Systemic Anaplastic Large Cell Lymphoma Research Articles

Patterns of Care and Clinical Outcomes in Peripheral T-Cell Lymphoma Patients Receiving First-Line Treatment in Routine Clinical Practice in France and the United Kingdom

INTRODUCTION Peripheral T cell lymphomas (PTCL) are a rare and heterogenous group of aggressive non-Hodgkin lymphomas (NHL) that develop from mature T- and natural killer cells. They comprise approximately 10% of all newly diagnosed cases of NHL in Western populations. The current study characterizes real-world treatment patterns and outcomes among patients with PTCL in France and the United Kingdom (UK) in the first-line (1L) setting. METHODS A retrospective medical chart review study was undertaken at geographically disparate clinical sites in France and UK, where treating physicians were responsible for patient selection and data collection via structured case report forms. Adults (≥18 years) with newly diagnosed with PTCL between January 1, 2014 and December 31, 2016 were randomly selected for inclusion in the study. Eligible patients had received at least 1L treatment (1LT) for PTCL and had available clinical data for ≥1 year after PTCL diagnosis or until death. Patients enrolled in a clinical trial for 1L PTCL at any time between diagnosis and end of follow-up or who had any prior unresolved malignancy within 5 years of PTCL diagnosis were excluded. Demographic, clinical, and immunophenotypic/cytogenetic profiles of PTCL patients were assessed at diagnosis. Treatments received and best response as reported by the treating clinician (categorized as complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]) at the end of 1LT are described. Data from both countries were pooled for the current analysis. RESULTS Overall, 32 haematologist/oncologists (France, 15; UK, 17) with a median of 12.5 years of clinical practice participated in the study. Most physicians in France practiced at a university hospital or a regional hospital centre (73.3%). In the UK, most physicians practiced at a specialist cancer/ tertiary referral treatment centre (47.1%). A total of 109 patients (France, 53; UK, 56) received at least 1L PTCL treatment during the study period. The median age at diagnosis was 63 years (range, 19 to 84 years), with a male predominance (57.8%). Eighty percent of patients had an ECOG performance status of 0-1 at diagnosis. B symptoms were present in 59.6% and extranodal disease was present in 35.8% patients at diagnosis. Most patients (72.5%) had stage III or IV disease and (64 of 102) 62.75% were classified as intermediate risk (score of 2-3) as per the International Prognostic Index. The most common histological subtypes were PTCL-not otherwise specified (NOS) (37.6%), angioimmunoblastic T-cell lymphoma (29.4%), and systemic anaplastic large cell lymphoma (20.2%). The median duration of follow-up was 34 months from the start of 1L PTCL treatment. Of those tested, 60.4% patients were positive for CD30 (information on threshold was not reported). Only 19.3% patients underwent testing for any cytogenetic marker. During follow-up, 28.4% of patients had died. In the 1L setting, 59.6% and 26.6% patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and with CHOEP/CHOEP‐like regimens (Table). Median duration of 1LT was 4.9 months. Stem cell transplant was undertaken in 29.4% patients as part of 1L treatment, of which 84.4% were autologous. PET-CT was used for response assessment in 56% of patients. Best response within 1 year of completing 1LT and before start of 2L treatment was assessed in 75/109 [68.8%] patients (Table); of whom 80% (60 patients) were reported to have a complete response (Table), and about 39% relapsed (within the first year) and went on to 2L treatment. The remaining 27 patients had best response assessed prior to completion of 1LT. Brentuximab vedotin (19%) and GemOx (19%) were the most common 2L treatments. CONCLUSIONS This retrospective observational study describes treatment patterns and key clinical outcomes among patients receiving 1L PTCL treatment in France and the UK. CHOP-based regimens were used to treat 59.6% of the study patients. Understanding distribution of PTCL subtypes and outcomes of treatment in routine clinical practice is complementary to data derived from clinical trials and crucial to facilitate improvement of survival outcomes through the introduction of novel therapies for this challenging group of rare malignancies. Disclosures Fox: Janssen: Consultancy; Adienne: Other: Travel Support; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Sunesis: Consultancy. Ashaye:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Shah:Pfizer: Research Funding; Merck: Research Funding; Bayer: Research Funding. Dalal:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Truemper:Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Roche: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding.

