Large Cell Transformation Research Articles

Unilesional follicular mycosis fungoides: report of two cases with progression to tumor stage and review of the literature

Mycosis fungoides (MF) is the most common type of cutaneous lymphoma and has protean clinicopathological manifestations. Follicular or folliculotropic MF (FMF) is a rare variant, which histopathologically is characterized by pronounced folliculotropism of neoplastic T cells, with or without follicular mucinosis, and clinically by an impaired prognosis compared to classic MF. In contrast, unilesional MF is a very rare variant with an excellent prognosis, with a single case of large-cell transformation reported to date. The combination of folliculotropic and unilesional MF is very unusual, with only two cases reported to date. Here we report two patients with unilesional folliculotropic MF with progression to tumor stage in both patients. To the best of our knowledge, this is the first report on the disease evolution with large-cell transformation and progression of unilesional FMF. Complete remission was achieved by local radiation therapy in both patients. The differential diagnoses, classification and implications for the treatment of unilesional FMF as well as the pertinent literature are discussed.

Outcome of Patients Treated With a Single-Fraction Dose of Palliative Radiation for Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) is a radiosensitive tumor. Presently, treatment with radiation is given in multiple fractions. The current literature lacks data that support single-fraction treatment for CTCL. This retrospective review assesses the clinical response in patients treated with a single fraction of radiation. This study reviewed the records of 58 patients with CTCL, primarily mycosis fungoides, treated with a single fraction of palliative radiation therapy (RT) between October 1991 and January 2011. Patient and tumor characteristics were reviewed. Response rates were compared using Fisher's exact test and multiple logistic regressions. Survival rates were determined using the Kaplan-Meier method. Cost-effectiveness analysis was performed to assess the cost of a single vs a multifractionated treatment regimen. Two hundred seventy individual lesions were treated, with the majority (97%) treated with ≥ 700 cGy; mean follow-up was 41.3 months (range, 3-180 months). Response rate by lesion was assessed, with a complete response (CR) in 255 (94.4%) lesions, a partial response in 10 (3.7%) lesions, a partial response converted to a CR after a second treatment in 4 (1.5%) lesions, and no response in 1 (0.4%) lesion. The CR in lower extremity lesions was lower than in other sites (P=.0016). Lesions treated with photons had lower CR than those treated with electrons (P=.017). Patients with lesions exhibiting large cell transformation and tumor morphology had lower CR (P=.04 and P=.035, respectively). Immunophenotype did not impact response rate (P=.23). Overall survival was significantly lower for patients with Sézary syndrome (P=.0003) and erythroderma (P<.0001). The cost of multifractionated radiation was >200% higher than that for single-fraction radiation. A single fraction of 700 cGy-800 cGy provides excellent palliation for CTCL lesions and is cost effective and convenient for the patient.

Expression of FOXP1 in mucosa-associated lymphoid tissue lymphoma suggests a large tumor cell transformation and predicts a poorer prognosis in the positive thyroid patients

The forkhead box protein P1 (FOXP1) expression resulted from chromosome translocation was found in MALT lymphoma, and its nuclear expression in diffuse large B cell lymphoma has been believed to be a poor prognostic factor. In our study, FOXP1 expression was investigated in its relationship to the occurrence of large tumor cells, clinical features, and prognosis in a series of 115 MALT lymphomas divided into two groups with or without the large tumor cells. All cases were morphologically reviewed, and FOXP1 expression was detected both in mRNA and protein levels by real-time PCR, immunochemical staining, and Western blot hybridization. All available clinical data were collected. In the MALT lymphoma with large cells, FOXP1 expression was higher at both mRNA (P = 0.008) and protein (P = 0.000) levels than that in group without large cells, and most large tumor cells showed FOXP1 positivity. It was also found that cases beyond Ann Arbor stage I have a higher FOXP1 expression rate than cases in stage I (P = 0.01), moreover, FOXP1-positive group has more plasmacytic differentiation (P = 0.025), deeper filtrating depth in digestive tract (P = 0.039), and a higher Ki67 proliferation index (P = 0.022). However, no statistical significance was identified in the involved anatomic sites and prognosis. Our data demonstrated the close relationship between FOXP1 nuclear expression and the occurrence of large tumor cells in MALT lymphoma, which suggested the possibility of large cell transformation of FOXP1-positive cases. And FOXP1 positivity was associated with enhanced invasion and proliferation ability of tumor cells. In the thyroid cases, the FOXP1 positivity showed a poorer prognosis (P = 0.043), but the significance was not found in the overall survival analysis (P = 0.1123).

