February 17, 2023

Kristi Rosa

Orca-Q when using myeloablative conditioning with only tacrolimus monotherapy in the haploidentical stem cell transplant setting had acceptable safety and resulted in encouraging outcomes for patients with high-risk hematologic malignancies.

Samer A. Srour, MD, MS

Orca-Q when using myeloablative conditioning (MAC) with only tacrolimus monotherapy in the haploidentical stem cell transplant (haplo SCT) setting had acceptable safety and resulted in encouraging outcomes for patients with high-risk hematologic malignancies, according to data from the dose-expansion phase of an ongoing phase 1 trial (NCT03802695) presented during the 2023 Transplantation & Cellular Therapy Meetings.

A low incidence of acute graft-vs-host disease (aGVHD) was reported with the precision-engineered cell therapy despite that only single-agent tacrolimus was used as GVHD prophylaxis in this setting. Only 8% (95% CI, 2%-27%) of patients experienced grade 2 or higher aGVHD; 5% (95% CI, 0%-25%) of patients had grade 3 or higher aGVHD.

Although the follow-up was relatively short, at a median of 211 days (range, 32-1125), and with 16 of the 23 patients already past the 3-month mark, no moderate-to-severe chronic GVHD (cGVHD) was observed. Only 1 patient (6%) developed mild cGVHD.

At 1 year, the GVHD-and–relapse-free survival (GRFS) achieved with Orca-Q was 75%, which was noted to compare favorably with prior data reported in context of MAC, haplo SCT, and posttransplant cyclophosphamide (PTCy).

“One of the most important outcomes [to pay attention to] these days, at least for me, is GRFS because this is more reflective for the quality-of-life issue [faced with] these patients; this is very, very encouraging,” said lead study author Samer A. Srour, MD, MS, of The University of Texas MD Anderson Cancer Center, in Houston, Texas, in a presentation of the data. “It’s a small sample size, but [seeing a GRFS of] 75% at 1 year—these patients are GVHD free and relapse free. We think this is very encouraging [and supports] proceed[ing] with this study.”

GVHD represents a very large problem, according to Srour, who added that the challenge for a successful haplo SCT is how to balance the equation of how to decrease GVHD and infections without increasing relapse. He noted that PTCy is a “practice-changing, cheap” approach that has allowed for more patients to undergo allogeneic SCT utilizing alternative haploidentical donors. Despite the strides made with this drug, GRFS in this population is relatively low.

“Forty percent or 50% of these patients will be relapse free and GVHD free at 1 year, and we need to do more for that,” Srour noted. “There’s 2 common pathways to [try] to improve these outcomes, which have right now been adopted: Either you reduce the intensity to improve some of the…GVHD and you end up having more relapses, [or you] intensify the conditioning…[and] you can improve relapse, but you end up having more GVHD…”

Srour then posed the question of whether haplo SCT outcomes can be improved by optimizing the allograft. With conventional transplants, he noted that there is an uncontrolled mix of over 50 cell types, which can include hematopoietic stem cells, progenitor cells, conventional T cells, memory cells, natural killer (NK) cells, invariant NK T cells, dendritic cells, and myeloid-derived suppressor cells.

“[With this approach,] you start adding cyclophosphamide, tacrolimus, and you explore other agents—and you still don’t know; it’s unpredictable,” Srour said. “So, the question is, can we improve that? We have tons of data about how some of these cells work. Can we improve it by manipulating the graft ex vivo? We’re not talking about complete T-cell depletion; just with precision-engineered cell therapy, [we can] purify some of these cells [to ensure] that they work, and then have better outcomes.”

With Orca-Q, high purity hematopoietic stem/progenitor cells (HSPCs) are intended to reconstitute the blood system and provide long-term reconstitution of the immune system. Moreover, high purity T regs are intended to control GVHD, high purity iNKT cells to strengthen T-reg function, and high purity CD4+/CD8+ T-cell subsets to improve the graft vs infection and vs leukemia, respectively.

