Anaplastic Lymphoma Research Articles

A Case of Small-Cell Lung Cancer With Novel Anaplastic Lymphoma Kinase Gene Rearrangement That Developed Intradural Extramedullary Spinal Metastases With Myelitis

A Case of Small-Cell Lung Cancer With Novel Anaplastic Lymphoma Kinase Gene Rearrangement That Developed Intradural Extramedullary Spinal Metastases With Myelitis

Malignant epithelioid tumors with EWSR1::CREB fusion involving the kidney: a report of two cases.

Soft tissue tumors with EWSR1/FUS fusion to genes encoding the cyclic adenosine monophosphate response element-binding (CREB) transcription factor family (ATF1, CREB1, and CREM) are rare and heterogeneous aggressive tumors, often found in the peritoneal cavity. Here, we report two cases of malignant epithelioid tumors with EWSR1::CREB fusion involving the kidney in females in their 30s. Both tumors appeared as solitary masses, measuring 5.4cm and 4.0cm in diameter. Histologically, the tumors were similar, growing invasively with unclear boundaries and composed of epithelial cells with eosinophilic and clear cytoplasm arranged in sheets, nests, and trabeculae. Immunohistochemically, case 1 showed focal AE1/AE3 positivity, whereas case 2 was negative. Anaplastic lymphoma kinase was diffusely positive in case 1 and focally positive in case 2. Both cases were positive for epithelial membrane antigen, mucin-4, and synaptophysin. High-throughput sequencing identified EWSR1::CREM fusion in case 1, whereas fluorescence in situ hybridization detected EWSR1::CREB1 fusion in case 2. These cases expand the morphological and immunophenotypic characteristics of malignant epithelioid tumors with EWSR1::CREB fusion, highlighting the diagnostic challenges of immunohistochemistry and value of molecular testing for accurate diagnosis.

Emerging Non-Breast Implant-Associated Lymphomas: A Systematic Review

Background: Medical devices used for functional or esthetic purposes improve health and quality of life; however, they are not risk-free. Anaplastic large-cell lymphoma (ALCL), associated with breast implants, is a well-known and recognized distinct lymphoma entity. More recently, additional lymphomas have been reported in relation to prosthesis other than breast implants, as these allow the pericyte to develop into a clone that undergoes a maturation process, progressing toward full malignancy. Methods: We performed a systematic review with a descriptive analysis of data extracted from primary studies following PRISMA guidelines, including the search string “(IMPLANT* OR PROSTHES*) AND LYMPHOM*” in the PubMed, Scopus, Embase, and Google-Scholar databases. Data such as patient sex, age, implant site, prosthesis material, and lymphoma type were analyzed. Statistical methods, including Student’s t-test and Fisher’s exact test, were employed to compare lymphoma characteristics, with significance set at a p-value < 0.05. Results: From a total of 5992 studies, we obtained 43 case reports and series on a total of 52 patients diagnosed with prosthesis-associated lymphomas. The majority of implant-related lymphoma cases (85%) were of the B-cell type, mostly fibrin-associated large B-cell lymphoma (LBCL). This lymphoma type was more associated with biological (non-human-derived biological tissue), metallic, and synthetic implants (synthesized from non-organic components) (p-value = 0.007). Patients with ALCL had equal frequencies of metal and silicone prostheses (37.5%, 3 cases each), followed by synthetic prostheses (25%, 2 cases). ALCL cases were most common at skeletal (50%) and muscular-cutaneous sites (25%), whereas B-cell lymphomas were predominantly found in cardiovascular implants (50%), followed by skeletal (27%) and muscular-cutaneous (21%) sites. Death attributed to lymphoma took place in 67% of the cases, mostly LBCL occurring in cardiovascular sites. Conclusions: Because the included studies were limited to case reports and series, a potential non-causal link might have been documented between different implant materials, implant sites and lymphoma types. This underscores the importance of further comprehensive research and monitoring of non-breast implants.

