. Available at: http:// www.cochranehandbook.org. Accessed: December 2017. 16. Vardiman JW, Harris NL, Bruning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100:2292-302. 17. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classifications of the myelodysplastic syndromes. Br J Haematol 1982; 15:189-99. 18. Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, 2017. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed: December 2017. 19. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22:719-48. 20. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7:177-88. 21. Santini V, Fenaux P, Mufti GJ, et al. Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*. Eur J Haematol 2010; 85:130-8. 22. Kantarjian H, Issa JPJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes. Cancer 2006; 106:1794-803. 23. Lübbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol 2011; 29: 1987-96. 24. Mawad R, Becker PS, Hendrie P, et al. Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS. Br J Haematol 2016; 172:238-45. 25. Müller-Tidow C, Tschanter P, Röllig C, et al. Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: the AML-AZA trial of the study alliance leukemia. Leukemia 2016; 30: 555-61. 26. Oliva N, Santarone S, Leoni P, et al. A randomized open-label study to evaluate the efficacy of azacitidine for post-remission therapy of acute myeloid leukemia in elderly patients (QOLESS AZA-AMLE). Abstract presented at the 55th Annual ASH Meeting and Exposition, New Orleans, LA 2013. 27. Seymour JF, Fenaux P, Silverman LR, et al. Effects of azacitidine compared with conventional care regimens in elderly ( 75 years) patients with higher-risk myelodysplastic syndromes. Crit Rev Oncol Hematol 2010; 76:218-27. 28. Gurion R, Vidal L, Gafter-Gvili A, et al. 5-Azacitidine prolongs overall survival in patients with myelodysplastic syndrome—a systematic review and meta-analysis. Haematologica 2010; 95:303-10. 29. Lee YG, Kim I, Yoon SS, et al. Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes. Br J Haematol 2013; 161:339-47. 30. Jabbour E, Short NJ, Montalban-Bravo G, et al. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood 2017; 130:1514-22. 31. Gafter-Gvili A, Fraser A, Paul M, et al. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev 2012; 1:CD00438. 32. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:e56-93. 33. Bainschab A, Quehenberger F, Greinix HT, et al. Infections in patients with acute myeloid leukemia treated with low-intensity therapeutic regimens: risk factors and efficacy of antibiotic prophylaxis. Leuk Res 2016; 42:47-51. 34. Lee JH, Lee KH, Lee JH, et al. Decreased incidence of febrile episodes with antibiotic prophylaxis in the treatment of decitabine for myelodysplastic syndrome. Leuk Res 2011; 35:499-503. 35. Lorenzana N, Avila LF, Alonso S, et al. The impact of antimicrobial prophylaxis in morbidity and infections during azacitidine treatment. Ann Hematol 2017; 96: 1833-40. 36. Robenshtok E, Gafter-Gvili A, Goldberg E, et al. M Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 2007; 25:5471-89. 37. Pomares H, Arnan M, Sánchez-Ortega I, Sureda A, Duarte RF. Invasive fungal infections in AML/MDS patients treated with azacitidine: a risk worth considering antifungal prophylaxis? Mycoses 2016; 59:516-9.
