Monday, October 2, 2023
| Characteristic | Number of patients, n = 39 (%) |
|---|---|
| Age (y), median (range) | 62 (25–77) |
| Female | 21 (53.8) |
| Median time from HCT to study entry (range), mo | 43 (6–173) |
| ECOG performance status | |
| 0 | 1 (2.6) |
| 1 | 27 (69.2) |
| 2 | 11 (28.2) |
| Indication for transplant | |
| AML | 18 (46.2) |
| MDS | 8 (20.5) |
| ALL | 5 (12.8) |
| CML | 2 (5.1) |
| MPD | 2 (5.1) |
| MPN with fibrosis | 2 (5.1) |
| Myelofibrosis | 1 (2.6) |
| NHL | 1 (2.6) |
| Stem cell source | |
| Bone marrow | 4 (10.3) |
| Peripheral blood stem cell | 35 (89.7) |
| Conditioning intensity | |
| Myeloablative | 24 (61.5) |
| Nonmyeloablative | 14 (35.9) |
| Unknown | 1 (2.6) |
| HLA matching (A, B, C, and DRB1) | |
| Matched related | 15 (38.4) |
| Matched unrelated | 22 (56.4) |
| Mismatched related | 1 (2.6) |
| Mismatched unrelated | 1 (2.6) |
| Baseline NIH cGVHD severity score | |
| Mild | 0 (0) |
| Moderate | 18 (46.2) |
| Severe | 21 (53.8) |
| Organs involved | |
| Number of organs involved, median (range) | 3 (2–7) |
| ≥4 organs involved | 19 (48.7) |
| Skin | 33 (84.6) |
| Mouth | 17 (43.5) |
| Eyes | 28 (71.7) |
| GI | 6 (15.3) |
| Liver | 9 (23.1) |
| Lung | 22 (56.4) |
| Joints | 32 (82.1) |
| Prior systemic therapy for cGVHD | |
| Prior lines of therapy, median (range) | 3 (1–8) |
| Corticosteroid (prednisone, methylprednisolone) | 39 (100) |
| Tacrolimus | 24 (61.5) |
| Mycophenolate mofetil | 15 (38.5) |
| Sirolimus | 11 (28.2) |
| Cyclosporine | 2 (5.1) |
| Rituximab | 10 (25.6) |
| Ruxolitinib | 7 (17.9) |
| Ibrutinib | 4 (10.3) |
| Aldesleukin | 7 (17.9) |
Table 1: Baseline patient characteristics
Baseline patient characteristics of the 39 patients enrolled in the trial including key transplant, cGVHD, and immunosuppressant management features.
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; ECOG, Eastern Cooperative Oncology Group; HCT, hematopoietic cell transplant; MDS, myelodysplastic syndrome; MPD, myeloproliferative disorder; MPN, myeloproliferative neoplasm; NHL, non-Hodgkin lymphoma.
| Patient | Time point | Skin | Mouth | Eyes | GI tract | Liver | Lung | Joints | Genital |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Baseline Final |
2 2 |
0 0 |
1 1 |
0 0 |
0 0 |
1 1 |
2 2 |
0 0 |
| 2* | Baseline Final |
2 2 |
1 1 |
1 1 |
3† 2† |
1‡ 0‡ |
2† 1† |
2 2 |
0 0 |
| 3 | Baseline Final |
3 3 |
0§ 1§ |
2 2 |
2‡ 0‡ |
1‡ 0‡ |
1‡ 0‡ |
2 2 |
0 0 |
| 4* | Baseline Final |
2† 1† |
0 0 |
1 1 |
0 0 |
0 0 |
0 1 |
2 2 |
0 0 |
| 5* | Baseline Final |
2 2 |
1‡ 0‡ |
2 2 |
1 1 |
1‡ 0‡ |
1‡ 0‡ |
2† 1† |
0 0 |
| 6 | Baseline Final |
3 3 |
0§ 1§ |
0 0 |
0 0 |
0 0 |
0 0 |
2 2 |
0 0 |
| 7 | Baseline Final |
2 2 |
1 1 |
2 2 |
0 0 |
0 0 |
1 1 |
2 2 |
0 0 |
| 8 | Baseline Final |
0 0 |
1 1 |
2 2 |
0 0 |
0 0 |
1§ 2§ |
1 1 |
0 0 |
| 9* | Baseline Final |
2 2 |
0 0 |
0 0 |
0 0 |
1‡ 0‡ |
1‡ 0‡ |
2† 1† |
0 0 |
| 10* | Baseline Final |
0 1 |
1 1 |
3† 2† |
0 0 |
3† 1† |
0 0 |
2† 1† |
0 0 |
| 11 | Baseline Final |
2§ 3§ |
2† 1† |
1 1 |
0 0 |
0 0 |
0 1 |
0§ 1§ |
0 0 |
| 12 | Baseline Final |
3 3 |
