Behind the FDA Approval: Omidubicel for Blood Cancers in Need of HSCT

Mitchell E. Horwitz, MD

A phase 3 trial (NCT02730299) showed that treatment with omidubicel (Omisirge) led to a median time to neutrophil engraftment of 12 days (95% CI, 10-14) compared with 22 days (95% CI, 19-25) for patients treated with a standard umbilical cord blood (UCB) graft (P < .001), leading to the FDA approval of omidubicel for patients with blood cancers in need of allogeneic hematopoietic stem cell transplant (HSCT).

In the open-label, international, multicenter, randomized, phase 3 trial, omidubicel was evaluated in comparison with transplantation of 1 or 2 unmanipulated, unrelated cord blood units in patients with various blood cancers, including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, or lymphoma. Patients enrolled in the study, no matter what cancer type, must have had disease features which rendered them from being eligible for allogeneic transplantation.

The cumulative incidence of neutrophil engraftment by day 42 after transplantation for patients given omidubicel was 96% with a median of 10 days (95% CI, 8-13) vs 89% and with median of 20 days (95% CI, 18-24) among patients treated with the control (P < .001). In the omidubicel arm, patients spent a median of 61 days (range, 0-89) out of the hospital in the first 100 days following transplant vs those in the control arm who spent a median of 48 days in the hospital (range, 0-84). The median time from transplant to discharge from the hospital was 27 days in the omidubicel arm vs 35 days in the control arm, respectively (P = .005).

Differences in graft-vs-host disease (GVHD) and survival between the 2 arms were not statistically significant, and the incidence of grade 2-4 acute GVHD at day 100 was 56% with omidubicel vs 43% with the control (13% difference: 95% CI, −6% to 30%; P = .18). Further, the cumulative incidence of first grade 2-3 bacterial or invasive fungal infections were 37% and 57%, respectively (P = .03), and the rate of first grade 3 viral infection in the first year post transplantation was 10% with omidubicel vs 26% with the control, respectively (P = .02).

In an interview with Targeted Oncology^TM, Mitchell E. Horwitz, MD, professor of medicine, director of the Adult Blood and Marrow Transplant Program, Duke Cancer Institute, Duke University Medical Center, discussed the FDA approval of omidubicel for the treatment of patients with blood cancers in need of an allogeneic HSCT.

Targeted Oncology: Can you discuss the mechanism of action of omidubicel?

Horwitz: Omidubicel is a cell therapy, and the product is derived from umbilical cord blood, allogeneic or donor umbilical cord blood, and the stem cells from the umbilical cord blood unit are expanded, they're grown ex vivo for 3 weeks, expanding considerably and multiplying the hematopoietic progenitor cells in the in the product. That allows us to deliver a higher stem cell and hematopoietic progenitor cell dose to recipients of allogeneic transplant.

What can you tell us about the phase 3 trial of omidubicel? What data led to its approval?

The phase 3 study was a multicenter, randomized, open-label study comparing omidubicel with a standard of care umbilical cord blood transplant. Recipients of the allogeneic umbilical cord blood transplant received either 1 or 2 umbilical cord blood grafts. Patients who received the omidubicel received the expanded umbilical cord blood stem cell graph. The primary end point of the study was the time to neutrophil recovery, the kinetics of hematopoietic recovery after allogeneic transplant. It's important to note that historically, after umbilical cord blood stem cell transplantation, recovery of blood counts is slower than it is after a stem cell transplant from a donor, like a healthy adult donor. That was historically 1 of the limitations of umbilical cord blood transplantation, the speed of recovery, particularly in adult patients.

The primary end point was the time to neutrophil recovery and the secondary end points were the time to platelet recovery, the time spent in the hospital after the stem cell transplant, and the incidence of infectious complications. Subjects were randomized throughout the world, including in the United States, Asia, and South America, and the results showed that the recipients of omidubicel had a considerably faster recovery. They recovered neutrophils, on average, in 12 days following the transplant compared with the control arm, which was 22 days. The primary point was a statistically significant difference, and that was the foundation for approval.

