Advanced-stage Cutaneous T-cell Lymphoma Research Articles

Allogeneic Hematopoietic Cell Transplantation (AHCT) for Primary Cutaneous T Cell Lymphoma (CTCL): a Center for International Blood and Marrow Transplant Research (CIBMTR) Review

AbstractAbstract 364Patients (pts) with advanced stage CTCL have a poor prognosis with standard therapy whereas AHCT possibly is curative. Published experience with AHCT for CTCL is modest. We report the outcomes of a large cohort of CTCL pts receiving AHCT (N=133) reported to the CIBMTR from 2000–2009. The majority of pts 129 (97%) were diagnosed with Mycosis Fungoides or Sezary Syndrome. Only 8 (6%) received AHCT in a complete remission (CR) while 46 pts (35%) never achieved CR pre-AHCT. Most pts (83%) were transplanted beyond 12 months from diagnosis. Median (range) time from diagnosis to transplant is 29 (4-206) months. Peripheral blood was the main graft source (83% vs. 14% marrow and 3% cord blood). Donor types included: 66 HLA-identical siblings (50%), 56 unrelated donors (42%), 11 from other related donors (8%). Reduced intensity conditioning (RIC) was used in 64%. Recipients of RIC were on average older (median age 51 vs. 44 yr for myeloablative) and transplanted in later study years. Among the myeloablative regimens, cyclophosphamide with total body irradiation was the most common (38%) whereas among RIC, fludarabine in combination with busulfan, cyclophosphamide or melphalan was used in 50%. GVHD prophylaxis regimens varied. Overall mortality at 30 and 100 days was 7% and 16%, respectively. Overall survival at 6 mo and 2 yr was 75% (95% CI 67–82%) and 44% (95% CI 34–53%), respectively. Conditioning intensity was not different statistically for the overall survival of these pts (figure 1). Treatment related mortality (TRM) at 6 mo and 2 yr was 10% (95% CI 5–17%). Progression/relapse of CTCL was 44% (95% CI 34–54%) at 6 mo and 58% (95% CI 47–68%) at 2 yr. Progression free survival at 6 mo was 46% (95% CI 36–57%) and at 2 yr 32% (95% CI 23–42%). The incidence of grade II-IV acute GVHD was 36% (95% CI 22–50%) and of chronic GVHD 31% (95% CI 19–45%) in a subset of reported pts. Infection as a cause of death does not seem to be increased in CTCL transplanted pts. Conditioning intensity did not impact TRM or the risk of progression. This very large series of allogeneic HCT demonstrates feasibility in pts with advanced CTCL with a low TRM and long term progression free survival in approximately one third of pts. Progressive disease was the primary cause of treatment failure in this cohort of pts with advanced disease. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Análisis comparativo de la expresión de moléculas de adhesión celular en linfomas cutáneos (micosis fungoide/síndrome de Sézary) y dermatosis inflamatorias mediadas por células T

Introduction Cell adhesion molecules play a pivotal role in the establishment of T-cell populations in the skin. In this study, we quantify the expression of cell adhesion molecules in patients with cutaneous T-cell lymphoma (CTCL) and compare it with the expression found in other skin diseases. Material and methods Frozen material was obtained from 42 patients in 5 different groups: early CTCL, comprising patients with patch- and plaque-stage of mycosis fungoides ( n=11); advanced CTCL ( n=7), comprising patients with mycosis fungoides ( n=3) and Sézary syndrome ( n=4); inflammatory skin disease ( n=12), comprising patients with psoriasis ( n=9) and atopic dermatitis ( n=3); chronic skin diseases with persistent plaques that do not fulfil the histological criteria for mycosis fungoides (pre-CTCL) ( n=8); and healthy volunteers ( n=4). Expression of the following cell adhesion molecules was analyzed: lymphocyte function-associated antigen 1, intercellular adhesion molecule 1 (ICAM-1), ICAM-3, cutaneous lymphocyte-associated antigen, E-selectin, very late antigen 4, vascular cell adhesion molecule 1, alphaEbeta7 integrin, and E-cadherin. Results The immunohistochemical analyses used here revealed statistically significant differences between CTCL and other skin diseases but not between early and advanced CTCL. The expression of alphaEbeta7 integrin and ICAM-3 in the epidermis per high-power field (400× magnification) allowed the different groups to be distinguished from each other, except for advanced CTCL and pre-CTCL. There were statistically significant differences between advanced CTCL and pre-CTCL in terms of the expression of E-selectin at 400× magnification and the expression of ICAM-1 in a honeycomb pattern in epidermal keratinocytes. Conclusions The expression of cell adhesion molecules involved in the adhesion and migration of lymphocytes in the skin does not differ significantly between initial and advanced stages of CTCL.

