---
title: "Calcineurin inhibitor monitoring in allogeneic HCT: why solid-organ targets may not apply"
id: "frontiers-in-immunology-11-calcineurin-inhibitor-monitoring-in-allogeneic-hematopoietic-cell"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-calcineurin-inhibitor-monitoring-in-allogeneic-hematopoietic-cell"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1940626"
published_at: "2026-09-22T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Calcineurin inhibitor monitoring in allogeneic HCT: why solid-organ targets may not apply
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-11-calcineurin-inhibitor-monitoring-in-allogeneic-hematopoietic-cell
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1940626)
- **Published At:** 2026-09-22T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Calcineurin inhibitors (CNIs), principally **cyclosporine** and **tacrolimus**, remain the central agents for graft-versus-host disease (GvHD) prophylaxis in allogeneic hematopoietic cell transplantation (HCT) across donor types and conditioning intensities. - Current therapeutic drug monitoring (TDM) targets for CNIs in HCT are largely extrapolated from solid organ transplantation, a practice the authors argue is scientifically unsound. - The HCT biological environment differs fundamentally from solid-organ transplantation due to conditioning-induced systemic inflammation, profound and rapid hematologic changes, frequent sepsis/critical illness, and an exceptionally complex polypharmacy landscape. - Conditioning causes mucosal barrier injury and cytokine release (TNF-α, IL-6, IL-1β) that suppress CYP3A4 and P-glycoprotein, altering CNI absorption and clearance. - Rapid changes in hematocrit during early post-transplant markedly affect whole-blood partitioning of CNIs, especially **tacrolimus**, which is predominantly erythrocyte-bound; identical whole-blood troughs can reflect very different plasma/tissue exposures depending on hematocrit. - Sepsis, hypoalbuminemia, hepatic dysfunction, and gastrointestinal mucositis common in HCT further disrupt CNI pharmacokinetics and oral bioavailability compared with stable kidney transplant recipients. - HCT features dense polypharmacy with potent CYP3A4/P-gp interactors (azole antifungals, letermovir) and multidrug interactions (e.g., voriconazole plus letermovir) that produce highly variable and shifting effects on CNI exposure. - Anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are important complementary GvHD strategies that interact pharmacologically and immunologically with CNI exposure; ATG pharmacokinetics vary with lymphocyte burden and may influence optimal CNI targets. - Misclassification of exposure by uncorrected whole-blood trough monitoring during HCT can lead to under- or over-immunosuppression with consequences including GvHD, nephrotoxicity, neurotoxicity, thrombotic microangiopathy, or impaired graft-versus-leukemia effect. - The review calls for HCT-specific pharmacological research and precision immunosuppression strategies rather than direct adoption of solid-organ-derived TDM targets.
## Clinical Analysis & Structured Key Points
Frontiers | Calcineurin inhibitor monitoring in allogeneic hematopoietic cell transplantation: time to move beyond solid organ transplant paradigms REVIEW article Front. Immunol. , 22 September 2026 Sec. Alloimmunity and Transplantation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1940626 Published in Frontiers in Immunology Alloimmunity and Transplantation 7 impact factor 11.3 citescore Part of a Research Topic Balancing alloantigen-induced immune responses and anti-tumor immunity in transplantation: Volume II Submission open 3772 views 4 articles Editor & Reviewers Edited by R M Rita Maccario Reviewed by K B Katarzyna Bogunia-Kubik E M Ezhilpavai Mohanan Outline Figures and Tables Figure 1 View in article REVIEW article Front. Immunol. , 22 September 2026 Sec. Alloimmunity and Transplantation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1940626 Calcineurin inhibitor monitoring in allogeneic hematopoietic cell transplantation: time to move beyond solid organ transplant paradigms P H Pedro Henrique Prata 1,2 * M L Marc Labriffe 2,3 P M Pierre Marquet 2,3 J W Jean-Baptiste Woillard 2,3 C M Caroline Monchaud 2,3 1. Department of Clinical Hematology and Cell Therapy, Centre Hospitalier Universitaire (CHU) de Limoges, Limoges, France 2. Pharmacology & Transplantation, Université de Limoges, Limoges, France 3. Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France See more Article metrics View details Abstract Calcineurin inhibitors, such as cyclosporine and tacrolimus, have been the backbone of graft-versus-host disease prophylaxis in allogeneic hematopoietic cell transplantation for more than four decades. Yet, the pharmacological framework governing their therapeutic drug monitoring has been significantly imported from solid organ transplantation. This critical narrative review argues that this extrapolation is scientifically unsound. The unique biological environment of allogeneic hematopoietic cell transplantation characterized by toxic conditioning regimens, profound hematologic changes, systemic inflammation, and an unparalleled drug interaction landscape creates pharmacokinetic and pharmacodynamic conditions for which solid organ transplant-derived targets are inadequate. We critically appraise the quality of evidence underpinning current therapeutic drug monitoring practices, examine the historical divide between cyclosporine and tacrolimus use, and propose a research agenda directed at developing hematopoietic transplant-specific precision immunosuppression strategies. 1 Introduction The first successful allogeneic bone marrow transplantation, reported by Thomas et al. in 1957 ( 1 ), opened a therapeutic frontier that would transform the treatment of hematologic malignancies, bone marrow failure syndromes, and inherited disorders of hematopoiesis. In the early era of allogeneic transplantation, transplant-related mortality exceeded 50–70%, driven by three interdependent complications: graft rejection, severe acute graft-versus-host disease (GvHD), and opportunistic infections ( 2 ). These outcomes defined the central problem of allogeneic transplantation: how to achieve durable immune reconstitution while preventing the graft from killing the host. The first immunosuppressive strategy to show efficacy came from animal models and used methotrexate (MTX) ( 3 ), based on its antiproliferative effects on rapidly dividing T cells. Subsequently, a randomized trial compared the efficacy of cyclosporine A against methotrexate, showing cyclosporine was an effective alternative, with less toxicity ( 4 ). However, it was the landmark randomized trial that established the combination of both drugs, cyclosporine and MTX, as the gold standard for GvHD prophylaxis ( 4 , 5 ), a benchmark that remains today the reference against which all subsequent strategies are compared. This study demonstrated that combination prophylaxis significantly reduced the incidence of acute GvHD and improved survival compared with cyclosporine alone. More than four decades later, calcineurin inhibitors (CNIs) continue to underpin GvHD prophylaxis across nearly all transplant platforms (matched sibling, matched unrelated, haploidentical, and cord blood) and across all conditioning intensities. Even the sharp expansion of post-transplant cyclophosphamide (PTCy)-based regimens in the last decade, which has transformed haploidentical and increasingly unrelated donor transplantation, has not displaced CNIs but rather incorporated them as essential partners in a multi-agent backbone ( 6 , 7 ). The question is no longer whether to use CNIs, but how to use them optimally. Still, there is a profound irony at the heart of modern transplant practice: despite this central and enduring role, the way we prescribe, monitor, and titrate CNIs in hematopoietic cell transplantation (HCT) is largely based on evidence generated in an entirely different clinical setting — solid organ transplantation. This critical narrative review challenges that paradigm, examines its scientific foundations, and argues that the time has come to develop HCT-specific pharmacological strategies. 2 The emergence of calcineurin inhibitors 2.1 Discovery of cyclosporine The story of cyclosporine begins in 1969 with a soil sample collected in Norway subsequently characterized as containing the fungus Tolypocladium inflatum . The Belgian biologist Jean-François Borel, working at Sandoz Pharmaceuticals in Basel, identified in 1972 that the cyclic undecapeptide produced by this organism possessed selective immunosuppressive properties without the broad cytotoxicity of existing agents ( 8 ). His work demonstrated dose-dependent suppression of lymphocyte proliferation with relative sparing of other rapidly dividing cell populations — a selectivity that distinguished cyclosporine from all preceding immunosuppressants, especially antimetabolites as MTX. The clinical translation was rapid. Roy Calne at Cambridge published the first results in renal transplant recipients in 1978 ( 9 ), reporting improvements in graft survival. Cyclosporine’s mechanism — the inhibition of calcineurin ( 10 ), a phosphatase required for nuclear factor of activated T cells (NFAT) dephosphorylation ( 11 , 12 ) and subsequent interleukin-2 transcription ( 13 ) — was subsequently elucidated and provided a rational framework for immunosuppression targeting antigen-driven T-cell activation. The impact on solid organ transplantation was revolutionary: one-year kidney graft survival rates improved from approximately 50% to over 80% ( 9 ), changing the therapeutic landscape. 