GRAVITAS-119: A phase I trial of itacitinib plus calcineurin inhibitor-based regimens for GvHD prophylaxis

Despite prophylactic measures, graft-versus-host disease (GvHD) remains a serious complication of allogeneic hematopoietic cell transplant (HCT). Janus kinase (JAK) signaling plays a key role in the pathogenesis of GvHD, and JAK inhibition is being actively pursued as a therapeutic option for steroid-refractory patients.

Itacitinib is a JAK1 inhibitor that has been investigated in combination with corticosteroids for the treatment of GvHD, although the combined regimen did not improve overall response rates in the phase III GRAVITAS-301 trial. The phase I GRAVITAS-119 study (NCT03320642) evaluated itacitinib in combination with calcineurin inhibitor (CNI)-based regimens for the prophylaxis of GvHD. Here, we are pleased to summarize the results presented by Hannah Choe and colleagues during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.¹

GRAVITAS-119 study design¹

GRAVITAS-119 is a single-arm, open-label, phase I study of itacitinib in combination with CNI-based regimens for prophylaxis of GvHD in adult patients undergoing allogeneic HCT for a hematologic malignancy. Enrolled patients were candidates for reduced-intensity conditioning and peripheral blood stem cell transplant. Other eligibility criteria included a Karnofsky score of ≥70% or ECOG score 0–2.

The primary endpoint was hematologic recovery at Day 28, defined by absolute neutrophil count (ANC) ≥500/mm³ and platelet count ≥20,000/mm³.

Secondary endpoints were GvHD-free, relapse-free survival (GRFS), transplant-related mortality, overall survival (OS), time to engraftment, incidence of GvHD, and safety.

The study design is shown in Figure 1.

ATG, anti-thymocyte globulin; CsA, cyclosporine A; ITA, itacitinib; MMF, mycophenolate mofetil; MTX, methotrexate; OS, overall survival, Tac, tacrolimus.

Patient disposition and characteristics

• For the 65 patients treated with itacitinib, the CNI-based regimen used was tacrolimus (Tac)/methotrexate (MTX) in 41 patients (with anti-thymocyte globulin [ATG]: 8; without ATG: 33), and cyclosporine A (CsA)/mycophenolate mofetil (MMF) in 24 patients (with ATG: 16; without ATG: 8).
• While 73.8% of patients received itacitinib for > 90 days (median exposure 140 days), the majority of patients discontinued treatment before Day 180 (73.2% in the itacitinib + Tac/MTX arm, 50.0% in the itacitinib + CsA/MMF arm).
• The most common reasons for itacitinib discontinuation were adverse events (21.5%) and relapse (16.9%).

Selected characteristics for patients receiving itacitinib plus CNI-based regimen, with or without ATG, are shown in Table 1.

• The most common underlying malignancy was acute myeloid leukemia (40%).
• Two-thirds of patients had an intermediate risk score.
• Half of transplant donors were matched related, and 40% were matched unrelated.
• The most common conditioning regimen was busulfan/fludarabine (50%), followed by fludarabine/melphalan (18%).

Table 1. Selected patient and transplant characteristics¹

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ATG, anti-thymocyte globulin; ECOG, Eastern Cooperative Oncology Group; HLA, human leukocyte antigen; MDS, myelodysplastic syndromes.
	Without ATG (n = 41)	With ATG (n = 24)
Patient characteristic
Median age, years (range)	65 (25–76)	64 (42–72)
ECOG grade, %               0               1               2	24.4 53.7 22.0	50.0 41.7 8.3
Underlying malignancy, %               AML               MDS               ALL               Lymphoma               Other	43.9 19.5 12.2 14.6 9.8	33.3 37.5 16.7 4.2 8.3
Disease risk index, %               Low               Intermediate               High	12.2 65.9 22.0	8.3 66.7 25.0
Transplant characteristic
HLA donor type, %               Matched related               Matched unrelated               7/8 mismatched unrelated	61.0 36.6 2.4	33.3 45.8 20.8

Hematologic recovery

• All patients achieved both neutrophil and platelet recovery (Table 2).
• Hematologic recovery was achieved at the Day 28 primary endpoint in 64 out of 65 patients; one patient with myelofibrosis achieved ANC recovery on Day 31.

