Clinical Advances in Hematology & Oncology

April 2021 - August 2024 - Volume 19, Issue 4, Supplement 14

Highlights in Graft-vs-Host Disease From the 2021 Transplantation & Cellular Therapy (TCT) Meetings of the ASTCT and the CIBMTR

Expert Commentary by:
Yi-Bin Chen, MD
Director, Hematopoietic Cell Transplant & Cellular Therapy Program
Cara J. Rogers Endowed Scholar
Division of Hematology/Oncology
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts

A Review of Selected Presentations From the 2021 TCT Meetings Digital Experience • February 8-12, 2021

 

Ruxolitinib Versus Best Available Therapy in Patients With Glucocorticoid-Refractory Chronic Graft-Vs-Host Disease: Primary Findings From the Phase 3, Randomized REACH3 Study

Chronic graft-vs-host disease (GVHD) occurs in approximately 30% to 70% of all patients who undergo allogeneic stem cell transplant (alloSCT), and this condition is a leading cause of nonrelapse mortality and morbidity.1,2 The standard first-line treatment is systemic corticosteroids. However, approximately 50% of patients become corticosteroid-refractory or corticosteroid-dependent.3 No standard second-line treatment has been defined. Ruxolitinib is a selective Janus kinase (JAK) 1 and 2 inhibitor. In the open-label, phase 3 REACH2 trial, ruxolitinib improved the median failure-free survival in patients with glucocorticoid-refractory acute GVHD compared with best available therapy.4

Dr Stephanie J. Lee presented the primary analysis of REACH3, a randomized, open-label, phase 3 study comparing ruxolitinib vs best available therapy in patients with corticosteroid-refractory or corticosteroid-dependent chronic GVHD.5 The trial enrolled 329 patients (median age, 49 years; range, 12-76 years) who had undergone alloSCT and had developed moderate or severe corticosteroid-refractory or corticosteroid-dependent chronic GVHD. Approximately 61% of patients were male. Chronic GVHD was moderate in 48% and severe in 52%. Patients were randomly assigned 1:1 to ruxolitinib at 10 mg twice daily or best available therapy. They received six 28-day treatment cycles. Patients could continue previous treatment with glucocorticoids and/or calcineurin inhibitors. The best available therapy was chosen by the investigator and could include extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, everolimus, sirolimus, infliximab, rituximab, pentostatin, imatinib, or ibrutinib. Infection prophylaxis was permitted per institutional practice.

The primary endpoint was overall response rate (ORR) per National Institutes of Health (NIH) consensus criteria at week 24.5 The key secondary endpoints were failure-free survival and improvement in the modified Lee symptom score (mLSS) of at least 7 points from baseline at week 24. On or after cycle 7, day 1 (week 24), patients in the control group could cross over to ruxolitinib if they did not achieve or maintain a complete response or a partial response, developed toxicity to the best available therapy, or had a chronic GVHD flare.

At the data cutoff of May 8, 2020, 50.3% of the ruxolitinib group and 25.6% of the control group remained on their randomly assigned treatment. In the control group, 37.2% crossed over to ruxolitinib. The most common reasons for discontinuation were lack of efficacy (14.5% with ruxolitinib vs 42.7% control), adverse events (AEs; 17.0% vs 4.9%), and relapse (5.5% vs 4.3%).

The median failure-free survival was significantly longer with ruxolitinib (not reached vs 5.7 months; hazard ratio [HR], 0.370; 95% CI, 0.268-0.510; P<.0001; Figure 1).5 The ORR at week 24 was 49.7% with ruxolitinib and 25.6% with best available therapy (odds ratio [OR], 2.99; 95% CI, 1.86-4.80; P<.0001). The best ORR was 76.4% with ruxolitinib and 60.4% with placebo (OR, 2.17; 95% CI, 1.34-3.52). The median duration of the best ORR was not reached in the ruxolitinib arm vs 6.24 months in the control arm (Figure 2). The mLSS responder rate also favored ruxolitinib (24.2% vs 11%; P=.0011).

Up to week 24, the AE rate was 97.6% (grade ≥3, 57%) with ruxolitinib and 98.1% (grade ≥3, 57.6%) with the control. The most common grade 3/4 AEs in the ruxolitinib and control arms were anemia (12.7% vs 7.6%), thrombocytopenia (15.2% vs 10.1%), neutropenia (8.5% vs 3.8%), pneumonia (8.5% vs 9.5%), and hypertension (4.8% vs 7.0%). Infections occurred in 63.6% of patients in the ruxolitinib arm and 56.3% of those in the control arm; they included viral (33.9% vs 29.1%), bacterial (27.9% vs 25.9%), and fungal (11.5% vs 5.7%) infections.

The investigators noted that ruxo­litinib is the first agent to demonstrate superior efficacy compared with the best available treatment in a phase 3 trial of patients with corticosteroid- refractory or corticosteroid-dependent chronic GVHD, as measured by a higher ORR, higher best ORR, longer failure-free survival, and greater symptom improvement. No unexpected safety signals were reported.

References

1. Arora M, Cutler CS, Jagasia MH, et al. Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(3):449-455.

2. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565-2579.

3. Jaglowski SM, Devine SM. Graft-versus-host disease: why have we not made more progress? Curr Opin Hematol. 2014;21(2):141-147.

4. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810.

5. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib (RUX) vs best available therapy (BAT) in patients (pts) with glucocorticoid-refractory chronic graft-vs-host disease (cGVHD): primary findings from the phase 3, randomized REACH3 study [TCT abstract 82]. Transplant Cell Ther. 2021;27(3 suppl).

 

Calcineurin Inhibitor–Free Graft-Versus-Host Disease Prophylaxis in Hematopoietic Cell Transplantation With Myeloablative Conditioning Regimens and HLA-Matched Donors: Results of the BMT CTN 1301 PROGRESS II Trial

Regimens that include a calci­neurin inhibitor are standard for the prevention of GVHD in patients undergoing hematopoietic stem cell transplant (HCT). Treatment with calcineurin inhibitor–free strategies using T-cell depletion, either through CD34-positive–selected T-cell depletion or post-transplant cyclophosphamide, has also been associated with low rates of chronic GVHD.1,2 Dr Marcelo C. Pasquini presented results from BMT CTN 1301, a phase 3 trial that compared 2 calcineurin inhibitor–free approaches vs a standard regimen among patients with acute leukemia or myelodysplasia and a human leukocyte antigen (HLA)-matched related or unrelated donor.3

The patients’ median age was 51 years (range, 13-66 years), and 43.1% were female. Patients were randomly assigned to receive a CD34-positive selected peripheral blood stem cell graft without posttransplant immunosuppression (n=114), cyclophosphamide after a bone marrow graft without additional immunosuppression (n=114), or tacrolimus/methotrexate after a bone marrow graft as the control (n=118). The primary endpoint was chronic GVHD (moderate/severe) relapse-free survival (CRFS) at 12 months after enrollment. Secondary endpoints included overall survival and transplant-related mortality.

