aGvHD

Management of patients with steroid-refractory acute graft-versus-host disease – treatment options and unmet clinical need

Of the patients that receive recommended first line treatment with systemic steroids for the treatment of acute graft-versus-host disease (aGvHD), around 35–50% develop steroid-refractory disease. The prognosis for these patients is poor, with high mortality rates, low quality of life, and an estimated 2-year survival below 20%.

A recent review by Florent Malard and colleagues evaluated both current and emerging treatment and management options for patients with steroid-refractory aGvHD (SR-aGvHD), and was recently published in Leukemia—below is a summary.1 

Treatment of SR-aGvHD

Despite the severity of SR-aGvHD, there is just one approved treatment for the condition, and a routine standard of care (SoC) is yet to be established. The lack of standardized endpoints and adequate trials dedicated to tackling SR-aGvHD are among the caveats in improving disease management. Most studies investigating SR-aGvHD are retrospective, single-arm studies which makes comparison of results difficult. Therefore, treatment decisions generally fall to the attending physician, and are largely based on personal experiences.

Despite the lack of SoC, efforts have been made to determine some uniformity in how SR-aGvHD is approached. Both the joint working group, established by the British Committee for Standards in Hematology and the British Society for Bone Marrow Transplantation, and the American Society for Blood and Marrow Transplantation (ASBMT) have developed guidelines for the treatment of SR-aGvHD based on critical literature reviews. These underline second- (Table 1) and third-line (Table 2) treatment options for aGvHD, and suggest that second-line treatments should be exhausted before moving on to a third-line therapy. Furthermore, the European Society for Blood and Marrow Transplantation (EBMT) – European Leukemia Net (ELN) consensus working group have generated recommendations on the treatment of aGvHD, which were presented at the first EBMT GvHD Summit. For a comprehensive summary of the updated EBMT-ELN guidelines on prophylaxis regimens and the management of post-transplant GvHD, click here.

Second-line treatments for aGvHD

Second-line treatments represent those that have been extensively investigated in the SR-aGvHD setting. Extracorporeal photopheresis (ECP) and anti-thymocyte globulin (ATG) are both used frequently for the treatment of SR-GvHD. ECP has proven particularly effective in skin, liver and gut GvHD involvement, but still requires confirmation in large double-blind clinical trials. The widespread use of ATG for the treatment of SR-aGvHD owes itself, in part, to the findings of the Minnesota study.2 The effectiveness of ATG, however, has since been questioned; appearing to initiate good preliminary responses without significantly impacting overall survival (OS). However, ongoing improvements in prophylaxis regimens have optimized the use of ATG, and it remains an essential treatment for SR-aGvHD.

Advances in knowledge of the pathological mediators of aGvHD has unearthed more specific treatment approaches. As key players in the pathophysiology of aGvHD, the IL-2 and tumor necrosis factor α (TNF-α) axes are rational targets for therapeutic intervention. In particular, monoclonal antibodies (mAbs) inhibiting TNF-α, or the α portion of the IL-2 receptor (IL-2Rα), as well as soluble TNF receptors, which is used to ‘mop up’ excess TNF-α, have demonstrated potent anti-inflammatory activity and are effective in treating patients with SR-aGvHD.

Table 1. Second-line treatment for patients with SR-aGvHD

Treatment

MoA/protocol

Response rate, %

Toxicity (%)

ECP

-Exposure of PBMCs to photoactivated 8-methoxypsoralen, followed by reinfusion of treated cells

-Immunosuppression of T cells

70–77

Infection (53)

Anemia (25)

Diarrhea (20)

Nausea (18)

ATG

-Depletion of T cells

-Induction of apoptosis in B-cell lineages

-Treg and NK cell activation

41–57

Fever and infection (≥ 80)

Anti-IL-2Rα mAbs

Inhibit activated T cells

 

 

Daclizumab

 

-Humanized

 

17–82

 

Infection (≤ 95)

 

Basiliximab

 

-Chimeric

 

71–92

 

-Any infections (0–65)

-CMV reactivation (0–29)

Inolimomab

-Murine

58–63

-No drug-related toxicity; infectious events (93)

TNF-α inhibitors

Dampen TNF-mediated inflammatory responses

Infliximab

-anti-TNF-α mAb

46–90

-Infection (90)

Etanercept

-soluble TNF receptor

28–55

-Infection (67–87)

mAb combinations

Etanercept plus

basiliximab

Dampen inflammatory responses and inhibit T-cell activation

91

-Cytopenia (49; Grade III/IV, 32)

-Hemorrhagic cystitis (28)

