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Mark A. Schroeder, MD:
aGVHD is still a major clinical challenge despite recent advances in prophylaxis. Moreover, aGVHD occurs in approximately 40% of individuals receiving allogeneic stem cell transplant.2 Furthermore, a subset of allogeneic stem cell transplant recipients will develop steroid-refractory aGVHD, which ultimately can lead to death.
Mark A. Schroeder, MD:
At ASH 2021, Holtan and colleagues presented data on urinary-derived human chorionic gonadotropin (uhCG) with epidermal growth factor (EGF) as a new treatment to support patients with aGVHD that are at high risk of morbidity and mortality from the disease.3 This represents a very novel treatment for this disease because it is not necessarily immunosuppressive. This agent could potentially lead to regeneration of the epithelium or an alteration in the ratio of regulatory T-cells to conventional T-cells, thereby leading to a treatment effect without immunosuppression. The investigators previously published the phase I results of this approach in patients with aGVHD,4 and they provided an update of their observations in this phase II prospective study.
Two categories of patients were enrolled: The first patient subset was undergoing first-line treatment with steroids and was classified as high risk based on the Minnesota Risk Stratification System. These patients would otherwise have a very high nonrelapse mortality and a low response rate to steroids; the second patient subset was receiving second-line therapy after having no response to first-line steroid treatment or after having a flare of their GVHD upon steroid taper. This second group was overall a high-risk group of patients who would be anticipated to have a nonrelapse mortality upward of 80%.
Patients in the Minnesota high-risk group were treated with uhCG at 2000 units/m2 subcutaneously every other day for 7 days plus high-dose steroids. Patients in the second-line treatment group were treated with 2000 units/m2 subcutaneously if they were steroid-dependent or 5000 units/m2 subcutaneously if they were steroid refractory every other day for 14 days plus standard-of-care immunosuppression. In total, 22 patients were enrolled in each arm, and the primary outcome of the study was Day 28 response. Secondary outcomes included safety and survival, exploratory metabolomics analyses, and biomarkers.
Mark A. Schroeder, MD:
The median age of patients in each study group was just more than 60 years; the graft source varied between those in the first-line group and the second-line group: 23% and 36% of patients received bone marrow grafts, 36% and 41% received peripheral blood, and 41% and 23% received umbilical cord grafts, respectively. In the first-line group and the second-line group, 45% and 23% received myeloablative conditioning, and 55% and 77% received reduced intensity conditioning, respectively.
Mark A. Schroeder, MD:
The majority of patients in the first-line group had severe Stage III/IV lower GI aGVHD (59%/9%), which is known to be associated with high mortality and a reduced response to steroids. Furthermore, the median albumin level was low in both groups (first-line: 2.7 g/dL [range: 1.9-3.4]; second-line: 2.5 g/dL [range: 0.9-4.0]), which is another poor prognostic factor for GVHD outcomes.
Finally, whereas patients in the first-line group were treated concomitantly with steroids, patients in the second-line group were treated concomitantly with a variety of standard-of-care agents, including antithymocyte globulin (n = 4), etanercept (n = 1), ruxolitinib (n = 5), sirolimus (n = 4), and steroids (n = 8).
Mark A. Schroeder, MD:
Day 28 responses were impressive with a 64% complete response (CR) rate for patients who were receiving first-line treatment and a 50% CR rate for those who were receiving second-line treatment. Furthermore, based on historical data, we would anticipate a median overall survival of approximately 6 months for high-risk aGVHD, but the median overall survival for the overall cohort of patients was much longer at 1.2 years. When comparing responders vs nonresponders, the 2-year survival probability was 67% vs 12% (P <.01), respectively.
Mark A. Schroeder, MD:
Overall, the treatment with uhCG/EGF was well tolerated with only one dose-limiting toxicity due to a cerebral venous sinus thrombosis that was treated successfully with anticoagulants. As expected in this patient population, the most common causes of death were aGVHD (n = 9), disease relapse (n = 9), infection (n = 3), and organ damage (n = 2).
In an exploratory analysis, investigators evaluated potential biomarkers that could predict response to therapy and found that high levels of linoleic acid were associated with higher complete and partial response (PR) rates and higher lactic acid levels were associated with treatment failure.
