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Abatacept as a novel agent for the treatment of steroid-refractory cGvHD: A phase II trial

Jun 13, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in chronic GvHD.

The results of a phase II clinical trial of abatacept for steroid-refractory chronic graft-versus-host disease (cGvHD) were presented by Anita Koshy1 at the 2022 Transplantation & Cellular Therapy (TCT) Meetings of ASTCT and CIBMTR. Here, we summarize the study as presented at the TCT meetings.

Background and study aim

cGvHD represents a significant cause of morbidity and mortality following allogeneic transplantation, with a cumulative incidence of 50%. Steroids remain the mainstay of treatment; however, inadequate responses and potential toxicity fuel the search for longer lasting, more effective treatment.

Abatacept is a selective costimulation modulator that is a recombinant fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 linked to the modified Fc portion of human immunoglobulin G1. It binds to CD80 and CD86 on antigen presenting cells, reducing CD28-mediated T-cell activation and differentiation.

Following the promising results of the ABA2 trial (NCT01743131), in which abatacept was added to calcineurin inhibitor and methotrexate-based acute GvHD prophylaxis, the U.S. Food and Drug Administration (FDA) granted it priority review. Furthermore, a phase I trial of abatacept for the treatment of steroid-refractory cGvHD showed promising results with a clinical partial response of 44%, a 51.3% reduction in prednisone dose in responders, and no dose-limiting toxicity.

The aim of this study was to evaluate the overall response rate of abatacept in the treatment of steroid refractory cGvHD.

Study design and patient characteristics

The eligibility criteria and abatacept dosing are shown in Figure 1. Clinical assessment of cGvHD was performed using the National Institutes of Health Consensus Development Conference on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease, with each organ or site given a score from 0 to 3, with 0 reflecting no involvement and 3 reflecting severe impairment.

Figure 1. Study design*

CR, complete response; PR, partial response; RIC, reduced intensity conditioning.
*Adapted from Koshy.1
A CR was defined as resolution of all manifestations in each organ/site and PR was defined as improvement in 1 organ/site without progression in any others.

The characteristics of the study participants and transplant characteristics are shown in Table 1. In total, 39 patients were included in the study, with a median age of 62 years. Peripheral blood stem cells were the stem cell source in the vast majority of patients.

Table 1. Participant and transplant characteristics*

Characteristic, % (unless otherwise stated)

N = 39

Participant baseline characteristics

Median time from transplant to study entry (range), months

43 (6173)

Median age (range), years

62 (2577)

Sex

 

              Female

53.8

              Male

46.2

ECOG PS

 

              0

2.6

              1

69.2

              2

28.2

Primary disease

 

              ALL

12.8

              AML

46.2

              CML

5.1

              MDS

20.5

              MPD

5.1

              NHL

2.6

              MPN with fibrosis

2.6

              Myelofibrosis

2.6

cGvHD severity

 

              Moderate

46.2

              Severe

53.8

Median prior treatments for cGvHD (range)

5 (111)

Most common sites of cGvHD involvement

 

              Skin

84

              Eyes

72

              Lung

56

              Joints

82

Transplant characteristics

Cell source

 

              BM

10.3

              PBSC

89.7

Conditioning intensity

 

              Myeloablative

61.5

              Non-myeloablative

35.9

HLA match

 

              Matched related

38.4

              Matched unrelated

56.4

              Mismatched related

2.6

              Mismatched unrelated

2.6

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; cGvHD, chronic graft-versus-host disease; CML, chronic myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; HLA, human leukocyte antigen; MDS, myelodysplastic syndromes; MPD, myeloproliferative disorders; NHL, non-Hodgkin lymphoma; MPN, myeloproliferative neoplasms; PBSC, peripheral blood stem cells.
*Adapted from Koshy.1

Results

Patients received a median of eight doses of abatacept (range, 218). The overall response rate was 58% (complete response, 0%; partial response, 58%). The sites most improved were skin, mouth, eyes, joints, and lung (Table 2), and progression of disease occurred in 33% of patients; progression by site is shown in Table 2. A durable reduction in prednisone dose was also observed with abatacept treatment, with a 27.5% reduction at 1 month and a 50% reduction at 4 months follow-up (from 20 mg daily at study entry to 10 mg daily after 4 months).

Table 2. Clinical response or disease progression by organ site*

Organ/site of disease

 

Patients with CR or PR by organ/site, %

Patients with progression of disease by organ/site, %

Skin

22

6

Mouth

22

14

Eyes

25

3

Gastrointestinal tract

8

Liver

17

3

Lung

36

8

Joints

22

6

CR, complete response; PR, partial response.
*Adapted from Koshy.1
From a total of 36 evaluable patients.

Adverse events are shown in Table 3. Of note, there were nine events of neutropenia (Grades 24), which occurred in four patients.

Serious adverse events included two Grade 3 lung infections and one Grade 4 lung infection. One patient developed Grade 4 hemolysis, respiratory failure, hepatic failure, and subsequently died of concurrent herpes simplex virus hepatitis.

Table 3. Adverse events in patients treated with abatacept*

Adverse event

Number of events

Common adverse events

 

Neutropenia

 

              Grade 2

5

              Grade 3

2

              Grade 4

2

Fatigue

 

              Grade 1

1

              Grade 2

4

Headache

 

              Grade 2

4

Upper respiratory tract infection

 

              Grade 2

3

              Grade 3

1

Serious adverse events

 

Lung infection

 

              Grade 3

2

              Grade 4

1

Hemolysis

 

              Grade 4

1

Respiratory failure

 

              Grade 4

1

Hepatic failure

 

              Grade 4

1

Death

1 (from concurrent HSV hepatitis)

HSV, herpes simplex virus.
*Adapted from Koshy.1
Occurred in a total of four patients.
Occurred in the same patient.

Conclusion

This phase II trial of abatacept for the treatment of steroid-refractory cGvHD presented by Koshy at the 2022 TCT Meetings of ASTCT and CIBMTR showed a promising response rate with a durable reduction in prednisone dosing. Infusions were well tolerated, and severe infections were uncommon. Koshy highlighted that the group are performing ongoing immune correlative studies to better understand the mechanism of action of abatacept, including cytokine profiling of patient plasma and single-cell RNA sequencing to understand changes in the immune microenvironment. Flow cytometry has been used to assess interlukin-10 and interferon-γ expression in CD4+ T cells, with no difference observed before and after treatment in clinical responders.

Larger randomized trials are required to further assess the efficacy of abatacept and to clarify where it fits in the treatment pathway for cGvHD.

  1. Koshy A. Phase II clinical trial of abatacept for steroid-refractory chronic graft versus host disease. Oral abstract #32. 2022 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; Apr 23, 2022; Salt Lake City, US.

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