RARE DISEASE
Anaplastic large cell lymphoma
Anaplastic large cell lymphoma
Anaplastic large cell lymphoma
Synonyms: ALCL, CD30 positive anaplastic large cell lymphoma, Ki-1 positive anaplastic large cell lymphoma, Primary systemic ALCL, sACL
Synonyms: ALCL, CD30 positive anaplastic large cell lymphoma, Ki-1 positive anaplastic large cell lymphoma, Primary systemic ALCL, sACL
Synonyms: ALCL, CD30 positive anaplastic large cell lymphoma, Ki-1 positive anaplastic large cell lymphoma, Primary systemic ALCL, sACL
Drug discovery
8
drugs
With orphan designations
Overview
Anaplastic large cell lymphoma (ALCL) is a rare CD30-positive T-cell non-Hodgkin lymphoma with distinct subtypes: systemic (ALK-positive or ALK-negative), primary cutaneous, and breast implant-associated (BIA-ALCL). ALK-positive cases, more common in children/young adults, have favorable prognoses with anthracycline-based chemotherapy (e.g., CHOP/CHOEP). ALK-negative disease, prevalent in older adults, has poorer outcomes. Brentuximab vedotin (anti-CD30) and stem cell transplantation are key for relapsed/refractory cases. BIA-ALCL is linked to textured implants and typically resolves with implant/capsule removal [1][6][7][12][18].
Therapies
First-line: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) ± etoposide (CHOEP) for ALK-positive [1][8][12].
Targeted therapy: Brentuximab vedotin (CD30-directed) for relapsed/refractory or frontline ALK-negative cases [1][12][14].
Advanced disease: Stem cell transplantation (autologous/allogeneic); BIA-ALCL requires implant removal with capsulectomy [3][8][18].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,420 drug discovery papers about Anaplastic large cell lymphoma, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,420 drug discovery papers about Anaplastic large cell lymphoma, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-15 | ALK-negative anaplastic large cell lymphoma in pediatric and adolescent patients: a mini-review.
Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a rare and diagnostically challenging entity in children, adolescents, and young adults. Although ALCL accounts for a meaningful subset of young patients diagnosed with non-Hodgkin lymphoma, the vast majority of cases are ALK-positive, while ALK-negative disease is seen predominantly in older adults. As a result, pediatric-specific data are limited to small series and case reports, with treatment strategies often extrapolated from adult peripheral T-cell lymphoma or pediatric ALK-positive ALCL clinical trials. Despite morphologic overlap with ALK-positive ALCL, ALK-negative ALCL is biologically heterogeneous, with recurrent alterations involving DUSP22, TP63, JAK/STAT pathway genes, TYK2, ROS1, ERBB4, and other potential molecular drivers. These alterations may have prognostic and therapeutic implications, but their frequency and significance in children and adolescents remain incompletely defined. Accurate diagnosis of ALK-negative ALCL requires expert hematopathology review, with integration of morphology, immunophenotype, and molecular testing. Emerging therapeutic approaches include CD30-directed therapy, JAK/STAT pathway inhibition, and checkpoint blockade. This review summarizes the diagnostic, biologic, and therapeutic challenges affecting young patients with ALK-negative ALCL and the healthcare teams that care for them. We highlight the need for further collaborative and multidisciplinary work, systematic molecular profiling, and consideration of this group in future clinical trials to ultimately advance care for this group of pediatric and adolescent cancer patients.
2026-08-01 | Intravenous pharmacologic ascorbate as a redox modulator and chemosensitizer in targeted Cancer therapies.