The expression of CXCR3 and CD30 in mycosis fungoides.

The clinical progression of mycosis fungoides (MF) often correlates with microscopic large cell transformation (LCT). It is reported that CD30 expression in the LCT of MF is associated with an absence of CXCR3 expression. This study investigates a large number of patients diagnosed with MF to determine the correlation between expression of CXCR3 and CD30 in additional sections. The study included archival skin specimens from 101 patients with MF. We analyzed these specimens by immunohistochemistry for expressions of CXCR3 and CD30. The biopsy specimens showed microscopic features of low grade MF (LG-MF) in 80 cases and transformed MF (T-MF) in 21 cases. Tumor lymphocytes expressed CXCR3 in 61 out of 80 cases (76.3%) of LG-MF and in 10 out of 21 cases (47.6%) of T-MF. CD30 positivity (CD30+) was seen in 16 of 80 cases (20%) of LG-MF and 12 of 21 cases (57.1%) of T-MF. The tumor cells in 8 of the 12 CD30+ T-MF cases showed scattered expression of CXCR3. CXCR3 expression was associated with epidermotropic T cell tumors but was greatly absent in dermal ones. Scattered or diffuse CD30 expression in T-MF was not associated with an absence of CXCR3 expression.

Recognizing large-cell transformation of mycosis fungoides

Although patients with mycosis fungoides (MF) typically experience an indolent disease course, a minority undergo a process of large-cell transformation (LCT), which often heralds more aggressive disease and shortened survival. Regrettably, most dermatologists are unfamiliar with LCT, and even fewer understand how to recognize it clinically. Because a diagnosis of LCT typically triggers more aggressive therapy and/or referral to cutaneous T-cell lymphoma (CTCL) centers, it is paramount for clinicians to be able to recognize suspect lesions visually. LCT is diagnosed histologically; however, diagnostic biopsy is performed only if transformed lesions are suspected clinically. Because the literature provides little information on what clinical features should lead to suspicion of LCT, we sought to identify and categorize the presentations of LCT to aid in its recognition. We identified 14 patients with biopsy-proven LCT confirmed by a board-certified dermatopathologist experienced with this diagnosis. The clinical presentations of LCT, timing of its evolution, and treatment regimens were evaluated by chart and photograph review. We devised 3 categories that clinically represent LCT: (1) LCT occurring as a new, solitary nodule within a classic MF patch or plaque, (2) LCT occurring as abrupt onset of multiple scattered papules and/or nodules without spontaneous resolution, and (3) LCT occurring within new or enlarging tumors. A larger number of reviewed cases might reveal additional clinical presentations of LCT. Dermatologists may use our categories of clinical indicators to recognize and diagnose LCT earlier, allowing implementation of more aggressive treatment regimens when appropriate.

Follicular Lymphoma with Diffuse Large B-Cell Component At Initial Diagnosis Appears to Be Associated with a Loss of BCL2 Translocation and Inferior Progression Free Survival

