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TABLE OF CONTENTS
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 6
OBJECTIVES.................................................................................................................................................................................................. 7
METHODS..................................................................................................................................................................................................... 7
Figure 1.................................................................................................................................................................................................. 9
RESULTS........................................................................................................................................................................................................ 11
Figure 2.................................................................................................................................................................................................. 12
Figure 3.................................................................................................................................................................................................. 13
DISCUSSION.................................................................................................................................................................................................. 14
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 14
ACKNOWLEDGEMENTS................................................................................................................................................................................ 14
REFERENCES................................................................................................................................................................................................ 15
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 18
DATA AND ANALYSES.................................................................................................................................................................................... 24
Analysis 1.1. Comparison 1: Rituximab with steroid versus steroid, Outcome 1: Complete response at 12 months...................... 24
ADDITIONAL TABLES.................................................................................................................................................................................... 25
APPENDICES................................................................................................................................................................................................. 26
HISTORY........................................................................................................................................................................................................ 28
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 28
DECLARATIONS OF INTEREST..................................................................................................................................................................... 28
SOURCES OF SUPPORT............................................................................................................................................................................... 28
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 28
INDEX TERMS............................................................................................................................................................................................... 28
[Intervention Review]
1Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
Citation: Liu A-yP, Cheuk DKL. Disease-modifying treatments for primary autoimmune haemolytic anaemia. Cochrane Database of
Systematic Reviews 2021, Issue 3. Art. No.: CD012493. DOI: 10.1002/14651858.CD012493.pub2.
Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Primary autoimmune haemolytic anaemia (AIHA) is an autoantibody mediated condition characterised by a variable disease course.
A myriad of immunomodulatory agents have been employed but there is a paucity of evidence to support their use or compare their
effectiveness.
Objectives
To determine the effects of various disease-modifying treatment modalities in people with AHIHA.
Search methods
We searched MEDLINE (Ovid) (1946 to 2021), Embase (Ovid) (1974 to 2021), Latin American and Caribbean Health Sciences Literature
(LILACS) (1982 to 2021), and the Cochrane Library (CENTRAL). Clinical trial registries and relevant conference proceedings were also
reviewed. Records were included as of 7 March 2021. We did not impose any language restrictions.
Selection criteria
Randomised controlled trials (RCTs) comparing immunosuppressive or immunomodulatory treatments against no treatment, placebo, or
another immunosuppressive or immunomodulatory treatment, for people of all age with idiopathic AIHA.
Main results
Two trials were included, enrolling a total of 104 adult participants (96 randomised) with warm AIHA in the setting of tertiary referral centres,
both comparing the effectiveness between rituximab (375 mg/m2 weekly for four weeks, or 1000 mg for two doses two weeks apart) plus
glucocorticoid (prednisolone 1.5 or 1mg/kg/day with taper) and glucocorticoid monotherapy. The average age of participants in the two
trials were 67 and 71, respectively. One of the included studies had good methodological quality with low risk of bias, whereas the other
study had high risk of performance and detection bias due to lack of blinding. Compared with glucocorticoid alone, adding rituximab may
result in a large increase of complete response at 12 months (n = 96, risk ratio (RR) 2.13, 95% confidence interval (CI) 1.34 to 3.40, GRADE:
low-certainty evidence).
Limited data on partial haematological response were reported. The evidence is very uncertain about the effect of adding rituximab to
glucocorticoids on partial haematological response at 12 months (n = 32; study = 1; RR 3.00, 95% CI 0.13 to 68.57; GRADE very low-certainty
evidence).
RBC transfusion need at 12 months was reported in one study, with four participants (mean number of packed red cell units 4.0 ± 2.82)
from the rituximab group and five participants from the placebo (corticosteroid only) (mean number of packed red cell units 5.6 ± 4.15)
group requiring transfusion, indicating very uncertain evidence about the effect of adding rituximab to glucocorticoids (n = 32, RR 0.80,
95% CI 0.26 to 2.45, GRADE very low-certainty evidence). The other study did not report transfusion requirement at prespecified time points
but reported no difference in transfusion requirement between the two groups when comparing responders from enrolment to end of
response or to the end of study follow-up (34 units versus 30 units, median [range]: 0 [1 to 6] versus 0 [1 to 5], P = 0·81).
Overall survival and RFS rates at prespecified time-points were not explicitly reported in either study. Data on QOL were not available.
Authors' conclusions
Available literature on the effectiveness of immunomodulatory therapy for primary AIHA is restricted to comparison between rituximab
plus glucocorticoid and glucocorticoid alone, in patients with newly diagnosed warm AIHA, calling for need for additional studies. The
current result suggests that combinatory therapy with rituximab and glucocorticoid may increase the rate of complete haematological
response over glucocorticoid monotherapy.
Red blood cells carry oxygen to all parts of the body. In healthy people, red blood cells live about 120 days. In AIHA the immune system
does not work properly and destroys red blood cells faster than rhe body can make them. Primary AIHA is when a person does not have
another condition that caused their AIHA.
Primary AIHA develops differently in different people. People often need to have repeated blood transfusions to keep their red blood cell
levels normal. The disease may be life-threatening for some people.
The aim of this review is to find out what research studies tell us about the safety and effectiveness of treating primary AIHA with immune
modulating agents. Immune modulating agents change how your immune system works. They are not a cure, but they can slow AIHA.
But how well do these agents work? Are some safer than others? The answers are important to help doctors and patients make treatment
decisions based on evidence.
We looked at studies that were finished by 7 March 2021. We found two studies that looked at an immune modulating agent called
rituximab, which targets immune cells, called B-cells.
The studies compared two groups of adults with primary AIHA who were treated:
It’s important to know that these studies were very small, including a total of 96 people. And the design of one study had a problem that
may have affected the results.
· At 12 months after beginning treatment, rituximab and steroid appear to help more people recover from primary AIHA than steroid
alone. Researchers think the quality of this research finding is low. They think future research is likely to change these results.
· At six months after beginning treatment, there was no difference in recovery between the adults treated with rituximab and a steroid and
those treated with a steroid alone.
Rituximab and steroid may help more people have a complete recovery from newly diagnosed, primary warm AIHA than steroid alone.
Side effects appear to be about the same for both treatments. But more research is needed to know for sure.
Doctors offer other treatments for primary AIHA that may be helpful, but there is a lack of research about how well they work. For now,
based on the little information we have, the patient and doctor will have to carefully make decisions together about treating primary AIHA.
Library
Cochrane
Rituximab plus corticosteroid compared with corticosteroid (+/- placebo) for warm AIHA
Better health.
Informed decisions.
Trusted evidence.
Intervention: rituximab plus corticosteroid
Outcomes Illustrative comparative risks* (95% Relative effect No of Partici- Quality of the Comments
CI) (95% CI) pants evidence
(studies) (GRADE)
Assumed risk Corresponding
risk
Complete haematological 313 per 1000 667 per 1000 RR 2.13 (1.34 to 96 ⊕⊕⊝⊝
response at 12 months 3.40) (2) low#
Frequency of adverse See comment See comment Not estimable See comment See comment The included studies did not report
events at two, six and 12 frequency of adverse events at two, six
months an 12 months
Partial haematological re- 0 per 1000 63 per 1000 RR 3.00 (0.13 to 32 (1) ⊕⊝⊝⊝ Only reported by Michel 2017
sponse at 12 months 68.57) very low$
Relapse-free survival at six See comment See comment Not estimable See comment See comment The included studies did not report
and 12 months RFS at specific time points
RBC transfusion require- 313 per 1000 250 per 1000 RR 0.80 (0.26 to 32 (1) ⊕⊝⊝⊝ Only reported by Michel 2017. The in-
ment after treatment at 12 (mean number (mean number of 2.45) very low cluded studies did not report trans-
months of packed red packed red cell fusion requirement at two and six
units 4.0 ± 2.82) months.