Liat Shargian-Alon et al Supplemental Table 1 Risk of Bias Assessment
Study Silverman et al,8 2002 (CALGB) Fenaux et al,2 2009 (AZA-001) Lübbert et al,23 2011 Kantarjian et al,22 2006 Kantarjian et al,3 2012 Dombert et al,4 2015 Mawad et al,24 2016 Müller-Tidow et al,25 2016 Oliva et al,26 2013
Sequence Generation (Selection Bias)
Allocation Concealment (Selection Bias)
Unclear Low risk
Unclear Low risk
Unclear Unclear Low risk Low risk Low risk Unclear Unclear
Low risk Low risk Unclear Low risk Unclear Unclear Unclear
Blinding
Incomplete Outcome Data (Attrition Bias)
Selective Outcome Reporting (Reporting Bias)
No No
Unclear/High risk Low risk
Unclear Low risk
No No No No Yes No No
Low risk Low risk Low risk Low risk Low risk Low risk Unclear
Low risk Unclear Low risk Low risk Low risk Low risk Unclear
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Hypomethylating Agents-associated Infections—Systematic Review and Meta-analysis of Randomized Controlled Trials Liat Shargian-Alon,1,2 Ronit Gurion,1,2 Pia Raanani,1,2 Dafna Yahav,2,3 Anat Gafter-Gvili1,2,4 Abstract Data regarding the effects of hypomethylating agents on the risk of infections are lacking. Therefore, we conducted a systematic review and meta-analysis of all randomized controlled trials comparing hypomethylating agent-containing regimens with any other regimen for patients with myeloid neoplasms. Treatment with hypomethylating agents was associated with an increase in the grade 3/4 infection rate compared with the comparator. Background: The reported data regarding the effects of hypomethylating agents (HMAs) on the risk of infections seem to be poorly documented and heterogeneous. We conducted a systematic review and meta-analysis of all randomized controlled trials comparing HMA-containing regimens with any other regimen administered to patients with myeloid neoplasms. Materials and Methods: A comprehensive search was conducted until February 2018. Two reviewers appraised the quality of the trials and the extracted data. The primary outcome was grade 3/4 infections. The secondary outcomes included febrile neutropenia, fever of unknown origin, grade 3/4 neutropenia, infection-related mortality, and all-cause mortality. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool the data unless significant heterogeneity was present, in which case a random-effects model was used. Results: We identified 9 trials reported from 2002 to 2016 and randomizing 2184 patients. HMAs were associated with an increase in grade 3/4 infections compared with the comparator (RR, 1.30; 95% CI, 1.02-1.66). This was true for the subgroup of patients aged >60 years (RR, 1.19; 95% CI, 1.01-1.39). In addition, HMAs resulted in an increase in the rate of fever of unknown origin and neutropenia (RR, 1.48; 95% CI, 1.151.92; RR, 1.48; 95% CI, 1.22-1.78, respectively). Although no difference was found in the incidence of fatal infections (RR, 1.44; 95% CI, 0.72 to 2.89), treatment with HMA reduced the incidence of all-cause mortality (RR, 0.74; 95% CI, 0.66-0.88). Conclusion: Treatment with HMAs was associated with an increase in the grade 3/4 infection rate. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2018 Elsevier Inc. All rights reserved. Keywords: Azacitidine, Decitabine, HMAs, Infection, Neutropenia
Introduction 1
Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, PetahTikva, Israel 2 Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel 3 Infectious Disease Unit 4 Department of Internal Medicine A, Rabin Medical Center, Petah-Tikva, Israel Submitted: Apr 5, 2018; Revised: May 12, 2018; Accepted: May 21, 2018 Address for correspondence: Liat Shargian-Alon, MD, Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah-Tikva 49100, Israel E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2018.05.017
The hypomethylating agents (HMAs), 5-aza-20 -deoxycytidine (decitabine) and 5-azacitidine (azacitidine) are pyrimidine analogues, that target aberrant DNA methylation and restore the expression of tumor suppressor genes by inhibiting DNA methyltransferase.1 At present, HMAs are considered the standard of care for elderly patients with high-risk myelodysplastic syndrome (MDS) who are not candidates for allogeneic stem cell transplantation2 and an emerging treatment option for those with acute myeloid leukemia (AML).3,4 Treatment with HMAs has demonstrated a survival benefit for patients with high-risk MDS and a borderline survival
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Hypomethylating Agents and Infections benefit for patients with AML.4 Although HMAs are considered to be safe and are usually administered within an outpatient setting, infectious complications remain a main concern.5-7 Data regarding the effects of HMAs on the risk of infection seem poorly documented and heterogeneous. Although early pivotal randomized controlled trials (RCTs) of HMAs demonstrated a low risk of infection,2,8 later retrospective studies reported a more substantial infection rate. For example, in a retrospective study of 173 patients, Merkel et al9 showed that 54% of high-risk MDS and AML patients treated with azacitidine developed infectious events. A significant proportion of these patients required hospitalization. In addition, the death rate was 16%.9 More recently, Schuck et al10 described a similar infectious rate, with 71% of high-risk MDS patients treated with azacitidine developing infectious complications, 6% of which culminated in death. Several risk factors for infections in patients treated with HMAs have been reported in retrospective studies, including early treatment cycles, poor cytogenetics, a high revised International Prognostic Scoring System (R-IPSS) score, previous intensive chemotherapy, higher HMA dose, and peripheral blood cytopenias.9,11-14 We conducted a systematic review and meta-analysis to assess the risk of infectious episodes in patients with high-risk MDS and AML treated with HMAs.
