Organ-specific response after low-dose interleukin-2 therapy for steroid-refractory chronic graft-versus-host disease

Kim, Haesook T.; Koreth, John; Whangbo, Jennifer; Nikiforow, Sarah; Reynolds, Carol; Stowe, Peter; Ho, Vincent T.; Cutler, Corey; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jérôme

doi:10.1182/bloodadvances.2022007773

Cited by 11 publications

(12 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we are encouraged by our collective pediatric data, which now includes 24 pediatric patients with multiple years of follow-up, it has become increasingly difficult to obtain insurance approval for LD IL-2 because new small molecules have achieved FDA approval for second-line therapy of cGVHD. While our results reflect only single-center experience, LD IL-2 has consistently been shown as a safe and effective therapy with 105 adult and 11 pediatric patients 29 treated across 5 clinical trials with efficacy at least on par with the FDA-approved agents. It is our hope that a Children’s Oncology Group–sponsored trial of LD IL-2 for refractory cGVHD in children, currently in development (Carrie Kitko, personal communication, 30 March 2023), can help to establish efficacy in a multicenter setting and subsequently advance the approval status of LD IL-2 for this indication.…”

Section: Discussionmentioning

confidence: 64%

Real-world experience with low-dose IL-2 for children and young adults with refractory chronic graft-versus-host disease

et al. 2023

Self Cite

View full text Add to dashboard Cite

The majority of patients with chronic graft-vs-host disease are steroid refractory (SR-cGVHD), creating a need for safe and effective therapies. Subcutaneous low-dose interleukin-2 (LD IL-2), which preferentially expands CD4+ regulatory T cells (Treg), has been evaluated in 5 clinical trials at our center with partial responses (PR) in ~50% of adults and 82% of children by week 8. We now report additional real-world experience with LD IL-2 in 15 children and young adults. We conducted a retrospective chart review of patients with SR-cGVHD at our center who received LD IL-2 from August, 2016 to July, 2022 not on a research trial. The median age at start of LD IL-2 was 10.4 years (range 1.2, 23.2) at a median of 234 days from cGVHD diagnosis (range 11, 542). Patients had median 2.5 (range 1, 3) active organs at LD IL-2 start and received median 3 (range 1, 5) prior therapies. The median duration of LD IL-2 therapy was 462 days (range 8, 1489). Most patients received 1 × 106 IU/m2/day. There were no serious adverse effects. The overall response rate in 13 patients who received >4 weeks of therapy was 85% (5 complete response, 6 PR) with responses in diverse organs. Most patients significantly weaned corticosteroids. Treg preferentially expanded with a median peak fold increase in Treg:CD4+ conventional T cell ratio of 2.8 (range 2.0, 19.8) by 8 weeks on therapy. LD IL-2 is a well-tolerated, steroid-sparing agent with a high response rate in children and young adults with SR-cGVHD.

show abstract

Section: Discussionmentioning

confidence: 64%

Real-world experience with low-dose IL-2 for children and young adults with refractory chronic graft-versus-host disease

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…From 2007 through 2017, one hundred twenty-three adult patients and eleven pediatric patients with SR-cGVHD were enrolled on five IL-2 clinical trials at our institution ( 17 ). Fourteen patients were not evaluable for response and were excluded from further analyses.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that overall Treg expansion and Treg phenotypes are similar between LD IL-2 responders and non-responders ( 18 ). A more recent organ-specific analysis of clinical and immune correlates of response to LD IL-2 in adult patients identify some early predictors of response such as higher Treg/Tcon ratio and lower terminal effector memory T cell counts within the first 4 weeks of therapy ( 17 ), but markers of continued response or disease progression during extended therapy have not been identified. Thus, predictive biomarkers to guide treatment duration for LD IL-2 and other second-line therapies remains an area of unmet need.…”

Section: Discussionmentioning

confidence: 99%

Durability of clinical and immunologic responses to extended low-dose interleukin-2 therapy in patients with refractory chronic graft-versus-host disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

Chronic graft-versus-host disease (cGVHD) remains a frequent cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. In our single center trials of low-dose interleukin-2 (LD IL-2), the immunomodulatory properties of regulatory T cells (Tregs) have been harnessed to treat steroid-refractory cGVHD (SR-cGVHD) safely and effectively in adults and children. In these trials, 50-60% of patients showed clinical improvement of their cGVHD manifestations with partial responses at the primary response endpoint of 8-12 weeks. Many patients continued extended duration LD IL-2 therapy and achieved deeper clinical responses, including some complete responses. However, the durability of the clinical and immunologic improvement following IL-2 discontinuation has not been reported previously. We examined 20 adult and 2 pediatric patients who received extended duration LD IL-2 for a median of 103 weeks (range, 21-258) and had stable improvement or resolution of their cGVHD symptoms before discontinuing LD IL-2 therapy. The median follow-up after stopping IL-2 was 203 weeks (range 92-599). During this time, 16 patients (73%) were able to wean off all systemic immunosuppression without disease flare or progression. Among 13 patients with available immune cell data, the median fold change in absolute Treg count was 0.58 between 1 to 10 weeks after stopping IL-2 whereas CD4+ conventional T-cell (Tcon) and CD8+ T-cell numbers remained stable. Despite a decline in Treg numbers after IL-2 discontinuation, Treg numbers remained above the pre-treatment baseline. In addition, many patients had sustained clinical improvement after stopping IL-2, suggesting that extended IL-2 therapy can lead to immune tolerance.

show abstract

“…Among 105 evaluated patients ORR was 48.6% and 53.3% at 8 and 12 weeks, respectively. Reported organ-specific response was highest in liver (66.7%), gastrointestinal tract (62.5%), skin (36.4%), joint/muscle/fascia (34.2%), and lung (19.2%) [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease

Kovalenko,

Saleem,

Shah

et al. 2023

Advances in Hematology

View full text Add to dashboard Cite

Background. Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplant. The mainstay of treatment is corticosteroids, which are ineffective in 30–50% of cases. Steroid-refractory GVHD (SR-GVHD) confers a poor prognosis, with high mortality rates despite appropriate therapy. While there is no reliable treatment for SR-GVHD, a variety of novel therapeutic options are slowly emerging and have yet to be examined simultaneously. Objectives. This review evaluates the potential of novel therapeutic options, as well as their efficacy and safety, for the treatment of SR-GVHD. Study Design. The literature search was conducted in PubMed, Cochrane, and Embase, employing MeSH terms and keywords. The studies had to be prospective phases 1, 2, or 3. We excluded retrospective and nonoriginal studies. Results. While the only approved drug for acute GVHD is ruxolitinib with an impressive overall response rate of 73.2% and a complete response of 56.3%, several monoclonal antibodies and other agents are currently under investigation, offering promising results. These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin. However, the toxicities associated with these novel drugs need further investigation. For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. Conclusion. While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future.

show abstract

Organ-specific response after low-dose interleukin-2 therapy for steroid-refractory chronic graft-versus-host disease

Cited by 11 publications

References 33 publications

Real-world experience with low-dose IL-2 for children and young adults with refractory chronic graft-versus-host disease

Real-world experience with low-dose IL-2 for children and young adults with refractory chronic graft-versus-host disease

Durability of clinical and immunologic responses to extended low-dose interleukin-2 therapy in patients with refractory chronic graft-versus-host disease

Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease

Contact Info

Product

Resources

About