Anaplastic T-cell Lymphoma Research Articles

Stanowisko polskich ekspertów dotyczące zastosowania leku brentuksymab vedotin w leczeniu chorych na pierwotne chłoniaki skóry CD30+

The group of primary cutaneous T-cell lymphomas (CTCLs) expressing CD30 + is consisted of primary cutaneous anaplastic T-cell lymphoma (pcACTL), lymphomatoid papulosis (LyP), some cases of mycosis fungoides (MF) and Sezary syndrome (SS). It is well known that patient cannot be cured completely by available therapeutic methods. In addition, the effectiveness of available therapies is especially limited in advanced stages of the disease. Based on the results of the most recent trials, the experts recommend that brentuximab vedotin (BV) should be reimbursed in Poland for the treatment of adult patients with CTCL expressing CD30 who have had at least one prior systemic treatment. In case of MF BV should be preferred to bexarotene or MTX therapy due to the higher efficacy in stage IIB or higher. BV treatment should be also considered as an alternative to bexarotene (after ineffectiveness of local treatment, phototherapy and IFN/MTX therapy) in early stages of MF (IB-IIA).

Dual Role of EZH2 in Cutaneous Anaplastic Large Cell Lymphoma: Promoting Tumor Cell Survival and Regulating Tumor Microenvironment

Primary cutaneous anaplastic T-cell lymphoma, characterized by the CD30+ anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma. Little is known about the mechanisms of disease progression. Here we report that enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 that mediates histone H3 lysine 27 trimethylation, is overexpressed in CD30+ anaplastic cells in primary cutaneous anaplastic T-cell lymphoma and large-cell transformed cutaneous T-cell lymphoma. Silencing EZH2 or inhibiting its histone methyltransferase activity conferred increased apoptosis and G1 cell-cycle arrest in primary cutaneous anaplastic T-cell lymphoma cells invitro and a xenograft model invivo. This was mediated by the de-repression of thioredoxin-interacting protein, a major redox control molecule, and consequent formation of reactive oxygen species. Silencing thioredoxin-interacting protein abrogated reactive oxygen species accumulation in EZH2 suppressed cells and rescued cell growth disadvantage. Moreover, EZH2 suppression de-repressed C-X-C motif chemokine ligand 10 and facilitated the recruitment of effector CD4+ and CD8+ T cells into the tumor microenvironment via a C-X-C motif chemokine ligand 10/receptor 3 interaction. These results demonstrate a dual role for polycomb repressive complex 2-mediated epigenetic silencing in tumor progression and antitumor immunity in primary cutaneous anaplastic T-cell lymphoma, and provide a rationale for the pharmacologic inhibition of EZH2 activity in large-cell transformed cutaneous T-cell lymphoma.

18F-fluorodeoxyglucose-positron emission tomography is more sensitive than computed tomography in initial staging of patients with an anaplastic T-cell lymphoma first presenting in the skin.

The role of 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in the evaluation of anaplastic large-cell lymphoma (ALCL) first presenting in the skin is not well established, while computed tomography (CT) is used as a standard procedure. The aim of this study was to evaluate the use of FDG-PET versus CT at initial staging of ALCL first presenting in the skin. Eleven cases of ALCL first presenting in the skin who underwent both FDG-PET and CT were retrospectively analysed. There were six males and five females, with a mean age of 59.7 years. Results of FDG-PET were compared with those of CT. Biopsy results of lesions served as a reference for the accuracy of PET and CT in the evaluation of local and metastatic lesions. In seven cases (64%), imaging revealed extracutaneous ALCL. FDG-PET results were concordant with CT results in five cases (45%); in four of these cases, FDG-PET was negative, consistent with CT, and one case had cutaneous and extracutaneous lesions detectable on both CT and FDG-PET. FDG-PET and CT were discordant in six cases (55%). Among these six cases, FDG-PET revealed extracutaneous lesions undetected on CT which consequently influenced the therapeutic decision in five cases (45%). The sensitivity of CT and FDG-PET was 18% and 64%, respectively.

