Curative potential of hematopoietic stem cell transplantation for advanced psoriasis

Psoriasis is the most prevalent autoimmune disease in humans, affecting 2%-5% of global population. In advanced stages, it can be life-altering and debilitating. Severity of psoriasis may be appreciated according to body surface area involved (as mild <5%, moderate 5%-10%, and severe >10%). However, it is worth noting that the surface area involved may not always correlate with disease severity. Thus, other tools such as Psoriasis Area and Severity Index (PASI) or Physician Global Assessment were developed and used concomitantly. While PASI has been preferred, it has limitations and is more difficult to perform.1 Pathogenesis of psoriasis involves dysregulation of the immune system, which leads to keratinocyte proliferation. Antigenic stimuli cause accumulation and activation of the dendritic cells (plasmacytoid, myeloid), which generate pro-inflammatory cytokines [INF-α, tumor necrosis factor (TNF)-α, interleukin (IL)-17A, IL-6, IL-21, IL-22, and IL-23], and in turn stimulate myeloid dendritic cells, accumulation of T cells in the skin as well as accumulation of neutrophils and macrophages.1 In this immune-mediated disorder, a major role is attributed to type 17 helper T cells (Th17). Environmental triggers or predisposing genotypes lead to activation of dendritic cells to secret TNF-α and IL-23. IL-23 induces differentiation of Th17 for naïve T cells. IL-17 secreted by Th17 cells activates keratinocytes and promotes epidermal hyperplasia. Moreover, Th17 cells stimulate dermal dendritic cells and macrophages causing destruction of keratinocytes and reduction in skin capillaries. Chemokines, S100 proteins, and antimicrobial peptides released by the keratinocytes subsequently activate helper T cells, cytotoxic T cells, and immune effector cells.1 These contribute to perpetuation of the cutaneous inflammation characteristic of this disease. According to American Academy of Dermatology recommendations, over the past decades, several biologic agents (TNF inhibitors, IL-12/IL-23 inhibitors, IL-17 inhibitors, and IL-23 inhibitors) have been approved as monotherapy or combination therapy for moderate to severe psoriasis.2 Presence of psoriatic arthritis can also be controlled with such biologic agents.1 Hematological malignancies account for 12.5% of all cancers associated with psoriasis. Hematopoietic stem cell transplantation (HSCT) is an established treatment for advanced hematological malignancies, and an emerging therapy for advanced autoimmune diseases, such as multiple sclerosis and severe scleroderma.3, 4 Prior studies have shown that psoriasis can be transmitted to a recipient of allogenic bone marrow transplant.5 Autologous transplantation has been attempted in patients with psoriasis; however, relapses have occurred. It was also suggested that complete remission is possible after allogenic, but not autologous HSCT.6 We hypothesized that allogenic HSCT has curative potential for patients with this disease and initiated a prospective observational study of patients with psoriasis receiving allogenic HSCT for an associated hematological malignancy. Patients with a diagnosis of psoriasis (confirmed by at least two dermatologists), in addition to a hematologic malignancy requiring transplantation, were prospectively enrolled in an institutional database between October 2010 and November 2015. Diagnosis of psoriatic arthritis was based on the classification criteria for psoriatic arthritis (CASPAR). Disease severity was classified based upon the body surface area involved, not on the characteristics of lesions. Clinical information was collected as part of the Department of Stem Cell Transplantation and Cellular Therapy database at University of Texas MD Anderson Cancer Center (MDACC). Patients provided written informed consent for transplantation and prospective data collection according to the Declaration of Helsinki. The Institutional Review Board of the MDACC approved the prospective data collection protocol of this study. Descriptive statistics were used to assess outcomes of these patients. Six patients with psoriasis and an associated hematological malignancy were identified prospectively and enrolled in this long-term longitudinal observational study. Clinical characteristics of all patients are presented in Tables 1 and 2. Median age was 57 years (range 21-65 years). The primary indication for allogenic HSCT was acute myeloid leukemia (AML; n = 3), diffuse large B-cell lymphoma (n = 2), and chronic neutrophilic leukemia (n = 1). Three of the four patients with myeloid malignancy had poor-risk cytogenetics. The median hematopoietic cell transplant comorbidity index (HCT-CI) was 4 (range 0-6). Half of the patients received an HLA-matched related donor, and half a 10/10 allele matched unrelated donor transplant. Standard graft-versus-host disease (GVHD) prophylaxis was used with tacrolimus, methotrexate ± rabbit antithymocyte globulin 6 mg/kg total dose. Half of the patients received myeloablative conditioning (busulfan-based, n = 3), while the others received a reduced-intensity conditioning (melphalan-based, n = 2; bendamustine-based, n = 1). Doses of chemotherapy agents are detailed in Table 2 (abbreviations). Engraftment occurred in all patients after a median time of 11 days. Grade 2-4 acute (aGVHD) occurred in two patients both involving the gastrointestinal tract (grade 2 in patient #4 and grade 3 in patient #1, Table 2). Patients with ≥grade 2 aGVHD were treated with high-dose systemic corticosteroids. Chronic GVHD (cGVHD) occurred in 3/6 patients (50%). Of the six patients transplanted, two died, one of cGVHD and