The State of Cutaneous Lymphomas: A Call to Action

Introduction Population-based and single-institution surveys from diverse geographic areas have consistently shown that in about 25%-40% of cases, malignant lymphomas originate from and exclusively progress or relapse within extranodal sites, with the skin and the gastrointestinal system representing the most common sites. The biology and clinical features of extranodal lymphomas are clearly distinct from those of lymphomas arising from the lymph nodes, and their etiology is different. For example, specific microbial triggers for extranodal B-cell lymphoma have been demonstrated. Therefore, diagnostic workup, treatment, assessment of relapse, and overall outcome are distinct from nodal lymphomas. Furthermore, the study of the development of cellular immune surveillance and of the mechanisms regulating lymphocyte homing to these critical areas of host-environment interfacing hold the key to understanding how these malignancies arise and progress. In the skin, lymphomas may originate from B cells, T cells, or natural killer (NK) cells, reflecting a significant heterogeneity in causation. However, unlike most other extranodal sites, T-cell rather than B-cell lymphomas are the most frequent and prevalent.1 Hypotheses about the reasons for this observation should be informed by features of T-cell immune surveillance and environmental exposures that are unique to the skin and different from the gastrointestinal and respiratory tract. Analysis of the specific functional features of malignant T cells in cutaneous lymphoma, such as antigen receptor use, cytokine and chemokine expression, and transcriptional profile, might provide clues to the etiological agent(s), as they have in other T-cell disorders.2 While a complete histogenetic and biologic characterization of primary cutaneous lymphomas has not been developed, we anticipate that future classifications schemes will be based on cell lineage, functional subset, molecular abnormalities, and clinical features, along the lines of the most current World Health Organization classification. It is conceivable that in the near future, old eponyms will be discarded in favor of more specific disease definitions. Finally, although historically the clinical and laboratory work on cutaneous lymphomas has mostly focused on the T-cell subsets, there is increasing awareness that a lack of knowledge about B-cell and NK-cell lymphomas is impairing the ability of physicians to counsel patients about risk factors, plans of care, and prognosis. One of the purposes of the Cutaneous Lymphoma Summit 2009, as reflected in the articles included in this issue, is to shed some initial light on this understudied subset of cutaneous lymphomas. The generic term cutaneous T-cell lymphomas (CTCLs) encompasses a spectrum of T-cell malignancies that include mycosis fungoides (MF), Sezary syndrome (SS), anaplastic large-cell lymphoma, and other rare subsets. In this article, we use the general term CTCL to discuss MF/SS. An estimated 2000 new cases of CTCL are diagnosed annually,3 with approximately 20,000 affected in the United States, more frequently affecting the elderly and black populations. Cutaneous T-cell lymphoma typically presents with scaly patches or thickened plaques of skin that often evolve from chronic dermatoses, years before biopsy confirmation.4 Disease progression from early clinical stages is variable, but the burden of chronic skin disease is constant. Increasing areas of skin surface involvement are accompanied by tumor formation, ulceration, and exfoliation (erythroderma), often complicated by infections and debilitation. Advanced stages are defined by extracutaneous involvement of lymph nodes, peripheral blood, and viscera. Sezary syndrome, a triad of generalized exfoliative erythroderma, peripheral blood involvement, and lymphadenopathy, is a common presentation of advanced-stage CTCL. Prognosis of CTCL is related to the extent of skin involvement and stage at the time of diagnosis. While early-stage CTCL treated with skin-directed (nonsystemic) therapies is associated with long-term survival,5 advance stages have a median survival of 2.5-5.0 years, depending on the degree of extracutaneous involvement.6,7 Cutaneous T-cell lymphoma, and all primarily cutaneous lymphomas, have now been unequivocally shown to be clinically and biologically distinct from its nodal counterparts, leading to the recognition that management of these malignancies requires a specialized approach. Over the past decade, there has been an increasing focus on cutaneous lymphomas from a variety of sectors, including academic, drug development, and patient advocacy. Professional societies and organizations have updated and revised cutaneous lymphoma classification, staging criteria, and consensus treatment guidelines.4,8,9 Pharmaceutical and biotechnology companies have developed new classes of therapeutic agents active in cutaneous lymphomas, such as targeted immunotoxins, retinoids, dihydrofolate reductase inhibitors, and histone deacetylase inhibitors.10-12 The Cutaneous Lymphoma Foundation (CLF) currently serves as the largest nonprofit organization devoted to the advocacy of patients with cutaneous lymphomas (www.clfoundation.org). Editorial

Comparative Analysis of the Expression of Cell Adhesion Molecules in Cutaneous T-Cell Lymphomas (Mycosis Fungoides/Sézary Syndrome) and Inflammatory Skin Diseases

