Long-Term Follow-up of Patients with Corticosteroid-Refractory Graft-Versus-Host Disease Treated with Ruxolitinib

Abstract We have previously reported on the efficacy of the JAK1/2 inhibitor ruxolitinib in corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) in 95 patients (pts) (Leukemia 2015;29(10):2062-8). To assess long-term follow-up results, we collected data from the same pts treated in 19 centers in Europe and the US. Pts were classified as SR-aGVHD (n=54, all grade III or IV) or SR-cGvHD (n=41, all moderate or severe). Median numbers of pre-ruxolitinib GVHD treatment lines were 3 (1-7) and 3 (1-10) for SR-aGVHD and SR-cGvHD, respectively. The median follow-up was 19 and 24 months for aGVHD and cGVHD, respectively. The 1-year overall survival (OS) from was 62.4% (CI: 49.4%-75.4%) and 92.7% (CI: 84.7%-100%) for SR-aGVHD and SR-cGvHD, respectively. The estimated median OS (50% death) was 18 months for aGVHD and not reached for cGVHD patients. The median duration of ruxolitinib treatment was 5 and 10 months for patients with SR-aGVHD and SR-cGVHD, respectively reflecting the different biology of the diseases. At follow-up, 22/54 (41%) of SR-aGVHD patients and 10/41 (24%) of SR-cGVHD patients have an ongoing response and are free of any immunosuppression. GVHD relapse or progression after achieved PR/CR was observed in 14/45 (31%) and 13/36 (36%) patients with SR-aGVHD and SR-cGVHD, respectively. Response to re-treatment with Ruxolitinib or any immunosupressive therapy was seen in 11/14 (78%) and 11/13 (86%) patients with SR-aGVHD and SR-cGVHD, respectively. Cytopenia (any grade) and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. These findings extend our previous report by showing that patients with SR-aGVHD and SR-cGVHD may benefit long-term from ruxolitinib treatment with an OS that is relatively high for steroid-refractory GVHD. GVHD-relapse or GVHD-progression rates were moderate and more than 75% of the relapse/progression patients responded to re-treatment with ruxolitinib or other immunosuppression. Disclosures Meyer: Stanford University: Patents & Royalties. Marks:Pfizer: Honoraria. Lübbert:Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding. Scheid:Novartis: Other: funding outside this work; Celgene: Other: funding outside this work; Janssen: Other: funding outside this work. Kobbe:Celgene: Honoraria, Other: travel support, Research Funding; Jansen: Honoraria, Other: travel support. Negrin:Stanford University: Patents & Royalties. Brune:Meda Pharma: Consultancy. Mielke:JAZZ Pharma: Speakers Bureau; Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Gilead: Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau. Kuball:Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Peschel:MophoSys: Honoraria. von Bubnoff:BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding.

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Clinical Manifestations of Cutaneous Graft-versus-host Disease after Allogeneic Haematopoietic Cell Transplantation: Long-term Follow-up Results in a Single Turkish Centre

Acta Dermato Venereologica ◽

10.1080/00015550410025840 ◽

2004 ◽

Vol 84 (4) ◽

pp. 296-300 ◽

Cited By ~ 9

Author(s):

Hatice Şanli ◽

Pelin Ekmekçi ◽

Mutlu Arat ◽

Günhan Gürman

Keyword(s):

Cell Transplantation ◽

Graft Versus Host Disease ◽

Clinical Manifestations ◽

Host Disease ◽

Graft Versus Host ◽

Haematopoietic Cell ◽

Long Term Follow Up ◽

Allogeneic Haematopoietic Cell Transplantation

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Long-Term Follow-Up Program and Chronic Graft-versus-Host Disease

Journal of Hematopoietic Cell Transplantation ◽

10.7889/hct.6.84 ◽

2017 ◽

Vol 6 (2) ◽

pp. 84-97

Author(s):

Yoshihiro Inamoto

Keyword(s):

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Long Term Follow Up

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Long-term follow-up of a randomized trial of graft-versus-host disease prevention by methotrexate/cyclosporine versus methotrexate alone in patients given marrow grafts for severe aplastic anemia [letter]

Blood ◽

10.1182/blood.v83.9.2749.bloodjournal8392749 ◽

1994 ◽

Vol 83 (9) ◽

pp. 2749-2750

Author(s):

R Storb ◽

W Leisenring ◽

HJ Deeg ◽

C Anasetti ◽

F Appelbaum ◽

...

