Briquilimab/Low-Dose TBI/Fludarabine Shows Promise in MDS/AML Undergoing AlloHCT

In an interview with Targeted Oncology, Lori Muffly, MD, discusses the subanalysis of a phase 1 study of briquilimab plus low-dose total body radiation and fludarabine which was presented at 2023 Tandem Meetings on Transplantation and Cellular Therapy.

Lori Muffly, MD

Lori Muffly, MD

The novel conditioning regimen of briquilimab (formerly known as JSP191) plus low-dose total body radiation (TBI) and fludarabine was safe and well-tolerated in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who are undergoing allogeneic hematopoietic stem cell transplantation (alloHCT), according to a sub-analysis from a phase 1 study (NCT04429191).

In this phase 1a/b study, investigators are assessing the safety and efficacy of briquilimab, low-dose radiation, and fludarabine for the treatment of patients with MDS and AML. Eligibility criteria for the trial required patients to be aged 18 years and older with MDS and AML in complete remission (CR) undergoing alloHCT, have human leukocyte antigen matched related or unrelated donors, and adequate end organ function.

A total of 12 patients with a median age of 70 yrs (range 62-79) were enrolled. Following infusion of briquilimab at a dose of 0.6 mg/kg, patients’ serum levels were evaluated to determine the start of fludarabine at 30 mg/m2/day.

Recent data showed that at 1-year of follow-up, 12 patients with AML had no infusion reactions and no briquilimab-related serious adverse events (AEs). The regimen was well tolerated and 8 of the 12 (67%) patients with AML were determined to be free from morphological relapse. Six of 9 (67%) patients who received a transplant with detectable AML reported no measurable residual disease at last follow-up.

Additionally, all patients enrolled in the trial were given engraftment with neutrophil recovery between day 13 and 24 (median time of 19 days). There were 11 evaluable patients at day 90 who achieved full donor myeloid chimerism (mean 98.5±1.3%) and total chimerism of 94% (mean 95.6±1.3%).

For safety, grade 2-4 acute graft-versus-host disease (aGVHD) was observed in 3 patients. There was 1 case of grade 2 skin aGVHD that was resolved, 1 case of late-onset grade 2 skin aGVHD, and 1 case of non-relapse mortality which resulted from late-onset grade 3 gastrointestinal aGVHD.

While 4 patients had moderate chronic graft-versus-host disease (cGVHD), no patients had severe cGVHD. At 2 months, 1 patient relapsed while 2 patients relapsed at 6 months.

In an interview with Targeted OncologyTM, Lori Muffly, MD, associate professor of medicine at Stanford University in the Division of Blood Marrow Transplant and Cellular Therapy, discusses the rationale of this subanalysis and findings which were presented at2023 Tandem Meetings on Transplantation and Cellular Therapy.

Targeted Oncology: How did this trial come about?

Muffly: This abstract is a sub-analysis from a phase 1 study of an agent called briquilimab, formerly called JSP191. This agent is a CD117 targeting monoclonal antibody and we studied it in a phase 1 study in combination with low-dose total body irradiation and fludarabine in older adults with acute myeloid leukemia and MDS undergoing allo transplant. The abstract that I presented on is a sub-analysis of the AML population who have reached the 1-year time point post-transplant.

This agent was developed with the idea of, can we do bone marrow stem cell transplant conditioning more safely and effectively? The target of CD117 is appealing because it's expressed on both hematopoietic stem cells, as well as on MDS and AML stem cells. If we can potentially use this antibody to eradicate both populations, at least to some extent, that could potentially lessen the need for intensive chemotherapy. This is why we chose to study, initially in AML and MDS, this antibody in an older adult population where we use a very low intensity conditioning regimen, because we know that with low intensity conditioning or nonmyeloablative conditioning, the big issue we have is not necessarily tolerability, but it's relapse. If we could potentially add something that's not toxic, but that improves the myeloablation and the disease control, could we improve outcomes?

Can you discuss the methods and design of the study?

