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Ixazomib for advanced chronic GvHD: Results of a phase II trial

Jun 25, 2020

Recipients of allogeneic hematopoietic stem cell transplantation may be affected by chronic graft-versus-host disease (cGvHD), typically showing skin involvement, ulcerations and sclerosis of the gastrointestinal tract, and other organ manifestations. cGvHD is an immune-mediated disorder, resulting in impaired quality of life, and prolonged immunosuppressive therapy and death. For some patients, steroid therapy provides adequate control of cGvHD, but for most, alternative immunosuppression therapies are required. While a variety of agents have been tested, no standard therapy approach has been identified, and treatment failure is common.

The first evidence for the involvement of the proteasome in cGvHD pathogenesis came from results obtained with the proteasome inhibitor bortezomib for the treatment of cGvHD.1 Ixazomib belongs to the same drug class and has the advantage of being orally available.

Joseph Pidala and colleagues recently published the results of their phase II trial (NCT02513498) in Biology of Blood and Marrow Transplantation,1 in which they examined the safety, clinical efficacy, and biological activity of ixazomib in advanced cGvHD.

Study design

This was a prospective, open-label phase II study open to patients ≥ 18 years who had National Institutes of Health consensus-defined cGvHD and at least one prior line of systemic immunosuppressive therapy for management of cGVHD. There were no additional limitations regarding prior or current steroid treatment, or any limit to the number of prior systemic immune therapies tried.

A 4 mg dose of ixazomib was administered orally, once weekly on Days 1, 8, and 15 of a 28-day cycle. The trial originally allowed six total cycles of treatment but was redesigned to allow up to 12 cycles for patients who were responding to treatment. Absolute neutrophil count, platelet count, and other non-hematologic toxicities were assessed before each new cycle could commence. If the delay in starting a cycle was > 3 weeks, ixazomib treatment was discontinued. Dose reductions to 3 mg or 2.3 mg were allowed to minimize hematologic and non-hematologic toxicity, but treatment was discontinued if further dose reductions were required.

The primary outcome was 6-month treatment failure (a composite endpoint including death, malignancy relapse, or requirement of a new line of systemic immunosuppressive therapy).

Patient characteristics

Fifty patients, mostly with acute leukemias (52%), were enrolled across six institutions. Table 1 provides details of baseline patient, disease, and prior transplantation characteristics. The enrolled population had advanced cGvHD characteristics, with 84% having severe disease and 80% having had three or more prior lines of immunosuppressive therapy (range, 1–9). Three or more organs were involved in > 80% of participants, with the skin, eyes, joints, and lungs commonly affected. Median time from cGVHD onset to enrollment was 2.8 years.

Table 1. Baseline characteristics1

(c)GvHD, (chronic) graft-versus-host disease; HLA, human leukocyte antigen; NIH, National Institutes of Health


(N = 50)


Median age, years (interquartile range)

58 (44–65)

Male, n (%)

38 (76)

Graft source, n (%)


Bone marrow

5 (10)

Peripheral blood

45 (90)

Conditioning, n (%)



28 (56)

Reduced intensity

10 (20)

Non myeloablative

11 (22)

Unknown (patient transplanted elsewhere)

1 (2)

Donor match, n (%)


HLA-identical sibling

18 (36)

HLA-matched other relative

4 (8)

Other mismatched family member

1 (2)

HLA-matched unrelated donor

24 (48)

HLA-mismatched unrelated donor

3 (6)

cGvHD NIH stage at inclusion, n (%)



8 (16)


42 (84)

Type of GvHD, n (%)


Overlap acute and chronic

10 (20)

Classic chronic

40 (80)

No. of organs involved, n (%)



8 (16)


28 (56)

≥ 5

14 (28)

Prednisone at enrollment, n (%)

39 (78)

Key findings

Adherence and safety

Of the 50 treated patients, 26 completed 6 months of planned therapy (22 patients had all planned 18 doses, and four patients had fewer than the planned 18 doses). The most common reasons for not completing six full cycles included unresolved toxicity (n = 8; 16%), treatment failure (n = 5; 10%), and withdrawal from the study (n = 4; 8%). Severe adverse events were seen in 38% of patients, of which pneumonitis, fatigue, skin infections, and progressive multifocal leukoencephalopathy were judged to be related to ixazomib. In addition, there were five deaths, two of which were considered to be potentially linked to treatment with ixazomib.


The primary endpoint of the trial was met, with 6-month treatment failure rate significantly lower compared with the historical benchmark (28% vs 44%; p = 0.01) for second-line therapy of cGVHD. Ten patients experienced treatment failure by Month 6, and 11 patients after Month 6, mostly due to treatment change. There was no association found between patient, transplant, or cGVHD variables and 6-month treatment failure. The majority of events in the composite endpoint were addition of a new line of systemic immunosuppressive therapy, while death and malignancy relapse were less common.

A total of 51% (24/47) of patients achieved a partial response at 3 months and 40% (17/43) were in partial response at 6 months, as calculated per the 2014 National Institutes of Health Response Criteria. A high prednisone dose (≥ 0.165 mg/kg/day) at study enrollment was associated with significantly lower treatment response at 6 months when compared to patients who did not receive prednisone at study start (odds ratio, 0.13; 95% CI, 0.02–0.8; p = 0.034).

Overall survival was 92% at 6 months and 90% at 12 months, while failure-free survival was 72% and 57%, respectively, which compared favorably to the examined historical benchmark (56% and 45% at 6 and 12 months, respectively).


This multicenter phase II trial has shown the potential for ixazomib as a treatment option for patients with advanced cGvHD across a range of cGVHD organ sites. It has shown significant improvements in treatment failure rate compared to a historical benchmark. In addition, treatment with ixazomib seems to be tolerable and safe, with more than half of patients completing six full cycles of therapy. A randomized trial comparing ixazomib with other second-line treatment options is warranted to conclude on its role in the treatment of severe cGvHD.

  1. Pai CC, Chen M, Mirsoian A, et al. Treatment of chronic graft-versus-host disease with bortezomib. Blood. 2014;124(10):1677-1688. DOI: 1182/blood-2014-02-554279

  2. Pidala J, Bhatt VR, Hamilton B, et al. Ixazomib for treatment of refractory chronic graft vs. host disease: A Chronic GVHD Consortium phase II trial. Biol Blood Marrow Transplant. Online ahead of print. DOI: 10.1016/j.bbmt.2020.05.015