4
Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Disease-modifying treatments for primary autoimmune haemolytic anaemia (Review)
cell units 5.6 ±
4.15)
Library
Cochrane
QOL as measured by val- See comment See comment Not estimable See comment See comment The included studies did not report
idated instruments at 12 QOL measures
months
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is
based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OS: overall survival; QoL: quality of life; RBC: red blood cell; RCT: randomised controlled trial; ; RFS: relapse-free survivalRR: Risk Ratio
Better health.
Informed decisions.
Trusted evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
#Evidence from RCT downgraded because of high risk of bias in study design and small sample size.
$Evidence from RCT downgraded because of imprecision in results and small sample size.
How the intervention might work idiopathic AIHA. As an uncommon condition, it remains uncertain
whether high-quality evidence exists to support any treatment
Immunosuppressive or immunomodulatory therapy interfere with regimen and what the more effective regimens are. This systematic
the immune destruction of RBCs. review will provide an evidence base for the selection of
immunomodulatory treatment that most likely benefits people
1. Glucocorticoids inhibit Fc receptor-mediated removal of
with idiopathic AIHA.
sensitised RBCs, and in the longer term reduce production of
autoantibodies (Zanella 2014).
OBJECTIVES
2. Splenectomy removes a major site of RBC destruction and
autoantibody production (Zanella 2014). To determine the effectiveness and safety of various disease-
3. Rituximab is an anti-CD20 monoclonal antibody given as modifying treatment modalities in people with autoimmune
four-weekly intravenous infusions. The antibody targets and haemolytic anaemia (AIHA).
depletes host B cells, which are responsible for the generation
of autoantibodies (Zecca 2003). Side effects include infusion METHODS
reactions, immunosuppression and hepatitis B reactivation.
Criteria for considering studies for this review
4. Alemtuzumab is an anti-CD52 monoclonal antibody targeting
CD52, which is an antigen expressed by mature lymphocytes. Types of studies
Lymphodepletion with alemtuzumab would effectively devoid
We included only randomised controlled trials (RCTs).
the host's capability of autoantibody generation (Cheung 2006).
Side effects include infusion reactions and immunosuppression. Types of participants
5. Cyclophosphamide is an alkylating agent with potent
myelosuppressive effect. Lymphocytes are highly sensitive We included male and female participants of all ages suffering from
to the drug and depletion would disrupt the autoimmunity idiopathic AIHA. Individuals with newly diagnosed, relapsing or
involved (Moyo 2002). Nausea, vomiting, alopecia, refractory disease; warm or cold AIHA were included. Studies on
myelosuppression, haemorrhagic cystitis, and gonadal toxicity people with secondary AIHA were excluded. There was no limitation
are potential adverse effects with the drug. on study settings.
6. Danazol is a semi-synthetic androgen with immunomodulatory Types of interventions
effect via decreasing IgG production and cell-bound IgG and
complement (Pignon 1993). Side effects include its androgenic We included trials evaluating specific, immunosuppressive or
effects and derangement in liver function. immunomodulatory treatments for AIHA, encompassing but
7. Cyclosporine is a calcineurin inhibitor that suppresses T helper not limited to: corticosteroids, intravenous immunoglobulin
cells activities, decreasing autoantibodies synthesis (Hershko (IVIG), rituximab, alemtuzumab, azathioprine, cyclosporine,
1990). Individuals should be monitored for hair growth, mycophenolate mofetil (MMF), plasma exchange and splenectomy.
gum hypertrophy, renal impairment, hypertension and rarely, We excluded trials of supportive treatment such as folic acid
neurological complications. supplement and transfusion alone. The control interventions could
be another specific treatment,supportive treatment alone, placebo
8. Mycophenolate mofetil (MMF) reversibly inhibits inosine
treatment, or no treatment. We also included trials comparing
monophosphate dehydrogenase and in turn inhibits purine
different dosing regimens of the same treatment.
synthesis required in the proliferation of B and T cells (Howard
2002). Adverse effects are gastrointestinal disturbances and Types of outcome measures
myelosuppression.
We did not use the outcomes listed below as criteria for study
9. Use of intravenous immunoglobulin (IVIG) in AIHA is based
inclusion.
on its effectiveness in immune thrombocytopenia, but its
efficacy with AIHA is more controversial. The mechanism of Primary outcomes
action is hypothesised to be through competitive inhibition of
autoantibody adsorption to patient blood cells, as well as by 1. Frequency of complete haematological response (complete
decreasing uptake of autoantibody-coated blood cells by the response (CR), defined as normalisation of haemoglobin
reticuloendothelial system through blockage of macrophage concentration, reticulocyte count, and indirect (or
Fc receptors (Flores 1993). Infusion reactions, fever, arthralgia, unconjugated] bilirubin level) at months two, six and 12.
haemolysis, and aseptic meningitis are possible complications. 2. Frequency of adverse events at two, six and 12 months.
10.Plasma exchange is usually reserved for people with fulminant
AIHA. The process effectively removes host circulating Secondary outcomes
immunoglobulins and complements that are responsible for 1. Frequency of partial haematological response (partial response
the immune destruction of RBCs (Smith 2003). Side effects (PR), defined as improvement in haemoglobin concentration) at
are attributed to the insertion of the apheresis catheter, and two, six and 12 months
the process of apheresis which may cause haemodynamic 2. RBC transfusion requirement after treatment (measured as units
disturbances, hypocalcaemia and coagulopathy. of RBCs transfused per month or millilitres (mL) per kg body
weight) at two, six and 12 months
Why it is important to do this review
3. Frequency of direct antiglobulin test (DAT) positivity after
Various immunosuppressive medications and other specific treatment at two, six and 12 months
treatment modalities are available for the management of 4. Overall survival at six and 12 months
5. Relapse-free survival (RFS) at six and 12 months 3. European Union Clinical Trial Register (http://
6. Frequency of relapse at six and 12 months www.clinicaltrialsregister.eu/)
7. Quality of life (QOL) as measured by validated instruments at 12
We also searched conference proceedings of the following scientific
months
meetings using the search terms " haemolytic anaemia" or
"hemolytic anemia" and "trials":
Search methods for identification of studies
Electronic searches 1. Annual Meeting of American Society of Haematology (ASH)
(2004 to 2021)
We searched MEDLINE (Ovid) (1946 to 2021) (Appendix 1), EMBASE
2. Annual Congress of the European Haematology Association
(Ovid) (1974 to 2021) (Appendix 2), LILACS (Latin American and
(EHA) (2006 to 2021).
Caribbean Health Sciences Literature) (1982 to 2021) (Appendix
3), and Cochrane Library (CENTRAL) (latest issue) (Appendix 4). We searched reference lists of relevant articles identified in all
The search strategies for the different electronic databases using the searches. We contacted authors of included studies to enquire
a combination of controlled vocabulary and text word terms are about additional studies. We did not apply any language restriction
shown in the appendices (Appendix 1; Appendix 2; Appendix 3; in our searches.
Appendix 4).