Lenalidomide with Ipilimumab for Lymphoid Malignancies after Allogeneic or Autologous Stem Cell Transplantation (SCT)

Background: Prevention or treatment of relapse after SCT for lymphoid malignancies requires novel strategies. Targeting immune checkpoints could result in lasting responses but only in few patients. Combination strategies with targeted agents, such as lenalidomide, could result in the release of tumor antigens to tumor-specific T cells. These T cells would become activated but also upregulate inhibitory checkpoints such as CTLA-4. These can be blocked with the anti CTLA-4 antibody, ipilimumab, to permit enhanced anti-tumor T cell responses (Sharma P and Allison JP. Cell 2015). In addition, the release of tumor antigens may focus the activated immune response on tumor antigens rather than self-antigens, resulting in fewer adverse events (AEs). Patients and Methods: Patients (pts.) with lymphoma or CLL who relapsed after alloSCT, with no active GVHD were eligible. Pts. with autoSCT were included within 6 months post-transplant, if they had high risk features for relapse. Treatment consisted of 4 total cycles of lenalidomide 10 mg PO daily for 21 days (cycles 1 and 3) alternating with ipilimumab 3 mg/kg IV on day 1 (Cycles 2 and 4). Lenalidomide dose reduction was permitted to 5 mg based on standard clinical practice. The primary objective was to evaluate safety and secondary objectives were to assess overall response rate (ORR) and survival. Results: Sixteen pts. were enrolled in the study. Autologous group (n=7): The median age was 55 yrs (range, 33 - 68). Lymphoma histologies included [Double-hit (DHL) (n=3), mantle cell (MCL) (n=3; including 2 with 2 prior transplants, one with CNS involvement), and Hodgkin's disease (n=1 with persistent PET+ post-SCT]. Median time to enrollment after SCT was 3.7 months. Median follow-up was 9.0 months (range, 5.3 - 27.1). All pts. remain alive. One DHL pt. transplanted during second remission relapsed at 1.6 months after just initiating cycle 2 of therapy. All others remain in complete remission (CR). The most common other AEs were 16 events of neutropenia (n=4, gr 4; n=2, gr 3, n=10, gr 2), thrombocytopenia (n=1, gr 2,) and one pt. developed pulmonary embolism on therapy. All AEs resolved. An immune-related AE occurred in one pt. (dermatitis, gr 2) after the second ipilimumab dose and resolved with steroids. Allogeneic group (n=9): The median age was 54 yrs (range, 44- 66). Histologies included [Follicular (n=3), CLL (n=2), MCL (n=2), DHL (n=1), diffuse large cell (n=1), and T-cell anaplastic lymphoma (n=1)]. The median number of therapies excluding the alloSCT was 3 (range 2- 7). Two failed a prior autoSCT, one had 2 prior alloSCT, and 3 failed prior DLIs. Two pts. relapsed within 2 months of their alloSCT prior to enrollment on study. One pt. was taken off study after cycle 1 of lenalidomide due to flare of previously diagnosed GVHD, which responded to steroids and pt. is now off immunosuppression. All others finished planned treatment without GVHD. ORR was 75% (CR 37.5% and PR 37.5%). With a median follow-up time of 9.2 months (range, 3.0-20.9), all pts. remain alive. Three pts. had recurrent disease at a median time of 5.4 months (range, 4.6 -12.0) after stopping therapy. One is showing ongoing response to retreatment. AEs included seven episodes of neutropenia (n=1, gr 4; n=2, gr 3; n =4, gr 2), anemia (n=1, gr 2), diarrhea (n=1, gr 2), nausea (n=1, gr 2), headache (n=1, gr 2), hypertension (n=1, gr 2). All AEs resolved. There were no immune mediated AEs. Immunologic analyses: We conducted 17-color flow cytometric analyses on PBMC pre-, during and post-treatment time points. We observed ~1.5-2-fold increase in ICOS+ CD4+T cells after ipilimumab+lenalidomide combination therapy. We previously identified an increase in ICOS+ CD4+ T cells as a phamacodynamic biomarker of ipilimumab therapy (Ng Tang et al., Cancer Immunology Research, 2014). Although we expected significant differences in immunologic impact of ipilimumab therapy in allogeneic versus autologous transplant pts., our preliminary data indicate similar immune responses in the two groups.Conclusions:Treatment with lenalidomide and ipilimumab after SCT for pts with lymphoid malignancies has a favorable toxicity profile. Our Immunological results, together with the fact that the frequency of AEs was not different between the allogeneic and autologous arms, suggest that combination therapy with lenalidomide and ipilimumab elicits measurable immunologic changes and clinical responses without inducing GVHD. DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Immunohistochemical Profile of Hodgkin and Non-Hodgkin Lymphoma.

