A Review of Selected Presentations From the 2022 Tandem Meetings
• April 23-26, 2022 • Salt Lake City, Utah
Noninvasive Genomic Characterization of Patients With Nonsclerotic and Superficially Sclerotic Chronic Cutaneous Graft-vs-Host Disease Identified a Novel Gene Signature in Responders to Ruxolitinib Cream
Chronic graft-vs-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (HSCT). There are currently no therapies approved by the US Food and Drug Administration (FDA) for the treatment of cutaneous GVHD.1 Ruxolitinib is an oral inhibitor of Janus kinase 1/2 that is approved for the treatment of acute and chronic GVHD in patients ages 12 years and older who had received unsuccessful treatment with 1 or 2 prior lines of therapy.2 In 2021, the FDA approved ruxolitinib cream 1.5% for the topical short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis in patients ages 12 years and older who lack other adequate or suitable therapies.3
A double-blind, randomized, controlled phase 3 trial evaluated the safety and efficacy of topical ruxolitinib cream 1.5% vs a vehicle cream, both applied twice daily, for the treatment of cutaneous chronic GVHD. Dr Alina Markova and colleagues presented data from an interim analysis, as well as a genomic analysis.4,5
Eligible patients had undergone allogeneic HSCT, were ages 12 years or older, and had 2% of body surface area clinically or histologically confirmed as nonsclerotic or superficially sclerotic, cutaneous chronic GVHD. Among patients who were receiving systemic therapy for GVHD, the regimen had to be stable for at least 4 weeks before study treatment began. Any cutaneous therapies were discontinued before the study treatment was initiated.
The patients received ruxolitinib cream applied to one side of the face and body and the vehicle cream applied to the other side. The primary outcome was the efficacy at day 28 of the ruxolitinib cream vs the vehicle cream, as measured by the involved proportion of body surface area.
The trial randomly assigned 13 patients to treatment. Their mean age was 52.6±20 years, and 53% were female. The most common diagnoses were acute leukemia (62%) and non-Hodgkin lymphoma (23%). The median time from transplant to study enrollment was 665 days (interquartile range [IQR], 433-1355 days), and the median time from chronic GVHD onset to enrollment was 283 days (IQR, 115-867 days). GVHD symptoms were severe in 62% of patients, moderate in 15%, and mild in 23%. The chronic GVHD subtype was classic in 85% and overlap in 15%. Nearly half of patients (46%) had 4 or more organs involved, and 31% had received 3 or more prior lines of systemic therapy. Among the 10 patients with nonsclerotic cutaneous chronic GVHD, subtypes included lichen planus–like (62%), papulosquamous (8%), and maculopapular rash (8%). Prior lines of therapy included topical corticosteroids (77%), topical calcineurin inhibitors (31%), and phototherapy (31%).
On day 14, the primary outcome of involved body surface area was lower on the side treated with ruxolitinib compared with the vehicle cream, but the difference did not reach statistical significance (P=.06). At day 28, the comparison was also not significant (P=.15). In contrast, secondary outcomes did show a significant improvement with ruxolitinib. The Composite Assessment of Index Lesion Severity (CAILS) score was significantly better on the side treated with ruxolitinib vs the vehicle cream at day 14 (P=.02), although not at day 28 (P=.09). The Physician’s Global Assessment (PGA) of clinical condition was significantly better with ruxolitinib vs the vehicle cream, at both day 14 (P=.02) and day 28 (P=.026).
Noninvasive skin samples were collected from all study participants using a skin-stripping method. There were 11 samples obtained from the active treatment side and 11 samples obtained from the vehicle treatment side. The study investigators performed RNA sequencing, which was followed by mapping to the human genome and quantification of gene expression levels. Expression analysis showed differential expression of 310 genes by at least 2-fold (P<.01) between patients treated with ruxolitinib cream 1.5% vs the vehicle cream (Table 1). Genes showing differential expression were most commonly involved in keratinization, transcriptional regulation by RUNX3, and NOTCH3 activation and signal transduction to the nucleus. The analysis identified 383 genes that were differentially expressed by at least 2-fold (P<.01) in patients who responded to treatment with ruxolitinib (n=8) vs those who did not respond (n=3).
References
1. Link-Rachner CS, Sockel K, Schuetz C. Established and emerging treatments of skin GvHD. Front Immunol. 2022;13:838494.
2. Jakafi [package insert]. Incyte Corporation; Wilmington, Delaware; 2021.
3. Opzelura [package insert]. Incyte Corporation; Wilmington, Delaware; 2021.
4. Markova A, Whitaker JW, Pan A, et al. Noninvasive genomic characterization of patients with nonsclerotic and superficially sclerotic chronic cutaneous graft-versus-host disease identified a novel gene signature in responders to ruxolitinib cream. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 33.
5. Markova A, Prockop SE, Dusza S, et al. Interim results of a pilot, prospective, randomized, double-blinded, vehicle-controlled trial on safety and efficacy of a topical inhibitor of Janus kinase 1/2 (ruxolitinib INCB018424 phosphate 1.5% cream) for non-sclerotic and superficially sclerotic chronic cutaneous graft-versus-host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 390.
Interim Results of a Pilot, Prospective, Randomized, Double-Blinded, Vehicle-Controlled Trial on Safety and Efficacy of a Topical Inhibitor of Janus Kinase 1/2 (Ruxolitinib INCB018424 Phosphate 1.5% Cream) for Non-Sclerotic and Superficially Sclerotic Chronic Cutaneous Graft-vs-Host Disease
Oral ruxolitinib is approved by the FDA for the treatment of acute and chronic GVHD, and it has demonstrated efficacy in clinical studies for the treatment of other pathologies of the skin, including psoriasis, atopic dermatitis, and vitiligo.1,2 Dr Alina Markova and colleagues presented data from an interim analysis of a double-blind, vehicle-controlled, phase 2 clinical study that evaluated topical ruxolitinib cream 1.5% in patients with chronic GVHD of the skin.3 A genomic analysis was presented separately.4
The trial enrolled patients with GVHD lesions that were histologically or clinically confirmed as cutaneous nonsclerotic (lichen-planus–like or poikilodermatous) or superficially sclerotic (lichen sclerosis or morphea-like), covering at least 2% of the body surface area. Patients receiving systemic therapy were eligible if their regimen had been stable for at least 4 weeks before the study treatment began. The patients were randomly assigned to receive ruxolitinib cream 1.5% applied to either the left or the right side of the face and body and vehicle cream applied to the other side. Each cream was applied twice daily for 28 days. The primary endpoint of this proof-of-concept study was the extent of cutaneous chronic GVHD, as measured by body surface area, on the ruxolitinib side vs the vehicle side on day 28.
Results from 13 evaluable patients were analyzed as part of the interim analysis.3 The patients were a median age of 52.6±20 years, and 53% were female. The diagnoses included acute leukemia (62%), non-Hodgkin lymphoma (23%), and myeloproliferative neoplasm (8%). Chronic GVHD was severe in 62% of patients, 85% had classic GVHD, and 77% had nonsclerotic cutaneous GVHD.
The extent of cutaneous chronic GVHD, as measured by body surface area, was not significantly different between the 2 treatment sides (Figure 1). However, ruxolitinib was associated with a superior PGA score starting at day 14 (3.3 for the treatment side vs 4.4 for the vehicle side; P=.024), with continued improvement at day 28 (2.5 vs 4.0; P=.026). Ruxolitinib also improved the CAILS score, starting at day 14 (9.0 vs 13.3; P=.02; Figure 2). Skin samples were collected by a noninvasive skin stripping method for gene expression analysis. RNA sequencing identified 310 genes that were differentially expressed by at least 2-fold in lesions that were treated with ruxolitinib cream vs the vehicle cream. The investigators identified 383 differentially expressed genes in patients who responded to ruxolitinib therapy vs those who did not. No serious adverse events (AEs) were reported.
