Kinase-positive Anaplastic Large Cell Lymphoma Research Articles

Outcome of childhood ALK-positive anaplastic large cell lymphoma relapses: Real-life experience of the French Society of Pediatric Oncology (SFCE) cohort of 75 French children.

To describe treatments and outcomes of French children treated for relapsed/refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL). We conducted the analysis of a series of 75 French children treated for a first relapsed/refractory ALK+ ALCL between 1999 and 2017. The median time to first relapse was 8.1months from initial diagnosis (2.9 after end of treatment), with 12 relapses during frontline treatment or within 1month of the end of treatment. Treatment of the first relapse varied according to the period of time and risk factors: 48 received multiagent chemotherapy, including 21 and 19 consolidated with allogeneic stem cell transplantation (SCT) and autologous-SCT, respectively. Twenty-one patients received weekly vinblastine, and six received ALK inhibitors (ALKi). Overall, 64/75 patients reached a second complete remission (CR2). Eight out of 11 patients who did not reach CR2 died and the other three were rescued with ALKi, vinblastine, and nivolumab. With a median follow-up of 8.2years, 60 patients are alive, 43 in CR2, 15 in CR3, two in CR4; and 15 patients died, six from toxicity and nine from disease progression. The 5-year event-free survival and overall survival after first relapse were 51.7% (95% confidence interval [CI]: 39.6%-62.6%) and 80.7% (95% CI: 69.6%-88.1%), respectively. Time to relapse greater than 12months from initial diagnosis was proven to be a prognostic factor in relapsed/refractory ALK+ ALCL. In relapsed ALK+ ALCL, high survival rate can be reached with various therapeutic strategies. The main challenge remains to prevent subsequent relapses, and to lower long-term morbidity.

Anaplastic Large Cell Lymphoma With Intraocular or Ocular Adnexal Involvement: A Case Report and Systematic Review.

To review the existing literature on patients with anaplastic large cell lymphoma (ALCL) affecting the globe and/or ocular adnexa, and to present a report documenting the clinical course of a patient with ALCL that involved their globe and ocular adnexa. PubMed, Scopus, and Google scholar were systematically searched for all cases of ALCL involving intraocular or adnexal ocular structures from inception to May 2023. Moreover, a new reported case added to the cases found in searches. The review identified 1680 studies, with 8 meeting inclusion criteria. A total of 9 patients were included with a mean age of 29.7 years (median: 30.0, range: 1.3-48). Primary ALCL was present in 5/9 (55.6%) patients. The most common ophthalmic manifestations included periorbital swelling (5/8), chemosis (5.8), and decreased vision (5/7). Misdiagnoses were initially made in 3 patients, and the lag time to correct diagnosis from 3 weeks to 3 months. CD30 expression was positive in all cases, and 6/9 patients were positive for anaplastic lymphoma kinase, resulting in 6/9 patients being diagnosed with anaplastic lymphoma kinase-positive ALCL. In terms of management modalities, chemotherapy was administered in 8/9 patients, while radiation therapy was utilized in 4/9 patients, and 2 underwent autologous stem cell transplantation. Five (55.6%) patients succumbed to ALCL while 4 (44.4%) were alive and disease-free at the last follow-up. The median times from the initial presentation of ALCL to death, ophthalmic presentation to death, and diagnosis to death were 4.12 months (range: 1.1-168.0), 2.62 months (range: 1.1-144), and 4.00 months (range: 0.10-168), respectively. The median follow-up duration was 21.0 months (range: 1.1-168.0). ALCL involving the globe and ocular adnexa is a rare and highly malignant tumor that can mimic benign clinical conditions. Early biopsy and aggressive treatment with chemotherapy regimens such as CHOP and radiation therapy may be useful.