Rare giant epithelioid inflammatory myofibroblastic sarcoma of the abdominal cavity in a child: a case report and review of the literature

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a distinct subtype of inflammatory myofibroblastoma tumor (IMT) that is recognized as a rare malignant tumor characterized by anaplastic lymphoma kinase (ALK) positivity, significant aggressiveness, treatment challenges, and a poor prognosis. We report on the case of an 8-year-old boy presenting with abdominal pain and vomiting. Computed tomography (CT) of the abdomen revealed a large tumor, and the pathology results following a biopsy confirmed the diagnosis of EIMS. The patient underwent radical tumor resection, and genetic testing identified the presence of the RANBP2–ALK fusion. To our knowledge, this represents the largest pediatric case of abdominal EIMS documented in the literature. Currently, there is no standard therapy for EIMS; however, existing studies advocate for the use of ALK tyrosine kinase inhibitors (TKIs) in its treatment. This case was reported to be in remission following treatment with crizotinib, thereby contributing to the understanding of the specific pathology of EIMS and facilitating accurate diagnosis and targeted therapy.

A positionally stable anatomic smooth breast implant

The voluntary recall of textured breast implants due to their association with breast implant-associated anaplastic large cell lymphoma has resulted in the loss of the primary advantage of the textured surface: positional stability. We have engineered a novel soft gel-filled smooth implant with a surface that promotes positional stability without texture, known as the positionally stable smooth implant (PSSI). Miniature anatomically shaped breast implant shells were fabricated from polydimethylsiloxane using 3D-printed molds. The implant shell design incorporates cylindrical wells 1-4 mm in diameter. Implants were filled with commercial breast implant-derived silicone gel. Smooth and textured implants were also fabricated, serving as controls. Six implants per group were implanted subcutaneously into the bilateral rat dorsum. Rotation was measured every 2 weeks for a total of 12 weeks to assess stability. Animals were sacrificed at 4 and 12 weeks, and implant-capsule units were explanted for histological and Micro-computed tomography (MicroCT) analyzes. Four weeks after implantation, PSSI conditions showed tissue ingrowth and conformation to well dimensions, as assessed by histological staining and MicroCT imaging. Twelve weeks post implantation, textured implants and PSSI conditions with larger widths, depths, and well number demonstrated statistically significant increased stability compared to smooth implants (p< 0.05). Tissue ingrowth into shell features occurred by 4 weeks and remained throughout longer time points. No significant differences were found in capsule thickness or collagen content between groups. These results suggest a promising alternative to textured surfaces for inducing implant positional stability.

Rare secondary lymphomas involving the brain

Central nervous system (CNS) involvement is rare in patients with Hodgkin lymphoma (HL). Accordingly, the clinical features and outcomes are not well described. Anaplastic large cell lymphoma (ALCL) is a rare and aggressive type of non-Hodgkin lymphoma that can arise in various parts of the body, including the central nervous system (CNS). Secondary ALCL involving the CNS is more common than primary disease. In general, these rare lymphomas in the CNS present with a predilection for parenchymal lesions with dural extension. Here we report two cases with metastatic/secondary lymphomas involving the CNS, with review of the literature. We believe awareness of these rare entities involving the CNS is beneficial for pathologists and neuropathologists.

A phase I study of romidepsin in combination with gemcitabine, oxaliplatin, and dexamethasone in patients with relapsed or refractory aggressive lymphomas enriched for T-cell lymphomas.