What were the results for the secondary outcome measures of the study?

We found in the study that as compared with a standard umbilical cord blood transplantation, patients spent less time in the hospital, so they were able to be discharged sooner, and they had fewer infections. They recovered platelets faster than a standard umbilical cord blood. These are all paradigm shifting findings of omidubicel with cell transplant.

What is your advice on how to manage toxicities that might come with omidubicel?

That typically applies to other drug approvals and pharmaceuticals. Omidubicel is given in the context of an intensive, risky procedure, and allogeneic transplant is risky, so the conventional metrics of toxicity don't necessarily apply. Safety was an important secondary end point of the study, and we were the first center, here at Duke, to perform the first stem cell transplant over 12 years ago. Since then, close to 150 patients have been transplanted with omidubicel, and long-term follow up has been carefully followed by the sponsor and the manufacturer.

My colleague, Chenyu Lin, MD, recently published a long-term follow up study looking at toxicity, safety, and durability of the product. It does not appear that there is any added toxicity but doesn't mean there's no toxicity or no adverse events. Those who are familiar with allogeneic transplant realize that it's a minority, unfortunately, of our patients who survive long-term. But the toxicity or adverse events or downsides were not apparent there and have not become apparent in the long-term follow-up studies that we've conducted so far.

What advice do you have for community oncologists who want to learn more about the approval?

One of the main messages that should be disseminated out is that there's a perception that if there is a patient is in need of a transplant but who doesn't have a match, for example, a matched donor is typically harder to find in minority populations who don't have siblings, or if they do have siblings, the siblings are not a match, it's been thought that those patients would not be candidates for a potentially curative allogeneic transplant. That has changed over the last 5 to 10 years for a variety of reasons. One important reason for that is that we now are able to use umbilical cord blood transplantation. We have been able to use it for a long time in children, but umbilical cord blood transplantation, with recent advances and techniques and now with the approval of omidubicel, is now quite feasible and successful for adult patients.

Umbilical cord blood grafts or stem cell products don't need to be matched. Those units and those products are derived from a brand-new human being who doesn't recognize that doesn't have the same ability to recognize a recipient as being foreign, so we don't have to match the umbilical cord blood donors. A community oncologist can be assured that if their patient is in need of a stem cell transplant, they will be able to find a suitable donor for everyone, and omidubicel further adds to that reality that we are living in today for patients in need of transplant. We have a donor for everyone.

What do you think is next for this space as a whole or for omidubicel specifically?

For patients who don't have a match, there have been a growing number of options. One option for patients who don't have a match is to use a half-match and to use a donor from the family who's not a match, such as a parent, a child, or a sibling that's a half match. Many, if not most, patients will have half-match options and that has over the years competed with the use of umbilical cord blood as a donor source. The half-matched option has become the most popular option for patients without a match because of the ease with which those products can be obtained. Patients, children or parents or siblings, are willing to give stem cells for their family members.

The downside of umbilical cord blood has been that it's costly, and that there were potential limitations in its efficacy. I think with the approval of omidubicel, we have another option that we need to study further. We need to reconsider umbilical cord blood as a stem cell source in the context of omidubicel and launch studies to answer important questions as to what the benefits and disadvantages are, and how this new stem cell product fits in our field. Those studies have been slow to emerge because we have had the feeling that we need to know about umbilical cord blood stem cells. But now, this changes everything. New questions arise, and that's incumbent on the stem cell transplant community to conduct these studies so that when a community oncologist refers a patient for a transplant or stem cell transplant, they know that their patients will have the best chance of survival and coming back to them for their long-term follow-up.

Some will also argue that there will be an additional cost that we assume will be part of omidubicel. But I think that, again, it will be incumbent on us as a community to do cost effectiveness analysis and take into account all these other positive characteristics of an omidubicel stem cell transplant and determine whether, in fact, it is worth the added costs.