References
1. Jakafi [package insert]. Incyte Corporation; Wilmington, Delaware; 2021.
2. Shalabi MMK, Garcia B, Coleman K, Siller A Jr, Miller AC, Tyring SK. Janus kinase and tyrosine kinase inhibitors in dermatology: a review of their utilization, safety profile and future applications. Skin Therapy Lett. 2022;27(1):4-9.
3. Markova A, Prockop SE, Dusza S, et al. Interim results of a pilot, prospective, randomized, double-blinded, vehicle-controlled trial on safety and efficacy of a topical inhibitor of Janus kinase 1/2 (ruxolitinib INCB018424 phosphate 1.5% cream) for non-sclerotic and superficially sclerotic chronic cutaneous graft-versus-host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 390.
4. Markova A, Whitaker JW, Pan A, et al. Noninvasive genomic characterization of patients with nonsclerotic and superficially sclerotic chronic cutaneous graft-versus-host disease identified a novel gene signature in responders to ruxolitinib cream. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 33.
Use of Belimumab for Prophylaxis of Chronic Graft-vs-Host Disease
The coordinated involvement of T cells and B cells in GVHD has raised the idea of targeting B cells to manage cutaneous disease.1 B-cell activating factor (BAFF) is a member of the tumor necrosis factor cytokine family that plays a key role in the survival and differentiation of antigen-activated B cells.2,3 BAFF regulates B-cell recovery and homeostasis in patients who have undergone allogeneic HSCT. BAFF is present at increased levels in patients with GVHD. Excess BAFF and alloantigen act together to produce alloantibodies and a pool of active B cells.
Belimumab is a human monoclonal antibody that prevents the binding of BAFF to its cognate receptors on B cells, thus reducing the survival of alloreactive B cells.4 Belimumab is FDA-approved for the treatment of patients with systemic lupus erythematosus and active lupus nephritis. An investigator-initiated, single-center phase 1 study evaluated the efficacy and tolerability of belimumab in the prevention of chronic GVHD.5 The study enrolled 10 adults in complete remission (CR) after allogeneic HSCT. All patients had received mobilized peripheral blood grafts from human leukocyte antigen (HLA)-matched donors who were related or unrelated. The patients had received a conditioning regimen. All patients were negative for minimal residual disease. They had received tacrolimus and methotrexate for prophylaxis of GVHD, and 1 patient had received cyclophosphamide after transplant. Starting 50 to 80 days after allogeneic HSCT, belimumab was administered intravenously at 10 mg/kg every 2 weeks for 3 doses, followed by 4 subsequent doses given at 1-month intervals.
Among 9 evaluable patients, the median follow-up was 28 months after allogeneic HSCT (range, 12-43 months). The median time since completing belimumab therapy was 23 months (range, 4-29 months). Eight of the 9 patients (89%) had received all 7 doses of belimumab. One patient (11%) had received only 3 doses of belimumab owing to thrombocytopenia and insurance issues.
After more than 20 months of follow-up after belimumab administration, 5 of the 8 patients (63%) who had received all 7 doses of the antibody were alive, not receiving immunosuppressive therapy, and showing no evidence of chronic GVHD. Immune reconstitution is shown in Figure 3. Chronic GVHD occurred in 2 patients (25%). In one of these patients, the severity improved to mild chronic after treatment with tacrolimus, ruxolitinib, and corticosteroids.
One patient died from complications related to pneumonia and liver failure. One patient (13%) relapsed with acute myeloid leukemia (AML) 1 month after receiving the seventh dose of belimumab. This patient developed mild chronic GVHD in the mouth and upper gastrointestinal tract, and was receiving tapering doses of prednisone 16 months after completing belimumab therapy. The 1 patient who received only 3 doses of belimumab experienced a lymphoma relapse 3 months after cessation of study treatment. After treatment with venetoclax and donor leukocyte infusion, this patient’s leukemia was in remission, and he was free of chronic GVHD more than 18 months after salvage therapy.
Belimumab was well tolerated, with no AEs of grade 3 or higher. There were no reports of infusion reactions or hypersensitivity. One patient developed reactivation of cytomegalovirus. However, there were no cases of clinically important infections or myelosuppression. Three patients (33%) developed stage 1 skin acute GVHD. This AE resolved completely with a corticosteroid pulse treatment in 2 of the patients, whereas the other patient developed a case of overlap GVHD.
References
1. McManigle W, Youssef A, Sarantopoulos S. B cells in chronic graft-versus-host disease. Hum Immunol. 2019;80(6):393-399.
2. Jia W, Poe JC, Su H, et al. BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation. Blood. 2021;137(18):2544-2557.
3. Saliba RM, Sarantopoulos S, Kitko CL, et al. B-cell activating factor (BAFF) plasma level at the time of chronic GvHD diagnosis is a potential predictor of non-relapse mortality. Bone Marrow Transplant. 2017;52(7):1010-1015.
4. Benlysta [package insert]. GlaxoSmithKline, LLC; Research Triangle Park, North Carolina; 2021.
5. Pusic I, Johanns T, Sarantopoulos S, et al. Use of belimumab for prophylaxis of chronic graft-versus-host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 34.
Prolonged Post-Transplant Ruxolitinib Therapy Is Associated With Protection From Severe GVHD After Allogeneic HCT
Two ongoing phase 2 clinical trials are evaluating the safety and efficacy of ruxolitinib administered around the time of allogeneic HSCT, with emphasis on outcomes related to GVHD. Clinical trial NCT03286530 enrolled patients with AML who were in their first CR.1 These patients received continuous ruxolitinib in 28-day cycles, for up to 24 cycles, starting 30 to 90 days after allogeneic HSCT. Clinical trial NCT03427866 enrolled patients with primary or secondary myelofibrosis.2 These patients received ruxolitinib before, during, and after allogeneic HSCT, in 28-day cycles starting 14 days prior to HSCT. Patients could receive up to 13 cycles.
Dr Zachariah DeFilipp and colleagues presented the results from an unplanned interim analysis of these 2 trials. The analysis included 54 patients (33 with AML and 21 with myelofibrosis).3 At the time of their HSCT, the patients were a median age of 67 years (range, 46-79 years). Donor types included matched unrelated donors (n=42; 78%), matched sibling donors (n=11; 20%), and mismatched unrelated donors (n=1; 2%). All HSCTs were conducted with a reduced-intensity conditioning regimen, grafts of peripheral blood stem cells, and standard GVHD prophylaxis with tacrolimus and methotrexate. The median follow-up was 18 months (range, 7-43 months). Among the 33 patients with AML included in the analysis, the median number of cycles of ruxolitinib received after HSCT was 19 (range, 1-24). Twenty-six patients (79%) were not receiving treatment. The 21 patients with myelofibrosis received a median of 12 cycles of ruxolitinib (range, 2-13) after allogeneic HSCT. The most common treatment-related AEs of grade 3 or higher were anemia (n=10), neutropenia (n=5), and thrombocytopenia (n=5).
Among all patients, the 6-month cumulative incidence of acute GVHD was 24% (95% CI, 14%-36%), and all cases were grade 2. In the study of patients with AML, 5 of the 6 cases of GVHD occurred before the initiation of ruxolitinib therapy. There were no cases of emergent grade 3 or grade 4 acute GVHD, including no reports of severe lower gastrointestinal tract GVHD. The 12-month incidence of all cases of chronic GVHD was 21% (95% CI, 11%-33%), and the 12-month incidence of moderate-to-severe chronic GVHD requiring systemic therapy was 3.8% (95% CI, 0.7%-12%; Figure 4).
