Utilizing obinutuzumab (Gazyva) to enhance B-cell depletion significantly reduced the need for corticosteroids and increased relapse-free survival in patients with steroid-requiring chronic graft-vs-host disease (cGVHD) undergoing well-matched hematopoietic stem cell transplant, according to results from a phase 2 study (NCT02867384) presented during the 2023 ASH Annual Meeting.

Primary findings from the study showed that the incidence of corticosteroid-requiring cGVHD significantly decreased at both 1 and 2 years with obinutuzumab compared with placebo (P = .029). One-year rates of steroid-requiring cGVHD were 12% (95% CI, 6.5%-20%) and 37% (95% CI, 27%-47%) with obinutuzumab vs placebo, respectively; 2-year rates for these respective groups were 30% (95% CI, 21%-40%) and 43% (95% CI, 32%-53%). Controlling for other established risk factors for cGVHD through multivariable analysis, such as age, gender, donor and conditioning type, and prior acute GVHD, study treatment was the sole significant risk factor for the development of steroid-requiring cGVHD (HR, 0.56; 95% CI, 0.33-0.94; P = .028). The obinutuzumab group also exhibited a lower occurrence of moderate to severe cGVHD at 1 and 2 years (P = .056), while the overall incidence of cGVHD remained unchanged (P = 0.87).

There were no significant differences in non-relapse mortality (NRM) or relapse between the 2 treatment groups. Obinutuzumab produced a 4-year NRM rate of 18% (95% CI, 10%-28%) and a relapse rate of 20% (95% CI, 12%-29%); these percentages were 5% (95% CI, 2%-11%; P = .22) and 27% (95% CI, 18%-37%; P = .24) with placebo. However, opposing non-significant trends were noted and are being investigated, lead author Corey Cutler, MD, of Dana-Farber Cancer Institute, Boston, Massachusetts, stated during a presentation of the data.

Additional efficacy analysis showed that prophylactic B-cell depletion with obinutuzumab did not affect progression-free survival (PFS) or overall survival rates (OS). The agent produced a PFS rate of 62% (95% CI, 50%-72%) and OS rate of 69% (95% CI, 58%-78%). These rates were 68% (95% CI, 56%-77%; P = .90) and 79% (95% CI, 69%-87%; P = .63) with placebo.

However, immunosuppression-free survival (IS-Free OS) was significantly improved among patients treated with obinutuzumab at 41% (95% CI, 30%-51%) vs 30% with placebo (95% CI, 20%-40%; P = .02)

“Prophylactic B-cell depletion after peripheral blood stem cell transplantation is associated with a reduced incidence of steroid-requiring cGVHD, meeting the primary end point of the trial,” Cutler said. “[It was also associated] with a reduction in overall moderate to severe cGVHD and an improvement in IS-Free survival, all with a low toxicity profile, making this a very feasible approach for most patients.”

Prior research has demonstrated that cGVHD can severely affect long-term morbidity, mortality, and quality of life in patients undergoing allogeneic transplant, making the prevention and control of this condition a critical concern, Cutler explained.

“Seminal studies…from the Ritz Laboratory [run by Jerome Ritz, MD at Dana-Farber Cancer Institute] demonstrated the importance of B cells in the pathogenesis of cGVHD. As a result, we now have therapeutics that target the B-cell pathway that are commonly used,” Cutler said.

Two single-center, phase 2 studies independently performed at Stanford University and Dana-Farber Cancer Institute suggested that prophylactic B-cell depletion could lead to a reduced incidence of cGVHD. Based on these data, investigators sought to replicate this finding in a larger, randomized trial, Cutler said.

The randomized, double-blind, placebo-controlled trial included patients receiving tacrolimus-based GVHD prophylaxis, excluding patients who received post-transplantation cyclophosphamide or anti-thymocyte globulin. Other key eligibility criteria included the presence of peripheral blood stem cells only, no active malignancies, donor chimerism above 80%, resolved acute GVHD, and adequate hematopoiesis.

Screening and enrollment occurred 3 months after initial transplantation. Patients were randomly assigned to receive obinutuzumab or placebo, both of which were administered at 3, 6, 9 and 12 months after transplantation. Responses to obinutuzumab and placebo were assessed at 6, 9, 12, and 24 months after transplant.

The study’s primary end point was the cumulative incidence of steroid-requiring cGVHD. Key secondary end points were National Institute of Health moderate to severe cGVHD, all cGVHD, NRM, relapse, PFS, OS, and IS-Free OS. Exploratory end points consisted of B-cell parameters and H-Y histocompatibility antibody responses. The median follow-up for the current analysis is 1 year.

A total of 974 patients were initially assessed for eligibility during the screening period, 449 of which were deemed eligible for enrollment. Of the 535 who were ineligible for participation, 215 were excluded for transplant related reasons. Other reasons for exclusion included adverse effects (AEs) on other trials (n = 140), cytopenia (n = 107), active malignancy (n = 45), and hepatitis or infection (n = 18). An additional 268 patients or physicians declined to participate.

“Drop off between eligibility and enrollment was largely due to patient preference and reflects the challenge of enrolling subjects to a trial following transplantation and during the COVID-19 pandemic,” Cutler explained in his presentation.