Data collection and analysis
We did not incorporate search in the China Journal Net database
(search date 7 March 2021) after submission of the protocol (Liu Selection of studies
2017) due to the extreme brevity of full-text articles published Both review authors independently examined identified studies to
which made interpretation of both quality and results impractical. select studies meeting the inclusion criteria. Discrepancies were
Searching other resources resolved by discussion. We reported the flow of studies as per the
PRISMA statement in a flow chart (Moher 2009), which included
We searched the following clinical trial registries on the Internet data on the number of records identified through database
using the search terms " haemolytic anaemia" or "hemolytic searching, number of additional records identified through other
anemia": sources, number of records after duplicates removed, number of
records screened, number of records excluded, number of full-
1. WHO International Clinical Trials Registry Platform (ICTRP) text articles examined for eligibility, number of full-text articles
(http://apps.who.int/trialsearch/) excluded with reasons, and numbers of studies included in
2. United States Clinical Trials Registry (https://clinicaltrials.gov/) qualitative and quantitative syntheses (Higgins 2011a); see Figure
1.
Data extraction and management the I2 statistic suggested by the Cochrane Handbook for Systematic
Reviews of Interventions (Deeks 2011) as follows:
Both review authors independently extracted data using a
standardised data collection form (Higgins 2011a). We extracted 1. 0% to 40%: may not be important;
data on study design and methods including study dates, location,
2. 30% to 60%: may represent moderate heterogeneity;
setting, type of study (parallel group or cross-over or other
designs), stratified randomisation variables, random sequence 3. 50% to 90%: may represent substantial heterogeneity;
generation, allocation concealment, and blinding methods. We 4. 75% to 100%: considerable heterogeneity.
extracted data on participant inclusion and exclusion criteria,
number of participants in each intervention and control group, We also used the Chi2 test of homogeneity to assess the strength of
and for each group, their demographics (age, sex, ethnicity), evidence regarding heterogeneity.
baseline laboratory parameters (haemoglobin level, reticulocyte
Assessment of reporting biases
count, bilirubin level, direct anti-globulin test (DAT) positivity),
baseline transfusion requirements, associated conditions and We planned to assess publication bias using a funnel plot
comorbidities, and previous intervention received (drug and (estimated differences in treatment effects against their standard
regimen). We extracted data on details of intervention for each errors) in case 10 or more studies are identified for a given outcome,
group, and dropouts of each group and follow-up duration. We although this was not probable as only two studies were included
extracted outcomes measured in each study that matched with our (Sterne 2011).
pre-specified outcomes. No transformation of reported data was
required. We also extracted data on funding source and declaration Data synthesis
of interests. Data were entered into Review Manager software With the assumption that the different studies would likely be
(RevMan 5.3) (RevMan 2014) by one review author (APYL) and estimating different, yet related, intervention effects, we used the
checked by the other review author (DKLC). random-effects model for meta-analysis to obtain the mean effect
Assessment of risk of bias in included studies across studies(Deeks 2011). In case different interventions are
identified in future updates, they will be summarised individually.
Both review authors independently assessed the risk of bias of Analysis was performed using Cochrane's statistical package
included studies with the Cochrane 'Risk of bias' tool (Higgins Review Manager (RevMan 5.3) (RevMan 2014).
2011b). The following domains were assessed: random sequence
generation, allocation concealment, blinding of participants, study Subgroup analysis and investigation of heterogeneity
personnel and outcome assessors, incomplete outcome data, We planned to perform subgroup analyses (Deeks 2011) for the
selective reporting, and other sources of bias. For each domain following subgroups as they may have different prognosis and
for each study, the risk of bias was graded as "high", "unclear" or response to treatment (different size of treatment effect).
"low" according to the criteria stated in the Cochrane Handbook
for Systematic Reviews of Interventions. Discrepancies between the 1. Different age groups (children < 18 years or adults >= 18 years).
review authors were resolved by discussion. 2. With or without associated conditions (such as
Measures of treatment effect thrombocytopenia or neutropenia, or other autoimmune
phenomena).
We estimated risk ratio (RR) with 95% confidence intervals (CI) for 3. Different degrees of anaemia (transfusion dependent or
dichotomous outcomes. We used hazard ratio (HR) with 95% CI for transfusion independent).
time-to-event outcomes and planned to use mean difference (MD)
4. Newly diagnosed versus refractory disease.
with 95% CIs for continuous outcomes. For continuous outcomes
using different scales (e.g. quality of life (QoL) data), we planned to We also planned to assess subgroup differences by examining
use standardised mean difference (SMD) with 95% CI (Deeks 2011). the I2 statistic and performing a Chi2 test for homogeneity
across subgroup results. In case heterogeneity was present, we
Unit of analysis issues
planned to investigate the probable reasons for heterogeneity
We planned to use appropriate unit of analysis for cluster- by examining the distribution of important participant factors
randomised trials and cross-over trials according to the Cochrane between trials (age, associated conditions, degrees of anaemia,
Handbook for Systematic Reviews of Interventions (Deeks 2011), if and previous interventions) and trial factors (randomisation
these types of trials had been found and included. concealment, blinding, dropouts, intervention regimens).
Dealing with missing data As the above are currently not applicable based on the studies
included, we will perform the above analyses in future updates as
We requested missing data from the corresponding authors of
necessary.
included studies (Birgens 2013; Michel 2017) and nonetheless failed
to acquire additional information with no response received. We Sensitivity analysis
included all participants with intention-to-treat (ITT) analyses.
We planned to perform sensitivity analysis to assess the impact
Assessment of heterogeneity of excluding studies with high risk of bias (Deeks 2011). We also
planned to perform sensitivity analysis to assess the impact of
We used the I2 statistic to evaluate the degree of heterogeneity excluding studies with significant amount (> 30%) of missing
of treatment effects. We followed the guide on interpretation of outcome data.
Summary of findings and assessment of the certainty of the In the study by Birgens and colleagues (Birgens 2013), 65
evidence participants with newly diagnosed warm AIHA (steroid use for
<1 week was allowed) were recruited in eight haematological
We produced a 'Summary of findings' table according to the
centres in Denmark between March 2005 and June 2012. With
recommendations in the Cochrane Handbook for Systematic
one patient withdrawing before randomisation (1:1 using pre-
Reviews of Interventions (Deeks 2011). The pre-defined outcomes
coded envelopes), 32 were randomised to receive rituximab plus
included were:
glucocorticoid (12 females [37.5%], median age [range] = 65 [41-89])
• frequency of complete haematological response (defined and 32 to receive glucocorticoid monotherapy (15 females [46.9%],
as normalisation of haemoglobin concentration, reticulocyte median age [range] = 67 [35-90]. All participants received oral
count, and indirect bilirubin level) at months two, six and 12 prednisolone 1·5 mg/kg/day for two weeks followed by tapering
months; according to this schedule: 0·75 mg/kg/day for one week (week
three), thereafter 0·5 mg/kg/day for one week (week four), followed
• frequency of adverse events at two, six and 12 months;
by a gradual reduction over the next four to eight weeks to
• overall survival at six and 12 months; the lowest dose that was effective in maintaining a normal
• relapse-free survival at six and 12 months; haemoglobin level. In the group allocated to a combination of
• RBC transfusion requirement after treatment (measured as units prednisolone and rituximab, rituximab was given at a dosage
of red cells transfused per month or mL per kg body weight) at of 375 mg/m2 as an intravenous infusion once a week for
two, six and 12 months; and four weeks. The primary objective of the study was to analyse
• QOL as measured by validated instruments at 12 months. differences in treatment responses between the two groups.