Keyword(s):

Disease Prevention ◽

Randomized Trial ◽

Aplastic Anemia ◽

Graft Versus Host Disease ◽

Severe Aplastic Anemia ◽

Host Disease ◽

Graft Versus Host ◽

Long Term Follow Up

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Trial in Progress: A Phase 3 Study of Itacitinib or Placebo in Combination with Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease (GRAVITAS-309)

Blood ◽

10.1182/blood-2019-128586 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3277-3277

Author(s):

Annie Im ◽

Rodica Morariu-Zamfir ◽

Maureen Bleam ◽

Ying Yan ◽

Steven Z. Pavletic

Keyword(s):

Graft Versus Host Disease ◽

Study Drug ◽

Jak Inhibitor ◽

Phase 3 ◽

Clinical Safety ◽

Host Disease ◽

Graft Versus Host ◽

Secondary Endpoints

Background Allogeneic hematopoietic cell transplantation (HCT) is indicated for several hematologic malignancies and nonmalignant disorders. Chronic graft-versus-host disease (cGVHD) develops in 30%-70% of long-term survivors of HCT and is a significant cause of nonrelapse mortality. Corticosteroids (CS) are the recommended first-line treatment for cGVHD; however, up to 60% of patients treated with CS require additional cGVHD therapy within 2 years. Furthermore, long-term exposure to CS is associated with a wide range of toxicities and increased risk of infection. Novel safe and effective therapies are needed to treat cGVHD and reduce CS dependence. Janus kinases (JAKs) mediate the signaling of proinflammatory cytokines involved in the pathogenesis of cGVHD. Itacitinib is a JAK-1 selective inhibitor that improved graft-versus-host disease (GVHD) and survival without affecting engraftment of donor leukocytes in murine models. In a phase 1 clinical study, itacitinib 200 or 300 mg once daily (QD) was well tolerated in patients with steroid-refractory or steroid-naive acute GVHD (aGVHD). Here we describe the trial design of the first clinical study evaluating the safety and efficacy of itacitinib for the treatment of cGVHD. Study Design and Methods GRAVITAS-309 (NCT03584516) is a 2-part phase 3 study of itacitinib or placebo in combination with CS as initial treatment for cGVHD. Patients aged ≥18 years who underwent allogeneic HCT from any donor type and graft source, with evidence of myeloid and platelet engraftment, and who have active, moderate, or severe cGVHD per National Institutes of Health Consensus Criteria are eligible to participate. Patients are excluded if they received >1 prior HCT (except autologous), had >3 days of systemic CS treatment for cGVHD, received any other systemic treatment for cGVHD, have presence of active uncontrolled infection, or had treatment with a JAK inhibitor within 8 weeks of randomization (patients who previously received a JAK inhibitor for aGVHD are eligible only if they achieved a complete or partial response). Part 1 is a randomized, open-label study to determine optimal dosing of itacitinib in combination with CS (~20 patients randomized 1:1 to itacitinib 200 mg QD or 300 mg QD; Figure 1). The primary endpoints for Part 1 are dose-limiting toxicities (DLTs) through Day 28 as well as clinical safety and laboratory assessments. Main secondary endpoints include pharmacokinetic (PK) parameters and efficacy outcomes (Table 1). After 20 patients have completed 28 days of treatment, an external data monitoring committee will review the data and provide a recommendation for an appropriate dose for Part 2 based on emergent adverse events, clinical laboratory parameters, PK data, and DLTs. Part 2 is a randomized, double-blind, placebo-controlled study using the dose selected in Part 1 to assess the efficacy and safety of itacitinib plus CS vs placebo plus CS (~246 patients stratified by cGVHD severity and randomized 1:1; Figure 1). Patients randomized to the placebo group will be permitted to cross over to the itacitinib group after completion of the primary analysis. The primary endpoint is overall response rate (proportion of patients with complete or partial response) at 6 months. Secondary endpoints include changes in symptom scores using health-related quality-of-life measures, additional efficacy outcomes, PK parameters, and clinical safety assessments (Table 1). Exploratory biomarker analyses will evaluate the effects of JAK inhibition on circulating inflammatory cells (ie, T-cell subsets, B cells, natural killer cells, cytokines) and biomarkers of GVHD in peripheral blood after transplant. Patients will remain on study for a total of 37 months, which includes treatment period, safety follow-up, and posttreatment GVHD follow-up, unless confirmed GVHD progression, start of a new GVHD therapy, or relapse/recurrence of underlying hematologic disease occurs earlier. Efficacy analyses will be performed on the intent-to-treat population; safety analyses will be conducted on all randomized patients who receive ≥1 dose of study drug. The PK-evaluable population will include all patients who receive ≥1 dose of study drug and provide ≥1 postdose plasma PK sample. Disclosures Morariu-Zamfir: Incyte Corporation: Employment. Bleam:Incyte Corporation: Employment. Yan:Incyte Corporation: Employment.

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