Histone deacetylase inhibitors (HDACi) and combination chemotherapy are independently used to treat relapsed/refractory (R/R) lymphoma. In vitro studies suggest that the addition of HDACi to platinum-based chemotherapy is synergistic. We conducted a phase I study of romidepsin, gemcitabine, oxaliplatin and dexamethasone (Romi-GemOxD) in R/R aggressive lymphomas with an expansion cohort in T-cell lymphomas. Twenty-four patients were enrolled with median age 70; 6 patients had diffuse large B-cell lymphoma (DLBCL) and 18 patients had peripheral T-cell lymphomas (PTCL-NOS: 10, angioimmunoblastic T-cell lymphoma [AITL]: 7, ALK-negative anaplastic large cell lymphoma: 1). Patients had received a median of 2 prior lines of therapy and 10 patients were refractory to last line of therapy. Using a standard 3+3 dose escalation design, the maximum tolerated dose of romidepsin was determined to be 10 mg/m2 in combination with GemOxD. There were no unexpected toxicities. The most common grade ≥3 treatment-emergent adverse events were thrombocytopenia (79%) and lymphopenia (46%). The overall response rate for Romi-GemOxD was 52% (12/23) with complete response (CR) rate of 43% (10/23). All six patients with AITL evaluable for efficacy achieved CR. Durable responses were seen in patients with AITL, PTCL-NOS and DLBCL. Without additional therapy, four patients remained in remission for more than two years, with three patients progressing at 46.5, 30.8, and 32.6 months and one remission ongoing at 83 months. Four patients proceeded to consolidative stem cell transplant following induction. Romi-GemOxD represents a well-tolerated, time-limited, effective option for patients, particularly for those with AITL in which durable responses were seen. NCT02181218Micro Abstract: In a phase I study of romidepsin in combination with gemcitabine, oxaliplatin and dexamethasone in patients with relapsed/refractory aggressive lymphomas, the maximum tolerated dose of romidepsin was 10 mg/m2. The complete response rate in patients with angioimmunoblastic T-cell lymphoma was 100% (6/6) with median duration of response of 28.9 months. This salvage option warrants further consideration, especially in T-cell lymphomas.

Sex and common germline variants impact the toxicity profile and pharmacokinetics of alectinib: a nation-wide cohort study in patients with ALK-positive non-small cell lung cancer

IntroductionAlectinib, a small-molecule kinase inhibitor, is used as first-line treatment for anaplastic lymphoma kinase–positive (ALK+) non-small cell lung cancer (NSCLC). Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity. MethodsIn this multicenter observational cohort study in patients with advanced ALK+ NSCLC receiving alectinib treatment, we investigated the association between toxicity, pharmacokinetics, and key genetic variants in ABCB1, CYP3A4, PPAR-α, POR, and CYP3A5. Data on demographics, adverse events, and alectinib trough levels were collected from five hospitals. ResultsAmong 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; p=0.001) and also had +35% higher alectinib trough levels (p<0.001). Homozygous carriers of the PPAR-α 209G>A variant exhibited a higher incidence of grade ≥ 3 toxicity (38%) compared to patients who carried at least one wild-type allele (11%) (p=0.004). This remained significant after Bonferroni correction. Patients who experienced severe toxicity had +18.5% (95%CI: 2.9–36.6%; p=0.019) higher trough levels. ConclusionsFemale patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. PPAR-α 209G>A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pre-treatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.

Immunotherapy Following Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients with Anaplastic Lymphoma Kinase‑Positive Non‑small Cell Lung Cancer in Japan.

Although anaplastic lymphoma kinase inhibitors (ALKis) are the effective initial treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), most patients experience resistance to ALKis, leading to the need for alternative therapies. Immune checkpoint inhibitors (ICIs) are a standard NSCLC treatment. On the other hand, their efficacy remains unclear for ALK-positive NSCLC. We aim to describe the treatment patterns and treatment outcomes for patients with ALK-positive NSCLC receiving later-line ICI treatment. This retrospective cohort study used claims data from Japanese acute care hospitals and included patients with lung cancer (International Classification of Diseases, 10th version (ICD-10), code: C34) diagnosed between 1 December 2015 and 31 January 2023. We extracted patients who received ALKis as first-line therapy and subsequent lines of treatment. Patient characteristics and treatment patterns and durations were descriptively summarized. Time to treatment discontinuation (TTD) for ICIs was examined using Kaplan-Meier estimates. Of 478 patients who received ALKi as first-line treatment, 30 received ICIs, 249 ALKis, and 154 non-ICI/ALKi therapy as second-line treatment. Most patient characteristics showed no differences among the groups. ICIs were more likely to be administered to patients who underwent shorter durations of ALKi treatment. The median TTD for ICIs was 66 days, with a 1 year TTD rate of 13%. Given the rarity of ALK-positive NSCLC, this study contributes to add evidence through an expanded database and increased sample size, supporting previous suggestions that ICIs have limited effectiveness in patients positive for ALK.

Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL (ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by differential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK-high group, which had more frequent copy number changes and was enriched with pathways associated with cell growth, proliferation, and metabolism. Altogether, these findings suggest that there is molecular heterogeneity within pediatric ALK+ ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.