Responses were evaluated at three, six and 12 months after
These tables summarised the results for the prioritised pre-defined treatment was initiated. Complete response (CR) was defined as
outcomes, namely: normalisation in haemoglobin concentration without any ongoing
immunosuppressive treatment and without any biochemical signs
• complete haematological response at 12 months; of haemolytic activity. Partial response (PR) was defined as being
• frequency of adverse events at two, six and 12 months; similar to CR but requiring continued low-dose prednisolone (<
• partial haematological response at 12 months; 10 mg/day), or appearing as compensated haemolytic anaemia
• overall survival at six and 12 months; entailing a stable, acceptable haemoglobin level without any need
of treatment except < 10 mg/day prednisone. Secondary objectives
• relapse-free survival at six and 12 months,
were to evaluate differences in relapse-free survival (RFS), red
• RBC transfusion requirement after treatment at 12 months; and blood cell transfusion requirement after treatment, the need for
• QOL as measured by validated instruments at 12 months; splenectomy, and safety profiles associated with the treatments up
to 12 months after enrolment. This trial was investigator-initiated
and provide grading of the certainty of evidence for each outcome but was supported in part by research funding from Roche A/S,
according to the GRADE system as recommended by the Cochrane Denmark. The design of the study, protocol writing, interpretation
Handbook for Systematic Reviews of Interventions (GRADEpro 2008; of the data, and preparation of the manuscript were conducted
Lefebvre 2011; Schünemann 2011). without any interference from Roche.
RESULTS In the study by Michel and colleagues (Michel 2017), 39 participants
with newly diagnosed warm AIHA (steroid use for < 6 weeks
Description of studies was allowed) were screened from 13 centres in France from
Results of the search 2011 to 2015. Thirty-two participants were randomised to receive
rituximab (n = 16) or placebo (n = 16) (17 females [53%], mean
We obtained a total of 11980 results from the electronic search of age at inclusion 71 ± 16 years) on top of glucocorticoid therapy
the databases, after de-duplication, 10610 articles remained. We in a double-blind manner. At inclusion, all participants received
screened the titles and abstracts of these against the inclusion and oral prednisone at a daily dose of 1 mg/kg for two weeks, and
exclusion criteria for study selection and excluded 10564 references then tapered according to a pre-defined recommended reduction
based on titles or abstracts alone. We obtained the full texts of scheme. Besides prednisone, randomised participants received
the remaining 46 articles and assessed for eligibility. Two studies two infusions of rituximab or placebo at a fixed dose of 1000
fulfilled the inclusion criteria and were included in the review mg two weeks apart. The primary endpoint was overall response
(Birgens 2013, Michel 2017), with one secondary citation to an rate (CR + PR) in anITT analysis at one year. CR in this study was
included study also identified (Michel 2015). The flow of records is defined as a haemoglobin (Hb) level ≥ 11 g/dL (women) or ≥ 12 g/
summarised in Figure 1. dL (men) without features of ongoing haemolysis (including normal
haptoglobin level), without any ongoing treatment for warm AIHA
Included studies
on two different occasions four weeks apart in the absence of any
Two studies were included (Birgens 2013, Michel 2017) with details recent transfusion. PR was defined as Hb level ≥ 10g/dL with at least
summarised in the ‘Characteristics of included studies’ table. Both a 2 g increase from baseline (i.e. at warm AIHA diagnosis) without
trials were multi-centre, Phase III randomised controlled trials any other treatment than prednisone given at a daily dose 10 mg
(RCTs) comparing the efficacy of rituximab plus glucocorticoid or recent transfusion. Secondary objectives were PR, cumulative
versus glucocorticoid monotherapy in adults with warm, primary, dose of steroids, and number of transfusions and hospitalisations
autoimmune haemolytic anaemia (AIHA). at one year and incidence and severity of adverse events in both
groups and CR/PR at two years. This study was promoted by the
Direction de la Recherche Clinique, Assistance Publique-Hôpitaux
Disease-modifying treatments for primary autoimmune haemolytic anaemia (Review) 11
Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
de Paris and supported by the Etablissement Français du Sang and 2015; Rossi 2018; Roth 2016; Shah 2013; Wang 2005; Williams 2020;
by Roche. Yang 2020; Zaja 2002; Zanella 2013; Zecca 2003). Two ongoing RCTs
on the use of fostamatinib (oral spleen tyrosine kinase inhibitor)
The median observation time was not reported in either study. and M281 (human, anti-neonatal Fc receptor antibody) respectively
for warm AIHA are identified but excluded from the current analysis
Excluded studies
(Cooper 2020; NCT04119050).
The current review excluded 41 studies as they were not RCTs in
design (Abdwani 2009; Almomen 2013; Aqrabawi 2012; Aqrabawi Risk of bias in included studies
2013; Barcellini 2012; Barcellini 2013; Bartko 2017; Bartko 2018; One of the two included studies (Michel 2017) had good
Berentsen 2017; Berentsen 2017a; Choudhry 1996; Crickx 2019; methodological quality with low risk of bias in all areas; the other
Dierickx 2015; Heidel 2007; Hill 2018; Jager 2017; Jilma 2016; study (Birgens 2013) had high risk of performance and detection
Lehrer-Graiwer 2016; Li 2020; Liu 2001; Mehmood 2016; Miano 2016; bias due to lack of blinding, but otherwise low risk in other areas.
Motto 2002; Moyo 2002; Osterborg 2009; Panicker 2016; Panicker These findings are summarised in the table Characteristics of
2016a; Rai 2018; Raschetti 2012; Reynaud 2015; Rice 2012; Rodrigo included studies and Figure 2.
Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.
Figure 3. Forest plot of comparison: 1 Rituximab with steroid versus steroid, outcome: 1.1 Complete
haematological response at 12 months.
Frequency of adverse events at two, six and 12 months. Birgens and colleagues (Birgens 2013) did not report transfusion
requirement at the predefined time points, but described no
Both studies (Birgens 2013, Michel 2017) did not report adverse difference in transfusion requirement between the rituximab/
effects at the specified time points. corticosteroid and the corticosteroid monotherapy group when
comparing responders (CR and PR) from enrolment to end of
Cumulative adverse effects and serious adverse events with a
response or to the end of study follow-up (34 units versus 30 units,
non-fatal or fatal outcome did not differ between the two groups
median [range]: 0 [1 to 6] versus 0 [1 to 5], P = 0·81).
in the study by Birgens and colleagues (Birgens 2013, Table 2).
The study by Michel and colleagues (Michel 2017) described no Frequency of DAT positivity after treatment at two, six and 12
post-infusion reactions in both groups, but four and 10 episodes months
of severe adverse events in participants who received rituximab
with corticosteroid and corticosteroid alone, respectively (Table 3). Study by Michel and colleagues (Michel 2017) reported positive DAT
Reduced gammaglobulin level was also reported to be associated at 12 months in 5/13 (38%) participants who received rituximab
with rituximab treatment (comparing mean level at inclusion 10.8 and corticosteroid and compared to 8/10 (80%) participants who
± 4.0 g/L versus that at 12 months 8.1 ± 2.2 g/L for rituximab group), received placebo (corticosteroid only). DAT positivity was not
although no difference was observed in evaluable participants from reported by study by Birgensand colleagues (Birgens 2013).
either group at 12 months (P = 0.499).
Overall survival at six and 12 months
Secondary outcome
Overall survival at these specific time points was not reported
Frequency of partial haematological response (defined as by either study. Michel and colleagues (Michel 2017) reported the
improvement in haemoglobin concentration) at two, six and 12 death of six participants treated with corticosteroid only versus
months none with combination of rituximab and corticosteroid at two years
(P = 0.017).
