Using Extracorporeal Photopheresis in the Treatment of Graft-Versus-Host Disease

Publication
Article
Oncology & Biotech NewsJune 2011
Volume 5
Issue 6

Extracorporeal photopheresis takes approximately 3 to 4 hours to complete and involves leukapheresis, separation of the buffy coat, photoactivation, and finally reinfusion.

Double Helix

Extracorporeal photopheresis (ECP) is a form of apheresis and photodynamic therapy in which blood is treated ex vivo with a photoactivable drug (ie, one that is activated with ultraviolet light). The whole process takes approximately 3 to 4 hours to complete and involves leukapheresis, separation of the buffy coat, photoactivation, and finally reinfusion. ECP has been approved by the FDA for cutaneous T-cell lymphoma (CTCL) since 1988.

The history of the photoactivable drug methoxsalen (8-methoxypsoralen) dates to ancient Egypt. Medicinal properties were observed in Ammi majus, a plant commonly known as Bishop’s weed, which was found next to the Nile River. The injudicious use of the weed, which the Egyptians used to treat skin ailments, caused skin damage. This damage is now understood to be activated by ultraviolet radiation (UVA) and is the result of phototoxic mechanisms that are dependent on the psoralen content of Bishop’s weed. The results are clinical changes such as erythema, bullae in the skin 24 to 72 hours later, and hyperpigmentation. Methoxsalen’s exact mechanism of action is not known, but in the presence of UVA methoxsalen intercalates with the patient’s DNA and produces adducts, thereby deranging DNA synthesis in those cells. A second mechanism, which is being recognized more often and is the subject of ongoing research, is the immune effects on macrophages, dendritic cells, and helper T cells. This second mechanism is thought to be more likely contributing to the benefits seen with ECP in graft-versus-host disease (GVHD).

Oral methoxsalen provides clinical benefit to patients with psoriasis, vitiligo, and CTCL. In CTCL, ECP is approved for the palliative treatment of the skin manifestations of CTCL that are unresponsive to other forms of treatment. Additional disease areas in which ECP has been shown to provide benefit are GVHD and autoimmune diseases such as multiple sclerosis.

Causes of GVHD

GVHD occurs when immune cells transplanted from a nonidentical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. The leading cause of GVHD is allogeneic hematopoietic cell transplantation (HCT), though solid organ transplants, blood transfusions, and maternal-fetal transfusions also reportedly cause GVHD.

GVHD has been classically divided into acute and chronic subtypes based on the time of onset from the HCT. Acute GVHD occurs when the disease presents within the first 100 days of HCT and chronic GVHD refers to the disease having onset after the first 100 days. However, this division at day 100 post-HCT is artificial, and there has been a shift toward defining acute and chronic GVHD based on the clinical manifestations, rather than the arbitrary cutoff of a particular date posttransplantation.

Clinically significant acute GVHD occurs in 9% to 50% of patients who receive an allogeneic HCT from a genotypically HLA-identical sibling, despite intensive prophylaxis with immunosuppressive agents such as methotrexate, cyclosporine, tacrolimus, corticosteroids, or antithymocyte globulin. Patients with acute GVHD commonly demonstrate a classic maculopapular rash, liver toxicity, diarrhea, and affects on the hematopoietic system.

Chronic GVHD occurs in more than 50% of long-term survivors of HLA-identical sibling transplants and can occur after previous or ongoing acute GVHD. It may also appear in patients without a history of acute GVHD (ie, de novo chronic GVHD). The target organs affected by chronic GVHD differ from those observed with acute disease. The skin involvement with chronic GVHD resembles lichen planus or the cutaneous manifestations of scleroderma. Patients may also have dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract, and a rising serum bilirubin concentration. Lung involvement also commonly occurs with chronic GVHD. With chronic GVHD, there is a marked immunodeficiency due to direct immunosuppressive effects and the consequences of the agents administered to treat the disease. Since chronic GVHD also causes a delay in the recovery of immune function, patients remain immunodeficient as long as the disease is active. In chronic GVHD, helper T cells react against major histocompatibility complex and generate excessive help. This enhanced help activates a subpopulation of selfreactive (possibly host) B cells, thereby causing autoantibody formation. Autoantibodies found in patients with chronic GVHD are similar to those observed in systemic lupus erythematosus and other rheumatologic disorders, implicating autoimmunity and autoimmune disease-related gene polymorphisms as important components of chronic GVHD.

Table 1: Complete Resolution Rates with ECP in Different Grades of Acute GVHDa

Table 1:Grade 2 86%; Grade 3 55%; Grade 4 30%

aAdapted from reference 5.