An Isolated Cutaneous Relapse in a Known Case of Systemic ALK-Positive Anaplastic Large Cell Lymphoma: A Rare Case Report with Review of Literature

AbstractAmong non-Hodgkin's lymphomas (NHLs), anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a relatively uncommon subtype that accounts for 3% of all adult NHLs. It typically affects young males, with a prevalence of three to one. Most cases present with nodal disease at the time of presentation. An extranodal involvement is seen in 60% of cases and skin involvement is seen in only 8 to 21% of cases. Cutaneous involvement in ALCL can manifest as primary cutaneous ALCL or secondary to systemic ALCL, and while CD30 positivity is common to both, ALK is not expressed by the former. A secondary skin involvement is usually associated with a poorer prognosis.We report a rare case of an isolated cutaneous relapse of systemic ALK-positive ALCL in a 62-year-old woman following the second cycle of chemotherapy. The acute febrile, widespread papulonodular eruption clinically resembled mycosis fungoides and lymphomatoid papulosis. With the introduction of oral crizotinib, a drastic improvement in the skin lesions and an exceptional response on positron emission tomography-computed tomography were noted.

The role of stem cell transplant (auto and allo) in PTCL and CTCL.

In contrast to B-cell lymphoma, the advent of modern targeting drugs and immunotherapeutics has not led to major breakthroughs in the treatment of peripheral T-cell lymphoma (PTCL) to date. Therefore, both autologous and allogeneic hematopoietic cell transplantation (HCT) continue to play a central role in the management of PTCL. Focusing on the most common entities (PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and ALK-negative anaplastic large cell lymphoma), we summarize evidence, indications, and points to consider for transplant strategies in PTCL by treatment line. Although cutaneous T-cell lymphomas (CTCLs) are biologically and clinically distinct from the aforementioned PTCL, both disease groups appear to be susceptible to the graft-versus-lymphoma effects conferred by allogeneic HCT (alloHCT), setting the stage for alloHCT as a potentially curative treatment in otherwise incurable CTCL, such as mycosis fungoides/Sezary syndrome. Nevertheless, specific aspects regarding indication and prerequisites for alloHCT in CTCL need to be considered. Given the inherent toxicity of alloHCT and the significant risk of relapse after transplant, only intelligent strategies embedding alloHCT in current PTCL/CTCL treatment algorithms in terms of patient selection, timing, pretransplant preparation, and posttransplant maintenance provide optimal results. New targeted and cellular therapies, either complementary or competitive to HCT, are eagerly awaited in order to improve PTCL/CTCL outcomes.

BV and beyond: how to incorporate novel agents into PTCL management.

Peripheral T-cell lymphomas (PTCLs) are a heterogenous yet aggressive group of lymphomas that arise from mature T- or NK-cell precursors. Nodal PTCLs include anaplastic large-cell lymphoma, PTCL not otherwise specified, and follicular helper T-cell lymphomas. Recent advances in understanding these heterogenous diseases have prompted investigation of novel agents to improve on treatment. Brentuximab vedotin, a CD30 antibody-drug conjugate, has been incorporated into frontline treatment regimens of CD30-expressing PTCLs based on the ECHELON-2 trial. Multiple ongoing trials are evaluating the addition of other targeted agents in the frontline and relapsed/refractory setting. These include single-agent brentuximab vedotin, histone deacetylase inhibitors, duvelisib, ruxolitinib, EZH2 inhibitors, and azacitidine, among others. Follicular helper T-cell lymphomas, given frequent mutations in epigenetic regulator genes, may preferentially respond to agents such as histone deacetylase inhibitors, EZH2 inhibitors, and hypomethylating agents. As these therapies evolve in their use for both relapsed/refractory disease and then into frontline treatment, subtype-specific therapy will likely help personalize care for patients with PTCL.