Among the 181 patients randomly assigned to treatment, 178 received an allocated intervention and were subsequently analyzed. Cutler notes that 2 subjects received an incorrect first dose due to an error in the research pharmacy, but were subsequently treated according to their randomization and were analyzed with their assigned group.

The median age of patients in both the obinutuzumab and placebo arms was 63 (respective ranges, 21-79; 20-75). Most patients were male (64.4% in obinutuzumab arm; 62.5% in placebo arm), had reduced intensity conditioning/nonmyeloablative conditioning (63.3%; 68.2%), and

an unrelated donor type (67.8%; 61.4%). Male recipients with female donors made up 13.3% and 14.8% of the obinutuzumab and placebo arms, respectively. The primary disease for patients included acute myeloid leukemia (38.9%; 39.8%), myelodysplastic syndrome (26.7%; 26.1%), acute lymphoblastic leukemia (13.3%; 6.8%), other lymphoid malignancies (13.3%; 11.4%), and other myeloid diseases (7.8%; 15.9%). Grade 2 to 4 acute GVHD had previously occurred in 5.6% of patients in the obinutuzumab arm and 9.1% of those in the placebo arm.

The median number of doses received by patients was 2.5 in the obinutuzumab arm and 2 in the placebo arm (P = .83)

“The most common causes for drug discontinuation included the development of cGVHD, relapse of the original malignancy, and patient preference,” Cutler stated. “Toxicity was not an important cause of discontinuation. In fact, this was seen as more doses of study compound were [administered] than placebo.”

Regarding safety, a total of 5 grade 3/4 infusion-related reactions occurred with obinutuzumab. However, Cutler noted that these infusion reactions were only seen with initial infusion and patients were able to resume treatment.

The incidence of neutropenia was high in the obinutuzumab group vs the placebo group. Fifteen patients experienced a grade 3 event, and 17 experienced a grade 4 event with obinutuzumab. Conversely, 2 grade 3 and 4 neutropenic events occurred in the placebo group. Only 1 patient developed grade 3/4 neutropenic sepsis.

“Globally, infections were rare, and there were no differences [in infection] between the obinutuzumab group and the placebo group. Modest decreases in platelet counts were common, although grade 3/4 thrombocytopenia was rare, and there were no bleeding complications noted on the study,” Cutler added.

As predicted, B-cell levels decreased to undetectable levels across all subsets. Low B-cell levels were maintained throughout the trial, although some subjects experienced B-cell reconstitution during year 2.

No differences in total T cells and T-cell subsets, including CD4-positive, CD8-positive, or regulatory T-cells were observed. Although natural killer (NK) cell levels were unaffected by obinutuzumab treatment, CD3-positive, CD56-negative, and NK T-cells decreased from 9 to 36 months. Cutler stated that this was of unclear significance.

Investigators conducted a separate analysis of H-Y antibody responses using a previously validated methodology in the subset of male patients. This was performed to determine whether obinutuzumab could prevent the generation of H-Y antibody responses, thereby preventing the development of steroid-requiring cGVHD and relapse.

Prior to the administration of the study compound, the distribution of isotype-switched H-Y antibodies were similar between the obinutuzumab and placebo groups. Antibody responses at 12 and 24 months were less prevalent in the obinutuzumab group but increased in the placebo group.

“We had hoped to prevent the development of these antibodies entirely but would have likely needed to have started or intervened earlier post-transplant to abrogate all antibody

responses. In fact, in our prior publication on the topic, H-Y antibodies were entirely absent at 2 months but began to develop at 3 months and increased over time,” Cutler said.

Evaluation of the relationship between pre-existing antibodies and treatment assignment showed that patients who did not display H-Y antibodies at the time of initial study administration appeared to have a low and delayed incidence of steroid-requiring cGVHD when treated with obinutuzumab. Conversely, those with pre-existing H-Y antibodies did have a higher incidence of cGVHD despite being treated with obinutuzumab.

“In subjects with pre-formed antibodies, T-cell priming may have already occurred and preventing the formation of further antibodies with obinutuzumab does not offer protection against cGVHD,” Cutler explained during the presentation. “However, B-cell depletion can offer protection against the development of cGVHD in patients who receive obinutuzumab prior to the formation of H-Y antibodies,” he concluded.

Editor's Note: Dr Cutler reported relationships with Pluristem Therapeutics, Allovir, Sanofi, InhibRx, Oxford Immune Algorithmics, Rigel, Astellas, and Cimeio.

Cutler C, Kim HT, Banna HE, et al. Effective prevention of steroid-requiring chronic graft-vs.-host disease with B cell depletion: a randomized, placebo-controlled trial. Blood. 2023;142(suppl 1):649. doi:10.1182/blood-2023-180142

Articles

Utilizing obinutuzumab to enhance B-cell depletion significantly reduced the need for corticosteroids and increased relapse-free survival in patients with steroid-requiring chronic graft-vs-host disease undergoing well-matched hematopoietic stem cell transplant.

