Primary Cutaneous Anaplastic Large Cell Lymphoma Research Articles

Spider bite presenting as fever, macrophage activation syndrome and a skin ulcer

Introduction: Fever of unknown origin (FUO) refers to a condition of prolonged increased body temperature, without identified causes. The most common cause of FUO worldwide are infections; arthropod bites (loxoscelism) should be considered in view of the spread of the fiddleback spider. Loxoscelism can present in a cutaneous form (a necrotic cutaneous ulcer) or in a systemic form with fever, haemolytic anaemia, rhabdomyolysis and, rarely, macrophage activation syndrome (MAS). For this suspicion, it is important to have actually seen the spider. Case description: A 71-year-old man was admitted to our department because of intermittent fever, arthralgia and a necrotic skin lesion on his right forearm that appeared after gardening. Laboratory tests were negative for infectious diseases, and several courses of antibiotics were administered empirically without clinical benefit. Whole-body computed tomography showed multiple colliquative lymphadenomegalies, the largest one in the right axilla, presumably of reactive significance. A shave biopsy of the necrotic lesion was performed: culture tests were negative and histological examination showed non-specific necrotic material, so a second skin and lymph node biopsy was performed. The patient developed MAS for which he received corticosteroid therapy with clinical/laboratory benefit. Cutaneous and systemic loxoscelism complicated by MAS was diagnosed. Subsequently, the second biopsy revealed morphological and immunophenotypic findings consistent with primary cutaneous anaplastic large cell lymphoma (PC-ALCL). Conclusions: Skin lesions and lymphadenomegalies of unknown origin should always be biopsied. It is very common to get indeterminate results, but this does not justify not repeating the procedure to avoid misdiagnosis.

Paediatric cutaneous lymphomas including rare subtypes: A 40-year experience at a tertiary referral centre.

Primary cutaneous lymphomas are neoplasms of the immune system with a distinct tropism for the skin and an absence of extracutaneous manifestations at the time of diagnosis. Studies focusing on cutaneous lymphomas in children and adolescents remain scarce and often do not encompass the rare subtypes. To address this knowledge gap by describing the clinical, histological and molecular characteristics of a large group of paediatric patients affected by primary cutaneous lymphoma. We also provided the Paediatric Primary Cutaneous Lymphoma Atlas that illustrates the clinicopathological spectrum of observed presentations, in the hope of supporting other physicians in the diagnostic process. Retrospective chart review of paediatric patients diagnosed with primary cutaneous lymphomas between 1980 and 2022 at the Paediatric Dermatology Unit of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan. A total of 101 patients (58 males, 43 females) met the inclusion criteria. The most common subtypes were lymphomatoid papulosis (n = 48) and mycosis fungoides (n = 31). These were followed by primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders (n = 7), primary cutaneous anaplastic large-cell lymphomas (n = 5), primary cutaneous marginal zone B-cell lymphomas (n = 3), primary cutaneous follicle centre lymphomas (n = 2), subcutaneous panniculitis-like T-cell lymphomas (n = 2), primary cutaneous peripheral T-cell lymphoma not otherwise specified (n = 1), primary cutaneous precursor B-lymphoblastic lymphoma (n = 1) and Sézary syndrome (n = 1). Clinical follow-up data covering a median of 70.8 months (range 1-324) were available for 74 patients, of whom three died due to cutaneous lymphoma. Our findings shed light on the peculiar aspects and long-term outcomes of paediatric cutaneous lymphomas, particularly emphasizing their distinctive features in comparison to their adult counterparts and exploring the less common subtypes. Further larger-scale studies are warranted to better characterize these entities and to achieve a more rapid and accurate diagnosis.

Primary cutaneous anaplastic large-cell lymphoma resembling infratemporal space infection: a case report

BackgroundPrimary cutaneous anaplastic large-cell lymphoma (PC-ALCL) is a rare T-cell lymphoma belonging to the CD30 + T-cell lymphoproliferative disorders. The case of PC-ALCL in the temporal region is exceedingly rare. Herein, we report a case of PC-ALCL involving the temporal region mimicking infratemporal space infection.Case presentationA 78-year-old woman presented to maxillofacial surgery service with a 6-month history of swelling and pain in the left side of her face. Laboratory investigations found an elevated C-reactive protein (CRP). Imaging findings showed enlarged lymph nodes and extensive thickening of subcutaneous tissue of the left temples. Based on these findings, the infratemporal space infection was suspected initially. The patient underwent incision and drainage, and we unexpectedly found no pus in the lesion area. Incisional biopsy showed necrosis and extensive involvement of the left temples by a diffuse infiltrate containing large, atypical cells. The tumor cells were positive for CD30, CD3, Ki67. They were negative for ALK (SP8), CD5, CD8, CD20 and PAX5. After considering these findings, a diagnosis of PC-ALCL was rendered. The patient was admitted to the lymphoma department for systemic chemotherapy and no relapse occurred during a follow-up period of six months.ConclusionsThis report suggests that if there are suspicious intraoperative manifestations, carrying out a biopsy simultaneously, using Hematoxylin and eosin (HE) staining, and a comprehensive Immunohistochemistry (IHC) panel are essential to diagnosing PC-ALCL to prevent misdiagnosis.