Among the 346 patients enrolled, 327 received HCT (300 per protocol).3 The arm receiving CD34-positive selection had the highest rate of noncompliance, with only 86% patients receiving per-protocol therapy. At 1 year, the rate of CRFS was 60.2% for the CD34-positive selection arm (vs control, P=.27), 60.3% for the cyclophosphamide arm (vs control; P=.41), and 52.6% for the control (Figure 3). There was no significant difference in the CRFS rate between the CD34-positive selection and cyclophosphamide arms (P=.72). The 1-year rate of overall survival was 75.7% for the CD34-positive selection arm (HR, 1.74; 95% CI, 1.09-2.80; P=.02), 84.6% for the cyclophosphamide arm (HR, 1.02; 95% CI, 0.60-1.72; P=.95), and 84.2% for the control. The HR for the comparison between the CD34-positive selection and cyclophosphamide arms for overall survival was 1.78 (95% CI, 1.09-2.89; P=.02). Transplant-related mortality rates at 1 year were 16.5% for the CD34-positive arm, 12% for the cyclophosphamide arm, and 7% for the control arm (CD34-positive vs control, P=.020; cyclophosphamide vs control, P=.09). The 2-year rates of grade 2/3 infection were 69.2% for the CD34-positive arm, 60.6% for the cyclophosphamide arm, and 43.9% for the control arm (P=.0006 for either experimental arm vs the control).

The study investigators concluded that neither of the calcineurin inhibitor–free strategies were superior to tacrolimus/methotrexate in terms of the primary endpoint, CRFS.3 Rates of infection were significantly higher with either calcineurin inhibitor–free strategy vs tacrolimus/methotrexate. Rates of overall survival were similar for cyclophosphamide without additional immunosuppression and tacrolimus/methotrexate, but those patients treated with CD34-positive–selected peripheral blood stem cell grafts had lower overall survival owing to increased transplant-related mortality.

References

1. Solomon SR, Sanacore M, Zhang X, et al. Calcineurin inhibitor–free graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide and brief-course sirolimus following reduced-intensity peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(11):1828-1834.

2. Barba P, Hilden P, Devlin SM, et al. Ex vivo CD34+-selected T cell-depleted peripheral blood stem cell grafts for allogeneic hematopoietic stem cell transplantation in acute leukemia and myelodysplastic syndrome is associated with low incidence of acute and chronic graft-versus-host disease and high treatment response. Biol Blood Marrow Transplant. 2017;23(3):452-458.

3. Pasquini MC, Luznik L, Logan B, et al. Calcineurin inhibitor-free graft-versus-host disease (GVHD) prophylaxis in hematopoietic cell transplantation (HCT) with myeloablative conditioning regimens (MAC) and HLA-matched donors: results of the BMT CTN 1301 Progress II trial [TCT abstract LBA1]. Transplant Cell Ther. 2021;27(3 suppl).

 

Ruxolitinib for the Treatment of Chronic GVHD and Overlap Syndrome in Children and Young Adults

In chronic GVHD, the JAK 1/2 inhibitor ruxolitinib is approved by the US Food and Drug Administration for the treatment of adults.1 Experience in children younger than 12 years is limited. Dr YunZu Michele Wang described a pediatric dosing strategy for the use of ruxolitinib in children with chronic GVHD.2 This retrospective chart review examined data from 20 patients (median age, 14.6 years; range, 5-26 years) who received ruxolitinib orally, either at 5 mg twice daily for children who weighed 25 kg or more or 2.5 mg twice daily for those who weighed less than 25 kg. The dose was halved at the study start in patients treated with concurrent triazole antifungal therapy. Doses increased to a maximum of 10 mg twice daily as tolerated. Responses were evaluated using the 2014 NIH consensus panel response criteria. Two hours after administration of ruxolitinib, phosphorylation of STAT5 on lymphocytes was evaluated in a subset of patients using flow cytometry as a surrogate of JAK/STAT5 inhibition. A lower percentage of phosphorylation indicated greater inhibition.

Among the 20 patients enrolled, chronic GVHD was severe in 10, moderate in 9, and mild in 1.2 The most common organs involved were the skin (n=17), eyes (n=8), mouth (n=6), and gastrointestinal (GI) system (n=6). Four patients had involvement of a single organ. Four patients had overlap syndrome. Sixteen patients were receiving daily prednisone at a median dose of 0.5 mg/kg/day (range, 0.08-1.5 mg/kg/day) at the time of ruxolitinib initiation. The median time from diagnosis of chronic GVHD to initiation of ruxolitinib was 181 days (range, 17-1792 days). The median dose of ruxolitinib at initiation was 5 mg daily (range, 2.5-10 mg daily). Eleven patients were receiving concurrent triazoles at the time of ruxolitinib initiation and began treatment at a 50% dose reduction. Six patients received the maximal daily dose of 20 mg (Figure 4).

Phosphorylation of STAT5 on lymphocytes was absent or decreased 2 hours after ruxolitinib in 5 of 6 evaluated patients, which suggests adequate JAK inhibition in the pediatric population.2 The ORR was 70%. Two patients with moderate cases of chronic GVHD manifesting in the skin achieved a complete response at 86 and 311 days after starting ruxolitinib, respectively. Twelve patients achieved a partial response, at a median of 48 days (range, 18-120 days) from the first ruxolitinib dose, including 2 of the patients with overlap syndrome at baseline. Among the patients without a response to treatment, 1 had stable disease and 5 had progressive disease. Organs that showed responses to ruxolitinib included the skin, joints, GI tract, liver, and muscle. All 7 patients with sclerotic-type chronic GVHD of the skin had responses to ruxolitinib. Among the 3 patients with lung involvement, pulmonary function tests stabilized in 2. Sixteen of the patients were receiving corticosteroids at the time of enrollment. During the study period, 13 of these patients were able to discontinue corticosteroid treatment or were in the process of doing so. Nine of the 12 patients with a response were continuing treatment with ruxolitinib at the time of the report. The responses were maintained at a median of 411 days (range, 84-1127 days) from the initiation of ruxolitinib.

All patients developed AEs. Ruxolitinib was discontinued in 3 patients, owing to 1 case each of neutropenia, thrombocytopenia, and elevated alanine aminotransferase. No patients developed fungal infections or pneumocystis pneumonia. Two patients died from complications of progressive severe chronic GVHD. The investigators concluded that the pediatric dosing strategy for ruxolitinib in this study was safely tolerated and demonstrated promise for treating chronic GVHD in children.

References

1. Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, Bubnoff NV. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018;10(5):391-402.

2. Wang Y, Teusink-Cross A, Myers K, et al. Ruxolitinib for the treatment of chronic GVHD and overlap syndrome in children and young adults [TCT abstract 298]. Transplant Cell Ther. 2021;27(3 suppl).