Obinutuzumab Use Decreases Incidence of Steroid-Requiring cGVHD After Transplant

The high-precision cellular product Orca-Q demonstrated early signals of clinical activity as well as an acceptable safety profile for patients undergoing haploidentical stem cell transplantation (haplo-SCT) without posttransplant cyclophosphamide (PTCy), according to findings from a phase 1 trial (NCT03802695) presented during the 

Results showed that both the graft-vs-host disease (GVHD) relapse-free survival (GRFS) rate and overall survival (OS) rate at 1 year was 82% (95% CI, 65%-94%) with Orca-Q. This is in comparison to historical data with conventional PTCy for haplo-SCT, with recent 1-year GRFS rates of 46%.

“These findings show promising safety and efficacy outcomes using Orca-Q cell therapy for haploidentical transplant,” said Samer A. Srour, MB ChB, MS, lead study author and assistant professor in the Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, in an oral presentation during the meeting. “No safety signals in this haploidentical setting were identified.”

Standard allogeneic SCT can be a curative approach for patients across many high-risk hematologic cancers, although access to this therapy was previously limited to those who have a fully matched donor. The introduction of PTCy as prophylaxis for GVHD increased the utility of haploidentical donors; however, it has also increased relapse rates and toxicity issues such as cytokine release syndrome (CRS), delayed engraftment and T-cell reconstitution, mucositis, infections, cardiac events, and non-relapse mortality, Srour added.

However, GRFS rates in this patient population remain low. Through allograft optimization, Orca-Q improves haplo-SCT with its fully defined stem and immune cells, which consist of hematopoietic stem and progenitor cells, invariant natural killer cells, regulatory T cells, and CD4+/CD8+ T-cell subsets.

Orca-Q is derived from granulocyte colony stimulating factor that is mobilized during peripheral blood apheresis and is manufactured centrally at a Current Good Manufacturing Practice Manufacturing Facility in Sacramento, California. Its administration involves a vein-to-vein time of less than 72 hours across the United States, Srour noted, adding that the vein-to-vein time was within 60 hours for most cases on the study.

The multicenter, dose-expansion trial enrolled patients aged 18 to 65 years with the following high-risk hematologic cancers: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), very high– or high-risk myelodysplastic syndrome, or myelofibrosis. Patients were required to be undergoing a haplo-SCT with negative donor-specific antibodies and were eligible for myeloablative chemotherapy with a Hematopoietic Cell Transplantation-specific Comorbidity Index 4 or lower, a Karnofsky performance score of at least 70, and adequate organ function.

Orca-Q’s regimen begins with myeloablative conditioning on days -10 to -2, followed only by single-agent tacrolimus on day -1—no PTCy or additional immunosuppressive therapies are administered. A fresh Orca-Q infusion is given on day 0, and tacrolimus is tapered on day +60 (posttransplant).

The study’s primary end points are dose-limiting toxicities and primary graft failure.

Off the 33 patients enrolled onto the study, the median age is 43 years (range, 21-63) and 27% of patients were female; a total 30.3% of patients identified as Hispanic or Latino. Patients were Asian (15.2%), Black or African American (21.2%), White (42.4%), or other (21.2%). Their primary disease was ALL (30.3%), AML (63.3%), or chronic myeloid leukemia (6.1%). Additionally, patients had high-/very high­–risk disease (18%), intermediate-risk disease (79%). Disease risk index was not applicable for 3% of patients.

Patients’ disease status at time of transplant encompassed those who achieved their first complete remission (CR1; 73%), second CR (CR2; 24%) and CML accel phase (3%). Patients either had a total body irradiation (TBI)-based conditioning regimen (51.5%) or busulfan-based one (48.5%). Donor characteristics showed that there were more male donors (73%) vs female donors (27%), and the CMV status was positive (30.3%), negative/not detected (36.3%), or not available (33.3%).

Rapid engraftment with Orca-Q was observed in the patients. The median engraftment time with neutrophils was 12.0 days (range, 8-25) and 15.5 days with platelets (range, 8-79). Two patients experienced secondary graft failure, and grade 1/2 CRS occurred in 3 patients (grade 1, n = 2; grade 2, n = 1).

Additional data showed a low incidence of severe Common Terminology Criteria for Adverse Events grade 2 (CTCAE; n = 9) and CTCAE grade ≥3 (n = 15) infections. There were 5 events (15%) of acute grade 2 to 4 GVHD and 1 event of grade 3 acute GVHD. At a median follow-up of 375 days (range, 73-1384), no patients have developed moderate to severe chronic GVHD. This in comparison to historical cohorts with PTCy, which show 1-year chronic GVHD rates of 24% to 33%.

The phase 1 trial is continuing to enroll patients across the United States. Srour stated that there are plans to increase the age criteria to 75 years and provide less-intensive conditioning therapy.

Editor’s Note: Dr Srour disclosed research funding from Orca Bio for this study.

Srour SA, Salhotra A, Lowsky R, et al. Safety and efficacy of Orca-Q with haploidentical donors for the treatment of advanced hematologic malignancies without the use of post-transplant cyclophosphamide. 

 2023;142(suppl 1):773. doi:10.1182/blood-2023-189534

Jagasia MH, Grinix HT, Arora M, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. 

. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001

The high-precision cellular product Orca-Q demonstrated early signals of clinical activity as well as an acceptable safety profile for patients undergoing haploidentical stem cell transplantation without posttransplant cyclophosphamide.

Orca-Q Showcases Early Efficacy, Acceptable Safety in Haploidentical Stem Cell Transplant Without PTCy

Treatment with ruxolitinib (Jakafi) led to prolonged failure-free survival and improved disease control vs best available treatment in patients with either steroid-refractory or -dependent chronic graft-vs-host disease (cGVHD), according to 3-year data from a final analysis of the phase 3 REACH3 trial (NCT03112603) presented during the 

“Ruxolitinib provided longer PFS and longer DOR vs [best available treatment], demonstrating sustained efficacy for patients with [steroid refractory or dependent] cGVHD, with a consistent and manageable safety profile,” Robert Zeiser, MD, professor in the department of medicine I at the Medical Center at University of Freiburg in Germany, said during a presentation of the data.

Median failure-free survival was longer in the ruxolitinib group compared with the best available treatment group (38.4 months vs 5.7 months; HR = 0.361; 95% CI, 0.268-0.485). The probability of failure-free survival at 12 months was 64.0% in patients assigned ruxolitinib (95% CI, 56.1%-70.8%) and 28.8% in those assigned best available treatment (95% CI, 21.8%-36.1%).

Median overall survival was not reached, and no difference was observed in the risk of death in both groups (HR = 0.851; 95% CI, 0.544-1.331).

Median duration of response was 6.4 months in patients assigned best available treatment (95% CI, 4.9-11.4) and not reached in those assigned ruxolitinib. The likeliness of maintaining duration of response at 3 years was higher in the ruxolitinib group (59.6%; 95% CI, 50.4%-67.6%) vs the best available treatment group (26.7%; 95% CI, 18.5%-35.5%).

The rates of non-relapse mortality were similar in the ruxolitinib (29 out of 165) and the best available treatment groups (34 out of 164). The rates of malignancy relapse events were similar in both arms for up to 3 years, occurring in 13 out of 156 patients assigned ruxolitinib and 11 out of 160 patients assigned best available treatment.

At week 24, the overall response rate in patients who crossed over from best available treatment to ruxolitinib was 50% (95% CI, 37.8%-62.2%). This included a complete response in 5.7% of patients and a partial response in 44.3% of patients. Best overall response during the crossover period was 81.4% (95% CI, 70.3%-89.7%), with complete response in 7.1% and partial response in 74.3%. Of note, 1 patient experienced disease progression.

During the main treatment period, almost all patients experienced 1 or more adverse events, affecting 100% of patients assigned ruxolitinib and 93.7% of patients assigned best available treatment. Rates of adverse events were higher in the ruxolitinib group vs the best available treatment group. This was likely due to longer follow-up and longer median exposure to ruxolitinib compared with best available treatment (52.9 weeks vs 24.1 weeks).

The most common adverse event was anemia, with 33.9% in the ruxolitinib group and 15.8% in the best available treatment group. Of note, the rate of grade 3 or higher anemia affected the ruxolitinib group more than the best available treatment group (17.6% vs 9.5%). Rates of grade 3 or worse thrombocytopenia, neutropenia, gamma-glutamyltransferase increase, and alanine aminotransferase increase were at 5% higher in patients assigned ruxolitinib compared with best available treatment.

The most common treatment-related adverse events in the ruxolitinib group were anemia, which occurred in 24.2% of patients. Grade 3 or higher anemia also occurred in 10.3% of patients in this group. For patients assigned best available treatment, the most common treatment-related adverse events were thrombocytopenia (3.8%).

Infections, not including tuberculosis, were the most common adverse event of special interest in the ruxolitinib and best available treatment groups (77.6% vs 68.4%, respectively). Grade 3 or higher infections occurred in 31.5% of patients assigned ruxolitinib and 26.6% of those assigned best available treatment.

Most deaths that occurred while on treatment were due to cGVHD, occurring in 10 out of 18 patients assigned ruxolitinib and in 6 out of 12 patients assigned best available treatment.

Patients aged 12 years and older with moderate or severe steroid-refractory cGVHD were randomized 1:1 to receive either 10 mg of ruxolitinib twice daily (n = 165) or best available treatment (n = 164), as selected by the investigator. All patients were followed for 3 years, until discontinuation or death.

The primary analysis of the study, which was conducted at week 24 (cycle 7, day 1) in all patients randomized to treatment, then patients entered an extension period from cycles 7 to 39, during which treatment continued, patients switched from best available treatment to ruxolitinib (crossover cohort), or discontinued treatment. Patients who discontinued treatment entered long-term survival follow-up.

At 3 years, researchers analyzed several outcomes including failure-free survival, duration of response, non-relapse mortality, overall survival, safety, and malignancy relapse. The final data cut off was December 15, 2022. In addition, other outcomes were assessed during the crossover treatment period — patients who switched from best available treatment to ruxolitinib on or after cycle 7, day 1—including overall response rate and best overall response.