Cytological features of oral malignant lymphoma in scraping liquid-based cytology: Cases of plasmablastic lymphoma and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma

The main purpose of cytological examination in the oral region is to screen for squamous cell carcinoma or intraepithelial neoplasms; thus, the background tends to be considered a deterrent for microscopy. From this perspective, liquid-based cytology (LBC) is favorable for preparing clear samples with few backgrounds. However, background hemocytes are sometimes of critical importance in the diagnosis. We report two cases of oral malignant lymphoma, plasmablastic lymphoma, and anaplastic large cell lymphoma in which careful observation of the background in scraping LBC sample contributed to the early diagnosis. Atypical lymphoid cells were observed only in a very small part of the LBC samples from the presented patients; however, cytological findings, such as large lymphoid cells with outstanding nucleoli, large mitotic cells, or intermediate-to-large lymphoid cells with pleomorphic nuclei were sufficient for obtaining a cytological diagnosis of malignant lymphoma. Although the number and cell size of leukocytes in LBC with Papanicolaou staining were significantly different from those in air-dried conventional smears with Romanovsky staining, which are commonly preferred for the discrimination of hemocytes, the corresponding cytological features could be observed. Therefore, attention should be paid to the background as well as squamous epithelium to prepare for such unexpected cases. The LBC examination with Papanicolaou staining alone can suggest the possibility of malignant lymphoma.

Plasma small‐extracellular vesicles enriched in miR‐122‐5p promote disease aggressiveness in pediatric anaplastic large‐cell lymphoma

Plasma small‐extracellular vesicles enriched in miR‐122‐5p promote disease aggressiveness in pediatric anaplastic large‐cell lymphoma

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Phase I Study of Tq-B3101 in Pediatric Patients with Relapsed/Refractory Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma

Background Anaplastic large cell lymphoma (ALCL) accounts for 10-30% of childhood lymphomas, and 90% of pediatric and adolescent patients (pts) are Anaplastic Lymphoma Kinase positive ALCL (ALK+ ALCL). The results of ADVL0912 (NCT00939770) and A8081013 (NCT01121588) studies suggest that the ALK inhibitor crizotinib has good efficacy and safety in the treatment of ALK+ALCL. The recommended pediatric dose of crizotinib is 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. TQ-B3101 is a novel kinase inhibitor for ROS1, ALK, and c-MET kinases. After oral administration, TQ-B3101 undergoes deacetylation to form crizotinib. In animal models, TQ-B3101 significantly inhibited the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2) in ALK downstream signaling pathway in tumor tissue, with a longer inhibition time and stronger inhibition compared to equimolar crizotinib. This study aimed to explore the safety and efficacy of TQ-B3101 in pediatric patients with ALK+ ALCL. Methods TQ-B3101-II-02 is an open-label, single-arm, phase I dose escalation and pharmacokinetic study. Eligible pts were 10 to 18 years of age with relapsed/refractory (R/R) ALK+ALCL. We used a 3+3 design to determine the maximum tolerated dose (MTD). The dose levels to be investigated were 200mg BID, 250mg BID, and 300mg BID. Dose-limiting toxicities (DLT) were defined in cycle one (28-day) as any grade 4 hematologic toxicity or any grade 3 non-hematologic toxicity, except for alopecia and electrolyte disturbances that resolved within 3 days. The primary endpoints were safety and pharmacokinetics (PK). Secondary endpoints included overall response rate (ORR), progression free survival (PFS), and overall survival (OS). Responses were evaluated by investigators per the 2014 Lugano classification based on positron emission tomography/computed tomography (PET/CT) scans. This trial was registered at www.clinicaltrials.gov as # NCT04306887. Results All seven patients enrolled were evaluable for toxicities and response, with four males/three females, a median age of 12 years (range, 10-14 years), a median weight of 40.0 kg (range, 32.9-68.0 kg), a median height of 152.0 cm (range, 143.5-169.5 cm), and a median body surface area (BSA) 1.27 m2 (range, 1.15-1.73 m2). Three patients, three patients, and one patient with ALCL were treated at doses of 200mg, 250mg, and 300mg, respectively. The majority of patients (57.1%) had a median Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 1. Two patients had a refractory disease and five had relapsed disease. Histological diagnosis of ALK-positive ALCL was confirmed by immunohistochemistry. The area under the curve (AUC)(0-t) of the three dose groups after the first administration were 492 ± 285, 606 ± 288, and 914 μg/L*h, respectively, and the AUC(0-t) after the last administration was 2311 ± 997, 3749 ± 407, 3311 μg/L*h. The in vivo exposure of deacetylated metabolites generated after a single dose was lower than that of crizotinib, and after 28 days of continuous dosing, the in vivo exposure was similar to that of crizotinib (BSA-adjusted dose). The most frequently reported treatment-related adverse events (TRAEs) were hypothyroidism (n = 6), vomit (n = 6), reduced neutrophil count (n = 6). Four pts (57.1%) had grade 3-4 TRAEs. No treatment-related death and DLTs were observed. The ORR was 100%, with four patients achieving complete response (CR) and three patients achieving a partial response (PR). The median time to respond was 1.9 months (range 1.8, 2.0). Six pts had a ≥ 60% tumor reduction. As of the cut-off date of July 22, 2022, the four pts with CR received TQ-B3101 beyond 20 cycles (range, 20-34 cycles) and remained progression-free at 18.7 to 27.9 months. The three pts with PR progressed after 3 to 4 cycles of treatment and discontinued TQ-B3101. One patient voluntarily withdrew from the study. All seven patients were still alive, with the longest survival time of more than 32 months. Conclusion Our preliminary results suggest that TQ-B3101 has significant clinical activity in children with R/R ALK+ ALCL. Responses were durable and ongoing, and treatment was well tolerated. Further investigation is warranted to find the MTD and confirm the efficacy of TQ-B3101. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinicopathologic and Genetic Features of Primary T-cell Lymphomas of the Central Nervous System: An Analysis of 11 Cases Using Targeted Gene Sequencing.