Because Orca-Q is composed of stem cells and a mixture of immune cells, investigators hypothesized that the product could result in reduced incidence of GVHD, relapse, and serious infections. They launched the early-phase trial to further explore the role of Orca-Q in those receiving haplo SCT using MAC and with GVHD prophylaxis in the form of tacrolimus monotherapy.

Srour noted that the dose-escalation portion of the 3-arm study has concluded. At the TCT meeting, Srour presented findings from the haplo-SCT arm of the dose-expansion phase.

The trial enrolled adult patients with high-risk hematologic malignancies that included acute leukemia, high-risk or very high-risk myelodysplastic syndrome, and myelofibrosis. Patients needed to be between the ages of 18 years and 65 years, and they needed to be eligible to receive MAC. Moreover, they required to have an HCT-CI of up to 4, a Karnofsky performance score of at least 70, and acceptable organ function.

In the standard-of-care arm, MAC was started on day -10 to day -2. Then, on day 0, they were infusion of the bone marrow or an apheresis product. “Then, you start throwing in agents like cyclophosphamide [days +3 and +4], [and at day +5,] tacrolimus/[mycophenolate mofetil],” Srour said.

In the Orca-Q arm, MAC was given from day -10 and day -2. “More or less, we use the same MAC; we’re not changing anything,” Srour explained. Then, tacrolimus is started at day -1, with no PTCy or other immunosuppressive therapies added. At day 0, fresh Orca-Q is infused. Orca-Q is derived from granulocyte colony-stimulating factor mobilized peripheral blood apheresis and has vein-to-vein times of under 72 hours across the United States. Moreover, it is centrally manufactured at a cGMP facility in Sacramento, California.

To date, “we treated over 75 patients in different arms with no manufacturer failures,” Srour said. They started to taper tacrolimus by day 60.

From January 2019 to July 2022, a total of 26 patients were enrolled to the trial. The median age in these patients was 43 years (range, 21-63), and most (69%) were male. Regarding disease subtype, 58% had acute myeloid leukemia, 34% had acute lymphocytic leukemia, and 8% had chronic myeloid leukemia in blast phase. In terms of risk, 23% had high or very-high risk disease, 65% had intermediate-risk disease, and 12% had low-risk disease. Most (62%) patients received a total body irradiation–based myeloablative regimen, and the remainder (38%) had busulfan, fludarabine, and thiotepa.

Regarding donors, the median age was 36 years (range, 18-58), and 54% were male. Sixty-five percent of patients had cytomegalovirus virus (CMV) positivity.

“Anytime we manipulate those grafts, we have to look at: Did you engraft or not? That’s the most stressful thing, and thankfully, we didn’t see any primary graft failures,” Srour reported. “Indeed, we saw robust engraftment.”

The median time to neutrophil and platelet engraftments were 12 days and 16 days, respectively. “For those of you who do a lot of haplo SCTs, then you know what these numbers mean,” Srour said. Moreover, 2 patients (7.7%) experienced grade 1 cytokine release syndrome, and 2 patients (8.8%) experienced secondary graft failure.

A relatively low incidence of serious infections was reported, Srour added. Nineteen percent (95% CI, 4%-44%) of patients experienced grade 3 or higher infections. Four patients (15%) had cytomegalovirus (CMV) viremia, but no end-organ damage linked with CMV was reported. Moreover, EBV viremia was experienced by 1 patient. Notably, there was no PTLD.

Two patients died of infectious causes. One of the patients died from pulmonary aspergillosis, and another patient died from COVID-19 pneumonia.

“Our findings demonstrate very encouraging outcomes with Orca-Q, which is, an ex-vivo manipulated graft, using MAC with only single-agent tacrolimus,” Srour concluded. “We’ve seen low rates of GVHD, a low adverse effect profile, and encouraging GRFS.”

The phase 1 study continues to accrue patients at several centers.

Editor’s Note: Dr Srour did not list any disclosures.

Reference

Srour SA, Salhotra A, Hoeg RT, et al. Orca-Q demonstrates favorable GVHD-and-relapse-free survival in haploidentical transplants without post-transplant cyclophosphamide. Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL. Abstract 33