1§ 2§ |
3 3 |
1‡ 0‡ |
0 0 |
2 2 |
3† 2† |
0 2 |
| 13* | Baseline Final |
1‡ 0‡ |
1‡ 0‡ |
0 0 |
0 0 |
0 0 |
0 0 |
2† 1† |
2 2 |
| 14* | Baseline Final |
2† 1† |
0 0 |
2† 1† |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
| 15* | Baseline Final |
2 2 |
0 0 |
1 1 |
0 0 |
0 0 |
0 0 |
2† 1† |
0 0 |
| 16* | Baseline Final |
2 2 |
1‡ 0‡ |
3† 2† |
0 0 |
1 1 |
0 0 |
2 2 |
0 1 |
| 17* | Baseline Final |
3 3 |
0 0 |
2 2 |
0 0 |
0 1 |
3† 2† |
2 2 |
0 0 |
| 18* | Baseline Final |
0 0 |
1‡ 0‡ |
1‡ 0‡ |
0 0 |
0 0 |
0 0 |
1 1 |
1 0 |
| 19* | Baseline Final |
0 0 |
2‡ 0‡ |
2† 1† |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
| 20* | Baseline Final |
3† 2‡ |
0 0 |
0 0 |
0 0 |
0 0 |
1‡ 0‡ |
2 2 |
0 0 |
| 21 | Baseline Final |
2† 1† |
0 0 |
0 0 |
0 0 |
0 1 |
1§ 2§ |
2 2 |
0 0 |
| 22 | Baseline Final |
1 1 |
0§ 1§ |
2† 1† |
0 0 |
0 1 |
2† 1† |
0 0 |
0 0 |
| 23 | Baseline Final |
2 2 |
0§ 1§ |
1§ 3§ |
0 0 |
0 0 |
1‡ 0‡ |
1 1 |
1 1 |
| 24* | Baseline Final |
0 0 |
1‡ 0‡ |
2‡ 0‡ |
0 0 |
0 0 |
2† 1† |
0 0 |
0 0 |
| 25* | Baseline Final |
2† 1† |
0 0 |
0 0 |
0 0 |
1‡ 0‡ |
0 0 |
1‡ 0‡ |
0 0 |
| 26* | Baseline Final |
2 2 |
1 1 |
3 3 |
0 0 |
0 0 |
1‡ 0‡ |
1 1 |
0 0 |
| 27* | Baseline Final |
3 3 |
0 0 |
1‡ 0‡ |
0 0 |
0 0 |
0 0 |
2 2 |
0 0 |
| 28 | Baseline Final |
1‡ 0‡ |
0 0 |
0 0 |
0 0 |
2§ 3§ |
0 0 |
0 0 |
0 0 |
| 29 | Baseline Final |
3 3 |
0 0 |
0 0 |
0 0 |
0 0 |
0 1 |
1 1 |
0 0 |
| 30 | Baseline Final |
3 3 |
1 1 |
1 1 |
0 0 |
0 0 |
1‡ 0‡ |
2§ 3§ |
0 0 |
| 31* | Baseline Final |
3 3 |
1‡ 0‡ |
0 0 |
0 0 |
0 0 |
0 0 |
2 2 |
0 0 |
| 32* | Baseline Final |
2† 1† |
0 0 |
0 1 |
0 0 |
0 0 |
3 3 |
2† 1† |
0 0 |
| 33* | Baseline Final |
0 0 |
0 0 |
2 2 |
1 1 |
0 0 |
2† 1† |
3 3 |
0 0 |
| 34* | Baseline Final |
2 2 |
0 0 |
1‡ 0‡ |
0 0 |
0 0 |
1‡ 0‡ |
2 2 |
0 0 |
| 35 | Baseline Final |
2§ 3§ |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
0 0 |
| 36 | Baseline Final |
3 3 |
0 0 |
1 1 |
1 1 |
0 0 |
1§ 2§ |
2 2 |
0 0 |
Table 2: Site-specific baseline and final cGVHD scores based on the organ system
Lung cGVHD was scored based on the NIH lung symptom score, as assessed by clinicians.
*Patients who had a partial overall response.
†PR.
‡CR.
§Progression.
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | |
|---|---|---|---|---|
| Decreased neutrophil count* | — | 5 | 1 | 1 |
| Fatigue | 3 | 6 | — | — |
| Headache | — | 4 | — | — |
| URI | — | 3 | — | — |
| AST increased | 2† | 1 | — | — |
| ALT increased | 1 | 2 | — | — |
| Lung infection | — | 2 | — | — |
| UTI | — | 1 | — | — |
| Viral URI | 1 | — | — | — |
| Eye infection | — | 1 | — | — |
| Nausea | 1 | — | — | — |
| Diarrhea | 1 | — | — | — |
| Pulmonary edema | — | — | 1 | — |
| Cough | 1 | 2 | 1 | — |
| Flu-like symptoms | 1 | — | — | — |
| Myalgia | 2 | — | — | — |
| Oral pain | — | 1 | — | — |
| Dyspnea | — | 1 | — | — |
| Cystitis, noninfective | — | 1 | — | — |
| Muscle weakness | 1 | 1 | — | — |
Table 3: Adverse events possibly related to abatacept
ALT, alanine aminotransferase; AST, aspartate aminotransferase; URI, upper respiratory infection; UTI, urinary tract infection.
