In an interview with Targeted Oncology, Sergio A. Giralt, MD, discussed recent data from the study.
Due to the toxicity that is associated with myeloablative conditioning, most patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) who are above the age of 55 years cannot undergo hematopoietic stem cell transplantation (HSCT), leaving these patients with limited treatment options.
Investigators led by Rajneesh Nath investigated a novel treatment strategy that may help get these older patients safely get patients to HSCT. Findings from conditioning with I apamistamab (Iomab-B) in older patients with R/R AML were reported this year during the 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.
The prospective SIERRA trial (NCT02665065) analyzed the safety and efficacy of Iomab-B versus conventional chemotherapy for the treatment of older patients with active or R/R AML. The study has an estimated enrollment of 150 participants randomized equally into 1 of 2 arms. In arm 1, patients received Iomab-B and a reduced intensity conditioning regimen containing fludarabine (Fludara) and low-dose total body irradiation (TBI) prior to allogeneic HSCT. In arm 2, patients received investigator’s choice of chemotherapy. Those who went into remission underwent HSCT.
At the time of the interim analysis, 75% of patients were randomized. The median dose of Iomab-B was 636 mCi (range 354-1027 mCi). The median dose of radiation delivered to the bone marrow in the Iomab-B group was 14.0 Gy. All patients treated with Iomab-B engrafted, with a median time of 14.5 days. The rate of marrow blasts prior to transplant was 27%.
The safety portion of the analysis showed no correlation between Iomab-B activity, mucositis, and sepsis. Additionally, the rate of adverse events was lower in the Iomab-B group than the control.
In an interview with Targeted Oncology, Sergio A. Giralt, MD, deputy division head, Division of Hematologic Malignancies; Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center and a co-investigators of the SIERRA trial, discussed recent data from the study.
TARGETED ONCOLOGY: Can you discuss the current unmet medical need for the group of older patients with R/R AML?
GIRALT: Patients with active acute myelogenous leukemia have worse outcomes after an allogeneic transplant because the risk of recurrence is so high. Many programs decided not to pursue transplant in a patient with acute myelogenous leukemia unless they're in remission.
However, the only curative strategy for these patients is actually an allogeneic transplant. It's associated with better outcomes than conventional chemotherapy. Either you get a transplant or people get phase 1 drugs. And we know that the best way to get these people in remission is to try to do a transplant. The thing is that the remissions don't last very long. So, new drugs that can help patients bridge to a transplant in a better situation with a lower tumor burden, are really needed. Iomab-B is one of those drugs that have shown to be very active and to still make transplant feasible. The other challenge when you try get patients in remission and the drugs are associated with toxicities, it either makes the transplant impossible, or it makes the transplant more difficult.
What were the key goal of the study?
The key goal for the SIERRA study was to determine and to demonstrate that Iomab-B followed by a reduced intensity conditioning regimen of fludarabine and low dose TBI would be associated with better outcomes defined as being in a sustained complete remission for more than 6 months after transplant. Then conventional chemotherapy followed by a regular transplant. So, these were 150 patients that were randomized equally to Iomab-B versus conventional chemotherapy. Patients with Iomab-B would go to a fludarabine low dose TBI conditioning regimen, and then an allogeneic transplant with a matched sibling or an unrelated donor. Patients in the control arm would get conventional chemotherapy. And if they achieve the complete remission, they would then go on to a reduced intensity conditioning regimen.
Looking further into the study design, what were the end points that were explored for the study?
To be eligible patients had to have refractory acute myeloid leukemia, as defined by primary induction failure after at least 2 cycles of induction or relapsed after first remission that lasted less than 6 months or in a second or higher relapse. They have to be over the age of 55. So again, looking at this older population. The experimental arm received Iomab-B at a maximum dose of calculated of 24 grade to the liver, and then fludarabine, and TBI and peripheral blood stem cell transplant. The control arm would get a physician choice of a variety of salvage chemotherapy options. And then if they achieved a complete remission, they would to a consolidative reduced-intensity conditioning regimen transplant. So primary endpoint was what I discussed, durable complete remission, as defined by durable complete remission lasting more than 6 months. And complete remission was defined by standard criteria. The secondary endpoints were obviously engraftment, toxicity and survival rates. And obviously looking at resource utilization, time in the hospital, occurs of graft versus host disease, and incidence of graft rejection.
Can you explain the results and what conclusions were drawn from these results?
There were 2 oral presentations regarding the SIERRA study at tandem. One was Rajneesh Nath, MD, of Banner Health, and the other one was Boglarka Gyurkocza, MD, from Memorial Sloan Kettering Cancer Center. Dr. Nath was presenting about the risk of mucositis. What's interesting is that the occurrence of mucositis was significantly less in the Iomab-B arm versus the control group. I reminded everybody what was presented, this was still preliminary data, we need the final trial to finish to get a better idea of how much different the toxicity profiles are. But it looked very interesting that the really the incidence of severe mucositis was much less with the Iomab-B, fludarabine, and TBI. Now whether that was because the people in the Iomab-B group were getting fludarabine, TBI conditioning regimen, which is very well tolerated. Or was it actually Iomab-B? We don't think Iomab-B protected against toxicity. What it allows you to do is give a much less intense conditioning regimen then what the people in the control group were getting, which usually was either fludarabine busulfan or fludarabine melphalan. And then the one thing that we still have to look at is the people in the Iomab-B group, many of them were getting many dose methotrexate while the people in the reduced conditioning regimen, we don't know how many of them were getting many dose methotrexate, and the dose of methotrexate does affect your risk of mucositis.
What were the results on successful and timely engraftment not related to radiation dose delivered?
One of the things is, when we started doing the study, there was a concern in patients who the dissymmetry predicted that you would give low doses of radiation, that there may be problems with engraftment. Many of us said this is unlikely because the fludarabine, low dose TBI platform had shown that it was very successful in getting engraftment in more than 90% of the patients. But still, we didn't have multi center experiences. I think what this study showed is that regardless of the dose of radiation received, patients engrafted successfully and there were no graft failures in the group that was randomized to Iomab-B. And I think there was only one patient who failed to engraft in the crossover group. But what we saw was universal engraftment, despite variation and doses delivered, the medium was 636mg, but it ranged from 354 to 1027. So again, the concern that there may be problems with engraftment, and patients who receive the lower dose of Iomab-B does not seem to be true.