To analyze the frequencies of histological types of lymphoma, diagnosed with complete immunohistochemical profile in younger and older age group. Cross-sectional analytical study. Dow Diagnostic Research and Reference Laboratory, Dow University of Health Sciences, Karachi, from January 2009 to September 2013. Consecutive cases of lymphomas, which were diagnosed using immunohistochemistry, were analyzed according to WHO classification. Frequency and percentages for different types of lymphomas were calculated. Hodgkin and non-Hodgkin lymphomas characteristics in two age groups of less than and more than 40 years were compared, applying chi-square test. Out of the 318 cases, 79 (25%) were Hodgkin Lymphomas (HL) and 239 (75%) were Non-Hodgkin Lymphomas (NHL). Mixed Cellularity Hodgkin Lymphoma (MCHL) was the commonest (n=48). Amongst the NHL, 215 (89.95%) were B cell lymphomas and 24 (10.05%) were T-cell lymphomas. Diffuse Large B-Cell Lymphoma (DLBCL) was the commonest lymphoma (n=165, 69.95% of NHL). Anaplastic T-Cell Lymphoma (ALCL, n=10) was the commonest T-cell lymphoma. The frequency of HLwas significantly higher in the younger age group and that of NHLwas higher in the older age group (p < 0.001). Primary lymph node involvement was reported in 175 (55%) and cervical lymph node was the most frequent site. Extra nodal involvement was seen in 93 (29%) of all cases and was reported in 87 (36.4%) of NHLand 6 (7.5%) of HL. The most common extra nodal site was the gastrointestinal tract. Hodgkin lymphoma comprises 25% and non-Hodgkin lymphoma comprises 75% of all lymphomas. Both occur in younger age groups than reported in the West. B-cell NHLis three times more common than T-cell lymphoma. DLBCLis the most frequent lymphoma. ALCLis the most common T-cell, and mixed cellularity is the most common Hodgkin lymphoma.

Second-Generation Relative Donor for T-Replete Haplo-Identical Allogeneic Stem Cell Transplantation with High-Dose Post-Transplant Cyclophosphamide: Towards Disappearance of the HLA Barrier