Introduction Cell adhesion molecules play a pivotal role in the establishment of T-cell populations in the skin. In this study, we quantify the expression of cell adhesion molecules in patients with cutaneous T-cell lymphoma (CTCL) and compare it with the expression found in other skin diseases. Material and methods Frozen material was obtained from 42 patients in 5 different groups: early CTCL, comprising patients with patch- and plaque-stage mycosis fungoides (n=11); advanced CTCL (n=7), comprising patients with mycosis fungoides (n=3) and Sézary syndrome (n=4); inflammatory skin disease (n=12), comprising patients with psoriasis (n=9) and atopic dermatitis (n=3); chronic skin diseases with persistent plaques that do not fulfil the histological criteria for mycosis fungoides (pre-CTCL) (n=8); and healthy volunteers (n=4). Expression of the following cell adhesion molecules was analyzed: lymphocyte function-associated antigen 1, intercellular adhesion molecule 1 (ICAM-1), ICAM-3, cutaneous lymphocyte-associated antigen, E-selectin, very late antigen 4, vascular cell adhesion molecule 1, αEβ7 integrin, and E-cadherin. Results The immunohistochemical analyses used here revealed statistically significant differences between CTCL and other skin diseases but not between early and advanced CTCL. The expression of αEβ7 integrin and ICAM-3 in the epidermis per high-power field (400× magnification) allowed the different groups to be distinguished from each other, except for advanced CTCL and pre-CTCL. There were statistically significant differences between advanced CTCL and pre-CTCL in terms of the expression of E-selectin at 400× magnification and the expression of ICAM-1 in a honeycomb pattern in epidermal keratinocytes. Conclusions The expression of cell adhesion molecules involved in the adhesion and migration of lymphocytes in the skin does not differ significantly between initial and advanced stages of CTCL.

Gemcitabine treatment in cutaneous T-cell lymphoma: a multicentre study of 23 cases

Primary cutaneous T-cell lymphomas (CTCLs) are malignancies characterized by a clonal T-cell infiltrate involving the skin. CTCLs often show resistance to conventional antineoplastic chemotherapy. Gemcitabine is a pyrimidine analogue which has shown efficacy and a favourable safety profile in solid tumours and haematological malignancies. We report a multicentre retrospective study of 23 patients who received gemcitabine for advanced-stage CTCL and emphasize the high incidence of serious unusual adverse events. We collected data from 23 patients with refractory CTCL (14 mycosis fungoides, six Sézary syndrome and three other CTCL). Gemcitabine was given weekly within a 21- or 28-day schedule. Response was evaluated after three and six cycles of chemotherapy. For each patient, all adverse events were recorded. Of the 16 patients who received at least three cycles of gemcitabine, 10 achieved a response (62.5%). Only five patients reached the sixth cycle of treatment and four still had a favourable response. Haematological toxicity was recorded in 15 cases with severe grade 3 or 4 neutropenia in seven patients (30%) and six serious infections (26%). Other serious adverse events were observed in six cases (26%): one haemolytic-uraemic syndrome, one severe capillary leak syndrome, one acute heart failure related to cardiac arrhythmia, two bullous and erosive dermatitis, and one recurrent influenza-like syndrome with altered general condition. Our study confirms the early efficacy of gemcitabine in advanced-stage CTCL. However, our results contradict the safety profile of gemcitabine previously reported and underline the high incidence of severe complications including visceral and cutaneous involvement.

Bexarotene therapy for mycosis fungoides and Sézary syndrome

Bexarotene (Targretin) is a synthetic retinoid which is licensed for the treatment of advanced refractory cutaneous T-cell lymphoma (CTCL). To summarize our experience with bexarotene for patients with CTCL with the aim of assessing efficacy and safety. A retrospective study of 66 patients (44 male, 22 female) with mycosis fungoides (40 patients) or Sézary syndrome (26 patients) who were commenced on bexarotene prior to August 2007 was carried out. Nineteen patients had early-stage (IB-IIA) refractory mycosis fungoides and 47 patients had advanced-stage CTCL (IIB-IVB). Fifty-two out of 66 (79%) patients completed over 1 month of therapy with an intention-to-treat response rate of 44% (29/66). Of the patients, six (9%) had a complete response, 23 (35%) had a partial response, 15 (23%) had stable disease and eight (12%) had progressive disease. Median time to maximal response was 3 months (1-9 months). Median response duration was 8 months (1 to > 48 months). Median time to progression was 9 months (3-44 months). Fourteen patients (21%) did not complete a month of bexarotene therapy. Adverse effects of the whole group included central hypothyroidism in 100% (all grade II and managed with thyroid replacement) and hyperlipidaemia in 100% (all managed with lipid-lowering therapy +/- dose reduction). Responses were seen in all stages and were higher in advanced stages: 26% (five of 19) with early-stage and 51% (24/47) of advanced-stage disease. Responses were seen in skin, blood and lymph nodes. Twenty-eight out of 66 patients were treated with bexarotene monotherapy and the remainder were on one or more additional anti-CTCL therapies. Our data demonstrate that bexarotene is well tolerated in most patients and responses are seen in almost half of patients with all disease stages. However partial responses were not graded and would include any improvement seen in the skin, blood and lymph node.

HLA-Identical Allogeneic Stem Cell Transplantation (alloSCT) for Patients with Primary Cutaneous T-Cell Lymphoma (CTCL): A Retrospective Analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation (EBMT-LWP).