Brief Report: Final overall survival and long-term safety of lorlatinib in patients with ALK-positive non-small cell lung cancer from the pivotal phase 2 study

IntroductionLorlatinib is a potent, brain-penetrant, third-generation inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases with broad coverage of ALK resistance mutations. We present overall survival (OS) and long-term safety of lorlatinib in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) from the final analyses of the pivotal phase 2 study. MethodsAdults with ALK-positive NSCLC, enrolled in expansion cohorts based on prior therapy (EXP1-5), received lorlatinib 100 mg orally once daily in continuous 21-day cycles. The primary endpoint was objective response rate; secondary endpoints included OS and safety. ResultsThirty patients were enrolled in EXP1 (treatment naïve), 59 in EXP2-3A (disease progression following crizotinib ± chemotherapy), 28 in EXP3B (disease progression following one second-generation ALK tyrosine kinase inhibitor [TKI] ± chemotherapy), 111 in EXP4-5 (disease progression following ≥2 ALK TKIs ± chemotherapy), and 139 in EXP3B-5 (disease progression following ≥1 ALK TKI ± chemotherapy). Median OS was not reached (NR) (95% CI, NR-NR) in EXP1, NR (95% CI, 51.5-NR) in EXP2-3A, 37.4 months (95% CI, 12.3-NR) in EXP3B, 19.2 months (95% CI, 15.4-30.2) in EXP4-5, and 20.7 months (95% CI, 16.1-30.3) in EXP3B-5. All-cause adverse events leading to dose reduction were reported in 77 (28%) patients, temporary treatment discontinuation in 158 (57%), and permanent discontinuation in 35 (13%). ConclusionsAfter a minimum follow-up of 5 years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC.

Breakthrough Biomarkers in Lung Cancer: Pioneering Early Detection and Precision Treatment Strategies.

There are several biological, genetic, and environmental variables that contribute to lung cancer, which is one of the main causes of cancer-related death globally. In addition to exposure to radon gas, air pollution, and occupational dangers like asbestos, smoking is a major risk factor because it releases carcinogens like nitrosamines and polycyclic aromatic hydrocarbons (PAHs) into the lungs. The risk of developing lung cancer is also influenced by genetic predispositions, such as variations in genes like EGFR, KRAS, and TP53. Additionally, new research emphasises how epigenetic changes, such as DNA methylation and histone acetylation, affect the expression of genes connected to the development of cancer. In determining risk and spotting early indicators of lung cancer, biomarkers have become important instruments. Cell-free DNA (cfDNA), circulating tumour cells (CTCs), and certain microRNAs (miRNAs) in blood are non-invasive biomarkers that indicate tumour heterogeneity and load. Molecular indicators include anaplastic lymphoma kinase (ALK) rearrangements, epidermal growth factor receptor (EGFR) mutations, and programmed death-ligand 1 (PD-L1) expression have proved very important in tailoring the therapy of lung cancer. Inflammatory indicators such as interleukins and C-reactive protein (CRP) are also linked to the prognosis of lung cancer. Finding and confirming these biomarkers is essential for improving early detection, tracking the course of the disease, and directing focused treatments. As research progresses, combining molecular, genetic, and environmental insights might improve lung cancer care, prevention, and early diagnosis, thereby lowering the disease's worldwide burden.

Anaplastic lymphoma kinase-negative primary systemic anaplastic large cell lymphoma mimicking a ruptured epidermal cyst of the scalp: a case report and literature review

Anaplastic lymphoma kinase-negative primary systemic anaplastic large cell lymphoma mimicking a ruptured epidermal cyst of the scalp: a case report and literature review

Abstract A040: A novel stroma-mediated positive interaction between resistant and sensitive cells in non-small cell lung cancer facilitates drug resistance