 

Phase I Study De-Intensifying Exposure of Post-Transplantation Cyclophosphamide After HLA-Haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies

The standard dosage (50 mg/kg/day) and timing (days +3/+4) of cyclophosphamide after HLA-haploidentical HCT were largely extrapolated from murine skin allografting models.1 In murine HCT, studies have demonstrated that 25 mg/kg/day was superior to 50 mg/kg/day on days +3/+4 at preventing GVHD, and that a single dose of 25 mg/kg given on day +4 was equivalent to 25 mg/kg/day on days +3/+4.2,3

Dr Meredith Jo McAdams presented data from a phase 1 dose de-escalation study of cyclophosphamide.4 The study enrolled 19 patients ages 21 to 47 years; 50% had a disease risk index of high or very high. The patients underwent myeloablative conditioning with daily intravenous busulfan/fludarabine, HLA-haploidentical bone marrow, and GVHD prophylaxis with cyclophosphamide. The first 5 patients received cyclophosphamide at 50 mg/kg/day on days +3/+4 for comparative data (dose level 1), followed by a 3+3 dose de-escalation to 25 mg/kg/day on days +3/+4 (dose level 2; n=7) and then 25 mg/kg on day +4 only (dose level 3; n=7). Then all patients received mycophenolate mofetil (days +5 to +35) and sirolimus (days +5 to +80). The primary endpoint was to evaluate whether lower doses of post-transplant cyclophosphamide could prevent cases of severe, acute GVHD.

The median duration of follow-up was 294 days (range, 40-473 days).4 No patients at dose levels 2 or 3 developed grade 3 or 4 acute GVHD (Figure 5), whereas 1 patient at dose level 1 developed grade 4 disease. At dose level 2, 1 patient developed maximal grade 1 acute GVHD. At dose level 3, 2 patients developed maximal grade 1 acute GVHD and 1 developed maximal grade 2 acute GVHD. Neutrophil and platelet engraftment occurred more quickly at dose levels 2 and 3 compared with dose level 1.

Poor graft function was seen in 1 patient at dose level 1. Primary graft failure occurred in 1 patient at dose level 2. Relapse before engraftment occurred in 1 patient at dose level 3. Two patients at dose level 3 developed engraftment syndrome, which resolved rapidly without therapy in both cases. Split chimerism (100% donor myeloid; 0%-6% donor T-cell) was reported in 1 patient treated at dose level 2 and 1 patient treated at dose level 3; the latter patient required a second HCT. Mucositis appeared to be less severe and shorter in duration with lower cyclophosphamide dosing. Fevers within the first month post-HCT were not substantially different at dose level 2 compared with dose level 1, but they were higher and more protracted at dose level 3.

The study investigators concluded that de-escalation of cyclophosphamide dosing after HLA-haploidentical HCT appears feasible and effective in maintaining protection against severe acute GVHD, while promoting more rapid engraftment and less early post-transplant toxicity.4 Further studies across larger cohorts of patients, as well as longer follow-up studies of the impact of de-escalated cyclophosphamide on immune reconstitution, chronic GVHD, relapse, and survival, are needed to confirm whether this strategy is superior to the current dosing schedule.

References

1. Mayumi H, Good RA. Long-lasting skin allograft tolerance in adult mice induced across fully allogeneic (multimajor H-2 plus multiminor histocompatibility) antigen barriers by a tolerance-inducing method using cyclophosphamide. J Exp Med. 1989;169(1):213-238.

2. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, Kanakry CG. Post-transplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest. 2019;129(6):2357-2373.

3. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Kanakry CG. Optimized timing of post-transplantation cyclophosphamide in MHC-haploidentical murine hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2020;26(2):230-241.

4. McAdams MJ, Dimitrova D, Sadler J, et al. Phase I study de-intensifying exposure of post-transplantation cyclophosphamide (PTCy) after HLA-haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies [TCT abstract 11]. Transplant Cell Ther. 2021;27(3 suppl).

 

Preliminary Safety and Efficacy of Itolizumab, a Novel Targeted Anti-CD6 Therapy, in Newly Diagnosed Severe Acute Graft-Versus-Host Disease: Interim Results From the EQUATE Study

CD6 is a co-stimulatory receptor predominantly expressed on T cells that acts as a crucial regulator of T-cell activation and is implicated in the pathogenesis of multiple autoimmune diseases. Activated leukocyte cell adhesion molecule (ALCAM), a CD6 ligand, is expressed on antigen-presenting cells, as well as epithelial and endothelial cells of acute GVHD target organs, including the skin and the GI tract.1,2 Previous studies in patients receiving alloHCT showed that ex vivo depletion of donor CD6-positive T cells lowered the incidence of acute GVHD, providing a rationale for therapeutically targeting CD6 in acute GVHD.3 Itolizumab, a humanized immunoglobulin G1 monoclonal antibody undergoing evaluation as treatment for acute GVHD, binds CD6 and blocks interaction with ALCAM to inhibit T-cell activity and trafficking.4

Dr John Koreth presented interim study results from EQUATE, an ongoing phase 1b/2 study of itolizumab in combination with corticosteroids for newly diagnosed severe acute GVHD (grade 3-4) after first alloHCT.5 The phase 1b portion is an open-label, 3+3 dose-escalation study evaluating doses of 0.4, 0.8, 1.6, and 2.4 mg/kg administered intravenously every 2 weeks through day 57. As of November 13, 2020, 10 patients completed treatment: 4 with 0.4 mg/kg, 3 with 0.8 mg/kg, and 3 with 1.6 mg/kg. All patients received corticosteroids at an initial dose of 1 to 2 mg/kg/day. Their mean age was 48 years (standard deviation, 15.7 years), 90% were male, and 90% were white. The graft source was peripheral blood for 80% and bone marrow for 20%, and 80% had an HLA-matched donor. The mean time to onset of GVHD was 43 days, and 100% of patients had GI involvement.

At day 57, the ORR was 50% with 0.4 mg/kg, 100% with 0.8 mg/kg, and 100% with 1.6 mg/kg.5 The median percent corticosteroid dose reduction at day 85 was 93%, 87%, and 91% for the 0.4, 0.8, and 1.6 mg/kg groups, respectively (Figure 6). Itolizumab decreased the CD6 levels on T cells in a dose-dependent manner within 24 hours of the first dose, a reduction that was maintained throughout the treatment period.

Across the dosing cohorts, all patients developed at least 1 AE. Most AEs were mild to moderate in severity.5 The most common AEs were hypomagnesemia (n=3) and peripheral edema (n=3). One mild infusion reaction was noted. Six patients had serious AEs, including recurrent GVHD (n=1), sepsis (n=2; 1 event was considered a dose-limiting toxicity), fever (n=1), COVID-19 (n=1), and disseminated nocardia (n=1).

References

1. Consuegra-Fernández M, Julià M, Martínez-Florensa M, et al. Genetic and experimental evidence for the involvement of the CD6 lymphocyte receptor in psoriasis. Cell Mol Immunol. 2018;15(10):898-906.

2. Ma C, Wu W, Lin R, et al. Critical role of CD6highCD4+ T cells in driving Th1/Th17 cell immune responses and mucosal inflammation in IBD. J Crohns Colitis. 2019;13(4):510-524.

3. Soiffer RJ, Weller E, Alyea EP, et al. CD6+ donor marrow T-cell depletion as the sole form of graft-versus-host disease prophylaxis in patients undergoing allogeneic bone marrow transplant from unrelated donors. J Clin Oncol. 2001;19(4):1152-1159.