Abstract 1577 Background:Based on the WHO classification, follicular lymphoma (FL) is classically divided into 3 grades. In addition, WHO also recommends that the presence of diffuse large B-cell lymphoma (DLBCL) in a FL be reported as an estimate of the proportion of DLBCL involvement. While the prognostic value of grading is well characterized in FL, the clinical significance of diffuse areas in patients with FL is less well described. Hence, this study aims to describe the morphological, molecular characteristics, and clinical significance of the diffuse component in FL. Methods:We retrospectively studied 48 newly diagnosed follicular lymphoma with a diffuse large B-cell component (FLDC) patients between January 2000 and June 2010. Only patients with more than 10% diffuse component were included and cases with a prior history of FL with large-cell transformation were excluded. 35 of the 48 patients had fluorescence in situ hybridization (FISH) performed, using breakapart FISH probes targeting BCL2, BCL6, C-MYC, CCND1, MALT1 and IgH genes. We also investigated the significance of the proportion of diffuse component in patients with FL by percentage in the categories as follows: <25%, 25–75%, >75%.The clinical characteristics and survival outcomes of these patients were compared with 511 DLBCL patients. Results:A total of 48 patients diagnosed with FLDC were included in this study with a median follow-up of 33.3 months. The median age of diagnosis is 57 years (26–81) and 42 (88%) FLDC patients were of grade 3 FL. 20 patients (41%) had a high FLIPI score (3–5), while 40% had a high IPI score. All 48 patients were treated with combination chemotherapy, with 85% of patients receiving rituximab based chemotherapy. Interestingly, the results from the FISH analysis revealed that more than half (54%) of the FLDC patients did not carry the BCL2 translocation. There were 5 patients (14%) with double translocations, 2 patients with both BCL2 and BCL6 translocations and 3 patients with both BCL2 and MYC translocations. Among the FLDC patients, prognostic factors for overall survival (OS) identified by univariate Cox regression analysis were high IPI (p=0.042), presence of >75% diffuse component (p=0.031) and the absence of FISH BCL2 translocation (p=0.018). The 3 year OS was 94% in patients with the BCL2 translocation vs 58% in patients with no BCL2 translocation (p=0.043). Further analysis of the subgroup of FLDC patients without BCL2 translocation, demonstrated that the presence of BCL6 translocation did not appear to influence survival. Next, when compared to DLBCL patients, there was a significantly higher number of FLDC patients who were more likely to be male (75% vs 54%, p=0.016), stage III-IV disease (75% vs 47%, p=0.001), but more patients received rituximab-based chemotherapy (81% vs 64%, p=0.049). There were however no significant difference in the two groups in the median age of diagnosis and IPI score. The 3-year progression free survival (PFS) of FLDC patients is 48% compared to 67% DLBCL, although the difference was not significant (p=0.128). The 3-year OS was however similar in both groups. Conclusions:FLDC is an aggressive entity with the majority of patients presenting with grade 3 FL, more advanced disease and with a 3-year PFS of 48%. More than 50% of patients demonstrated a loss of BCL2 translocation and is associated with a poorer prognosis. A diffuse component of > 75% also portends an inferior outcome. Lastly, the IPI appears to be a more useful prognostic tool than FLIPI in patients with FLDC. Disclosures:No relevant conflicts of interest to declare.

Mycosis fungoides exhibiting features of a dermatofibroma: a case report and review of the literature

We present the case of a 60-year-old male with known stage IA mycosis fungoides (MF) who developed a suspicious tumor within a pre-existing lymphomatous plaque of the right forearm. Microscopy revealed an unusual mixed fibrohistiocytic proliferation as well as atypical intraepidermal and dermal lymphocytes. There was no evidence of large-cell transformation. Histopathological, immunohistochemical and clinical clues suggest this lesion might not have represented a dermatofibroma, but rather a hitherto unreported dermatofibroma-like process arising within a lesion of MF. The potential impact of this atypical lesion on the prognosis and clinical management of this patient highlights the importance of recognizing unusual clinical presentations of more common, benign lesions within this patient population.

Cutaneous Richter syndrome: Report of 3 cases from one institution

Richter syndrome (RS) is large-cell transformation of chronic lymphocytic leukemia (CLL). It commonly involves lymph nodes and bone marrow, but may rarely manifest in skin. Certain triggering factors, such as Epstein-Barr virus infection and p53 overexpression, have been implicated in the pathogenesis of RS. Here, we present 3 cases of cutaneous RS from our institution with a follow-up period of up to 8 years. We present a series of cutaneous RS from a single institution with the longest follow-up period (up to 8 years) to date. Clinical characteristics were collected and histopathological findings of skin biopsy specimens were analyzed. All 3 patients had prior CLL and later developed cutaneous RS lesions. The mean age at the diagnosis of cutaneous RS was 67 years old. The time intervals between CLL and cutaneous RS were 3 to 8 years. Skin biopsy specimens demonstrated dermal nodular or perivascular infiltrates of large B cells, showing similar immunophenotypes to the lesional cells in the original CLL. Overexpression of p53 and positive stain for Epstein-Barr virus--encoded small RNA was found in one patient. One patient remained alive 8 years after the diagnosis whereas the other two died of the disease at 5 years and 3 weeks, respectively, after the onset of cutaneous RS. Three patients with RS were followed up for up to 8 years. Our findings suggested that, in contrast to extracutaneous RS, cutaneous RS generally has a less aggressive course with longer survival unless other worse prognostic factors are present.