Imatinib +/- Brentuximab Vedotin Induces Sustained Complete Remission in Chemotherapy-Resistant Anaplastic Large Cell Lymphoma Expressing PDGFR

Background. Anaplastic lymphoma kinase positive systemic anaplastic large cell lymphoma (ALK+ ALCL) represents an aggressive T-cell malignancy that primarily affects children and younger adults. Upon treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens its prognosis is relatively favourable compared to other aggressive T-cell lymphomas, however, the rare event of disease reoccurrence remains particularly challenging. ALCL is CD30 positive, and mono treatment with brentuximab vedotin (BrV) can achieve long term remissions in only few relapsed patients not receiving consolidating stem cell transplantation (Pro B. et al. Blood 2017). A subset of ALCL patients express platelet derived growth factor receptor (PDGFR) alpha or beta in their tumour cells which is induced by ALK via AP-1 transcription factor activation. We previously demonstrated that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib is an effective treatment concept for ALK+ ALCL in experimental mouse models (Laimer D. et al. Nature Med. 2012). Here we aimed to assess the prognostic value of PDGFR expression and to probe the clinical value of its targeting by imatinib in ALK+ ALCL patients. Methods. The impact of PDGFR expression to predict clinical outcome was analyzed in samples of 98 ALK+ ALCL patients included in the studies NHL-BFM 90, 95 and ALCL99 between 1992 and 2006. Six patients (age 18-45) with chemo-refractory ALK+ ALCL were prospectively treated with imatinib plus (4) or minus (2) BrV. 33% (2/6) had previously received salvage treatment with stem cell transplantation (SCT). Three of the patients had been enrolled in a prospective single-arm study combining imatinib and BrV, a trial that was terminated due to poor patient recruitment (AGMT ALCL1 trial, EudraCT No.: 2013-003505-26, supported by Takeda®). PDGFR alpha and beta expression analyses were performed on tumour samples of treated patients. Results. ALK+ ALCL patients with high PDGFR expression on tumor cells (n=11) had a significantly lower event-free survival rate (EFS) at 5 years compared to patients with no or low expression (n=87) (27±13% versus 70±5%, respectively, p<0.001, figure 1a). Four of the six patients with relapsed/ refractory ALK+ ALCL responded to imatinib +/- BrV with a rapid metabolic complete remission (CR). At a median clinical follow-up of 52 months (range 20 to108) all responding patients demonstrated an ongoing CR without SCT even after imatinib was discontinued with an average time on imatinib of 49 weeks (range 32 to 130; figure 1b). Half (2/4) of responding patients received no or only 1 infusion of BrV; both non-responding patients had received BrV. Importantly, despite the few patients that could be prospectively treated, PDGFR expression status had a significant impact on clinical course. All patients (4/4) who expressed either PDGFR alpha or beta in tumour cells and in the lymph node microenvironment responded with an ongoing metabolic CR, whereas the two patients whose lymphoma cells had negative PDGFR expression failed to respond (EFS: 4 versus 210 weeks, p = 0.018; figure 1c). Conclusions. 1) PDGFR expression is a poor risk factor in ALK+ ALCL. 2) Imatinib alone or in combination with BrV overcomes chemo-resistance conferred by PDGFR expression. 3) Imatinib treatment can be discontinued with ongoing CR. 4) These observations suggest that PDGFR expressing ALK+ ALCL patients might benefit from early treatment with imatinib. Disclosures Staber: Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Mayerhoefer:Siemens: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Greil:Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ratiopharm: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; GSK: Research Funding; Sandoz: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Boehringer Ingelheim: Honoraria; Mundipharma: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Imatinib - bcr-abl Inhibitor

A Phase 2 Study of Retreatment with Brentuximab Vedotin in Patients with cHL, sALCL or Other CD30-Expressing PTCL

