In an interview with Targeted Oncology™, Rajneesh Nath, MD, discussed the need for novel treatment for elderly patients with relapsed/refractory AML and how the SIERRA trial is designed to help.
Certain radiotherapy techniques can impact non-hematologic organs, like the gastrointestinal (GI) tract. The novel strategy of performing myeloablative conditioning is hypothesized to cause less toxicity, specifically in elderly patients with relapsed or refractory acute myeloid leukemia (AML).
The theory is currently being investigated in the phase 3 SIERRA trial (NCT02665065) of the radio immunotherapy Iomab-B versus the standard of care (SOC). Preliminary safety data from the study showed that myeloablative conditioning with Iomab-B led to lower rates of severe mucositis, febrile neutropenia, and sepsis compared with SOC, even though radiation was administered at a high dose. The early findings suggest that use of myeloablative conditioning with Iomab-B may be beneficial to elderly patients with relapsed/refractory AML prior to hematopoietic stem cell transplantation.
One-hundred fifty patients will be enrolled in the study, and preliminary safety results were available for 54. The cohort received a median dose of 636 mCi (range, 354-1027 mCi) of Iomab-B. The median dose of radiation to the marrow in the Iomab-B group was 4.9 Gy (range, 4.6-32 Gy) and to the GI tract was 2.8 Gy to GI tract.
In an interview with Targeted Oncology™, Rajneesh Nath, MD, director of Stem Cell Transplant at Banner MD Anderson, discussed the need for novel treatment for elderly patients with relapsed/refractory AML and how the SIERRA trial is designed to help.
TARGETED ONCOLOGY™: What are outcomes like for patients who cannot tolerate transplant. What was additionally done to help these patients in your study?
Nath: Acute myeloid leukemia is the disease of the elderly. The median age at diagnosis is about 68 years and it's continuing to increase 1 to 2 years. Traditionally, and in different database, we saw that as the patients get older with the diagnosis of AML, they don't tend to do well with whatever treatment we throw at them. And 1 to 2 years survival is of the order of 10% or less. Traditionally, these patients will get an induction chemotherapy, if they can tolerate it. If they go into complete remission, patients who would be eligible for as allogeneic stem cell transplant. There are a lot of beliefs about the elderly patients, most hematologists in have a set cutoff age for after which they will not refer patients to a transplant, but this is not the case anymore. There's several studies that have shown that older patients who undergo allergenic stem cell transplant are able to do equally as well as some of the younger patients.
What was the hypothesis targeted delivery of Iomab-B to the marrow in patients with relapsed/refractory AML?
Generally speaking, there are 2 kinds of transplant myeloablative and reduced intensity. Myeloablation goes with increased intensity of chemotherapy and higher doses of radiation. What happens is this increase intensity increases toxicity. With targeted Myeloablation, what we are doing is delivering radiation where it is needed, and that is to the bone marrow. So, what we are able to do is target radiation to the sites where there is leukemia, and at the same time, save the critical orders that include heart, lungs, kidneys.
In the particular study, what we show is that while we are able to deliver myeloablative doses of chemotherapy to the bone marrow, we can spare the GI tract, which means that there will be less mucositis and GI toxicity which will translate to a decrease in neutropenic fever and sepsis.
Can you provide an overview of the study?
This was an interim analysis of the SIERRA trial of Iomab-B in elderly relapsed/refractory patients with AML. The way that trial worked was if you are over the age of 55, and have a relapsed or refractory acute myelogenous leukemia, and you have a fully matched donor. These patients are randomized one to one either to the Iomab-B, which is the experimental arm or the standard of care arm. If they go to the Iomab-B, they get a transplant, even though they have an active disease at the time. If they go into remission, we look at what is the duration of remission, and the primary end point of the trial is 6-month duration of remission.
In that case that they are randomized to the standard of care, they can get whatever chemotherapy of the choosing of the treating oncologist, if they go into remission after receiving that chemotherapy, they can get a standard stem cell transplant or the treating physicians oncologist team, or if they do not go into remission, they can be crossed over to the Iomab-B arm. What we looked at was the toxicity in these 2 groups of patients.
What were the result of this study?
Only about 4% of the patients in Iomab-B arm had sepsis. This was in contrast to 13% of the patients who receive standard of care treatment. Also, with Iomab-B, we saw 40% neutropenic fever, which would be expected, and less than 10% of the patients had grade 3 or 4 mucositis.
What is next for this study?
Only 75% of the land enrollment is a complete. We expect to complete the study this year when total of 150 patients will be randomized. And the next million-dollar question is we have shown in several of the interim analyses that the procedure is safer and is not toxic. The next real question is, is this effective as compared to the standard of care treatment? Once the analysis is complete, we'll know the answer to that.
As this treatment strategy moves forward in clinical trial development, what is your vision for its future use in this patient population? Are there any other exciting strategies emerging for the older subgroup?
It's an exciting time to be treating elderly patients with acute myeloid leukemia. Until a couple of years ago, we didn't have anything for them, we would just see which patients would be eligible for induction which many of these patients were not. We recently had several new approvals for this disease.
One of the particular areas that I'm excited about is the use of combination of hypomethylating agents with venetoclax [Venclexta]. This combination is able to free a lot of elderly patients and put them into remission. It serves as a pathway to take them to stem cell transplant because the outcomes of stem cell transplant are better if they are done in remission. So, on one hand, we are able to put an increasing number of patients into remission and provide them a pathway for stem cell transplant. On the other hand, if this study works out, we will be having a pathway for patients who do not go into remission, also to proceed with an allergenic stem cell transplant.
In your opinion, what promise does myeloablative targeted conditioning have for the future?
This technology, while initially may be approved for acute myeloid leukemia in the elderly, may have role in several other clinical situations, like patients who have comorbidities and are not able to get full intensity chemotherapy. We can also use this technology in patients who go into transplant with minimal residual disease, though these patients may be technically considered in remission. Because they have small amount of disease, they do not do as well as those patients who are transplanted who are in an MRD-negative state. So, it will open up a lot more areas where we can consider using this technology.
Nath R, Choe H, Stiff P, et al.Myeloablative Targeted conditioning with anti-cd45 iodine (131I) apamistamab [Iomab-b] spares the GI tract and has low incidence of severe mucositis, febrile neutropenia and sepsis in the prospective, randomized phase 3 SIERRA trial for patients with relapsed or refractory acute myeloid leukemia (AML). Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract 59.