GVHD treatment with extracorporeal photopheresis in Brazil: a national survey

Graft-versus-host disease (GVHD) is a common complication after HCT, impacting on overall survival and quality of life.¹,² There are few effective treatments for steroid-refractory/ dependent acute and chronic GVHD. A treatment option for acute and chronic GVHD is extracorporeal photopheresis (ECP).³,⁴ An advantage of ECP is its low toxicity, especially in frail patients and those with uncontrolled infections, in whom systemic immunosuppressive therapy may be deleterious. Nevertheless, ECP shortfalls include requirement of a venous central line in many patients, limited access as it is only available in specialized centers, need for frequent visits, and cost. While in Brazil ECP has been approved by the Brazilian Health Regulatory Agency (ANVISA), the procedure still has to be incorporated by the National Committee for Health Technology Incorporation (CONITEC) into the public system and the National Agency of Supplementary Health (ANS) into the private setting. For this reason, the reimbursement of ECP to health facilities is not mandatory and ultimately depends on the judgment of local hospitals and insurance companies.

To understand the landscape of ECP as second line therapy or beyond for GVHD in Brazil, we sent a survey invitation to HCT centers via the Brazilian Society of Bone Marrow Transplantation and Cell Therapy (SBTMO) in May 2020. The survey was available on the platform SurveyMonkey and remained open from May 7^th to June 17^th, 2020.

Of the 78 centers contacted, 28 responded, corresponding to 27 HCT centers authorized to carry out allogeneic HCT and one ambulatory service that offered treatment with ECP. The 27 transplant centers represented 56% of those performing allogeneic HCTs in 2019.⁵ Of the 27 centers,15 were private services. Among the responding centers, 14 of 27 (51%) had performed at least one ECP procedure for GVHD since the beginning of their HCT program. Six of these 14 centers (43%) started using ECP before 2010 while the remaining after 2011. Most procedures took place at services with a volume > 20 allogeneic HCTs/year.

The total number of patients treated with ECP was 215, with 120 (56%) having received this treatment in the last five years. We estimate that this figure represents only 12% of patients (out of 999) requiring second line therapy or beyond for GVHD at the responding centers in the last five years. Approximately, half of the patients were treated at three public academic centers, and 69% were treated with ECP for steroid-refractory/dependent chronic GVHD while the remaining were treated for acute GVHD. Regarding funding sources, the Brazilian public health system (SUS, Sistema Unico de Saude) reimbursed 55% of the ECP procedures, while private health insurance companies 37%. The coverage for the cost of ECP treatment was only achieved via litigation in 32% of patients (Figure 1).

Figure 1
ECP reimbursement sources

Twenty-one of the 27 centers (78%) reported difficulty in performing ECP (more than one may apply): unavailable equipment to deliver ECP (n=12), lack of funding (n=11), unavailable apheresis kits (n=11), lack of expertise (n=2), catheter-related infectious complications (n=1) and distance from the nearest HCT center with ECP (n=1).

By using data from Associação Brasileira de Transplante de Orgaos (ABTO),⁵ the Brazilian Bone Marrow Transplantation Registry/CIBMTR and the literature,⁶,⁷ we estimate that 895 and 613 patients with acute and chronic GVHD, respectively, required second line therapy or beyond in Brazil from 2015 to 2019. These patients could have potentially benefitted from ECP in case the procedure were more easily available.

This survey shows that ECP has been used in many Brazilian HCT centers for treatment of acute and chronic GVHD despite barriers to equipment/supply acquisition, procedure reimbursement and access. Similar challenges to incorporate ECP into national health systems have been reported in other countries.⁸ Most procedures were performed at public health care entities, mainly three academic centers. These centers had a structured long term follow-up service with a considerable number of patients with GVHD and approval of reimbursement of ECP by the local hospital budget. Economic analyses have demonstrated that ECP may deliver greater benefit as second-line therapy for GVHD at a lower cost in a 4 to 5-year timeframe compared to mycophenolate, pentosta-tin, imatinib, and rituximab.⁸,⁹ These results led to the approval of reimbursement for ECP by health systems in many countries.¹⁰ However, in Brazil efforts are still needed towards improving access to ECP to treat patients with GVHD by having such a therapy reimbursed in the public and private health systems.

The treatment of steroid-refractory/dependent acute and chronic GVHD has been a dynamic field in recent years. Ibruti-nib was the first drug approved by FDA for patients with chronic GVHD failing at least one line of therapy. The approval was based on the results of a phase 1b/2, open-label, multicenter study showing a best overall response rate of 67%.¹¹ Ruxolitinib has recently emerged as the therapeutic agent for chronic GVHD with best evidence to date based on the phase 3 REACH3 trial (chronic GVHD), showing superior overall responses compared to other standard of care therapies, including ECP.¹² A recent American analysis found ECP was more cost-effective than ruxolitinib and ibrutinib for chronic GVHD.¹³ In Brazil, a 6-month estimate of direct costs of ECP to treat an adult patient with chronic GVHD is US$ 50,000 (Therakos^R Cellex^R, 28 sessions) vs. US$67,200 for ibrutinib (420mg QD) and US$ 35,000 for ruxolitinib (10 mg BID). A formal cost-effectiveness analysis between these therapies is warranted and has to consider indirect costs with personnel, other medical supplies, facility costs and therapy-related complications. Regardless its relative overall efficacy and cost-effectiveness, it is noteworthy to point out that ECP is less immunosuppressive and myelotoxic than other systemic treatments for chronic GVHD, and thus especially interesting for the treatment of patients with active uncontrolled infection, particularly viral, or significant cytopenias. ECP might also prove to be as efficacious or superior to ruxolitinib and ibrutinib for certain involved organs (e.g., skin), which will be better appreciated once the final results of REACH3 (NCT03112603) and iNTEGRATE (NCT02959944) are published.

