Salvage therapy with basiliximab and etanercept for severe steroid‐refractory acute graft‐versus‐host disease
Authors: Craig W. Freyer, Shannon Gier, Alison Carulli, Saar I. Gill, Elizabeth O. Hexner, Alison W. Loren, Mary Ellen Martin, David L. Porter
Journal: American Journal of Hematology (2022)

Acute graft-versus-host disease (aGVHD) remains a significant complication of allogeneic hematopoietic cell transplantation (alloHCT). At best, only half of patients respond to initial corticosteroids, with limited long-term overall survival (OS) observed in steroid-refractory (SR) patients. Ruxolitinib (Rux) is approved for SRaGVHD; however, ~40% of patients do not respond by day 28 and only ~40% maintain response at day +56.1 We read with interest three recent articles in the journal characterizing novel approaches for managing SR aGVHD. Zhao et al. prospectively combined Rux and etanercept in 64 patients with severe (grade 3–4) SRaGVHD, 86% of which had received haploidentical (haplo) alloHCT. An impressive overall response rate (ORR) of 87.5% was observed at day +28, of which 73.4% were complete responses (CR).2 Most responses were observed within 7 days, more rapidly than observed with Rux alone.1, 2 Importantly, CMV infection occurred in 50%, and 39% experienced grade ≥3 infections. Two-year overall survival (OS) was 61.2%, and 15.7% relapsed. Patients in this study were younger (median 29 years)2 than in the Rux registration trial (median 54 years),1 which may have contributed to these favorable outcomes. Liu et al. retrospectively assessed basiliximab as initial therapy for SRaGVHD in 230 patients, 90% of which had underwent haplo alloHCT, with a reported ORR of 78.7% (60.9% CR). However, severe aGVHD was less responsive (HR for ORR 0.50, 95% CI 0.32–0.76, p = .001). Response occurred quickly at a median of 12–15 days from basiliximab initiation. Basiliximab was initiated early, at a median of 5 days after GVHD diagnosis, at which time only 16.9% of patients had severe GVHD, which likely contributed to the high ORR. Long-term outcomes were favorable; at 4 years, OS was 61.7%, with severe chronic (c) GVHD present in only 2.2% and a low rate of malignancy relapse (11.3%).3 The most recently published report of basiliximab in SRaGVHD by Mo et al. included 940 patients, ~80% of which underwent haplo alloHCT (including those previously reported3 with additional follow up). Severe SRaGVHD was present in 48.1% at the time of basiliximab initiation.4 Patients started basiliximab early, at a median of 5 days from aGVHD occurrence. The ORR was 79.4%, with CR observed in 52.2%. Again, patients with severe SRaGVHD were less likely to have any response or a CR compared with those with grade 2 aGVHD (ORR: 80.9% vs. 61.7%, CR: 65.6% vs. 31.4%, respectively). Furthermore, CR was less frequent in patients who received other salvage agents prior to basiliximab (51.7% vs. 32.8%). At 3 years, the incidence of cGVHD, relapse, and OS were 44.8%, 13.1%, and 64.3%, respectively.4 The combination of basiliximab + etanercept was assessed in a prospective study as initial treatment of severe SRaGVHD. Sixty-five patients, ~60% of whom underwent haplo alloHCT, were enrolled at a median of 8 days following GVHD diagnosis and received a median of four doses of basiliximab and nine doses of etanercept. Despite the treatment-refractory nature of severe SRaGVHD, ORR was 90.8%, with 75% CR. Invasive fungal infection was observed in 36% (12% fatal). While OS was improved compared with a historical cohort receiving other SRaGVHD therapies, 2-year OS was only 54.7%, with a low relapse rate of 19%, highlighting significant non-relapse mortality (NRM) despite a favorable response to treatment.5 Encouraged by the high ORR observed with Rux + etanercept, basiliximab, and basiliximab + etanercept earlier in SRaGVHD therapy, we treated a series of patients with SRaGVHD that was also refractory to numerous other agents, including tocilizumab and Rux, with basiliximab + etanercept salvage therapy and report our outcomes here. Patients who received basiliximab + etanercept were retrospectively identified. GVHD was classified as acute if onset was before day +100 or if onset was after day +100 but presented with symptoms typical of aGVHD, or if GVHD occurred while tapering immunosuppression. GVHD was considered SR if progression occurred despite 3 days of corticosteroids or not improved by 7 days.6 Initial treatment was prednisone 1–2 mg/kg/day (or equivalent) with continuation of GVHD prophylaxis if present at onset of GVHD. Basiliximab 20 mg was administered intravenously on days +1 and +4, then weekly. Etanercept 25 mg was administered subcutaneously twice weekly for 4 weeks, then once weekly. Therapy was continued until GVHD response, hospital discharge (if not feasible to continue therapy outpatient), or severe toxicity. CR was defined as resolution of all signs and symptoms of aGVHD. A partial response (PR) was defined as improvement in ≥1 organ(s) without worsening in other organs not meeting CR criteria. Anti-herpetic, mold-active antifungal, and pneumocystis prophylaxis were used. Screening for cytomegalovirus (CMV) was performed weekly via peripheral blood polymerase chain