Introduction: Allogeneic stem cell transplantations (allo-SCT) using alternative donors are increasingly used in patients lacking suitable matched sibling or unrelated donor. Recently, the use of post-transplant cyclophosphamide (CY) has allowed to re-consider first-generation relatives (brother, sister, father, mother, son or daughter) as haplo-identical donors for allo-SCT. Indeed, the incidence of severe acute GVHD is lowered by post-transplant administration of CY, due to the early destruction of putative alloreactive T cells. Still, some patients may not have a suitable relative donor for various reasons such as older age of the parents, no siblings nor children, no cord blood available, or because use of a graft from a first-generation haplo-identical relatives is contra-indicated. The probability of having a haplo-identical donor among siblings is 50% while it is almost 100% when considering both biological parents and offspring. When considering as a potential donor the child of a matched or haplo-identical sibling, the probabilities for the donor to be haplo-identical with the recipient remain 50% and 25%, respectively. Thus, second-generation relative donor (i.e. nephew or niece) may be finally considered as a source of stem cell graft.Methods: Here we report the case of a 61-year old man who received a T-replete haplo-identical allo-SCT with high-dose post-transplant CY from his second-generation relative nephew. In 2010, the patient was diagnosed with ALK- CD30+ anaplastic T-cell lymphoma and received 8 cycles of CHOD allowing to obtain morphologic and metabolic partial response. The patient received an allo-SCT from a sibling matched donor (brother) on November 2010 after an FB2A2 reduced-intensity conditioning regimen but secondary graft failure was rapidly documented in spite of donor lymphocyte infusions. Relapse occurred in September 2014 and brentuximab vedotin was administered each 21 days for seven cycles allowing to obtain a complete morphologic and metabolic response. It was decided to perform a second allograft using a different donor. The patient was childless and no unrelated donor or cord blood units were available. It was thus chosen to ask for donor the son of the matched brother, who was haplo-identical and had no antibodies directed against the patient's HLA specificities. This nephew had a O- blood group and negative CMV serology while the recipient was O+ and CMV+.Results: The second allograft was performed on April 2nd 2015 using the Baltimore (Luznik, BBMT 2008) conditioning regimen with 2 days of post-transplant CY. A megadose of peripheral blood stem cell was administered (14.16x106 CD34+ cells/Kg) at day 0. Neutrophils and platelets recovery (>50 Giga/L) were achieved as early as days +18 and +33, respectively, with full donor whole blood chimerism (99.8%) at day +30, persisting on day +60 and +100 (both whole blood 99.9%, CD3+ T cells: 99.9%).Grade 2 acute cutaneous GVHD occurred at day +21. The evolution was favorable after initiating corticosteroids at 2 mg/kg/day with tapering thereafter. Not surprisingly, CMV reactivation was documented at day+22, controlled by ganciclovir treatment. Immune reconstitution evaluated at days +30, +60 and +100 showed normal monocyte counts while B lymphocytes were undetectable. NK cells increased from 42/mm3 at day+30 to 453/mm3 at day +60 and 665/mm3 at day +100. Interestingly, after profound lymphopenia within the first 100 days post-transplant, CD8+ T large granular lymphocytes expansion was documented at day + 110. At four months post-transplant, the patient is alive in persistent metabolic remission with no active acute or chronic GVHD nor active infection. His outcomes will be updated for the meeting.Conclusion: T-replete haplo-identical allo-SCT with high-dose post-transplant CY using a second-generation relative donor was feasible allowing for full engraftment and moderate acute GVHD in our patient. This result expands the possibility to find a donor for a selected patient, meanwhile paving the way for using unrelated haplo-identical donor, which could be of interest when considering solid transplantation. Indeed, combining solid organ transplantation and allo-SCT from the same haplo-identical donor may open the door to withdraw immunosuppression in this particular setting, because stable tolerance may be induced, as it has been already reported for kidney transplant (Kawai, NEJM 2013). DisclosuresMoreau:Celgene: Honoraria, Other: Adboard; Amgen: Other: Adboard; Takeda: Other: Adboard; Janssen: Other: Adboard; Novartis: Other: Adboard.

Genomic signatures in T-cell lymphoma: How can these improve precision in diagnosis and inform prognosis?

The novel genetic information gained from genome-wide high throughput techniques has greatly improved our understanding of peripheral T-cell lymphoma (PTCL). PTCL consists of numerous distinct entities and is currently diagnosed using a combination of clinical and morphologic features and immunophenotyping together with limited molecular assays leading to an often fragmented, complicated diagnostic system. The diagnosis of many cases is challenging even for expert hematopathologists and more than a third of the cases cannot be further classified and thus put into the PTCL–NOS category. Gene expression profiling (GEP) has significantly improved the molecular classification of PTCLs and identified robust molecular signatures for common nodal subtypes of PTCL including angioimmunoblastic T-cell lymphoma (AITL), anaplastic T-cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL) and extra-nodal NK/T cell lymphoma (ENKTL). These studies also led to identification of novel molecular subtypes with distinct prognosis, that otherwise could not be identified by conventional methods. Integration of massive sequencing strategies and gene expression has characterized driver genetic alterations in common subtypes like AITL, ALCL, ENKTL and other PTCLs. These studies have identified oncogenic pathways and genes affected in specific disease subtypes that can be potentially targeted by specific therapies. Novel treatment options with FDA approved drugs directed towards mutant IDH2, the NF-κB, JAK/STAT, or mTOR pathways illustrate the usefulness of genome-wide techniques to identify targets for therapy. In this review, we highlight recent advances in the molecular diagnosis and prognosis of PTCL using these genome-wide techniques.

