ALBERT

Description: Key Points Distinct T-cell patterns characterize the acute and chronic forms of cutaneous GVHD. Increased TSLP expression is an indicator of acute cutaneous GVHD development.

Description: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HCT). GVHD is classified into an acute (aGVHD) and a chronic form (cGVHD) based on NIH-defined, clinical criteria. In skin, aGVHD presents as a maculopapular rash, while cGVHD shows at the beginning the signs of lichenoid tissue inflammation (chronic inflammatory GVHD, ciGVHD) and, later, exhibits scleroderma-like features (chronic sclerotic GVHD, csGVHD). Mechanisms involved in the initiation and propagation of the different forms of GVHD are a main focus of HCT research, but remain controversially discussed. Acute GVHD has long been thought to mainly involve a type 1 T cell response, but more recent data have shown an involvement of Th2, Th17 and Treg cells. These T cell subsets, and particularly an altered regulatory T cell homeostasis, have also been reported to play a role in chronic GVHD, the pathogenesis of which is much less understood. Taken together, it is unclear which exact mechanisms are operative in the T cell immunopathogenesis of cutaneous GVHD. In this study, we searched for cellular and molecular patterns that would allow us to distinguish between the different forms of cutaneous GVHD and to draw conclusions about the pathomechanisms involved. To address this issue, we collected lesional skin biopsies from patients diagnosed with aGVHD (n=25), ciGVHD (n=17) and csGVHD (n=7). Clinical grading of acute and chronic GVHD was performed according to the modified Glucksberg criteria and the NIH consensus criteria, respectively. 14 HCT recipients underwent serial skin biopsies at different time points prior/after HCT (prior/after conditioning, day 20-30 post-HCT, day 100-120 post-HCT). Skin biopsies obtained were subjected to phenotypic and functional analyses. The cellular infiltrate was assessed by immunofluorescence stainings; interleukins and chemokines were measured by real-time RT-PCR. Cytokine secretion profiles of stimulated T cells from collagenase-digested GVHD skin biopsies were analyzed by intracellular flow cytometry. While CD4+ and CD8+ T cells dominated the inflammatory infiltrate in both acute and chronic GVHD skin lesions, the analysis of the quality of the T cell-mediated immune response revealed striking differences. In acute cutaneous GVHD, we found a “Th2 signature” as evidenced by highly increased transcripts of Th2 cytokines (IL-4, IL-5 and IL-13) and chemokines (CCL17, CCL20). Surprisingly, we also observed a strong up-regulation of IL-22, but not IL-17 mRNA, which was paralleled by an increase of IL-22-single-producing CD4+ T cells. IL-17/IL-22 double-positive T cells were almost absent. In sharp contrast to aGVHD, the immune response occurring in ciGVHD showed a mixed Th1/Th17 signature. This was evidenced by an up-regulation of Th1/Th17 cytokine (IFN-γ, IL-12/IL-23p40 and IL23p19) and chemokine transcripts (CCL5, CCR5, CXCL9, CXCL10). In accordance with this finding, increased numbers of IFN-ү- and IL-17-single-producing CD8+ T cells infiltrated ciGVHD skin lesions.Chronic sclerotic GVHD exhibited distinct features, including an abundance of mast cells and a down-regulation of T cell cytokines and chemokines relative to normal skin. In an attempt to identify a factor predicting the occurrence of acute cutaneous GVHD, we analyzed the cellular and molecular signatures in skin of HCT recipients before GVHD onset. In accordance with the finding of a Th2 response occurring in aGVHD, levels of TSLP, a keratinocyte-derived cytokine skewing the immune response towards a Th2 direction, were increased at day 20 after HCT in non-lesional skin of patients who would later develop aGVHD. In conclusion, the present study provides new insights into the diverse pathomechanisms operative in the acute and chronic form of cutaneous GVHD, respectively. Our findings allow to more accurately distinguish aGVHD from ciGVHD based on different cellular and molecular patterns. The analysis of TSLP expression in skin (before disease onset) could be helpful in identifying HCT recipients at risk for developing acute cutaneous GVHD. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Mycosis Fungoides (MF) and its leukemic variant Sezary syndrome (SS) are disorders of malignant, skin homing helper/memory T-cells. MF presents with patches, plaques, or tumors, while SS presents with generalized erythroderma and blood involvement. Either can involve lymph nodes, blood, and viscera. A multi-center, open label, single arm clinical trial previously demonstrated the safety and efficacy of ECP as a monotherapy in the treatment of patients with advanced/refractory MF/SS (Edelson, et al, 1987, N Engl J Med, 316:297–303). The primary endpoint of this study was a ≥25% improvement in skin score maintained for at least 4 weeks. We present a long-term, secondary analysis of these patients to further evaluate clinical outcomes and predictors of response for ECP as a monotherapy in MF/SS. Partial (≥50%) and complete (≥90%) skin score responses, extent of skin disease, number of ECP treatments administered, and the time required to achieve 50% and 90% improvement in skin involvement were evaluated. Patients and Methods: Thirty-nine patients (pts) who met eligibility criteria were included in the secondary efficacy analysis as the intent-to-treat (ITT) patient population. Thirty-one pts with generalized erythroderma (GE) and 8 pts with extensive patch plaque (EPP) were treated with ECP on 2 consecutive days every 4–5 weeks for 3 months. No concomitant systemic medications for MF/SS were allowed on study; however, topical steroids could be applied to the hands and feet. Patients had received an average of 3.7 (range 0–13) prior therapies (systemic and topical). Immediately prior to undergoing ECP, all pts received oral doses of methoxsalen in order to achieve blood level concentrations ≥50 ng/mL. Skin improvement was calculated by comparing baseline skin score to skin scores on all subsequent treatment dates. The mean baseline skin score of the 39 ITT patients was 262 (median = 291) based on a maximum possible skin score of 400 points. Results: The median follow-up of the 39 ITT pts was approximately 4 years (range 9 days–7.8 years). Twenty-nine pts (74%) achieved at least a ≥50% improvement in skin score, and 16 pts (41%) achieved ≥90% improvement on ECP monotherapy. The type and extent of skin disease (GE vs. EPP) prior to the start of treatment did not predict response. Patients received a median of 12 (range 4–65) or 30.0 (range 12–109) individual ECP treatments to achieve a ≥50% or ≥90% response, respectively. The mean times to reach a ≥50% or ≥90% response were 8.4 ± 6 months (median=6.5) or 25.2 ±14.9 mos (median=19.6), respectively. The mean duration of a ≥50% response was 32.5 ± 28.6 mos, which included a median of 20 (range 0–153) ECP treatments. Median survival from date of diagnosis and from date of first ECP treatment was 10.6 yrs and 5.4 yrs, respectively. Conclusions: In this long-term, follow-up analysis, ECP monotherapy was associated with a significant and durable improvement in skin score in the majority of patients with MF/SS.