The 18-month cumulative incidence of nonrelapse mortality was 8% (95% CI, 2.5%-18%), and only 1 death was attributed to GVHD. The 18-month cumulative incidence of disease relapse was 24% (95% CI, 13%-37%). The 18-month overall survival rate was 79% (95% CI, 64%-88%). At 18 months, the GVHD relapse–free survival rate was 67% (95% CI, 52%-78%; Figure 5).
References
1. ClinicalTrials.gov. Ruxolitinib + allogeneic stem cell transplantation in AML. https://clinicaltrials.gov/ct2/show/NCT03286530. Identifier: NCT03286530. Accessed May 22, 2022.
2. ClinicalTrials.gov. Ruxolitinib pre-, during- and post-HSCT for patients with primary or secondary myelofibrosis. https://clinicaltrials.gov/ct2/show/NCT03427866. Identifier: NCT03427866. Accessed May 22, 2022.
3. DeFilipp Z, Kim HT, Knight L, et al. Prolonged post-transplant ruxolitinib therapy is associated with protection from severe GVHD after allogeneic HCT. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 393.
Interim Analysis of T-Cell Specific Predictive Biomarkers of Graft-vs-Host Disease and Relapse Following Post-Transplant Cyclophosphamide Prophylaxis
A key feature of the pathogenesis of GVHD is the reactivity of donor T cells, which attack host tissues such as the gut, liver, and mucous membranes.1 Biomarkers of T-cell activation are under investigation as potential predictors of acute GVHD. Investigators developed a preclinical model using nonconditioned, immunodeficient NBSGW mice to assess the ability of human T cells to cause GVHD.2,3 Total mononuclear human bone marrow cells were transplanted into the mice at various doses. GVHD symptoms included lymphocyte infiltration of the liver, kidney, lung, and salivary glands, and the anticipated organ pathology. The mice who developed GVHD also showed decreased body weight. Not all mice who received the xenograft transplant developed GVHD; rather, development of GVHD was associated with the transplant dose, the inflammatory markers of the transplant recipient, and the type of graft. Hallmarks associated with the subsequent development of GVHD included proliferation of the human T cells during the first 1 to 3 weeks after transplant and an increase in the level of human interferon gamma in the plasma. Moreover, these markers of T-cell activation predicted the onset of GVHD up to 6 weeks prior to the development of signs and symptoms. Donor T cells were necessary and sufficient for the development of GVHD in this mouse model.
A clinical study conducted at a single center evaluated the characteristics of human T cells after allogeneic HSCT.4 This prospective study enrolled patients with any hematologic malignancy, without regard to the conditioning regimen, the GVHD prophylaxis regimen, the graft source, or the type of HLA matching. However, patients were required to have received GVHD prophylaxis with cyclophosphamide after transplant. Starting on day 7 after allogeneic HSCT, blood samples were collected every week for 98 days. T-cell analysis included only cells that were CD45RO+. Eleven metrics pertaining to T cells were evaluated for their ability to predict various patient outcomes, including relapse, acute GVHD of any grade, and acute GVHD of grade 2 or higher.
The investigators collected 417 blood samples from 35 patients during the first 100 days after allogeneic HSCT. Among the 34 patients who were included in the analysis, 5 patients (15%) had relapsed, 10 (29%) had not relapsed and did not have GVHD, 6 (18%) had grade 1 GVHD, and 13 (38%) had grade 2 to 4 GVHD.
Variations in the levels of CD3+/CD45RO+ cells are shown in Figure 6. Three T-cell characteristics were of particular interest. A low number of CD45RO+ T cells was predictive of the likelihood of relapse (P=.026), but not the development of acute GVHD. A reduced proportion of regulatory T cells was predictive of relapse (P<.001), the development of acute GVHD of any grade (P=.048), and the development of GVHD of grade 2 or higher (P<.001). In blood samples taken between day 5 and day 22 after allogeneic HSCT, a higher proportion of CD4+/CD8+ T cells significantly correlated with any-grade acute GVHD (P=.003), as well as acute GVHD of grade 2 or higher (P=.025). Decreased expression of the T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains was associated with the development of acute GVHD.
References
1. Jiang H, Fu D, Bidgoli A, Paczesny S. T cell subsets in graft versus host disease and graft versus tumor. Front Immunol. 2021;12:761448.
2. Hess NJ, Brown ME, Capitini CM. GVHD pathogenesis, prevention and treatment: lessons from humanized mouse transplant models. Front Immunol. 2021;12:723544.
3. Hess NJ, Hudson AW, Hematti P, Gumperz JE. Early T cell activation metrics predict graft-versus-host disease in a humanized mouse model of hematopoietic stem cell transplantation. J Immunol. 2020;205(1):272-281.
4. Hess NJ, Nadiminti K, Hematti P, Capitini CM. Interim analysis of T cell specific predictive biomarkers of graft-vs-host disease and relapse following post transplant cyclophosphamide prophylaxis. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 6.
Validation of Amphiregulin as a Monitoring Biomarker During Treatment of Life-Threatening Acute GVHD: A Secondary Analysis of 2 Prospective Clinical Trials
Up to half of patients who undergo allogeneic HSCT develop acute GVHD, which can be life-threatening.1,2 Patient monitoring could be improved with a biomarker that predicts symptom severity. A phase 1 study investigated biomarker levels in the blood of patients with acute GVHD who received urinary-derived human chorionic gonadotropin (uhCG) plus epidermal growth factor (EGF) to enhance epithelial repair.3 In patients whose GVHD responded to therapy, levels of plasma amphiregulin, a marker of tissue damage, decreased by 4.6-fold from baseline to day 28 of the study (P=.006). ST2 and REG3α have also been identified as potential biomarkers related to the severity of acute GVHD.4
Blood samples from 2 clinical trials, a trial from the University of Minnesota (UMN) and the REACH1 trial, were evaluated to determine the utility of amphiregulin, ST2, and REG3α as biomarkers of acute GVHD severity in patients who have undergone allogeneic HSCT.5 Patients in the UMN study received uhCG/EGF, whereas those in the REACH1 study received ruxolitinib. Blood samples from both studies had been taken at baseline and on days 7, 14, 29, and 56. In the UMN study, plasma samples were evaluated with an enzyme-linked immunosorbent assay to measure levels of amphiregulin. Levels of ST2 and REG3α were measured using a bead-based multiplex assay. In the REACH1 study, levels of all 3 biomarkers were evaluated by a microfluidic immunoassay.
In the UMN study, the mean level of amphiregulin decreased by 3-fold from baseline to day 28 in patients who achieved a CR (P=.006). This level did not change in patients with a partial response (PR) or no response on day 28. From baseline to day 28, the level of ST2 decreased by 1.4-fold (P=.02), whereas the REG3α level did not decrease. Several biomarker cutoff levels were associated with a rapidly fatal course: higher than 212 pg/mL for amphiregulin (median survival, not reached vs 62 days; P=.006), higher than 292 ng/mL for ST2 (median survival, not reached vs 239 days; P<.001), and higher than 13.5 ng/mL for REG3α (median survival, not reached vs 416 days; P=.01). Based on a multivariate analysis, the factors associated with survival were the day 28 response (no response vs CR/PR; relative risk [RR], 4.94; P=.02) and the baseline amphiregulin level (>212 pg/mL; RR, 2.50; P=.03).