Mark A. Schroeder, MD:
Taken together, this study by Holtan and colleagues3 showed that uhCG/EGF may be a promising new adjunctive treatment for patients with aGVHD. This study also showed that uhCG/EGF may be used successfully in combination in patients who are receiving standard-of-care treatments like ruxolitinib for steroid-refractory aGVHD, which may help to augment epithelial regeneration and provide some additional therapeutic benefit without added immunosuppression.
Mark A. Schroeder, MD:
The MAGIC study previously reported a correlation between ST2 and REG3a levels with mortality.5 Moreover, investigators from UMN reported a correlation between amphiregulin levels and outcomes in patients with aGVHD.4 At ASH 2021, Pratta and colleagues6 reported pooled data from 2 prospective studies to assess the utility of these 3 biomarkers as monitoring biomarkers for aGVHD and validate them in an independent cohort. The first study was conducted at UMN with patients receiving uhCG/EGF (UMN cohort; N = 51), and the second study was the REACH1 study, which evaluated ruxolitinib for the treatment of steroid refractory aGVHD (REACH1 cohort; N = 60). In both studies, investigators evaluated serial sampling of plasma for the respective biomarkers (UMN, bead-based multiplex; REACH1, by microfluidic immunoassay) on Days 0, 7, 14, 28, and 56 and evaluated biomarker level measurements with survival outcomes. Primary study objectives included comparing biomarker concentration across response groups, change of biomarkers from baseline to study days analyzed, and biomarker cutoffs predictive of overall survival identified in the UMN cohort and assessed for validity in the REACH1 cohort.
Mark A. Schroeder, MD:
Both the UMN and REACH1 studies enrolled high-risk patients, although the UMN study did enroll more grade III (31%-81%) to IV (12%-35%) aGVHD patients. Median ages in the UMN and REACH1 studies were 61 and 52 years, and males made up approximately 20% and 30% of study participants, respectively.
Mark A. Schroeder, MD:
Both studies included in the analyses observed that Day 28 CR was associated with a 2.8-fold (P = .006) to 3.0-fold (P = .007) reduction in amphiregulin biomarker levels compared with baseline. Of importance, patients in REACH1 with a PR rate at Day 28 exhibited a twofold (P = .017) decrease in amphiregulin from baseline to Day 56. By contrast, in both UMN and REACH1 studies, patients who did not achieve a response by Day 28 or who had progressive disease had no change in amphiregulin levels over time. Finally, both studies showed there were no substantial changes in ST2 or REG3a between baseline and Day 28.
Mark A. Schroeder, MD:
In the UMN cohort, an amphiregulin cutoff of >212 pg/mL was associated with a significant probability (P = .006) for a rapidly fatal course with a median survival of 62 days, whereas a cutoff of >292 ng/mL for ST2 was associated with a median survival of 239 days (P = .001), and a cutoff of >13.5 ng/mL for REG3a was associated with a median survival of 416 days (P = .01). Similarly, in the REACH1 cohort, an amphiregulin cutoff of >336 pg/mL was associated with a significant probability (P = .005) for a rapidly fatal course with a median survival of 74 days, whereas a cutoff of >188 ng/mL for ST2 or a cutoff of >3.6 ng/mL for REG3a were not associated with a rapidly fatal course and significant decrease in median survival.
Mark A. Schroeder, MD:
In both UMN and REACH1 studies, the risk ratio for progressive disease compared with PR or better was statistically significant at Day 28 (P = .02 and P <.0001, respectively). Analyses from both studies also demonstrated that elevated amphiregulin above the identified cutoff, but not ST2 or REG3a, was associated with a significant risk ratio in this patient population.
Mark A. Schroeder, MD:
In summary, amphiregulin was validated as a novel monitoring biomarker for patients with life-threatening aGVHD. This biomarker may have prognostic implications in patients who are being treated with ruxolitinib as standard of care for steroid-refractory aGVHD and may help gauge who is at highest risk for mortality. The investigators of the study suggest monitoring amphiregulin in patients with aGVHD using serial assessments on a consistent platform.
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