Description: Despite posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of sickness and death. Second-line therapies for steroid-refractory acute GVHD have been used with limited success. Extracorporeal exposure of peripheral blood mononuclear cells to the photosensitizing agent 8-methoxypsoralen and UV-A radiation (ECP) has been shown to be effective in the treatment of selected diseases mediated by T cells. We have reviewed the responses and long-term outcome of 59 hematopoietic stem cell transplant (HSCT) patients treated from 1996 to 2003 with ECP for steroid-refractory acute GVHD, defined as progression or no improvement of acute GVHD after a minimum of 4 (range, 4–49, median 17) days of treatment with prednisone (n=37) or steroid-dependent acute GVHD, defined as flare-up of GVHD during prednisone taper (n=22). Patients received HSCT from 17 related and 42 unrelated donors. In 28 cases an HLA-mismatch between recipient and donor was present. Prior to ECP, grade III–IV GVHD was observed in 23 patients (39%) and grade II GVHD in 36 (61%). Organs involved included skin in 97% of patients, liver in 39%, and GI tract in 17%. Treatment consisted of ECP on two consecutive days per week (=1 cycle) for a median of 7 (range, 1–45) cycles administered within a median of 3 (range, 0.5–31) months in addition to cyclosporine A and prednisone. Three months after initiation of ECP complete resolution of GVHD was achieved in 82% of patients with cutaneous, 61% with liver, and 61% with gut involvement. Complete responses were obtained in 86% of patients with grade II, 55% of patients with grade III, and 30% of patients with grade IV acute GVHD. Probability of transplant-related mortality (TRM) at 4 years after HSCT is 15% in patients with complete response to ECP compared to 88% in patients not responding completely. After a median follow-up of 46 (range, 9–45) months since discontinuation of ECP, 28 (47%) patients are alive including 22 without chronic GVHD. Probability of survival (OS) at 4 years after HSCT is 59% in patients with complete response to ECP compared to 11% in patients not responding completely. Besides response to ECP only organ involvement and grade of GVHD at start of ECP, and ability to timely taper steroids during ECP had a significant impact on both TRM and OS. Thus, ECP is an effective adjunct therapy for acute steroid-refractory and steroid-dependent GVHD. Our long-term results demonstrate durability of responses without adverse events.