-Invasive pulmonary fungal infection

(36)

-CMV reactivation (57)

-EBV reactivation (6)

ATG, antithymocyte globulin; CMV, cytomegalovirus; EBV, Epstein-Barr virus; ECP extracorporeal photopheresis; IL, interleukin; IL-2Rα, α chain of IL-2 receptor; mAb, monoclonal antibody; MoA, mechanism of action; PBMC, peripheral blood mononuclear cell; SR-aGvHD, steroid-resistant acute graft-versus-host disease; TNF-α, tumor necrosis factor α; Tregs, regulatory T cells

Third-line treatments for aGvHD

Should a patient be irresponsive to second-line treatment, there are a number of alternative therapeutic approaches. Despite being less well investigated, certain third-line treatments such as mesenchymal stem cells (MSCs) and methotrexate appear especially promising and have demonstrated favorable outcomes in patients with SR-aGvHD. The anti-CD52 receptor mAb, alemtuzumab, and the chemotherapeutic, pentostatin are amongst other third-line treatments under investigation.

Two studies in particular have highlighted the potential of methotrexate for the treatment of SR-aGvHD; a retrospective study of low dose methotrexate, and a pooled data analysis, both of which found methotrexate to be tolerable in the dosing schedules employed. The pooled data suggested the prospective use of methotrexate for SR-aGvHD, but randomized controlled studies are imperative for drawing final conclusions.

As for the use of MSCs, the GvHD Hub presented results from an analysis carried out across 17 EBMT centers, which highlighted inconsistencies in the manufacture of MSCs. Despite these discrepancies, a number of clinical trials have reported the effectiveness of MSC-based treatment. A summary of the results presented by Peter Bader at 60th American Society of Hematology (ASH) Annual Meeting & Exposition outlines the success of a novel MSC manufacturing protocol (MSC-FFM) and improved outcomes for patients with SR-aGvHD in response to MSC-therapy. The GvHD Hub also held an interview with Prof Bader on the topic, which can be viewed here. Encouragingly, MSCs stand as a promising approach to tackling SR-aGvHD in pediatric patients. The MSC-based treatment, remestemcel-L, for example, has recently shown to be safe and effective in pediatric patients with high-risk SR-aGvHD, read the GvHD Hub coverage of the phase III study here.

Table 2. Third-line treatment for patients with SR-aGvHD

Treatment

MoA

Response rate, %

Toxicity (%)

MSC

-Multipotent progenitor cells

-Immunomodulatory activity of IL-10

50–83

Acute transient nausea/vomiting and

blurred vision during infusion (4)

Methotrexate

Inhibits dihydrofolate reductase and production of

thymidylate and purines; suppresses T-cell response,

proliferation, and expression of adhesion molecules

58–70

-Grade III/IV hematologic toxicity (42)

-Grade III elevation of transaminases (4)

IL-10, interleukin 10; MoA, mechanism of action; MSC mesenchymal stem cell

Novel therapies under investigation

Immense efforts are underway to tackle the unmet needs in SR-aGvHD, and novel therapeutic targets and treatments are continually emerging (Table 3).

Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) activation is closely linked with aGvHD pathogenesis and progression. The orally bioavailable JAK1/2 inhibitor, ruxolitinib, has demonstrated high specificity and potent anti-inflammatory and immunosuppressive effects in pre-clinical studies. The agent acts to alleviate aGvHD by targeting a number of stages in the pathogenic pathway, including the activation of natural killer (NK) cells, dendritic cells, T helper, and regulatory T cells (Tregs). Ruxolitinib has been approved by the US Food and Drug Administration (FDA) for the treatment of SR-aGvHD, and further clinical trials are underway in attempt to optimize ruxolitinib for the application. Importantly, data from the phase III, REACH2 trial (NCT02913261), comparing ruxolitinib with best available treatment for SR-aGvHD showed that ruxolitinib treatment resulted in significant improvements in efficacy outcomes, making it a promising emerging therapeutic for the treatment of SR-aGvHD.3

Fecal microbiota transplant (FMT) is the process of fecal infusion from a healthy donor into a patient’s gastrointestinal (GI) tract, with the aim to re-establish a healthy gut microbiota. Growing evidence emphasizes the role of the gastrointestinal microbiome as an immune mediator, and perturbed GI microbiota balance has been strongly associated with augmented aGvHD symptoms.4 Although studies investigating FMT have involved relatively low patient cohort sizes, it has induced improvement in patient outcomes in up to 100% of cases (Table 3).