Materials and Methods Meta-analyses are exempt from institutional or national ethical committee approval, because they do not include individual participants.
Data Sources The following data sources were searched: the Cochrane Central Register of Controlled Trials (CENTRAL) reported in the Cochrane Library (issue 12, December 2017), PubMed (1966 to December 2017), and conference proceedings of the American Society of Hematology (2005-2017), the American Society of Clinical Oncology (2005-2017), and the European Hematology Association (20052017), and the databases of ongoing and unpublished trials (available at: http://www.controlled-trials.com/; http://www.clinicaltrials.gov/ ct; and http://clinicaltrials.nci.nih.gov/). We cross-searched the terms: hypomethylating, azacitidine, and decitabine. The results were limited to RCTs using a highly sensitive filter.15 We scanned the references of all included trials and reviews identified to find additional studies.
Study Selection
2
-
Eligible studies included all RCTs assessing adult patients aged >18 years with a morphologically proven diagnosis of AML or MDS. According to the current World Health Organization classification system, AML is defined as the presence of > 20% blasts in the marrow or blood.16 Previously, using the French-American-British (FAB) classification system, patients with 20% to 29% blasts in the blood or marrow were classified in the MDS subgroup of refractory anemia with an excess of blasts in transformation.17 We thus also included earlier studies in which MDS was defined as 30% of blasts. We included trials comparing HMA-containing regimens (alone or combined with other chemotherapeutic agents) with any other
Clinical Lymphoma, Myeloma & Leukemia Month 2018
regimens. We included both patients receiving an HMA as first-line therapy and patients receiving an HMA as maintenance therapy. Trials were included regardless of publication status, date of publication, and language. For cases in which several reports were available for the same study, the most relevant data were included. Two of (L.S., A.G.) conducted the search and applied the inclusion criteria independently.
Data Extraction and Quality Assessment Two of us (L.S., A.G.) independently extracted the data from the included trials. In the event of a disagreement between the 2 reviewers, a third reviewer (R.G.) extracted the data, and the results were attained by consensus. Both reviewers (L.S., A.G.) independently assessed the risk of bias in the included trials using the Cochrane Collaboration’s tool for assessing the risk of bias. We individually assessed the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcomes assessment, incomplete outcome data reporting, and selective outcome reporting. We separately assessed each domain and graded it as a low risk of bias, unclear risk, or high risk of bias according to the criteria specified in the Cochrane Handbook, version 5.1.0.15
Definition of Outcomes The primary outcome measure was grade 3/4 infection as defined in the individual trials. When the definition in the trials was unclear, we defined grade 3/4 infection using the Common Terminology Criteria for Adverse Events, version 4.03, as an infection treated with intravenous antibiotic, antiviral, or antifungal agents or a lifethreatening infection associated with septic shock, hypotension, or acidosis.18 The secondary outcomes included febrile neutropenia, fever of unknown origin (FUO), grade 3/4 neutropenia, infectionrelated mortality, and all-cause mortality. In addition, data regarding other infections such as bronchitis, pneumonia, cellulitis, and herpes simplex were collected.
Data Synthesis and Analysis Dichotomous data were analyzed by calculating the risk ratio (RR) for each trial with 95% confidence intervals (CI) (Review Manager [RevMan], version 5.2, for Windows, The Cochrane Collaboration, Oxford, UK). We assessed the heterogeneity of the trial results using a c2 test to calculate the heterogeneity and the I2 measure for inconsistency. We used a fixed-effects model with the Mantel-Haenszel method to pool the trial results throughout the review,19 unless statistically significant heterogeneity was found (P < .10 or I2 > 50%), in which case, we used a random-effects model and the DerSimonian and Laird method.20 The comparisons were subcategorized by the type of drug. The subgroup analyses for grade 3/4 infection were planned for MDS patients and patients aged 60 years.