This report has several limitations. Only a little over half of the active Brazilian centers licensed to perform allogeneic HCT answered the survey, yet nearly all larger centers, which are the ones more likely to offer ECP, are included. The distinction between acute vs. chronic GVHD was not centrally adjudicated, which may lead to inconsistencies. Neither did we have access to individual patient data, preventing further analyses on efficacy and safety of ECP in Brazil.

In conclusion, despite the rapidly changing landscape in the treatment of GVHD, ECP is still an effective therapy for some patients with good level of evidence and may be the only option for frail patients. There are significant hindrances to a wider use of this therapy in Brazil, mainly reimbursement related. We suggest a collaborative effort to generate data about efficacy and cost-effectiveness of ECP for GVHD in Brazil, supporting governmental agencies in making an evidence-based decision on whether the access to this procedure should be expanded.

Acknowledgments

We thank Afonso Vigorito, Andresa Melo, Antonio Macedo, Celso Rodrigues, Celso Massumoto, Fabio Kerbauy, Fernando Barroso, Gustavo Machado Teixeira, Jaqueline Sapelli, Jayr Schmidt, João Feliciano, Juliana Folloni, Renato Cunha, Ricardo Chiattone, Rodolfo Soares, Roselene Passos, Victor Zechin and Virgilio Colturato for contributing with data from their centers for this study.

REFERENCES

• ¹
  Arora M, Cutler CS, Jagasia MH, Pidala J, Chai X, Martin PJ, et al. Late acute and chronic graft-versus-host disease after alloge-neic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(3):449–55.
• ²
  Fatobene G, Storer BE, Salit RB, Lee SJ, Martin PJ, Cheng GS, et al. Disability related to chronic graft-versus-host disease after alternative donor hematopoietic cell transplantation. Haematologica. 2019;104(4):835–43.
• ³
  Greinix HT, Worel N, Just U, Knobler R. Extracorporeal photo-pheresis in acute and chronic graft-versus-host disease. Transfus Apher Sci. 2014;50(3):349-57.
• ⁴
  Flowers ME, Apperley JF, van Besien K, Elmaagacli A, Grigg A, Reddy V, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. 2008;112(7):2667–74.
• ⁵
  Registro Brasileiro de Transplante - RBT. Dimensionamento dos Transplantes no Brasil e em cada estado (2012-2019). Veic Of da Assoc Bras Transpl Orgaos - ABTO. 2019;XXV(4):1–88.
• ⁶
  Axt L, Naumann A, Toennies J, Haen SP, Vogel W, Schneida-wind D, et al. Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2019;54(11):1805–14.
• ⁷
  Westin JR, Saliba RM, De Lima M, et al. Steroid-refractory acute GVHD: predictors and outcomes. Adv Hematol. 2011;2011:1–8.
• ⁸
  de Waure C, Capri S, Veneziano MA, Specchia ML, Cadeddu C, Di Nardo F, et al. Extracorporeal photopheresis for second-line treatment of chronic graft-versus-host diseases: results from a health technology assessment in Italy. Value Heal. 2015;18 (4):457–66.
• ⁹
  Crespo C, Pérez-Simón JA, Rodríguez JM, Sierra J, Brosa M. Development of a population-based cost-effectiveness model of chronic graft-versus-host disease in Spain. Clin Ther. 2012;34(8):1774–87.
• ¹⁰
  Drexler B, Buser A, Infanti L, Stehle G, Halter J, Holbro A. Extracorporeal photopheresis in graft-versus-host disease. Transfus Med Hemotherapy. 2020;47(3):214–25.
• ¹¹
  Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243–50.
• ¹²
  Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Flowers ME, et al. Ruxolitinib (RUX) Vs best available therapy (BAT) in patients with steroid-refractory/steroid-dependent Chronic Graft-Vs-Host Disease (cGVHD): primary findings from the phase 3, randomized REACH3 study. Blood. 2020;136(Supplement 1):22–4.
• ¹³
  Yalniz FF, Murad MH, Lee SJ, Pavletic SZ, Khera N, Shah ND, et al. Steroid refractory chronic graft-versus-host disease: cost-effectiveness analysis. Biol Blood Marrow Transplant. 2018;24(9):1920–7.

Publication Dates

• Publication in this collection
  10 Oct 2022
• Date of issue
  Jul-Sep 2022

History

• Received
  09 Nov 2021
• Accepted
  19 Nov 2021
• Published
  25 Jan 2022