All but 1 of the first 19 patients with relapsed/refractory AML randomized to receive iodine-131 apamistamab had a complete response and went on to have successful engraftment of allogeneic hematopoietic stem cell transplant, according to preliminary results from the ongoing, randomized, phase III SIERRA trial that were presented at the 2019 Transplantation and Cellular Therapy Meetings.
Sergio A. Giralt, MD
Sergio A. Giralt, MD
All but 1 of the first 19 patients with relapsed/refractory acute myeloid leukemia (AML) randomized to receive iodine-131 apamistamab (Iomab-B) had a complete response (CR) and went on to have successful engraftment of allogeneic hematopoietic stem cell transplant (HSCT), according to preliminary results from the ongoing, randomized, phase III SIERRA trial that were presented at the 2019 Transplantation and Cellular Therapy Meetings.
The 1 patient who did not have successful engraftment did not receive a therapeutic dose of the iodinated CD45-targeted antibody Iomab-B. Additionally, 9 out of 10 patients who crossed over from conventional treatment had successful engraftment.
Clinical and engraftment characteristics did not differ substantially between patients randomized to Iomab-B and those who crossed over.
“This is the only ongoing randomized phase III clinical trial that offers a transplant option to patients 55 or older with active, relapsed, or refractory AML,” said co-study author Sergio A. Giralt, MD, professor of medicine at Weill Cornell Medical College, the Melvin Berlin Family Chair in Multiple Myeloma, and chief attending of adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center, in a presentation of the findings.
“This is a historically underserved patient population that has a dismal survival prognosis. We have limited options for patients with active disease,” he added. “These are encouraging results that suggest we have the potential to broaden transplant eligibility and improve outcomes.”
CD45 is expressed by a variety of hematopoietic cells, including leukemia, lymphoma, and all immune cells. An accumulation of evidence showed that delivery of high doses of Iomab-B depletes hematopoietic stem cells. Additionally, targeted radiation to leukemia cells elicits a direct antitumor effect.
Phase II clinical evaluation of Iomab-B in patients with active, refractory, and relapsed AML produced compelling evidence of activity. Combined phase I/II data from 271 patients, across 9 clinical trials, offered robust safety and efficacy outcomes in multiple populations, said Giralt.
Encouraging results from the preceding clinical evaluations of Iomab-B led to the randomized, phase III SIERRA trial for patients ≥55 with active, refractory, or relapsed AML. Eligible patients had a bone marrow blast count ≥5% or the presence of peripheral blasts, a Karnofsky score ≥70, and an 8/8 allele-level related or unrelated matching donor.
In the ongoing trial (NCT02665065), 150 patients are randomized 1:1 to receive Iomab-B followed by HSCT or to different standard chemotherapy regimens that were deemed acceptable to treating physicians. Patients who achieve a CR to chemotherapy can continue treatment with a standard-of-care regimen or proceed to HCT. Patients who do not achieve a CR can cross over to Iomab-B. The Iomab-B dose is individualized to achieve radiation exposure to the liver no greater than 24 Gy.
The primary endpoint of the study is durable CR rate, defined as a morphologic CR lasting for at least 180 days; the secondary endpoint was overall survival (OS) at 1 year.
The first 38 randomized patients had similar baseline characteristics, including a median age of about 63 and median bone marrow blasts of 30% in the Iomab-B arm and 26% in the patients randomized to conventional therapy. Four patients in the Iomab-B arm had relapsed/refractory disease, and 10 had primary induction failure, whereas 8 patients in the conventional therapy arm had relapsed/refractory disease, followed by primary induction failure in 6.
The 10 patients who crossed over from conventional therapy to Iomab-B had a median age of 63 (range, 58-72), and 6 patients had relapsed/refractory disease. The patients had 24% bone marrow blasts (range, 6-70) at randomized and 45% (range, 10-70) at the time of crossover.
The 19 patients randomized to Iomab-B had a median time to absolute neutrophil count engraftment of 13 days and a median time to platelet engraftment of 18 days. Full-dose chimerism (>95% prior to day 100) occurred in 16 of 18 evaluable patients. Median time to HSCT, following randomization, was 28 days (range, 23-38) compared with 67 days for 4 patients in the conventional therapy arm who achieved a CR and underwent HSCT.
Giralt said the 10 patients who crossed over to Iomab-Bof the 15 who were eligible—had engraftment parameters nearly identical to those randomized to Iomab-B. Nine of the patients achieved full chimerism and the tenth patient had reached 86% by day 180. The median radiation dose delivered to bone marrow was 18 Gy in the patients randomized to Iomab-B and 16 Gy in those who crossed over.
“In the conventional arm, there was no delay to transplant with crossover to Iomab-B,” said Giralt, who noted that all doses of Iomab-B were administered on time in the randomized and crossover groups, even though the radioisotope was prepared at a central facility and shipped to the treatment center.
Regarding safety, grade 3/4 febrile neutropenia occurred more than twice as often in patients randomized to conventional therapy at 47.4% versus 21.1% with Iomab-B. Hypertension (15.8% vs 5.3%), and hyperbilirubinemia (15.8% vs 5.3%) also occurred more often with conventional therapy than with Iomab-B. Moreover, grade 3/4 fatigue occurred more often in the Iomab-B arm (15.8% vs 5.3%). There were no cases of grade 3/4 infusion-related reactions in the Iomab-B arm.
There were no non-relapse mortalities in the Iomab-B arm at 100 days, compared with 1 patient (25%) on the conventional care arm and 1 (10%) who crossed over to Iomab-B. Based on investigator feedback, Giralt said the protocol was recently amended for earlier crossover at day 14 for progression to potentially reduce such mortality.
Agura E, Gyurkocza B, Nath R, et al. Novel re-induction and anti-CD45 targeted conditioning with iodine (131I) apamistamab [Iomab-B] yields encouraging results in older patients with active, relapsed or refractory AML (R/R AML): safety & feasibility data from the prospective randomized phase III SIERRA trial. Presented at: 2019 Transplantation & Cellular Therapy Meetings; February 20-24, 2019; Houston, TX. Abstract LBA3.