In the REACH1 study, the mean amphiregulin level decreased by 2.8-fold from baseline to day 56 in patients with a CR at day 28 (P=.007) and by 2.0-fold in patients with a PR at day 28 (P=.017). The level did not decrease in those with disease progression. As measured on day 56 vs baseline, the mean level of ST2 decreased by 2.2-fold (P=.021) in patients who achieved a CR by day 28. Levels of REG3α did not change significantly in any disease response cohort. The biomarker cutoff levels associated with a rapidly fatal course were higher than 336 pg/mL for amphiregulin (median survival, not reached vs 74 days; P=.005; Figure 7), higher than 188 ng/mL for ST2 (P=.09), and higher than 3.6 ng/mL for REG3α (P=.3). Based on a multivariate analysis, factors independently associated with survival were the day 28 response (progressive disease vs CR/PR/very good PR; RR, 9.14; P<.0001) and the baseline amphiregulin level (>336 pg/mL; RR, 2.72; P<.05; Figure 8).
References
1. Nassereddine S, Rafei H, Elbahesh E, Tabbara I. Acute graft versus host disease: a comprehensive review. Anticancer Res. 2017;37(4):1547-1555.
2. Zeiser R, Blazar BR. Acute graft-versus-host disease—biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167-2179.
3. Holtan SG, Hoeschen AL, Cao Q, et al. Facilitating
resolution of life-threatening acute GVHD with human chorionic gonadotropin and epidermal growth factor. Blood Adv. 2020;4(7):1284-1295.
4. Major-Monfried H, Renteria AS, Pawarode A, et al. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood. 2018;131(25):2846-2855.
5. Pratta M, Jurdi NE, Rashidi A, et al. Validation of amphiregulin as a monitoring biomarker during treatment of life-threatening acute GVHD: a secondary analysis of 2 prospective clinical trials. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 70.
Prospective Trial of Ibrutinib for the Treatment of Pediatric Chronic Graft-vs-Host Disease
No medications are approved by the FDA to treat patients with chronic GVHD who are younger than 12 years. The oral immunomodulatory drug ibrutinib inhibits Bruton tyrosine kinase, which mediates key functions of B cells. Preclinical studies have shown that ibrutinib interferes with the activity of interleukin-2–inducible T-cell kinase in T cells, thus attenuating key T-cell activities.1-3 Ibrutinib is approved for the treatment of adults with chronic GVHD who received unsuccessful treatment with prior systemic therapy.4,5
The prospective, open-label, international phase 1/2 IMAGINE study evaluated ibrutinib in children with moderate-to-severe chronic GVHD.6 Part A of the study enrolled patients ages 1 year to younger than 12 years who had received unsuccessful treatment with at least 1 prior line of systemic therapy. The daily dose of ibrutinib was initiated at 120 mg/m2 (approximately half of the standard dose for adults) and was escalated to 240 mg/m2 after 14 days in patients without grade 3 or higher toxicity. Patients in part B were ages 12 years to younger than 22 years and had newly diagnosed GVHD or had previously received unsuccessful treatment with at least 1 prior line of therapy. These patients received once-daily ibrutinib at a dose of 420 mg. Ibrutinib was available in a pill form or as a liquid suspension. Primary endpoints included pharmacokinetics and safety.
The study enrolled 12 patients into part A and 47 into part B. The median follow-up was 20 months. In the overall study population of 59 patients, 12 patients were treatment-naive. At baseline, the most common site of GVHD involvement was the skin (Figure 9). The median time from the initial diagnosis of chronic GVHD to study enrollment was 12 months (range, 0.1-163 months). Previously treated patients had received a median of 2 prior therapies for their chronic GVHD (range, 1-12 prior therapies). Plasma-concentration profiles in these young patients were comparable with those of adults with chronic GVHD who received ibrutinib at a dose of 420 mg once daily. This finding resulted in a recommended pediatric equivalent dose of 240 mg/m2 once daily for patients younger than 12 years and of 420 mg once daily for patients ages 12 years or older.
The objective response rate (ORR) was 78%, with 5 CRs. At 20 weeks, sustained responses were observed in 70% of treatment-naive patients and 58% of previously treated patients who responded to ibrutinib therapy. The response duration was at least 1 year in 60% of treatment-naive patients and in 58% of previously treated patients.
The safety profile was consistent with prior reports of ibrutinib therapy in adult patients with GVHD. A treatment-associated AE of grade 3 or higher was reported in 64% of patients, and 24% experienced an AE that required discontinuation of study treatment. The most common AE of grade 3 or higher was pyrexia (8.5%), followed by neutropenia, stomatitis, hypoxia, and osteonecrosis (each reported in 6.8% of patients). Any-grade stomatitis was observed in 17% of patients. One patient died from causes that were potentially attributable to ibrutinib.
References
1. De Novellis D, Cacace F, Caprioli V, Wierda WG, Mahadeo KM, Tambaro FP. The TKI era in chronic leukemias. Pharmaceutics. 2021;13(12):2021.
2. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539-2549.
3. Shirley M. Bruton tyrosine kinase inhibitors in B-cell malignancies: their use and differential features. Target Oncol. 2022;17(1):69-84.
4. Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243-2250.
5. Imbruvica [package insert]. Pharmacyclics, LLC; South San Francisco, California; 2022.
6. Carpenter PA, Kang HJ, Zecca M, et al. Prospective trial of ibrutinib for the treatment of pediatric chronic graft-versus-host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 126.
Phase II Clinical Trial of Abatacept for Steroid-Refractory Chronic Graft-vs-Host Disease
Abatacept is a recombinant protein that consists of the extracellular domain of the human cytotoxic T lymphocyte–associated antigen fused to a modified Fc domain of human immunoglobulin G1.1 In the placebo-controlled phase 2 ABA2 trial, abatacept was evaluated in combination with calcineurin inhibition and methotrexate for the prevention of acute GVHD among adults and children who had undergone an allogeneic HSCT with an unrelated donor.2 The addition of abatacept reduced the incidence of severe, acute GVHD compared with placebo and improved the rate of severe, acute GVHD–free survival.
A phase 1 trial evaluated abatacept for the treatment of patients with corticosteroid-refractory chronic GVHD.3 The treatment was generally well tolerated, and 44% of patients achieved a PR. These findings led to a phase 2 clinical study that evaluated the efficacy and safety of abatacept in patients with corticosteroid-refractory chronic GVHD.4 Eligible patients had undergone an allogeneic bone marrow or stem cell transplant at least 100 days prior to study enrollment. All patients had received a stable immunosuppressive regimen for 2 weeks before study enrollment. Abatacept was administered at a dose of 10 mg/kg every 2 weeks, for a total of 3 doses. After a 1-month interval, the patients received abatacept at 10 mg/kg every 4 weeks for 3 doses. Clinical responses were assessed 1 month after the sixth dose of abatacept. Patients who achieved a CR or PR were eligible to receive up to 12 additional doses of abatacept, administered at 1-month intervals.
Among the 39 enrolled patients, 4 (10.3%) had received a bone marrow transplant and 35 (89.7%) had received a stem cell transplant. The conditioning regimen was myeloablative in 61.5% and nonmyeloablative in 35.9%. The HLA status was matched, unrelated in 56% of patients; matched, related in 38%; mismatched, related in 2.6%; and mismatched, unrelated in 2.6%. The patients had received a median of 5 previous treatments for chronic GVHD (range, 1-11 prior treatments). The symptoms of chronic GVHD were moderate in 18 patients and severe in 21 patients. Symptoms most commonly manifested in the skin (84%), joints (92%), eyes (72%), and lungs (56%).