one of pneumonia in the setting of treatment for cGVHD, at 224 days and 362 days posttransplant (Table 2). All six patients had cutaneous psoriatic lesions at the time of transplant, two had severe, three moderate, and one patient had mild-to-moderate psoriasis. PASI scores were not available as patients were initially diagnosed with psoriasis at outside institution. Three patients had psoriatic arthritis. Half of the patients (3/6 - patient #3, #4, and #5, Table 1) were diagnosed with psoriasis 15-20 years before the onset of hematological malignancies. All patients received treatment with topical corticosteroids. One patient (patient #3, Table 1) with severe psoriasis received systemic therapy with methotrexate for 10 years. Following allogeneic HSCT, skin lesions and joint pain/inflammation disappeared in all patients, with median time-to-resolution of 50 days posttransplant (range 30-71 days). After a median follow-up of 5.3 years (range 2.9-7.4 years), none of these patients had recurrent skin lesions or arthralgia/arthritis. One patient (patient #5, Table 2) remains on treatment for cGVHD with sirolimus and ibrutinib at the time of last follow-up. Treatment for the two patients with acute GVHD included systemic steroids, one received photopheresis and pentostatin, while treatment for the three patients who had significant cGVHD included systemic steroids, calcineurin inhibitor (tacrolimus, sirolimus), two of them had ruxolitinib and one had photopheresis and ibrutinib. Treatment for patients with aGVHD was initiated after day 60, while psoriatic lesions resolved before initiation of systemic steroids for these patients. Treatment for patients with cGVHD was initiated after day 100 posttransplant and is unlikely that it would have influenced resolution of psoriatic lesions in these patients. Recently, HSCT has been shown to be effective in several autoimmune diseases, like severe scleroderma or multiple sclerosis. We explored effectiveness of allogenic HSCT for patients with psoriasis in a cohort of patients with hematologic malignancies, as relapses were previously seen after autologous HSCT. Here we showed that patients with severe psoriasis could be potentially cured after allogenic HSCT. Psoriatic skin lesions and arthritic symptoms resolved rapidly after transplant and never recurred in any of the patients, with the longest follow-up of more than 7 years posttransplant. It is well known that methotrexate or calcineurin inhibitors may suppress symptoms of psoriasis and psoriatic arthritis; however, lack of recurrence of symptoms in the long term suggests that the change in immune system contributed to definitive elimination of the disease in these patients. Although this treatment appears to be curative, significant risks remain. Treatment of older patients, use of more intense (myeloablative) conditioning required to prevent relapse posttransplant in patients with high-risk hematological malignancies, and high median HCT-CI of 4 might have contributed to higher treatment-related mortality in this group. Patients with hematological malignancies tend to be older (median age of AML diagnosis of 68 years) compared with patients with psoriasis (median age 25-30 years). In addition, as compared with patients who received myeloablative conditioning (2/3 died of treatment-related complications), none of the patients receiving reduced-intensity/non-myeloablative conditioning died, suggesting that this latter approach is likely safer, especially for patients with nonmalignant diseases who usually do not require intensive conditioning. We have also observed that psoriasis tended to resolve very fast (within 1-2 months after the new graft) and did not recur even in patients receiving lower intensity conditioning, suggesting that the mere change in the immune system with full donor chimerism might be enough to eliminate this disease, as compared with most hematological malignancies in which myeloablative conditioning is usually needed to prevent relapse posttransplant.7 Development of GVHD posttransplant remains a concern. Although the incidence of severe grade 3-4 aGVHD and cGVHD is not higher in our series compared with data from hematopoietic transplantation literature (16.6% and 50%, respectively), development of any significant GVHD may represent an important limitation, especially for patients with nonmalignant diseases. Although all our patients received conventional GVHD prophylaxis, a novel method to prevent severe acute and mostly cGVHD using posttransplantation cyclophosphamide (PTCy) has already revolutionized the field of transplantation,8 and could represent an important next step in decreasing treatment-related mortality in these patients. We conclude that allogenic HSCT can be curative for patients with severe psoriasis. No recurrence was observed after long-term follow-up. Reduced-intensity conditioning is likely needed, as psoriasis appears to be very susceptible to immune manipulation. Although GVHD remains a concern, better prevention of GVHD, especially cGVHD, can now be effectively achieved with PTCy-based GVHD prophylaxis. A reduced-intensity conditioning and PTCy-based GVHD prophylaxis should probably be evaluated in the future as possible treatment for patients with advanced psoriasis. S.O.C. designed the study, collected the data and wrote the manuscript; P.H. contributed to manuscript writing, reviewed and approved the manuscript; J.C. contributed with data collection, reviewed and approved the manuscript; A.M.C., S.H., C.H., U.P., and R.E.C. treated the patients, contributed to data interpretation, reviewed and approved the manuscript. The authors declare no potential conflict of interest.