Section Structure
1. Highlights
2. Clinical Background and Unmet Need
3. Why CD117 Is an Attractive Conditioning Target
4. Study Design and Methods
5. Key Efficacy Findings
6. Safety and Engraftment
7. Translational and Mechanistic Findings
8. Clinical Interpretation and Limitations
9. Implications for Practice and Future Research
10. Funding, Trial Registration, and Citation
Highlights
This phase 1 study tested briquilimab, an anti-CD117 monoclonal antibody, combined with nonmyeloablative fludarabine and low-dose total body irradiation as conditioning before matched-donor allogeneic hematopoietic cell transplantation in older adults with high-risk AML or MDS.
No briquilimab infusion reactions, dose-limiting toxicities, primary graft failures, or unexpected pharmacokinetic variability were reported, supporting feasibility in a medically vulnerable transplant population with a median age of 70 years.
Bone marrow analyses showed biologic proof of concept: AML/MDS hematopoietic stem and progenitor cells fell by a mean of 62.4% ± 22.7% after briquilimab, accompanied by an approximately threefold rise in serum stem cell factor.
Early clinical outcomes were encouraging in patients transplanted in remission or with MDS, although the small sample size and single-arm design preclude conclusions about comparative benefit.
Clinical Background and Unmet Need
Allogeneic hematopoietic cell transplantation remains the only potentially curative strategy for many patients with high-risk acute myeloid leukemia and myelodysplastic syndrome. Yet the procedure is fundamentally limited by the toxicity of conditioning. Conventional myeloablative regimens can be highly effective at disease control and host marrow ablation, but older adults and those with comorbid illness often cannot tolerate them. Nonmyeloablative or reduced-intensity approaches broaden eligibility, but may provide less reliable clearance of recipient hematopoietic stem cells and less direct antileukemic activity, creating a persistent tension between tolerability and disease control.
This problem is particularly relevant in modern transplant practice. The median age of patients with AML and MDS is in the older-adult range, and measurable residual disease is increasingly recognized as a major determinant of relapse risk before transplant. As a result, there is strong interest in conditioning platforms that reduce nonspecific toxicity while selectively depleting host hematopoietic stem and progenitor cells and, ideally, malignant progenitors. Antibody-based conditioning is therefore an important translational direction.
Why CD117 Is an Attractive Conditioning Target
CD117, also known as c-Kit, is a receptor tyrosine kinase expressed on hematopoietic stem and progenitor cells and on many myeloid malignant precursors. Its ligand, stem cell factor, supports stem-cell survival and niche occupancy. Briquilimab is a monoclonal antibody designed to block stem cell factor binding to CD117. Preclinical studies suggested that disrupting this pathway can deplete normal hematopoietic stem and progenitor cells and potentially dislodge malignant cells from the marrow niche, thereby creating biologic space for donor engraftment with less collateral injury than cytotoxic chemotherapy alone.
That concept is especially attractive in AML and MDS, where older patients often need a conditioning strategy that is gentler than standard myeloablation but stronger than minimal-intensity immune suppression alone. The study by Muffly and colleagues directly evaluates whether this mechanism can be translated into a clinically usable transplant-conditioning platform.
Study Design and Methods
This was a phase 1 clinical trial registered as NCT04429191. Investigators enrolled 32 older adults with high-risk myeloid malignancies undergoing matched-donor allogeneic transplantation. The disease distribution was 13 patients with AML in complete remission, 3 patients with AML in relapse, and 16 patients with MDS. The median age was 70 years, underscoring the relevance to a population in whom conditioning tolerability is often the central limiting issue.
Most patients had detectable measurable residual disease at screening, marking this as a biologically high-risk cohort despite remission status in part of the AML population. Briquilimab was administered 10 to 14 days before transplant day 0. The backbone nonmyeloablative regimen consisted of fludarabine 30 mg/m2 on transplant days -4 to -2 and total body irradiation 2 to 3 Gy on transplant day 0. Graft-versus-host disease prophylaxis included tacrolimus, sirolimus, and mycophenolate mofetil.