2.2 Development of tacrolimus Tacrolimus (FK506) was isolated in 1984 from the soil bacterium Streptomyces tsukubaensis by researchers at Fujisawa Pharmaceutical Company in Japan ( 14 ). Despite sharing the same molecular target, the calcineurin-NFAT axis, tacrolimus operates through a structurally and mechanistically distinct pathway: it binds FKBP12 (FK-binding protein 12) ( 15 ), whereas cyclosporine binds cyclophilin A ( 16 ). The resulting complexes both inhibit calcineurin but with substantially different potencies; in vitro studies demonstrate that tacrolimus is approximately 10- to 100-fold more potent on a molar basis than cyclosporine ( 17 ). Tacrolimus was first approved for clinical use in liver transplantation in the United States in 1994, following pivotal trials demonstrating superior rejection prevention compared with cyclosporine-based regimens ( 18 – 20 ). Its rapid adoption in solid organ transplantation over the subsequent decade was driven by this enhanced efficacy profile, and it progressively displaced cyclosporine as the preferred CNI in most solid organ transplant programs ( 21 ). 3 How calcineurin inhibitors became the backbone of GvHD prevention The trajectory of GvHD prophylaxis spans five decades and reflects the progressive layering of immunosuppressive strategies over an increasingly complex transplant landscape. MTX alone represented the first era, followed by the pivotal demonstration that cyclosporine alone could prevent GvHD ( 4 ), and then the establishment of cyclosporine-MTX combination as the standard ( 5 ). The introduction of tacrolimus combined with MTX added a more potent CNI-based option ( 22 ), and the subsequent incorporation of mycophenolate mofetil (MMF) as an alternative to or complement of MTX further expanded the toolkit ( 23 ). A second major pillar of GvHD prophylaxis, anti-thymocyte globulin (ATG) evolved alongside CNIs. Polyclonal rabbit-derived serums, chiefly anti-human thymocyte globulin (marketed as Thymoglobulin®) and ATG-Fresenius (anti-Jurkat T cell globulin, marketed as Grafalon®), act through a complementary mechanism: in vivo host and donor T-cell depletion, inhibition of inflammatory cell trafficking, and relative preservation of regulatory T cells. Their clinical role was established through a series of phase 3 randomized controlled trials conducted predominantly in the unrelated donor setting. The pivotal ATG-Fresenius Trial demonstrated that adding ATG-Fresenius to standard cyclosporine-methotrexate prophylaxis in the myeloablative conditioning regimen (MAC) setting significantly reduced both grade III–IV acute GvHD (11.7% versus 25.5%) and extensive chronic GvHD (12.2% versus 45%), without increasing relapse or compromising overall survival ( 24 ). In the matched sibling setting, ATG-Fresenius added MAC significantly reduced chronic GvHD and improved the composite endpoint of chronic GvHD-free and relapse-free survival, again without detriment to overall survival ( 25 ). Data favors a survival benefit for Thymoglobulin® in unrelated donor transplantation, MAC and reduced intensity conditioning (RIC) regimens, and demonstrated that the primary clinical benefit was a sustained reduction in the requirement for long-term systemic immunosuppression ( 26 ) and a lower risk for both acute and chronic GvHD without compromising disease control ( 27 ). Importantly, ATG does not replace CNIs in these protocols; it is added to them. All pivotal ATG trials were conducted against a CNI-based prophylaxis backbone. ATG and CNIs function as pharmacologically complementary agents: ATG depletes alloreactive T cells pre- and peri-engraftment, while CNIs suppress ongoing calcineurin-mediated T cell activation during the weeks and months that follow. ATG itself exhibits marked pharmacokinetic variability driven by inter-patient differences in lymphocyte burden, which determines the consumption and clearance of active ATG ( 28 ). There is growing evidence that ATG exposure modulates the effective immunosuppressive environment in ways that could directly influence optimal CNI targets ( 29 ). Another significant