Background Brentuximab vedotin is an antibody-drug conjugate composed of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Targeted delivery of MMAE to CD30-expressing cells is the primary mechanism of action of brentuximab vedotin (Sutherland 2006). Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cell. In addition, the direct cytotoxicity associated with brentuximab vedotin may be augmented by secondary effects, including the bystander effect (Li 2016) and several important immuno-oncology related effects, such as immunogenic cell death (Gardai 2015; Muller 2014) and antibody-dependent cellular phagocytosis (Oflazoglu 2007). Brentuximab vedotin has been approved for several indications, including the recent US Food and Drug Administration approval for the treatment of adults with previously untreated systemic anaplastic large cell lymphoma (sALCL) and other CD30-expressing peripheral T-cell lymphomas (PTCL). Given that CD30 expression has been shown to persist during treatment with brentuximab vedotin, and after treatment when patients have relapsed (Porpaczy 2013), there is rationale to support evaluation of brentuximab vedotin in a retreatment setting. Encouraging safety and antitumor activity were observed in a phase 1 study (Clinicaltrials.gov: NCT00947856) of brentuximab vedotin retreatment in patients with relapsed/refractory classic Hodgkin lymphoma (cHL) or sALCL. The objective response rate (ORR) for retreatment of cHL was 60% (12 of 20 evaluable patients) with a complete response (CR) rate of 30% (6 of 20 evaluable patients). For retreated sALCL, the ORR was 88% (7 of 8 patients) with a CR rate of 63% (5 of 8 patients). The estimated median duration of response (DOR) for patients with an objective response was 9.5 months, and for patients with a CR, the estimated median DOR was 12.3 months (Bartlett 2014). However, interpretation from this study is limited because it did not include patients who received brentuximab vedotin as part of frontline treatment or in patients with non-sALCL PTCL. The potential of retreatment with brentuximab vedotin to offer a meaningful treatment option throughout the continuum of these diseases is under investigation. Study Design and Methods This is a phase 2, multicenter, single-arm study to determine the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory cHL, sALCL, or other CD30-expressing PTCL who experienced CR or partial response with a brentuximab vedotin-containing regimen and subsequently experienced disease progression or relapse. Patients who previously discontinued brentuximab vedotin due to any Grade 3 or higher toxicity or have existing Grade 2 or higher peripheral neuropathy will not be eligible. It is anticipated that approximately 50 patients will enroll in this study. All patients will be administered 1.8 mg/kg brentuximab vedotin intravenously, up to a maximum of 180 mg, over 30 minutes once per 21-day cycle. Patients who previously required a dose reduction due to adverse events (AE) will be administered brentuximab vedotin at 1.2 mg/kg. The primary efficacy endpoint of this study is ORR (per blinded independent central review), a direct measure of anti-tumor activity. To further assess the significance of ORR in this study, durability, CR rate, overall survival, and progression-free survival will be evaluated as secondary endpoints. Safety will be monitored throughout the trial via laboratory values and AE collection. The study's sample size was chosen to allow adequate precision of estimates of response rates and characterization of safety data. Enrollment in this study is expected in September 2019 (Clinicaltrials.gov: NCT03947255). Disclosures Lisano: Seattle Genetics, Inc.: Employment, Equity Ownership. Newhook:Seattle Genetics, Inc.: Employment. OffLabel Disclosure: Brentuximab vedotin is being investigated as a retreatment option.

Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): The Experience at European Institute of Oncology (EIO)

INTRODUCTION AND BACKGROUND: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T-cell non-Hodgkin lymphoma, recently recognized by the World Health Organization classification of lymphoid neoplasms. Clinical and histologic findings suggest a distinct entity from systemic ALCL. Except in advanced cases, BIA-ALCL usually has an indolent course. The prognosis is often favorable and complete surgical excision for localized disease is generally the only treatment. The disease often presents with a delayed seroma around the breast implant - almost exclusively with a textured surface - breast pain, swelling and asymmetry, capsular contracture, but it can also present with a breast mass and lymph node involvement. Tumor nodules, axillary node involvement, bilateral breast involvement and infiltrative pattern on capsule histology are associated with more aggressive behavior. Systemic involvement has also been less commonly reported. In accordance with the FDA recommendation, all cases of histologically confirmed BIA-ALCL should be reported to the BIA-ALCL PROFILE Registry. In Italy, the Ministry of Health sensitizes to notify each BIA-ALCL diagnosis through the compilation of a specific online form. Since 2015 all the notified cases were collected in the Italian Ministry of Health's database, named Dispovigilance. So far, 47 cases have been reported, as of the last updated survey. METHODS: We report our single center experience at European Institute of Oncology (IEO) in Milan, Italy. A total of 27.588 breast implants has been placed in our Institute between 01/2001 and 12/2018.The first case of BI-ALCL was diagnosed in july 2015 and a total of 7 cases have been diagnosed to date. In 4 cases implants were placed at EIO. Median age at diagnosis was 52 (32-71). All patients presented with monolateral and localized disease, with stage IA (TNM classification). In 6 patients periprosthetic seroma preceded diagnosis and fine needle aspirate of the periprosthetic effusion documented BIA-ALCL, while breast pain and tumor nodule were present in one patient. In 5 out of 7 patients breast implantation was performed for reconstruction after breast cancer surgery, in 2 patients for cosmetic purposes. Textured devices had been implanted in all of them. All but one patients with previous hIstory of breast cancer had 2 surgery for reconstruction. Overall, interval between first implant and ALCL diagnosis ranged between 5 and 22 years (median: 11 ys). Interval between second implant and ALCL diagnosis was of 4-11 years (median: 6 ys). Presurgery PET/CT scan and MRI were performed in most patients. Treatment included total capsulectomy in all patient, bilateral surgery in case of bilateral implants. One patient received RT after surgery for higly suggestive residual disease. Immediate reconstruction was performed in 1 patient. With a median follow up of 16 months (range 1-49), all patients are alive with no relapse observed to date. CONCLUSIONS: This report represents the largest single centre experience in Italy. Given the peculiarity of this new recently recognized malignancy, a multidisciplinary approach is essential for the diagnosis and management of these patients. Management requires experts in diagnostic imaging, pathology, hematology/oncology, plastic surgery and surgical oncology and radiation oncology. It is critical that physicians are educated about the clinical presentation, diagnostic criteria, and treatment modalities. This comprehensive approach allows a quite favorable outcome in this rare and challenging complication of breast reconstruction. Disclosures Derenzini: TG-THERAPEUTICS: Research Funding.