Primary Follicular Lymphoma of the Gastrointestinal Tract Presenting as an Isolated Colon Polyp

Purpose: A 56 year-old male presented for a routine screening colonoscopy. A 1.5cm polyp found in the sigmoid colon was excised. Analysis of the polyp demonstrated a dense lymphoid infiltrate involving the submucosa and lamina propria. The infiltrate coalesced into vague nodular pattern structures resembling follicles with destruction and gland drop-out appreciated by immunostains of CD20 and CD3. Portions of colonic tissue with extensive infiltration of mainly small mature lymphocytes with scattered larger lymphocytes displayed prominent nucleoli. Immunohistochemical stains showed B-cells positive for CD10, CD20, Bcl-2, Bcl-6. The proliferation index Ki-67 was low overall, ranging from 5% to 15%. The CD3 stain highlighted small T-cells outside the follicular structures. The CD21 stain revealed residual disrupted follicular dendritic meshwork. Stains for cyclin-D1 on P53 were negative. The morphology in conjunction with immunohistochemical studies was diagnostic for follicular lymphoma, grade 1-2/3. No evidence of large cell transformation in the specimen.Staging for NHL with CT revealed no evidence suggestive of lymphoma. Primary GI lymphoma is a relatively rare disease, accounting for 11 to 34% of all non-Hodgkin's lymphomas. These lymphomas are mostly B-cell type with the predominate subtype being the diffuse large-cell type.Primary follicular lymphomas (FL) of the GI tract are very rare, accounting for less than 7% of all non-Hodgkin's lymphomas at this site. Primary follicular lymphoma of the GI tract has a predominant female preponderance. The most common site is the small intestine.The clinical manifestations and gross appearance of the lesions are related to the site of the GI involvement, with obstructing masses or wall thickening frequently seen with small intestine involvement and polyps in the colon and rectum.FL of the GI tract can be morphologically and immunophenotypically indistinguishable from nodal FL, with expression of CD20, CD10, and BCL2. As primary FL of GI tract is very rare, no definitive therapeutic approaches have been defined. Therapeutic interventions like surgery and chemotherapy are no indicated unless clinical symptoms are present or the disease is progressive.Figure: A: POSITIVE FOR CD20, CD10, Bcl-6, & Bcl-2. Ki-67=low (5 to 15%). CD21 & CD3 negative. Figure B: Sigmoid polyp.

CD30+ Neoplasms of the Skin

Cutaneous T-cell lymphomas (CTCLs) are subdivided by lesion morphology, behavior, and surface receptors. Mycosis fungoides (MF) and Sézary syndrome (SS) are derived from CD4+ effector or central memory T-cells respectively. MF presents clinically as patches, plaques, or tumors, and SS presents with erythroderma. After MF/SS, the next most common CTCLs are CD30+ lymphoproliferative disorders: self-regressing lymphomatoid papulosis (LyP) or tumors of anaplastic large-cell lymphoma (ALCL), which express high levels of tumor necrosis factor death receptor member 8, also called CD30. Although MF is not considered to be a CD30+ lymphoproliferative disorder, MF may co-exist with LyP lesions, and MF may express CD30, especially in the setting of large-cell transformation. The development of targeted therapy for CD30+ CTCLs will help in understanding the importance of the CD30 death receptor in pathogenesis and will improve treatment options.

Erythema gyratum repens‐like eruptions with large cell transformation in a patient with mycosis fungoides

Erythema gyratum repens‐like eruptions with large cell transformation in a patient with mycosis fungoides

Primary Follicular Lymphoma of the Duodenum Is a Distinct Mucosal/Submucosal Variant of Follicular Lymphoma: A Retrospective Study of 63 Cases

