Phase II results of natalizumab plus steroids for gastrointestinal GvHD

 Acute lower gastrointestinal tract graft-versus-host disease (GI aGvHD) frequently presents with severe symptoms and is often less responsive to treatment with corticosteroids alone. α4ß7 integrin, which mediates homing of lymphocytes to the GI tract, is strongly expressed on naïve and memory T cell subsets in patients who develop intestinal aGvHD and may present a therapeutic target.

In order to improve efficacy of treatment of GI aGvHD, Natasha Kekre and colleagues¹ conducted a phase II clinical trial (NCT02176031) to investigate the safety and efficacy of an antibody targeting the α4 chain of α4ß7 integrin, natalizumab, in combination with corticosteroids for the initial treatment of GI aGvHD. The research findings were published in 2020 in Bone Marrow Transplantation, and we hereby present a summary of the study.

Methods

Inclusion criteria:

• Diagnosis of newly-onset GI aGvHD
• Involvement of extra-GI organs permitted
• Biopsy confirmation of GI GvHD
• Diarrhea of > 500 mL/day
• No evidence for infectious causes of diarrhea

Important exclusion criteria included prior use of natalizumab, GvHD overlap syndromes, patients requiring mechanical ventilation or vasopressor support, or the presence of concurrent hepatic veno-occlusive disease.

Patients initially received a single dose of natalizumab (300 mg) intravenously, with a second dose 4 weeks later for patients not showing a complete response.  Patients also received a concomitant daily dose of methylprednisolone (2 mg/kg), with a recommendation to reduce the dose by 10–25% every 1–2 weeks.  The natalizumab dose was administered within 3 days of steroid initiation.

The primary endpoint of this phase II trial was GvHD-free survival rate 56 days from enrollment. Response rates at Day 28 and 56, steroid dose at Days 28, 56, 100, 180, and 365, incidence of infections at Day 56 and 180, and overall survival were all secondary endpoints.

Results

Patient characteristics

The median age of the 21 included patients, 15 of whom were male, was 63 years. Twenty patients received peripheral blood stem cells, and one patient was transplanted with bone marrow stem cells. Donors were mostly matched unrelated (n = 15) or a matched related (n = 5), with only one mismatch unrelated donor. The majority of patients were either in first (n = 9) or second remission (n = 5), and most received non-myeloablative conditioning (n = 18). In addition to GI aGvHD, four patients showed cutaneous involvement, and one patient had hepatic aGvHD at study inclusion. At study launch, the median time from hematopoietic stem-cell transplantation was 72 days (range, 21–266).

Efficacy

Sixteen patients were included in the response assessment.

The GvHD-free survival rate on Day 56 was 33.3%. The overall response rate for GI aGvHD at Day 28 and Day 56 was 57% and 52%, respectively, and this included patients that showed a partial or a complete response.

The steroid dose was reduced for all surviving participants by Day 56, with patients experiencing a median reduction steroid dose reduction of 85%. 

Both overall survival and progression-free survival at 2 years were 43%, and the rate of non-relapse mortality was 52% (95% CI, 29–71%). Of the eight patients showing a complete response, six were able to maintain it for at least 1 year.

Median follow-up was 362 days for survivors; 12 patients died (six from GvHD, one from relapsed malignancy, four from infection, and one from an unknown cause).

Safety

Treatment-emergent toxicity possibly related to natalizumab was observed in five patients (three patients with Grade 3 hepatic toxicity, one patient with Grade 5 hepatic failure, and one patient with Grade 5 encephalopathy).

During the study, three patients developed chronic GvHD.

With regards to non-hematological adverse events, ten patients documented an infectious disease in the first 100 days following enrollment.  Furthermore, seven patients had measurable JC polyoma viremia at baseline, and 17 patients had measurable JC polyoma viremia at Day 56 (median, 107; range, 0–17,943 copies/mL), however, only one patient had a viral load > 1,000 copies/mL. None of the participants developed JC myeloma virus-associated progressive multifocal leukoencephalopathy (PML).  

Conclusion

In this patient population with newly diagnosed GI aGvHD, the combination therapy of natalizumab with corticosteroids as initial treatment demonstrated high overall response rates but did not meet its primary endpoint of 50% or more GvHD-free responses at Day 56. Regarding safety, the high rate of infections in almost half of the patients is consistent with findings from other GvHD trials. In a large retrospective study in almost 100,000 patients treated with natalizumab, JC virus-induced PML was detected in about 2.1 cases per 1,000 patients, leading to voluntary withdrawal of natalizumab from the market. No case of PML was seen in this study, however, 17 of 21 participants developed JC viremia, albeit at low levels.

Limitations of this study are the small number of participants and the lack of a comparator arm, which hampers the interpretation of response and survival rates. Although the outcome of this study is negative in terms of GvHD-free responses, durable response and a significant reduction in steroid use was observed. Therefore, the inhibition of T-cell homing to the GI tract with α4ß7 integrin may still play a role in the treatment of GI GvHD, and additional studies investigating α4ß7 integrin inhibition are warranted.