Results The search yielded 516 potentially relevant titles, 31 of which were considered for further investigation. Of these, 23 trials were excluded for various reasons (Figure 1). We found 9 trials in 11 publications conducted from 1994 to 2014 and reported from 2002 to 2016, randomizing 2184 patients, that fulfilled the inclusion criteria.
Liat Shargian-Alon et al Figure 1 Trial Flow According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Abbreviation: RCTs ¼ randomized controlled trials.
Characteristics of Included Trials The characteristics of the included trials are listed in Table 1.2-4,8,21-26 One of the trials, CALGB (Cancer and Leukemia Group B) 9221, was a crossover trial.8 That trial included 2 arms: azacitidine and best supportive care (BSC). After a minimum interval of 4 months of supportive care, the patients whose disease was worsening were permitted to cross to the azacitidine arm. Therefore, 49 patients crossed to the azacitidine arm. The remaining studies included no crossover options. Because data regarding infections from the AZA (azacitidine)-001 trial were lacking in the original report, data extraction was performed using a more recent report.21 Although the AZA-001 trial
compared 3 treatment arms, data regarding infections were reported only for the BSC arm. Three trials included only MDS patients (FAB classification, 30% blasts).2,22,23 Four trials included AML patients: 2 according to the earlier FAB classification (> 30% blasts)4,26 and 2 using the current World Health Organization classification (>20% blasts).3,25 Two trials8,24 included both AML and MDS patients. The HMA arm consisted of azacitidine in 5 trials2,4,8,25,26 and decitabine in 4 trials.3,22,24 In 6 trials, HMA was administered as a standalone treatment for patients in the first-line setting. The comparator consisted of BSC in 3 trials.8,22,23 In an additional 3
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Study
Myeloid Neoplasm
BM Blasts, %
Treatment Setting
Regimen
Schedule and Dose SC AZA, 75 mg/m2/d for 7 d q28d; BSC, blood products and antibiotics without growth factors IV DEC, 15 mg/m2 over 3 h q8h for 3 d q6wk; BSC, blood products, antibiotics, and growth factors SC AZA, 75 mg/m2/d for 7d q28d; conventional care, blood products, antibiotics, and growth factors; SC LDAC, 20 mg/m2/d for 14 d q28d; intensive chemotherapy (induction 7 þ 3) IV DEC, 15 mg/m2 over 4 h q8h for 3 d q6wk; BSC IV DEC, 20 mg/m2/d over 1 h for 5 d q4wk; supportive care, SC LDAC 20 mg/m2/d for 10 d q4wk SC AZA, 75 mg/m2/d for 7d q28d; SC LDAC 20 mg/m2/d BID for 10 d q4wk; IC (7 þ 3 followed by 2 consolidation cycles) DEC, 20 mg/m2/d for 5 d q35d; tosedostat, 120 mg on D1-21; DEC, 20 mg/m2/d for 5 d q35d; cytarabine 1 g/m2/d for 5 d SC AZA, 75 mg/m2/d for 5 d before each cycle of 7 þ 3 or HIDAC; 7 þ 3/HIDAC SC AZA, 75 mg/m2/d for 7 d (first cycle, 50 mg/m2/d); BSC
Silverman et al,8,21 2002 (CALGB 9221)
MDS
< 20%, 66; 20%-30%, 24; 30%, 10
First line
AZA; BSC
Kantarjian et al,22 2006
MDS
< 20%, 82; 20%-30%, 18; 30%, 0
First line
DEC; BSC
Fenaux et al,2,21 2009 (AZA-OO1)
MDS
< 20%, 65; 20%-30%, 35; 30%, 0
First line
AZA; conventional care
Lübbert et al,23 2011
MDS
First line
DEC; BSC
Kantarjian et al,3 2012
AML
< 20%, 68; 20%-30%, 32; 30%, 0 < 20%, 0; 20%-30%, 25; 30%, 75
First line
DEC; treatment choice
Dombert et al,4 2015
AML
< 20%, 0; 20%-30%, 0; 30%, 100
First line