Of the 329 patients who were randomized to treatment, 53 patients completed the treatment period and 276 patients discontinued. In addition, 115 patients entered survival follow-up, with 73 out of 165 patients from the ruxolitinib group and 42 out of 164 in the best available treatment group. Seventy patients crossed over from best available treatment to ruxolitinib, of whom 16 completed the crossover treatment period and 24 patients entered survival follow-up.

Zeiser R, Russo D, Ram R, et al. Ruxolitinib in Patients With Chronic Graft-Versus-Host Disease: 3-Year Final Analysis of Efficacy and Safety From the Phase III REACH3 Study. 

 2023;142(1):654. doi:10.1182/blood-2023-172590

Treatment with ruxolitinib led to prolonged failure-free survival and improved disease control vs best available treatment in patients with either steroid-refractory or -dependent chronic graft-vs-host disease.

Ruxolitinib Shows Sustained Efficacy Over Best Available Therapy in Steroid-Refractory/Dependent cGVHD

Axatilimab induced rapid and durable responses with an acceptable toxicity profile at all doses analyzed with highest efficacy observed at the 0.3-mg/kg dose in patients with recurrent or refractory chronic graft-vs-host disease (cGVHD), according to data from the phase 2 trial (NCT04710576) presented in a Plenary Session during the 

The agent elicited an objective response rate (ORR) of 74% (95% CI, 63%-83%) when given at a dose of 0.3 mg/kg every 2 weeks (n = 80). When given at a dose of 1.0 mg/kg every 2 weeks (n = 81) or 3.0 mg/kg every 4 weeks (n = 80), axatilimab resulted in ORRs of 67% (95% CI, 55%-77%) and 50% (95% CI, 39%-61%), respectively. The primary end point of the trial, which was ORR in the first 6 cycles as defined by National Institutes of Health (NIH) 2014 Consensus criteria, was met in all cohorts.

The median time to response in the 0.3-mg/kg, 1.0-mg/kg, and 3.0-mg/kg cohorts with axatilimab was 1.7 months (range, 0.9-8.1), 1.9 months (range, 0.9-8.6), and 1.4 months (range, 0.9-5.6), respectively. Moreover, 60% (95% CI, 43%-74%), 60% (95% CI, 43%-74%), and 53% (95% CI, 30%-71%) of patients in these cohorts, respectively, had responses that continued for at least 1 year.

“Axatilimab, with its unique mechanism of action, may represent a new therapeutic strategy in chronic GVHD,” Daniel Wolff, MD, PhD, of the University Hospital of Regensburg in Germany, said in a presentation of the data. “The AGAVE-201 trial met its primary end point in all 3 doses assessed, but the highest ORR and the least toxicity was observed with the lowest dose; that underlines the crucial importance of sufficiently powered studies in this vulnerable patient population.”

cGVHD represents a major cause of late morbidity, affecting 30% to 50% of patients who undergo transplant, Wolff noted. It is a multiorgan, inflammatory, fibrotic, difficult-to-treat disease that frequently requires several lines of treatment with decreasing efficacy, he added. cGVHD also impairs quality of life (QOL) and results in significant disease burden in those who are otherwise cured from underlying malignancies. As such, new effective and tolerable options are needed.

“CSF-1R–dependent monocytes and macrophages mediate inflammation and fibrosis. Axatilimab is an investigational monoclonal antibody that targets CSF-1R on monocytes and macrophages,” Wolff said. Data from a phase 1/2 study (NCT03604692) showed that in all evaluable patients, axatilimab elicited an ORR of 67% (95% CI, 50%-81%) in the first 6 cycles of treatment.

 The agent was also reported to have a favorable safety profile.

The phase 2 AGAVE-201 trial enrolled patients with active cGVHD defined as 2014 NIH Consensus criteria who were at least 2 years of age who had received at least 2 prior lines of systemic treatment.1 They also needed to have “Karnofsky performance equal to or above 60% and adequate bone marrow and organ function,” Wolff said. Although concomitant use of corticosteroids (65%), calcineurin inhibitors (28%), and mTOR inhibitors (12%) was permitted, it was not required. No additional systemic treatment for cGVHD was allowed.

Study participants were enrolled at a total of 121 clinical sites in 16 countries and 4 continents (North America, n = 51; Europe/Middle East, n = 58; Asia, n = 10; Australia, n = 2). A total of 241 patients were randomized to 1 of 3 doses/schedules: 0.3 mg/kg every 2 weeks, 1.0 mg/kg every 2 weeks, and 3.0 mg/kg every 4 weeks.

In addition to the primary end point being ORR in the first 6 cycles by NIH 2014 Consensus criteria, secondary and exploratory end points included clinically meaningful improvement in modified Lee Symptom Scale (mLSS), organ-specific response rates, duration of response, failure-free survival (FFS), overall survival, and safety.

Baseline characteristics and demographics were well balanced across the cohorts, according to Wolff. In the total population, the median age was 53 years (range, 7-81). Most patients were male (63%), White (83%), and had severe disease (80%). The median time from diagnosis of cGVHD to randomization was 4 years. The median number of organs involved at baseline was 4, and 54% of patients had 4 or more organs involved.