Abstract Resistance to targeted therapies, particularly those inhibiting oncogenic tyrosine kinases (TKIs), presents a significant challenge in the treatment of advanced non-small cell lung cancer (NSCLC). Despite initial robust clinical responses, tumors often relapse due to the emergence of resistant cell populations. The origins of this resistance—whether it is pre-existing in a subset of tumor cells or arises de novo during treatment—remains a critical question in understanding and combating therapeutic failure. To investigate this, we developed in silico mathematical models that integrate both pre-existing and de novo resistance mechanisms within a framework that explicitly integrates the stromal niche. Our study focused on the evolutionary dynamics of NSCLC in response to therapy, using a hybrid agent-based spatial modeling framework (HAL) to simulate tumor behavior under treatment. These models were designed to simulate the complex interactions between resistant and sensitive tumor cells, mediated by the stroma, and to predict the timing of relapse based on these interactions. Our findings suggest that stroma-mediated interactions play a crucial role in the evolutionary dynamics of therapy responses, influencing the fitness and survival of both resistant and sensitive cells. Specifically, our models predict that pre-existing resistance is unlikely to be compatible with the long remission periods observed in a substantial subset of patients treated with advanced anaplastic lymphoma kinase (ALK) inhibitors. This conclusion was supported by the observed relapse times and volumetric tumor growth data from subsequent animal models. Moreover, our analyses highlight the importance of ecological factors within the tumor microenvironment in shaping the response to therapy. The spatial models we developed reveal that the stroma can foster positive interactions between resistant and sensitive cells, thereby accelerating the emergence of resistance. These insights underscore the need to consider the stromal niche when developing new therapeutic strategies and when interpreting the dynamics of drug resistance. In conclusion, our study provides new insights into the role of stroma in mediating resistance to TKIs in NSCLC. By combining mathematical modeling with experimental data, we have elucidated how stroma-mediated interactions between tumor cells can influence the evolution of resistance, challenging the assumption that pre-existing resistance alone drives relapses in TKI-treated patients. Our findings emphasize the need for adaptive therapeutic approaches that anticipate and disrupt these microenvironmental interactions to improve patient outcomes. Citation Format: Rishi M. Shah, Sagnik Yarlagadda, Mark Robertson-Tessi, Bina Desai, Tatiana Miti, Daria Miroshnychenko, David Basanta, Andriy Marusyk, Alexander Anderson. A novel stroma-mediated positive interaction between resistant and sensitive cells in non-small cell lung cancer facilitates drug resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A040.

Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer

Targeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase–positive non-small cell lung cancer (ALK + NSCLC) patient–derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth. We confirmed knockdown of both TNKS1/2 in DTP cells recovered the sensitivity to alectinib. Further, our study suggested knockdown of TNKS1/2 increased stability of Axin1/2, which induced β-catenin degradation and decreased its nuclear translocation, thereby suppressing transcription of antiapoptotic and proliferation-related genes (survivin, c-MYC). Targeting both pathways with alectinib+pan-HER inhibitor and alectinib+TNKS1/2 inhibitor suppressed alectinib-induced DTP cells, and the triple combination almost completely prevented the appearance of DTP cells. In conclusion, combination with ALK-TKI, pan-HER and TNKS1/2 inhibitors has the potential to prevent the emergence of DTP in ALK + NSCLC.

Clinicopathologic features of primary central nervous system anaplastic large cell lymphoma: a multicenter study identifies age and ALK status as prognostic factors.

Anaplastic large cell lymphoma with primary presentation in, and disease limited to, the central nervous system (primary CNS ALCL) is a rare and aggressive lymphoma found in a sensitive anatomic site. We report the clinical and pathologic characteristics of 17 primary CNS ALCL cases that are newly reported from six academic medical centers. We are investigating the characteristics of these cases, alongside their commonalities and differences from systemic ALCL arising at conventional anatomic sites. Clinical, pathologic, and outcome data were extracted by medical record review. The median patient age was 32years with a male-to-female ratio of 2.4:1. Cases presented with either localized or multifocal central nervous system (CNS) disease without coinciding systemic disease. Histologically, the common pattern prevailed, and loss of pan-T-cell markers was frequent. There was a similar proportion of anaplastic lymphoma kinase (ALK) positivity in primary CNS ALCL (12/17, 71%) compared to that reported in systemic ALCL (70-80%). Our data indicate a 5-year overall survival (OS) rate of 65% and a 5-year progression-free survival (PFS) rate of 48%. Five patient deaths occurred in this study of which all were in the ALK-negative group, and all were patients over 40years old. ALK-positive patients were significantly younger than ALK-negative patients, and survival analyses showed that both ALK-positive and younger age (≤ 40years) were favorable prognostic factors. This is the largest series of primary CNS ALCL reported to date, which demonstrates a high proportion of ALK-positive cases and favorable outcomes for both younger and ALK-positive patients despite the involvement of a sensitive anatomic site.

Integrative transcriptomic analysis identifies emetine as a promising candidate for overcoming acquired resistance to ALK inhibitors in lung cancer.

Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further interpreted its impact on the resistant signatures through drug-induced RNA-sequencing data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy.