Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

Dubovsky, Jason A.; Flynn, Ryan; Du, Jing; Harrington, Bonnie K.; Zhong, Yun‐Shi; Kaffenberger, Benjamin H.; Yang, Carrie; Towns, William H.; Lehman, Amy; Johnson, Amy J.; Muthusamy, Natarajan; Devine, Steven M.; Jaglowski, Samantha; Serody, Jonathan S.; Murphy, William J.; Munn, David H.; Luznik, Leo; Hill, Geoffrey R.; Wong, Henry K.; MacDonald, Kelli P. A.; Maillard, Ivan; Koreth, John; Elias, Laurence; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jérôme; Panoskaltsis‐Mortari, Angela; Byrd, John C.; Blazar, Bruce R.

doi:10.1172/jci75328

Cited by 171 publications

(150 citation statements)

References 63 publications

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“…Furthermore, prolonged administration of ibrutinib ameliorated cGvHD in two complementary murine models: a model interrogating T cell-driven sclerodermatous cGvHD and an antibody-driven model that induces bronchiolar obliterans. 30 Another murine model showed similar results. 31 Finally, a phase I/II trial (NCT 02195869) evaluating ibrutinib for the treatment of steroid-dependent/refractory chronic GvHD showed good tolerability and promising efficacy in the phase I part.…”

Section: Discussionmentioning

confidence: 74%

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

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Teipel

Heidenreich

et al. 2016

Bone Marrow Transplant

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Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cellmediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

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Section: Discussionmentioning

confidence: 74%

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

Link

Teipel

Heidenreich

et al. 2016

Bone Marrow Transplant

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“…Inducible caspase 9 (iC9) suicide gene expressing T cells have been used to decrease incidence of GVHD and improve immune reconstitution and has shown promising results [168]. Various other agents, including ibrutinib [169], are being explored in different stages of development at this time.…”

Section: Future Directionsmentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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owing to the advancement in reduced intensity conditioning (RIC) and in patients without HLA-matched donors due to the use of cord blood and haploidentical HSCT [4][5][6]. Although marked improvement has been made in supportive care, immunosuppressive therapy and DNA-based Human Leukocyte Antigen (HLA) typing, graft vs host disease (GVHD) remains a major cause of morbidity and non-relapse mortality among allogeneic HSCT recipients. It was first described by Billingham in 1966 as a syndrome where immunocompetent T cells from the donor recognize and damage the host tissue in an immunocompromised recipient. It presents with heterogeneous symptoms involving multiple organ systems including gastrointestinal tract, skin, mucosa, liver and lungs [7]. In the past clinical features occurring within 100 days after HSCT was called acute GVHD (aGVHD) and those happening after 100 days were labeled chronic GVHD (cGVHD) [8,9]. This definition was rather unsatisfactory thus National Institute of Health (NIH) consensus criteria were developed and have been revised. The criteria have added new categories such as late-onset aGVHD (acute GVHD occurring after 100 days) and overlap syndrome which includes features of both acute and chronic GVHD to the classification, and also have introduced new definitions for organ system involvement [10][11][12]. The categorization of acute vs chronic GVHD is based on the combination of clinical symptoms rather than the time of onset. Depending upon a number of variables associated with patients, donors, and types of transplant, the incidence of aGVHD varies with incidence of grade II-IV GVHD at 40 % in matched related donor (MRD) transplant to 50 % in MUD transplant. The main risk factors for aGVHD include degree of HLA mismatch, age of the patient, previous all immunization of the donor and the kind of GVHD prophylaxis used. About 30-70 % of allogeneic HSCT recipients alive after 100 days will Abstract Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

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“…The emerging work suggests that murine models, which individually can recreate certain spectra of tissue pathology and immunopathology associated with GVHD, can be used to test efficacy and decipher the mechanisms of novel pharmacologic agents. 4,5 Previous reports demonstrate the importance of germinal center (GC) maintenance by T follicular helper (TFH) cells. 4,6,7 This specialized T-cell subset expresses the transcriptional regulator B-cell lymphoma 6 (Bcl6), which is negatively regulated by signal transducer and activator of transcription 5 (Stat5) activation.…”

Section: Introductionmentioning

confidence: 99%

Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism

Flynn

Paz

et al. 2016

Blood

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161

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• The ROCK2 inhibitor, KD025, decreases chronic GVHD pathology in multiple murine models.• KD025 inhibits STAT3 phosphorylation to decrease RORgt and Bcl6 expression in both murine and human cells.Chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic bone marrow transplantation (BMT). The discovery of novel therapeutics is dependent on assessment in preclinical murine models of cGVHD. Rho-associated kinase 2 (ROCK2) recently was shown to be implicated in regulation of interleukin-21 (IL-21) and IL-17 secretion in mice and humans. Here, we report that the selective ROCK2 inhibitor KD025 effectively ameliorates cGVHD in multiple models: a full major histocompatibility complex (MHC) mismatch model of multiorgan system cGVHD with bronchiolitis obliterans syndrome and a minor MHC mismatch model of sclerodermatous GVHD. Treatment with KD025 resulted in normalization of pathogenic pulmonary function, which correlates with a marked reduction of antibody and collagen deposition in the lungs of treated mice to levels comparable to non-cGVHD controls. Spleens of mice treated with KD025 had decreased frequency of T follicular helper cells and increased frequency of T follicular regulatory cells, accompanied by a reduction in signal transducer and activator of transcription 3 (STAT3) and concurrent increase in STAT5 phosphorylation. The critical role of STAT3 in this cGVHD model was confirmed by data showing that mice transplanted with inducible STAT3-deficient T cells had pulmonary function comparable to the healthy negative controls. The therapeutic potential of targeted ROCK2 inhibition in the clinic was solidified further by human data demonstrating the KD025 inhibits the secretion of IL-21, IL-17, and interferon g along with decreasing phosphorylated STAT3 and reduced protein expression of interferon regulatory factor 4 and B-cell lymphoma 6 (BCL6) in human peripheral blood mononuclear cells purified from active cGVHD patients. Together these data highlight the potential of targeted ROCK2 inhibition for clinical cGVHD therapy. (Blood. 2016; 127(17):2144-2154

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Ibrutinib treatment ameliorates murine chronic graft-versus-host disease

Cited by 171 publications

References 63 publications

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

State-of-the-art acute and chronic GVHD treatment

Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism

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