Challenges in utilizing ALK expression to distinguish primary cutaneous from systemic anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a CD30+ peripheral T-cell lymphoma with a clinical spectrum including cutaneous and systemic presentations. While primary cutaneous ALCL (pcALCL) has a favorable prognosis, systemic ALCL (sALCL) has poorer survival outcomes. Expression of anaplastic lymphoma kinase (ALK) by malignant cells has been suggested to distinguish sALCL from pcALCL. However, there have been documented cases of ALK-positive ALCL confined to the skin. The present study reviewed characteristics of published cutaneous ALK-positive ALCL cases to distinguish between these two entities. In 23 identified adults with ALK-positive pcALCL, 26% developed systemic involvement and 74% had skin-limited disease. In 14 pediatric patients, 36% had both cutaneous and systemic involvement and 64% had cutaneous disease only. This analysis revealed that pcALCL and sALCL could not reliably be distinguished by ALK expression or nuclear vs. cytoplasmic localization. Localized treatment with frequent monitoring may be sufficient in ALK-positive pcALCL until there is evidence of progression. Physicians should be aware of the overall spectrum of ALCL, including cutaneous limited disease, systemic disease, disease with NPM-ALK translocation, disease with ALK positivity and disease with skin recurrence.

Primary cutaneous anaplastic large-cell lymphoma: a case report

Primary cutaneous anaplastic large-cell lymphoma: a case report

A Multicenter Real-World Analysis (RWA) of Primary Cutaneous Anaplastic Large Cell Lymphoma (PCALCL) Treated in the Modern Era

Introduction: The real-world outcomes in patients (pts) with PCALCL in the era of targeted therapies like Brentuximab Vedotin (BV) is not well defined due to lack of large multicenter studies. We conducted a multicenter retrospective RWA to assess patient and disease characteristics, treatment patterns, survival outcomes and impact of novel therapies in this rare type of cutaneous T cell lymphoma (CTCL). Methods: A total of 95 adult (≥18 years) pts from 8 academic institutions in the United States diagnosed from 2010-2022 were included in the analysis. The study was approved by the Institutional Review Boards at the respective sites. Demographic and disease factors were summarized by descriptive statistics. Overall survival (OS) was estimated by Kaplan-Meier method and compared using log rank method. Results: In our cohort, the median age at diagnosis was 63 (range 18-93) years. The majority of pts were male 60%, white 79%, and had good performance status (PS) ECOG 0-1 (93%). Median time from initial presentation to diagnosis was 1.8 (range 0-211) months. Most common initial skin presentation was tumor 46% (44/95), followed by plaques 27% (26/95) and patches 15% (14/95). No pt presented with erythroderma. Median size of the largest lesion was 2 (range 0.5-20) cm. 63% had early stage (IA-IIA) disease and 86% had <5 skin lesions at the time of initial diagnosis. Furthermore, palpable lymph node (LN) (10%) and elevated LDH (18%) were uncommon at diagnosis. Initial treatments include localized radiation 60%, surgical excision 21% and topical steroids 11%. A small subset of pts received systemic treatments like CHOP 13% (12/95), BV 8% (8/95) and oral methotrexate 7% (7/95) as frontline therapy. A proportion of pts received XRT with CHOP (6/12) and BV (2/8). The overall response rate (ORR) to initial therapy was 68% (65/95) with 61% achieving a CR and 17% had primary refractory disease (stable and progressive disease). Relapse rate after 1st line therapy was 52% (49/95). In our cohort a total of 22 pts received BV after frontline therapy, of which 19 were BV naïve and 3 were re-treated. At the time of last follow up, 27% of our cohort were still on treatment, 78% were alive and 21% were dead; only 3% of deaths were attributed to the lymphoma. The median OS was 128 months (95% CI: 78.4-NA) (Figure 1) with a median follow up of 42 (range 0.5-123.5) months. The 5-year OS was 77%. On univariate analysis, older age (≥65 vs <65 years) (median OS 78 vs 128 months; p=0.004) and higher number of lesions (5-10 vs <5) (mOS 34 vs 128 months; p=<0.0001) were significant associated with OS (Table 1). Type and size of the skin lesions, presence of palpable LN, elevated LDH, stage, and treatment modalities had no impact on OS. Results of multivariate analysis will be presented at the conference. Conclusion: In this large multicenter RWA of PCALCL, excellent long-term survival was observed following frontline therapies that were mostly skin directed. The use of systemic therapies including BV were infrequent even in relapsed disease. Older age and increased number of skin lesions were associated with poor OS.