An International Multicentre Study of Consecutively Diagnosed Patients with ALCL: Outcomes Following First-Line Therapy in Routine Clinical Practice

An International Multicentre Study of Consecutively Diagnosed Patients with ALCL: Outcomes Following First-Line Therapy in Routine Clinical Practice

Examining the Role of CD30 in an Anaplastic Large Cell Lymphoma Mouse Model

Anaplastic large cell lymphoma (ALCL) represents a heterogeneous group of T-cell non-Hodgkin lymphoma (NHL) mainly affecting children and young adults. About 70% of systemic ALCLs are associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in the NPM-ALK fusion gene, its over-expression and constitutive kinase activity. Immunophenotypic characterization of human ALCL revealed highly CD30-positive cells of T- or Null-Cell-origin and resulted in promising clinical trials with CD30-coupled antibodies. However, the impact of CD30 on disease development remains unclear and the relationship between NPM-ALK and CD30 has been investigated mostly using cell line models. Syngeneic mouse models of cancer can serve as useful models since the tumors develop in situ where the contribution made by the immune system and the extracellular matrix can be investigated. Here, we focus on the involvement of CD30 in a retroviral murine bone marrow transplantation model of ALCL. In this model, the BM of Lck-Cre-transgenic mice is infected with a MSCV-Stop-NPM-ALK-IRES-EGFP vector leading to expression of NPM-ALK in early T-cells. With a latency of 3-4 months, mice develop lymphomas and die from neoplastic T-cell-infiltration of BM and lymphatic organs. To investigate the impact of abrogation of CD30 signals on the development of NPM-ALK+ ALCL in our model, CD30 knockout mice were crossed with Lck-Cre mice. Both Lck-Cre NPM-ALK CD30 wt and Lck-Cre NPM-ALK CD30 ko recipients develop a human ALCL-like lymphoma with a pure T-cell phenotype characterized by Thy1.2+ cells infiltrating the thymus, lymph nodes, spleen and BM. First results from Lck-Cre NPM-ALK CD30 ko transplanted mice showed impaired disease induction and prolonged survival compared to CD30 wt animals. Moreover, secondary transplantation of NPM-ALK thymic lymphomas led to distinct deceleration of disease development upon CD30 deletion. Microarray analyses have shed some light on the mechanisms underlying the delayed lymphoma progression of CD30 deleted tumors with an upregulation of inflammatory pathways and proteins that are master players in inflammation and immune responses. Further characterization of the role of CD30-mediated immune response in disease progression using this mouse model and immunocompromised mice is ongoing. An improved understanding of how the immune system affects tumor progression will extend the rationale in translational strategies to use immunotherapies for patients with T-NHLs. Disclosures No relevant conflicts of interest to declare.

Autologous hematopoietic stem cell transplantation for relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the lymphoma working party (LWP) of the EBMT.

Systemic anaplastic large cell lymphoma (sALCL) is a rare histological entity expressing the CD30 antigen that comprises around 11% of peripheral T-cell lymphoma. We analysed the outcome of patients with relapsed/refractory sALCL treated with autologous stem cell transplantation (auto-HCT). We included 65 adult patients (42 males; median age, 44 years); 24 patients had an ALK-ve sALCL. Fifty-one patients had chemosensitive disease at the time of transplant. Ten patients (15%) were treated with brentuximab vedotin (BV) before auto-HCT (median number of doses: 5). The median follow-up for surviving patients was 35 months (3-71). Three-year cumulative incidence of nonrelapse mortality and of relapse were 1.7% and 34%, respectively. Three-year progression-free survival and overall survival were 64% and 73%, respectively. No prognostic factors for any of the outcomes analysed were found in univariate analysis. There were no significant differences in any of the outcomes between patients who had received BV and the remainder. This is the largest analysis presented so far analysing the role of auto-HCT in patients with relapsed/refractory sALCL, showing a promising PFS and OS in this high-risk population. The potential impact of the administration of BV as salvage strategy before the procedure needs to be further elucidated.

Allogeneic hematopoietic stem cell transplantation for patients with relapsed/refractory systemic anaplastic large cell lymphoma. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation.