Small series with limited follow-up have suggested primary follicular lymphoma of the duodenum (FL-D) to be an indolent disease. We report our experience on a large series of patients followed for a median time period of longer than 6 years. The study comprised 63 patients with primary FL-D defined as stage I disease. Endoscopy and detailed pathologic work-up was performed at diagnosis and at restaging to monitor the behavior of the neoplastic process. Histologically, all 63 patients had FL, low grade (1 to 2). Duodenal endosonography demonstrated lesions confined to mucosa/submucosa in 19 of 20 patients. At an overall median follow-up of 77 months (range, 12 to 177 months), only two untreated patients had developed nodal disease, the remaining 61 patients never experienced extrasmall intestinal disease and large cell transformation did not occur at all. Among 24 patients followed by watch and wait strategy, seven showed spontaneous complete regression and 17 had stable disease; radiotherapy resulted in complete regression in all 19 patients; anti-CD20 antibody monotherapy achieved complete regression in four patients and stable disease in one patient. Various chemotherapy protocols in eight patients caused complete regression in all of them, but local relapses occurred in three. No patients required surgery or died of disease. These findings characterize primary FL-D as a remarkably indolent FL variant, which, even left untreated, does not develop tumorous growth, very rarely disseminates (two of 63 patients) and does not transform to high grade disease. A watch and wait approach appears to be the most sensible strategy.

Features of large cell transformation of indolent lymphomas as observed on sequential PET/CT

Detection of large cell transformation (LCT) has been reported with the increasing use of PET/computed tomography (CT) in patients with indolent lymphomas. However, there is little information on PET/CT characteristics, specifically, the distribution of lesion maximum standardized uptake value (SUV(max)) within a patient, or SUV(max) changes before and after LCT. Our objectives were to compare SUV(max) values and distribution between nontransformed and LCT patients; to compare SUV(max) of LCT and nontransformed lesions in patients with documented focal transformation; and to measure the SUV(max) changes in patients before and after LCT. Retrospective study of patients with LCT (n=29)compared with nontransformed (n=41), and comparison of LCT and nontransformed lesions within patients and over time. On average, the highest SUV(max) was greater in LCT patients than in nontransformed patients. In addition, there was a wider range of SUV(max) values in the LCT group compared with the nontransformed group (P<0.05). The median ratio of the SUV(max) of 12 LCT to nontransformed biopsy-proven lesions in the same patient was 4.3, P value of less than 0.05 (range 2.6-15.5). In 10 of 12 patients it was greater than or equal to 3. No change in highest SUV(max) and distribution was shown on serial PET in untreated nontransformed patients. LCT is often focal and is associated with higher SUV(max) than nontransformed. The emergence of a focus with SUV(max) three times or higher than others on a single scan, or that has tripled or more in value on serial scans, should raise suspicion for LCT.

Large cell transformation of mycosis fungoides： a case report

The clinical course of mycosis fungoides is indolent except when large cell transformation occurs. Large cell transformation of MF is rare and easy to misdiagnose. A case of large cell transformation of mycosis fungoides is reported. A 40-year-old man presented with a 10-year history of pruritic erythema and papules in the trunk and extremities as well as a 5-month history of nodules on the nape of the neck.Histopathologically, the erythematous patch showed typical changes of mycosis fungoides, while the tumor cells were small and expressed CD3 and CD4, and only a small number of tumor cells expressed CD30. Pathological examination of nodular lesions revealed the infiltration of large pleomorphic lymphoid cells expressing CD3 and CD4 throughout the entire dermis. There was an epidermotropism of large cells, and about 40% of these cells expressed CD30. Based on the medical history and histological findings, the patient was diagnosed with large cell transformation of mycosis fungoides. The lesions improved markedly after 3-week treatment with oral acitretin （30 mg once daily）, subcutaneous interferon-alpha （2 × 106 IU thrice a week） and local superficial X-ray irradiation for nodular lesions. Up to the time of this writing, the patient had been followed. Key words: Mycosis fungoides; Large cell transformation; Antigens, CD30

Le MF interstitiel : une variante rare de mycosis fongoïde

Mycosis fungoids can present with various clinical and histological features, with only a few of them being recognized as distinct entities in the current WHO and EORTC classifications. Histologically, mycosis fungoids (MF) usually show a superficial perivascular or band-like lymphocytic infiltrate with epidermotropism. We here report two cases of a rare histological variant of MF, called interstitial in the literature. Our first patient, a 71-year-old male, had a previously diagnosed MF, which clinically evolved towards nodules, showing histologically an interstitial lymphocytic infiltrate without epidermotropism and without large cell transformation. The second patient was a 64-year-old female with widespread plaques and nodules. Histologically, a dense dermal interstitial infiltrate was observed, with foci of epidermotropism, without large cell transformation. At relapse after treatment, she presented with plaques, papules and nodules, histologically showing a slight interstitial lymphocytic infiltrate that resembled granuloma annulare or inflammatory morphea. In both patients, clinical aspect suggested MF and a dominant T-cell clone was found in lesional skin. Nodules in MF are not always the hallmark of large cell transformation, but may correspond to unusual interstitial lesions. Diagnosis of such rare variant may be difficult and requires a good clinical pathological correlation together with the search for foci of epidermotropism on skin biopsy and for a dominant cutaneous T-cell clone.