4. Bughani U, Saha A, Kuriakose A, et al. T cell activation and differentiation is modulated by a CD6 domain 1 antibody itolizumab. PLoS One. 2017;12(7):e0180088.

5. Koreth J, Loren AW, Nakamura R, et al. Preliminary safety and efficacy of itolizumab, a novel targeted anti-CD6 therapy, in newly diagnosed severe acute graft-versus-host disease: interim results from the EQUATE study [TCT abstract LBA4]. Transplant Cell Ther. 2021;27(3 suppl).

 

Durable Discontinuation of Immunosuppressive Therapy: Clinical Results From the Chronic GvHD Consortium

Successful treatment of chronic GVHD often requires long-term use of systemic immunosuppressive agents, which can impair immune function, increase the risk of opportunistic infections, and confer a high toxicity burden. Among patients stopping immunosuppressive therapy for the first time, approximately 50% will need to resume therapy, after a median of 3 months.1 Therefore, durable discontinuation of immunosuppressive therapy may represent a true cure. Prior studies of immunosuppressive therapy discontinuation reported long-term rates between 27% and 68%.1,2 This variation might be explained by differences in the population, treatment, and graft sources, among other factors.

Dr George L. Chen reported the results of a retrospective analysis of factors associated with durable discontinuation of immunosuppressive therapy.3 The data were drawn from 2 prospectively followed cohorts from the Chronic GVHD Consortium (n=684). Durable discontinuation of immunosuppressive therapy was defined as cessation of all immunosuppressive therapy for at least 12 months. Data for patients who discontinued immunosuppressive therapy for less than 12 months were censored. Immunosuppressive therapy that was stopped and then restarted before 12 months had elapsed was considered continuous therapy.

The patients’ median age was 51.9 years (range, 18.0-78.0 years). The donor type was HLA-matched related for 37.6%, HLA-matched unrelated for 44.7%, and other in 18%. The transplant source was peripheral blood for 89%, bone marrow for 6.6%, and cord blood for 4.4%. The severity of chronic GVHD was mild for 15.2%, moderate for 51.2%, and severe for 32.2%. The median time from alloHCT to chronic GVHD diagnosis was 7.7 months (range, 1.0-141.3 months), and the median time from chronic GVHD onset to enrollment was 0.9 months (range, 0.0-12.0 months).

During the median follow-up of 95.3 months (range, 11.3-181.5 months), 33% (95% CI, 28%-37%) of patients were able to discontinue immunosuppressive therapy for 12 or more months (Figure 7).3 In the multivariate analysis controlling for clinical and patient-reported variables, durable immunosuppressive therapy discontinuation was less likely in patients who received myeloablative conditioning, had a platelet count of 100,000/µL or higher, had moderate/severe lower GI involvement, and had a higher (worse) Lee symptom overall score. In contrast, mild lower GI involvement and cord blood (vs peripheral blood) as a graft source were associated with a greater likelihood of immunosuppressive therapy discontinuation. In a second analysis including NIH overall chronic GVHD severity, patients with severe disease were less likely to attain durable discontinuation (HR, 0.53; 95% CI, 0.31-0.90; P=.02).

The investigators noted that most patients in this study with chronic GVHD were unable to discontinue immunosuppressive therapy for 12 months or longer.3 They suggested that chronic GVHD may behave more like an ongoing autoimmune disease without resolution that requires ongoing immunosuppression, rather than a temporary state where eventual tolerance is expected.

References

1. Lee SJ, Nguyen TD, Onstad L, et al. Success of immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24(3):555-562.

2. Curtis LM, Pirsl F, Steinberg SM, et al. Predictors for permanent discontinuation of systemic immunosuppression in severely affected chronic graft-versus-host disease patients. Biol Blood Marrow Transplant. 2017;23(11):1980-1988.

3. Chen GL, Onstad L, Pidala JA, et al. Durable discontinuation of immunosuppressive therapy: clinical results from the chronic GvHD Consortium [TCT abstract 8]. Transplant Cell Ther. 2021;27(3 suppl).

 

Belumosudil for Chronic Graft-Versus-Host Disease After 2 or More Prior Lines of Therapy: The ROCKstar Study (KD025-213)

Rho-associated coiled-coil kinase 2 (ROCK2) is a critical regu‌lator of both interleukin-21 and interleukin-17. The inhibition of ROCK2 reduces the generation of proinflammatory T helper 17 cells while upregulating the generation of anti-inflammatory regulatory T cells.1 ROCK2 is also critical in profibrotic processes, including activation of myofibroblasts. ROCK2 inhibitors, which are in development, have prevented collagen deposition, fibrosis, and scarring in multiple tissue and experimental models.2

Belumosudil is a novel oral selective ROCK2 inhibitor specifically designed for the treatment of chronic GVHD. In a previous dose-finding phase 2a trial of belumosudil, the ORR was 65% for the dose of 200 mg daily and 69% for the dose of 200 mg twice daily among the 54 enrolled patients.3 Based on these data, the pivotal phase 2 ROCKstar trial investigated the safety and efficacy of these 2 doses of belumosudil for chronic GVHD in patients already treated with 2 or more lines of therapy. Dr Corey Cutler presented results from a follow-up analysis.4

The patients were a median age of 56 years (range, 21-77 years) and had received a mean of 4 (range, 2-5) prior lines of therapy for chronic GVHD.4 Approximately 66% had severe disease, 34% had received prior ibrutinib, and 52% had involvement of at least 4 organs. Patients were stratified according to chronic GVHD severity and prior ibrutinib use, and then were randomly assigned to receive belumosudil at 200 mg once daily (n=66) or 200 mg twice daily (n=66). Treatment was continued until the patient developed clinically significant progression or unacceptable toxicity. The primary endpoint was ORR per the 2014 NIH response criteria, as assessed by the investigators. Additional endpoints included duration of response, failure-free survival, improvement in the mLSS of at least 7 points from baseline, and corticosteroid dose reductions or discontinuations.

The ORR was 73% (95% CI, 60%-83%; P<.0001) with daily dosing and 77% (95% CI, 65%-87%; P<.0001) with twice-daily dosing. A complete response was reported in 7 patients.4 The responses were consistent across key subgroups. The median duration of response for both groups pooled was 50 weeks. At 12 months, the median failure-free survival for both groups pooled was 58% (Figure 8). Improvement in the mLSS of at least 7 points from baseline was seen in 60% of patients. Corticosteroid discontinuation and dose reductions were reported in 21% and 64% of patients, respectively.

The most common grade 3/4 AEs were pneumonia (9% in the daily group vs 6% in the twice daily group), hypertension (6% in both groups), and hyperglycemia (5% in both groups).4 Eight patients died during the study; 5 from AEs (1 possibly related to belumosudil) and 3 during long-term follow-up (>28 days after the last dose). There was 1 case of cytomegalovirus reactivation and 1 case of Epstein-Barr virus reactivation.

References

1. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A. 2014;111(47):16814-16819.

2. Riches DW, Backos DS, Redente EF. ROCK and Rho: promising therapeutic targets to ameliorate pulmonary fibrosis. Am J Pathol. 2015;185(4):909-912.

