Allogeneic hematopoietic cell transplantation (alloHCT) has been found to be a possible curative therapy for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, significant morbidity and mortality can be associated with them based on the risk of graft-versus-host disease (GVHD), relapse, and infection. Moreover, the traditional conditioning regimen for alloHCT is intensive and can be difficult to tolerate for older or frail patients. Therefore, researchers have been working to develop a less-intensive conditioning regimen that can still achieve successful outcomes.
Study Details
In a recent subanalysis from a Phase I study (NCT04429191), a monoclonal antibody called JSP191 (briquilimab); low-dose total body radiation (TBI); and fludarabine, a novel conditioning regimen for alloHCT, were shown to be safe and well-tolerated in patients with AML and MDS.
The Phase Ia/b study assessed the safety and efficacy of briquilimab, low-dose radiation, and fludarabine when treating patients with MDS and AML. Briquilimab inhibits stem cell factor binding to CD117 (c-Kit), depleting hematopoietic stem and progenitor cells (HSPC). Pre-clinical experiments suggest that briquilimab works synergistically with low-dose TBI to deplete normal and malignant HSPC, facilitating donor cell engraftment. This report covers the 1-year follow-up of the 12 subjects with AML in morphologic complete remission (CR) who participated in this study. Subjects with MDS were excluded from this subanalysis due to their significantly shorter median follow-up time.
The trial administered the regimen to 12 eligible patients with a median age of 70 years (range 62-79). Requirements for the study included that patients be aged 18 years and older with MDS and AML in CR undergoing alloHCT, have human leukocyte antigen-matched related or unrelated donors, and have adequate end-organ function. Safety, tolerability, and briquilimab pharmacokinetics were primary endpoints of the study.
After administering briquilimab at a dose of 0.6 mg/kg and evaluating the patients' serum levels, fludarabine was started at 30 mg/m2/day. No infusion reactions or serious adverse events (AEs) related to briquilimab occurred, and the regimen was well-tolerated. At the 1-year follow-up, eight of the 12 patients with AML were found to be free from morphological relapse, and six of the nine patients who received a transplant and had detectable AML showed no measurable residual disease at the last follow-up.
Furthermore, all the patients who participated in the trial received engraftment, and neutrophil recovery occurred between Days 13 and 24 (median time of 19 days). Of the 11 evaluable patients at Day 90, three patients experienced Grade 2-4 acute graft-versus-host disease (aGVHD). Specifically, there was one case of resolved Grade 2 skin aGVHD, one case of late-onset Grade 2 skin aGVHD, and one case of non-relapse mortality resulting from late-onset Grade 3 gastrointestinal aGVHD. Additionally, four patients had moderate chronic graft-versus-host disease (cGVHD), and no patients had severe cGVHD. At 2 months, one patient relapsed, while at 6 months two patients relapsed. The mean full donor myeloid chimerism was 98.5+/-1.3 percent, and the mean total chimerism was 95.6+/-1.3 percent.
Overall, the findings of the study are promising, as the conditioning regimen was well-tolerated and no serious AEs were observed. The use of briquilimab in combination with low-dose TBI and fludarabine appeared to be effective in achieving full donor myeloid chimerism and promoting engraftment of the donor cells.
For additional insights, Oncology Times reached out to study author Lori Muffly, MD, Associate Professor of Medicine at Stanford University, whose interests include clinical research with a focus on improving outcomes in acute leukemia and blood and marrow transplantation.
Oncology Times: What was the rationale of selecting and investigating the agent briquilimab in patients with MDS and AML who are undergoing alloHCT?
Muffly: "Briquilimab is a monoclonal antibody that targets the stem cell factor binding site on CD117, thereby inhibiting stem cell survival. CD117 is also expressed on MDS/AML stem cells. The idea of targeting CD117 on transplant recipients with MDS/AML is that the antibody could help clear out host stem cells and host malignant stem cells prior to donor cell infusion without added toxicity of intensive chemotherapy/radiation."
Oncology Times: What is the pharmacokinetics of briquilimab in older adults with high-risk MDS/AML undergoing alloHCT?
Muffly: "In the patients treated, we found that briquilimab has consistent and reproducible clearance. This is useful because we are able to reliably administer the antibody within 2 weeks of donor stem cell infusion, and likely will not require real-time pharmacokinetics in future studies given the data we have generated."
Oncology Times: What is the event-free survival (EFS) and overall survival (OS) at 1 year in older adults with high-risk MDS/AML undergoing alloHCT with briquilimab in combination with low-dose irradiation and fludarabine conditioning?
Muffly: "In the AML cohort presented at the Tandem meeting with at least 1 year of post-transplant follow-up, we found a 1-year EFS of 67 percent and 1-year OS of 75 percent."
Oncology Times: What other ongoing clinical trials/developing therapies for these patient populations are you intrigued by?
Muffly: "I am excited about approaches that seem to be making transplant safer and more effective for patients with acute leukemia and related disease. The data presented at the Tandem meeting were very impressive with extremely low rates of transplant-related mortality and GVHD. Targeted conditioning, as seen with briquilimab, is the next horizon of transplantation and gene therapy."
Dibash Kumar Das is a contributing writer.