AZA; conventional care
Mawad et al,24 2016
MDS þ AML
< 20%, 19; 20%, 81
First line
DEC plus tosedostat; cytarabine plus tosedostat
Müller-Tidow et al,25 2016
AML
< 20%, 0; 20%-30%, 19; 30%, 81
Priming
AZA þ 7 þ 3/HIDAC; 7 þ 3/HIDAC
Oliva et al,26 2013
AML
< 20%, 0; 20%-30%, 0; 30%, 100
Maintenance
AZA; BSC
Study Design
Patients Randomized, n
Median Age, y (Range)
Crossover
92; 99
69 (31-92); 67 (35-88)
Parallel
89; 81
70 (65-76); 70 (62-74)
Parallel
179; 179
69 (42-83); 70 (38-87)
Parallel
119; 114
Parallel
242; 243
69 (60-90); 70 (60-86) 73 (64-89); 73 (64-91)
Parallel
241; 247
75 (64-91); 75 (65-89)
Parallel
13; 13
70; 72
Parallel
105; 109
69.6; 69.4
Parallel
8; 11
72.5 6.2; 72.5 6.2
Abbreviations: AML ¼ acute myeloid leukemia; AZA ¼ azacitidine; BM ¼ bone marrow; BSC ¼ best supportive care; CALGB ¼ Cancer and Leukemia Group B; DEC ¼ decitabine; HIDAC ¼ high-dose cytarabine; IV ¼ intravenous; LDAC ¼ low-dose cytarabine; MDS ¼ myelodysplastic syndrome; SC ¼ subcutaneous.
Hypomethylating Agents and Infections
Clinical Lymphoma, Myeloma & Leukemia Month 2018
Table 1 Characteristics of Included Randomized Controlled Trials
Liat Shargian-Alon et al trials, the comparator arm was decided by physician preference from several options: BSC, low-dose cytarabine, and intensive chemotherapy.2-4 Of the remaining 3 trials, 1 trial24 compared the combination of tosedostat, an oral aminopeptidase inhibitor, with either decitabine or cytarabine as first-line treatment. Another trial25 compared chemotherapy and chemotherapy with azacitidine, added as an epigenetic priming agent applied before each cycle of intensive chemotherapy. The last trial evaluated azacitidine as a maintenance postremission treatment versus BSC.26 The median age of the patients in the different trials ranged from 67 to 75 years. The incidence of infections was highly variable among the trials. The infection rate in the HMA arm versus the comparator arm in each of the trials is listed in Table 2. None of the trials included antibacterial or antifungal prophylaxis. Two trials were assessed as having a low risk of selection bias (adequate allocation concealment and sequence generation). Seven trials did not report the methods of allocation concealment or sequence generation, or both, and were judged to have an unclear risk of selection bias. The other parameters of the risk of bias assessment are shown in Supplemental Table 1 (available in the online version).
Primary Outcome Four trials with 894 patients reported relevant data for the analysis of grade 3/4 infections.2,8,23,25 Treatment with HMA was associated with a statistically significant greater rate of grade 3/4 infections compared with the comparator arm (RR, 1.30; 95% CI, 1.02-1.66), with significant heterogeneity (I2 ¼ 57%) found with the random-effects model (Figure 2). The subgroup analysis of the patients aged > 60 years included 2 trials that included only patients aged > 60 years and a trial that was a subgroup of that AZA001 study that included patients > 75 years.27 That analysis showed similar results, with a greater rate of infections among the HMA arm patients (RR, 1.19; 95% CI, 1.011.39; 3 trials; Figure 3). The subgroup analysis of only MDS patients revealed a trend toward an increase in grade 3/4 infections among MDS patients treated with HMA compared with the comparator arm (RR, 1.38; 95% CI, 0.93-2.05; 3 trials, 686 patients; Figure 4).