Management of GVHD

The management of a patient who has developed acute GVHD primarily includes steroids, and the durable remission rate with steroids in acute GVHD ranges from 24% to 40%.1,2,3,4 The second-line agents, such as cyclosporine, are generally less successful. A prospective phase II trial of ECP in steroidrefractory GVHD or steroid-dependent GVHD showed complete resolution of GVHD in 82% of patients with cutaneous involvement, 61% with liver involvement, and 61% with gut involvement (Table 1).5 Patients were treated on 2 consecutive days (1 cycle) at 1- to 2-week intervals until improvement and thereafter every 2 to 4 weeks until maximal response. An analysis of the relationship of response of acute GVHD to transplant-related mortality and survival was also conducted. The 4-year survival for those in whom acute GVHD had a complete resolution was 59%, which compares very favorably to the 11% of those who did not achieve complete resolution of acute GVHD. Overall, the study confirmed that ECP allows for accelerated tapering of corticosteroids, which had a significantly favorable impact on transplant-related mortality (Figure 1).

Figure 1: Relationship of Complete Resolution with ECP to Long-Term Survivala

Figure 1: survival probably higher year after year after transplantation with ECP

ECP indicates extracorporeal photophoresis; CR, complete resolution.

aAdapted from reference 5.

The treatment of chronic GVHD is determined in part by the severity of the disease. The severity is graded as either limited or extensive and is based on the clinical severity and target organs affected. Treatment is individualized and commonly includes combination of steroids with other immunosuppressants, such as cyclosporine or azathioprine. Patients with limited chronic GVHD have a favorable prognosis even without therapy, while those who have extensive GVHD, particularly those with multiorgan involvement, have poor longterm outcomes. There are numerous studies that have shown significant clinical benefit of ECP in chronic GVHD.6,7,8 The phase II study by Alcindor and colleagues included 25 patients with chronic GVHD who were treated with ECP either weekly or on 2 consecutive days once every 2 weeks. Skin improvement was shown in 71% of patients and response rates were similar in patients who were treated early (<18 months from transplant) versus late (>18 months from transplant). Steroid sparing or tapering of immunosuppression was seen in more than 80% of the patients. A correlation of the response rates with various baseline clinical characteristics is provided in Table 2.

Table 2: Correlation Between Response to ECP and Baseline Clinical Characteristicsa

Table 2: Prognostic Variable, Group, response and P Value

ECP indicates extracorporeal photophoresis.

aAdapted from reference 6.

Conclusion

The data in both acute and chronic GVHD largely are case series or single-center phase II studies. Though these data have the limitation of selection bias, the responses seen are generally very impressive in patients who are refractory to conventional measures. There are also several advantages of ECP when compared to conventional therapies. There is selective benefit in GVHD without the increased rates of infection and malignant disease relapse associated with the use of conventional immunosuppressants. In responding patients, ECP treatment can lead to a reduction and, often, a cessation of treatment with corticosteroids and other immunosuppressive agents. ECP is associated with few acute side effects from the therapy itself; these effects include occasional hypotensive episodes, mild pyrexia, and general tiredness and lethargy. There are no reported long-term side effects of this treatment, despite more than 5 years of follow-up in many patients. Analysis of survival data reveals increased survival in patients who respond. This confirms that the benefit of controlling GVHD is not lost through toxicity of the therapy or disease relapse, which are major problems with alternative therapies.

Reference

  1. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graftversus- host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood. 1990;75(4): 1024-1030.
  2. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment. Blood. 1990;76(8):1464-1472.
  3. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graftversus- host disease: secondary treatment. Blood. 1991;77(8):1821-1828.
  4. Antin JH, Chen HR, Couriel DR, et al. Novel approaches to the therapy of steroid-resistant acute graft-versus-host disease. Biol Blood Marrow Transplant. 2004;10(10):655-668.
  5. Greinix HT, Knobler RM, Worel N, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica. 2006;91(3):405-408.
  6. Alcindor T, Gorgun G, Miller KB, et al. Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease. Blood. 2001;98(5):1622-1625.
  7. Gonzalez Vicent M, Ramirez M, Sevilla J, Abad L, Diaz MA. Analysis of clinical outcome and survival in pediatric patients undergoing extracorporeal photopheresis for the treatment of steroid-refractory GVHD. J Pediatr Hematol Oncol. 2010;32(8):589-593.
  8. Jagasia MH, Savani BN, Stricklin G, et al. Classic and overlap chronic graft-versus-host disease (cGVHD) is associated with superior outcome after extracorporeal photopheresis (ECP). Biol Blood Marrow Transplant. 2009. 15(10):1288-1295.

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