Early Immunosuppression Conditioning Regimens For Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-analysis of Cytokine Release Syndrome Incidence
Bibliographic record
Abstract
This systematic review aims to evaluate the impact of early immunosuppression conditioning regimens on the incidence and severity of cytokine release syndrome (CRS) in patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT). While haplo-HSCT has become an increasingly accessible and effective curative therapy for patients lacking an HLA-matched donor, it remains associated with significant immunologic complications—most notably graft-versus-host disease (GVHD) and CRS. CRS, a systemic hyperinflammatory response triggered by immune activation, can range from mild, self-limited fever and malaise to severe, life-threatening multi-organ dysfunction, substantially influencing post-transplant morbidity and mortality. The standard immunosuppression protocol in haplo-HSCT, involving post-transplant cyclophosphamide (PT-CY) on days +3 and +4 followed by a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF), has effectively reduced GVHD rates and improved survival. However, emerging evidence suggests that the timing of immunosuppressive therapy initiation may further influence early inflammatory complications. Specifically, starting immunosuppression prior to the traditional post-transplant days—such as day 0 or even pre-transplant (day -1)—could mitigate early cytokine-driven toxicity, including CRS. Early initiation of agents like cyclosporine, tacrolimus, or MMF has been preliminarily associated with lower CRS incidence without compromising engraftment or increasing relapse risk. To address this knowledge gap, this systematic review will comprehensively synthesize available evidence from clinical trials and observational studies evaluating early immunosuppression regimens—defined as any strategy administering PT-CY before days +3/+4, or MMF/CNI before day +5—across diverse conditioning intensities, graft sources, and transplant settings (inpatient and outpatient). The primary outcome is the pooled incidence of CRS following early immunosuppression, while secondary outcomes include time-to-event measures such as overall survival, progression-free survival, relapse-free survival, graft-versus-host/relapse-free survival, and cumulative incidence of acute and chronic GVHD. All eligible studies will be identified through comprehensive searches of MEDLINE, SCOPUS, LILACS, EMBASE, Web of Science, and clinicaltrials.gov, with no language or year restrictions. Data extraction and study selection will be conducted independently and in duplicate using DistillerSR, adhering to PRISMA guidelines. Risk of bias will be evaluated using validated instruments appropriate for each study design (RoB-2, Newcastle-Ottawa Scale, and JBI tools). Quantitative synthesis will employ generalized mixed-effects models and random-effects meta-analyses to pool proportions and hazard ratios, respectively, while exploring heterogeneity and publication bias using I² statistics, Egger’s regression, and funnel plots. Expected outcomes: This project aims to establish whether early immunosuppression regimens can consistently reduce CRS incidence and severity following haplo-HSCT without compromising key post-transplant outcomes. Findings may inform optimization of immunosuppressive timing to enhance the safety and feasibility of haplo-HSCT, particularly in resource-constrained or outpatient settings. Ultimately, this review seeks to generate a robust evidence base for refining conditioning strategies and improving the early post-transplant inflammatory landscape in haploidentical transplantation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.012 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.013 | 0.002 |
| Bibliometrics | 0.003 | 0.017 |
| Science and technology studies | 0.002 | 0.003 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.008 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".