Home | About IJMPO | Editorial board | Search | Ahead of print | Current Issue | Archives | Instructions | Subscribe | Advertise | Contact us |  Login 
Indian Journal of Medical and Paediatric Oncology
Search Article 
  
Advanced search 
 

 Table of Contents      
REPORT ON INTERNATIONAL PUBLICATION
Year : 2020  |  Volume : 41  |  Issue : 5  |  Page : 733-734  

Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease: A giant leap -To start with baby steps


Department of Clinical Haematology and Stem Cell Transplantation, Dayanand Medical College, Ludhiana, Punjab, India

Date of Submission03-Jun-2020
Date of Decision30-Jun-2020
Date of Acceptance03-Jul-2020
Date of Web Publication29-Oct-2020

Correspondence Address:
Dr. Suvir Singh
Department of Clinical Haematology and Stem Cell Transplantation, Dayanand Medical College, Basement, Cancer Building, Ludhiana - 141 001, Punjab
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmpo.ijmpo_275_20

Rights and Permissions

How to cite this article:
Singh S. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease: A giant leap -To start with baby steps. Indian J Med Paediatr Oncol 2020;41:733-4

How to cite this URL:
Singh S. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease: A giant leap -To start with baby steps. Indian J Med Paediatr Oncol [serial online] 2020 [cited 2020 Nov 28];41:733-4. Available from: https://www.ijmpo.org/text.asp?2020/41/5/733/299555

The study by Zeiser et al. published in the New England Journal of Medicine represents a significant landmark as the first major randomized controlled trial for patients with steroid-refractory-acute graft-versus-host disease (SR-aGVHD).[1] This randomized Phase 3 trial compared ruxolitinib with other available treatment options for SR-aGVHD and found significantly better responses at 28 days and 56 days post transplant. Even with a plethora of options available for second-line treatment of aGVHD, the lack of efficacy data has precluded the recommendation of a preferred second-line agent. Most studies have cited that overlapping response rates, cost, toxicity, and availability in the market are the major factors in choosing the treatment for SR-aGVHD.[2] This study represents the first step in filling these lacunae and in improving our understanding of treating SR-aGVHD.

However, this study raises two important questions, which have to be answered before we can truly endorse ruxolitinib as the de facto option for SR-aGVHD.

First, the heterogeneity in the control arm may falsely amplify the benefit noted with ruxolitinib. The options included in this arm have variable response rates and time to onset of maximal action, making it difficult to standardize this group. In observational studies, many agents used in the control arm have response rates comparable to those seen with ruxolitinib in the present study. For instance, studies with interleukin-2 inhibitors, such as basiliximab and daclizumab, have reported response rates above 60%.[3],[4] Similar responses have been noted with methotrexate and etanercept.[5] This is much higher than the overall response rates (39%) noted in the control arm of this study. In addition, mycophenolate mofetil has not shown any benefit when added to steroids for treating aGVHD, that led to the early closure of the randomized BMT CTN0802 trial due to futility.[6]

Second, the use of ruxolitinib in this setting may be inundated with unavoidable pharmacokinetic variables. The presence of diarrhea in GVHD is associated with malabsorption of food and oral drugs.[7] As initial dose finding studies with ruxolitinib have included predominantly Caucasian populations, variability in absorption and metabolism may conceal its true efficacy and toxicity.[8] Ruxolitinib is metabolized by the CYP3A4 enzymes, and over 70% of its efficacy is attributable to active metabolites. CYP3A4 enzyme activity has been noted to vary with ethnicity and may lead to varying drug effects in different populations.[9]

Many treatment modalities for SR-aGVHD, including mesenchymal stem cells, extracorporeal photopheresis, and anti-thymocyte globulin, are beset with formidable toxicity and costs. For ruxolitinib to truly emerge as an evidence-based first-line option for SR-aGVHD, we will need to look at subgroup analyses and comparison with individual second-line modalities. In addition, indigenous pharmacokinetic studies will be vital to assess the absorption and metabolism of this drug in different ethnic populations.

The REACH2 trial is an important landmark. While discussing the same with patients and families, it may help us to highlight ruxolitinib as a new treatment option with comparable or superior efficacy and manageable toxicity. This in itself is a giant leap in this field.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med 2020;382:1800-10.  Back to cited text no. 1
    
2.
Malard F, Huang XJ, Sim JPY. Treatment and unmet needs in steroid-refractory acute graft-versus-host disease. Leukemia 2020;34:1229-40.  Back to cited text no. 2
    
3.
Schmidt-Hieber M, Fietz T, Knauf W, Uharek L, Hopfenmüller W, Thiel E, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol 2005;130:568-74.  Back to cited text no. 3
    
4.
Bordigoni P, Dimicoli S, Clement L, Baumann C, Salmon A, Witz F, et al. Daclizumab, an efficient treatment for steroid-refractory acute graft-versus-host disease. Br J Haematol 2006;135:382-5.  Back to cited text no. 4
    
5.
Nassar A, Elgohary G, Elhassan T, Nurgat Z, Mohamed SY, Aljurf M. Methotrexate for the treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. J Transplant 2014;2014:980301.  Back to cited text no. 5
    
6.
Bolaños-Meade J, Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood 2014;124:3221-7.  Back to cited text no. 6
    
7.
van der Meij BS, Wierdsma NJ, Janssen JJ, Deutz NE, Visser OJ. If the gut works, use it! But does the gut work in gastrointestinal GvHD? Bone Marrow Transplant 2017;52:466-9.  Back to cited text no. 7
    
8.
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: Results of a median 2-year follow-up of COMFORT-I. Haematologica 2013;98:1865-71.  Back to cited text no. 8
    
9.
Guttman Y, Nudel A, Kerem Z. Polymorphism in cytochrome P450 3A4 is ethnicity related. Front Genet 2019;10:224.  Back to cited text no. 9
    




 

Top
 
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
   References

 Article Access Statistics
    Viewed121    
    Printed0    
    Emailed0    
    PDF Downloaded16    
    Comments [Add]    

Recommend this journal