3. Jagasia M, Salhotra A, Bachier CR, et al. KD025 for patients with chronic graft-versus-host disease (cGVHD)—long-term follow-up of a phase 2a study (KD025-208) [ASH abstract 872]. Blood. 2019;134(suppl 1).

4. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: the ROCKstar study (KD025-213) [TCT abstract 9]. Transplant Cell Ther. 2021;27(3 suppl).

 

Health Care Resource Utilization and Costs of Steroid-Related Complications in Patients With Graft-Versus-Host Disease

Corticosteroids are often prescribed to treat GVHD. However, the prevalence, health care resource utilization, and costs of corticosteroid-associated complications are not well quantified. Dr Elizabeth J. Bell described the results of a retrospective cohort study that analyzed the health care resource utilization and costs of complications from corticosteroid use in patients with GVHD.1 The investigators reviewed the Optum Research Database to identify patients in the United States with a diagnosis of GVHD who received systemic corticosteroids between July 1, 2010 and August 31, 2019 and who were insured with commercial insurance plans or Medicare Advantage plans. Patients with a baseline diagnosis of GVHD were included. Health care resource utilization and costs associated with corticosteroid complications during the 24 months after corticosteroid initiation were calculated, according to International Classification of Diseases codes for any corticosteroid complication in position 1 or 2 on the claims. Corticosteroid complications related to the bone/muscle, GI tract, infections, and metabolic/endocrine system were also described, based on their clinical relevance.

This study included 689 patients.1 Their median age was 55 years (standard deviation, 18 years), and 60% were male. The median length of corticosteroid use during the 24 months after corticosteroid initiation was 126 days (range, 52 to 273 days). Overall, 97% of patients developed at least 1 type of complication, including infection (80%) and events involving the metabolic/endocrine system (32%), the GI tract (29%), or bone/muscle (20%). Among patients with at least 1 corticosteroid complication, the mean and median costs associated with corticosteroid complications throughout the 24 months from corticosteroid initiation were $164,787 and $50,834, respectively (Figure 9). The mean and median costs in the 408 patients treated with corticosteroids for 3 months or more were $171,434 and $56,542, respectively. In those who had only acute GVHD (n=146), the mean and median costs were $183,944 and $46,093, whereas in those with chronic GVHD (n=142), these costs were $113,199 and $34,285, respectively. Costs were driven primarily by hospitalizations (Figure 10).

The study investigators concluded that there are substantial health care resource utilization and costs associated with corticosteroid-related complications in patients with GVHD.1 Acute GVHD was associated with higher health care resource utilization and costs than chronic GVHD. A limitation to this study is that some conditions were present at baseline, and worsening of these conditions after corticosteroid initiation could not be accurately identified. Future studies will be needed to elucidate the clinical aspects of the complications, including severity and suspected causality.

Reference

1. Bell EJ, Yu J, Bhatt V, et al. Healthcare resource utilization and costs of steroid-related complications in patients with graft versus host disease [TCT abstract 12]. Transplant Cell Ther. 2021;27(3 suppl).

 

Secondary Graft-Versus-Host Disease Prophylaxis With Oral Proteasome Inhibitor Ixazomib Is Associated With Low Incidence of Recurrent, Late Acute, and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper Within the First Year Post-Allogeneic Stem Cell Transplantation

Recipients of reduced-intensity and nonmyeloablative conditioning with calcineurin inhibitor–based prophylaxis often develop GVHD during tapering of immunosuppression drugs. Ixazomib is an oral proteasome inhibitor with immunomodulatory properties that has a tolerable safety profile.1 Natasia T. Rodriguez, BSN, RN, presented data from an open-label, prospective, single-center pilot study of ixazomib for secondary GVHD prophylaxis and facilitation of calcineurin inhibitor taper.2

Eligible patients had a hematologic malignancy treated with reduced intensity or non-myeloablative alloHCT and calcineurin inhibitor–based GVHD prophylaxis, had undergone HCT between 100 and 150 days prior to enrollment, and did not have active acute or chronic GVHD.2 Patients received ixazomib at 4 mg orally once weekly administered in a 3 weeks on, 1 week off schedule. The treatment was continued for 1 year or until the prophylactic calcineurin inhibitor was completely tapered, whichever came first. The primary endpoint was the efficacy of ixazomib for the prevention of recurrent or late grade 2 to 4 acute GVHD or chronic GVHD at 1 year post-HCT. Additional endpoints included treatment-related mortality, relapse rate, survival analysis, safety, and immune reconstitution.

The trial enrolled 18 patients.2 Their median age was 58 years (range, 45-69 years). Most patients (89%) were male. All patients had received a peripheral blood stem cell graft, and 16 of the patients (89%) were 10/10 HLA-matched. Four patients developed GVHD, and had either severe overlap syndrome (n=2), mild de novo chronic GVHD (n=1), or recurrent grade 2 acute GVHD (n=1). At 1 year post-HCT, the cumulative incidence of grade 2 to 4 acute and chronic GVHD was 33.3% (95% CI, 10.95%-57.9%; Figure 11). No patients died during the study. The incidence of relapse was low; 1 patient who discontinued ixazomib early relapsed with low-grade follicular lymphoma that did not require therapy.

Progression-free survival at 1 year was 88% (95% CI, 67%-100%), and GVHD-free/relapse-free survival at 1 year was 77% (95% CI, 56%-100%).2 There was a rapid and sustained recovery in T-cell subpopulations and B-cell reconstitution at 3, 6, and 12 months post-HCT. Grade 3/4 AEs included decreased neutrophil count (n=5), decreased lymphocyte count (n=2), anemia (n=1), and rash (n=1). Seven patients required a dose reduction of ixazomib owing to side effects, and 5 patients left the study owing to toxicity.

References

1. Chhabra S, Visotcky A, Pasquini MC, et al. Ixazomib for chronic graft-versus-host disease prophylaxis following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2020;26(10):1876-1885.

2. Rodriguez NT, Lee J, Flynn L, et al. Secondary graft-versus-host disease (GVHD) prophylaxis with oral proteasome inhibitor ixazomib is associated with low incidence of recurrent, late acute and chronic GVHD and facilitated calcineurin inhibitor taper within the first year post allogeneic stem cell transplantation [TCT abstract 84]. Transplant Cell Ther. 2021;27(3 suppl).

 

Highlights in Graft-vs-Host Disease From the 2021 Transplantation & Cellular Therapy (TCT) Meetings of the ASTCT and the CIBMTR: Commentary

 

Yi-Bin Chen, MD

Director, Hematopoietic Cell Transplant & Cellular Therapy Program
Cara J. Rogers Endowed Scholar
Division of Hematology/Oncology
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts

 

Several interesting abstracts on graft-vs-host disease (GVHD) were presented at the 2021 Transplantation & Cellular Therapy (TCT) meetings, which were the combined, all-virtual annual meetings of the American Society for Transplantation and Cellular Therapy and the Center for International Blood & Marrow Transplant Research. There were studies with implications for current clinical practice, as well as future research, in both acute and chronic GVHD.