This study is phase 1. The primary objectives are to understand the dosing of the antibody, how it should be best given, and the safety and toxicity profile with this combination. We treated up to 30 plus patients in this study with both AML and MDS, but I presented on 12 patients. These were the AML patients who were in morphologic remission at time of transplant and have reached at least 1 year of follow-up post-transplant.

Interestingly, and kind of what we had expected since this was targeting older adults with AML and MDS patients, the median age of the population of these 12 patients was 70, and the upper age was 79 years of age. We found in terms of the primary aims of the study, 1 of the things that was important was looking at the pharmacokinetics, or the clearance of this antibody since it's targeting CD117, which is expressed as hematopoietic stem cells. Since we subsequently infused donor hematopoietic stem cells, it was important to make sure that the antibody would clear before the donor cell infusion.

What findings were presented at the Tandem meeting?

We were pleased with the fact that the pharmacokinetic data showed consistent and predictable clearance of this antibody to the point where in subsequent studies, we believe that the clearance is so predictable that real time pharmacokinetics would not be needed after dosing this agent.

This was a safe combination. There were no significant infusion reactions, there was no briquilimab associated with severe serious adverse events, and no patients experienced graft failure. All patients had full engraftment. In terms of the efficacy, of the 12 AML patients, 9 of them entered transplant with detectable MRD and the MRD was assessed by either flow cytometry, next generation sequencing, or a combination thereof. That's a high-risk population with a median age of 70, 9 out of 12 MRD-positive at time of transplant. At the 1-year follow-up time, 67% of these patients, or 8 of 12, are alive and are MRD-negative. MRD clearance occurred in the 9 who came in positive and occurred in 6 patients with the median time of clearance of 90 days. The overall survival at 1-year was also 67%, so 8 of 12 patients were alive, and half of the patients, so 6 of the 12 were alive at 1 year without the need for ongoing immunosuppression.

We were excited about these results. I think they confirmed that this antibody that targets hematopoietic stem cells can be given to older patients with this backbone of flu/TBI. With predictable clearance, it's very safe. There were really no adverse events with the antibody and a 67% relapse-free survival at 1 -year post-transplant. That was quite exciting for us, and the non-relapse mortality was only 8%. Only 1 patient died of transplant-related factors. The MRD clearance occurred in the majority. So, we are excited about these data and about what they say about the future of targeted conditioning in transplant.

What do you anticipate the next steps for this research are?

This antibody, briquilimab, is being studied in a whole array of different transplant settings. The majority are in non-malignant diseases where transplant is more readily utilized in children. We know that the use of cytotoxic therapies can lead to effects. [Jasper Therapeutics] has a whole bunch of different abstracts that they presented, and also ongoing studies in sickle cell disease, aplastic anemia, and some others. In terms of the myeloid malignancy population, this is the first data to come out with this antibody. My hope is that we continue to study this antibody in AML and MDS conditioning. I think it would be interesting to look at this antibody in combination with different conditioning regimens and different patient populations.

One of the things that's important to note about this antibody is that the preclinical data and Jasper believe strongly that it synergizes with radiation therapy. It is important when choosing the conditioning regimen, that it's a radiation-based regimen. That is something that is important as we think about next steps, whether to use this fludarabine/TBI backbone or to build off of this experience with additional backbones.

What unmet needs still exist in this space?

There are many unmet needs and our biggest problem with allo transplant remains leukemia, relapse, MDS, and AML relapse. We have a great need to reduce post-transplant relapse rates. We have been working diligently over the last 10 years or so on reducing toxicity of transplant with a bunch of different novel and new approaches. That work continues, but as we reduce toxicity, I think continuing to focus on efficacy and reducing post-transplant relapse rates is incredibly important. I think this backbone including the briquilimab is exciting because it's so safe and it allows for even thinking about additional add-ons that could be explored.

Muffly L, Lee CJ, Varcma A, et al. Subanalysis from phase 1 study of JSP191, an anti-CD117 monoclonal antibody, in combination with low dose irradiation and fludarabine conditioning, shows durable remissions in older adults with acute myeloid leukemia in complete remission undergoing allogeneic hematopoietic cell transplantation. 2023 Transplantation and Cellular Therapies Meeting. February 15-19, 2023. Orlando FL. Abstract 59
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