Both trials (Birgens 2013, Michel 2017) did not report complete
response rate at two months (Table 4). One study (Birgens 2013) Relapse-free survival (RFS) at six and 12 months
reported six-month partial response in figure format, but the
corresponding data at 12 months were not reported. The other RFS rates at six and 12 months was not explicitly reported by either
study (Michel 2017) did not report response at six months. The study. In the study byBirgens and colleagues Birgens 2013), RFS in
evidence is very uncertain about the effect of adding rituximab to all responders was higher in the participants receiving rituximab
glucocorticoids on partial haematological response reported at six and prednisolone combined (P = 0·02) corresponding to a hazard
months (n = 64; study = 1; RR 0.80, 95% CI 0.24 to 2.71; RR and ratio (HR) of 0·33 (95% Cl 0·12 to 0·88; RR and CI calculated by review
CI calculated by review authors; GRADE very low certainty) or 12 authors). In the study by Michel and colleagues (Michel 2017), RFS
months (n = 32; study = 1; RR 3.00, 95% CI 0.13 to 68.57; GRADE very was better for the rituximab group (P = 0.023).
low certainty).
Frequency of relapse at six and 12 months
RBC transfusion requirement after treatment (measured as
units of RBCs transfused per month or millilitres (mL) per kg Frequency of relapse at six an 12 months was not reported in
body weight) at two, six and 12 months either study. Birgens 2013 reported that at 36 months, about 70%
of the participants who showed either CR or PR were still relapse-
Study by Michel and colleagues (Michel 2017) reported RBC free in the combination treatment group, versus about 45% in the
transfusion received by participants up to 12 months, with four prednisolone monotherapy group (P = 0.02).
participants (mean number of packed red cell units 4.0 ± 2.82)
from the rituximab group and five participants from the placebo Quality of life (QOL) as measured by validated instruments at 12
(corticosteroid only) (mean number of packed red cell units 5.6 ± months
4.15) group requiring transfusion, the evidence is very uncertain
about the effect of adding rituximab to glucocorticoids (n = QOL measures were not reported by either included study.
32, RR 0.80, 95% CI 0.26 to 2.45, GRADE very low certainty).
REFERENCES
References to studies included in this review Bartko 2018 {published data only}
Birgens 2013 {published data only} Bartko J, Schoergenhofer C, Schwameis M, Firbas C, Beliveau M,
Chang C, et al. A randomized, first-in-human, healthy volunteer
Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH,
trial of sutimlimab, a humanized antibody for the specific
Nielsen OJ, Kjeldsen L, et al. A phase III randomized trial
inhibition of the classical complement pathway. Clinical
comparing glucocorticoid monotherapy versus glucocorticoid
Pharmacology and Therapeutics 2018;104(4):655-63.
and rituximab in patients with autoimmune haemolytic
anaemia. British Journal of Haematology 2013;163(3):393-9. Berentsen 2017 {published data only}
Michel 2017 {published data only} Berentsen S, Randen U, Oksman M, Birgens H, Tvedt TH,
Dalgaard J, et al. Bendamustine plus rituximab for chronic cold
Michel M, Terriou L, Roudot-Thoraval F, Hamidou M, Ebbo M,
agglutinin disease: results of a Nordic prospective multicenter
Guenno GL, et al. A multi-centre randomized and double-blind
trial. Blood 2017;130(4):537-41.
controlled trial of rituximab for warm autoimune hemolytic
anemia in adults. In: Blood. Vol. 126. 2015:3338. Berentsen 2017a {published data only}
* Michel M, Terriou L, Roudot-Thoraval F, Hamidou M, Ebbo M, Berentsen S, Randen U, Oksman M, Birgens H, Tvedt TH,
Le Guenno G, et al. A randomized and double-blind controlled Dalgaard J, et al. Bendamustine and rituximab combination
trial evaluating the safety and efficacy of rituximab for warm therapy for cold agglutinin disease: results of a prospective
auto-immune hemolytic anemia in adults (the RAIHA study). Nordic trial. In: Haematologica. Vol. 102. 2017:241.
American Journal of Hematology 2017;92(1):23-7.
Choudhry 1996 {published data only}
Choudhry VP, Passi GR, Pati HP. Clinico-hematological
References to studies excluded from this review spectrum of auto-immune hemolytic anemia: an Indian
experience. Journal of the Association of Physicians of India
Abdwani 2009 {published data only} 1996;44(2):112-4.
Abdwani R, Mani R. Anti-CD20 monoclonal antibody in acute life
threatening haemolytic anaemia complicating childhood onset Crickx 2019 {published data only}
SLE. Lupus 2009;18(5):460-4. Crickx E, Poullot E, Moulis G, Goulabchand R, Fieschi C,
Galicier L, et al. Clinical spectrum, evolution, and
Almomen 2013 {published data only} management of autoimmune cytopenias associated with
Almomen A, Aleem A, Hasanato R, Al Saleh K, Anjum F. Efficacy angioimmunoblastic T-cell lymphoma. European Journal of
of rituximab in autoimmune hemolytic anemia. Haematologica Haematology 2019;103(1):35-42.
2013;1:706.
Dierickx 2015 {published data only}
Aqrabawi 2012 {published data only} Dierickx D, Kentos A, Delannoy A. The role of rituximab in adults
Aqrabawi HE. 762 The use of pentaglobulin in neonatal immune with warm antibody autoimmune hemolytic anemia. Blood
hemolytic anaemia. In: Archives of Disease in Childhood. Vol. 2015;125(21):3223-9.
97. 2012:A219-20.
Heidel 2007 {published data only}
Aqrabawi 2013 {published data only} Heidel F, Lipka DB, von Auer C, Huber C, Scharrer I, Hess G.
Aqrabawi HE. The use of pentaglobulin in neonatal immune Addition of rituximab to standard therapy improves
hemolytic anaemia. Rawal Medical Journal 2013;38(1):64-5. response rate and progression-free survival in relapsed
or refractory thrombotic thrombocytopenic purpura and
Barcellini 2012 {published data only} autoimmune haemolytic anaemia. Thrombosis & Haemostasis
Barcellini W, Zaja F, Zaninoni A, Imperiali FG, Battista ML, 2007;97(2):228-33.
Di Bona E, et al. Low-dose rituximab in adult patients with
idiopathic autoimmune hemolytic anemia: clinical efficacy and Hill 2018 {published data only}
biologic studies. Blood 2012;119(16):3691-7. Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology-
American Society of Hematology Education Program
Barcellini 2013 {published data only} 2018;2018(1):382-9.
Barcellini W, Zaja F, Zaninoni A, Imperiali FG, Di Bona E,
Fattizzo B, et al. Sustained response to low-dose rituximab in Jager 2017 {published data only}
idiopathic autoimmune hemolytic anemia. European Journal of Jager U. AGMT-AIHA-Reg: PATIENT REGISTRY Autoimmune
Haematology 2013;91(6):546-51. Hemolytic Anemia (AIHA) with corresponding biobank. In:
Memo - Magazine of European Medical Oncology. Vol. 10.
Bartko 2017 {published data only} 2017:S41-2.
Bartko J, Derhaschnig U, Gilbert J, Panicker S, D'Sa S,
Jager U, et al. Safety and efficacy of the C1s complement Jilma 2016 {published data only}
inhibitor TNT009 in a first-inhuman trial. Clinical Therapeutics Jilma B, Gilbert JC, Panicker S, Parry GC, Fillitz M, Thomas S,
2017;39(8):e6-7. et al. Chronic inhibition of complement C1s By TNT009
Disease-modifying treatments for primary autoimmune haemolytic anaemia (Review) 15
Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
produces sustained, complete remission in patients with severe, Panicker 2016a {published data only}
transfusion-dependent cold agglutinin disease (CAD). Blood Panicker S, Parry GC, Fillitz M, Schenk T, Sillaber C, Bartko J, et
2016;128(22):2435. al. TNT009, a monoclonal antibody inhibitor of C1s, induces
a rapid and complete remission of anemia in primary cold
Lehrer-Graiwer 2016 {published data only}
agglutinin disease patients. Immunobiology 2016;221(10):117-1.