Primary cutaneous CD30+ lymphoproliferative disorders with DUSP22 translocation.

Primary cutaneous CD30+ lymphoproliferative disorders (LPD) encompass abroad category of clonal Tcell proliferations with varied clinical presentations. Classically, lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL) have been recognized as distinct clinicopathological entities according to their differing clinical features. Recently, asubset of LyP and both cutaneous and systemic ALCL have been shown to carry aDUSP22 translocation [1-3], adefining molecular feature for the novel entity "LyP with DUSP22t" [1]. In cutaneous biopsies, both primary cutaneous DUSP22-translocated ALCL and LyP with DUSP22 rearrangements are characterized by abiphasic pattern with significant small cell epidermotropism. Adistinct protein expression profile with preserved T Cell Receptor (TCR) expression, positivity for CD30, LEF1, HLA, and CD58, and negativity for cytotoxic marker expression as well as phospho-STAT3 protein is consistently found in these cases.

Updates in pathobiological aspects of anaplastic large cell lymphoma.

Anaplastic large cell lymphomas (ALCL) encompass several distinct subtypes of mature T-cell neoplasms that are unified by the expression of CD30 and anaplastic cytomorphology. Identification of the cytogenetic abnormality t(2;5)(p23;q35) led to the subclassification of ALCLs into ALK+ ALCL and ALK- ALCL. According to the most recent World Health Organization (WHO) Classification of Haematolymphoid Tumours as well as the International Consensus Classification (ICC) of Mature Lymphoid Neoplasms, ALCLs encompass ALK+ ALCL, ALK- ALCL, and breast implant-associated ALCL (BI-ALCL). Approximately 80% of systemic ALCLs harbor rearrangement of ALK, with NPM1 being the most common partner gene, although many other fusion partner genes have been identified to date. ALK- ALCLs represent a heterogeneous group of lymphomas with distinct clinical, immunophenotypic, and genetic features. A subset harbor recurrent rearrangement of genes, including TYK2, DUSP22, and TP63, with a proportion for which genetic aberrations have yet to be characterized. Although primary cutaneous ALCL (pc-ALCL) is currently classified as a subtype of primary cutaneous T-cell lymphoma, due to the large anaplastic and pleomorphic morphology together with CD30 expression in the malignant cells, this review also discusses the pathobiological features of this disease entity. Genomic and proteomic studies have contributed significant knowledge elucidating novel signaling pathways that are implicated in ALCL pathogenesis and represent candidate targets of therapeutic interventions. This review aims to offer perspectives on recent insights regarding the pathobiological and genetic features of ALCL.

Anaplastic Large Cell Transformation of Mycosis Fungoides: Case Report and Review of the Literature.

We report a 48-year-old man with CD30+ large cell transformation of mycosis fungoides (tMF) with distinctive anaplastic morphology. The patient initially presented with folliculotropic and syringotropic mycosis fungoides (MF) manifested as occipital scalp plaque and trunk and extremities patches. Six years later, he progressed to the tumor stage from his scalp lesion and developed cervical lymphadenopathy. Lymph node and scalp biopsies showed diffuse infiltration of CD30+ anaplastic cells with multinucleated, hallmark-like, Hodgkin-Reed-Sternberg-like, histiocytoid forms, indistinguishable from anaplastic large cell lymphoma (ALCL). T-cell receptor gamma gene (TCRg) rearrangement studies revealed identical clones in the initial MF scalp lesion and nodal anaplastic lesion, confirming the transformation. Ancillary studies showed absence of IRF4/DUSP22 and ALK rearrangements and positive RB1, SMARCA4, SOCS1, and TP53 mutations. The patient achieved partial response with systemic chemotherapy. Our case is an example of tMF presenting as the morphology and phenotype of ALCL. Because clinical behavior and therapeutic options of tMF and primary cutaneous ALCL may be different, it is clinically relevant to differentiate these 2 entities. The proof of clonal relationship may be useful in diagnostically challenging cases with features overlapping between tMF and primary cutaneous ALCL.

Primary Cutaneous Anaplastic Large Cell Lymphoma-A Review of Clinical, Morphological, Immunohistochemical, and Molecular Features.

Primary cutaneous anaplastic large cell lymphoma (ALCL) is the second most common cutaneous T-cell lymphoma after mycosis fungoides and belongs to the spectrum of cutaneous CD30+ T-cell lymphoproliferative disorders. Although primary cutaneous ALCL usually presents as a localized nodule or papule with or without ulceration, multifocal lesions may occur in up to 20% of cases. Histologically, primary cutaneous ALCL consists of a diffuse dermal infiltrate of medium to large anaplastic/pleomorphic cells with abundant amphophilic-to-eosinophilic cytoplasm, horseshoe-shaped nuclei, strong and diffuse expression of CD30, and with focal or no epidermotropism. The neoplastic infiltrate may show angiocentric distribution and may extend to the subcutis. Patients with localized or multifocal disease have a similar prognosis with a 10-year overall survival rate of 90%. Approximately 30% of primary cutaneous ALCLs harbor a DUSP22 (6p25.3) gene rearrangement that results in decreased expression of this dual-specific phosphatase, decreased STAT3 activation, and decreased activity of immune and autoimmune-mediated mechanisms regulated by T-cells.

Spatially Resolved Transcriptomes of CD30+-Transformed Mycosis Fungoides and Cutaneous Anaplastic Large-Cell Lymphoma

Mycosis fungoides with large-cell transformation (MF-LCT) occurs in a minor proportion of aggressive lesions, which express CD30 similar to primary cutaneous anaplastic large-cell lymphoma (pcALCL). We investigated the differences in spatially resolved transcriptome profiles of MF-LCT and pcALCL using CD30 morphology markers and 28 and 24 regions of interest (ROIs) in MF-LCT and pcALCL, respectively. Differentially expressed genes, pathway analysis, and immune-cell deconvolution by selective analysis of CD30-positive tumor cells and CD30-negative extratumoral areas were undertaken. In CD30-positive ROIs of MF-LCT, 190 differentially expressed genes were upregulated (29 were directly or indirectly associated with extracellular matrix remodeling), whereas 255 differentially expressed genes were downregulated, compared with those of pcALCL. Except for cornified envelope formation and keratinization, all six pathways enriched in CD30-positive ROIs of MF-LCT were associated with extracellular matrix remodeling. In CD30-positive ROIs in MF-LCT compared with those in pcALCL, immune-cell deconvolution revealed significantly increased fibroblasts and M2 macrophages (P= 0.012 and P= 0.023, respectively) but decreased M1 macrophages (P= 0.031). In CD30-negative ROIs in MF-LCT compared with those in pcALCL, memory B (P= 0.021), plasma (P= 0.023), and CD8 memory T (P= 0.001) cells significantly decreased, whereas regulatory T cells (P= 0.024) increased. Predomination of extracellular matrix remodeling pathways and immunosuppressive microenvironment in MF-LCT indicates pathophysiological differences between MF-LCT and pcALCL.

Een pleister of zalf op de wonde is niet altijd voldoende, of toch?

A band-aid or ointment on the wound is not always enough, or is it? A healthy 68-year-old man presents with a progressive, ulcerated, livid swelling on the right elbow. After clinicopathological correlation, the diagnosis of a primary cutaneous anaplastic large-cell lymphoma (ALCL) is made. This entity is part of the heterogeneous group of ALCL, which is a subtype of T-cell lymphoma with a similar morphology, but a variable clinical presentation, therapy and prognosis. An ALCL usually occurs in adults, rarely in children and adolescents. Locally or scattered over several sites, large single or multiple slow-growing erythematous papules, nodules or tumours develop. These lesions may ulcerate, exudate and/or itch. Generally, the prognosis is favourable, with a 5-year survival rate of 90%. Spontaneous regression is observed in 25% of the cases. Recurrences are frequent (up to 30% of the cases), but usually remain cutaneous. If technically feasible, a solitary or localized primary cutaneous ALCL can be excised, but if inoperable, radiotherapy is initiated, as in the discussed patient. Case series also describe good responses to a low dose of methotrexate (15-20 mg per week), but recurrences are frequent and the evidence is limited. In case of multifocal skin involvement, combination chemotherapy is used.

Brentuximab-vedotin in combination with cyclophosphamide, doxorubicin, prednisolone for the treatment of aggressive CD30-positive cutaneous T-cell lymphomas

Aggressive CD30-positive cutaneous T-cell lymphomas (CD30+CTCL) are associated with unfavorable prognosis. Anthracycline-based polychemotherapy (CHOP) and brentuximab-vedotin (BV) monotherapy are related to poor outcomes in case of extracutaneous involvement or rapidly-progressing disease. Our objective was to assess the effectiveness of BV + CHP in aggressive CD30+CTCL. We included 7 patients treated with BV + CHP from April 2015 to January 2022: 4 had mycosis fungoides with large-cell transformation, 2 had primary cutaneous anaplastic large-cell lymphoma, and 1 harbored a primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma. After a median [IQR] follow-up of 17.2 [13.2–21.0] months, 6/7 patients achieved an ORR lasting ≥4 months. The median [IQR] duration of response was 9.5 [5.9–11.1] months and the median [IQR] progression free survival was 14.9 [11.6–16.4] months. Four patients displayed progression with a median (range) time to next treatment of 15.8 (6.5–16.3) months. Two grade-3 adverse events were reported: febrile neutropenia and thromboembolic event. BV + CHP displayed substantial antitumor activity and favorable safety profile in 7 patients with aggressive CD30+CTCL.