Patients with aggressive forms of Mycosis Fungoides (MF), Sézary syndrome (SS) and other less common subtypes of primary CTCL have a dismal prognosis with conventional therapy. A potential role for alloSCT in these patients has been suggested by a number of case-reports and small series. We conducted a retrospective registry analysis of 64 recipients who received an alloSCT from HLA-identical donors (52 related, 12 unrelated) for advanced CTCL reported to EBMT between 1997 and 2006: 23 MF, 21 SS, 16 primary cutaneous anaplastic large cell lymphoma and 4 subcutaneous panniculitis-like T-cell lymphoma; 38 patients were male, 26 were female; median age was 46 years (5–65); median follow up of survivors was 28 months. AlloSCT was performed at a median of 22 (3–313) months from initial diagnosis, following a median of 3 (1–8) prior lines of therapy, the stem cell source was PB in 54 cases and BM in 10 cases, reduced-intensity conditioning (RIC) was used in 41 (64%) cases. Twenty-three percent of patients were in complete response (CR) and 26% in partial response (PR) at the time of alloSCT. All other patients were primary refractory (RE, 25%) or progressed after a previous response (PG, 26%). Non-relapse mortality was 24% at 3 years, and appeared higher in patients receiving myeloablative conditioning (MAC) than in those receiving RIC alloSCT (35% vs 16%; p=0.06). Acute graft versus host disease (GVHD) occurred in 37% of patients at risk, and chronic GVHD in 69% of patients alive at day +100. The cumulative incidence of disease relapse (36% at 3 years) was significantly higher in patients with advanced disease status at alloSCT (RE/PG 46% vs CR/PR 21%; p=0.01), but similar in patients with related and unrelated donors (p=0.39) and receiving MAC or RIC (p=0.6). Progression free survival (PFS) at 3 years was 41%, with a significant advantage for patients in CR/PR at alloSCT (58% vs 26%; p<0.01), but not for type of conditioning (MAC 45% vs RIC 44%; p=0.4) or donor type (related 46% vs unrelated 33%; p=0.2). Out of 22 patients who relapsed, 10 remain alive and 4 of these were in CR at last follow up, possibly indicating that a proportion of patients achieved a better control of CTCL following relapse after alloSCT. Overall survival for the whole series was 55% at 3 years, with a trend towards an improved OS for patients with disease in CR/PR at transplant (65% vs 46%; p=0.1). Overall, outcome after allogeneic transplantation appears superior to that expected for such patients under conventional therapy. Our analysis reinforces the important role of alloSCT in advanced stage CTCL in a relatively large registry-based series.

Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation

AbstractAlthough mycosis fungoides (MF) is typically an indolent disease, patients with advanced-stage disease (stages IIB-IVB), including Sézary syndrome (SS), often have a poor outcome. A 31-year, retrospective analysis of our cutaneous lymphoma database, of 297 patients with MF and SS, was undertaken to study long-term outcomes and identify clinical predictors of outcome in patients with advanced-stage disease (ASD, n = 92) and large cell transformation (LCT, n = 22). Two-thirds of patients with ASD presented with de novo ASD. The median overall survival (OS) for ASD was 5 years with a 10-year predicted OS of 32%. Age at initial diagnosis (P = .01), tumor stage (P = .01), and clinical stage (P = .001) were found to be significant predictors of outcome. Patients who presented with de novo ASD demonstrated better outcomes that were not statistically significant than those with a prior diagnosis of early-stage MF (P = .25). Transformation developed in 22 of the 297 MF/SS patients (7.4%), with a transformation rate of only 1.4% in patients with early-stage disease, compared with stage IIB (27%) and stage IV (56%-67%) disease. The median OS from diagnosis of LCT was 2 years. We confirm that the incidence of LCT is strongly dependent on tumor stage at diagnosis, and we demonstrate a much lower overall risk of LCT than previously reported.

Rexinoids Modulate Steroid and Xenobiotic Receptor Activity by Increasing Its Protein Turnover in a Calpain-dependent Manner

The steroid and xenobiotic receptor SXR (human pregnane X receptor) is a nuclear receptor that plays a key role in the body's detoxification response by regulating genes involved in drug metabolism and transport. SXR ligands include a wide range of compounds, which induce transcription of SXR target genes via activation of a heterodimeric transcription factor consisting of SXR and the related nuclear receptor retinoid X receptor (RXR). We investigated the effect of RXR-selective ligands, rexinoids, on SXR/RXR activity. In agreement with previous reports, we found that rexinoids are weak activators of SXR, but we also found that they can antagonize SXR activation by the potent SXR agonist rifampicin. This antagonism included suppression of rifampicin-induced expression of SXR target genes, as well as reduced binding of SXR/RXR to SXR response elements both in vivo and in vitro. Interestingly, two rexinoids, bexarotene (LGD1069/Targretin) and LG100268, caused a rapid and sustained decrease in the protein levels of both SXR and RXR. The decrease in SXR level was due to an enhanced rate of protein degradation and was dependent on calpain activity, as opposed to rexinoid-induced RXR degradation, which is mediated via the proteasome. Thus, we have demonstrated a novel, rexinoid-modulated mechanism regulating SXR protein stability, which may explain why rexinoids are only weak activators of SXR/RXR-mediated transcription, despite reports that they bind to SXR with high affinity. We suggest that the ability of rexinoids to induce degradation of both SXR and RXR, in combination with competition for binding to SXR, can also explain why rexinoids antagonize the activation of SXR by drugs like rifampicin.