The ORR was 58%, with no CRs. Responses most often occurred in the lungs (36%), eyes (25%), skin (22%), mouth (22%), and joints (22%). Disease progression occurred in 33% of patients. Treatment with abatacept led to durable reductions in the prednisone dose (P<.05; Figure 10).
Abatacept was generally well tolerated. Serious AEs possibly related to treatment with abatacept included grade 3 lung infection (2 events) and grade 4 lung infection (1 event). In addition, a single patient experienced grade 4 hemolysis, respiratory failure, and liver failure. This patient’s eventual death was attributed to concurrent infection with herpes simplex virus.
References
1. Blazar BR, Taylor PA, Linsley PS, Vallera DA. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood. 1994;83(12):3815-3825.
2. Watkins B, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021;39(17):1865-1877.
3. Nahas MR, Soiffer RJ, Kim HT, et al. Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Blood. 2018;131(25):2836-2845.
4. Koshy AG, Kim HT, Stroopinsky D, et al. Phase II clinical trial of abatacept for steroid-refractory chronic graft versus host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 32.
Highlights in Graft-vs-Host Disease From the 2022 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR: Commentary
Presentations on graft-vs-host disease (GVHD) at the Tandem Meetings | Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and the Cellular Therapy (ASTCT) and Center for International Blood and Marrow Transplant Research (CIBMTR) provided important new insights regarding prevention and treatment of this disease. Studies presented included evaluations of treatments such as urinary-derived human chorionic gonadotropin (uhCG) plus epidermal growth factor (EGF), belimumab, abatacept, axatilimab, ibrutinib, and ruxolitinib in systemic and topical formulations. Data were also presented for amphiregulin as a monitoring biomarker in patients treated for acute GVHD and for assessment of patient-reported response as an endpoint in chronic GVHD trials.
Acute GVHD
Dr Nicholas Hess presented data from an interim analysis that evaluated T cell–specific biomarkers after post-transplant cyclophosphamide (PTCy)-based transplants, with a focus on disease relapse and acute GVHD.1 For years, a goal in the transplant community has been to develop noninvasive predictive biomarkers that can help guide management. Many of the complications that occur after transplant are immunologically mediated, and the cascade for these complications starts weeks before the frank clinical manifestations appear. Knowledge of the immunologic processes that precede clinical manifestations might allow clinicians to intervene preemptively and prevent them. Although there are commercially available noninvasive biomarkers in use for risk stratification of acute GVHD, there are no data to suggest that clinical decisions should be based on the measurement of these biomarkers, although ongoing clinical trials are evaluating this issue.
Dr Hess and colleagues had previously performed experiments in a xenogeneic mouse transplant model, which suggested that certain T-cell metrics could predict clinical outcomes.2 This finding is intuitive because T cells are thought to be the primary driver for acute GVHD, and they also contribute to preventing relapse through a graft-vs-leukemia mechanism. This analysis enrolled 35 patients who received post-transplant yclophosphamide-based prophylaxis for GVHD at the University of Wisconsin. The patients had weekly samples collected prospectively for the first 98 days. The investigators analyzed specific T-cell subsets through immunophenotyping. It should be noted that the patients were heterogeneous in terms of their underlying disease, conditioning regimens, and donor types, and the analysis was performed on fresh samples.
Dr Hess and colleagues found that increased numbers of CD3+/CD45RO+ cells were associated with the subsequent development of grade 3 to 4 acute GVHD.1 Lower numbers of these cells were associated with a higher incidence of disease relapse. It should be emphasized that these associations were found early, in the first month after transplant, when the immune system is just beginning to reconstitute. The study also found that higher early numbers of regulatory T cells predicted for a lower risk of GVHD, which confirms previous findings.3 Dr Hess also discussed a unique population of so-called “double-positive cells,” which are T cells that express both CD4 and CD8. Interestingly, this population was observed to increase approximately 2 to 3 weeks before the clinical presentation of acute GVHD. These double-positive cells have not been a focus of interest in the past, and some researchers have even ignored them as an artifact of analysis. Based on these findings, however, it appears that the role of these “double-positive” T cells that express both CD4 and CD8 merits further study. The investigators also analyzed expression of costimulatory molecules on specific T-cell subsets, showing that expression of certain molecules correlated with certain outcomes.
Overall, this interesting analysis evaluated specific T-cell metrics in a transplant platform that is becoming increasingly more common and contributes to our understanding of the mechanisms at play after PTCy. Previous studies have also explored this concept.4,5 The findings from this analysis merit further study in a larger number of patients to determine if T-cell immunophenotyping can not only add to our understanding of immune reconstitution after PTCy, but also influence management of patients in real time.
Dr Shernan Holtan and colleagues presented results from a phase 2 trial that evaluated uhCG/EGF as an adjunct treatment for high-risk acute GVHD.6 This product is mainly used to induce ovulation and manage other fertility issues.7 It was chosen by the investigators for this application because human chorionic gonadotropin helps to promote immune tolerance, as evidenced in the natural relationship of the maternal-fetal chimera. EGF is thought to promote healing or organ resilience, specifically enhanced epithelialization of the gastrointestinal mucosa. Traditionally, treatment for advanced acute GVHD focused on agents with broad immunosuppression. Newer areas of focus in GVHD treatment now include immunologic tolerance, tissue repair, and organ resiliency. It is important to note that uhCG/EGF has been studied as an adjunct to standard immunosuppression, and is not a treatment unto itself.
This study enrolled 44 patients. Twenty-two patients with Minnesota high-risk disease treated in the first-line setting received uhCG/EGF plus corticosteroids. Another cohort of 22 patients with corticosteroid-refractory disease received uhCG/EGF plus their physician’s choice of standard-of-care second-line therapy. The dosing was administered subcutaneously, and the regimen varied according to the indication.
In the first-line setting, the overall response rate by day 28 was 64%. All of the observed responses were complete responses, which is fairly impressive. In the second-line setting, the overall response rate was 73%, with a complete response rate of 50%. Although these results are compelling, it is important to again emphasize that uhCG/EGF was administered as an adjunct to standard-of-care immunosuppressive therapy. A limitation to the interpretation of outcomes in the second-line cohort is that various therapies were chosen for second-line therapy. From a safety perspective, there were some cases of injection-site reactions, headaches, and lower-extremity edema. There was 1 dose-limiting toxicity, which occurred in a patient who developed a cerebral venous sinus thrombosis.
Overall, this study provides compelling evidence for the use of uhCG/EGF as an adjunct in the treatment of acute GVHD. Interest in this agent is driven not only by the novel mechanism of action, but also by the tolerable toxicity profile. Larger, definitive trials will be needed to determine whether uhCG/EGF improves outcomes. A prospective randomized study comparing a standard second-line therapy with placebo vs the same treatment with uhCG/EGF would be very helpful to truly assess benefit.
Dr Holtan also presented data from a secondary analysis of 2 prospective trials that evaluated the use of the molecule amphiregulin as a biomarker for monitoring acute GVHD.8 Amphiregulin is a ligand of the EGF receptor, which is expressed in many tissues, including the intestine, and is thought to be released at times of injury. A prior study from investigators at the University of Minnesota using uhCG/EGF as an adjunct for GVHD treatment had suggested that amphiregulin has potential use as a monitoring biomarker.9 The current study was undertaken to validate amphiregulin in a larger cohort of patients treated with uhCG/EGF, as well as in patients in the REACH1 trial who received ruxolitinib for the treatment of corticosteroid-refractory acute GVHD.10 There were 51 samples from patients treated with uhCG/EGF and 60 samples from patients treated with ruxolitinib in the REACH1 study. This analysis found that both trials showed a significant decrease in amphiregulin from day 0 to day 56 among patients with a complete response at day 28.