Intravenous pharmacologic ascorbate represents a re-emerging oncologic adjunct that exploits concentration-dependent pro-oxidant effects to selectively induce oxidative stress in malignant cells while preserving normal tissue. Supported by recent clinical data in metastatic pancreatic ductal adenocarcinoma, where high-dose ascorbate combined with gemcitabine and nab-paclitaxel has improved survival outcomes, this review proposes a broader therapeutic paradigm. This paper presents a hypothesis-driven translational perspective that synthesises current mechanistic evidence with a novel therapeutic proposal. Using Brentuximab Vedotin-based therapy for CD30-positive lymphomas as a representative model, we delineate the multi-mechanistic potential of intravenous pharmacologic ascorbate to enhance targeted treatment regimens. Intravenous pharmacologic ascorbate may act as both a redox disruptor and chemosensitizer-amplifying antibody-drug conjugate cytotoxicity through oxidative stress potentiation, apoptotic enhancement, and tumour microenvironment modulation. While preclinical evidence from related chemotherapy contexts suggests potential for synergistic interactions, direct evidence for this specific combination is currently lacking, and the mechanisms discussed remain hypothetical until validated in appropriate models. Notably, the redox-modulating properties of intravenous pharmacologic ascorbate could theoretically address common resistance pathways in cancer, such as the upregulation of endogenous antioxidant defences. Furthermore, emerging data suggests intravenous pharmacologic ascorbate may also influence epigenetic regulation in cancer cells through modulation of α-ketoglutarate-dependent dioxygenases, including ten-eleven translocation enzymes and histone demethylases, potentially reversing hypermethylation-associated silencing of tumour suppressor genes. This paper advocates for preclinical validation followed by well-designed phase II clinical trials to evaluate the safety, efficacy, and pharmacodynamics of intravenous pharmacologic ascorbate combined with targeted therapies. If the hypothesised benefits are confirmed, this approach could position intravenous pharmacologic ascorbate as an accessible, low-toxicity adjunct capable of improving long-term outcomes and quality of life for patients with aggressive malignancies.
2026-07-31 | Breast implant associated anaplastic large cell lymphoma is a heterogeneous T cell disease with active pro-tumour cross-talk and immune suppression.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T cell lymphoma in women with textured implants. Little is known about the cell of origin (COO) and whether the tumour immune microenvironment (TIME) is critical for BIA-ALCL survival. Single-cell RNA sequencing revealed BIA-ALCL cells were heterogeneous with unique gene profiles per patient and signature genes BATF3, SERPINS, TNFSFR8, and IL2RA. The COO is a CD4+ or CD8+ memory T cell identified through rearranged TCR and gene expression. The BIA-ALCL TIME included distinct myeloid clusters, dendritic cells (DCs), and monocytes, which may support lymphoma cells. Cytokines IL-13, IL-10, TNF and secretory PDL1 were increased in BIA-ALCL seroma, indicating an immunosuppressive TIME. Interactome analysis revealed a complex network among lymphoma cells, dominated by IL-13, IL-10, and TNF members. Endogenous CD8+ T cells exhibit higher checkpoint expression than benign seromas. No clonal relationship exists between BIA-ALCL and endogenous T cells. Tissue-archetype and gene-expression analysis revealed T-cell exclusion and immunosuppressive TIME in invasive disease. In summary, BIA-ALCL cells are diverse with markedly different TIME across stages. The TIME provides immunosuppressive signals to activated/exhausted T cells and homeostatic signals that promote BIA-ALCL proliferation. These new findings may offer novel therapeutic targets for advanced disease patients.
2026-07-31 | Arsenic trioxide promotes a glue‑like interaction to drive STUB1-mediated NPM-ALK degradation in ALK+ ALCL.