Primary central nervous system lymphoma (PCNSL) of peripheral T-cell lineage (T-PCNSL) is rare, and its genetic and clinicopathologic features remain unclear. Here, we present 11 cases of T-PCNSL in immunocompetent individuals from a single institute, focusing on their genetic alterations. Seven cases were subject to targeted panel sequencing covering 120 lymphoma-related genes. Nine of the eleven cases were classified as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), of which one was of γδT-cell lineage. There was one case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma and another of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) of αβT-cell lineage. The male to female ratio was 7 : 4 and the age ranged from 3 to 75 years (median, 61 y). Most patients presented with neurological deficits (n=10) and showed multifocal lesions (n=9) and deep brain structure involvement (n=9). Tumor cells were mostly small-to-medium, and T-cell monoclonality was detected in all nine evaluated cases. PTCL-NOS was CD4-positive (n=4), CD8-positive (n=3), mixed CD4-positive and CD8-positive (n=1), or CD4/CD8-double-negative (n=1, γδT-cell type). Cytotoxic molecule expression was observed in 4 (67%) of the 6 evaluated cases. Pathogenic alterations were found in 4 patients: one PTCL-NOS case had a frameshift mutation in KMT2C, another PTCL-NOS case harbored a truncating mutation in TET2, and another (γδT-cell-PTCL-NOS) harbored NRAS G12S and JAK3 M511I mutations, and homozygous deletions of CDKN2A and CDKN2B. The ENKTL (αβT-cell lineage) case harbored mutations in genes ARID1B, FAS, TP53, BCOR, KMT2C, POT1, and PRDM1. In conclusion, most of the T-PCNSL were PTCL-NOS, but sporadic cases of other subtypes including γδT-cell lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and ENKTL were also encountered. Immunophenotypic analysis, clonality test, and targeted gene sequencing along with clinicoradiologic evaluation, may be helpful for establishing the diagnosis of T-PCNSL. Moreover, this study demonstrates genetic alterations with potential diagnostic and therapeutic utility in T-PCNSL.

