Transplant Possible For Recurrent AML With Iomab-B Conditioning Regimen

Edward Agura, MD

A targeted conditioning regimen may help to bridge patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to allogeneic hematopoietic cell transplantation (HCT), according to preliminary feasibility and safety findings from the pivotal randomized phase III SIERRA trial.¹

Iodine (¹³¹I) apamistamab (Iomab-B) was well tolerated among patients with R/R AML who were 55 years or older. A faster time to transplant was observed among patients randomized to receive Iomab-B compared with those who received conventional care.

“SIERRA is designed to prove for the first time in a randomized fashion that if you are 55 years of age or older, if you have leukemia and the leukemia has come back, [Iomab-B] is a treatment option which seems to eradicate leukemia in a way that does not produce unusually harsh adverse effects and appears to be easier to undergo than a standard transplant,” said the study’s lead author, Edward Agura, MD, who presented the findings at the 60th American Society of Hematology (ASH) Annual Meeting & Exposition.

Iomab-B, a murine anti-CD45 targeted agent, delivers targeted radiation directly to the leukemia cells. By targeting CD45, which is expressed on hematopoietic cells, Iomab-B given at high doses can deplete these stem cells.

Findings from earlier trials among patients with R/R AML suggested a 1-year overall survival (OS) rate of 30% with Iomab-B before transplant compared with 10% with salvage chemotherapy.^2,3

SIERRA is an ongoing multicenter, randomized phase III trial investigating targeted conditioning therapy with Iomab-B prior to stem cell transplant (NCT02665065). In the trial, patients with R/R or active AML were randomized 1:1 to either Iomab-B followed by HCT or conventional chemotherapy, which could be followed by HCT or standard-of-care therapy at the physician’s discretion if patients achieved a complete response (CR). Those in the control arm who did not achieve a CR were able to cross over to receive Iomab-B.

“SIERRA is the first randomized phase III study that is comparing [this kind of] transplant treatment, one using a radioiodinated antibody to ablate the marrow, with conventional chemotherapy,” said Agura, of Baylor University Medical Center in Dallas, Texas, in an interview withTargeted Therapies in Oncology. “It is a randomized comparison, and that has never been done before. It is specifically designed for patients who are 55 years or older and who have recurrent or relapsed leukemia. That puts them in a very challenging group who are difficult to treat by chemotherapy or other methods.”

To be eligible for the trial, all patients must have had primary induction therapy failure after &ge;2 cycles of chemotherapy, first early relapse after remission of <6 months, disease refractory to salvage combination chemotherapy with high-dose cytarabine, or second or subsequent relapse. Additionally, patients needed to have bone marrow blast count of &ge;5% or peripheral blasts and a Karnofsky performance status of &ge;70. The primary endpoint of the study is durable CR rate, defined as morphologic CR lasting &ge;180 days, and the secondary endpoint is the 1-year OS rate.

Nineteen days before transplant, Iomab-B was administered at approximately 10 to 20 mCi with dosimetry for 7 days, followed by 24 Gy to the liver at a mean of 600 mCi. In the 4 days leading up to HCT, fludarabine was administered at 30 mg/m²/day for 3 days followed by 1 day off, then total body irradiation at 200 cGy.

During his ASH presentation, Agura focused on feasibility and safety findings from the first 25% (n = 38) of enrolled patients. The patients&rsquo; median age was 63 years (range, 55-76) and primary induction failure was the most common disease status (42%). At randomization, there was a median of 30% (range, 4%-74%) bone marrow blasts in the patients randomized to Iomab-B versus 26% (range, 6%-97%) in the group randomized to conventional care.

Following treatment, 15 patients (79%) in the control arm did not achieve a CR, and of these, 10 (67%) crossed over to receive Iomab-B and were able to undergo transplant.

In the investigational arm, 18 of 19 patients proceeded to transplant; 1 patient could not due to unfavorable dosimetry. All 18 patients successfully engrafted despite the high blast count seen at randomization, with a median of 13 days (range, 9-22) to absolute neutrophil count (ANC) engraftment and 16 days (range, 13-26) to platelet engraftment. HCT was performed after a median of 28 days (range, 23-38).

In the group of patients who crossed over to receive Iomab-B, ANC engraftment was completed by a median of 13 days (range, 9-20); the median was 17 days (range, 10-20) to platelet engraftment. HCT was performed after a median of 66 days (range, 57-161).

HCT was performed in the conventional care arm for those who achieved a CR at a median of 67 days (range, 66-86).

A safety assessment was completed up to 100 days post transplant or until crossover. However, as per protocol, the adverse event (AE) profile was not collected post crossover.

Fewer grade 3/4 nonhematologic AEs were noted in the group of patients randomized to Iomab-B versus those randomized to receive conventional care, notably including febrile neutropenia (21.1% vs 47.4%, respectively), sepsis (0 vs 21.1%), hypotension (5.3% vs 15.8%), and hyperbilirubinemia (5.3% vs 15.8%). However, there were more observed cases of fatigue in the investigational arm versus the control arm (15.8% vs 5.3%, respectively).

Rates of nonhematologic grade 3/4 AEs in patients who crossed over to receive Iomab-B and then transplant were similar to rates in those who had been randomized initially to Iomab-B, with the exception of sepsis (30% vs 0%, respectively) and fatigue (0% vs 16%).

&ldquo;The adverse effects are the same in terms of the numbers of patients in both treatment arms, so it appears to be no better or no worse than the effects patients would have if they did not participate in the trial,&rdquo; Agura commented.

Grade 3/4 acute graft-versus-host disease (GVHD) was observed in 1 patient randomized to Iomab-B and in 2 patients who crossed over; chronic GVHD was seen in 2 patients in the Iomab-B arm and 2 who crossed over, but all cases were mild. One case of grade 2 veno-occlusive disease was seen in the Iomab-B arm from days 9 to 17 post transplant, but it was resolved, and no grade 3/4 infusion-related reactions were observed from Iomab-B treatment.

After 100 days from transplant, 1 patient who crossed over and 1 patient in the control arm who achieved a CR died, and not from relapse. The causes were diffuse alveolar hemorrhage and septic shock, respectively.

No nonrelapse mortality was observed in patients who were randomized to the Iomab-B arm, nor were there increases in nonrelapse mortality with additional salvage therapy before transplant.

Agura noted that the trial protocol was recently amended based on investigator feedback to allow for earlier crossover, at day 14, to potentially reduce the degree of mortality and reduce the time to transplant. Further updates are planned from the SIERRA trial for 50% and 75% of enrolled patients.

References:

1. Agura E, Gyurkocza B, Nath R, et al. Targeted conditioning of Iomab-B (¹³¹I-anti-CD45) prior to allogeneic hematopoietic cell transplantation versus conventional care in relapsed or refractory acute myeloid leukemia (AML): preliminary feasibility and safety results from the prospective, randomized phase 3 Sierra trial. Presented at: 60th American Society of Hematology Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 1017. ash.confex.com/ash/2018/webprogram/Paper111914.html.
2. Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.Blood.2009;114(27):5444-5453. doi: 10.1182/blood-2009-03-213298.
3. Armistead PM, de Lima M, Pierce S, et al. Quantifying the survival benefit for allogeneic hematopoietic stem cell transplantation in relapsed acute myelogenous leukemia.Biol Blood Marrow Transplant.2009;15(11):1431-1438. doi: 10.1016/j.bbmt.2009.07.008.