Prevention of GVHD

Historically, prevention of GVHD has focused on acute GVHD, given the timing of presentation and early effects on long-term outcomes. However, clinical research has recently emphasized the prevention of chronic GVHD as an increasingly important outcome. This shift is emphasized in the composite primary endpoints of several recent major clinical trials.

The phase 3 Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1301 PROGRESS II​ trial enrolled patients who had received myeloablative, fully matched transplants from a related or unrelated donor.1 The motivation behind this trial was to develop a calcineurin inhibitor–free regimen for the prevention of GVHD, possibly as a platform to deliver maintenance therapy or cellular therapy to decrease the risk of disease relapse. The trial randomly assigned patients (≤65 years) undergoing myeloablative transplant to 3 different platforms to prevent graft-vs-host-disease. The control arm consisted of tacrolimus and methotrexate (MTX) with a bone marrow graft source. The second arm evaluated a bone marrow graft source with post-transplant high-dose cyclophosphamide given on days 3 and 4 after transplant. Treatment in the third arm consisted of ex vivo T-cell depletion using CD34-selected peripheral blood stem cells.

The study used an interesting primary endpoint of chronic GVHD-free and relapse-free survival, which was referred to as CRFS.1 The analysis showed that there was no statistically significant difference in the primary endpoint among the 3 treatment arms. A key secondary endpoint was overall survival, and participants who received T-cell depletion had a lower overall survival of 75.7% at 1 year, compared with approximately 84% in the other 2 arms, which was mostly driven by an increase in transplant-related mortality. It should be noted that chronic GVHD was significantly reduced in the T-cell depleted arm.

Based on these results, it appears that tacrolimus/MTX remains the standard of care in this setting, although post-transplant cyclophosphamide alone appears to be a reasonable alternative. Notably, in routine practice, post-transplant cyclophosphamide is usually given with tacrolimus and mycophenolate, and one wonders if the inclusion of these other agents would have significantly changed the observed results.

Dr Muna Qayed presented data from a subanalysis of the ABA2 trial.2 The ABA clinical trials are studying the role of abatacept, which is a co-stimulatory inhibitor, for the prevention of GVHD. The ABA2 trial had 2 arms and enrolled patients with fully matched donors (8/8 human leukocyte antigen [HLA]-matched), as well as patients with single-antigen mismatched, unrelated donors (7/8 HLA-matched). The trial compared standard treatment with a calcineurin inhibitor (CNI) plus MTX vs CNI/MTX with the addition of abatacept. Previously published results from the ABA2 trial suggested that the addition of abatacept improved outcomes, especially in patients receiving grafts from 7/8 matched, unrelated donors.3 This secondary analysis of the ABA2 data compared the outcomes of these 7/8 patients, who received a CNI with MTX plus abatacept, to the fully matched 8/8 patients treated with CNI/MTX on the ABA2 trial. The primary endpoint was the incidence of severe acute (overall, grades 3-4) GVHD at 6 months. The incidence was strikingly lower in the patients who received abatacept, at 2.3%, vs 14.8% in the 8/8 CNI/MTX arm. There were no significant differences in other outcomes, such as chronic GVHD or overall transplant-related mortality. However, the decrease in severe acute GVHD was quite compelling, with trends toward better progression-free survival and overall survival in the patients who received abatacept.

These results lay the groundwork for the ongoing ABA3 trial, which is focusing on patients receiving 7/8 matched grafts to confirm whether the addition of abatacept can improve outcomes.4 Currently, there is no standard of care for these patients. Historically, treatment had included the addition of polyclonal antithymocyte globulins. More recently, many clinicians have shifted toward the use of post-transplant cyclophosphamide-based regimens for these patients. It would be an important advance to have data from large clinical trials in this group of patients to determine the standard of care.

Dr Meredith McAdams presented data from a phase 1 study that evaluated de-intensified exposure to post-transplant cyclophosphamide given af­ter HLA haploidentical hematopoietic cell transplant.5 Post-transplant high-dose cyclophosphamide-based regimens have emerged as the standard of care for patients undergoing haploidentical and mismatched, unrelated donor transplants. As mentioned above, this platform is also being studied in the setting of transplants from fully matched and mismatched unrelated donor transplants. Historically, post-transplant cyclophosphamide is administered at a dose of 50 mg/kg/day given on days 3 and 4 after transplant. Although this schedule appears to successfully prevent GVHD, it is associated with toxicities, such as acute fluid shifts, electrolyte abnormalities, and cardiac events, and it also appears to significantly delay engraftment compared with conventional CNI-based regimens.

The study by Dr McAdams examined whether the dose of cyclophosphamide could be safely reduced.5 These investigators showed in murine models that 50 mg/kg was not absolutely necessary; instead, 25 mg/kg given only on day 4 seemed to confer equivalent efficacy.6,7 This phase 1 study followed a dose de-escalation design to test this hypothesis. All of the patients received a myeloablative conditioning regimen, followed by a haploidentical bone marrow graft, and then GVHD prophylaxis consisting of post-transplant cyclophosphamide, sirolimus, and mycophenolate. The dose of cyclophosphamide was then successively lowered in the different cohorts. The first 5 patients received the standard 50 mg/kg/day on both days 3 and 4. The next cohort received 25 mg/kg/day on both days, followed by a third cohort that received 25 mg/kg only on day +4.

Impressively, none of the 11 patients in the dose de-escalated cohorts developed grade 3 to 4 acute GVHD. Although the number of patients in this phase 1 trial was small, the results are compelling. In addition, engraftment of neutrophils and platelets appeared to be faster among patients receiving lower doses of cyclophosphamide. However, some patients in the dose de-escalated cohorts had significant delays in assuming full donor chimerism. Moving forward, as post-transplant cyclophosphamide–based regimens become increasingly popular, these early findings do merit further study, as it should be essential to define the minimum dose of cyclophosphamide needed for utility.

Dr Andrea Henden presented the results of a basic science investigation that evaluated how interferon lambda protects gastrointestinal stem cells from acute GVHD in murine transplant models.8 Acute GVHD of the lower intestine is responsible for the majority of the morbidity and mortality observed with acute GVHD. Recently, studies have shown that the earliest site of infiltration of donor cells in acute GVHD appears to be localized to the crypt base of the intestine, specifically the niche that houses intestinal stem cells.9 A significant injury to the intestinal stem cell niche impairs the ability of the intestine to heal and re-epithelialize the mucosa, and this is potentially why some patients do not respond clinically to multiple lines of immunosuppressive therapy for acute GVHD.

Recently, novel approaches to the treatment of acute GVHD have not focused on donor T cells, but rather aim to protect the recipient’s intestinal stem cells. This study evaluated recombinant interleukin 29, an interferon-lambda receptor ligand. When mice were administered this ligand, their intestinal stem cells appeared to be protected by preservation of gastrointestinal tissue, and clinical outcomes in gastrointestinal GVHD improved. This study provides further preclinical support for the idea that acute GVHD can and should be treated by methods targeting not only adaptive immunity, but organ resiliency as well. The transplant community has acknowledged that the historical limited focus on cumulative immunosuppression for the treatment of acute GVHD has not improved outcomes. Investigation into other avenues, such as targeting specific inflammatory pathways or other mechanisms including intestinal stem cell preservation, are worthy of further study.

