Selective JAK1 Inhibition with Itacitinib Enhances Haploidentical Transplantation Outcomes by Mitigating GvHD and CRS

Haploidentical hematopoietic cell transplantation (haplo-HCT) has become a transformative treatment option for patients with hematologic malignancies, especially those who lack a fully HLA-matched donor. Advances in post-transplant management, particularly the introduction of post-transplant cyclophosphamide (PtCy), have significantly improved the feasibility and safety of haplo-HCT by reducing the risk of graft-versus-host disease (GvHD). Despite these advancements, significant challenges remain, threatening patient survival and quality of life. GvHD, an immune-mediated attack by donor cells on the recipient’s tissues, continues to be a major complication of allogeneic stem cell transplantation. Acute GvHD (aGvHD) affects nearly half of all haplo-HCT recipients, with severe forms leading to life-threatening outcomes. Chronic GvHD (cGvHD), meanwhile, often develops in survivors, compromising long-term recovery and causing debilitating health issues. Existing prophylactic strategies, while effective in reducing the incidence of GvHD, are far from ideal and are often associated with significant toxicities and suboptimal efficacy. Furthermore, these treatments can impair the graft-versus-leukemia (GvL) effect, a critical mechanism by which donor immune cells eliminate residual malignancy, increasing the risk of relapse.

Cytokine release syndrome (CRS) is another formidable obstacle in haplo-HCT. Triggered by the massive activation of donor immune cells, CRS results in a surge of inflammatory cytokines like interferon-gamma (IFN-γ) and interleukin-6 (IL-6). Severe CRS not only contributes to graft failure and organ damage but also increases non-relapse mortality (NRM). While interventions like anti-IL-6 therapies have shown promise, they are reactive treatments rather than proactive measures, and their use may be associated with further immune suppression. Recognizing these persistent gaps, new study published in Blood Journal and conducted by Dr. Ramzi Abboud, Dr. Mark   Schroeder, Dr.  Michael Rettig, Dr.  Reyka Jayasinghe, Dr.  Feng Gao, Dr.  Jeremy Eisele, Dr. Leah Gehrs, Dr. Julie   Ritchey, Dr. Jaebok Choi, Dr. Camille  Abboud, Dr.  Iskra Pusic, Meagan Jacoby, Professor Peter Westervelt, Matthew Christopher, Dr.Amanda Cashen, Dr.Armin Ghobadi, Professor Keith Stockerl-Goldstein, Professor Geoffrey Uy, and led by Professor John DiPersio from the University of Washington, investigated novel, targeted approach to improve haplo-HCT outcomes. Preclinical studies have identified the Janus kinase (JAK) pathway, particularly JAK1 signaling, as a central mediator of both GvHD and CRS. Blocking this pathway offers the potential to mitigate these complications while preserving the critical immune functions necessary for engraftment and tumor control. Building on the success of other JAK inhibitors, such as ruxolitinib, in treating GvHD, the researchers turned their attention to itacitinib, a selective JAK1 inhibitor with a theoretically more favorable safety and efficacy profile.

In their quest to improve outcomes in haploidentical hematopoietic cell transplantation (haplo-HCT), the researchers conducted a carefully designed open-label study that combined a JAK1-selective inhibitor, itacitinib, with standard GvHD prophylaxis. This trial, conducted at the Siteman Cancer Center, enrolled 42 patients, each with hematologic malignancies requiring transplantation. The patients received daily doses of itacitinib starting three days before transplantation and continuing for up to 180 days, depending on their clinical progression. Alongside this, they were administered standard immunosuppressive drugs, including tacrolimus, mycophenolate mofetil, and PtCy, to ensure comprehensive GvHD prevention. From the outset, the researchers sought to evaluate whether the addition of itacitinib would affect the critical process of engraftment. Monitoring the time to neutrophil and platelet recovery, they found that all patients successfully achieved engraftment, with no cases of graft failure. This was a pivotal finding, as it confirmed that the JAK1 inhibition did not interfere with the donor cells’ ability to establish themselves in the recipient’s bone marrow. By day 30, all patients demonstrated complete donor chimerism, a key indicator of successful engraftment.