Elucidating the Characteristics of Two Tumor Cell Populations in Small Cell Variant of Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma

The small cell variant of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (SC-ALCL) is a subtype defined as comprising two distinct tumor cell populations in immunohistochemistry: small cells staining negative or weakly positive for ALK and CD30 protein; and large cells staining strongly positive for those proteins. Although the constitution of these two different cell populations might contribute to the poor prognosis, detailed characterization of each population by molecular-based approaches has not been done due to the difficulty of cell separation from solid tumor sample. In this paper, we have analyzed the characterization of each tumor cell population using the patient sample from SC-ALCL leukemic phase obtained from peripheral blood by molecular-based approaches. Flow cytometric analysis revealed two distinct abnormal populations. The major population comprising 74% of total leukocytes was positive for CD3 and CD8, and negative for CD4, CD5, CD25 and CD30. The minor population comprising 5% of total leukocytes was positive for CD25, CD30, CD11b and CD13. Fluorescent in situ hybridization with ALK break-apart probes and RT-PCR analysis confirmed that most of the cells including both populations were rearranged with NPM-ALK gene. To elucidate the cause underlying the distinct levels of ALK protein expression in each population, we separated those tumor cells by CD30-PE antibody and a magnetic bead separation kit, extracted DNA and RNA from each population, and compared NPM-ALK mRNA expression levels by droplet digital polymerase chain reaction. The expression level of NPM-ALK mRNA in the CD30-negative population was ten-fold less than that in the CD30-positive population (Table). This result indicated that the two tumor cell populations expressed the distinct level of NPM-ALK mRNA, although both populations possessed NPM-ALK fusion gene. To assess the effectiveness of various chemotherapies in each tumor cell population, we monitored each population in peripheral blood by flow cytometric analysis (small cell; CD30-5-8+, large cell; CD30+) over time. Intriguingly, CD30-negative population behaved as chemo-resistant cells in clinical course, however alectinib, a second-generation ALK-inhibitor, eradicated both populations inducing first complete remission. This study revealed two definitive features regarding the small CD30-negative population of SC-ALCL, with a lower expression level of NPM-ALK mRNA transcripts and chemoresistance. The cause of distinct ALK staining levels in immunohistochemistry was revealed depending on the distinct expression level of NPM-ALK mRNA transcripts. Finally, since both populations were sensitive to ALK-inhibitor, early administration of ALK-inhibitor might be the reasonable option for SC-ALCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Successful Treatment of Mature T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: The Largest Multicenter Retrospective Analysis

Successful Treatment of Mature T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: The Largest Multicenter Retrospective Analysis

B7-H3 Chimeric Antigen Receptor Redirected T Cells Target Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma.

Simple SummaryAlthough chemotherapy is associated with high relapse rates and numerous side effects, it is still used as the front line treatment of anaplastic large cell lymphoma (ALCL). Therefore, alternative treatment options for ALCL are needed. In this study, we show that B7-H3 is a novel and promising target in ALCLs, and demonstrate that B7-H3 directed chimeric antigen receptor (CAR) T cells have therapeutic potency in controlling ALCL tumor growth.Potent CAR-T therapies that target appropriate antigens can benefit the treatment of anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL), which is the most common subtype of T cell lymphoma. In this study, we observed overexpression of B7-H3 in ALCL cell lines derived from clinical samples and differential expression of B7-H3 in an ALK-induced T cell transformation model. A B7-H3-redirected CAR based on scFv from mAb 376.96 was developed. B7-H3 CAR-T cells showed strong cytotoxicity and cytokine secretion against target ALCL cells (SUP-M2, SU-DHL-1, and Karpas 299) in vitro. Furthermore, the B7-H3 CAR-T cells exhibited proliferative capacity and a memory phenotype upon repeated antigen stimulation. We demonstrated that B7-H3 CAR-T cells could promptly eradicate ALCL in murine xenografts. Taken together, B7-H3 is a novel and promising target in ALCLs and B7-H3 CAR-T may be a viable treatment option for ALCL.