Hemophagocytic Lymphohistiocytosis Associated with Adult Vaccination: A Case of Cytokine Flurries

Hemophagocytic Lymphohistiocytosis (HLH) is an often-fatal condition characterized by an overactive but ineffective immune response. Secondary HLH in adults is often caused by infection, autoimmune disease, and malignancy. A 67-year-old woman presented to hospital with a five-day history of malaise beginning hours after receiving influenza and pneumococcal vaccinations. Her medical history was significant for rheumatoid arthritis, controlled with methotrexate and prednisone. In hospital, she was found to have a new febrile pancytopenia that persisted despite empiric antibiotics and discontinuation of methotrexate. The patient did not have any additional clinical or laboratory evidence of an infectious focus or rheumatoid arthritis flare. She had splenomegaly, but there was no definitive evidence of malignancy. Further testing revealed hepatitis, coagulopathy, and an elevated ferritin. Bone marrow biopsy demonstrated hemophagocytosis, and a diagnosis of HLH was made. She was successfully treated with a modified HLH 94 protocol, using dexamethasone and etoposide. Unfortunately, following hospital discharge after being well for 18 months with no HLH relapses, the patient was diagnosed with anaplastic T-cell lymphoma. HLH was likely secondary to a two-hit process with vaccinations in the context of immune dysregulation secondary to rheumatoid arthritis and subclinical lymphoma. To the best of our knowledge, vaccinations have not been linked to adult HLH; therefore, this case illustrates a potentially novel association in a susceptible patient. We propose that HLH should be considered in all patients with unexplained fever and cytopenias, and diagnosis should prompt evaluation for underlying causes, including vaccinations.

Englis

Hemophagocytic Lymphohistiocytosis (HLH) is an often-fatal condition characterized by an overactive but ineffective immune response. Secondary HLH in adults is often caused by infection, autoimmune disease, and malignancy. A 67-year-old woman presented to hospital with a five-day history of malaise beginning hours after receiving influenza and pneumococcal vaccinations. Her medical history was significant for rheumatoid arthritis, controlled with methotrexate and prednisone. In hospital, she was found to have a new febrile pancytopenia that persisted despite empiric antibiotics and discontinuation of methotrexate. The patient did not have any additional clinical or laboratory evidence of an infectious focus or rheumatoid arthritis flare. She had splenomegaly, but there was no definitive evidence of malignancy. Further testing revealed hepatitis, coagulopathy, and an elevated ferritin. Bone marrow biopsy demonstrated hemophagocytosis, and a diagnosis of HLH was made. She was successfully treated with a modified HLH 94 protocol, using dexamethasone and etoposide. Unfortunately, following hospital discharge after being well for 18 months with no HLH relapses, the patient was diagnosed with anaplastic T-cell lymphoma. HLH was likely secondary to a two-hit process with vaccinations in the context of immune dysregulation secondary to rheumatoid arthritis and subclinical lymphoma. To the best of our knowledge, vaccinations have not been linked to adult HLH; therefore, this case illustrates a potentially novel association in a susceptible patient. We propose that HLH should be considered in all patients with unexplained fever and cytopenias, and diagnosis should prompt evaluation for underlying causes, including vaccinations.

Post-transplant T-cell lymphoma in pleural fluid cytology: a case report

<h3>Background</h3> Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid proliferations of varying clonal composition secondary to immunosuppression in solid-organ transplant. Most commonly are of B-cell in origin; T-cell lymphomas are rare (15% of all PTLD). <h3>Case presentation</h3> A 75-year-old man with 15-year post-heart transplant for dilated cardiomyopathy presented with a large left-sided pleural effusion. Pleural fluid cytology was highly cellular and contained dispersed large malignant cells having small to moderate amount of granular cytoplasm with pleomorphic nuclei and prominent nucleoli; many cells had multiple chromocentres; some were binucleate. Occasional mitoses and apoptotic bodies were present. Phenotypically, cells were positive for CD3, CD30, and EMA but negative for CD4, CD8, CD5 and CD7. They were negative for ALK and EBV markers. Flow cytometry showed positivity for T-cell and NK-cell markers (CD2, CD3, CD7, CD56, CD57 and TCR). <h3>Discussion</h3> Only a few cases of post-transplant T-cell lymphoma have been described in literature. To our knowledge, this is the first reported case of an ALK and EBV negative anaplastic T-cell lymphoma in pleural fluid cytology following cardiac transplant. Similar to B-cells proliferation, they have a predilection for skin, abdomen and pleura; only a minority are associated with EBV infection, in contrast to B-cells proliferation. The prognosis is generally poor.