Lehrer-Graiwer J, Hemmaway C, Howard J, Telfer P, Layton M,
Awogbade M, et al. GBT440, a novel HBS polymerization Rai 2018 {published data only}
inhibitor, increases HB oxygen affinity and results in a rapid Rai MP, Lee EJ, Bussel JB. Rituximab (RITUX) maintenance
improvement in hemolysis and anemia. Haematologica infusions in immune thrombocytopenia (ITP) to prolong
2016;101 (Supplement 1)(Supp 1):125. remission following relapse after initial Ritux induction but
responded to a second course. In: Blood. Vol. 132. 2018:3753.
Li 2020 {published data only}
Li H, Ji J, Du Y, Huang Y, Gu H, Chen M, Wu R, Han B. Sirolimus Raschetti 2012 {published data only}
is effective for primary relapsed/refractory autoimmune Raschetti R, Caimmi D, Lambotte O, Rodiere M, Jeziorski E.
cytopenia: a multicenter study. Experimental Hematology Severe refractory auto-immune hemolytic anemia treated with
2020;89:87-95. a chemiotherapy protocol. Allergy 2012;67(Supp 96):649.
Liu 2001 {published data only} Reynaud 2015 {published data only}
Liu H, Shao Z, Jing L. The effectiveness of cyclosporin A in Reynaud Q, Durieu I, Dutertre M, Ledochowski S, Durupt S,
the treatment of autoimmune hemolytic anemia and Evans Michallet AS, et al. Efficacy and safety of rituximab in auto-
syndrome. Zhonghua Xue Ye Xue Za Zhi [Chinese Journal of immune hemolytic anemia: a meta-analysis of 21 studies.
Hematology] 2001;22(11):581-3. Autoimmunity Reviews 2015;14(4):304-13.
Mehmood 2016 {published data only} Rice 2012 {published data only}
Mehmood T, Taylor M, Winters JL. Management of thrombotic Rice HE, Crary SE, Langer JC, Kemper AR. Comparative
microangiopathic hemolytic anemias with therapeutic plasma effectiveness of different types of splenectomy for children
exchange: when it works and when it does not. Hematology - with congenital hemolytic anemias. Journal of Pediatrics
Oncology Clinics of North America 2016;30(3):679-94. 2012;160(4):684-9.
Miano 2016 {published data only} Rodrigo 2015 {published data only}
Miano, M, Ramenghi, U, Russo, G, Rubert, L, Barone, A, Tucci, Rodrigo C, Rajapakse S, Gooneratne L. Rituximab in the
F, et al. Mycophenolate mofetil for the treatment of children treatment of autoimmune haemolytic anaemia. British Journal
with immune thrombocytopenia and Evans syndrome. of Clinical Pharmacology 2015;79(5):709-19.
A retrospective data review from the Italian association
of paediatric haematology/oncology. British Journal of Rossi 2018 {published data only}
Haematology 2016;175:490-5. Rossi G, Gramegna D, Paoloni F, Fattizzo B, Binda F, D'Adda M, et
al. Short course of bortezomib in anemic patients with relapsed
Motto 2002 {published data only}
cold agglutinin disease: a phase 2 prospective GIMEMA study.
Motto DG, Williams JA, Boxer LA. Rituximab for refractory Blood 2018;132(5):547-50.
childhood autoimmune hemolytic anemia. Israel Medical
Association Journal 2002;4(11):1006-8. Roth 2016 {published data only}
Roth A, Bommer M, Huttmann A, Herich-Terhurne D,
Moyo 2002 {published data only}
Kuklik N, Rekowski J, et al. Eculizumab in cold agglutinin
Moyo VM, Smith D, Brodsky I, Crilley P, Jones RJ, Brodsky RA. disease (DECADE): an open-label, prospective,
High-dose cyclophosphamide for refractory autoimmune bicentric, nonrandomized phase 2 trial. Blood Advances
hemolytic anemia. Blood 2002;100(2):704-6. 2018;2(19):2543-9.
Osterborg 2009 {published data only} Shah 2013 {published data only}
Osterborg A, Karlsson C, Lundin J. Alemtuzumab to treat Shah B. Darbepoetin in cancer related anemia. In: Indian
refractory autoimmune hemolytic anemia or thrombocytopenia Journal of Hematology and Blood Transfusion. Vol. 29.
in chronic lymphocytic leukemia. Current Hematologic 2013:270-1.
Malignancy Reports 2009;4(1):47-53.
Wang 2005 {published data only}
Panicker 2016 {published data only}
Wang SW, Cheng TT. Systemic lupus erythematosus with
Panicker S, Drucker C, Hussain S, Parry GC, Gilbert JC, Jilma B, refractory hemolytic anemia effectively treated with cyclosporin
et al. TNT009 prevents erythrocyte c3 fragment opsonization A: a case report. Lupus 2005;14(6):483-5.
and rescues reticulocytes from destruction in patients with cold
agglutinin disease. In: Blood. Vol. 128. 2016:94. Williams 2020 {published data only}
Williams O, Bhat R, Badawy SM. Sirolimus for treatment of
refractory primary warm autoimmune hemolytic anemia in
children. Blood Cells Molecules & Diseases 2020;83:102427.
Disease-modifying treatments for primary autoimmune haemolytic anaemia (Review) 16
Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
Yang 2020 {published data only} refractory to corticosteroids, splenectomy and rituximab.
Yang N, Wang B, Gao F, Huang XY, Zhao XL, Wang YY, Zhang XP. Haematologica 2006;91(Supp 5):ECR 13.
Evaluation of Efficacy and Safety of Blood Transfusion
Clark 1992
and Hormone Therapy in 40 Patients with Autoimmune
Hemolytic Anemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi Clark JA, Tanley PC, Wallas CH. Evaluation of patients with
2020;28(4):1307-1311. positive direct antiglobulin tests and nonreactive eluates
discovered during pretransfusion testing. Immunohematology
Zaja 2002 {published data only} 1992;8(1):9-12.
Zaja F, Iacona I, Masolini P, Russo D, Sperotto A, Prosdocimo S,
Davidson 2001
et al. B-cell depletion with rituximab as treatment for
immune hemolytic anemia and chronic thrombocytopenia. Davidson RN, Wall RA. Prevention and management of
Haematologica 2002;87(2):189-95. infections in patients without a spleen. Clinical Microbiology and
Infection 2001;7(12):657-60.
Zanella 2013 {published data only}
Deeks 2011
Zanella A, Barcellini W. Autoimmune hemolytic anemia. In:
Haematologica. Vol. 98. 2013:252-5. Deeks JJ, Higgins JP, Altman DG, editor(s). Chapter 9: Analysing
data and undertaking meta-analyses. In: Higgins JP, Green
Zecca 2003 {published data only} S (editors). Cochrane Handbook for Systematic Reviews
Zecca M, Nobili B, Ramenghi U, Perrotta S, Amendola G, of Interventions Version 5.1.0 (updated March 2011). The
Rosito P, et al. Rituximab for the treatment of refractory Cochrane Collaboration, 2011. Available from www.cochrane-
autoimmune hemolytic anemia in children. Blood handbook.org.
2003;101(10):3857-61.
Eaton 2007
Eaton WW, Rose NR, Kalaydjian A, Pedersen MG, Mortensen PB.
References to ongoing studies Epidemiology of autoimmune diseases in Denmark. Journal of
Autoimmunity 2007;29(1):1-9.
Cooper 2020 {published data only}
Cooper N, Numerof RP, Tong S, Kuter DJ. Fostamatinib for the Flores 1993
treatment of warm antibody autoimmune hemolytic anemia Flores G, Cunningham-Rundles C, Newland AC, Bussel JB.