Because this was an early-phase trial, the principal objectives were feasibility, safety, engraftment, and pharmacologic and biologic proof of concept rather than formal comparative efficacy. Even so, the investigators reported clinically meaningful 1-year event-free survival and overall survival estimates by disease subgroup.
Key Efficacy Findings
Among patients with AML transplanted in complete remission, the 1-year event-free survival was 69.2%, and the 1-year overall survival was 75.0%. In the MDS cohort, the corresponding 1-year event-free survival was 53.8%, and the 1-year overall survival was 76.4%.
These outcome estimates are best interpreted as signals rather than definitive benchmarks. The cohort was small, nonrandomized, and clinically heterogeneous. Still, several aspects are notable. First, these survival figures were observed in an older population with predominantly measurable residual disease-positive disease, a setting usually associated with elevated relapse risk. Second, the results suggest that adding CD117-directed conditioning did not compromise the practicality of a nonmyeloablative transplant platform. Third, the findings support further study in remission-stage AML and MDS, where the biologic goal of niche clearance and donor engraftment may be most relevant.
The relapsed AML subgroup was too small to support firm inference. Of the 3 patients transplanted with AML in relapse, 1 had a transient response. That limited activity is a useful reminder that an antibody-based conditioning strategy is unlikely to be sufficient on its own in overtly refractory disease with high leukemia burden. In such patients, disease cytoreduction remains critical, and future regimens may need to combine targeted conditioning with stronger antileukemic therapy.
Safety and Engraftment
The safety profile reported in this trial is clinically important. There were no briquilimab infusion reactions, no dose-limiting toxicities, and no primary graft failure events. In an older transplant population, those are meaningful observations. Conditioning-related complications, delayed engraftment, and graft failure can erase the benefit of expanding transplant eligibility. The absence of primary graft failure suggests that CD117 blockade did not impair, and may have supported, the engraftment process when layered onto a standard nonmyeloablative backbone.
The investigators also reported predictable briquilimab clearance across patients. In early-phase transplantation studies, pharmacokinetic consistency matters because underexposure may lead to inadequate stem-cell depletion, whereas excessive or prolonged target saturation might complicate timing, donor-cell uptake, or toxicity. Predictable clearance therefore strengthens the practical feasibility of this approach and supports future dose and schedule optimization.
Although the abstract does not provide a granular catalog of all adverse events, the high-level safety findings are reassuring. For clinicians, the central message is that briquilimab did not appear to add obvious acute toxicity to a regimen already designed for older or more vulnerable patients.
Translational and Mechanistic Findings
The most compelling aspect of this report may be its translational data. Bone marrow samples obtained before briquilimab, after briquilimab, and before fludarabine/total body irradiation showed depletion of AML/MDS-associated hematopoietic stem and progenitor cells by a mean of 62.4% ± 22.7%. At the same time, serum stem cell factor increased approximately threefold.
These findings are mechanistically coherent. If briquilimab blocks stem cell factor binding to CD117 and depletes or functionally displaces target cells, a rise in circulating stem cell factor would be an expected pharmacodynamic consequence. Taken together, the marrow and serum data provide proof of concept that the antibody is not merely present in circulation but is engaging the intended biologic axis in patients.
This matters because many transplant-conditioning innovations fail at the level of mechanism even when they appear clinically tolerable. Here, the study demonstrates a measurable effect on the stem/progenitor compartment that conditioning is designed to target. That does not yet prove superiority over conventional approaches, but it markedly strengthens the rationale for continued development.
Clinical Interpretation and Limitations
This trial should be viewed as an encouraging early step rather than a practice-changing study. Its main strengths are biologic plausibility, careful translational sampling, inclusion of an older high-risk population, and clear demonstration of feasibility and short-term safety. The absence of primary graft failure is particularly reassuring given that any host-stem-cell-directed strategy must ultimately preserve donor engraftment reliability.