Autologous Stem Cell Transplantation with Benda-BEAM (Bendamustine, Etoposide, Cytarabine, Melphalan) in Aggressive Non Hodgkin and Hodgkin´s Lymphoma

Autologous Stem Cell Transplantation (ASCT) is standard of care in relapsed diffuse large B-cell lymphoma (DLBCL) and other lymphoproliferative disorders (relapsed Hodgkin´s disease, mantle or T-cell lymphoma). BCNU, Etoposide, Ara-C, Melphalan (BEAM) is a standard conditioning regimen, but BCNU is associated with interstitial pneumonia (range 2 to 20%) and a increased risk of death compared with busulfan or TBI based regimens. Therefore a less toxic regimen might improve the results in (relapsed) lymphoma patients. Bendamustine showed promising results in B- and T-cell lymphoma and dose escalation is safe and feasible. Here we report promising results with bendamustine replacing BCNU in the BEAM regimen described as Benda-BEAM, recently published in a phase two dose finding study (Visani, Blood 2011).Thirty-eight patients with Hodgkin´s (HL)(n=9) or Non-Hodgkin (n=29) lymphoma were consecutively treated with Benda-BEAM (bendamustine on two consecutive days at a dose of 200 mg/m2per day). Ten patients were diagnosed with DLBCL, also ten patients with mantle cell lymphoma, four patients with an anaplastic T-cell lymphoma, four patients with follicular lymphoma and one patient with an greyzone lymphoma. Twenty-four patients were male and fourteen female with a median age of 52 years (range 22-71) and 25% were above the age of sixty. The median lines of previous therapies were 2 (range: 1-4). 36 patients were treated with Benda-BEAM and 2 patients with mantle cell lymphoma received additionally Zevalin.All patients had chemosensitive disease and before transplantation 31 patients (82%) were in complete (CR) and 7 (18%) in partial remission (PR). A median number of 4,10*106 CD34+ cells/kg (range: 1,60-11,10) were infused. All patients showed engraftment with a median time to achieve an absolute neutrophil count > 1*109/L of 10 days (range 7-13) and to platelets >20*109/L of 11 days (range 5-26). The median time of fever was 6 days (range: 0 -22). The most common grade 3 and 4 toxicity during the whole treatment period were diarrhoea (n=10), mucositis (n=7) and febrile neutropenia (n=6), followed by nausea (n=4) and cardiologic toxicities (n=3). There were no pulmonary toxicities observed and no transplant related mortality occurred. After a median follow-up of 22 months, thirty-three patients were evaluable for response, with 21 patients (64%) still in CR, while 12 patients (36%) showed progression after a median time of 6 months after transplantation (range 2-22 months), Until today seven patients (21%) have died (5 DLBCL, 1 HL, 1 mantle cell lymphoma), all due to lymphoma progression. The 1-year PFS is 72% and the 1-year OVS 85%.Thus Benda-BEAM seems to be feasible with a promising response rate und a randomized phase II trial comparing Benda-BEAM with BEAM is planned. DisclosuresOff Label Use: bendamustine as part of conditioning regimen before autologous stem cell transplanatation.

Molecular genetics of peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCL) are rare neoplasms that in most instances respond poorly to conventional chemotherapies. Four varieties--PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK+ anaplastic T-cell lymphoma (ALCL), and ALK- ALCL--account for about 60 % of them. Their classification is difficult because of the wide spectrum of morphologic features and the lack of robust immunohistochemical markers. Thus, high-throughput technologies can importantly contribute to their better understanding. In particular, gene expression profiling has cleared the borders among PTCL/NOS, ALK- ALCL and AITL. In fact, gene signatures have been developed even from formalin-fixed paraffin-embedded tissue samples that definitely distinguish one tumor from the other(s). This has important practical implications: for instance on routine diagnostics PTCL/NOS expressing CD30 can be easily confused with ALK- ALCL, but has a much worse prognosis. Therefore, the clear-cut distinction between the two conditions is pivotal to understand the results of ongoing trials with Brentuximab Vedotin, targeting the CD30 molecule. Besides improving the diagnosis, molecular studies have provided the rationale for the usage of novel drugs in the setting of PTCLs, such as ALK inhibitors in ALK+ ALCL, anti-angiogenetic drugs in AITL, and tyrosine kinase inhibitors in PTCL/NOS and ALK+ and ALK- ALCLs.

Progressive multifocal leucoencephalopathy (PML): A novel complication of brentuximab vedotin from the Southern Network on Adverse Reactions (SONAR) project.

e22181 Background: BV is FDA approved for angio-immunoblastic large cell lymphoma and refractory Hodgkin’s lymphoma (HL). BV-linked PML cases reviewed. Methods: Case 1—Age:47/HIV negative male relapsed stage IIIB mixed cellularity undergoing treatment with BV. Prior therapies: 8 cycles of ABVD, ESHAP, BEAM, autologous stem cell transplant, involved field radiotherapy to the neck and mediastinum in 2008 and GVD ending in 2009. A 2011 relapse treated with BV q 3 weeks. Patient complained of impaired coordination and left greater than right dysdiadokinesis after 2 BV doses. Third BV cycle administered. Patient formed dysarthria, left-sided hemianopsia, hemiparesis. CSF analysis for JC virus DNA by PCR positive. Patient died shortly after. Case 2—Age:38/female revealed cutaneous anaplastic T-cell lymphoma refractory started on BV in mid-2011 led to loss of cutaneous tumors. A day after 2ndBV dose, difficulty finding words and unsteady gait. MRI revealed multifocal white matter lesions in bilateral cerebral hemispheres. Brain biopsy revealed PML. Prednisone initiated. Patient continued mixed non-fluent aphasia, quadriparesis, gait ataxia. MRI showed white matter lesions and contrast enhancement consistent with IRIS. High dose oral corticosteroids continued. Repeat MRI shows decreased lesion load, resolution of enhancement. Patient improving. Case 3—Age:72/female stage IB mycosis fungoides (MF) controlled with topical steroids and nitrogen mustard, phototherapy and interferon alpha, developed painful ulcerated plaques and tumors 4 years after diagnosis. BV administered, clinical response of skin tumors, decreased pain. Two weeks after 3rdBV dose: disoriented, poor short term memory. MRI revealed right frontal white matter. CSF sent for JC virus DNA was negative. Patient died 2 months after last BV dose. Autopsy: demyelination associated JC virus positive cells. Results: Shown. Conclusions: Unexpected PML occurrences after 2 or more BV doses, with IRIS and survival in 1 patient.

PML-IRIS in a patient treated with brentuximab

A 38-year-old woman was diagnosed with cutaneous anaplastic T-cell lymphoma that proved refractory to methotrexate, bexarotene, denileukin diftitox, interferon γ-1b, interferon α-2b, vorinostat, and pralatrexate. She was therefore started on the newly approved monoclonal anti-CD30 antibody brentuximab vedotin. Treatment with brentuximab 1.8 mg/kg IV every 3 weeks quickly led to disappearance of her cutaneous tumors. The day after her second brentuximab infusion she developed word-finding difficulties and unsteady gait. Due to further neurologic deterioration, she was admitted to an outside hospital. Brain MRI revealed multifocal enhancing white matter lesions throughout bilateral cerebral hemispheres and posterior fossa (figure, A-C). Brain biopsy was performed 15 days after her last brentuximab dose to rule out metastases and she was diagnosed with progressive multifocal leukoencephalopathy (PML) (figure, J). The patient was discharged home with hospice care. Upon discharge, she was started on prednisone 50 mg daily to help treat her eczema. Her family brought her to our clinic for a second opinion.