Rapidly Enlarging Primary Cutaneous Anaplastic Large-Cell Lymphoma of the Eyelid.

Rapidly Enlarging Primary Cutaneous Anaplastic Large-Cell Lymphoma of the Eyelid.

How to Diagnose Anaplastic Large Cell Lymphoma on Cytological Samples? A Series with Emphasis on Diagnostic Clue and Pitfalls

Introduction: Anaplastic large cell lymphoma (ALCL) is a rare mature T-cell non-Hodgkin’s lymphoma characterized by large and pleomorphic neoplastic CD30-positive T cells. ALCL includes different subtypes with different clinical and biological features: systemic ALCL, primary cutaneous ALCL, breast implant-associated ALCL (BIA-ALCL). Anaplastic lymphoma kinase (ALK) is overexpressed and rearranged in some systemic cases. Diagnosis of ALCL may be challenging on cytological samples, but the correct diagnosis is mandatory for the management of the patient. Methods: A retrospective series of 12 ALCLs diagnosed by cytology is reported. Cytological samples included lymph nodes and skin lesions fine needle aspiration cytology, peritoneal effusion, and periprosthetic fluid. Microscopic evaluation was performed on direct smears, cell-block sections, and cytocentrifugated slides. Immunocytochemistry was performed on cell-block sections, direct smears, and cytocentrifugated slides. Molecular evaluation by fluorescent in-situ hybridization (FISH) was performed on cell-block sections. Results: The series included 4 ALK+ ALCLs, 5 ALK− ALCLs, and 3 BIA-ALCLs. FNAC was performed on lymph nodes in 8 cases and on skin lesion in 1 case. In this last case, a peritoneal effusion was also evaluated. Breast periprosthetic fluids were evaluated in 3 cases. A large immunocytochemical panel was performed in each case, and FISH in 3 cases, demonstrating ALK rearrangement in a case of ALK+ ALCL. A final diagnosis was rendered in all cases. In the case of skin lesion, the differential diagnosis between systemic ALCL and primary cutaneous ALCL was possible. Conclusion: The cytological diagnosis of ALCL may be challenging, and the proper management of the collected sample is mandatory. The rapid on-site evaluation and the realization of a cell block are strongly recommended. Immunocytochemistry is mandatory for the diagnosis and a large antibodies panel is needed as differential diagnosis includes many different neoplasms. FISH may be useful to evaluate ALK rearrangements. When properly managed, cytology can lead to a reliable final diagnosis of ALCL.

Clinical Characteristics, Survival Outcomes, and Prognostic Factors in Primary Cutaneous CD30+ T-Cell Lymphoma: National Cancer Database Analysis (2004-2018)

Introduction Primary cutaneous CD30+ T-cell lymphoma (CD30+ PCTCL) is a very rare entity, accounting for about 30% of all cutaneous T-cell lymphomas and consists of primary cutaneous anaplastic large cell lymphoma (PCALCL) and lymphomatoid papulosis (LyP). Large-scale studies describing the natural history of this entity are lacking. Materials and Methods The National Cancer Database (NCDB) was queried for patients diagnosed with CD30+ PCTCL between 2004 and 2018. All patients aged 18 years or older diagnosed with CD30+ PCTCL were included, and we excluded patients who lost to follow-up (unknown vital status of last contact). Kaplan-Meier and multivariate Cox regression were used in the analyses. Results The total cohort consisted of 2017 patients with CD30+ PCTCL. The specific subtype, PCALCL vs LyP, was not available. 1168 (58%) were males, 1684 (84%) Caucasian, and 232 (12%) African American, 1317 (65%) had confirmed early-stage disease (stage I and II) and 226 (11%) had confirmed advanced stage disease (stage III and IV). The median age at diagnosis was 64 years (range 18-90) and the median overall survival (OS) for the whole cohort was 166 months (95% CI 150.5-181). Compared to patients with early-stage disease, patients with advanced stage were more likely to be African American (16.8% vs 9.8% P=0.005), have B-symptoms (21.7% vs 4.3%, P<0.001), have high IPI score (2.2% vs. 0.3%, P <0.001) and to be female (50.4% vs 39.9%, P=0.003). Patients with early-stage disease had better median OS compared to patients with advanced stage disease (178 vs. 35 months, P<0.001). There was no significant difference between patients with early and advance stage disease in terms of age, facility type where they received treatment, insurance status, or Charlson-Deyo score. In patients with early-stage disease, there was no statistically significant difference in the median OS between patients who received radiation only (N=144) compared to patients who had surgical resection alone (N=255) (not reached in both groups, P=0.676) with 5-year OS of 83% in both groups. In patients with advanced stage disease, there was no statistically significant difference in median OS between patients who received chemotherapy (N=131) and patients who did not receive chemotherapy (N=90) (30 vs. 43 months, P=786). Also, among patients who received chemotherapy, there was no statistically significant difference in the median OS between patients who received single agent chemotherapy and patients who received multiagent chemotherapy (35 vs 30 months, P=0.934). Conclusion This large real-world analysis indicates that CD30+ PCTCL predominantly affects elderly patients and is associated with excellent long-term survival. Intensive therapies such as multi-agent chemotherapy are not associated with survival benefit. Surgical excision and radiation treatments are equally efficacious in early-stage disease. We suggest that overtreatment with intensive therapies should be avoided, and conservative therapeutic approach is warranted in most patients. Further research is warranted to determine well-defined indications for intensive therapies.