At the same time, several limitations deserve emphasis. The sample size was small, with only 32 patients overall and just 3 with relapsed AML. The study was single-arm, so efficacy cannot be compared directly against standard nonmyeloablative fludarabine/low-dose total body irradiation conditioning. The disease groups were heterogeneous, including AML in remission, AML in relapse, and MDS. The abstract reports 1-year event-free and overall survival, but does not provide confidence intervals, relapse incidence, nonrelapse mortality, chronic graft-versus-host disease rates, or longer-term disease control in the summary provided here.
Another key question is whether stem/progenitor cell depletion of about 62% is enough to translate into durable relapse reduction or improved transplant outcomes. Proof of target engagement is necessary, but not sufficient. It remains possible that the clinical value of briquilimab lies more in reducing toxicity than in enhancing antileukemic intensity, or vice versa; randomized data will be needed to define its true contribution.
Generalizability is also limited. These patients underwent matched-donor transplantation with a specific graft-versus-host disease prophylaxis regimen. It is not yet clear whether similar results would be seen with mismatched donors, haploidentical transplantation, different prophylaxis platforms, more advanced disease burden, or younger patients receiving more intensive conditioning.
Implications for Practice and Future Research
For now, briquilimab should be considered an investigational conditioning adjunct. The present study does not justify routine off-trial use, but it does provide a meaningful signal that antibody-based conditioning for myeloid malignancy is clinically viable. In practical terms, the findings support several future directions.
First, randomized studies should compare briquilimab-containing conditioning against standard nonmyeloablative or reduced-intensity regimens, ideally with stratification by measurable residual disease status and disease type. Second, correlative studies should determine whether the degree of CD117-targeted stem/progenitor depletion predicts donor chimerism, relapse risk, or survival. Third, studies in combination with contemporary antileukemic therapies may be especially relevant for patients with persistent MRD or active disease. Finally, long-term follow-up will be crucial to understand relapse patterns, immune reconstitution, graft-versus-host disease, and nonrelapse mortality.
The broader significance is conceptual. Transplant conditioning has historically relied on chemotherapy and radiation that are effective but biologically blunt. This study adds to the growing movement toward targeted conditioning, in which stem-cell niche clearance and immunologic preparation may be achieved with greater specificity. If that approach succeeds in later-phase trials, it could expand transplant access, reduce toxicity, and allow more rational tailoring of conditioning intensity in older adults with AML and MDS.
Conclusion
In this phase 1 study, briquilimab combined with nonmyeloablative fludarabine and low-dose total body irradiation appeared feasible and safe in older adults with high-risk AML or MDS undergoing matched-donor allogeneic transplantation. The absence of infusion reactions, dose-limiting toxicities, and primary graft failure supports practical use in a frail population. Equally important, marrow and serum pharmacodynamic data showed clear biologic activity against the CD117/stem cell factor axis, with substantial depletion of hematopoietic stem and progenitor cells.
The early survival results in AML in remission and MDS are encouraging, but they should be interpreted cautiously given the small, noncomparative design. The main contribution of this study is not definitive proof of improved outcomes, but rather demonstration that targeted anti-CD117 conditioning can be integrated into a standard transplant platform and can achieve measurable stem-cell depletion in patients. That is a meaningful translational advance and a strong rationale for larger comparative trials.
Funding, Trial Registration, and Citation
Clinical trial registration: www.clinicaltrials.gov, NCT04429191.
Funding information was not specified in the source material provided here and should be confirmed from the full article.
Citation: Muffly L, Lee CJ, Gandhi A, Varma A, Scott BL, Patel SS, Shiraz P, Youn M, Yanagiba C, Arulprakasam J, Le A, Kwon HS, Long-Boyle J, Shizuru JA, Pang WW, Artz AS. Nonmyeloablative conditioning combined with the anti-CD117 antibody briquilimab in older adults with high-risk AML and MDS. Blood. 2026-May-28;147(22):2610-2620. PMID: 41785374. URL: https://pubmed.ncbi.nlm.nih.gov/41785374/