The investigators then compared the utility of amphiregulin as a biomarker with plasma levels of ST2 and REG3α, which are well-described, commercially available prognostic biomarkers for acute GVHD.8 In the study from the University of Minnesota, baseline levels of ST2 and REG3α correlated with clinical response, whereas baseline levels of amphiregulin did not. Among patients with a complete response at day 28, amphiregulin levels at day 56 were much lower relative to baseline and had a stronger correlation to clinical response than levels of ST2 or REG3α. In the REACH1 trial, baseline levels of amphiregulin and ST2 correlated with response to ruxolitinib, whereas baseline levels of REG3α did not. Among patients who had a complete response at day 28 with ruxolitinib, lower levels of amphiregulin at day 56 had a stronger correlation to overall results than levels of ST2 or REG3α.
It is important to note that amphiregulin was not compared with the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP), which is the best-studied commercially available algorithm that incorporates measurements of both REG3α and ST2, rather than the raw individual levels.11 It should also be mentioned that the change from baseline to day 56 levels correlated with clinical response at day 28. Therefore, the utility of measuring these biomarkers in real time is unclear. Monitoring might help to refine the assessment of prognosis moving forward at day 56, or it might be more useful for predicting flares of GVHD from day 28 through day 56. Overall, these interesting findings support the further study of amphiregulin as another potential biomarker for acute GVHD. Moving forward, amphiregulin should be compared with MAP or even incorporated into the algorithm as a third biomarker to see if it is better able to refine the prognostic utility.
Prevention of Chronic GVHD
Traditionally, studies of GVHD prevention focused mostly on acute GVHD, given its historical effect on nonrelapse mortality. More recently, studies have begun to focus specifically on the prevention of chronic GVHD. Some of these trials have explored whether intervention after engraftment could potentially mitigate the risk for chronic GVHD. Throughout the past decade, data have indicated a clear role for B cells in the pathophysiology of chronic GVHD, which has led to the use of therapies that target B cells, such as rituximab and ibrutinib.12 Ibrutinib was the first of these agents to receive approval from the US Food and Drug Administration (FDA) for the treatment of corticosteroid-refractory chronic GVHD. In addition, studies have shown that levels of B-cell–activating factor (BAFF) are higher in patients with significant chronic GVHD.13 These high levels of BAFF are thought to promote B-cell survival and to increase production of alloreactive antibodies, contributing to the pathogenesis of chronic GVHD in some patients.
Belimumab is a monoclonal antibody that targets BAFF and inhibits its interaction with cell-surface receptors. Belimumab is approved by the FDA for the treatment of lupus and active lupus nephritis. Dr Iskra Pusic and colleagues presented the results of a phase 1 investigator-initiated trial prompted by the hypothesis that targeting BAFF with belimumab early after transplant might decrease the incidence of chronic GVHD.14 The presentation included results for the first 9 participants enrolled in the trial. All patients had received peripheral blood stem cell grafts, with a variety of conditioning regimens. Most patients received tacrolimus-based prophylaxis, including 7 who also received antithymocyte globulin (ATG), and 1 patient received post-transplant yclophosphamide. Treatment with belimumab began 50 to 80 days after transplant and was administered every other week for 3 doses, followed by every 4 weeks for 4 doses, for a total of 7 doses.
From a safety perspective, no grade 3 or higher adverse events attributable to treatment were observed. Among the 9 patients, 8 received all 7 planned doses of belimumab. One patient, who developed thrombocytopenia and relapsed disease, received only 3 doses. Importantly, there were no reports of infusion reactions or cytopenias considered related to belimumab. At the time of the presentation, 5 patients were alive and not receiving any immunosuppressive therapy. Two patients developed chronic GVHD: 1 patient with overlap disease and 1 patient with classic severe multiorgan chronic GVHD. There did not appear to be any excess infections in this small cohort. Correlative analyses showed delayed B-cell reconstitution in all patients, consistent with the known mechanism of action of belimumab.
Overall, belimumab appeared to be safe and well tolerated when administered early after hematopoietic cell transplant (HCT). With the very small number of patients in this study, it is impossible to know if treatment with belimumab had an impact on subsequent development of chronic GVHD, especially because the majority of patients also received ATG as part of GVHD prophylaxis. Larger studies in more homogeneous populations, perhaps without the use of ATG, would be crucial to determine whether this strategy is worth exploring.
Janus kinase (JAK) inhibitors are now approved for the treatment of corticosteroid-refractory acute and chronic GVHD. There is interest in using JAK inhibitors in other phases of GVHD treatment, specifically as first-line therapy or even as prevention. Dr Zachariah DeFilipp and colleagues are conducting two phase 2 investigator-initiated studies that introduce ruxolitinib early after the transplant course for patients with either AML or myelofibrosis (MF).15,16 Dr DeFilipp presented results from an unplanned interim analysis that included participants from both of these studies to describe the incidence of chronic GVHD when initiating ruxolitinib early after transplant and continuing treatment for months afterwards.17 The analysis provided data for 54 patients: 33 with AML and 21 with MF. All patients received ruxolitinib early after transplant; patients with MF actually started treatment during conditioning therapy and continued throughout the peri-HCT period. Treatment with ruxolitinib continued for 2 years in the AML study and for 1 year in the MF study. The transplants used conventionally fully matched donors, with related or unrelated peripheral blood stem-cell grafts. The patients received reduced-intensity conditioning regimens, as well as standard tacrolimus and methotrexate GVHD prophylaxis.
The median follow-up for survivors was 18 months. Ruxolitinib was well tolerated and feasible for administration early after HCT. As expected, some patients developed cytopenias, specifically anemia and thrombocytopenia, consistent with the known adverse event profile of ruxolitinib. The 6-month cumulative incidence of grade 2 to 4 acute GVHD was 24%; all cases were grade 2. The 12-month cumulative incidence of all cases of chronic GVHD was 21%. Most notably, the incidence of moderate-to-severe chronic GVHD that required systemic therapy was 3.8%, an impressively low figure. No excess opportunistic infections or relapses were observed. These compelling data have led to much excitement in the field, where there was already strong enthusiasm for JAK inhibitors and their activity in acute and chronic GVHD. Larger, formal, prospective randomized trials are needed with JAK inhibitors paired with standard GVHD prevention to see if progress can be made.
Treatment of Chronic GVHD
Abatacept, in combination with tacrolimus and methotrexate, was recently approved for the prevention of GVHD in patients undergoing unrelated donor transplants. Abatacept is a recombinant fusion protein that consists of the extracellular domain of CTLA-4 fused to the modified Fc region of human immunoglobulin G1, which binds to CD80 and CD86. Through this mechanism, abatacept inhibits CD28-mediated T-cell activation. In a prior phase 1 trial evaluating abatacept for the treatment of corticosteroid-refractory chronic GVHD, the overall response rate was 44%.18
Dr Anita Koshy and colleagues presented the interim results of a phase 2 trial evaluating the efficacy of abatacept for the treatment of corticosteroid-refractory chronic GVHD.19 Abatacept was administered at a dose of 10 mg/kg every other week for 3 doses followed by 10 mg/kg every 4 weeks for 3 doses, for a total of 6 doses. Responders were able to receive long-term maintenance therapy. The trial enrolled and treated 39 patients with heterogeneous transplant platforms, donor types, conditioning regimens, and underlying diseases, but all patients had corticosteroid-refractory chronic GVHD, with a median number of 4 organs involved and a median of 5 prior lines of therapy.