Description: Abstract 4896 Background: Primary Cutaneous T-cell Lymphomas (CTCLs) are a heterogenous group of lymphomas, as outlined in the WHO classification. Due to the rarity of CTCL, very few prospective randomized trials have been performed for this disease. EORTC consensus recommendations for the treatment of early CTCL have been published, but treatment of advanced stage disease remains largely empirical, based on small non-randomized, uncontrolled studies with uncertain response data and limited chances to affect clinical practice. Methods: The CTCL platform has been designed by the EORTC Cutaneous Lymphoma Task Force to address critical unadressed questions to move forward the standards of care of CTCL in advanced stage disease. It was built following a sequential approach. Following a European consensus defining the key clincial questions to improve disease control in CTCL, ideas regarding the biology of the disease and all possible emerging targets which may lead to a better understanding of the disease were explored. The candidate targets were selected and prioritized by their scientific and clinical relevance. The maturity and relevance of agents in development to tackle these pathways and targets were analyzed. Methodologically and statistically robust clinical trials were designed to allow the enrollment of patients through the evolution of their disease. Endpoints and translational research programs that could address and help identify mechanisms of action and clinical efficacy were also evaluated as to feasibility and scientific relevance. This comprehensive process lead to the design of early phase randomized trials on solid scientific grounds with the use of innovative drugs. Study protocol 21081 is a multicenter, randomized, open-label, phase III study and is suitable for patients who have not previously had other intravenous chemotherapy, and are therefore relatively treatment-naïve. The accrual goal is 105 patients. The objective of this trial is to test the hypothesis that lenalidomide is able to increase progression free survival in patients achieving a complete (CR) or partial (PR) response after standardized debulking treatment. A sister protocol, 21082, is addressed to patients who have had previous chemotherapy. Patients in that study will be treated with the histone deacetylase inhibitor vorinostat, with or without the addition of the proteosome inhibitor bortezomib. The primary objective of this trial will be to determine if the combination of bortezomib plus vorinostat is more effective than a histone deacetylase inhibitor alone in terms of prolonging progression free survival. The presentation will address details of the disease biology which gave rise to these trials and the selection of innovative agents, the procedures of the strategy adopted and the challenges of designing methodologically valid trials addressing this rare disease. Disclosures: Ortiz-Romero: MSD: Consultancy; Ferrer: Honoraria.

