Antibody Therapy in Acute Myeloid Leukemia Conditioning: Can We Improve Upon the Depth of Response?

Study Title: Study of Iomab-B Prior to HCT vs. Conventional Care in Older Subjects With Active, Relapsed or Refractory AML (SIERRA)

ISRCTN Number:NCT02665065

Sponsor: Actinium Pharmaceuticals

Accrual Goal: 150 patients

Participating Centers: 16 centers around the United States

Study Design: This is a phase III randomized study of adding Iomab-B, a monoclonal antibody directed at CD45 and linked to radioisotope iodine-131, to a reduced-intensity conditioning (RIC) regimen and protocol-specified allogeneic hematopoietic stem cell transplantation (HSCT) for patients with relapsed or refractory acute myeloid leukemia (AML) older than 55 years.

Primary Endpoint: Durable Complete Remission (dCR): defined as CR or CRp lasting at least 180 days.

Secondary Endpoints: Overall Survival (OS) at one year from randomization.

Rationale: Relapsed or refractory AML is a devastating condition. Once CR is achieved, approximately 50 percent of patients younger than 60 years, and up to 90 percent of patients older than 60 years will relapse despite consolidation strategies. Primary refractory disease is present in between 20 to 25 percent of patients. Allogeneic stem cell transplantation (ASCT) offers the best hope of durable remission or cure, yet many older patients have health conditions that prevent the use of myeloablative strategies (such as whole-body radiation) during conditioning. This puts them at high risk for post-transplantation relapse.

Strategies that have tried to increase the intensity of preparative regimens may increase non-relapse mortality. This study incorporates targeted marrow ablation with a CD45 monoclonal antibody conjugated to the radioisotope iodine-131 as part of a reduced-intensity conditioning regimen. The aim is to test the hypothesis that a radioimmunoconjugate provides improved pretransplantation disease control and prolongs the remission duration in this very high-risk population.

Comment: There is no true standard of care for relapsed/refractory AML. For patients with fitness to proceed to ASCT, salvage chemotherapy is aimed at inducing a remission, or at least disease reduction, as a bridge to transplantation. Salvage regimens vary, and few have been rigorously compared against one another to establish relative efficacy or toxicity. Most include high-dose cytarabine, purine analogs, or anthracyclines.

And yet, we know that disease control prior to transplantation is a key factor in that undertaking’s success. Either failure to achieve a remission or the presence of minimal residual disease prior to allogeneic hematopoietic cell transplantation have been associated with increased risk of relapse and death in patients with AML.^1,2  It is unclear whether even myeloablative conditioning can overcome inadequate disease control.³  And what about patients with comorbidities? Reduced-intensity transplantation, which banks at least a portion of its success on graft-versus-tumor effect, may be especially handicapped by residual disease.

Thus, this is an area ripe for clinical research. There have been several approaches. One option is a bridging strategy where patients are taken directly to transplantation if they achieve at least some cytoreduction with salvage therapy — typically roughly two weeks after attempt at reinduction.⁴  A second approach is the use of mutation-directed agents such as incorporating therapy targeted against the Fms-like tyrosine kinase 3-internal tandem duplication, or aberrant isocitrate dehydrogenase. Incorporating antibodies into salvage or conditioning is also an option.

In 2009, researchers at the Fred Hutchinson Cancer Center published results of 58 patients older than 50 years who were treated with this iodine-131–labeled anti-CD45 antibody.⁵  The agent was designed to deliver targeted hematopoietic irradiation to the marrow, spleen, and lymph nodes prior to transplantation and was combined with a standard reduced-intensity conditioning regimen. The combination produced complete remission in all patients without impairment of engraftment. Twelve percent of patients died of non-relapse causes by day 100, and the rate of recurrent disease was 40 percent at one year. A similar study of 16 patients younger than 50 years was published in 2014.⁶  Both were aimed at finding a maximal-tolerated dose of the ¹³¹I-BC8 AB, now called “Iomab-B.”

The current study aims to test this preliminary data in a large number of patients at multiple centers. Researchers are recruiting patients older than 55 years with active, relapsed, or refractory AML. Patients will then be randomized to salvage therapy or to the Iomab-B treatment group. In the investigative arm, patients will get an individualized dose of the radioimmunoconjugate and then proceed to a fludarabine and low-dose TBI conditioning regimen following by infusion of donor cells. Patients on the control arm will get salvage therapy. They may cross over to the radioimmunoconjugate arm if not in CR.

Whether this strategy works and produces durable remissions remains to be seen. However, it does emphasize a true need in this patient population. While improvements in supportive care and graft-versus-host disease treatments are essential, relapse is the greatest threat to survival after an allograft for high-risk AML. Deeper pretransplantation remissions achieved safely must remain a key investigative priority.