Combining the mTOR Inhibitor Everolimus and Gemcitabine in Relapsed/Refractory Peripheral T-Cell Lymphomas

Background: Relapsed/refractory Peripheral T-cell lymphomas (PTCL) is an aggressive and heterogeneous Non-Hodgkin's T cell lymphoma, which is resistant to conventional chemotherapy with poor prognosis. Therefore, there is an urgent need to exploit potential therapeutics and novel treatment for R/R PTCL. Targeting PI3K/AKT/mTOR pathway is an effective therapy for PTCL. However, recent research demonstrated that the mTOR inhibitor everolimus monotherapy has low response rate and short duration time in treating with R/R PTCL. Methods:We retrospectively reviewed 18 patients with pathologically diagnosed T cell lymphoma who received the mTOR inhibitor everolimus combined with gemcitabine for six cycles (everolimus 10mg qd, gemcitabine 1000mg/m2 d1, every 21 days a cycle) and sequential autologous stem cell transplantation, at Guangdong Provincial People's Hospital from November 2015 through October 2019. We evaluated the objective response rate (ORR), progressive free survival (PFS) and safety. Results:Of the 18 patients, 33.3% (n=6) had PTCL-not otherwise specified (PTCL-NOS), 27.8% (n=5) had angioimmunoblastic T-cell lymphoma(AITL), 27.8% (n=5) had anaplastic large cell lymphoma(ALCL) (anaplastic lymphoma kinase positive ALCL: 20.0%, n=1; anaplastic lymphoma kinase negative ALCL: 80.0%, n=4), and 11.1%(n=2) had other subtypes. The median age was 46.5 years (range 26-64) old and most patients were males (66.7%) with advanced stage disease (III/IV, 73.7%). The ORR was 55.6% (n=10), with complete response rate of 50% and partial response rate of 5.6%. One patient was stable disease (5.6%), and seven patients were progressive disease (33.8%). For subtypes, the ORR was 80% in ALCL, 66.7% in PTCL-NOS and 20% in AITL, respectively. With a median follow-up time of 18.9 months (range 3.1-99.6), the median PFS was 4.5 months and overall survival(OS) was 18.9 months, respectively. The most frequent hematological adverse events were thrombocytopenia (27.8%), anemia (22.2%), leukopenia (11.1%). The non-hematological adverse events were inappetence (22.2%), diarrhea (11.1%), rash(11.1%), fatigue (11.1%). Conclusions:Our pilot studies have shown that combined everolimus with gemcitabine have better efficacy than monotherapy reported previously for R/R PTCL patients, but the mechanism is still unclear. It suggests that further investigation for mechanisms and predictive biomarker is needed. Figure Disclosures No relevant conflicts of interest to declare.

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as diffuse pulmonary infiltrates.

Anaplastic large cell lymphoma has a characteristic sinusoidal growth pattern that presents as pulmonary lymphangitic involvement causing respiratory distress. Recognition and prompt treatment of this entity can result in dramatic response to therapy.

Cutaneous Involvement of Systemic Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma

Cutaneous Involvement of Systemic Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma

TRAF1-ALK Fusion Predicts Poor Prognosis for ALK Positive Anaplastic Large Cell Lymphoma Patients with Chemotherapy and ALK Inhibitor