The overall response rate was 58%, which consisted entirely of partial responses, which is not surprising in a refractory chronic GVHD population. Responses were observed in all of the organs involved. Interestingly, an improvement was seen in 36% of patients with pulmonary involvement, which is notoriously difficult to treat. Worrisomely, there were 9 cases of neutropenia, including two grade 3 events and two grade 4 events. If treating with abatacept, physicians should remain alert for neutropenia, given the fragile immunologic status of these patients. Larger trials are needed, as are correlative immunologic studies to understand the mechanism of action, but abatacept appears to be another promising treatment for corticosteroid-refractory chronic GVHD.
The pathologic hallmark of chronic GVHD is fibrosis or scarring.20 Scleroderma and bronchiolitis obliterans syndrome are considered to be the most difficult-to-treat clinical manifestations of chronic GVHD, and are especially fibrotic in nature. Axatilimab is a humanized monoclonal antibody that targets the colony-stimulating factor 1 receptor (CSF1R) on activated macrophages, which are thought to play a crucial role in the fibrotic process.21,22 Dr Carrie Kitko and colleagues presented the preliminary results of a phase 1/2 study evaluating axatilimab for the treatment of corticosteroid-refractory chronic GVHD.22 Participants enrolled were ages 6 years or older and had received unsuccessful treatment with 2 or more lines of therapy. A phase 1 dose-finding part was followed by a phase 2 expansion phase in which patients received 1 mg/kg every other week. A total of 40 patients were treated: 17 in the phase 1 portion and 23 in the phase 2 portion. Patients had received a median of 4 prior lines of therapy for chronic GVHD; several had already received ruxolitinib, belumosudil, or ibrutinib.
From a safety standpoint, only 13% of patients reported grade 3 or higher adverse events, which appeared to be dose-dependent. The notable events included elevations in liver function tests, creatinine kinase, and lipase, as well as periorbital edema. The elevation in liver function tests is thought to be an on-target effect of the expression of CSF1R on the Kupffer cells in the liver. It is important to mention that there were no cases of end organ damage, and full reversibility of liver enzymes was observed once the agent was stopped.
Treatment with axatilimab led to an overall best response rate of 68%, with a median time of 1 month to response. The majority of the responses were partial remissions, as would be expected in this heavily treated population. There were notable improvements in several patients with cutaneous scleroderma and bronchiolitis obliterans syndrome. A significant improvement in the Lee Symptom Scale, the best patient-reported outcome scale to help validate responses in chronic GVHD, was reported in 53% of patients. Among patients with scleroderma that responded to treatment, correlative studies appeared to show tissue-macrophage depletion, as well as reduction in levels of transforming growth factor β consistent with the hypothetical mechanism of action. These findings are exciting for the field and build momentum for the ongoing AGAVE-201 study, which is a pivotal trial evaluating 3 dosing schedules of axatilimab in the treatment of chronic GVHD.23
In 2017, ibrutinib was the first agent approved for the treatment of adults with chronic GVHD who had received at least 1 prior unsuccessful systemic therapy. The real-world experience of ibrutinib in this setting has not been as impressive, with fewer responses and more adverse events compared with the reported clinical trial data.24 Dr Paul Carpenter presented the results of a multicenter, collaborative phase 1/2 trial of ibrutinib among pediatric patients with moderate-to-severe chronic GVHD.25 Part A evaluated ibrutinib in 12 patients ages 1 year to younger than 12 years who had received unsuccessful treatment with at least 1 line of systemic therapy. Part B evaluated ibrutinib among 47 patients ages 12 years to younger than 22 years. Part A used weight-based dosing, which began at a lower dose of 120 mg/m2 and then escalated to 240 mg/m2, if tolerated, after 2 weeks. The weight-based dosing was thought to approximate the flat-based dose used in adults. Part B used a standard flat dose.
In both parts A and B, the best overall response rate was 78%, specifically 83% as first-line therapy and 77% in the relapsed/refractory population. Importantly, the median duration of remission has not been reached thus far, suggesting a durability to these clinical responses. Adverse events led 24% of patients to discontinue ibrutinib, which is a higher rate than that seen in adults. In younger patients, the plasma concentration of ibrutinib achieved with the lower doses was similar to that seen in adults, suggesting that the chosen doses were appropriate.
Overall, this study showed higher response rates for ibrutinib than those described in adults, in both clinical trials and real-world experience. These results merit further study of ibrutinib in larger pediatric populations for confirmation and to hopefully add another treatment option for these patients.
Dr Alina Markova and colleagues presented findings from 2 partner abstracts revolving around the use of topical ruxolitinib for the treatment of cutaneous chronic GVHD.26,27 Multiple corticosteroid formulations, topical tacrolimus, and other supportive creams are commonly used for chronic GVHD, yet none are approved in this setting by the FDA. Topical ruxolitinib was approved for the treatment of atopic dermatitis in 2021, and there is much enthusiasm in the field for the use of topical ruxolitinib for cutaneous GVHD, given the success with systemic ruxolitinib. Topical ruxolitinib is attractive because it has less toxicity than topical corticosteroids and is thought to spare cutaneous stem cells.
The first abstract presented clinical findings from a randomized phase 2 trial comparing topical ruxolitinib vs a vehicle cream in patients with chronic cutaneous GVHD who did not have deep sclerotic changes.26 The study was double-blinded. For each patient, topical ruxolitinib was applied to one side of the body, and a vehicle cream was applied to the contralateral side. The primary endpoint of the study was day 28 involvement as measured by body surface area, comparing one side of the body to the other. The secondary endpoints were findings from 2 instruments measuring skin condition: the Physician’s Global Assessment and the Composite Assessment of Indexed Lesion Severity, which is a tool used to measure involvement in cutaneous T-cell lymphoma.
This trial enrolled 13 patients. Most participants had moderate-to-severe disease, and they had received multiple ineffective systemic and topical therapies. The overall results showed a trend toward improvement in involved body surface area at day 28 on the side treated with ruxolitinib, although there were improvements observed in both treatment arms.26 Treatment with topical ruxolitinib significantly improved scores in the Physician’s Global Assessment and the Composite Assessment of Indexed Lesion Severity. One interesting finding mentioned in the presentation was that some patients who were receiving systemic ruxolitinib had improvements in response to topical ruxolitinib as well. These preliminary findings suggest that topical ruxolitinib may have a role in the treatment of chronic cutaneous GVHD and raise the question of how to best design a study to adequately measure the impact of topical ruxolitinib to gain regulatory approval and access for our patients.
A second abstract provided information about the genomic characterization of skin samples from patients treated in this study.27 The investigators analyzed pairs of samples from the skin at day 28. Through RNA-sequencing technology, they then compared gene expression profiles of different populations. First, the investigators compared samples of skin treated with ruxolitinib vs the vehicle cream taken from the same patient. The comparison identified 310 differentially expressed genes, with the most disparate involved in keratinization and Th1/Th2 differentiation. The investigators then compared genomic expression of 8 patients who responded to topical ruxolitinib vs 3 patients who did not respond. This analysis identified 383 differentially expressed genes, with a heat-map analysis showing a characteristic gene profile that was representative of a signature associated with response to ruxolitinib.
Overall, the findings of this small correlative study were interesting and offer potential insight into the mechanism of response to ruxolitinib and whether there may be biomarkers predictive of response that can help guide therapy. To better understand these results, further larger studies are needed that incorporate more controls for gene expression analysis, such as pretreatment baseline samples and samples that were not treated with a vehicle cream.