Information regarding the curative role of allogeneic stem cell transplantation (allo-HCT) in systemic anaplastic large cell lymphoma (sALCL) is scarce. We analyzed the results of allo-HCT in patients with relapsed/refractory sALCL with special emphasis on the role of brentuximab vedotin (BV) as a bridge to allo-HCT. Forty-four patients (24 females, median age 38 years) with sALCL were included. Twenty-three patients (52%) received BV before allo-HCT; BV-treated patients were more heavily pretreated (≥3 lines of therapy in 74% vs. 38%, p = 0.04). Twenty-three patients (52%) were in complete remission (CR) at allo-HCT. Three-year nonrelapse mortality and incidence of relapse (IR) after allo-HCT were 7% and 40%, respectively. With a median follow-up of 39 (12-69) months for survivors, 3-year progression-free survival (PFS) and overall survival were 53% and 74%, respectively. Univariate analysis showed that heavily pretreated patients and those not in CR had a higher IR and a lower PFS. The use of BV before transplant did not impact on any of the outcomes. Allo-HCT is a curative therapeutic strategy in a significant proportion of patients with relapsed/refractory sALCL; BV does not seem to modify transplant-related outcomes but might be able to render more patients candidates for this curative treatment.

Case report of primary cutaneous anaplastic large cell lymphoma of adult female patient visiting dermatology clinic of King Abdul-Aziz Medical City, National Guard Health Affairs, Jeddah, Saudi Arabia, 2018

<p class="abstract">Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a rare T-cell cutaneous lymphoma consisting of CD30 positive typically anaplastic-appearing cells. PCALCL had been distinguished from systemic anaplastic large cell lymphoma (ALCL) and lymphomatous papulosis by World Health Organization classification of lymphoid neoplasms. Previous studies have shown PCALCL has an excellent overall survival with few patients dying from disease. This is a case report study design with detailed history, examination of 54-years-old female patient with a painful nodular lesion in the left thigh, which is misdiagnosed as Pyoderma Gangrenosum.</p>

Systemic anaplastic large cell lymphoma presenting as a huge mediastinal mass in a case of hyper IgE syndrome: a case report

BackgroundHyper IgE syndrome is a rare heterogeneous immunodeficiency syndrome which is characterized by recurrent episodes of cutaneous and respiratory tract infections and development of cold abscesses. This syndrome is also associated with malignancies, most notability hematologic malignancies.Case presentationIn this case report, we discuss a 27-year-old male with proven hyper IgE syndrome and effected by tuberculosis, who developed an anaplastic large cell lymphoma, a very rare and aggressive subtype of lymphoma. We will discuss imaging findings in this rare case. The case presented here had a large mediastinal mass, which had encircled the aorta, and was accompanied by subcarinal lymphadenopathy and inguinal lymphadenopathy.ConclusionsSystemic anaplastic large cell lymphoma is a rare subtype of lymphoma which is rarely associated with hyper IgE syndrome. In this case, both lymphoma and tuberculosis infection were witnessed in the same patient, showing a classic example of immune dysregulation.

Hematopoietic Stem Cell Transplantation and Brentuximab Vedotin for Patients with Relapsed or Refractory Hodgkin Lymphoma and Systemic Anaplastic Large-Cell Lymphoma.

Brentuximab vedotin (BV) is an antibody–drug conjugate that has demonstrated effectiveness as a monotherapy for patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large-cell lymphoma via several clinical trials. Salvage chemotherapy followed by autologous or allogeneic hematopoietic stem cell transplantation (HSCT) has been performed as a second- or later-line regimen for improving the survival of patients with lymphoma. In particular, the effectiveness of autologous HSCT and the importance of achieving a complete response prior to autologous HSCT are established in Hodgkin lymphoma. Several clinical trials have reported that salvage chemotherapy followed by autologous HSCT showed high response rates, although significant treatment-related hematological toxicity was observed. In the present article, we review clinical reports for assessing the efficacy and safety of relatively less toxic BV as a bridging therapy before HSCT or as a consolidation therapy post-HSCT in patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large-cell lymphoma. Generally, the reported BV regimens seem to be effective and well tolerated in such patients, and no significant influence of BV treatment is noted on hematopoietic stem cell harvest before HSCT. Large-scale clinical studies and long-term follow-up are expected to establish the safety and efficacy of these regimens.Funding: Takeda Pharmaceutical Co., Ltd., Tokyo, Japan.

PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma.