Background: Relapsed/refractory anaplastic lymphoma kinase (ALK) positive anaplastic large cell lymphomas (ALCLs) respond to ALK inhibitors, but resistance, which bear a poor prognosis. No biomarkers were found to predict long duration of response to ALK inhibitors. The ALK gene was first identified as the fusion partner of the nucleophosmin (NPM1) gene in the recurrent t(2;5)(p23;q35) found in a subset of ALCL. However, several distinct ALK fusions which result in highly different characteristics have also been described in lymphomas. Methods: We retrospectively reviewed seven relapsed/refractory ALK positive ALCLs who received ALK inhibitors (six with Crizotinib and one with Alectinib) at Guangdong Provincial People's Hospital from June 2007 through March 2019. We did next generation sequencing (NGS) with paraffin-embedded tissue for two patients who quickly developed resistance. Results: Of the seven patients, four were male and three were female, with a median age of 18 years (range 15-51) old. The median line of therapies was four (range 3-7) and that of ALK inhibitor usage was three (range 2-5). The overall response rate was 7 of 7 (100%) and the median overall survival of 21.2 months (8.5-86 months). Three patients obtained complete response (CR) on Crizotinib and then received autologous stem cell transplantation, and are still CR. One patient obtained CR, but died of serious infection five months after allogeneic stem cell transplantation. One patient is in CR under continuous crizotinib administration. One patient received Crizotinib obtained CR, but three months later got progression disease, the NGS showed TNF receptor-associated factor 1 gene (TRAF1) exon 6-ALK exon 20 fusion junction. The last patient was CR on alectinib, but quickly developed resistance, with a progression free survival of 1 month, the NGS indicated TRAF1 exon 7-ALK exon 20 fusion. Conclusions: ALK inhibitors improved survival of relapsed/refractory ALK positive ALCLs. TRAF1-ALK fusion may predict poor clinical outcome to chemotherapy and ALK inhibitors. This ALK fusion may reflect a trend to aggressive behaviour in lymphomas. Disclosures Li: Guangdong Province Hospital: Employment.

Clinical Characteristic and Survival Outcome of Peripheral T Cell Lymphoma in a Chinese Population

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group comprising about 10-15% of non-Hodgkin lymphomas in Western populations. Only a minority (~30%) of patients with the most common PTCL subtypes achieve a durable remission and long-term survival. Data on the clinical features of PTCL in a Chinese population are limited. Methods: We retrospectively reviewed 342 patients with pathologically diagnosed T cell lymphoma at Guangdong Provincial People's Hospital from June 2007 through March 2019. We evaluated the incidence of PTCL subtypes, clinical characteristics and survival status. Results: Of the 342 patients, 17.3% (n=59) had PTCL-not otherwise specified(NOS), 9.4% (n=32) had angioimmunoblastic T-cell lymphoma(AITL), 19.6% (n=67) had anaplastic large cell lymphoma(ALCL) (anaplastic lymphoma kinase positive ALCL:12.0%, n=41; anaplastic lymphoma kinase negative ALCL: 9.6%, n=26), 36.2%(N=124) had NK/T cell lymphoma, 12.9% (n=44)had lymphoblastic lymphoma(LBL), and 4.6%(n=16) had other subtypes. For next data analysis, NK/T cell lymphoma and LBL were excluded. Finally, a total of 164 patients with integrally follow-up information were analyzed. The median age was 49.5 years (range 15-87) old and the median follow-up time was 15.8 months (range 0.5-124.3). Most patients were males (62.0%) with advanced stage disease (III/IV, 74.5%), and 51.0% of patients presented with B symptoms and 83.0% with no bulky disease. For the total population, the median progression-free survival(PFS) and overall survival(OS) was 6.5 months and 13.5 months, respectively. ALCL patients had better PFS and OS than PTCL-NOS and AITL (PFS: 51.2 vs. 5.8 vs.4.7 months, P = 0. 000; OS: not reached vs. 13.4 vs. 8.8 months, P = 0.000). There were no difference of PFS and OS between PTCL-NOS and AITL(P = 0. 550 and P = 0. 333, respectively). Conclusions: ALCL has better outcome than other PTCL subtypes. However, no efficacy therapy has emerged for patients with relapsed/refractory PTCL and outcomes in this setting are still poor. Novel potential targets for PTCL, with particular focus on identifying markers of response and resistance need further investigation. Disclosures Li: Guangdong Province Hospital: Employment.