Real-World Treatment Patterns and Clinical Outcomes with Brentuximab Vedotin or Other Standard Therapies in Patients with Previously Treated Cutaneous T-Cell Lymphoma (CTCL): A Retrospective Chart Review Study in the United States

INTRODUCTION: CTCLs such as primary cutaneous anaplastic large-cell lymphomas (pcALCLs) uniformly express CD30, whereas mycosis fungoides (MF) heterogeneously express CD30. In ALCANZA (Horwitz 2021), patients with CD30-positive pcALCL or MF randomized to brentuximab vedotin (BV) vs physician's choice of methotrexate or bexarotene had a significantly higher objective response rate (ORR) lasting ≥4 months (ORR4; 54.7% vs 12.5%; P<0.001) and longer median progression-free survival (PFS; 16.7 vs 3.5 months; P<0.001) and time to next treatment (TTNT; 14.2 vs 5.6 months; P<0.001) at a median follow-up of 45.9 months. This study describes real-world patient characteristics, treatment patterns, clinical outcomes, and healthcare resource use (HRU) in CTCL patients treated with BV or other standard therapies (OST) after ≥1 systemic therapy. METHODS: A retrospective, longitudinal physician chart review was conducted from Oct 2021-Jan 2022 (approved by WCG IRB). Physicians were oncologists/hematologists with access to complete medical records for ≥1 eligible patient. Eligible adult patients had pcALCL or MF, previously received ≥1 systemic therapy, and were treated with BV or OST from Nov 2017-Mar 2021. The index date was the initiation of second-line (2L) CTCL systemic therapy. The observation period was from index to the earliest of death, loss to follow-up, or chart abstraction. Treatment patterns were assessed from CTCL diagnosis to end of observation period; clinical outcomes for 2L systemic therapy and HRU were assessed during the observation period. Treatment response was recorded via the Global Response Score (Olsen 2011). TTNT was from index to the earlier of initiation of a new line of therapy or death. Real-world PFS (rwPFS) was from index to earliest of progression, treatment discontinuation due to progression, or death. Overall survival (OS) was from index to death. Median times-to-event were computed using Kaplan-Meier (KM) analysis. Since median times-to-event were not reached in both cohorts for multiple outcomes, restricted mean survival time (RMST), a measure of the average event-free survival time during a specific period estimated by the area under the KM curve, at 1 and 2 years was also estimated. RESULTS: Physicians (n=125; 68.0% community, 75.2% practiced >10 years) abstracted medical charts for 303 patients (BV/OST: n=139/164; male, 66.9%/67.7%; MF, 56.8%/65.9%; ECOG PS 0-1, 86.3%/67.1%). The median observation period for BV and OST was 8.1 (interquartile range: 7.1-10.8) and 8.8 (4.8-11.5) months. Most patients in the BV cohort (96.4%) received BV as 2L systemic therapy. In the OST cohort, the most common 2L therapies were methotrexate (11.6%), mogamulizumab (9.1%), and bendamustine (9.1%) monotherapies. The median (95% CI) duration of 2L therapy for BV and OST was 8.4 (7.1-15.4) and 5.2 (3.9-7.3) months. The rwORR for BV and OST was 82.1% and 66.5%; rwORR4 was 42.5% and 25.0% (Table 1). Median (95% CI) TTNT was not reached (NR; 17.5-NR) for BV and was 13.2 (9.2-NR) months for OST; RMST for TTNT was higher for BV vs OST (1-year: 11.2 [10.8-11.7] vs 8.1 [7.4-8.9] months, P<0.01; 2-years: 20.5 [18.6-22.4] vs 13.7 [11.9-15.5] months, P<0.01). RMST (95% CI) for rwPFS for BV and OST at 1 year was 11.1 (10.5-11.6) vs 8.9 (8.1-9.6) months (P<0.01) and at 2 years was 21.0 (19.1-22.9) vs 15.7 (13.6-17.8) months (P<0.01) (Table 2). Median OS was NR in both cohorts; for BV and OST, 9% and 36% of patients died. RMST (95% CI) for OS for BV and OST at 1 year was 11.3 (10.9-11.7) vs 9.0 (8.3-9.7) months (P<0.01) and at 2 years was 21.3 (19.7-22.8) vs 15.8 (14.1-17.5) months (P<0.01). During the observation period, 30.2% and 39.0% of the BV and OST cohorts had an emergency department visit, and 29.5% and 36.6% had a hospitalization; median (95%CI) hospital length of stay for those with ≥1 hospitalization was 13.7 (CI: 12.6-14.9) and 21.1 (19.9-22.4) days. CONCLUSION: Real-world outcomes with BV in patients with CTCL who received ≥1 prior systemic therapy were consistent with results from ALCANZA, demonstrating favorable clinical outcomes with BV. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TP63 Fusions Drive Enhancer Rewiring, Lymphomagenesis, and Dependence on EZH2

Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas, which is highly unique among chromosomal translocations. Specifically, TP63 rearrangements were found in 5-10% of ALK-negative anaplastic large cell lymphoma (ALK- ALCL), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and primary cutaneous ALCL, 7% of mycosis fungoides with large cell transformation (MF-LCT), and 1% of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending on cohorts. This contrasts with rearrangements of DUSP22, which are also observed in ALK- ALCLs and confer a good prognosis. The function and mechanisms of TP63 rearrangements and TP63 fusion proteins in tumorigenesis are poorly understood. As a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to understand how TP63 fusions contribute to tumorigenesis and to translate the findings into novel therapeutic options for these patients. Here, we demonstrated that TP63 fusions are essential for the propagation of T-cell lymphomas (TCLs). Knockdown of TP63 fusions with specific shRNAs in TCL cell lines harboring TP63 rearrangements suppressed both cell growth in vitro and tumor growth in vivo. Retroviral expression of TBL1XR1-TP63, the most common TP63 fusion, conferred cytokine independence in Ba/F3 cells, consistent with its role as an oncogene. To investigate the role of TP63 fusions in T- and B-cell development and lymphomagenesis, we engineered a CAG-Loxp-Stop-Loxp-TBL1XR1-TP63 conditional knock-in mouse model and crossed with hCD2-Cre mice, which results in expression beginning during early lymphoid development. Transgenic mice had both cytokine and transcriptional evidence of immune activation as well as T cell repertoire narrowing, consistent with clonal selection. As observed in patients, transgenic mice developed multiple subtypes of both T- and B-cell lymphoma that mimicked ALCL, PTCL-NOS and MYC-expressing DLBCL. To define the effects and mechanisms of TP63 fusions within T cells, we performed CRISPR screening, transcriptomic, epigenomic, and proteomic analyses. We also performed a domain-focused CRISPR-Cas9 knockout scan using 452 sgRNAs tiling the entire coding regions of TBL1XR1 and TP63 to clarify essential oncogenic domains within TBL1XR1-TP63. Our data showed that domains within both the N-terminal TBL1XR1 and C-terminal TP63 portions contribute to the function of this fusion. We found that the N-terminal component of TP63 fusions (TBL1XR1, FOXK2, etc.) interacts with components of the NCOR/SMRT complex. At the same time, the C-terminal portion of TP63 fusions (which recapitulates the deltaNp63 isoform expressed in some carcinomas) interacts with the enhancer modifier KMT2D and its complex members. TBL1XR1-TP63 binds to a novel distal enhancer to drive MYC expression, and thus upregulates the expression of EZH2, which encodes the histone H3K27 methylase. Knockdown of the TP63 fusion in TCL cell lines led to complete loss of H3K27me3. Finally, we assessed whether EZH2 is a vulnerability of TP63-rearranged lymphomas. We found that knockdown of EZH2 in TP63-rearranged lines significantly impaired cell growth, as did treatment with the EZH2 inhibitor tazemetostat and the EZH2 and 1 dual inhibitor valemetostat. Valemetostat, which is now being tested in patients with lymphoma, was highly effective in three different in vivo models of TP63-rearranged TCL. Together, our results identify the TP63 fusion as a highly unique oncogenic driver in lymphomagenesis capable of recruiting multiple epigenetic modifier complexes and inducing a targetable dependence on EZH2.