The programmed cell death 1 (PD-1) pathway is a recently recognized mechanism of tumor immune evasion. In this study, programmed cell death ligand 1 (PD-L1) expression was evaluated in 95 patients with systemic anaplastic large cell lymphoma: 45 ALK+ and 50 ALK-. ALK+ anaplastic large cell lymphoma was more often positive for PD-L1 than ALK- anaplastic large cell lymphoma (76% vs 42%, p = 0.002). ALK- anaplastic large cell lymphoma showed a strong correlation between PD-L1 expression and STAT3 activation (measured by pSTAT3Tyr705) (r = 0.8, p < 0.0001). In contrast, the PD-L1/pSTAT3 correlation was weaker in ALK+ anaplastic large cell lymphoma (r = 0.4, p = 0.08). In ALK- anaplastic large cell lymphoma, the PD-L1+ subgroup was more often EMA positive (69% vs 20%, p = 0.02) and tended to be less often CD2+ (50% vs 83%, p = 0.059). In ALK+ anaplastic large cell lymphoma, PD-L1 was not associated with pathologic features (all p > 0.05). Negative ALK status and high IPI score (≥3) were associated with shorter overall survival (p = 0.009 and p = 0.0005, respectively). Overall survival was not different between patients with PD-L1+ vs PD-L1- anaplastic large cell lymphoma (p = 0.44), regardless of ALK status and International Prognostic Index (IPI) score. We conclude that PD-L1 expression is more common in ALK+ anaplastic large cell lymphoma than ALK- anaplastic large cell lymphoma. In ALK- anaplastic large cell lymphoma, PD-L1 is strongly correlated with STAT3 activation and is associated with more frequent EMA and less frequent CD2 expression. PD-L1 has no prognostic significance in predicting the outcome of patients with systemic anaplastic large cell lymphoma, regardless of ALK status. PD-L1 expression on the anaplastic large cell lymphoma cells suggests these patients as potential candidates for PD-1 blockade immunotherapy.

PS1070 THE ECHELON‐2 TRIAL: RESULTS OF A RANDOMIZED, DOUBLE‐BLIND PHASE 3 STUDY OF BRENTUXIMAB VEDOTIN AND CHP (A+CHP) VERSUS CHOP IN FRONTLINE TREATMENT OF PATIENTS WITH CD30+ PERIPHERAL T‐CELL LYMPHOMAS

Please indicate where the abstract has been published before: The data in this abstract have been published in the Lancet (Horwitz 2019).Background:Peripheral T‐cell lymphoma (PTCL) is a heterogeneous group of aggressive non‐Hodgkin lymphoma (NHL) accounting for approximately 10% of all NHL cases worldwide, with a higher incidence reported in certain Asian countries. The most common frontline regimen for PTCL is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP‐like regimens; however, anthracycline‐containing regimens result in a low rate of complete remission (CR) (Savage K, et al. Ann Oncol 2004). Based on the encouraging activity and manageable safety profile observed in a phase 1 study (Fanale M, et al. Blood 2018), the ECHELON‐2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus CHOP for the treatment of CD30‐positive PTCL.Aims:To compare the effects of frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus CHOP as frontline therapy in patients with CD30‐positive peripheral T‐cell lymphoma (PTCL).Methods:ECHELON‐2 (ClinicalTrials.gov No. NCT01777152) is a phase 3, randomized, double blind, double‐dummy, placebo controlled, active‐comparator, multicenter study. Eligible adults with previously‐untreated CD30‐positive PTCL (targeting 75% ± 5% with systemic anaplastic large cell lymphoma [sALCL]) were randomized 1:1 to receive either A+CHP or CHOP for 6 or 8 21‐day cycles. Randomization was stratified by histological subtype as per local pathology assessment and by international prognostic index (IPI) score. The primary endpoint, progression free survival (PFS) per blinded independent central review (BICR), was analyzed for the intent‐to‐treat population. Key secondary endpoints were overall survival (OS), PFS in sALCL, CR rate, and objective response rate (ORR). Consolidative stem cell transplantation or radiotherapy was permitted at the investigator's discretion after end of treatment.Results:A total of 452 patients were enrolled between January 2013 and November 2016 and 226 patients were randomly assigned to each arm. Overall, the median age was 58 years (range, 18 to 85). The study enrolled patients with advanced disease (Stage III [27%] and Stage IV [53%]; IPI ≥2 [78%]) and most patients (316 patients [70%]) had sALCL (218 patients [48%] anaplastic lymphoma kinase [ALK]‐negative and 98 patients [22%] ALK‐positive). The hazard ratios of both PFS (0.71 [95% confidence interval {CI}: 0.54, 0.93], P = 0.01) and the OS (0.66 [95% CI: 0.46, 0.95], P = 0.02) favored A+CHP over CHOP. The median PFS was 48.2 months (95% CI: 35.2, not evaluable) versus 20.8 months (95% CI: 12.7, 47.6) for A+CHP and CHOP, respectively. The 3‐year PFS was 57.1% (95% CI: 49.9, 63.7) for A+CHP compared with 44.4% (95% CI: 37.6, 50.9) for CHOP. Median OS was not reached for either arm. Adverse events (AEs), including incidence and severity of neutropenia and peripheral neuropathy, were similar between arms. AEs leading to death occurred in 7 patients (3%) in the A+CHP arm and 9 patients (4%) in the CHOP arm.Summary/Conclusion:Frontline treatment with A+CHP is superior to CHOP for patients with CD30‐positive PTCL as demonstrated by a statistically significant improvement in PFS and OS, with a manageable safety profile.image

Response to A+CHP by CD30 expression in the ECHELON-2 trial.