Notably, the median number of previous systemic treatments received for cGVHD was 4; 55% of patients were refractory to their last cGVHD treatment. Eighty-five percent of patients previously received ruxolitinib (Jakafi; 74%), ibrutinib (Imbruvica; 31%), and/or belumosudil (Rezurock; 23%).

“Surprisingly, [none] of the patient characteristics impact[ed] the response rate, including age—in fact, only 7 patients in the whole study were below the age of 17—and severity [of cGVHD at screening,” Wolff noted. “Most importantly, high response rates were seen in patients who received prior FDA-approved agents, including belumosudil, underlying the distinct mechanism of action of axatilimab.”

In those younger than 17 years of age (n = 4), the ORR with the agent was 75% (95% CI, 19%-995); in those who were at least 17 years but under 65 years (n = 55), the ORR was 78% (95% CI, 65%-88%). In those who were 65 years of age or older (n = 21), the ORR was 62% (95% CI, 38%-82%). In those with mild or moderate cGVHD at the time of screening (n = 17), the ORR with the agent was 65% (95% CI, 38%-86); in those with severe cGVHD at screening (n = 63), the ORR was 76% (95% CI, 64%-86%). In those who previously received ibrutinib (n = 27), ruxolitinib (n = 57), or belumosudil (n = 16), the ORRs with axatilimab were 82% (95% CI, 62%-94%), 79% (95% CI, 66%-89%), and 75% (95% CI, 48%-93%), respectively.

“In terms of organ-specific response, complete remission [CR] was seen across all organs involved,” Wolff said. Responses with axatilimab at 0.3 mg/kg every 2 weeks were also seen in fibrosis-dominated organs. CRs were observed in the following organs: lower gastrointestinal (GI; n = 9; 89%), upper GI (n = 11; 82%), esophagus (n = 23; 65%), joints/fascia (n = 55; 20%), mouth (n = 40; 42%), lungs (n = 32; 42%), liver (n = 10; 20%), eyes (n = 59; 10%), and skin (n = 64; 9%).

Forty-four percent of patients had reduction in body surface area involved by sclerosis and 66% experienced an improvement in skin and joint tightening severity, Wolff added. “The discrepancy is best explained by the fact that 94% of the patients enrolled in the trial has steroidal skin lesions and the nature of the NIH response criteria require complete resolution of deep sclerosis for a remission documentation.”

The median FFS with axatilimab was 17.3 months (95% CI, 14.2-not evaluable). “Only 2 patients in the 0.3-mg/kg cohort died. Both had severe lung GVHD; 1 died as a direct consequence of progressive lung disease and the other had a preceding lung infection which led to death,” Wolff said.

In terms of symptom burden as assessed by mLSS, 55% of patients experienced a clinically meaningful change of equal to or above 7 points. “Eighty-seven percent of patients experienced improvement compared with baseline,” Wolff noted. Moreover, 73% of patients experienced improved mLSS skin thickened score vs baseline, “underlying the crucial importance of capturing patient-reported outcomes in this patient population,” he said. “Symptom improvement was fairly rapid and followed the trajectory seen in the overall response.”

In the 0.3-mg/kg cohort, adverse effects (AEs) led to dose decrease for 6.3% of patients and discontinuation for 6.3% of patients. The most common any-grade AEs experienced in at least 20% of patients in this cohort included fatigue (22.8%), headache (19.0%), periorbital edema (2.5%), and COVID-19 (16.5%).

Laboratory abnormalities included increased aspartate aminotransferase (13.9%), increased creatinine phosphokinase (11.4%), increased lipase (11.4%), increased lactate dehydrogenase (13.9%), increased alanine aminotransferase (12.7%), and increased amylase (3.8%).

Additionally, 17.7% of patients experienced at least 1 related grade 3 or higher AE and 1 patient had an AE that proved to be fatal.

“At higher doses, periorbital edema was a very specific AE of axatilimab,” Wolff concluded. “…AEs were mostly low grade, reversible, and increased with higher doses.”

Wolff D, Cutler C, Lee SJ, et al. Safety and efficacy of axatilimab at 3 different doses in patients with chronic graft-versus-host disease (AGAVE-201). 

. 2023;142(suppl 1):1. doi:10.1182/blood-2023-186963

Kitko CL, Arora M, DeFilipp Z, et al. Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: results of a phase I/II study. 

. 2023;41(10):1864-1875. doi:10.1200/JCO.22.00958

Axatilimab induced rapid and durable responses with an acceptable toxicity profile at all doses analyzed with highest efficacy observed at the 0.3-mg/kg dose in patients with recurrent or refractory chronic graft-vs-host disease.

Axatilimab Elicits Responses With Manageable Safety in Recurrent/Refractory cGVHD

The high-precision cell therapy Orca-T demonstrated high rates of relapse-free survival (RFS), overall survival (OS), and graft-vs-host disease RFS (GRFS) at 1 year, as well as a low incidence of GVHD in patients with intermediate- to high-risk myelodysplastic syndrome (MDS), according to subanalysis data of a phase 1b study that were presented at the 2023 ASH Annual Meeting.