Secondary Outcomes The rate of FUO events and neutropenia was greater in the HMA arm compared with the other treatment options, and the difference was statistically significant (RR, 1.48; 95% CI, 1.15-1.92 [5 trials]; RR, 1.48; 95% CI 1.22-1.78 [5 trials], respectively). When assessing febrile neutropenia, no statistically significant difference was found between the 2 study arms (RR, 1.65; 95% CI, 0.60-4.52; 5 trials). However, subcategorizing according to the disease revealed that patients with MDS who were treated with an HMA had a significantly greater rate of febrile neutropenia (RR, 2.84; 95% CI, 1.2-6.73; 3 trials) compared with the AML patients. An increase of borderline significance in grade 3/4 pneumonia was found in the HMA arm compared with the comparator arm (RR, 1.25; 95% CI, 0.99-1.59; 6 trials). No significant difference between the study arms was noted regarding sepsis (RR, 1.03; 95% CI, 0.65-1.62; 5 trials), cellulitis (RR, 1.04; 95% CI, 0.53-2.05; 3 trials), and acute bronchitis grade 3/4 (RR, 0.79; 95% CI, 0.4-1.58; 4 trials). No difference was found in infection-related mortality between patients treated with HMA and those treated in the comparator arm (RR, 1.44; 95% CI, 0.72-2.89; 3 trials). However, the all-cause mortality at 6 months was significantly decreased among patients treated with HMAs compared with those treated in the comparator arm (RR, 0.74; 95% CI, 0.66-0.88; 8 trials). Subcategorizing the data according to the type of drug revealed similar results for each agent with respect to the infection rate. Although decitabine was significantly associated with lower mortality rates (RR, 0.75; 95% CI, 0.64-0.88; 4 trials), azacitidine trials displayed only a nonsignificant trend for decreased mortality (RR, 0.76; 95% CI, 0.57-1.02; 4 trials). Data on hospitalization rates, hospital duration (in days), quality of life, and transfusion requirements were not available from the included trials; therefore, we could not analyze these outcomes in our meta-analysis.
Discussion Our systematic review compiled all RCTs comparing HMAcontaining regimens with other treatment regimens in patients with myeloid lineage malignancies. Our results have demonstrated that HMAs are associated with an increase in grade 3/4 infections compared with the comparator treatment. This was true for the whole
Table 2 Infection Rates in Included Randomized Controlled Trials Grade 3/4 Infection, % Study Silverman et al,8 2002 (CALGB 9221) Kantarjian et al,22 2006 Fenaux, et al2 2009 (AZA-OO1) Lübbert et al,23 2011 Kantarjian et al,3 2012 Dombert et al,4 2015 Mawad et al,24 2016 Müller-Tidow et al,25 2016 Oliva et al,26 2013
Regimen
HMA Arm
Comparator Arm
AZA versus BSC DEC versus BSC AZA versus conventional care DEC versus BSC DEC versus treatment choice AZA versus conventional care DEC plus tosedostat versus cytarabine plus tosedostat AZA plus 7 þ 3/HIDAC versus 7 þ 3/HIDAC AZA versus BSC
19 NR 24 58 NR NR NR
17 NR 48 50 NR NR NR
66
56
NR
NR
Abbreviations: AZA ¼ azacitidine; BSC ¼ best supportive care; CALGB ¼ Cancer and Leukemia Group B; DEC ¼ decitabine; HIDAC ¼ high-dose cytarabine; HMA ¼ hypomethylating agent; NR ¼ not reported.
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Hypomethylating Agents and Infections Figure 2 Incidence of Grade 3/4 Infections Between Hypomethylating-containing Regimens Compared With Other Regimens
Abbreviations: AZA ¼ azacitidine; CALGB ¼ Cancer and Leukemia Group B; CI ¼ confidence interval; M-H ¼ Mantel-Haenszel method.