paradigm shift of the past two decades has been the emergence of PTCy ( 6 , 7 ), originally developed for haploidentical transplantation and subsequently demonstrated to be effective across donor types including unrelated donors. The hypothesized mechanism of PTCy — selective elimination of alloreactive T cells at peak activation while sparing regulatory T cells and non-alloreactive lymphocytes — is very different from CNI-mediated suppression. Nonetheless, even within PTCy protocols, CNIs (originally tacrolimus) remain a cornerstone, combined with MMF to provide complementary immunosuppression during engraftment. The persistence of CNIs across all these platforms is not historical inertia alone; it reflects the need for a reliable, titratable immunosuppressive anchor during the period of maximal alloimmune risk. Therefore, the quality of CNI therapeutic drug monitoring (TDM) in HCT is a matter of direct clinical consequence. Subtherapeutic exposure risks GvHD; supratherapeutic exposure risks nephrotoxicity, neurotoxicity, and transplant-associated thrombotic microangiopathy ( 30 ), or even the suppression of the graft-versus-leukemia effect ( 31 , 32 ). The precision with which we navigate this narrow therapeutic window determines GvHD risk and both relapse and non-relapse mortality. 4 The HCT environment is not solid organ transplantation The central argument of this review is that, because the biological context of allogeneic HCT differs fundamentally from solid organ transplantation limiting the direct transferability of CNI therapeutic targets between these settings. The major differences affecting CNI pharmacokinetics and the interpretation of therapeutic drug monitoring are summarized in Figure 1 . The next section examines the most important sources of divergence. Figure 1 Why solid-organ CNI targets cannot be directly applied to allogeneic HCT. Although calcineurin inhibitors (CNIs) are monitored using the same whole-blood assays in both kidney transplantation and allogeneic hematopoietic cell transplantation (HCT), the biological determinants of drug exposure differ substantially. In kidney transplantation, therapeutic drug monitoring is typically performed in clinically stable recipients with preserved hematocrit, limited inflammatory perturbation, and relatively predictable pharmacokinetics. In contrast, early post-transplant HCT is characterized by conditioning-induced inflammation, profound fluctuations in hematocrit, critical illness, organ dysfunction, and frequent exposure to interacting medications such as azoles and letermovir. These factors alter CNI distribution, metabolism, and bioavailability, resulting in highly variable exposure despite similar measured trough concentrations. Consequently, therapeutic targets established in solid-organ transplantation cannot be assumed to be directly applicable to the HCT setting. 4.1 Conditioning-induced inflammation Conditioning regimens generate an unparallelled systemic inflammatory state. Total body irradiation (TBI) and high-dose alkylating agents produce profound gastrointestinal epithelial barrier disruption, mucositis, and the liberation of pathogen and damage-associated molecular patterns (PAMP and DAMP, respectively) within 24–72 hours of administration ( 33 ). This results in the translocation of bacterial lipopolysaccharide and other microbial products into the systemic circulation, triggering the release of pro-inflammatory cytokines as TNF-α, IL-6, and IL-1β. These conditioning-induced inflammatory changes have direct consequences for CNI pharmacokinetics. Cytokine-mediated suppression of CYP3A4 and P-glycoprotein expression alters both intestinal absorption and hepatic clearance of tacrolimus and cyclosporine ( 34 ). The inflammatory milieu also modulates protein binding, as both CNIs are protein-bound (to lipoproteins and in erythrocytes), and the acute-phase protein shifts and anemia that characterize the early post-transplant stage alter binding dynamics in ways that cannot be captured by whole-blood concentration monitoring. Besides, a kidney transplant recipient at any time after transplant is in an extremely different inflammatory state than an HCT recipient on day +5. 