At a median follow-up of 19.1 months (range, 6.3-32.2), results showed that the 1-year RFS rate with Orca-T was 94% (95% CI, 63%-99%), the 1-year modified GRFS was 75% (95% CI, 50%-96%), the 1-year non-relapse mortality rate was 0% (95% CI, 0%-0%), and the 1-year OS rate was 94% (95% CI, 63%-99%).

Additionally, Orca-T was successfully manufactured in one centralized GMP manufacturing facility for the 16 patients enrolled on the study, and was also distributed and infused throughout the United States in under a 72-hour vein-to-vein time.

“Orca-T demonstrated promising results in this high-risk MDS patient population, including high RFS, low incidence of GVHD, and very high OS at 1 year,” Arpita Gandhi, MD, MS, assistant professor of medicine, Division of Hematology/Medical Oncology, School of Medicine, Oregon Health and Science University, and coinvestigators wrote in the poster presented at the meeting.

Allogeneic hematopoietic cell transplant (alloHCT) is theorized to be a curative therapeutic approach for patients with MDS. At 1 year, the OS rate and RFS rate are approximately 65% and 69% in patients with MDS who underwent myeloablative conditioning, as seen in the RIMAC study.2

However, investigational treatments, such as the allogeneic, high-precision cell therapy Orca-T, could potentially reduce alloHCT-related toxicities, which could ultimately help improve outcomes for this patient population. Orca-T comprises both stem and immune cells derived from allogenic donors; its mechanism involves leveraging highly purified, polyclonal donor regulatory T cells in order to control alloreactive immune responses.

In the phase 1b trial, investigators explored the efficacy and safety of Orca-T in patients with intermediate- to high-risk MDS who were eligible for transplant, as per the 2017 International Expert Panel recommendations.

Sixteen patients were enrolled to receive Orca-T. All patients underwent myeloablative conditioning on day -10 to day -2. Patients underwent infusion of HSPCs and Tregs at 3 x 106 Treg/kg with a vein-to-vein time within 72 hours on day 0. On day +2, Tcon was infused at 3 x 106 T cells/kg, and single-agent tacrolimus was given at 5 to 10 ng/mL target on day +3. No methotrexate, PTCy, or other immunosuppressive therapies were given.

Historically, on day -1 in the standard therapy arm of alloHCT, patients receive tacrolimus at 5 to 10 ng/mL target, followed by infusion of the apheresis product at a cell dose of 108 to 109 T cells/kg; methotrexate prophylaxis is given on days +1, +3, +6, and +11.

Regarding baseline characteristics in the 16 patients, the median age was 59 years (range, 43-65) and 56% of patients were female. Patients either had a low (6%), moderate low (6%), moderate high (19%), high (44%), or very high (25%) Molecular International Prognostic Scoring System (IPSS-M) prognostic score. The baseline Hematopoietic Cell Transplantation-Specific Comorbidity Index was 0 (38%), 1 (19%), 2 (13%), 3 (19%), or 4 (13%). More than half of patients had an unrelated 8/8 HLA-matched donor relationship (56%).

Further findings showed that, at 1 year, no patients experienced grade 3 or higher acute graft-vs-host disease (GVHD). Two patients had moderate to severe chronic GVHD.

The authors noted that 1 patient who harbored a 

 mutation and complex karyotype remained in complete response and had no active signs of acute or chronic GVHD at 500 days following alloHCT.

The multicenter, controlled, randomized, phase 3 trial is comparing Orca-T with standard of care in patients with MDS, acute myeloid leukemia, and acute lymphoblastic leukemia (NCT05316701).

Gandhi A, Hoeg RT, Patel SS, et al. High disease-free survival in patients with high-risk MDS treated with Orca-T. 

. 2023;142(suppl 1):2230. doi:10.1182/blood-2023-188994

Alam N, Atenafu EG, Kuruvilla J, et al. Outcomes of patient with therapy-related AML/myelodysplastic syndrome (t-AML/MDS) following hematopoietic cell transplantation. 

. 2015;50(9):1180-1186. doi:10.1038/bmt.2015.151

The high-precision cell therapy Orca-T demonstrated high rates of relapse-free survival, overall survival, and graft-vs-host disease RFS at 1 year, as well as a low incidence of GVHD in patients with intermediate- to high-risk myelodysplastic syndrome.

Orca-T Shows High Survival Rates in Intermediate-/High-Risk Myelodysplastic Syndrome

The use of Orca-T with myeloablative chemotherapy conditioning had comparable safety and efficacy in younger and older patients with hematologic malignancies, according to findings from a single-arm, phase 1b study (NCT04013685) that were presented at the 

The 12-month relapse-free survival (RFS) rate in the younger age group (n = 39; 18 to <55) was 84.8% (95% CI, 67.0%-93.5%) vs 82.3% (95% CI, 59.4%-93.0%) in the older age group (n = 25; ≥55). Moreover, the 1-year rate of non–relapse mortality remained at 0 in both populations. The 1-year overall survival (OS) rate was 100% (95% CI, 100%-100%) in the younger cohort vs 95.5% (95% CI, 71.9%-99.3%) in the older cohort.

