Baricitinib use in patients with aGvHD receiving HLA-matched PBSCT

Janus kinase (JAK) inhibitors, such as baricitinib and ruxolitinib, are effective in treating steroid-refractory graft-versus-host disease (GvHD).¹ However, up to 50% of patients become refractory to ruxolitinib; therefore, alternative JAK inhibitors are needed.¹

At the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, Schroeder¹ presented results from a phase I, open-label trial of baricitinib for the treatment of acute (a)GvHD, which we are pleased to summarize here. Baricitinib has been shown to be most effective in preventing GvHD when used early after transplant.

Study design

A total of 24 adult patients were enrolled to receive baricitinib in two dosing cohorts (2 mg or 4 mg, with 12 patients in each). The study design is shown in Figure 1. To be included in the study, patients had to be aged >18 years, diagnosed with a hematologic malignancy, and received a transplant from a human leukocyte antigen-matched peripheral blood stem cell donor. The primary objectives were graft failure and incidence of aGvHD by Day 100, with a secondary objective of treatment-related mortality at Day 180.

MAC, myeloablative conditioning; MTX, methotrexate; MUD, matched unrelated donor; PBSC, peripheral blood stem cells; RIC, reduced intensity conditioning, Tac, tacrolimus.
*Adapted from Schroeder.¹ 

Results

Baseline patient characteristics are shown in Table 1. The majority of patients had a diagnosis of acute myeloid leukemia, and more patients in the 2 mg cohort compared with the 4 mg group were minimal residual disease negative at the start of the study (83.3% vs 41.6%, respectively).

Table 1. Baseline patient characteristics*

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; GvHD, graft-versus-host disease; MAC, myeloablative conditioning; MDS, myelodysplastic syndromes; MMF, mycophenolate mofetil; MRD+, minimal residual disease positive; MRD−, minimal residual disease negative; MTX, methotrexate; MUD, matched unrelated donor; PTCy, post-transplant cyclophosphamide; RIC, reduced intensity conditioning; Tac, tacrolimus; Thymo, thymoglobulin. *Adapted from Schroeder.1 †All AML subjects were required to be in morphologic complete remission and ALL subjects were required to be MRD−.
Characteristic, number of patients (unless otherwise stated)	2 mg baricitinib (n = 12)	4 mg baricitinib (n = 12)	Total (N = 24)
Age, years	28–71	42–72	28–72
Diagnosis
AML	8	8	16
MDS	2	4	6
ALL	2	0	2
Remission status at transplant†
MRD+	2	6	8
MRD−	10	5	15
Donor source
Sibling	6	4	10
MUD	6	8	14
Conditioning
MAC	11	8	19
RIC	1	4	5
GvHD prophylaxis
Tac/MTX	12	7	19
PTCy/Tac/MMF	0	5	5
Thymo added for MUD	3	2	5

Safety

Adverse events of interest are shown in Table 2. Mucositis was the most common adverse event and occurred in 41.3% of patients. There were more patients in the 4 mg cohort who had thrombosis compared with the 2 mg cohort (three patients vs one patient, respectively).

Table 2. Adverse events of interest*

SAE, serious adverse event. *Adapted from Schroeder.1 †One case of intracranial hemorrhage at 2 mg and one case of pneumonia in the 4 mg baricitinib group, but both occurred after discontinuation of baricitinib.
Adverse event, number of patients	Overall (N = 24)
Non-hematologic Grade 3–4 SAEs
Mucositis	10
Hypertension	7
Febrile neutropenia	7
Infections/sepsis	7
Anorexia	5
Diarrhea	4
Thrombosis	4
BK polyomavirus cystitis	2
Deep vein thrombosis	4
Death	2†

Efficacy

There was a median follow-up of 320 days (range, 63–368 days). Outcome measures are shown in Figure 2. A total of 20 patients were evaluable for engraftment at Day 100, and there were no cases of graft failure in either dosing cohort. There were two patients in the 2 mg cohort and three patients in the 4 mg cohort who relapsed at Day 300. The overall survival at 1 year was 71%. Chronic GvHD was recorded in nine patients (three mild cases and six moderate). In total, eight cases of Grade 2–4 GvHD were recorded, with 25% being steroid refractory, while all cases of Grade 2 aGvHD were steroid responsive.

aGvHD, acute graft-versus-host disease; ANC, absolute neutrophil count; BM, bone marrow; MAC, myeloablative conditioning; RIC, reduced intensity conditioning.
*Adapted from Schroeder.¹

Conclusion

This study demonstrates that both 2 mg and 4 mg baricitinib dosing regimens can be given effectively to patients who have undergone peripheral blood stem cell transplantation. There was a low incidence of Grade 3 and 4 aGvHD, with an acceptable safety profile, although cases of thrombosis were higher in the 4 mg-treated patients. There were no cases of graft failure in either cohort, with higher bone marrow engraftment seen in patients who had received myeloablative conditioning compared with reduced intensity conditioning. There is an expansion planned to use the 2 mg dose of baricitinib in patients receiving myeloablative conditioning.