The next focus of the study was acute GvHD, a severe and often life-threatening complication. Remarkably, none of the patients developed grade 3 or 4 aGvHD, outcomes far better than the historical rates associated with standard haplo-HCT. Mild cases of grade 2 aGvHD occurred in a small subset of patients, but these were effectively managed without resorting to aggressive immunosuppression. Chronic GvHD, another significant concern in transplantation, was observed in only a handful of patients, with the vast majority remaining free from moderate or severe forms of this condition even a year after their transplant. The authors also targeted CRS, an inflammatory complication driven by the activation of donor immune cells. The inclusion of itacitinib drastically reduced the severity of CRS, with no cases of grade 2 or higher reported. Most patients experienced either mild grade 1 CRS or no CRS at all, highlighting the drug’s ability to modulate the immune response without extinguishing it entirely. These findings aligned with earlier hypotheses about JAK1 inhibition’s role in reducing inflammation mediated by cytokines like IL-6 and IFN-γ. In terms of relapse and survival, the outcomes were equally encouraging. The one-year survival rate stood at 80%, with a relapse incidence of just 14% at two years. Importantly, the reduced CRS severity did not compromise the GvL effect, as the relapse rates were comparable to or better than historical controls. This balance between controlling immune complications and maintaining anti-tumor activity underscored the promise of itacitinib as a prophylactic agent in transplantation.

The researchers also conducted extensive immune profiling to understand the impact of itacitinib on various immune cell subsets. They observed increased activation markers on circulating monocytes, suggesting that the drug bolstered certain innate immune functions without triggering harmful alloreactivity. T-cell analysis revealed a reduction in naïve T cells, often implicated in severe GvHD, and a relative increase in memory T cells, which are associated with a less inflammatory response. Meanwhile, NK cells, critical for antiviral defense and GvL activity, remained unaffected in terms of number and function.

Overall, the study by Professor John DiPersio and colleagues marks a significant leap forward in the field of HCT, specifically for patients undergoing haploidentical transplants. By demonstrating that the selective JAK1 inhibitor itacitinib can effectively prevent life-threatening complications such as GvHD and CRS, the research provides a blueprint for improving survival rates while maintaining the critical GvL effect. The implications of authors’ findings are profound. First and foremost, the study addresses a long-standing challenge in transplantation: balancing the immune system’s dual roles of fighting residual cancer cells while avoiding overactivation that leads to GvHD and CRS. Itacitinib’s ability to selectively modulate inflammatory pathways without impairing immune function resolves a crucial bottleneck, potentially reshaping standard protocols for haplo-HCT. The absence of grade 3–4 GvHD and severe CRS among the study participants underscores its potential to redefine safety benchmarks in transplantation. Moreover, the results pave the way for a reduction in long-term toxicities associated with traditional immunosuppressive therapies. Extended reliance on calcineurin inhibitors or steroids often results in organ damage and infection risks. Itacitinib offers a safer alternative, with fewer adverse effects, making it a candidate for broader application not only in haplo-HCT but also in other transplantation platforms.

We also believe the new study also holds implications beyond the individual patient. By improving survival rates and reducing relapse risks, it could lead to more cost-effective transplantation practices. Fewer severe complications mean shorter hospital stays, reduced need for additional interventions, and better resource utilization—all critical factors for healthcare systems dealing with the complexity of allogeneic transplantation. Furthermore, the detailed immune profiling in this study provides critical mechanistic insights that extend its impact beyond clinical practice. The observed effects on monocytes and T-cell subsets offer clues about how specific immune pathways can be fine-tuned to prevent alloimmune reactions. These findings could catalyze additional research into targeted immunomodulation, not only in transplantation but also in autoimmune disorders and other inflammatory diseases. Finally, the trial underscores the importance of integrating precision medicine into transplant protocols. By targeting the JAK1 pathway, this approach exemplifies how selective inhibition of key molecular processes can yield dramatic improvements in outcomes. This is particularly relevant in an era where personalized interventions are increasingly prioritized.