Table 2. Hematologic recovery¹

ANC, absolute neutrophil count; CsA, cyclosporine A; ITA, itacitinib; MMF, mycophenolate mofetil; MTX, methotrexate; Tac, tacrolimus. *The first day of three consecutive assessments showing ANC ≥ 500/mm3. † The first day of three consecutive assessments showing platelet count ≥ 20,000/mm3. ‡Patients who experienced baseline ANC < 500/mm3 and/or platelet count < 20,000/mm3.
	ITA + Tac/MTX (n = 41)	ITA + CsA/MMF (n = 24)	Total (n = 65)
ANC recovery*
Evaluable‡, n               Recovery, %               Median time to recovery (range), days	38 100 17.0 (4–31)	23 100 18.0 (11–26)	61 100 17.0 (4–31)
Platelet recovery†
Evaluable‡, n               Recovery, %               Median time to recovery (range), days	23 100 14.0 (11–26)	16 100 14.0 (10–18)	39 100 14.0 (10–26)

Graft failure

Secondary graft failure occurred in two patients, both of whom received a second transplant. One graft failure occurred on treatment, at Day 65, the other at Day 182 during follow-up, approximately 4 months after the last itacitinib dose.

GvHD, relapse, and survival outcomes

Outcomes for secondary endpoints are summarized in Table 3.

• Rates of acute GvHD compared favorably with historical data for CNI-based regimens.
• For patients receiving ATG-containing regimens, cumulative incidence of moderate or severe chronic GvHD and of relapse at 1 year were lower, and 1-year GRFS rate was higher, compared with patients not receiving ATG.

Table 3. Secondary endpoints¹

ATG, anti-thymocyte globulin; GRFS, GvHD-free and relapse-free survival; GvHD, graft-versus-host disease; OS, overall survival.
Endpoint, %	Without ATG (n = 40)	With ATG (n = 23)
Acute GvHD, cumulative incidence at Day 180               Grades II-IV               Grades III/IV	10.2 5.1	13.0 4.3
Chronic GvHD, cumulative incidence at 1 year               Any severity               Moderate or severe	43.6 31.3	44.6 10.4
Relapse or progression, cumulative incidence at 1 year	28.2	4.3
Estimated GRFS at 1 year	23.1	60.9
Estimated OS at 1 year	74.3	82.6

Adverse events

• The most common hematologic adverse events leading to itacitinib dose modification/discontinuation were thrombocytopenia (9.2%), mixed chimerism (6.2%), and neutropenia (3.1%).
• Other common non-hematological Grade ≥3 side effects were diarrhea (15.4%), hypertension (13.8%), and hypertriglyceridemia (12.3%).
• Grade ≥3 infections occurred in 33.3% of patients receiving ATG-containing regimens, and 26.8% of patients not receiving ATG.
• Cytomegalovirus (CMV) infection of any grade occurred in 16.9% of patients; all cases had donor- and/or recipient-positive CMV serostatus.
• Primary cause of death on treatment was infection (two patients), and primary causes of death during follow-up were disease relapse (five patients) and infection (three patients).

Conclusion

The addition of itacitinib to CNI-based regimens was well tolerated, with 64 out of 65 patients achieving the primary endpoint of hematologic recovery within 28 days. While the incidence of acute GvHD was low and 1-year GRFS rates were encouraging, treatment appeared to have little impact on the frequency of chronic GvHD, except for patients receiving ATG.

Larger and more homogeneous study cohorts are required to further evaluate the efficacy of this combination for GvHD prophylaxis. Evaluation of an itacitinib + post-transplant cyclophosphamide combination is currently underway in the GRAVITAS-119 trial.