The efficacy and safety of ofatumumab plus prednisone in cGvHD

Improved understanding of the pathophysiology of chronic graft-versus-host disease (cGvHD) has led to new opportunities for frontline therapeutic intervention. One promising avenue is the depletion of B-lymphocyte signalling using anti-CD20 agents. Current clinical trials for novel agents utilize a combinatorial approach with approved glucocorticosteroids that are the current standard of care in the frontline setting. The key aim is to increase the efficacy of steroidal therapy without compromising safety.

Ofatumumab is a novel anti-CD20 monoclonal antibody therapy investigated in combination with the glucocorticoid therapy prednisone. After demonstrating tolerable toxicity in 12 patients from a phase I trial, a phase II expansion for this combination was implemented. Efficacy and safety data were compiled and published by Lazaryan et al.¹ in Blood Advances, which we summarize below. 

Study design

It was a multicenter phase II trial that investigated a combination of ofatumumab given at two timepoints: Day 0 and Day 14 (1,000 mg); and prednisone (1 mg/kg up to a maximum of 2 mg/kg if cGvHD activity increased) received daily, with a follow-up of 24 months. The duration of treatment was driven by individual physicians according to their institutional guidelines.

Inclusion criteria included:

• Adults aged ≥18
• cGvHD diagnosis using the National Institutes of Health (NIH) consensus criteria
• Patients had to begin ofatumumab therapy within 14 days from initiation of 1 mg/kg/day of prednisone therapy for cGvHD

Key study endpoints

• The primary endpoint was overall response rate (ORR; composite of complete response [CR] and partial response [PR] at 6 months after initial prednisone therapy). The key secondary endpoint was assessment of ORR at 6 months based on the 2014 NIH consensus response criteria.
• The study was powered to detect an increased ORR of 80% with ofatumumab plus prednisone, based on a historical benchmark of a 60% ORR from previous publications, with a power of 90%.

Results

A total of 38 patients, with a median age of 59.5 (range, 26–84), were treated. The most common hematologic disease in this cohort was acute myeloid leukemia (AML) (36.8%). Baseline characteristics are summarized in Table 1 below.

Table 1. Patient characteristics*

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; cGvHD, chronic graft-versus-host disease; HL, Hodgkin lymphoma; KPS, karnofsky performance status; MDS, myelodysplastic syndromes; MM, multiple myeloma; MPN, myeloproliferative neoplasms; NHL, non-Hodgkin lymphoma; NIH, National Institutes of Health. *Adapted from Lazaryan et al.1 †Includes follicular lymphoma (FL), mantle cell lymphoma (MCL), and small lymphocytic lymphoma (SLL).
Characteristic, % (unless otherwise stated)	N = 38
Age, median (range)	59.5 (26–84)
Female	34.2
Disease type
AML	36.8
MDS	23.7
MPN	10.5
ALL	10.5
NHL†	13.2
HL	2.6
MM	2.6
KPS
80–100%	81.6
<80%	13.2
Missing	5.3
Graft source
Bone Marrow	2.6
Peripheral blood	92.1
Umbilical cord blood	5.3
Graft type
Mismatched unrelated donor	7.9
Matched related donor	23.7
Matched unrelated donor	63.2
Umbilical cord blood	5.3
cGvHD type
Classic	26.3
Overlap	73.7
NIH score overall severity
2 (moderate)	63.2
3 (severe)	36.8

Efficacy

After a 6-month follow-up, the ORR according to clinician reporting and NIH response criteria was 62.5% (95% confidence interval [CI], 44–79%) and did not demonstrate superiority over the null hypothesis of pre-specified benchmark of 60% (p = 0.035). A more recent analysis from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0801 study, reported an ORR of 48.6% for a two-drug approach (sirolimus/prednisone). When Lazaryan et al.¹ compared their results to the above analysis, they found a suggestion of difference (lower CI limit of 51.5%; p = 0.056) in favor of the ofatumumab/prednisone combination. When comparing physician-reported and NIH calculated ORR, there was a moderate correlation over 9, 12, 18, and 24 months.

A total of 21 treatment failure events were reported. This included three relapses, five nonrelapse deaths, 13 events leading to new systemic immunosuppressive therapy, while 17 subjects were censored. Failure-free survival (FFS) at 6 months was 64.2% (95% CI, 46.5–77.4%), and 53.1% (95% CI, 35.8–67.7%) at 12 months. The median time to initiation of second-line therapy was 5.4 months (range, 0.9–15.1 months).

FFS with PR/CR at 12 months with the ofatumumab combination was 33.5%, presenting a statistically significant improvement from the benchmark of 15% taken from other studies (p = 0.019). Patients with FFS and PR/CR at 12 months were eight times more likely (OR, 8; 95% CI, 1.21–52.7) to complete steroid continuation at 24 months than those with a FFS with non-CR/PR response (p = 0.025).

Finally, the causes of mortality during follow-up included pneumonia/respiratory failure (n = 2), multiple organ failure (n = 1), gastrointestinal (GI) bleeding (n = 1), unknown (n = 4), and relapsed disease (n = 2).

Safety

Infusion-related toxicity with ofatumumab was acceptable, with Grade 1 events occurring in four patients and Grade 2 events occurring in 13 patients. However, all but one of these patients were able to continue with a second dose. Grade 1–2 adverse events (AEs) included infusion reaction (n = 9), abdominal discomfort (n = 2), and atrial fibrillation, diaphoresis, hypotension, presyncope, sore throat, and urticaria (each, n = 1).

Grade 3–4 AEs reported were mostly related to infections. After a median follow-up of 23 months, a total of 15 patients experienced viral infections, of which nine had multiple infections. In total, 26 (34.2%) bacterial infections were reported; 13 (68.4%) viral, 8 (21.1%) fungal, and 14 (36.8%) unidentified.

Focusing on infections, the investigators analyzed whether there was a correlation between infection density and immune depletion, approximated by prednisone exposure and quantitative immunoglobulins. Infection density was measured over three distinct time periods (within 30 days, 31–180 days, and 181–365 days) after initiation of study therapy, and was greater in the first two time frames. This data supports the increased infection density within 30 days for those with immunoglobulin G (IgG), IgA, and IgE below median values.

Conclusion

Overall, the phase II study demonstrates acceptable efficacy and safety when combining ofatumumab with prednisone for frontline treatment of cGvHD. Although improvement in ORR over a prespecified benchmark was not reached, FFS was significantly improved when analysed with CR/PR at 12 months, indicating durable responses in a certain subgroup of patients. Moving forward, the authors highlighted the potential for investigating further combinations with ofatumumab that are steroid free.

Limitations of this study include the inter-variability of physician response assessment, which affected ORR data. Also, comparisons made on ORR and FFS from this study with current best estimates were post-hoc and so cannot fully support a conclusion of superiority. Finally, given the relatively small cohort of patients included (N = 38), further data is needed to investigate which baseline characteristics may infer durable response.