Studies have shown that older patients with either active, relapsed, or refractory acute myeloid leukemia have had lower survival rates, poor risk assessments, and limited therapeutic options. The standard care of these patients is salvage chemotherapy. Investigators are pretreating patients in this high-risk population with Iomab-B, a novel radiolabeled antibody–drug conjugate as part of a stem cell transplantation regimen in hopes of improving remission and survival outcomes.
John M. Pagel, MD, PhD
Studies have shown that older patients with either active, relapsed, or refractory acute myeloid leukemia (AML) have had lower survival rates, poor risk assessments, and limited therapeutic options. The standard care of these patients is salvage chemotherapy. In a currently accruing clinical trial, investigators will be pretreating patients in this high-risk population with Iomab-B, a novel radiolabeled antibodydrug conjugate, as part of a stem cell transplantation regimen, in hopes of improving remission and survival outcomes.
“For a high-risk refractory AML patient, and one who may be older, it is highly unlikely that they will have significant long-term survival. So, this is an opportunity for them to get something that willhopefully—control their disease, allow them to get a transplant, and give them some long-term survival advantage,” said John M. Pagel, MD, PhD, chief of hematologic malignancies and director of stem cell transplantation at the Swedish Cancer Institute in Seattle, Washington and study chair for the trial assessing Iomab-B.
Currently enrolling, the phase III SIERRA trial (NCT02665065) plans to randomize patients to Iomab-B or conventional chemotherapy as a preconditioning regimen before allogeneic hematopoietic cell transplantation (HCT). The primary endpoint for the study is durable complete remission; a secondary endpoint will be overall survival (OS). Participants in the control arm who do not achieve a complete response by day 42 will have the option of moving to the Iomab-B arm.
Patients eligible for the trial must be older than 55 years with active replaced or refractory AML. Participants cannot have received HCT or prior radiation to maximally tolerated levels to any critical normal organ or have any central nervous system involvement. They must also demonstrate a Karnofsky score of 70 or higher and CD45 expression by leukemic cells via flow cytometry.
Iomab-B is a radioimmunoconjugate consisting of BC8, a murine monoclonal antibody, and iodine-131 radioisotope. Its purpose is to target CD45, a pan-leukocytic antigen widely expressed on white blood cells and the hematopoietic stem cell system.1
“We give a very high dose of radioiodine that’s targeted to the sites of disease, so the antibody will localize to the bone marrow and other hematolymphoid organs but won’t deliver radiotherapy to normal organs. The concept is, you’re delivering targeted radiation to sites of disease, and you’re trying to limit the amount that’s going to normal organs. When you do that, you can escalate the dose to a higher level, so that you can, hopefully, eradicate all of the leukemia," Pagel said.
This method leads to the ablation of the patient’s bone marrow. This is part of the stem cell transplantation regimen. Through ablation of bone marrow via CD45 targeting, Iomab-B may facilitate hematopoietic cell transplantation by the destruction of leukemia cells and hosting of immune system cells, which also prevents rejection of the donor cells.1
According to a study published in Blood by Pagel and colleagues, clinicians treating older patients with AML are limited in their ability to use the high-dose preconditioning myeloablative regimens which have proven effective in candidates for HCT, primarily due to the risks of nonrelapse mortality and graft-versus-host disease.2
“[The study] showed that survival rates in these high-risk patients could be about 40%, and that would be a major improvement over what we would expect with the standard stem cell transplant or, certainly, with standard cytoreductive chemotherapy,” added Pagel.
Iomab-B was generally well tolerated. Most adverse events discovered are being manageable. Of a total of 58 patients, 17% had chills, with 20% requiring treatment with meperidine; 12% experienced nausea and vomiting; and 26% developed respiratory symptoms, such as throat or chest tightness. In addition, 2% of patients developed grade 2 hypotension that required treatment with parenteral fluids.2The drug also can cause mucositis but is otherwise well tolerated, Pagel said.
“All patients will have reduction in their blood counts, and that could lead to subsequent risk for infection,” Pagel said.
The study estimated OS and disease-free survival, according to the Kaplan-Meier method. A 1-year survival estimate of 41% (95% CI, 28%-54%) among all 58 patients was found in the assessment of the study. The 1-year survival estimate was 46% (95% CI, 20%-71%) in patients with AML in remission, 46% (95% CI, 20%-71%) in patients with AML in relapse, 38% (95% CI, 12%-65%) in patients with refractory disease, and 33% (95% CI, 9%-57%) in patients with high-risk myelodysplastic syndrome.2
Serving now as the basis for the SIERRA trial, this study demonstrated that the drug warranted further testing.
“If [the SIERRA] trial is successful, the next steps could be to explore [Iomab-B’s] use in other patients with perhaps favorable-risk AML, in other hematologic malignancies, as well as other nonhematologic malignancies as an option for curative intent."
Based in New York, New York, iomab-B is developed by Actinium Pharmaceuticals, Inc.