Combination of Mitoxantrone Hydrochloride Liposome with Cyclophosphamide, Vincristine and Prednisone (CMOP) in Treatment-Naïve Patients with Peripheral T-Cell Lymphoma: A Multicenter, Open-Label, Single-Arm, Phase Ib Clinical Trial

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas accounting for 25% to 30% of non-Hodgkin lymphomas in China. Although CHOP remains backbone of frontline treatment in PTCL, outcomes are typically poor. Front-line treatment with brentuximab vedotin plus CHP only provided moderate improvement in CD30-positive PTCL. Therefore, the development of novel agents for this population is still urgently needed. In 2020 ASH annual meeting (Abstracts 42), we reported mitoxantrone hydrochloride liposome (PLM60) monotherapy yielded effective antitumor activity, durable response with mild toxicity in patients with relapsed or refractory PTCL for the first time. This trial aimed to explore the safety, efficacy and pharmacokinetics (PK) of PLM60 plus cyclophosphamide, vincristine and prednisone in patients with treatment-naïve PTCL (TN-PTCL). Methods: Patients aged 18-75 years with histologically confirmed treatment-naïve PTCL (including PTCL-NOS, AITL, ALCL- ALK+/-; other subtypes that investigators consider to be appropriate), ECOG performance score 0-1 and avid-FDG PTCL by PET/CT were recruited. Main exclusion criteria were patients with ENKTL, MF/SS, primary cutaneous-ALCL and ATLL, central nervous system involvement, hemophagocytic syndrome. This study consisted of two parts. In part 1, 3+3 dose-escalation design with four dose levels of PLM60 (12, 15, 18 and 21 mg/m2) was used to identify the MTD, DLT and recommended Phase II dosage (RP2D) of PLM60 plus cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2 with maximum dose of2 mg) on day 1 and prednisone 100 mg orally administered on day 1-5 (CMOP) of every cycle (28 days) for 6 cycles. Part 2 was dose expansion at the RP2D. The primary endpoints were safety. Adverse events were defined according to the CTCAE 5.0. The secondary endpoint was efficacy including complete response (CR) rate, duration of complete remission (DoCR), objective response rate (ORR) and progression-free survival (PFS) assessed according to Lugano 2014 criteria and PK profile. This trial is registered at ClinicalTrials.gov (NCT04548700). Results: At the cut-off data of June 23, 2022, 31 patients were screened in the 6 institutions in China, of which 26 eligible patients (19 males) with a median age of 51.5 (range, 28-70) were enrolled in phase Ib study. Enrolled patients included the following PTCL subtypes: AITL (53.8%), PTCL-NOS (15.4%), ALCL-ALK+ (7.7%), ALCL-ALK- (7.7%) and other subtypes (15.4%). 10 patients (38.5%) presented with B symptom and 20 patients (76.9%) were at the stage III or IV. No dose-limiting toxicities occurred, RP2D was 18 mg/m2. Treatment-related adverse events (TRAEs) of any grade occurred in all 26 patients, in which 22 (84.6%) were ≥ grade 3. The most common ≥ grade 3 TRAEs was neutropenia (73.1%), leucopenia (73.1%), lymphocytopenia (38.5%), thrombocytopenia (11.5%), febrile neutropenia (11.5%), infectious pneumonia (7.7%), anemia (7.7%). After a median follow-up of 10.8 (range 1.6-16.9) months, 25 patients were evaluable for response. CR rate and ORR of the whole cohort were 52.0% (13/25) and 84.0% (21/25). While ORR were 92.3% (12/13), 75.0% (3/4), 50.0% (1/2), 50.0% (1/2), 100.0% (4/4) and the CR rates were 76.9% (10/13), 25.0% (1/4), 50.0% (1/2), 50.0% (1/2), 0% (0/6) for AITL, PTCL-NOS, ALCL ALK+, ALCL ALK-, and other subtypes, respectively. Median DoCR was 6.1 months (3.45-NA), median PFS was 8.8 months (7.26-10.71), and 6-month PFS rate were 78.2%. Conclude: This was the first clinical study demonstrated that new combination of CMOP showed promising antitumor activity in TN-PTCL with manageable safety profiles and dose expansion study at RP2D is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Recurrent primary cutaneous anaplastic large cell lymphoma in young female patient from Ethiopia: A Case Report

Primary Cutaneous Anaplastic Large Cell Lymphoma (PC-ALCL) is a CD30+ lymphoproliferative disease of the skin characterized by single or focal nodules or plaques that ulcerate over time. Diagnosis of PC-ALCL relies heavily on clinicopathological correlations because of the potential morphological, clinical, and molecular overlap with other cutaneous CD30+ LPDs. Histopathologic features include diffuse nonepidermotropic infiltrates with an adherent layer of large undifferentiated CD30+ tumor cells. The Exact incidence of PC-ALCL is not known partially because of the difficulty differentiating from the variety of CD30+ Lymphoproliferative disorders. Only a few cases are reported even from developed countries &amp; reports from developing countries are lacking. We present a possible case of primary cutaneous Anaplastic Large cell Lymphoma in a 20 years old Female patient who presented with a 2 months history of lateral neck swelling.