*Events occurred in total of 4 patients.
†Events occurred in 1 patient.
| Grade | Number of events | |
|---|---|---|
| Elevated AST | 3 | 1 |
| Upper respiratory infection | 3 | 1 |
| Lung infection | 3 4 |
1 1 |
| Hemolysis | 4 | 1* |
| Respiratory failure | 4 | 1* |
| Hepatic infection | 4 | 1* |
| Hepatic failure | 4 | 1* |
| Death | 5 | 1* (concurrent HSV hepatitis) |
Table 4: Serious adverse events possibly related to abatacept
AST, aspartate aminotransferase; HSV, herpes simplex virus.
*Events that occurred in the same patient.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for transplant clinicians, hematologists, oncologists, internists, and other clinicians who treat and manage patients with chronic graft-versus-host disease.
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Steroid-refractory chronic graft-versus-host disease (cGVHD) after allogeneic transplant remains a significant cause of morbidity and mortality. Abatacept is a selective costimulation modulator, used for the treatment of rheumatologic diseases, and was recently the first drug to be approved by the US Food and Drug Administration for the prophylaxis of acute graft-versus-host disease. We conducted a phase 2 study to evaluate the efficacy of abatacept in steroid-refractory cGVHD. The overall response rate was 58%, seen in 21 out of 36 patients, with all responders achieving a partial response. Abatacept was well tolerated with few serious infectious complications. Immune correlative studies showed a decrease in interleukin -1α (IL-1α), IL-21, and tumor necrosis factor α as well as decreased programmed cell death protein 1 expression by CD4+ T cells in all patients after treatment with abatacept, demonstrating the effect of this drug on the immune microenvironment. The results demonstrate that abatacept is a promising therapeutic strategy for the treatment of cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01954979.
Chronic graft-versus-host disease (cGVHD) after allogeneic transplant remains a leading cause of morbidity, with a cumulative incidence up to 50%.[1] Transplant recipients with cGVHD have decreased quality of life, indicating the substantial burden of this phenomenon despite the curative intent of allogeneic transplant.[2] The rates of cGVHD indicate a need for effective and long-lasting therapies for this disease.[3] Although systemic corticosteroids are considered as first-line therapy, their use is often associated with incomplete response and significant toxicity. Of patients with cGVHD, <20% maintain a partial response (PR) or complete response (CR) and survive 1 year after initial therapy without additional systemic therapy.[4] Currently, there are 3 US Food and Drug Administration (FDA)-approved treatments for cGVHD after failure of prior lines of therapy, namely, ibrutinib, belumosudil, and ruxolitinib, with overall response rates (ORR) of 67%, 73%, and 76%, respectively.[5–7] These drugs have meaningfully affected the treatment of steroid-refractory cGVHD and have improved outcomes for patients. Nonetheless, many patients do not respond to currently available treatments, and for the majority of patients, a PR is achieved, demonstrating the need for novel approaches to treating cGVHD. We hypothesized that immunomodulation through costimulatory blockade has the potential to block T-cell activation and mitigate clinical manifestations of cGVHD.
Abatacept is the first of a class of agents called selective costimulation modulators that is used for the treatment of rheumatologic diseases, such as rheumatoid arthritis.[8,9] In December 2021, abatacept in combination with a calcineurin inhibitor and methotrexate was approved by the FDA for the prophylaxis of acute GVHD among patients undergoing allogeneic transplant from a matched or 1-allele mismatched unrelated donor.[10] Abatacept is a recombinant fusion protein comprised of the extracellular domain of human cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) linked to a fragment of the Fc portion of human immunoglobulin G1 that has been modified to prevent complement fixation and antibody-dependent cellular cytotoxicity.[11] Abatacept competes with CD28 on T cells to bind specifically to CD80 and CD86 on antigen-presenting cells, attenuating CD28-mediated T-cell activation. In a murine model, administration of CTLA4Ig was shown to prevent both acute GVHD and cGVHD as well as reverse manifestations of cGVHD.[12] Thus, immunomodulation with abatacept may be an innovative and promising therapeutic strategy for the treatment of cGVHD.
We previously reported results from a phase 1 clinical trial that evaluated the safety and clinical efficacy of abatacept among patients with steroid-refractory cGVHD. The study demonstrated safety of the drug and promising clinical results (#NCT01954979).[13] Here we report results from the phase 2 study performed to evaluate the overall clinical response rate of abatacept among patients with steroid-refractory cGVHD.