4.2 Profound hematologic changes Arguably, the most underappreciated pharmacokinetic challenge in HCT is the rapid and dynamic change in hematocrit. Following conditioning, hematocrit may fall from close to normal to 20% within one to two weeks, before recovering progressively over the ensuing months as donor engraftment proceeds. This is clinically critical because both cyclosporine and tacrolimus exhibit extensive partitioning into erythrocytes, making whole-blood concentrations highly dependent on hematocrit. Cyclosporine distributes predominantly between erythrocytes (approximately 40–50%), plasma (30–40%), and leukocytes (10–20%) ( 35 ), whereas tacrolimus displays even greater erythrocyte binding, with the majority of circulating drug residing within red blood cells ( 21 , 36 ). The clinical implication is significant: can whole-blood trough concentrations be interpreted similarly in a patient whose hematocrit zigzags 10–20 percentage points over a single week? The answer is, probably, no. A given whole-blood CNI concentration in a patient with a hematocrit of 35% reflects a substantially different free plasma concentration than the same trough in a patient with a hematocrit of 18%. Because CNIs extensively partition into erythrocytes, a lower hematocrit reduces red blood cell binding and results in a greater proportion of the drug remaining in plasma. Consequently, for the same whole-blood concentration, patients with low hematocrit may have substantially higher pharmacologically active plasma concentrations and tissue exposure. Standard TDM, which reports whole-blood concentrations without hematocrit correction, may misclassify exposure status during the critical early post-transplant period , i.e. , precisely when accurate dosing matters most. 4.3 Sepsis and critical illness Sepsis during the neutropenic phase of HCT is common and frequently complicated by hypoalbuminemia, hepatic dysfunction, and reduction in intestinal absorptive capacity (mucositis). Each of these perturbations affects CNI pharmacokinetics. Hepatic clearance, the main elimination pathway for both agents, is reduced in the setting of hepatic dysfunction or sinusoidal obstruction syndrome. Diarrhea decreases oral bioavailability, which is already highly variable for both CNIs. In stable renal transplant recipients (the population from which most TDM targets are derived) such episodes of critical illness are uncommon. In HCT, they are very frequent at the early post-transplant course. The pharmacokinetic models and target ranges validated in a population of medically stable kidney recipients sitting in a transplant outpatient clinic bear limited relevance to a febrile, inflamed, neutropenic HCT recipient on broad-spectrum antibiotics in hospital. 4.4 Drug interactions: HCT as a pharmacological maze Allogeneic HCT creates a drug interaction environment of exceptional complexity, unmatched in any other area of medicine. The polypharmacy burden derives from simultaneous requirements for antifungal and antiviral prophylaxis, antibacterial agents, antiemetics, analgesics, mucositis management, and conditioning-related supportive care, all administered to patients whose CYP3A4 and P-glycoprotein activity are already perturbed by inflammation and conditioning. Azole antifungal agents are potent CNI interactants in clinical practice. Voriconazole and posaconazole are strong CYP3A4 and CYP2C19 inhibitors, increasing manyfold tacrolimus and cyclosporine exposure without dose adjustment ( 37 , 38 ). The magnitude of the interaction is highly variable between individuals and fluctuates as antifungal therapy is started, modified in dose, or discontinued — creating an ever-shifting baseline against which trough concentrations must be interpreted. Letermovir, now widely used for CMV prophylaxis post-HCT ( 39 , 40 ), inhibits the CYP3A4/P-glycoprotein pathway and leads to significant increases in CNI exposure that are not always dose-adjusted appropriately in clinical practice. A further layer of complexity arises from the voriconazole – letermovir interaction: letermovir is a CYP2C19 inducer, whereas voriconazole is a CYP3A4 inhibitor. In patients receiving the triple combination of a CNI, voriconazole, and letermovir, these opposing effects on drug metabolism create a highly unpredictable net impact on CNI exposure, underscoring the critical importance of intensive TDM monitoring in this setting. Likely, the cumulative pharmacokinetic impact of this polypharmacy – which shifts dynamically as individual drugs are added, removed, or dose-adjusted — cannot be adequately managed by trough monitoring alone. 5 Cyclosporine versus tacrolimus: the great divide 5.1 The use of cyclosporine The historical divergence in transplant practices concerning CNI choice represents one of the most striking geographical differences in evidence-based medicine. The use of cyclosporine is reinforced by a body of observational data demonstrating adequate outcom
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