ALK Positive Anaplastic Large Cell Lymphoma of Oral Cavity: A Case Report

Introduction: Anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma is a rare subtype of non-Hodgkin lymphomas, which is usually presented as a systemic advanced stage disease. Extranodal involvement is common in skin, bone, soft tissue, lung and liver. Primary presentation in oral cavity is extremely rare. Case Presentation: Here, a 28-year-old man with gingival swelling in the left mandibular molar area after tooth extraction and regional lymphadenopathy is reported. Microscopic examination revealed anaplastic large lymphoid cells with the positive expression of ALK protein. Conclusions: Although the overall survival of ALK-positive anaplastic large cell lymphoma is better than other types of T-cell lymphomas, it is not clear for its oral counterparts.

Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: an analysis of patients from LYSA centers

BackgroundPeripheral T-cell lymphoma (PTCL) remains a therapeutic challenge. Due to the rarity and the heterogeneity of PTCL, no consensus has been achieved regarding even the type of first-line treatment. The benefit of autologous stem-cell transplantation (ASCT) is, therefore, still intensely debated. Patients and methodsIn the absence of randomized trials addressing the role of ASCT, we performed a large multicentric retrospective study and used both a multivariate proportional hazard model and a propensity score matching approach to correct for sample selection bias between patients allocated or not to ASCT in intention-to-treat (ITT). ResultsAmong 527 patients screened from 14 centers in France, Belgium and Portugal, a final cohort of 269 patients ≤65years old with PTCL-not otherwise specified (NOS) (N=78, 29%), angioimmunoblastic T-cell lymphoma (AITL) (N=123, 46%) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-ALCL) (N=68, 25%) with partial (N=52, 19%) or complete responses (N=217, 81%) after induction was identified and information about treatment allocation was carefully collected before therapy initiation from medical records. One hundred and thirty-four patients were allocated to ASCT in ITT and 135 were not. Neither the Cox multivariate model (HR=1.02; 95% CI: 0.69–1.50 for PFS and HR=1.08; 95% CI: 0.68–1.69 for OS) nor the propensity score analysis after stringent matching for potential confounding factors (logrank P=0.90 and 0.66 for PFS and OS, respectively) found a survival advantage in favor of ASCT as a consolidation procedure for patients in response after induction. Subgroup analyses did not reveal any further difference for patients according to response status, stage disease or risk category. ConclusionsThe present data do not support the use of ASCT for up-front consolidation for all patients with PTCL-NOS, AITL, or ALK-ALCL with partial or complete response after induction.

IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas.

Systemic anaplastic large cell lymphomas (ALCL) are a category of T-cell non-Hodgkin’s lymphomas which can be divided into anaplastic lymphoma kinase (ALK) positive and ALK negative subgroups, based on ALK gene rearrangements. Among several pathways aberrantly activated in ALCL, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) is shared by all ALK positive ALCL and has been detected in a subgroup of ALK negative ALCL. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we combined gene expression profiling analysis and RNA interference functional approaches. A shRNA screening of STAT3-modulated genes identified interferon regulatory factor 4 (IRF4) as a key driver of ALCL cell survival. Accordingly, ectopic IRF4 expression partially rescued STAT3 knock-down effects. Treatment with immunomodulatory drugs (IMiDs) induced IRF4 down regulation and resulted in cell death, a phenotype rescued by IRF4 overexpression. However, the majority of ALCL cell lines were poorly responsive to IMiDs treatment. Combination with JQ1, a bromodomain and extra-terminal (BET) family antagonist known to inhibit MYC and IRF4, increased sensitivity to IMiDs. Overall, these results show that IRF4 is involved in STAT3-oncogenic signaling and its inhibition provides alternative avenues for the design of novel/combination therapies of ALCL.

Blood cytokine concentrations in pediatric patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.

Patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma often present with B-symptoms or hemophagocytosis and generate an anti-tumor immune response. Specific serum cytokine levels or profiles may reflect the tumor burden, non-specific immune stimulation by the tumor or differences in the strength of the patients’ anti-lymphoma immunity. We systematically correlated pretreatment concentrations of 25 cytokines with clinical and biological characteristics in a well-characterized cohort of 119 uniformly treated pediatric patients with anaplastic large cell lymphoma. Fifteen patients with anaplastic large cell lymphoma in remission and 11 patients with low-stage B-cell lymphoma served as controls. Concentrations of interleukin-9, interleukin-10, interleukin-17a, hepatocyte growth factor, soluble interleukin-2 receptor, and soluble CD30 were significantly higher in initial sera of patients than in the sera of subjects from both control groups, indicating an anaplastic large cell lymphoma-type cytokine signature. The levels of interleukin-6, interferon-γ, interferon γ-induced protein, and soluble interleukin-2 receptor correlated with the stage, initial general condition, minimal disseminated disease, anaplastic lymphoma kinase-antibody titers, and the risk of relapse among patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Only interleukin-6 showed an independent prognostic value in multivariate analyses. Pretreatment cytokine profiles in patients with anaplastic large cell lymphoma reflect a tumor signature as well as tumor burden and also differences in the strength of the patients’ immune response.

A Case of Colonic ALK-Positive Anaplastic Large Cell Lymphoma

Background: Primary colonic lymphoma is rare, comprising 0.2 - 1.2% of colonic malignancies1, the majority are cecal diffuse large b cell lymphoma. Gastric lymphoma is the most common gastrointestinal lymphoma followed by the small intestine. Anaplastic Large Cell Lymphoma (ALCL) is a peripheral T-Cell lymphoma divided into primary cutaneous or systemic. Systemic ALCL is further categorized by the presence of a surface protein Anaplastic Lymphoma Kinase (ALK). ALK positive ALCL denotes a better prognosis.3 Here we report a case of colonic ALK positive ALCL. Case Presentation: A previously well 23-year-old male presented with three weeks of non-bloody diarrhea, sweats, nausea and vomiting. Upon presentation to hospital, the patient was tachypnic and requiring O2. Physical examination revealed bibasilar crackles, his abdomen was tender throughout, he did not have hepatosplenomegaly, nor lymphadenopathy. He was admitted with presumed aspiration pneumonia secondary to gastroenteritis and started on empiric antibiotics. His WBC was 28 x 10ˆ9/L, lactate 3.3 mmol/L, CRP 421. CT showed multiple enlarged abdominal lymph nodes. He had positive EBNA serology in keeping with prior EBV infection. Colonoscopy showed small erosions and polypoid lesions in the transverse colon. He was transferred to a tertiary care center because of increasing O2 requirements and multi-organ failure requiring intubation, ECMO and dialysis. Pathology of the colonic polypoid lesion revealed ALK positive ALCL. CHOP chemotherapy began during his ICU stay, vincristine and doxorubicin were held because of deteriorating liver dysfunction. With treatment, his organ failure improved and within days he was extubated, dialysis and ECMO were stopped and he was transferred to the hematology ward where he continues with chemotherapy.Figure: Enhanced coronal CT scan demonstrating massive abdominal lymphadenopathy.Figure: Enhanced axial CT scan demonstrating massive abdominal lymphadenopathy.Figure: Enhanced sagittal CT scan demonstrating massive abdominal lymphadenopathy.Discussion: Lymphoma is an important diagnosis to consider when evaluating a patient with diarrhea and lymphadenopathy. Few cases report ALCL involving the gastric mucosa, most include the stomach in isolation or the colon.4,5,6 Despite active cancer being a relative contraindication to ECMO, the severity of this patient's presentation necessitated this intervention. There have been case series reporting the use of ECMO in patients with active hematologic malignancies, where ECMO preceded the diagnosis of malignancy7. This case illustrates the importance of a high index of suspicion for lymphoma given diffuse adenopathy and taking biopsies.