High-Risk ALK Negative Anaplastic Large-Cell Lymphoma Presenting with Hypereosinophilic Syndrome in a 2.5-Year-Old Child

The hypereosinophilic syndromes (HES) are characterized by prolonged nonreactive peripheral blood hypereosinophilia with tissue damage. The lymphocytic HES variant can precede malignant clonal T-cell disease in adults but it is extremely rare to be the presenting feature of lymphomas in children. Here we present a 2.5-year-old boy with HES and mediastinal T-cell anaplastic lymphoma kinase (ALK) negative systemic anaplastic large-cell lymphoma. Mature and immature eosinophils without blasts were shown on bone marrow aspiration while biopsy revealed malignant infiltration. The patient responded well to initial corticosteroid therapy, but high-risk features make a challenge of finding the cure in this extremely rare case.

Combined Modality Treatment for PET-Positive Non-Hodgkin Lymphoma: Favorable Outcomes of Combined Modality Treatment for Patients With Non-Hodgkin Lymphoma and Positive Interim or Postchemotherapy FDG-PET

To evaluate outcomes of patients treated for aggressive non-Hodgkin lymphoma (NHL) with combined modality therapy based on [(18)F]fluoro-2-deoxy-2-d-glucose positron emission tomography (FDG-PET) response. We studied 59 patients with aggressive NHL, who received chemotherapy and radiation therapy (RT) from 2001 to 2008. Among them, 83% of patients had stage I/II disease. Patients with B-cell lymphoma received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-based chemotherapy, and 1 patient with anaplastic lymphoma kinase-negative anaplastic T-cell lymphoma received CHOP therapy. Interim and postchemotherapy FDG-PET or FDG-PET/computed tomography (CT) scans were performed for restaging. All patients received consolidated involved-field RT. Median RT dose was 36 Gy (range, 28.8-50 Gy). Progression-free survival (PFS) and local control (LC) rates were calculated with and without a negative interim or postchemotherapy FDG-PET scan. Median follow-up was 46.5 months. Thirty-nine patients had negative FDG-PET results by the end of chemotherapy, including 12 patients who had a negative interim FDG-PET scan and no postchemotherapy PET. Twenty patients were FDG-PET-positive, including 7 patients with positive interim FDG-PET and no postchemotherapy FDG-PET scans. The 3-year actuarial PFS rates for patients with negative versus positive FDG-PET scans were 97% and 90%, respectively. The 3-year actuarial LC rates for patients with negative versus positive FDG-PET scans were 100% and 90%, respectively. Patients who had a positive interim or postchemotherapy FDG-PET had a PFS rate of 90% at 3 years after combined modality treatment, suggesting that a large proportion of these patients can be cured with consolidated RT.

Radiographically Negative, Asymptomatic, Sentinel Lymph Node Positive Cutaneous T-Cell Lymphoma in a 3-Year-Old Male: A Case Report

We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB) was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

Dermatomyositis As the Initial Presentation of a Large Anaplastic T-Cell Lymphoma

Dermatomyositis As the Initial Presentation of a Large Anaplastic T-Cell Lymphoma

ALK-negative systemic intravascular anaplastic large cell lymphoma presenting in the skin

Systemic cases of the CD30-positive T-cell neoplasm, anaplastic large cell lymphoma (ALCL), are typically anaplastic lymphoma kinase (ALK)-positive. The failure to express ALK protein has been shown to portend a worse prognosis. We describe a case of ALK-negative systemic ALCL that presented as a violaceous plaque on the scalp of a 79-year-old man. Interestingly, the neoplastic cells were confined largely within vascular spaces, a configuration that is exceedingly rare in the skin and is more typically seen with intravascular large B-cell lymphoma. In addition, bcl-2 immunohistochemical staining was strongly positive in this case, which may portend a more aggressive clinical course. To our knowledge, this report represents the first case of an ALK-negative ALCL to present intravascularly in the skin. Therefore, the recognition of systemic anaplastic T-cell lymphoma present within the intravascular spaces is important to avoid misdiagnosis.

F-18 FDG PET/CT in the Assessment of Recurrent Anaplastic T-Cell Lymphoma of the External Auditory Canal

F-18 FDG PET/CT in the Assessment of Recurrent Anaplastic T-Cell Lymphoma of the External Auditory Canal