Efficacy and safety of denileukin diftitox (Dd) in cutaneous T-cell lymphoma (CTCL) patients: Integrated analysis of three large phase III trials

8551 Background: ONTAK (Dd), a fusion protein targeting IL-2 receptor in malignant cells, is approved for the treatment of persistent/recurrent CTCL expressing CD25. Dd has been studied in 307 early or advanced stage CTCL patients in three large Phase III trials, Studies #10, #11, #14, the last two recently completed. Integrated efficacy and safety analysis of the trials is presented. Methods: Dd doses were 9 or 18 μg/kg IV, daily for 5 days, repeating every 21 days, up to 8 courses. Patients in Study #10 and #11 were CD25(+) (ie. had CD25 immunostaining in > 20% of malignant cells); Study 14 also included CD25(-) patients. Response confirmation required 3 consecutive courses and was adjudicated by an independent Data Endpoint Review Committee in each trial, using a weighted severity skin, blood and lymph node count. Primary endpoint: Overall Response (ORR, including complete [CR], clinical complete [CCR], or partial [PR] response). Key secondary endpoint: Progression-Free Survival (PFS). Results: Demographics: similar across trials and between arms on each study. Integrated efficacy results are shown in the Table below. Placebo data provides the first detailed measure of spontaneous responses in CTCL patients. Both Dd doses showed significantly better ORR and PFS and lower rates of PD than placebo. Both CD25(+) and CD25(-) patients responded to Dd. Retreated patients also showed significant benefit. Many (70%) Dd responses were confirmed at Course 5 or later. Most AEs were mild or moderate. Grade 3/4 AEs (Dd 74%, Placebo 36%), and SAEs (Dd 41%, Placebo 20%) decreased to placebo levels after course 2 or 3. Conclusions: This analysis represents the largest investigation of a single agent for treatment of CTCL with a placebo arm. The data provide evidence of efficacy and clinical benefit for Dd in all patients with CTCL, regardless of CD25 status. Integrated Efficacy Results Efficacy Endpoint Placebo (N=44) All Dd-treated (N=263) Dd HD CD25(+) (N=118) Dd HD CD25(-) (N=36) Dd Retreated* (N=29) ORR (%) 15.9 38.0** 47.5** 30.6 27.6 CR/CCR 2.3 9.1 11.0 8.3 6.9 PR 13.6 28.9 36.4 22.2 20.7 PD 52.3 17.5 11.0 25.0 34.5 PFS (median days) 124 794** 870** >487** 205** * Patients who responded to Dd on Study 10 or 11, then relapsed and were retreated on Study 14. ** P<0.02 or better compared with Placebo. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eisai Eisai Eisai Ligand

Rexinoids and Breast Cancer Prevention

In this issue of Clinical Cancer Research , Li et al. investigate the chemopreventive potential of the retinoid, LG100268 ([1][1]). The application of retinoids to cancer chemoprevention has a long history which predates the identification of retinoid receptors ([2][2], [3][3]). Early clinical

Hypertriglyceridemia presenting as “pink blood” and elevated hemoglobin level

American Journal of HematologyVolume 83, Issue 3 p. 253-253 Images in HematologyFree Access Hypertriglyceridemia presenting as “pink blood” and elevated hemoglobin level Donald E. Tsai, Corresponding Author Donald E. Tsai detsai@mail.med.upenn.edu Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PennsylvaniaUniversity of Pennsylvania Medical Center, 16 Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104Search for more papers by this authorAnthony Mato, Anthony Mato Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PennsylvaniaSearch for more papers by this authorDavid L. Porter, David L. Porter Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PennsylvaniaSearch for more papers by this authorDan T. Vogl, Dan T. Vogl Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PennsylvaniaSearch for more papers by this author Donald E. Tsai, Corresponding Author Donald E. Tsai detsai@mail.med.upenn.edu Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PennsylvaniaUniversity of Pennsylvania Medical Center, 16 Penn Tower, 3400 Spruce Street, Philadelphia, PA 19104Search for more papers by this authorAnthony Mato, Anthony Mato Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PennsylvaniaSearch for more papers by this authorDavid L. Porter, David L. Porter Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PennsylvaniaSearch for more papers by this authorDan T. Vogl, Dan T. Vogl Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, PennsylvaniaSearch for more papers by this author First published: 27 August 2007 https://doi.org/10.1002/ajh.21054AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Duvic M,Hymes K,Heald P, et al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: Multinational phase II–III trial results. J Clin Oncol 2001; 19: 2456– 2471. 2 Tsai DE,Aqui NA,Vogl RD, et al. Successful treatment of T-cell posttransplant lymphoproliferative disorder with the retinoid analog bexarotene. Am J Transplant 2005; 5: 2070– 2073. 3 Shah PC,Patel AR,Rao KRP. Hyperlipidemia and spuriously elevated hemoglobin values. Ann Int Med 1975; 82: 382– 383. Volume83, Issue3March 2008Pages 253-253 ReferencesRelatedInformation

Pegylated liposomal doxorubicin (PLD) as an alternative treatment of cutaneous T-cell lymphoma