Cutaneous T-Cell Lymphoma

Cutaneous T-Cell Lymphoma

Expression of Thymidine Phosphorylase in Lymph Nodes Involved with Mycosis Fungoides and Sézary Syndrome

Thymidine phosphorylase may be overexpressed in both neoplastic cells and tumor stromal cells in a variety of malignancies. Our study explores thymidine phosphorylase expression in lymph nodes (LNs) from patients with mycosis fungoides (MF) or Sézary syndrome (SS). In MF/SS, the LNs may have a pathologic diagnosis of either dermatopathic lymphadenopathy (LN-DL) or involvement by MF/SS (LN-MF). We performed immunohistochemical staining on MF/SS lymph nodes using antibodies to thymidine phosphorylase, CD68, CD21, CD3, and CD4. In both LN-DL and benign nodes, thymidine phosphorylase staining was noted only in macrophages, dendritic cells, and endothelial cells. In LN-MF, thymidine phosphorylase expression was also noted in subsets of intermediate to large neoplastic T cells. Concurrent CD68, CD21, CD3, and CD4 staining supported the above observations. Similar results were noted in the skin and in LN-MF with large cell transformation. Other T-cell lymphomas were also examined (total 7 cases); only enteropathy-type T-cell lymphoma (1 case) showed TP positivity in neoplastic T lymphocytes. We demonstrated that thymidine phosphorylase staining is present in neoplastic T cells in mycosis fungoides. The exact mechanism needs further investigation.

Low Dose Bexarotene and Ultraviolet A Photochemotherapy (PUVA) In a Prospective Phase II Clinical Study for Refractory and/or Resistant Cutaneous T Cell Lymphomas (CTCL)

AbstractAbstract 3953Oral bexarotene, a novel retinoid that selectively activates retinoid × receptors, is approved for the treatment of cutaneous manifestations of refractory or relapsed cutaneous T cell lymphomas (CTCL) as monotherapy. Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of CTCL who were refractory or intolerant to the previous therapy but the recommended bexarotene dose of 300 mg/m2/day is associated with significant side-effects. Novel studies are looking for synergistic therapies combining lower bexarotene doses in order to reach the same or even better outcomes while avoiding a negative impact on the quality of life. Early studies with bexarotene and psoralen plus ultraviolet A photochemotherapy (PUVA) show promise. Synergy between bexarotene and PUVA may derive from retinoid-induced reductions in epidermal thickness, which consequently improves UVA penetrations, and/or from retinoid-specific enhancement of immune functions. The aim of this study was to assess the efficacy and safety of a 2 stage-protocol (induction and maintenance) with low dose bexarotene (Targretin) and PUVA in refractory and/or resistant patients with Mycosis Fungoides (MF) and Sézary Syndrome (SS).A prospective, phase 2 clinical study was conducted between February 2007 and May 2010 by two Italian academic hospital centers. We enrolled 15 patients with stages I through IV MF/SS; all patients had failed PUVA or several systemic regimens. Response to treatment was assessed with clinical endpoints such as remission of symptoms (pruritus, pain, sleep disturbance) and signs (erythema, scaling, thickness of plaques, presence of nodules, tumours, peripheral lymphadenopathy). Complete remission (CR) was defined as the disappearance of all clinical evidence of disease for at least 4–6 weeks, partial remission (PR) as 50% or more decrease in extent or severity of disease. Overall response (OR) rate was defined as the combination of CR/PR. Patients with MF/SS were started with bexarotene (150 mg/day) and PUVA (three times weekly). Increments of bexarotene to a maximum of 300 mg/day were scheduled. Patients who achieved CRs and PRs during the induction remained on the same dose in the maintenance period, whereas the frequency of PUVA was gradually reduced. A preventive therapy to lower triglycerides and elevated thyroid hormone levels in the blood, was administered in all cases; therapeutic dietary and lifestyle changes were often recommended.Primary endpoint were OR rate at the end of induction and maintenance; secondary endpoints were safety and event-free survival (EFS). Kaplan-Meyer method and long-rank test was used for statistical analysis.All 15 patients (8 M and 7F) were evaluable for response; ten patients had early-stage (IB) and 5 had advanced stage (2 IIB, 1 IIIA, 1 IIIB, 1 IV). The median age was 68 years (34-81). The OR rate was 93% with 33% CR after induction period and 93% with 47% CR at the end of the protocol. A response was observed even in 1 case with SS and in 2 cases with MF in large cell transformation. Significantly, patients treated previously with PUVA monotherapy achieved better and faster CR compared with those treated with more than one systemic therapy (83% and 22% respectively; χ2 test, P=0.041; median time to maximal response 4 weeks and 8 weeks respectively, P=0.007). Median EFS at 37 months, for the whole group was 27 months. All patients have been closely monitored for adverse events during treatment; 2 of 15 patients (13%) had mild grade I-II asthenia, hypercholesterolemia and central hypothyroidism, 2 patients developed elevations of CPK (grade 3). With regard to hematologic toxicity, leukopenia was mild (grade I) and occurred in 3 patients (20%).In conclusion, our study have demonstrated a greater than 90% response rate in patients with all stages of CTCL refractory or intolerant to the previous therapies; the efficacy is more pronounced in patients previously treated with PUVA monotherapy. Starting treatment at lower dose of bexarotene followed by dose escalation may improve the efficacy and safety of both bexarotene and PUVA. Moreover the additional maintenance phase seems to improve the OR and length of remissions. Disclosures:Leoni:Celgene: Honoraria.