7538 Background: Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30. The ECHELON-2 (E-2) study demonstrated significantly longer progression-free and overall survival with BV plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus CHOP in frontline treatment of patients (pts) with CD30+ peripheral T-cell lymphoma (PTCL). Complete remission (CR) rate (A+CHP 68%; CHOP 56%) and objective response rate (ORR) (A+CHP 83%; CHOP 72%) were also significantly increased. Expression of CD30 is universal in systemic anaplastic large-cell lymphoma (sALCL) but variable among non-sALCL subtypes. As ORR is a direct measure of antitumor activity, we examined response to A+CHP by CD30 expression. Methods: Pts with CD30+ (≥10% by local review) PTCL were included in E-2. Eligible histologies included ALK+ sALCL (IPI ≥2), ALK− sALCL, PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma, enteropathy-associated T-cell lymphoma, and hepatosplenic T-cell lymphoma. We analyzed the relationship between CD30 expression (IHC Ber H2 antibody) above and below the median (median CD30=18% PTCL-NOS; 25% AITL) and CR rate, ORR, and duration of CR (DOCR) in pts with AITL and PTCL-NOS treated with A+CHP. Results: Most (26/29, 90%) AITL pts had CD30 expression between 10% and 30%. PTCL-NOS pts were more evenly distributed across levels of CD30 expression ranging from 10% to 100%. CD30 levels were neither predictive of response (Table) nor significantly associated with DOCR in pts with AITL (P=0.30) or PTCL-NOS (P=0.90) (log-rank test). Response by CD30 expression. Clinical trial information: NCT01777152. Conclusions: CD30 expression above vs below median (or at 10%) did not predict response to A+CHP in E-2 non-ALCL subtypes, as responses were seen across CD30 levels. This may be due to intra- and inter-tumoral heterogeneity of CD30 expression, limitations of IHC, the nature of CD30 on the cell surface, and multiple mechanisms of action of BV. Further evaluation of the expression-response relationship in PTCL pts with CD30 &lt;10% is warranted.[Table: see text]

Systemic, primary cutaneous, and breast implant-associated ALK-negative anaplastic large-cell lymphomas present similar biologic features despite distinct clinical behavior.

Despite distinct clinical presentation and outcome, systemic, primary cutaneous, and breast implant-associated anaplastic large cell lymphomas (S-, PC-, BI-ALCL) ALK-negative (ALK-) show similar histopathological features including the presence of the "hallmark" cells with horseshoe-shaped nuclei and CD30 protein expression. The purpose was to better characterize these three entities using immunohistochemistry and FISH (Fluorescent in situ hybridization) to identify biomarkers differently expressed and that might be involved in their pathogenesis. Twenty-two S-ALCL ALK-, 13 PC-ALCL, and 2 BI-ALCL were included. Cases were tested for P53, P63, MUM1, MYC, GATA3, p-STAT3, PD1, and PDL1 protein expression and DUP22, TP53, TP63, MYC, and PDL1 chromosomal aberrations. As expected, S-ALCL ALK- patients had adverse outcome compare to PC and BI-ALCL. No difference was observed between the three groups concerning protein expression except for MUM1 that was significantly more frequently expressed in S-ALCL ALK- compared to PC-ALCL. In particular, constitutive activation of the STAT3 pathway and PDL1/PD1 immune-checkpoint expression was present in the three entities. TP53 deletion and PDL1 gene amplification were the commonest cytogenetic alterations and were present in the three entities. None of the studied biological parameters was associated with prognosis. Despite distinct clinical behavior, S-ALCL ALK-, PC-ALCL, and BI-ALCL share similar biological features. Larger series should be investigated with the current approach to determine more precisely the activity and the prognostic value of these biomarkers and pathways in each group.

P53 and β-Catenin Expression Predict Poorer Prognosis in Patients With Anaplastic Large-Cell Lymphoma

BackgroundThe Wnt/β-catenin signaling pathway is a major target of p53. β-Catenin/p53 coexpression predicts poorer survival in carcinoma patients. Conversely, CD99 inhibits tumor metastasis through the Wnt/β-catenin pathway. We therefore assessed p53, β-catenin, and CD99 by immunohistochemistry. Patients and MethodsWe studied 45 patients with systemic anaplastic large-cell lymphoma (ALCL), including 20 anaplastic lymphoma kinase (ALK)-positive and 25 ALK-negative ALCL. β-Catenin expression was analyzed using phospho-β-catenin-S552 antibody because its nuclear localization indicates Wnt signaling. ResultsIn this cohort, p53 expression was associated with ALK-negative ALCL. Furthermore, p53 or β-catenin expression alone or β-catenin/p53 double expression showed poorer overall survival and disease-free survival in patients with ALCL overall and in patients with ALK-negative ALCL. CD99 expression was more frequent in ALK-positive ALCL but had no prognostic significance. ConclusionThis is the first study to evaluate phospho-β-catenin-S552 expression in ALCL. The results of this study, although limited by small patient size, suggest that β-catenin and p53 may play a role in pathogenesis and may be helpful in risk stratification of ALCL patients.