“Orca-T has the potential to be a reduced toxicity alternative to conventional allogeneic transplant,” lead study author Caspian H. Oliai, MD, MS, medical director of the UCLA Bone Marrow Transplantation Stem Cell Processing Center, Jonsson Comprehensive Cancer Center at the University of California Los Angeles in California, said in a presentation of the data.

The multicenter, single-arm study enrolled patients with acute leukemia in complete remission (CR)/CR with incomplete count recovery (CRi); myelodysplastic syndrome (MDS); and chronic myeloid leukemia (CML) in chronic phase. Patients were between the ages of 18 and 75 years with an 8/8 matched related or unrelated donor. They had to have a Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) of 4 or less, a Karnofsky performance score (KPS) of at least 70, adequate organ function, and be eligible to receive a myeloablative regimen of intravenous busulfan at 9.6 mg/kg, fludarabine at 160 mg/m2, and thiotepa (BFT) at 10 mg/kg plus GVHD prophylaxis with single-agent tacrolimus.

The primary end points were the incidence of primary graft failure and the incidence of severe acute graft-vs-host disease (GVHD).

In the younger patient population, the median age was 47 years and the median duration on study was 12 months. Approximately half of patients were female (49%) and 13% were Hispanic or Latino. Baseline HCT-CI scores were 0, 1, 2, 3, or 4 in 51%, 8%, 8%, 23%, and 10% of patients, respectively. Acute myeloid leukemia (AML; 74%) was the most common primary disease, followed by high-/very high–risk MDS (10%), ALL (8%), and CML (8%). In this group, 31% of patients had minimal residual disease (MRD) positivity.

In the older patient population, the median age was 59 years and the median duration on study was 12 months. Thirty-six percent of patients were female and 12% were Hispanic or Latino. Baseline HCT-CI scores were 0, 1, 2, 3, or 4 in 32%, 16%, 16%, 24%, and 12% of patients, respectively. Similarly, AML was the most common primary disease (44%) followed by high-/very high–risk MDS (32%), ALL (12%), CML (8%), and mixed phenotype leukemia (MPAL; 4%). Twenty-four percent of patients had MRD-positive disease.

Regarding the frequency of GVHD, grade 3 or greater acute GVHD occurred in only 1 older patient. Moderate-to-severe chronic GVHD occurred in 3 younger patients, all of which were moderate events, and 3 older patients, 1 of which was a severe event.

With a median follow-up of 12 months, 1 younger patient experienced graft failure. Grade 4 infections occurred only in 3 older patients; no grade 5 events occurred. Grade 3 mucositis occurred in 1 younger patient and 1 older patient; no cases of grade 4/5 events occurred.

The median donor chimerism at 3 months was greater than 90% in both age groups.

“Using Orca-T with myeloablative BFT conditioning has the potential to improve outcomes for older patients, based on more than 95% OS and 1-year transplant-related mortality of 0%,” Oliai concluded.

Orca-T is being compared with standard-of-care therapy in the ongoing phase 3 Orca Precision-T trial (NCT05316701). To be eligible for enrollment, patients must have AML, ALL, MPAL, and undifferentiated leukemia in CR/CRi; or high-risk or therapy-related MDS, including those who have active disease at the time of transplant and no greater than 10% bone marrow blast burden. Patients must be planning to undergo myeloablative allogeneic hematopoietic stem cell transplant including myeloablative therapy with BFT, total body irradiation (TBI)/etoposide, or TBI/cyclophosphamide. Additional eligibility criteria require an 8/8 matched related or unrelated donor, HCT-CI of 4 or less, KPS of at least 70, age between 18 and 65 years, and adequate organ function.

In the trial, patients will be randomly assigned to experimental therapy (n = 87) with Orca-T plus single-agent tacrolimus prophylaxis or standard of care (n = 87) consisting of unmanipulated allograft plus prophylactic therapy with tacrolimus and methotrexate.

Chronic GVHD-free survival will be the primary end point, and secondary end points include GVHD-free RFS, moderate-to-severe chronic GVHD, and RFS.

Oliai CH, Pantin JM, Hoeg RT, et al. Optimizing outcomes with myeloablative conditioning in older patients: efficacy and safety of precision engineered Orca-T in patients > 55 years old with hematologic malignancies. 

. 2023;142(suppl 1):230. doi:10.1182/blood-2023-186749

The use of Orca-T with myeloablative chemotherapy conditioning had comparable safety and efficacy in younger and older patients with hematologic malignancies, according to data from a phase 1b study.

2023 ASH Meeting Reporter: Updates in GVHD | Supplements and Featured Publications

Obinutuzumab Use Decreases Incidence of Steroid-Requiring cGVHD After Transplant

Orca-Q Showcases Early Efficacy, Acceptable Safety in Haploidentical Stem Cell Transplant Without PTCy

Ruxolitinib Shows Sustained Efficacy Over Best Available Therapy in Steroid-Refractory/Dependent cGVHD

Axatilimab Elicits Responses With Manageable Safety in Recurrent/Refractory cGVHD

Orca-T Shows High Survival Rates in Intermediate-/High-Risk Myelodysplastic Syndrome

Orca-T Demonstrates Feasibility in Older Patients With Hematologic Malignancies