Pralatrexate Is An Effective Treatment for Heavily Pretreated Patients with Relapsed/Refractory Transformed Mycosis Fungoides (tMF)

AbstractAbstract 1762 Background:Cutaneous T-cell lymphoma, which includes mycosis fungoides (MF) and the Sézary Syndrome, is an indolent T-cell lymphoma. Large-cell transformation (tMF) is a well-defined histopathological disease that is distinguished from primarily cutaneous MF by the presence of large cells that exceed 25% of total lymphoid infiltrate (Barberio et al. Br J Dermatol 2007; 157:284-9) and occurs in 11% to 23% of cases. tMF represents a significantly poorer prognostic subset of MF patients with median overall survival of 12 to 22 months from the time of diagnosis of large-cell transformation (Arulogun et al. Blood 2008; 112:3082-7). There is no standard therapy for tMF and most patients are treated with multiagent systemic chemotherapy regimens. Because of its poor outcome similar to that of aggressive peripheral T-cell lymphomas (PTCLs), tMF patients were included in PROPEL, the pivotal study that led to the accelerated approval of pralatrexate (FOLOTYN®) in the United States for the treatment of relapsed or refractory PTCL. Methods:Of 109 evaluable patients in the PROPEL trial, 12 patients had histologically confirmed tMF. All patients received pralatrexate at a dose of 30 mg/m2 weekly for 6 weeks in a 7 week cycle. Results:Of the 12 patients with tMF, the median age was 56.5 years. The median number of prior therapies was 6.5 (range 1 to 12), and 5 patients (42%) received ≥5 prior systemic regimens. The majority of patients had received prior multiagent chemotherapy, including cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) or CHOP-based therapy in 67% of patients and other multiagent regimens in 17% of patients. Only 1 of 12 patients had a response to their most recent prior chemotherapy regimen. The objective response rate (ORR) to pralatrexate in this group of refractory tMF using International Workshop Criteria based on investigator assessment, was 58%. Consistent with the overall study population, the ORR by independent central review was 25%. The difference in ORR between independent central review and investigator assessment for tMF is mainly due to challenges with photodocumentation of response assessment of cutaneous lesions. The 12 patients with tMF received a median of 10 doses of pralatrexate and remained on treatment for a median of 89 days. The median response duration was 4.4 months and median PFS was 5.3 months, per investigator assessment. The median survival in this group of patients was 13 months. Mucosal inflammation was reported in 7 patients (58%) including 1 patient with grade 3. Grade 4 adverse events (AEs) were fatigue (1 patient) and thrombocytopenia (1 patient). Overall, patients with tMF were able to tolerate full-dose pralatrexate treatment, with no patients discontinuing due to an AE. Conclusions:Pralatrexate demonstrated significant activity in the 12 refractory tMF patients enrolled in the PROPEL trial with an investigator assessed response rate of 58%. Pralatrexate should be considered as a treatment option for patients with tMF. Disclosures:Foss:Allos Therapeutics, Inc.: Consultancy, Speaker. Horwitz:Allos Therapeutics, Inc.: Consultancy, Research Funding. Pinter-Brown:Allos Therapeutics, Inc.: Consultancy. Goy:Allos Therapeutics, Inc.: Consultancy, Honoraria. Pro:Allos Therapeutics, Inc.: Research Funding. Savage:Allos Therapeutics, Inc.: Consultancy, Honoraria. Shustov:Allos Therapeutics, Inc.: Honoraria, Research Funding. Zain:Allos Therapeutics, Inc. : Speakers Bureau. Koutsoukos:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.