FDA Approval Summary: Brentuximab Vedotin in First-Line Treatment of Peripheral T-Cell Lymphoma.

In November 2018, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP). Approval was based on ECHELON-2, a randomized, double-blind, actively controlled trial that compared BV+CHP with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in 452 patients with newly diagnosed, CD30-expressing PTCL. Efficacy was based on independent review facility-assessed progression-free survival (PFS). The median PFS was 48.2 months with BV+CHP versus 20.8 months with CHOP, resulting in a hazard ratio (HR) of 0.71 (95% confidence interval [CI]: 0.54-0.93). The trial also demonstrated improvement in overall survival (HR 0.66; 95% CI: 0.46-0.95), complete response rate (68% vs. 56%), and overall response rate (83% vs. 72%) with BV+CHP. The most common adverse reactions (incidence ≥20%) observed ≥2% more with BV+CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Peripheral neuropathy rates were similar (52% with BV+CHP, 55% with CHOP). Through the Real-Time Oncology Review pilot program, which allows FDA early access to key data, FDA granted this approval less than 2 weeks after official submission of the application. IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration approval for treatment of patients with newly diagnosed peripheral T-cell lymphomas (PTCL). Improvement in progression-free and overall survival over cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, which has been the standard of care for decades, is unprecedented. The new regimen represents a major advance for the frontline treatment of patients with CD30-expressing PTCL.

47. Limb amputation of a CD30 positive cutaneous T cell lymphoma

Background: Primary cutaneous lymphomas form a spectrum of disease and the overlapping features pose a diagnostic challenge. The differential diagnosis of CD30 positive primary cutaneous lymphomas includes transformation of mycosis fungoides, lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Cutaneous involvement from systemic anaplastic large cell lymphoma is also a possibility.

Breast Implant–Associated Anaplastic Large Cell Lymphoma: What We Know

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare peripheral T-cell lymphoma, first reported in 1997. It is pathologically confirmed as a CD30-positive, anaplastic lymphoma kinase (ALK)-negative ALCL by immunohistochemistry. Unlike systemic ALK-negative ALCL, breast implant-associated disease has a much more favorable prognosis overall. In most cases, BIA-ALCL will present with delayed seroma more than 1 year after breast implantation indicated for either cosmetic or reconstructive purposes. The average onset of seroma presentation is 8 to 9 years after implantation. Breast implant-associated anaplastic large cell lymphoma may arise in one of two distinct forms: either in situ or infiltrative disease. In situ disease is confined within a seroma, while infiltrative disease may present with lymph node involvement either with or without palpable breast mass or tumor. Infiltrative disease has an overall worse prognosis in regards to disease-related mortality, up to 40% within 2 years. Appropriate pathological consultation with an experienced hematopathologist and oncologist is imperative when making a diagnosis of BIA-ALCL. There are several theorized risk factors associated with the disease; however, the exact pathophysiology is not yet known. Our objective in writing this review article is to provide an overview of what we know about the epidemiology, disease characteristics, and current management strategies. In doing so, we aim to bring awareness and familiarity to the advanced practitioner population in recognizing and treating BIA-ALCL.

What Cytokines Can Tell Us About the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL).

Cytokines, their receptors, and downstream signaling partners, especially JAK1/2 and STAT3, are key biomarkers in lymphoproliferative disorders including systemic anaplastic large cell lymphoma (ALCL). Here we review their role in breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). Early results suggest that, in addition to CD30, IL-9, IL-10, and IL-13 can distinguish malignant from benign seromas. IL-6 is increased in both benign and malignant seromas. IFNγ may identify a subset of BIA-ALCL with a different clinical course. Immunohistochemical detection of nuclear transcription factors-which regulate cytokine signaling-and phosphorylated janus kinases/signal transducers and activators of transcription can inform the identification and malignant potential of CD30+ cells. The innate immune response is the first line of defense against microbes suspected to initiate BIA-ALCL. Innate lymphoid cells are grouped according to the cytokines they produce and could potentially be identified as precursors to BIA-ALCL. Cytokines modulate the tumor microenvironment and hence the pathology of BIA-ALCL such as the influx of eosinophils and capsular fibrosis mediated by IL-13. The plasticity of T cells and innate immune cells theoretically can enable therapeutic manipulations toward a less aggressive phenotype. Cytokine receptors targeted in clinical trials of inflammatory and autoimmune disorders could afford opportunities for immunotherapy of BIA-ALCL.