Turning to treatment of acute GVHD, Dr John Koreth presented early findings studying the safety and efficacy of itolizumab, a monoclonal antibody targeting CD6, for the treatment of severe acute GVHD.10 This study is based on older data showing that CD6 is a costimulatory receptor that is expressed on activated T cells. Research in the 1990s provided some evidence that depletion of CD6-positive cells early in transplant could decrease the risk of acute GVHD.11

This phase 1b/2 trial evaluated the addition of itolizumab to corticosteroids for the initial treatment of severe, grade 3/4 acute GVHD.10 The presentation provided early results for the first 10 patients who completed treatment through 8 weeks. Three different doses were tested, and all patients also received corticosteroids at the initial standard dose of 1 to 2 mg/kg/day of the prednisone equivalent. The investigators reported an impressive overall response rate of 80% at day 29, with a complete response in 70% and a very good partial remission in 10%. Importantly, in all of the responding patients, the overall response was sustained through the day 57 follow-up period. Strong correlative data showed that the administration of itolizumab reduced the expression of CD6, or at least decreased the number of cells that expressed CD6. Although the study included a very small number of patients, these early results are compelling, and we look forward to more mature data on a larger number of treated patients.

Chronic GVHD: Insights Into Current Treatment Strategies

Several abstracts at the TCT meeting provided data regarding current thinking and treatments for chronic GVHD. An interesting analysis presented by the Chronic Graft-vs-Host Disease Consortium evaluated rates of successful, durable discontinuation of immunosuppressive therapy in approximately 700 patients.12 Durable discontinuation, in this study, referred to cessation of immunosuppressive therapy for at least 12 months. Long-term follow-up showed that only one-third of subjects were able to discontinue immunosuppression for longer than one year, whereas all other patients continued to receive therapy or needed to resume treatment after symptoms flared.

The study investigators concluded that, for the majority of patients, chronic GVHD behaves like an ongoing chronic autoimmune disease that requires continued therapy.12 It is therefore not a temporary state that can be cured with a limited course of therapy, and we should change how we frame expectations for our patients. For most patients, it is likely not possible to achieve a complete remission after chronic GVHD sets in with the currently available therapeutic strategies. These sobering data raise the questions of not only where we should focus future investigation, but also how to design more relevant endpoints for clinical trials focusing on chronic GVHD.

Dr Ben Watkins presented results of a study that questioned whether there is an immunologic signature in patients who develop de novo GVHD.13 This study examined a subgroup of patients enrolled in the aforementioned ABA2 study who received standard tacrolimus/MTX for the prevention of GVHD. The investigators compared blood samples from 19 patients who developed de novo chronic GVHD (meaning they had no prior acute GVHD) vs 7 patients without GVHD. Around day 100, patients who developed de novo chronic GVHD had a significantly increased proportion of naive CD4-positive T cells relative to controls who never developed chronic GVHD. RNA sequencing of the CD4 T cells revealed a gene signature that differed from that in the patients without chronic GVHD. This study does not yet define a usable platform, but it suggests that there are different immunologic signatures in patients at certain time points after transplant that can help predict events like development of chronic GVHD. In routine clinical practice, if patients can be categorized in real time as higher or lower risk for specific complications such as chronic GVHD, it may be possible to intervene preemptively and perhaps alter outcomes before chronic GVHD is firmly established.

Dr Elizabeth Bell presented results from a multicenter study that evaluated the Optum research database to identify US commercial and Medicare Advantage patients with acute or chronic GVHD who were treated with corticosteroids.14 This study evaluated medical records to attempt to quantify the burden and cost of corticosteroid-associated complications. Unfortunately, systemic corticosteroids remain the standard of care for both acute and chronic GVHD. Any successful therapy should not only improve outcomes, but should also allow clinicians to taper corticosteroids quicker, thereby reducing the amount of systemic exposure for patients. Ultimately, one goal is to find a treatment for acute and/or chronic GVHD that can replace corticosteroids for certain subsets of patients. Corticosteroids are well-known to cause a variety of toxicities, including immunosuppression, hypertension, osteoporosis, diabetes, cataracts, mood issues, and body dysmorphia. This study evaluated factors such as bone, muscle, and metabolic endocrine complications, as well as gastrointestinal infections, to quantify the cost of treatment. The investigators found a significant burden of health care resource utilization from corticosteroids, with the majority of the costs quantified within the first year of use and driven by hospitalizations. The study provides an important step in the right direction toward the eventual development of endpoints that could measure the reduction of corticosteroid toxicity in trials to treat GVHD.

Dr Zachariah DeFilipp presented results of an analysis of more than 900 patients who required new systemic therapy from the Chronic Graft-vs-Host Disease Consortium that aimed to identify causes of long-term nonrelapse mortality in patients with chronic GVHD.15 The patients had undergone transplant between 1987 and 2017, and the median follow-up was 4 years. Approximately one-quarter of the deaths were attributable to disease relapse, meaning relapse of the patient’s cancer. Nonrelapse mortality accounted for approximately 40% of deaths, with no plateau observed on the Kaplan-Meier curve. The most common identifiable causes of nonrelapse mortality were chronic GVHD plus infection, followed by infection alone. These events are closely related owing to inherent chronic GVHD-associated immune dysregulation and the nature of treatments used for chronic GVHD.

The results of the study underscore the observation that for patients with chronic GVHD, the risk for morbidity and mortality does not end.15 As patients continue to experience the clinical burden of disease, their cumulative risk of nonrelapse mortality continues to increase. This analysis clearly illustrates the unmet need for effective treatments not only to improve chronic GVHD but also to spare patients the toxicities associated with current therapies.

Chronic GVHD: Clinical Trial Data

Dr Corey Cutler presented results from the pivotal, randomized phase 2 ROCKstar trial, which evaluated belumosudil, an oral rho-associated coiled-coil kinase 2 (ROCK2) inhibitor, for the treatment of patients with chronic GVHD who had already received 2 previous therapies.16 Data from the previously presented phase 2a study were compelling.17 In this phase 2 trial, 132 patients were randomly assigned to 1 of 2 doses of belumosudil: 200 mg daily or 200 mg twice daily. The observed overall response rate was more than 70% in each arm. Responses were seen across all severities of chronic GVHD, all sites of organ involvement, and in patients previously treated with ibrutinib or ruxolitinib. Belumosudil appeared to have an acceptable toxicity profile, without any signals of increased infections. Inhibition of ROCK2 is thought to decrease inflammation and fibrosis, and the development of this agent is in line with the general theme in newer trials in chronic GVHD: less global immunosuppression and more targeting of specific pathways of inflammation or fibrosis. It should be noted that the ROCKstar trial did not include a placebo arm, and assessment of chronic GVHD can be quite subjective. Based on these data, however, there is a strong chance that the US Food and Drug Administration (FDA) will approve belumosudil for this indication.