reaction. Routine cytomegalovirus prophylaxis was not used. Seven patients with SRaGVHD received basiliximab + etanercept as third- or fourth-line therapy between May 2018 and December 2019. Transplant and GVHD characteristics are summarized in Table 1. The median age at alloHCT was 61 years (range 42–67). Four of seven patients received myeloablative conditioning, four of seven had a matched related donor, and one had a haplo-identical donor. Biopsy-proven aGVHD was diagnosed at a median of 166 days (range 34–232) following alloHCT. At initial diagnosis, GVHD was grade 1 (n = 3), grade 2 (n = 1) or grade 3 (n = 3); however, all patients had progressed to severe SRaGVHD at basiliximab + etanercept initiation. The median time from aGVHD diagnosis to starting basiliximab + etanercept was 36 days (range 7–53), with a median of 3 (range 2–3) prior therapies. Four patients received prior tocilizumab. Five patients received Rux for a median of 16 days (range 3–26) prior to basiliximab + etanercept and for a median of 20 days (range 9–73) with concurrent basiliximab + etanercept. The median prednisone dose at basiliximab + etanercept initiation was 1 mg/kg (80 mg) per day. Patients received a median of six basiliximab doses (range 3–12) and eight etanercept doses (range 3–17). Three patients died prior to day +28 of basiliximab + etanercept, all with progressive GVHD. Four of seven (57%) responded by day +56. One response was a CR and three were PRs. At day +56, prednisone doses were reduced by a median of 84% (range 75%–89%). Two Rux-naïve patients with PR started Rux for residual GVHD following basiliximab + etanercept, resulting in limited improvement in both cases. Subsequent cGVHD was observed in one of three patients who survived > 100 days following alloHCT. This patient, who obtained a CR with basiliximab + etanercept, developed severe pulmonary cGVHD. He underwent bilateral lung transplant ~32 months following GVHD diagnosis and at 42 months after alloHCT remains in CR from both AML and GVHD. Severe infectious complications were common and are summarized in Table 1. Six of seven patients died at a median follow-up of 92 days from basiliximab + etanercept initiation (range 27–1280). The four responders had a median OS of 460 days (range 92–1280) from GVHD diagnosis and 419 days (range 58–1235) from basiliximab + etanercept initiation. No patients experienced malignancy relapse. This single-center series of seven patients with heavily pretreated severe SRaGVHD demonstrated an ORR of 57% to basiliximab + etanercept, including one durable PR lasting >2 years and a durable CR lasting >3 years. A significant steroid-sparing effect (75%–89% prednisone dose reduction) was observed in all patients evaluable at day +56. No cases of GVHD progression or recurrence were observed in responders. This high response rate is notable despite all patients having grade 3–4 GVHD including many with lower GI or hepatic involvement and many patients receiving prior tocilizumab and Rux. Despite this ORR and lack of malignancy relapses, OS remained limited due to high NRM. In this series, only those responding to basiliximab + etanercept survived past day +28 following initiation. All patients experienced severe infectious complications, with three patients succumbing to complications directly related to persistent GVHD. While this is a retrospective analysis, and basiliximab + etanercept was chosen at the treating physician's discretion, this regimen was our institutional preference for patients with lower gastrointestinal (LGI) or hepatic SRaGVHD refractory to Rux (and/or tocilizumab, if LGI) during this timeframe. While such cases tend to be less responsive to basiliximab monotherapy and other salvage approaches, we were encouraged by an ORR >70% reported with basiliximab + etanercept when used earlier in the course of SRaGVHD management.5 The ORR was lower and the incidence of severe infections was higher than observed in the aforementioned studies when used earlier in the management of SRaGVHD,2-5 which is expected given these patients received basiliximab + etanercept as third- or fourth-line treatment, and all had grade 3–4 SRaGVHD. We found basiliximab + etanercept salvage therapy to result in a high ORR in severe SRaGVHD in this small, single-center, “real world” analysis, including responses in patients with inadequate response to novel agents such as tocilizumab and Rux. While two patients had long durable responses exceeding 2 years in duration, NRM and infectious complications remain significant barriers to improving outcomes in SRaGVHD. However, the high ORR in our experience and in other reports provides some optimism that this is an active regimen and outcomes may be improved if employed earlier in the course of the disease. All authors declare they have no relevant conflicts of interest to disclose in relation to this research. Craig W. Freyer and Shannon Gier collected and assembled the data. All authors contributed to the analysis and interpretation of the data. Craig W. Freyer wrote the manuscript. All authors provided revision for important intellectual content and approved the final manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.