In Situ Vaccination with TLR9 Agonist Combined with Local Radiation In Mycosis Fungoides: Analysis of Phase I/II Study

AbstractAbstract 286 Background:In a murine model, our in situ vaccination therapy combining tumor antigens with TLR9 agonist cured mice of lymphoma. Our phase I/II study in indolent B-cell lymphoma demonstrated that this in situ vaccination maneuver utilizing local radiation to expose tumor antigens combined with CpG ODN was well-tolerated without treatment limiting toxicities. It induced meaningful systemic clinical responses and tumor-reactive memory CD8 T-cells. In parallel, we explored this in situ vaccination strategy in cutaneous T-cell lymphoma (CTCL), specifically mycosis fungoides (MF). Our objectives were to determine the feasibility and safety and to assess the local and systemic antitumor effects in MF. Methods:Patients with MF stages IA-IVA who failed ≥1 standard therapy were eligible. Immunization site was treated with low-dose radiation (2 Gy × 2 d), bracketed by intratumoral injection of CpG followed by weekly intratumoral CpG × 8. Local (immunized site) and systemic antitumor responses were assessed at wk 0, 2, 4, 8, 12, then monthly until PD/off-study. Clinical response was evaluated by assessing skin disease burden at sites not treated with immunization procedure. Results:Study enrollment was completed with total of 15 patients. Median age was 57 yrs (range 18–71 yrs), 12 of 15 were male. Six patients had stage IB and 9 with stage IIB (3 with large-cell transformation). Median number of prior therapies was 5 with range of 2–9. After the initial 6 patients, a second immunization site was added at wk 4 to enhance systemic response. Total of 5 partial responses were observed (30% OR); 2 of 6 treated with single immunization and 3 of 9 with dual immunization. Median time to response was 8 wks (range 4–12 wks), duration of response 7 wks (range 4–44 wks), and time to progression 20+ wks (range 3–44+ wks). Patients with large-cell transformed MF did not respond. Common toxicities were injection site and flu-like symptoms; mostly grade 1–2 and all transient. No clinical or laboratory findings of any autoimmune disorder were observed. Local tissue tumor/immune responses were assessed by immunostaining. CpG + local radiation treated immunization site showed a significant reduction of CD25+, Foxp3+ T-cells (p<0.01) consisting of MF cells and tumor-infiltrating lymphocytes. Similar reduction in S100+, CD1a+ dendritic cells (DCs) was observed post immunization (p < 0.025). A qualitative analysis suggested more remarkable reduction of CD25+ T-cells and skin DCs in clinical responders vs. non-responders (p= 0.058, 0.121). CpG dose-responsive activation of peripheral blood pDCs was observed in vitro. Conclusions:Our novel in situ vaccination strategy using a combination of intratumoral CpG ODN and low-dose radiation is feasible in CTCL/MF with acceptable toxicities. Depletion of tissue T-regs may be observed at immunized sites. Reduction of skin DCs may suggest cross-priming and migration of DCs to regional lymph nodes. Clinical responses in subset of patients and CpG responsiveness of pDCs may warrant further study with modifications to augment therapeutic effects. [Display omitted] Disclosures:No relevant conflicts of interest to declare.