8096 Background: Therapy of cutaneous T-cell lymphoma (CTCL) at early stages consists of various modalities. The advanced or transformed stage of CTCL is treated by the CHOP regimen as standard chemotherapy; has a 40% response rate and relapses within 6 months in &gt; 60% of pts. Methods: A prospective open multicentre Phase II study to evaluate the use of PLD as a CTCL therapeutic agent, with 25 pts, (59±12 years). Eligibility criteria: Pts with histologic proof of CTCL stage II to IV, unresponsive to at least 2 lines of therapy; transformed CTCL or non epidermotropic lymphoma CD30 + or CD30. PLD was administered i.v., 40 mg/m2 every 4 wks for 8 cycles. Objective of study was overall response rate (ORR); secondary objectives were safety, disease-free survival (DFS) and overall survival (OS). Results: Phase II study of 14pts with CTCL stage IIb/III, and 11pts with transformed CTCL, at baseline. Treatment duration was 8 cycles in 13 pts, 2–6 cycles in 10pts, and 2 pts were withdrawn during cycle 1 due to anaphylactic-like reactions. Among 23 treated pts, 5pts (22%) achieved a complete response (CR), 9pts (39%) a partial response (PR), with 61% ORR. DFS was 18 ± 4.5 mos; longest treatment duration was 24 mos. Median OS was 28 ± 3 mos. In general, PLD treatment was well tolerated. The main adverse events were grade 3 neutropenia (4%); grade 3 septicemia (8%) and 1 case of bilateral grade 3 pneumopathy. There were only 3 cases of grade 1 palmoplantar erythrodysesthesia. Conclusions: This is the first prospective multicentric study investigating activity and tolerance of 40 mg/m2 q28days of PLD in CTCL. The current study confirmed effectiveness of PLD(∼61%) in CTCL treatment, but did not show improved efficacy with dose increases (Wollina, Cancer, 2003). This data combined with Wollina’s data, support the use of PLD as a promising therapy in advanced stages of CTCL. The duration of response is superior to that achieved with CHOP. This has been confirmed in a small, trial, and needs to be confirmed in a larger trial. No significant financial relationships to disclose.

A Pilot Study of Alemtuzumab Plus Combination Chemotherapy for Newly Diagnosed Patients with Peripheral T-Cell Lymphomas.

The results of combination chemotherapy for peripheral T cell lymphoma (PTCL) still showed poor, although alemtuzumab monotherapy has therapeutic activity in PTCL. We evaluated the safety and effectiveness of several combination chemotherapies with alemtuzumab for treating newly diagnosed PTCL including advanced stage cutaneous T-cell lymphoma. Nine patients with PTCL were included. The pathologic subtypes were as follows: cutaneous T cell lymphoma (CTCL) in 2 patients, peripheral T cell lymphoma unspecified (PTCLu) in 2 patients, extranodal NK/T cell lymphoma, nasal type in 3 patients, angioimmunoblastic T cell lymphoma (AITL) in 2 patient. Patients received a 30mg of alemtuzumab intravenously over about 8 hours on the first day of combination chemotherapy. The combination chemotherapy regimens included: CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) in 2 patients; EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide and adriamycin) in 2 patients; IMVP16-PL (ifosfamide plus mesna, methotrexate, etoposide and prednisolone) in 5 patients. Complete remission was achieved in 2 patients, and partial remission was achieved in 5 patients, only one patient encountered treatment related mortality (septic shock). Nine patients received nineteen cycles of alemtuzumab plus combination chemotherapy. Alemtuzumab infusion related adverse events were reported in 10 of 19 cycles and were mainly mild to moderate in severity. The most common events were shivers and chills during the alemtuzumab infusion period, which occurred in 8 of 19 cycles. Six (32%) cycles had one or more episodes of new onset NCI-CTC grade 3 or 4 anemia. In addition, erythropoietin use was reported in 7 patients. All of the cycles had grade 3 or 4 neutropenia and 8 (42%) cycles had grade 3 or 4 thrombocytopenia. Grade 3 hyponatremia and grade 3 or 4 hypokalemia were observed in 1 and 4 cycles, respectively. Ten cycles (53%) with neutropenic fever occurred during the treatments. Six (32%) sepsis, 1 septic shock, 2 pneumonia, 2 fungal infection and 2 herpes zoster were observed. There was no cytomegalovirus reactivation during the treatment. Although alemtuzumab plus combination chemotherapy had significant hematologic and infection complications, we concluded that alemtuzumab plus combination chemotherapy was well tolerated and could be recommended for treating newly diagnosed PTCL. However, evaluation in more patients with long-term follow up is warranted.Patients characteristicsSexAgeStageRegimenCyclesAdditional TxResponseCTCL1Female22IVAAlemtuaumab+EPOCH3RTx4 + 2 IMVP16-PLPartial remissionCTCL2Female48IIIAAlemtuaumab+IMVP16-PL2RTx4Partial remissionPTCLuFemale70IIIAAlemtuaumab+CHOP33 CHOPComplete remissionPTCLuFemale50IVBAlemtuaumab+IMVP16-PL1NoPartial remissionNK/T3Male51IVBAlemtuaumab+IMVP16-PL1NoPartial remissionNK/T3Male46IIEAAlemtuaumab+IMVP16-PL3RTx4 + 1 IMVP16-PLComplete remissionNK/T3Male74IIEAAlemtuaumab+CHOP2NoTRM5(Sepsis)AITLFemale75IIIBAlemtuaumab+EPOCH2NoProgressionAITLMale70IVBAlemtuaumab+IMVP16-PL2NoPartial remission1Subcutaneous panniculitis T cell lymphom2Cutaneous gamma-delta T cell lymphoma3Extranodal T/NK cell lymphoma, nasal type4Radiotherapy5Treatment related mortality

LBH589, a Novel Deacetylase Inhibitor (DACi), Treatment of Patients with Cutaneous T-Cell Lymphoma (CTCL). Skin Gene Expression Profiles in the First 24 Hours Related to Clinical Response Following Therapy.