cohort and for the subgroup of patients aged > 60 years. In addition, we found an increase in the rate of FUO events and neutropenia. A trend toward an increased rate of grade 3/4 pneumonia was also noted. In addition, treatment with HMAs reduced the rate of all-cause mortality, despite more grade 3/4 infections in this treatment arm. Our findings have confirmed previous retrospective reports that HMAs are associated with a greater risk of infective complications compared with other conventional regimens.9-11 An important finding from our systematic review is that although treatment with HMAs was associated with an increase in the grade 3/4 infection rate compared with BSC and other common comparators, we found no difference in infection-related mortality. Moreover, all-cause mortality at 6 months was significantly lower among the patients treated with HMAs, as previously shown.28 It is possible that the detrimental rate of infectious complications during the treatment period is counterbalanced by the favorable effect of HMAs on
disease-related mortality. Thus, the overall survival advantage of HMAs is achieved despite the greater toxicity profile of these drugs. Our systematic review and meta-analysis demonstrated similar results for decitabine and azacitidine. A previous propensity scorematched retrospective cohort from Korea that included MDS patients reported significantly greater infection rates with decitabine.29 A RCT comparing low-dose decitabine with low-dose azacitidine in low-risk MDS patients reported similarly low rates of infections and neutropenic fever between the 2 study arms.30 However, because the population enrolled and the dosage tested were not common, their randomized comparison does not contribute much to the understanding of the differences in the safety profile between the 2 drugs when used for high-risk MDS and AML, such as in our meta-analysis. A subgroup analysis in our systematic review, according to type of drug, showed that the point estimates were in the same direction.
Figure 3 Incidence of Grade 3/4 Infections Between Hypomethylating-containing Regimens Compared With Other Regimens for Patients Aged > 60 Years
6
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Abbreviations: AZA ¼ azacitidine; CALGB ¼ Cancer and Leukemia Group B; CI ¼ confidence interval; M-H ¼ Mantel-Haenszel method.
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Liat Shargian-Alon et al Figure 4 Incidence of Grade 3/4 Infections Between Hypomethylating-containing Regimens Compared With Other Regimens for Myelodysplastic Syndrome Patients
Abbreviations: AZA ¼ azacitidine; CALGB ¼ Cancer and Leukemia Group B; CI ¼ confidence interval; M-H ¼ Mantel-Haenszel method.
The propensity for infections raises the issue of antibacterial prophylaxis. However, whether antibacterial prophylaxis might benefit patients with MDS and AML receiving HMAs has not been established. Antibacterial prophylaxis was shown to significantly reduce the risk of death from all causes in neutropenic patients with hematologic malignancies who are receiving chemotherapy, including AML, according to a meta-analysis of 109 RCTs.31 Nevertheless, trials of patients treated with HMAs were not included in that meta-analysis, because no RCTs have assessed antibacterial prophylaxis in this setting. Moreover, the latest Infectious Diseases Society of America guidelines for neutropenic fever in patients with cancer did not address the issue in MDS patients.32 Approaches to infection prevention during and after HMA therapy vary and rely only on data derived from retrospective studies, some of which have demonstrated a significant decrease in infectious complications with antibiotic prophylaxis among patients treated with HMAs,33,34 especially among neutropenic patients.35 However, the conclusions drawn from these studies should be interpreted with caution, because different antibacterial drugs were used, and the administration of these agents was not randomly assigned but was left to the discretion of the physicians. The RCTs included in our study did not administer antibiotic prophylaxis routinely; thus, this parameter could not be assessed. Data regarding fungal infections and antifungal prophylaxis were reported even less. In a meta-analysis of 67 RCTs, antifungal prophylaxis administered to allogeneic hematopoietic stem cell transplantation and acute leukemia patients decreased all-cause mortality compared with that in the comparator arm.36 Nevertheless, trials of patients treated with HMAs were also not included in that meta-analysis. Retrospective studies of patients treated with HMAs have reported nonsubstantial numbers of invasive fungal infections and reported that these numbers do not justify the use of antifungal prophylaxis.11,37 Future randomized prospective trials, specifically addressing the issue of infections, will be important in resolving the question of prophylaxis and might also provide data regarding the role of further improvement in supportive care techniques, including antibacterial prophylaxis as a method to further improve the substantial survival advantage of HMA administration in these patients. To the best of our knowledge, ours is the first systematic review and meta-analysis performed with the primary aim of evaluating the
incidence and severity of infectious complications in MDS and AML patients treated with HMAs. Several limitations of our analysis merit consideration. The included trials were highly heterogeneous regarding the definitions of MDS and AML according to the blast percentage cutoff, with different agents and regimens in the HMA arm, different chemotherapy regimens in the comparator arm, and different treatment lines (ie, first-line, maintenance). Consequently, we could not perform a highly informative subgroup analysis to assess MDS and AML patients separately. In addition, data regarding some types of infections in the individual trials were too scarce to analyze. Although we could assess important specific types of bacterial infections, such as sepsis, pneumonia, cellulitis, and bronchitis, data regarding bacterial pathogens were scarce and data regarding fungal and viral infections per se were not sufficient. As previously stated, no data were available regarding antibacterial or antifungal prophylaxis in the trials that could contribute to our understanding of their role in this setting. Using data from RCTs to report severe adverse events, such as infections, might be debatable, because severe events might be too rare to be captured by a design such as a RCT. Moreover, the recording of adverse events might be less rigorous and more biased than that of the primary efficacy outcomes in such studies. However, the infections in the included trials were not rare and were reported by all the trials.
