Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have underpinned graft-versus-host disease (GvHD) prophylaxis in allogeneic hematopoietic cell transplantation (HCT) for more than four decades. Despite their central role across donor types and conditioning intensities, current therapeutic drug monitoring (TDM) and dosing paradigms in HCT are predominantly imported from solid organ transplantation. This review critiques that extrapolation and outlines why HCT-specific pharmacological strategies are needed.
Cyclosporine was discovered from a fungal product identified in the late 1960s and translated rapidly into clinical use in solid organ transplantation, improving graft survival in kidney transplant recipients. Its mechanism—calcineurin inhibition leading to suppressed NFAT-driven IL-2 transcription—provided a rational and selective approach to T-cell suppression.
Tacrolimus (FK506), isolated in the 1980s from Streptomyces, shares the calcineurin–NFAT target but binds FKBP12 rather than cyclophilin A and displays substantially greater potency on a molar basis in vitro. Tacrolimus emerged clinically as a more potent alternative in solid organ transplantation and has largely displaced cyclosporine in many programs.
The historical evolution of GvHD prophylaxis progressed from methotrexate alone to cyclosporine, then to cyclosporine–methotrexate combination, and later to tacrolimus-based regimens with methotrexate or mycophenolate mofetil. Polyclonal anti-thymocyte globulin (ATG) and strategies such as post-transplant cyclophosphamide (PTCy) were incorporated as complementary approaches rather than replacements for CNIs.
ATG trials were conducted on CNI backbones and showed reductions in acute and chronic GvHD without apparent compromise of overall survival in many settings. PTCy, developed for haploidentical transplantation and extended to unrelated donors, operates by selectively eliminating activated alloreactive T cells; nonetheless, CNIs (often tacrolimus) remain integral components together with MMF in many PTCy regimens.
Precision in CNI dosing is consequential: subtherapeutic exposure increases GvHD risk, while overexposure raises risks such as nephrotoxicity, neurotoxicity, transplant-associated thrombotic microangiopathy, and possible suppression of graft-versus-leukemia effects. Thus, accurate TDM during HCT matters clinically.
The application of solid-organ CNI targets to HCT assumes comparable pharmacokinetic and pharmacodynamic contexts. The review highlights multiple fundamental differences that challenge this assumption and affect both distribution and clearance of CNIs.
Conditioning regimens (total body irradiation, high-dose alkylators) rapidly disrupt epithelial barriers and generate intense systemic inflammation through release of pathogen- and damage-associated molecular patterns. Resulting cytokine surges (TNF-α, IL-6, IL-1β) suppress CYP3A4 and P-glycoprotein expression, altering intestinal absorption and hepatic clearance of tacrolimus and cyclosporine. Acute-phase changes in plasma proteins and anemia further shift protein and erythrocyte binding, modifying the relationship between whole-blood concentrations and pharmacologically active free drug.
A distinctive HCT pharmacokinetic challenge is rapid and large fluctuations in hematocrit after conditioning: hematocrit may fall substantially within days to weeks before donor engraftment restores counts. Both CNIs partition extensively into erythrocytes—tacrolimus particularly concentrates within red blood cells—so whole-blood concentrations are markedly hematocrit-dependent.
For a given whole-blood trough, a low hematocrit will shift the proportion of drug into plasma and tissues, potentially increasing pharmacologically active exposure relative to a patient with a higher hematocrit. Standard whole-blood TDM does not routinely correct for hematocrit, risking misclassification of exposure precisely during the early post-transplant window when dosing accuracy is most critical.
Neutropenic sepsis, hypoalbuminemia, hepatic dysfunction, and severe mucositis are common during early HCT and further perturb CNI pharmacokinetics. Hepatic impairment reduces CNI clearance; diarrhea and mucositis diminish oral bioavailability. These acute factors are far less frequent in the stable renal transplant populations from which many TDM targets were derived, limiting the external validity of those targets in the acutely ill HCT setting.
Allogeneic HCT involves intensive polypharmacy: antifungal and antiviral prophylaxis, broad-spectrum antibacterials, antiemetics, analgesics, and supportive agents are often coadministered. Azole antifungals such as voriconazole and posaconazole are strong CYP3A4 inhibitors and can markedly increase CNI exposure if doses are not adjusted. Letermovir, increasingly used for CMV prophylaxis post-HCT, inhibits pathways relevant to CNI metabolism and can lead to significant exposure increases.
Complex combinations—such as voriconazole plus letermovir—produce opposing effects on metabolic enzymes (letermovir as a CYP2C19 inducer versus voriconazole as a CYP3A4 inhibitor), producing an unpredictable net impact on CNI levels. The dynamic addition, removal, or dose-modification of interacting drugs produces shifting baselines that complicate interpretation of trough concentrations and may not be managed adequately by trough monitoring alone.
There has been a geographic and temporal divergence in CNI preference. Cyclosporine has a substantial historical evidence base in HCT, while tacrolimus offers greater potency and has become widely used in many centers. Both agents share the same class effect—calcineurin inhibition—but differ in erythrocyte partitioning, potency, and interaction profiles, which may influence their monitoring and target ranges in HCT.
ATG and PTCy regimens interact conceptually and pharmacologically with CNIs: ATG exposure varies with lymphocyte burden and can modulate the immunosuppressive milieu, potentially altering optimal CNI targets. PTCy has a distinct mechanism that may influence how CNIs are best combined and dosed. The review emphasizes that choices between cyclosporine and tacrolimus and their monitoring strategies should be informed by HCT-specific data rather than by solid-organ paradigms alone.
The authors conclude that solid-organ-derived CNI TDM targets are not directly transferable to allogeneic HCT because of the unique and dynamic biological, hematologic, infectious, and pharmacologic factors in this population. Whole-blood trough concentrations without hematocrit correction or consideration of inflammation and co-medications risk misclassifying exposure.
They call for a research agenda to develop HCT-specific precision immunosuppression strategies, including pharmacokinetic models that incorporate hematocrit, inflammatory status, critical illness, and evolving drug-interaction networks, and for prospective studies to define exposure–response relationships specific to the HCT setting. Details of trial designs, specific target ranges, or quantitative thresholds were not reported in the source and would require primary research.