FDA Grants Ibrutinib Approval for Pediatric Graft-Versus-Host-Disease

The FDA greenlighted ibrutinib (Imbruvica) for patients aged 1 year or older who have chronic graft-versus-host-disease.¹

Notably, formulations include capsules (70 mg and 140 mg), tablets (140, 280 mg, 420 mg, and 546 mg), and oral suspension (70 mg/mL).

"Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening. If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options — until now," Paul A. Carpenter, MD, physician at Seattle Children's Hospital and an iMAGINE study investigator, stated. "The iMAGINE trial showed encouraging safety results and sustained response rates in children, and the new [ibrutinib] oral suspension formulation helps address challenges children may have with swallowing capsules or tablets.”

The efficacy of ibrutinib was examined as part of the open-label, multicenter, single-arm, phase 1/2 iMAGINE trial (NCT03790332), which enrolled pediatric and young adult patients aged 1 year to less than 22 years who had moderate or severe cGVHD.²

All patients had a platelet count of at least 30 x 109/L, an absolute neutrophil count of at least 1.0 x 109/L, aspartate or alanine aminotransferase of ≤ 3 x the upper limit of normal (ULN), total bilirubin of ≤ 1.5 x ULN, and estimated creatinine clearance of at least 30 mL/min.

If single organ genitourinary involvement was the only manifestation of cGVHD in a patient, they were excluded.

The median age of patients was 13 years (range, 1-19). Of the evaluable 47 who required additional therapy following failure of 1 or more lines of systemic therapy, 70% were male, 36% were White, 9% were Black or African American, and 55% were other or unreported. Eighty-seven percent of patients had at least 2 organs involved at baseline, with lung involvement at baseline in 49% of patients.

Moreover, 26% of patients had a Karnofsky/Lansky performance score of less than 80. The median daily corticosteroid dose received at baseline was 0.47 mg/kg/day, and more than half of patients (61%; n = 19/31) were receiving ongoing immunosuppressants and systemic corticosteroids at baseline.

Additionally, prophylaxis for infections was managed in accordance with institutional guidelines; 72% of patients received combinations of sulfonamides and trimethoprim and 70% had systemic antifungal agents.

Patients aged 12 years or older received oral ibrutinib at a once-daily dose of 420 mg; those aged 1 year to less than 12 years, received the agent at 240 mg/m2 once daily. Notably, concomitant treatment with supportive care therapies for cGVHD was allowed.

Overall response rate (ORR) through week 25 served as the main efficacy outcome measure of the trial; this comprised complete responses (CRs) or partial responses (PRs) per 2014 National Institutes of Health Consensus Development Project Response criteria.

Findings showed that the ORR achieved with ibrutinib by week 25 was 60% (95% CI, 44%-74%); this included a CR rate of 4% (n = 2) and a PR rate of 55% (n = 26). The median duration of response in these patients was 5.3 months (95% CI, 2.8-8.8).

Moreover, the median time to first response was 0.9 month (range, 0.9-6.1), and the median time from first response to death or new systemic therapies for cGVHD was 14.8 months (95% CI, 4.6–not evaluable).

The ORR findings were supported by data from exploratory analyses of patient-reported symptom bother, which revealed at least a 7-point decrease in Lee Symptom Scale overall summary score through week 25 in half (50%; 13/26) of patients aged 12 years and older.

Regarding safety, the most common toxicities to occur in 20% or more of patients included anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.

Diarrhea is especially common, and children will need to be routinely hydrating while on this medication.

The agent comes with warnings for hemorrhage, infections, cardiac arrythmias, hypertensions, cytopenia, second primary malignancies, and tumor lysis syndrome.

At baseline, patients should be assessed for TLS. Their blood counts, cardiac function, and TLS risk should be regularly monitored. Blood counts should be checked monthly to monitor cytopenia risk.

The recommended dose for this age group is 240 mg/m taken orally once daily. The maximum recommended amount for these patients is 420 mg. Tablets or capsules should be taken with a full glass of water. The capsules should not be opened or chewed, and the tablets should not be cut, crushed, or chewed.

Parents may administer an oral solution of ibrutinib to their child at home and therefore should be instructed on proper handling and safety.

References

1. FDA approves ibrutinib for pediatric patients with chronic graft versus host disease, including an new oral suspension. News release. FDA. August 24, 2022. Accessed August 24, 2022. https://bit.ly/3PJtwXD
2. Imbruvica. Prescribing information. Janssen Biotech, Inc.; 2022. Accessed August 24, 2022. https://bit.ly/3AKmaih