Description: Extracorporeal exposure of peripheral blood mononuclear cells to the photosensitizing compound 8-methoxypsoralen and ultraviolet A radiation has been shown to be effective in the treatment of several T-cell–mediated diseases, including cutaneous T-cell lymphoma and rejection after organ transplantation. We present 21 patients (10 men and 11 women) with hematological malignancies with a median age of 36 years (range, 25 to 55 years) who had received marrow grafts from sibling (n = 12) or unrelated (n = 9) donors. Six patients had acute graft-versus-host disease (GVHD) grade II to III not responding to cyclosporine A (CSA) and prednisolone when referred to extracorporeal photochemotherapy (ECP). In 15 patients, 2 to 24 months after bone marrow transplantation (BMT), extensive chronic GVHD with involvement of skin (n = 15), liver (n = 10), oral mucosa (n = 11), ocular glands (n = 6), and thrombocytopenia (n = 3) developed and was unresponsive to conventional therapy, including steroids. All patients were treated with ECP on 2 consecutive days every 2 weeks for the first 3 months and thereafter every 4 weeks until resolution of GVHD. ECP was tolerated excellently without any significant side effects. After a median of 14 cycles of ECP, acute GVHD resolved completely in 4 of 6 patients (67%) and partially in another 2 patients. Cutaneous chronic GVHD completely resolved in 12 of 15 (80%) patients. Contractures of knees and elbows due to scleroderma resolved partially. Oral mucosal ulcerations resolved in all patients. Seven of 10 patients (70%) with liver involvement had complete responses after ECP. After discontinuation of ECP, no severe infections were observed. Our findings suggest that ECP is a safe and effective adjunct therapy for both acute and extensive chronic GVHD with skin and visceral involvement and resistance to conventional therapy. © 1998 by The American Society of Hematology.

Description: Extracorporeal exposure of peripheral blood mononuclear cells to the photosensitizing agent 8-methoxypsoralen and UV-A radiation has been shown to be effective in the treatment of selected diseases mediated by T cells, rejection after solid organ transplantation, and chronic graft-versus-host disease (GVHD). We present 21 patients with a median age of 38 years who developed steroid-refractory acute GVHD grades II to IV after stem cell grafting from sibling or unrelated donors and were referred to extracorporeal photochemotherapy (ECP). Three months after initiation of ECP 60% of patients achieved a complete resolution of GVHD manifestations. Complete responses were obtained in 100% of patients with grade II, 67% of patients with grade III, and 12% of patients with grade IV acute GVHD. Three months after start of ECP complete responses were achieved in 60% of patients with cutaneous, 67% with liver, and none with gut involvement. Adverse events observed during ECP included a decrease in peripheral blood cell counts in the early phase after stem cell transplantation (SCT). Currently, 57% of patients are alive at a median observation time of 25 months after SCT. Probability of survival at 4 years after SCT is 91% in patients with complete response to ECP compared to 11% in patients not responding completely. Our findings suggest that ECP is an effective adjunct therapy for acute steroid-refractory GVHD with cutaneous and liver involvement. However, in patients with acute GVHD grade IV or gut involvement other therapeutic options are warranted.

Description: The ISCL/EORTC recommends revisions to the Mycosis Fungoides Cooperative Group classification and staging system for cutaneous T-cell lymphoma (CTCL). These revisions are made to incorporate advances related to tumor cell biology and diagnostic techniques as pertains to mycosis fungoides (MF) and Sézary syndrome (SS) since the 1979 publication of the original guidelines, to clarify certain variables that currently impede effective interinstitution and interinvestigator communication and/or the development of standardized clinical trials in MF and SS, and to provide a platform for tracking other variables of potential prognostic significance. Moreover, given the difference in prognosis and clinical characteristics of the non-MF/non-SS subtypes of cutaneous lymphoma, this revision pertains specifically to MF and SS. The evidence supporting the revisions is discussed as well as recommendations for evaluation and staging procedures based on these revisions.

Description: Primary cutaneous CD30+ lymphoproliferative disorders (CD30+ LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30+ LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30+ LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30+ LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30+ LPDs.