Conclusion Although the use of HMAs increased the grade 3/4 infection rates compared with other common regimens, all-cause mortality remained lower owing to a favorable effect on the underlying disease. Most of the trials assessed high-risk MDS and AML patients in the first-line setting. Thus, our results and conclusions mainly apply to this subgroup of patients. Future RCTs should assess not only the mortality rate, an outcome that encompasses both efficacy and safety, but also the rate of adverse events such as infections, in patients treated with HMA. Furthermore, these trials should separately assess targeted populations such as elderly patients, those with recurrent and refractory disease, or patients after allogeneic hematopoietic transplantation, who have a greater risk of infection. In addition, trials should better report specific infectious events. Future RCTs evaluating antibiotic or antiviral prophylaxis, especially during the course of HMA therapy, are warranted.
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Hypomethylating Agents and Infections Clinical Practice Points The reported data regarding the effects of HMAs on the risk of
infections seem to be poorly documented and heterogeneous. We conducted a systematic review and meta-analysis of all RCTs
comparing HMA-containing regimens with any other regimen administered to patients with myeloid neoplasms to assess the risk of infection. Nine trials reported from 2002 to 2016 that had randomized 2184 patients were included; most of the trials assessed high-risk MDS and AML patients in the first-line setting. HMAs were associated with an increase in grade 3/4 infections versus the comparator (RR, 1.30; 95% CI, 1.02-1.66). In addition, the rate of FUO events and neutropenia was increased (RR, 1.48; 95% CI, 1.15-1.92; and RR, 1.48; 95% CI, 1.22-1.78, respectively). HMA usage reduced all-cause mortality (RR, 0.74; 95% CI, 0.66-0.88). Although treatment with HMAs was associated with an increase in grade 3/4 infections compared with best supportive care in mortality, it is possible that the detrimental rate of infectious complications during the treatment period was counterbalanced by the favorable effect of HMAs on disease-related mortality. Thus, the overall survival advantage of HMAs was achieved despite the greater toxicity profile of these drugs. Future RCTs should better document the infections and specific types of infections. By addressing the issue of infections, this could help resolve the question of prophylaxis and might also provide data regarding the role of further improvements in supportive care.
Disclosure The authors have stated that they have no conflicts of interest.
Supplemental Data The supplemental data accompanying this article can be found in the online version at https://doi.org/10.1016/j.clml.2018.05.017.
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Liat Shargian-Alon et al Supplemental Table 1 Risk of Bias Assessment
Study Silverman et al,8 2002 (CALGB) Fenaux et al,2 2009 (AZA-001) Lübbert et al,23 2011 Kantarjian et al,22 2006 Kantarjian et al,3 2012 Dombert et al,4 2015 Mawad et al,24 2016 Müller-Tidow et al,25 2016 Oliva et al,26 2013
Sequence Generation (Selection Bias)
Allocation Concealment (Selection Bias)
Unclear Low risk
Unclear Low risk
Unclear Unclear Low risk Low risk Low risk Unclear Unclear
Low risk Low risk Unclear Low risk Unclear Unclear Unclear
Blinding
Incomplete Outcome Data (Attrition Bias)
Selective Outcome Reporting (Reporting Bias)
No No
Unclear/High risk Low risk
Unclear Low risk
No No No No Yes No No
Low risk Low risk Low risk Low risk Low risk Low risk Unclear
Low risk Unclear Low risk Low risk Low risk Low risk Unclear
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