Background: LBH589 is a novel DACi in Phase I trials. Pre-clinical studies have demonstrated that DACi alter gene expression and other DACi have induced disease regression in CTCL. Indeed, CTCL is an ideal disease to assess variation in tumor gene expression over time following drug administration. In this study we evaluated the safety and activity of LBH589 in CTCL and examined changes in tumor gene expression in the first 24 hours following oral LBH589.Methods: Pts with advanced-stage CTCL, who had progressed following prior systemic therapy were entered into the oral DLT dose level 30 mg M,W,F cohort (n=1), the subsequent MTD dose level 20 mg M,W, F weekly (n=9). LBH589 was continued until disease progression or unacceptable toxicity. Intensive cardiac monitoring was performed. Six pts had 3 mm punch biopsies from CTCL-involved skin lesions at 0, 4, 8 and 24 h after administration, which were subjected to gene expression profiling using Affymetrix U133 plus 2.0 GeneChips with 47,000 probesets. Alteration in gene expression patterns was confirmed by QRT-PCR of selected genes. Individual gene expression analysis is underway, utilizing set enrichment analysis to elucidate the functional categories which correlate with degree of patient response.Results: 10 pts are currently evaluable for response. 2 of the pts attained a complete response (CR), 4 attained a partial response (PR), 1 achieved stable disease (SD) with ongoing improvement, and 2 progressed on treatment (PD). (RR = 6/10; 60%). Microarray data on 5 pts demonstrated distinct gene expression response profiles between pts. Individual gene expression within patient tumors varied over the timepoints in the first 24 hours following treatment. To demonstrate effects of LBH589 as an epigenetic modulator, global changes in gene expression patterns in responding versus progressing patients have been delineated. In addition, functional categories of genes which correlate with degree of patient response have been identified.Conclusions: LBH589 induces CR's in CTCL pts. Preliminary microarray analysis of tumor samples have identified distinct gene expression profiles.

Biologic Correlates of Response and Survival in Patients with Cutaneous T-Cell Lymphoma Treated with Denileukin Diftitox

BackgroundDenileukin diftitox, a fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domains of diphtheria toxin and human interleukin, resulted in a response rate of 30% in the phase III registration trial in patients with recurrent or persistent cutaneous T-cell lymphoma (CTCL). Little is known with regard to the biologic correlates of response or the impact of denileukin diftitox on disease progression and survival. Patients and MethodsIn our single-center series of 37 patients with earlyand advanced-stage disease with CTCL treated with denileukin diftitox at a dose of 9 μg/kg or 18 μg/kg per day, we observed an overall response rate of 51%. ResultsIn 8 patients with early-stage (< IIA) CTCL, there were 5 responses (62.5%), and the median survival has not been reached, with 70% of patients still alive at 46 months. In 29 patients with advanced-stage (≥ IIB) disease, there were 14 responses (49.3%), and the median survival was 31 months. Changes in the number of CD4+CD25+ T-cell populations were observed in 7 of 19 responders, with no overall changes in the absolute lymphocyte counts during the course of therapy. Decrease in lactate dehydrogenase was strongly correlated with clinical response (P < 0.05). ConclusionDenilekin diftitox was a well-tolerated treatment in early- and advanced-stage CTCL and was not associated with detrimental immunologic efects on lymphocyte populations.

LBH589, a novel histone deacetylase inhibitor (HDACi), treatment of patients with cutaneous T-cell lymphoma (CTCL). Changes in skin gene expression profiles related to clinical response following therapy

7501 Background: LBH589 is a novel histone deacetylase inhibitor in Phase I trials. Since other HDACi have induced disease regression in CTCL, we evaluated the activity of LBH589 and resulting changes in gene expression of LBH589 in CTCL patients (pts). Methods: Pts with advanced-stage CTCL, who had progressed following prior systemic therapy were entered into the DLT dose level 30mg M,W,F cohort (n = 1) or the subsequent MTD dose level 20mg M,W, F weekly (n = 10). LBH589 was continued until disease progression or unacceptable toxicity. The first three pts had 3mm punch biopsies from CTCL-involved skin lesions at 0, 4, 8 and 24h after administration, which were subjected to gene expression profiling using Affymetrix U133 plus 2.0 GeneChips with 47,000 probesets. Results: Eleven pts with CTCL have been entered to date. Two of the pts attained a complete response (CR), 3 attained a partial response (PR), 2 achieved stable disease (SD) with ongoing improvement, and 4 progressed on treatment (PD). Of particular interest, 2 pts who were initially SD required discontinuation because of toxicities (Grade III diarrhea at week 4, Grade II fatigue at week 12). Both had ongoing improvement in their disease achieving a CR and PR, respectively 3 months later. Of the 5 responding pts, one with a CR (discontinued after 10 doses due to Grade III diarrhea) progressed at 8m. Microarray data on the first 3 pts (2CR and 1PD) demonstrated distinct gene expression response profiles between the 3 pts. Surprisingly, the pt with PD showed the greatest transcriptional response with more than 16,000 genes activated or repressed over the 24 hr time course. Of these responsive genes, close to 60% were activated while 40% were repressed. In contrast, less than 1000 genes showed a 2-fold change in expression in the 2 pts with a CR with greater than 85% of the genes being repressed. Conclusions: LBH589 induce CR’s in CTCL pts. Regression of disease can occur some weeks after discontinuation of therapy. Preliminary microarray analysis of tumor samples indicated that LBH589 mediates changes in gene expression in vivo with an unexpected observed inverse relationship between the number of genes altered and clinical outcome. [Table: see text]

Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion

Bexarotene is an oral retinoid therapy that is effective for the treatment of early and advanced-stage cutaneous T-cell lymphoma (CTCL) in patients who have failed on other therapies. However, bexarotene treatment is associated with unavoidable side-effects, in particular hypertriglyceridaemia and hypothyroidism, which are manageable with adequate concomitant medications and are reversible on cessation of treatment. A pragmatic strategy for minimizing bexarotene-associated hypertriglyceridaemia and hypothyroidism is suggested, based on data from the studies with bexarotene in CTCL and on day-to-day experience with this agent in the clinical setting. The strategy anticipates that these common adverse events are likely to occur and recommends the early use of preventive therapy to lower triglycerides and elevate thyroid hormone levels in the blood, followed by subsequent monitoring, dose adjustment during bexarotene treatment, and titration of the daily bexarotene dose from 150 to 300 mg m(-2), which is optimal for most patients. When further information becomes available on how bexarotene interacts with lipid metabolism and thyroid function, the management approach suggested here may need to be changed.

Management of Refractory Early-Stage Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin's lymphomas that manifest primarily in the skin. Mycosis fungoides is recognized as the most common type of CTCL. Patients with early-stage CTCL usually have a benign and chronic disease course. However, although there is a wide array of therapeutic options for early-stage CTCL, not all patients respond to these individual therapies, resulting in refractory cutaneous disease over time. Refractory early-stage CTCL poses an important therapeutic challenge, as one of the principal treatment goals is to keep the disease confined to the skin, thereby preventing disease progression. Much of the focus of current research has been on the evaluation of already available skin-directed therapies and biologic response modifiers and combination regimens thereof, such as the combination of psoralen and UVA (PUVA) with interferon-alpha or retinoids. Recent novel developments include oral bexarotene, a retinoid X receptor-selective retinoid that has activity in all stages of CTCL and has been shown to be effective in patients with refractory early-stage disease as well as advanced-stage disease. Likewise, the topical gel formulation of bexarotene has proved to be an important therapeutic option in patients with refractory or relapsed lesions. Oral bexarotene and topical bexarotene have been approved by the US FDA for the treatment of refractory CTCL. Systemic chemotherapy is typically reserved for advanced-stage CTCL and is usually not recommended for early-stage, skin-limited disease. However, recent exploratory studies indicate that low-dose methotrexate may represent an overall well tolerated therapy in a subset of patients with refractory early-stage CTCL, as may pegylated liposomal doxorubicin, which is currently being investigated in this specific clinical setting. Another recently FDA-approved therapy is the interleukin-2 fusion toxin denileukin diftitox, which is now well established to play a role in the treatment of refractory CTCL, including early-stage extensive plaque disease. The value of other agents, such as topical tazarotene, topical methotrexate, and topical imiquimod, and of novel immunomodulatory approaches including monoclonal antibodies, still needs to be assessed for refractory early-stage CTCL.

Health-Related Quality-of-Life Assessment in Patients With Cutaneous T-Cell Lymphoma

To measure and evaluate the health-related quality of life (HRQOL) in patients with cutaneous T-cell lymphoma (CTCL), a visible cutaneous malignancy that may have a profound effect on patients' lives. Monocenter, cross-sectional study. The Skin Oncology Program, Department of Dermatology, and the Photopheresis Unit of Boston Medical Center. A total of 22 adult patients with confirmed CTCL. (1) Evaluation of general oncologic and skin disease-specific HRQOL using, respectively, the Functional Assessment of Cancer Therapy-General (FACT-G) and Skindex-29 profiles; (2) assessment of HRQOL association with disease stage (early stage, IA-IIA; late stage, IIB-IVB). Patients with more advanced CTCL stages reported more effects on general health (FACT-G), particularly in the physical, emotional, and functional domains (P < .05). Patients with early-stage CTCL reported better skin-specific HRQOL overall (Skindex-29; P = .002) and for each specific domain than did patients with late-stage disease. The Skindex-29 scales had high internal consistency, and the confirmatory factor structure was similar to that of previous studies. The HRQOL of patients with CTCL can be evaluated using the Skindex-29 and FACT-G instruments. Patients with more advanced stages of CTCL had lower HRQOL scores.