Historically, clinical trials in chronic GVHD have been difficult to conduct. Chronic GVHD patients represent a heterogeneous population in terms of number and specific organ involvement, among other factors. Response criteria developed by the National Institutes of Health (NIH) have helped improve communication and conduct of clinical trials. However, the criteria are far from perfect, and the introduction of patient-reported outcomes into clinical trials of chronic GVHD is meant to help validate the meaningfulness of certain responses. Modern trials in chronic GVHD are now all using patient-reported outcomes as a standard measure of effect.
Dr Annie Im and colleagues performed an interesting analysis of a specific patient-reported outcome: patient-reported response for chronic GVHD.28 The aim of the study was to help validate the meaningfulness of a response in chronic GVHD, particularly in cases when formal criteria might not indicate a clinical response. The investigators attempted to correlate patient assessment of response to treatment with various standard patient-reported outcomes, as well as chronic GVHD symptom measures and organ response. The analysis included 382 patients enrolled in 2 prospective observational studies from the Chronic Graft Versus Host Disease Consortium.
The findings showed that patient-reported response in chronic GVHD had a limited correlation to response as assessed by the physician or with formal NIH response criteria. It is fascinating to learn that what a patient considers to be a response may significantly differ from the physician’s assessment, as well as consensus NIH criteria. A multivariate analysis of specific organs showed that responses in the eyes, the mouth, and the lungs were associated with a patient-reported response. A separate multivariate analysis of standard patient-reported outcome tools showed limited correlation with the 36-Item Short Form Survey and the Lee Symptom Scale measures, although specific components of those scales did have some correlation. Interestingly, there was a significant association between failure-free survival and patient-reported response. Failure-free survival has become a highly regarded composite endpoint in modern trials of chronic GVHD.
Overall, the investigators make a strong case for the further study of patient-reported response in detail and in larger cohorts of chronic GVHD. This study also suggests that patient-reported response should be an important endpoint for consideration in future chronic GVHD clinical trials.
Disclosure
Dr Chen has performed consulting for Incyte, Magenta, Jasper, CTI BioPharma, and Gamida Cell. He is a member of the data safety monitoring board or endpoint adjudication committees for clinical trials sponsored by AbbVie, Daiichi, Equillium, Celularity, and Actinium.
References
1. Hess NJ, Nadiminti K, Hematti P, Capitini CM. Interim analysis of T cell specific predictive biomarkers of graft-vs-host disease and relapse following post transplant cyclophosphamide prophylaxis. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 6.
2. Hess NJ, Hudson AW, Hematti P, Gumperz JE. Early T cell activation metrics predict graft-versus-host disease in a humanized mouse model of hematopoietic stem cell transplantation. J Immunol. 2020;205(1):272-281.
3. Beres AJ, Drobyski WR. The role of regulatory T cells in the biology of graft versus host disease. Front Immunol. 2013;4:163.
4. Bejanyan N, Brunstein CG, Cao Q, et al. Delayed immune reconstitution after allogeneic transplantation increases the risks of mortality and chronic GVHD. Blood Adv. 2018;2(8):909-922.
5. Massoud R, Gagelmann N, Fritzsche-Friedland U, et al. Comparison of immune reconstitution between anti-T-lymphocyte globulin and posttransplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation. Haematologica. 2022;107(4):857-867.
6. Holtan SG, Ustun C, Hoeschen A, et al. Phase 2 results of urinary-derived human chorionic gonadotropin/epidermal growth factor as treatment for life-threatening acute GVHD. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 68.
7. Smitz J, Platteau P. Influence of human chorionic gonadotrophin during ovarian stimulation: an overview. Reprod Biol Endocrinol. 2020;18(1):80.
8. Pratta M, Jurdi NE, Rashidi A, et al. Validation of amphiregulin as a monitoring biomarker during treatment of life-threatening acute GVHD: a secondary analysis of 2 prospective clinical trials. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 70.
9. Holtan SG, Hoeschen AL, Cao Q, et al. Facilitating resolution of life-threatening acute GVHD with human chorionic gonadotropin and epidermal growth factor. Blood Adv. 2020;4(7):1284-1295.
10. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020;135(20):1739-1749.
11. Srinagesh HK, Özbek U, Kapoor U, et al. The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease. Blood Adv. 2019;3(23):4034-4042.
12. McManigle W, Youssef A, Sarantopoulos S. B cells in chronic graft-versus-host disease. Hum Immunol. 2019;80(6):393-399.
13. Sarantopoulos S, Stevenson KE, Kim HT, et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clin Cancer Res. 2007;13(20):6107-6114.
14. Pusic I, Johanns T, Sarantopoulos S, et al. Use of belimumab for prophylaxis of chronic graft-versus-host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 34.
15. ClinicalTrials.gov. Ruxolitinib + allogeneic stem cell transplantation in AML. https://clinicaltrials.gov/ct2/show/NCT03286530. Identifier: NCT03286530. Accessed May 16, 2022.
16. ClinicalTrials.gov. Ruxolitinib pre-, during- and post-HSCT for patients with primary or secondary myelofibrosis. ttps://clinicaltrials.gov/ct2/show/NCT03427866. Identifier: NCT03427866. Accessed May 16, 2022.
17. DeFilipp Z, Kim HT, Knight L, et al. Prolonged post-transplant ruxolitinib therapy is associated with protection from severe GVHD after allogeneic HCT. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 393.
18. Nahas MR, Soiffer RJ, Kim HT, et al. Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Blood. 2018;131(25):2836-2845.
19. Koshy AG, Kim HT, Stroopinsky D, et al. Phase II clinical trial of abatacept for steroid-refractory chronic graft versus host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 32.
20. Kitko CL, White ES, Baird K. Fibrotic and sclerotic manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2012;18(1)(suppl):S46-S52.
21. Alexander KA, Flynn R, Lineburg KE, et al. CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest. 2014;124(10):4266-4280.
22. Kitko CL, Arora M, Zaid MA, et al. Safety, tolerability, and efficacy of axatilimab, a CSF-1R humanized antibody, for chronic graft-versus-host disease after 2 or more lines of systemic treatment. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 35.
23. ClinicalTrials.gov. A study of axatilimab at 3 different doses in participants with chronic graft versus host disease (cGVHD) (AGAVE-201). https://clinicaltrials.gov/ct2/show/NCT04710576. Identifier: NCT04710576. Accessed May 16, 2022.
24. Chin KK, Kim HT, Inyang EA, et al. Ibrutinib in steroid-refractory chronic graft-versus-host disease, a single-center experience. Transplant Cell Ther. 2021;27(12):990.e1-990.e7.
25. Carpenter PA, Kang HJ, Zecca M, et al. Prospective trial of ibrutinib for the treatment of pediatric chronic graft-versus-host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 126.
26. Markova A, Prockop SE, Dusza S, et al. Interim results of a pilot, prospective, randomized, double-blinded, vehicle-controlled trial on safety and efficacy of a topical inhibitor of Janus kinase 1/2 (ruxolitinib INCB018424 phosphate 1.5% cream) for non-sclerotic and superficially sclerotic chronic cutaneous graft-versus-host disease. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 390.
27. Markova A, Whitaker JW, Pan A, et al. Noninvasive genomic characterization of patients with nonsclerotic and superficially sclerotic chronic cutaneous graft-versus-host disease identified a novel gene signature in responders to ruxolitinib cream. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 33.
28. Im A, Pusic I, Onstad, L, et al. Patient-reported treatment response in chronic graft-vs-host disease: unique dimension of clinical benefit associated with failure-free survival. Presented at: the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, Utah. Abstract 55.