Dr Stephanie Lee presented results from the international, randomized phase 3 REACH3 study, which compared ruxolitinib vs best available therapy among patients with corticosteroid-refractory chronic GVHD.18 Ruxolitinib is a Janus kinase inhibitor (JAK) 1/2 inhibitor that is already approved for the treatment of patients with corticosteroid-refractory acute GVHD.19 JAK inhibitors are currently being studied in all phases of GVHD, from prevention to initial therapy to treatment of refractory disease. The primary endpoint in REACH3 was the overall response rate at 24 weeks. After that time, patients in the control arm were permitted to cross over to the ruxolitinib arm. This trial was a major undertaking, and the investigators should be applauded for conducting the first phase 3 trial in corticosteroid-refractory chronic GVHD that yielded a positive outcome.

At 24 weeks, the patients who received ruxolitinib had a much higher overall response rate than those receiving best available therapy (which was chosen at the discretion of the investigator), at 50% vs only 26%.18 Ruxolitinib also significantly improved key secondary endpoints, such as the median failure-free survival and the percentage of patients who had a significant symptom response (as measured by the modified Lee symptom scale).

The adverse events were those expected with ruxolitinib in this population. There was a slight signal of more infections in the ruxolitinib arm, but the difference was not statistically significant. Based on these results, the FDA will likely approve ruxolitinib in this setting, thereby allowing more patients to access this treatment. There remain several questions regarding the use of ruxolitinib for chronic GVHD, such as the duration of therapy and the durability of responses. Another question that requires study is how to safely discontinue therapy, as a tapering schedule might be necessary for this agent.

A report from Dr YunZu Michele Wang described a single-center case series that evaluated ruxolitinib for the treatment of refractory chronic GVHD among the pediatric population.20 These investigators developed a weight-based algorithm to determine the starting dose of ruxolitinib. Patients weighing less than 25 kg received a dose of 2.5 mg twice daily. Patients who weighed 25 kg or more received an initial starting dose of 5 mg twice daily. In both arms, the dose was gradually escalated to 10 mg twice daily, when tolerated. Among the 20 patients treated, 14 had a meaningful response, with 12 partial remissions and 2 complete remissions. Impressively, 13 of these responses were durable. As expected, in the majority of patients, it was possible to decrease the dose of systemic corticosteroids. These cases illustrated the safety of a dosing strategy for ruxolitinib in children and young adults with GVHD, and hopefully, ruxolitinib will also become an option for the pediatric population.

Disclosure

Dr Chen has performed consulting for Incyte and Magenta. He is a member of the DSMB Committees of AbbVie, Daiichi, Equillium, Celularity, and Actinium.

References

1. Pasquini MC, Luznik L, Logan B, et al. Calcineurin inhibitor-free graft-versus-host disease (GVHD) prophylaxis in hematopoietic cell transplantation (HCT) with myeloablative conditioning regimens (MAC) and HLA-matched donors: results of the BMT CTN 1301 Progress II trial [TCT abstract LBA1]. Transplant Cell Ther. 2021;27(3 suppl).

2. Qayed M, Watkins B, Gillespie S, et al. Comparable outcomes for matched and mismatched unrelated donor (URD) transplantation with the addition of abatacept to standard graft-versus-host disease prophylaxis [TCT abstract 33]. Transplant Cell Ther. 2021;27(3 suppl).

3. Watkins B, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD [published online January 15, 2021]. J Clin Oncol. doi:10.1200/JCO.20.01086.

4. ClinicalTrials.gov. Extended vs short-term abatacept dosing for graft versus host disease prophylaxis (ABA3). https://clinicaltrials.gov/ct2/show/NCT04380740. Identifier: NCT04380740. Accessed March 21, 2021.

5. McAdams MJ, Dimitrova D, Sadler J, et al. Phase I study de-intensifying exposure of post-transplantation cyclophosphamide (PTCy) after HLA-haploidentical hematopoietic cell transplantation (HCT) for hematologic malignancies [TCT abstract 11]. Transplant Cell Ther. 2021;27(3 suppl).

6. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Gress RE, Kanakry CG. Post-transplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. J Clin Invest. 2019;129(6):2357-2373.

7. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Kanakry CG. Optimized timing of post-transplantation cyclophosphamide in MHC-haploidentical murine hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2020;26(2):230-241.

8. Henden AS, Robb R, Foreron A, et al. Interferon lambda protects gastrointestinal stem cells from acute GVHD [TCT abstract 81]. Transplant Cell Ther. 2021;27(3 suppl).

9. Fu YY, Egorova A, Sobieski C, et al. T cell recruitment to the intestinal stem cell compartment drives immune-mediated intestinal damage after allogeneic transplantation. Immunity. 2019;51(1):90-103.e3.

10. Koreth J, Loren AW, Nakamura R, et al. Preliminary safety and efficacy of itolizumab, a novel targeted anti-CD6 therapy, in newly diagnosed severe acute graft-versus-host disease: interim results from the EQUATE study [TCT abstract LBA4]. Transplant Cell Ther. 2021;27(3 suppl).

11. Soiffer RJ, Murray C, Mauch P, et al. Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow. J Clin Oncol. 1992;10(7):1191-1200.

12. Chen GL, Onstad L, Pidala JA, et al. Durable discontinuation of immunosuppressive therapy: clinical results from the chronic GvHD Consortium [TCT abstract 8]. Transplant Cell Ther. 2021;27(3 suppl).

13. Watkins BK, Kaminski J, Tkachev V, et al. Predicting immune pathology after hematopoietic stem cell transplant (HCT) with day 100 transcriptomics: naïve CD4 T cell expansion versus regulatory programming predicts patients who develop de novo chronic GVHD (cGVHD) versus those displaying operational immune tolerance [TCT abstract 10]. Transplant Cell Ther. 2021;27(3 suppl).

14. Bell EJ, Yu J, Bhatt V, et al. Healthcare resource utilization and costs of steroid-related complications in patients with graft versus host disease [TCT abstract 12]. Transplant Cell Ther. 2021;27(3 suppl).

15. DeFilipp Z, Onstad L, Arai S, et al. Non-relapse mortality among patients diagnosed with chronic graft-versus-host disease: an updated analysis from the Chronic GVHD Consortium [TCT abstract 83]. Transplant Cell Ther. 2021;27(3 suppl).

16. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: the ROCKstar study (KD025-213) [TCT abstract 9]. Transplant Cell Ther. 2021;27(3 suppl).

17. Jagasia M, Salhotra A, Bachier CR, et al. KD025 for patients with chronic graft-versus-host disease (cGVHD)—long-term follow-up of a phase 2a study (KD025-208) [ASH abstract 872]. Blood. 2019;134(suppl 1).

18. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib (RUX) vs best available therapy (BAT) in patients (pts) with glucocorticoid-refractory chronic graft-vs-host disease (cGVHD): primary findings from the phase 3, randomized REACH3 study [TCT abstract 82]. Transplant Cell Ther. 2021;27(3 suppl).

19. Jakafi [package insert]. Wilmington, Delaware: Incyte Corporation; 2020.

20. Wang Y, Teusink-Cross A, Myers K, et al. Ruxolitinib for the treatment of chronic GVHD and overlap syndrome in children and young adults [TCT abstract 298]. Transplant Cell Ther. 2021;27(3 suppl).