Ruxolitinib and FMT are currently the front-runners in innovative approaches to treating patients with SR-aGvHD. There are, however, a number of alternative therapeutic strategies that have demonstrated promising early outcomes such as α1-Antitrypsin (AAT), the anti-α4β7 mAb, vedolizumab, and a therapeutic consisting of two immunotoxins; antibodies against CD3 and CD7, separately conjugated to recombinant ricin A.

Table 3. Novel treatments under investigation for the application to SR-aGvHD1

Treatment

MoA

Response rate, %

Toxicity (%)

Clinical studies

Ruxolitinib

-JAK1/JAK2 inhibitor

-Immunosuppression

-Anti-inflammatory

45–82

-Anemia (60)

-Hypokalemia (48)

-Decreased platelet count (44)

-Peripheral edema (44)

-Decreased neutrophil count (37)

-Cytomegalovirus (13)

-Viremia (6)

-Chorioretinitis (1)

NCT02953678

NCT02913261

NCT02396628

FMT

Infusing of fecal suspension from a healthy donor into a patient’s GI tract

100

Abdominal pain and diarrhea (100)

NCT03148743

NCT03812705

NCT03359980

NCT03214289

AAT

-Downmodulates inflammation

-Increases Treg:Teff

65

-Infections (33)

-Bacteremia (13)

-CMV reactivation (5)

NCT03172455

Anti-CD3/CD7 immunotoxin

-Depletion of T and NK cells

-Suppression of TCR activation

60

-Worsening of hypoalbuminemia (10), microangiopathy (10), and thrombocytopenia (45)

-Bacteremia (25)

-CMV reactivation (15)

-EBV reactivation (15)

NCT04128319

Vedolizumab

 

-mAb to α4β7 integrin

-Inhibits lymphocyte migration to the GI tract

40–100

In ≥ 3 patients (300mg; 600mg):

-Anemia (50; 33)

-Nausea (38; 0)

-Peripheral edema (38; 33)

-Hypokalemia (38; 56)

-Hyperglycemia (38; 22)

-Hypoalbuminemia (25; 33)

-Dizziness (13; 33)

-Hypomagnesemia (13; 33)

-Neutropenia (13; 33)

-Fatigue (0; 33)

Serious infections, ≥ 2 patients:

 -Sepsis (25; 11)

NA

AAT, α1-antitrypsin; CMV cytomegalovirus; EBV, Epstein-Barr virus; FMT, fecal microbiota transplant; GI, gastrointestinal; IL, interleukin; JAK, Janus kinase; MoA, mode of action; mAb, monoclonal antibody NA, not applicable; NK, natural killer; TCR, T cell receptor; Teff, effector T cell; TNF-α, tumor necrosis factor α; Treg, regulatory T cell

Other treatment options that have been trialed in patients with SR-aGvHD include the anti-CD30 mAb, brentuximab vedotin, and the anti-CD26 mAb, begelomab, but studies evaluating these agents have since been terminated.

Conclusion

Identifying safe and effective treatment options for patients with SR-aGvHD will become more and more important with increasing numbers of patients being transplanted. Significant progress has been made towards establishing effective treatment options for patients with SR-aGvHD. Second- and third-line therapies are being successfully employed for the treatment of the condition. A major downfall is the lack of routine guidelines for the treatment of patients with steroid-refractory disease.

However, more evidence is building for targeted treatment modalities such as JAK inhibition, IL-2 and TNF-α inhibition, AAT, the anti-α4β7 mAb. All things considered, increasing understanding of the pathogenesis of GvHD is leading the way to future therapies, providing more effective and less toxic options for this condition with a high unmet medical need.

References
  1. Malard F, Huang XJ, Sim JPY. Treatment and unmet needs in steroid-refractory acute graft-versus-host disease. Leukemia. 2020;34(5):1229-1240. DOI: 10.1038/s41375-020-0804-2

  2. Dugan MJ, DeFor TE, Steinbuch M, Filipovich AH, Weisdorf DJ. ATG plus corticosteroid therapy for acute graft-versus-host disease: predictors of response and survival. Ann Hematol. 1997;75(1-2):41-46. DOI: 10.1007/s002770050310

  3. Abedin SM, Hamadani M. Ruxolitinib: a potential treatment for corticosteroid refractory acute graft-versus-host disease. Expert Opin Investig Drugs. 2020;19:1-5. DOI: 10.1080/13543784.2020.1757069

  4. Shouval R, Geva M, Nagler A, Youngster I. Fecal Microbiota Transplantation for Treatment of Acute Graft-versus-Host Disease. Clin Hematol Int. 2019;1(1):28-35. DOI: 10.2991/chi.d.190316.002

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