(WAIHA): A phase 3, randomized, double-blind, placebo- Efficacy of intravenous immunoglobulin in the treatment of
controlled, global study. Blood 2020;136(Supp 1):1-3. autoimmune hemolytic anemia; results in 73 patients. American
Journal of Hematology 1993;44(4):237-42.
NCT04119050 {published data only}
Efficacy and Safety of M281 in Adults With Warm Autoimmune Gehrs 2002
Hemolytic Anemia. clinicaltrials.gov/show/NCT04119050. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia.
American Journal of Hematology 2002;69:258-71. [DOI: 10.1002/
ajh.10062]
Additional references
Aladjidi 2011 GRADEpro 2008 [Computer program]
Aladjidi N, Leverger G, Leblanc T, Picat MQ, Michel G, Bertrand Y, GRADE Working Group GRADEpro. Version 3.2 for Windows.
et al. New insights into childhood autoimmune hemolytic Brozek JL, Oxman A, Shünneman H. GRADE Working Group,
anemia: a French national observational study of 265 children. 2008.
Haematologica 2011;96(5):655-63.
Hershko 1990
Barcellini 2014 Hershko C, Sonnenblick M, Ashkenazi J. Control of steroid-
Barcellini W, Fattizzo B, Zaninoni A, Radice T, Nichele I, Di resistant autoimmune haemolytic anemia by cyclosporine.
Bona E, et al. Clinical heterogeneity and predictors of outcome British Journal of Haematology 1990;76:436-7.
in primary autoimmune hemolytic anemia: a GIMEMA study of
Higgins 2011a
308 patients. Blood 2014;124(19):2930-6.
Higgins JP, Deeks JJ, editor(s). Chapter 7: Selecting studies
Barcellini 2018 and collecting data. In: Higgins JP, Green S (editors). Cochrane
Barcellini W, Zaninoni A, Fattizzo B, Giannotta JA, Lunghi M, Handbook for Systematic Reviews of Interventions Version
Ferrari A, et al. Predictors of refractoriness to therapy and 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011.
healthcare resource utilization in 378 patients with primary Available from www.cochrane-handbook.org.
autoimmune hemolytic anemia from eight Italian reference
Higgins 2011b
centers. American Journal of Hematology 2018;93:E243-6.
Higgins JP, Altman DG, Sterne JA, editor(s). Chapter 8:
Cheung 2006 Assessing risk of bias in included studies. In: Higgins JP, Green
Cheung WW, Hwang GY, Tse E, Kwong YL. Alemtuzumab S (editors). Cochrane Handbook for Systematic Reviews
induced complete remission of autoimmune hemolytic anemia of Interventions Version 5.1.0 (updated March 2011). The
Cochrane Collaboration, 2011. Available from www.cochrane- RevMan 2014 [Computer program]
handbook.org. The Nordic Cochrane Centre, The Cochrane Collaboration
Review Manager (RevMan). Version 5.3. Copenhagen: The
Howard 2002
Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Howard J, Hoffbrand AV, Prentice HG, Mehta A. Mycophenolate
mofetil for the treatment of refractory autoimmune haemolytic Sankaran 2016
anemia and autoimmune thrombocytopenic purpura. British Sankaran J, Rodriguez V, Jacob EK, Kreuter JD, Go RS.
Journal of Haematology 2002;117:712-5. Autoimmune hemolytic anemia in children: Mayo Clinic
Experience. Journal of Pediatric Hematology/Oncology
Johnson 2007
2016;38(3):e120-4.
Johnson ST, Fueger JT, Gottschall JL. One center's experience:
the serology and drugs associated with drug-induced Schünemann 2011
immune hemolytic anemia—a new paradigm. Transfusion Schünemann HJ, Oxman AD, Vist GE, Higgins JP, Deeks JJ,
2007;47(4):697-702. Glasziou P, et al. Chapter 12: Interpreting results and drawing
conclusions. In: Higgins JP, Green S (editors). Cochrane
Katkhouda 1998
Handbook for Systematic Reviews of Interventions Version
Katkhouda N, Hurwitz MB, Rivera RT, Chandra M, Waldrep DJ, 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011.
Gugenheim J, et al. Laparoscopic splenectomy: outcome Available from www-cochrane-handbook.org.
and efficacy in 103 consecutive patients. Annals of Surgery
1998;228(4):568-78. [PMID: 9790346] Smith 2003
Smith JW, Weinstein R, Hillyer KL. Therapeutic apheresis: a
Klein 2010
summary of current indication categories endorsed by the
Klein NP, Ray P, Carpenter D, Hansen J, Lewis E, Fireman B, et al. AABB and the American Society for Apheresis. Transfusion
Rates of autoimmune diseases in Kaiser Permanente for use in 2003;43:820-2.
vaccine adverse event safety studies. Vaccine 2010;28(4):1062-8.
Sokol 1992
Lefebvre 2011
Sokol RJ, Booker DJ, Stamps R. The pathology of autoimmune
Lefebvre C, Manheimer E, Glanville J, editor(s). Chapter 6: haemolytic anaemia. Journal of Clinical Pathology
Searching for studies. In Higgins JP, Green S (editors). Cochrane 1992;45(12):1047.
Handbook for Systematic Reviews of Interventions Version
5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Sterne 2011
Available from www.cochrane-handbook.org. Sterne JA, Egger M, Moher D, editor(s). Chapter 10: Addressing
reporting biases. In Higgins JP, Green S (editors). Cochrane
Liu 2017
Handbook for Systematic Reviews of Intervention. Version
Liu AP, Cheuk DK. Disease-modifying treatments for primary 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011.
autoimmune haemolytic anaemia. Cochrane Database of Available from www.cochrane-handbook.org.
Systematic Reviews 2017, Issue 1. Art. No: CD012493. [DOI:
10.1002/14651858.CD012493] Zanella 2014
Zanella A, Barcellini W. Treatment of autoimmune hemolytic
Moher 2009
anemias. Haematologica 2014;99:1547-54.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA
statement. Annals of Internal Medicine 2009;151(4):264-9. * Indicates the major publication for the study
Pignon 1993
Pignon JM, Poirson E, Rochant H. Danazol in autoimmune
haemolytic anaemia. British Journal of Haematology
1993;83:343-5.
CHARACTERISTICS OF STUDIES
Birgens 2013
Study characteristics
Participants People treated at eight haematological centres in Denmark participated in the study.
Interventions Eligible participants were randomised 1:1 by use of pre-coded envelopes. All participants received
prednisolone 1·5 mg/kg/day for 2 weeks followed by tapering according to this schedule: 0·75 mg/kg/
day for 1 week (week 3), thereafter 0·5 mg/kg/day for 1 week (week 4), followed by a gradual reduction
over the next 4–8 weeks to the lowest dose that was effective in maintaining a normal Hb level.
In the group allocated to a combination of prednisolone and rituximab, the participants received pred-
nisolone at the same dose and schedule as in the monotherapy group and were given rituximab at a
dosage of 375 mg/m2 as an intravenous infusion once a week for 4 weeks. All participants received
oral folic acid 5 mg/day, and those given a rituximab infusion also received premedication with aceta-
minophen 1 g and clemastine 2 mg intravenously 30 to 60 minutes before the infusion.
Outcomes The participants underwent a full clinical examination and complete blood counts including haemolyt-
ic parameters (Hb, reticulocyte count, total bilirubin, lactate dehydrogenase, and haptoglobin) at en-
rolment, on days +7, +14, +21, +28, +42, +56, +70 and +84, then monthly until month 6, and finally, every
third month until the end of follow-up. This applied to all participants until they showed a lack of re-
sponse necessitating either a switch to some other immunosuppressive treatment or splenectomy, or
they relapsed after an initial positive response. The minimum and maximum follow-up times after initi-
ating treatment were 12 and 48 months, respectively.
