Five-Year Outcomes of the “Abatacept Combined with a Calcineurin Inhibitor and Methotrexate for Graft Versus Host Disease (GVHD) Prophylaxis: A Randomized Controlled Trial” (‘ABA2‘)
Notice bibliographique
Résumé
Background: GVHD remains a major cause of non-relapse mortality (NRM) after hematopoietic cell transplant (HCT). Abatacept, a costimulatory blockade agent targeting the CD28:CD80/86 pathway, was FDA-approved in 2021 for GVHD prophylaxis in patients undergoing an 8/8 HLA-matched unrelated donor (MUD), or 7/8-HLA mismatched unrelated donor (MMUD) HCT for a hematologic malignancy, in part based on the ABA2 trial (NCT01743131). Here, we present 5-yr follow-up data for ABA2. Methods: ABA2 patient eligibility criteria (described in detail in PMID: 33449816) included patients ≥ 6 yr with heme malignancies undergoing MUD or MMUD HCT after intensive conditioning. MUD patients were enrolled on the randomized, double-blind placebo-controlled arm, with patients randomized to either 4 doses of abatacept (10mg/kg/dose on Day -1, +5, +14 +28) or placebo. MMUD patients all received 4 doses of abatacept. 185 patients were enrolled: 69 MUD-placebo, 73 MUD-abatacept, 43 MMUD-abatacept. GVHD prophylaxis also included a calcineurin inhibitor (CNI, continued through Day +100 followed by a wean) and methotrexate (MTX, 15mg/m2 on day +1 and 10mg/m2 on Day +3, +6, +11). Both bone marrow and PBSC grafts were used. All patient data were independently monitored through 5 yr by the NMDP CRO. Here we report cumulative incidence (CI) data at 2-, 3- and 5-yr for overall survival (OS), relapse, relapse-free survival (RFS), non-relapse mortality (NRM), systemic therapy (ST)-requiring chronic GVHD (cGVHD), and grade 3-4 acute GVHD (aGVHD)-free/ST-requiring cGVHD-free/relapse-free survival (GRFS). Results: The median follow-up was 53.8 months, 56.1 months and 60 months for the MUD-placebo, MUD-abatacept, and MMUD-abatacept cohorts, respectively. The 2-, 3- and 5-yr OS was 65.2%, 62.3% and 54.3% for MUD-placebo, 75.2%, 68.0% and 61.0% for MUD-abatacept, and 78.8%, 74.0% and 71.7% for MMUD-abatacept cohorts, respectively. The 2-, 3- and 5-yr CI of relapse was 25.7%, 27.5% and 27.5% for MUD-placebo, 21.7%, 25.0% and 25.0% for MUD-abatacept, and 9.7%, 9.7% and 12.6% for MMUD-abatacept cohorts, respectively. The 2-, 3- and 5-yr CI of NRM was 18.1%, 20.0%, 28.7% for MUD-placebo, 14.4%, 18.1% and 22.5% for MUD-abatacept, and 15.0%, 20.2% and 20.2% for MMUD-abatacept cohorts, respectively. The 2-, 3- and 5-yr CI of RFS was 60.9%, 58.0% and 51.7% for MUD-placebo, 67.0%, 61.4% and 58.1% for MUD-abatacept, and 76.7%, 72.1% and 69.8% for MMUD-abatacept cohorts, respectively. The 1-yr CI of grade 3-4 acute GVHD was 14.8% for MUD-placebo, 8.4% for MUD-abatacept, and 2.3% for MMUD-abatacept cohorts, respectively. The 2-, 3- and 5-yr CI of ST-requiring chronic GVHD was 49.6%, 52.0% and 52.0% for MUD-placebo, 54.1%, 58.5% and 58.5% for MUD-abatacept, and 72.5%, 75.2% and 78.0% for MMUD-abatacept cohorts, respectively. The 2-, 3- and 5-yr cumulative incidence of GRFS was 27.5%, 26.1%, and 26.1% for MUD-placebo, 27.4%, 21.9% and 21.9% for MUD-abatacept, and 23.3%, 20.9% and 16.3% for MMUD-abatacept cohorts, respectively. Conclusions: Here we demonstrate that the central outcomes previously reported for ABA2 at 2 yr post-HCT (PMID: 33449816) were durable at 3- and 5-yr, with relatively stable OS, relapse, NRM, cGVHD and RFS. These data are important given new CIBMTR comparisons demonstrating that, for both MUD and MMUD recipients at 2 yr, abatacept/CNI/MTX is superior for OS and RFS compared to both CNI/MTX and CNI/MTX/ATG, and is similar to post-transplant cyclophosphamide (PT-Cy, Blood 2024, PMID:39028876). Moreover, the 3-yr outcome data for MMUD patients presented here for ABA2 also appear similar to the recently reported 3-yr outcomes for myeloablative conditioning (MAC) and PT-Cy for the MMUD-15 trial (PMID: 36584941, 5-yr outcomes not yet reported for MMUD-15). Most notable is the fact that despite increased cGVHD in ABA2 compared to MMUD-15, the GRFS is similar in both trials (20.9% GRFS at 3 yr for ABA2 versus 16.9% for PT-Cy after MAC HCT). These similar composite endpoints may be driven by lower apparent relapse rates in ABA2 (9.7% at 3-yr for ABA2 and 50.5% at 3-yr for MAC PT-Cy in MMUD-15). Together, these data lead to two key conclusions: (1) That the addition of abatacept continues to abrogate historic disparities in OS and RFS for HLA-mismatched vs HLA-matched HCT (extending our previous comparison (PMID:34753172) to 5-yrs post-HCT). (2) That a head-to-head randomized trial of abatacept- versus PT-Cy-based prophylaxis is warranted.
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Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,003 | 0,003 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,002 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».