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Novel Radiolabeled ADC Could Improve Outcomes in High-Risk AML

Ariela Katz
Published: Monday, Apr 02, 2018

John Pagel, MD, PhD
John Pagel, MD, PhD
Older patients with active, relapsed, or refractory acute myeloid leukemia (AML) have a low survival rate, very poor risk assessments, and limited therapeutic options, with conventional care consisting primarily of salvage chemotherapy. To address this high-risk population, investigators are pretreating these patients with a novel radiolabeled antibody–drug conjugate, Iomab-B, as part of a stem cell transplantation regimen aimed at 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,” said John M. Pagel, MD, PhD, chief of hematologic malignancies and director of stem cell transplantation at the Swedish Cancer Institute in Seattle, Washington. “So, this is an opportunity for them to get something that will—hopefully—control their disease, allow them to get a transplant, and give them some long-term survival advantage.” Pagel is the study chair for the trial assessing Iomab-B.

The phase III SIERRA trial (NCT02665065), which is currently recruiting, will randomize patients to Iomab-B or conventional chemotherapy as a preconditioning regimen before allogeneic hematopoietic cell transplantation (HCT). The primary endpoint is durable complete remission, with overall survival (OS) as the secondary endpoint. Notably, participants in the control arm who do not achieve a complete response by day 42 will have the option of crossing over to the Iomab-B arm.

Patients who are eligible for the trial must be over 55 years old and have 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 also must have a Karnofsky score of 70 or greater and documented CD45 expression by leukemic cells via flow cytometry.

Iomab-B is a radioimmunoconjugate consisting of BC8, a murine monoclonal antibody, and iodine-131 radioisotope. It is designed 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,” Pagel said. “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.” This method leads to the ablation of the patient’s bone marrow, which is part of the stem cell transplantation regimen. Through ablation of bone marrow via CD45 targeting, Iomab-B may facilitate hematopoietic cell transplantation via destruction of leukemia cells and host immune system cells, which also prevents rejection of the donor cells.1

Currently, clinicians who treat older patients with AML are limited in their ability to use the high-dose preconditioning myeloablative regimens that have proved effective in candidates for HCT, primarily because of the risks of nonrelapse mortality and graft-versus-host disease, according to a study published in Blood by Pagel and colleagues.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,” commented Pagel.

Iomab-B was generally well tolerated, with most adverse events being manageable. “All patients will have reduction in their blood counts, and that could lead to subsequent risk for infection,” Pagel said. 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.2 The drug also can cause mucositis but is otherwise well tolerated, Pagel said.

The same trial estimated OS and disease-free survival according to the Kaplan-Meier method. The assessment showed a 1-year survival estimate of 41% (95% CI, 28%-54%) among all 58 patients. The 1-year survival estimate was 46% (95% CI, 20%-71%) among 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


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