The primary objective of the study was to analyse differences in treatment responses between the two
groups. Responses were evaluated at 3, 6 and 12 months after treatment was initiated. Complete re-
sponse (CR) was defined as normalisation in Hb concentration without any ongoing immunosuppres-
sive treatment and without any biochemical signs of haemolytic activity. Partial response (PR) was de-
fined as being similar to CR but requiring continued low-dose prednisolone (<10 mg/day), or appearing
as compensated haemolytic anaemia entailing a stable, acceptable Hb level without any need of treat-
ment except < 10 mg/day prednisone.
Secondary objectives of our investigation were to evaluate differences in relapse-free survival (RFS),
red blood cell transfusion requirement after treatment, the need for splenectomy, and safety profiles
associated with the treatments up to 12 months after enrolment.
Notes
Risk of bias
Incomplete outcome data Low risk All outcome data accounted for
(attrition bias)
All outcomes
Selective reporting (re- Low risk Results reported matching methodology listed on protocol
porting bias)
Other bias Low risk No other potential sources of bias were identified
Michel 2017
Study characteristics
Participants Inclusion criteria were (1) age ≥18 years at inclusion; (2) warm AIHA defined at time of diagnosis by
Hb level ≤10 g/dL with signs of haemolysis (at least haptoglobin level<4 mg/L), and a positive direct
antiglobulin test (DAT) result (IgG or IgG1 complement C3d pattern); (3) warm AIHA diagnosed and
treated<6 weeks before inclusion; (4) serum gammaglobulin level >5 g/L at inclusion; (5) absence of
detectable lymph nodes on total body CT-scan (performed before inclusion if not performed at warm
AIHA diagnosis); (6) Evans’ syndrome accepted with presence of the other inclusion criteria and platelet
count>30x109/L at inclusion; (7) females of childbearing age with negative pregnancy test results and
effective contraceptive method within at least 6 months after inclusion; and (8) informed and written
consent.
Outcomes The primary outcome was the efficacy of rituximab by comparing the overall response rate (PR+com-
plete response [CR]) at 1 year in both groups.
Secondary objectives were PR, cumulative dose of steroids, and number of transfusions and hospitali-
sations at 1 year and incidence and severity of adverse events in both groups and CR/PR at 2 years.
CR was defined as Hb level ≥11 g/dL (women) or ≥12 g/dL (men) without features of ongoing haemol-
ysis (including normal haptoglobin level), without any ongoing treatment for wAIHA on two different
occasions 4-weeks apart in the absence of any recent transfusion. CR could be considered even with a
positive DAT result.
Notes
Risk of bias
Random sequence genera- Low risk Central computerised randomisation procedure used
tion (selection bias)
Blinding of outcome as- Low risk Statistician blinded to study conduct and monitoring
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk All outcome data accounted for
(attrition bias)
All outcomes
Selective reporting (re- Low risk Results reported matching methodology listed on protocol
porting bias)
Other bias Low risk No other potential sources of bias were identified
AIHA: autoimmune haemolytic anaemia; CT: computerised tomography; DAT: direct antiglobulin test ; Hb: haemoglobin;ITT: intention-
to-treat; RFS: relapse-free survival
Cooper 2020
Study name Fostamatinib for the treatment of warm AIHA: A phase 3, randomised, double-blind, placebo-con-
trolled, global study
Participants Adults with primary or secondary warm AIHA who failed one or more prior therapy
Outcomes Haemoglobin response (haemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline in the
absence of rescue therapy); duration of haemoglobin response; need for warm AIHA rescue treat-
ment; and incidence of adverse events.
Notes NCT03764618
NCT04119050
Study name Efficacy and safety of M281 in adults with warm autoimmune haemolytic anaemia
NCT04119050 (Continued)
1. Number of Participants That Attain Hemoglobin (Hgb) Response [ Time Frame: Up to Week 20 ]
Secondary outcomes:
1. Percentage of Participants That Achieve any Reduction in the Daily Dose of Corticosteroids While
Maintaining Hgb Response [ Time Frame: Baseline (Day 1, Week 0) through 24 weeks ]
2. Percent Reduction in Daily Corticosteroid Dose [ Time Frame: Baseline (Day 1, Week 0) through
24 weeks ]
3. Hgb Range at Steady State [ Time Frame: Baseline (Day 1, Week 0) through 24 weeks ]It will be es-
timated using a model-based longitudinal analysis of Hgb/hemolysis parameters in relationship
to IgG level and dose regimen.
4. Percentage of Participants With Hgb Within the Normal Range for Their Gender [ Time Frame:
Baseline (Day 1, Week 0) through Week 16 and Week 24 ]
5. Change From Baseline in Hgb [ Time Frame: Baseline (Day 1, Week 0) through Week 16 and Week
24 ]
6. Percentage of Participants who Experience at Least a 2 g/dL Increase in Hgb From Baseline and
Normalization of Lactate Dehydrogenase and Haptoglobin [ Time Frame: Baseline (Day 1, Week
0) through Week 24 ]
7. Mean Time During Which the Primary Endpoint is Maintained [ Time Frame: Baseline (Day 1, Week
0) through Week 24 ]
8. Change From Baseline in the Total Score From the Functional Assessment of Chronic Illness Ther-
apy (FACIT) Fatigue Scale [ Time Frame: Baseline (Day 1, Week 0) through Week 24 ]
Notes NCT04119050
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1.1 Complete response at 12 months 2 96 Risk Ratio (M-H, Fixed, 95% CI) 2.13 [1.34, 3.40]
Analysis 1.1. Comparison 1: Rituximab with steroid versus steroid, Outcome 1: Complete response at 12 months
ADDITIONAL TABLES
(n = 64 randomised)
(n = 32 randomised)
Nausea 0 10 0.1
Vertigo 0 10 0.1
Insomnia 10 10 1.0
Non-infectious 2 2
Fatal events 0 4
Birgens 2013 n.r. 4 (based on figure n.r. n.r. 5 (based on figure N/A
from study) from study)
(n = 64 randomised)
(n = 32 randomised)
APPENDICES
4. (haemolyt$ or hemolyt$).tw.
5. Evans.tw.
6. AIHA.tw.
8. or/1-7
11. randomi?ed.ab.
12. placebo.ab.
14. randomly.ab.
15. trial.tw.
16. groups.ab.
17. or/9-16
18. human.sh.
19. 17 and 18
20. 19 and 8
4. (haemolyt$ or hemolyt$).tw.
5. Evans.tw.
6. AIHA.tw.
8. or/1-7
11. or/9-10
13. (book or conference paper or editorial or letter or review).pt. not exp randomized controlled trial/
14. (random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not exp randomized controlled trial/
16. 8 and 15
HISTORY
Protocol first published: Issue 1, 2017
Review first published: Issue 3, 2021
CONTRIBUTIONS OF AUTHORS
APY Liu: conceiving of the review, protocol development, searching for trials, selection of studies, quality assessment of trials, data
extraction, data entry, data analyses, data interpretation, development of final review, disagreement resolution, review updates,
corresponding author.
DKL Cheuk: conceiving of the review, protocol development, searching for trials, selection of studies, quality assessment of trials, data
extraction, data entry, data analyses, data interpretation, development of final review, disagreement resolution, review updates.
DECLARATIONS OF INTEREST
APY Liu: none known.
SOURCES OF SUPPORT
Internal sources
• The University of Hong Kong, Hong Kong
External sources
• No sources of support supplied
INDEX TERMS