The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion constitutively activates ALK tyrosine kinase, driving oncogenesis in anaplastic large cell lymphoma (ALCL). While arsenic trioxide (ATO) exhibits therapeutic potential, its precise mechanism remains elusive, limiting clinical application. Here, we used a combined approach of E3 ligase library screening, ATO chemical proteomics, and NPM-ALK immunoprecipitation-mass spectrometry to reveal that ATO regulates NPM-ALK stability via the E3 ligase STUB1. Clinically, high STUB1 expression correlates with improved survival, identifying it as a candidate favorable prognostic biomarker in NPM-ALK+ ALCL. Mechanistically, ATO promotes a glue‑like interaction that stabilizes the ternary complex of STUB1 and NPM-ALK, promoting ubiquitination at K174 and subsequent proteasomal degradation. Furthermore, structural modeling, domain mapping, and point mutations support a proposed arsenic-dependent interaction model involving STUB1 Cys83, Cys103, and NPM-ALK Cys599, which may modulate the STUB1-NPM-ALK interface and enhance their interaction, thereby promoting ubiquitin-mediated degradation. Crucially, we demonstrate that STUB1 overexpression or pharmacological activation using the FDA-approved cardiac glycoside Deslanoside synergizes profoundly with ATO to inhibit tumor growth both in vitro and in vivo. These findings provide novel mechanistic insight into ATO's action in NPM-ALK+ ALCL and reveal new therapeutic strategies and candidate prognostic biomarkers for patient management.
2026-07-28 | CD4+ T cells orchestrate the immune response to ALK-positive T-cell lymphoma.
Immunotherapy has revolutionized the treatment of solid cancers in recent years. However, T-cell lymphomas (T-NHLs) originate from immune cells themselves and are biologically heterogeneous, rendering investigations of immune checkpoint inhibitor (ICI) mechanisms of action complex. While case reports and individual Anaplastic Large Cell Lymphoma (ALCL) cases enrolled in T-NHL trials demonstrated favourable responses to ICI, hyperprogression was observed in other T-NHL subtypes. We therefore utilized a syngeneic mouse model of ALK+ ALCL to investigate immune surveillance and ICI-induced immune response. Transplantation experiments combined with depletion of relevant immune axes revealed that ALCL immune surveillance is mediated by CD4+ T cells and NK cells. Innate and adaptive immune cell infiltration was confirmed on a large series of primary human ALK+ ALCL samples. ICI monotherapy demonstrated robust efficacy in murine ALCL, inducing complete remissions in approximately 50% of treated animals. Mechanistically, PD-L1 blockade reversed Treg-mediated immunosuppression and increased the frequency of circulating effector CD8+ T lymphocytes, thereby prolonging survival significantly. Importantly, CD4+ T cells proved indispensable for driving and sustaining immunotherapy-induced anti-tumour responses in murine ALCL. CD4+ T cells of non-responder animals exhibited an exhausted phenotype and a transcriptomic Th22-like signature, implicating persistent T-cell exhaustion and polarization as a meaningful immune-evasion mechanism. Our findings uncover CD4+ T cells as key players in spontaneous and immunotherapy-mediated anti T-cell lymphoma immunity, which demonstrates the critically needed preclinical proof-of-concept for the safe and effective use of immunotherapy for ALCL.
2026-08-15 | ALK-negative anaplastic large cell lymphoma in pediatric and adolescent patients: a mini-review.
Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a rare and diagnostically challenging entity in children, adolescents, and young adults. Although ALCL accounts for a meaningful subset of young patients diagnosed with non-Hodgkin lymphoma, the vast majority of cases are ALK-positive, while ALK-negative disease is seen predominantly in older adults. As a result, pediatric-specific data are limited to small series and case reports, with treatment strategies often extrapolated from adult peripheral T-cell lymphoma or pediatric ALK-positive ALCL clinical trials. Despite morphologic overlap with ALK-positive ALCL, ALK-negative ALCL is biologically heterogeneous, with recurrent alterations involving DUSP22, TP63, JAK/STAT pathway genes, TYK2, ROS1, ERBB4, and other potential molecular drivers. These alterations may have prognostic and therapeutic implications, but their frequency and significance in children and adolescents remain incompletely defined. Accurate diagnosis of ALK-negative ALCL requires expert hematopathology review, with integration of morphology, immunophenotype, and molecular testing. Emerging therapeutic approaches include CD30-directed therapy, JAK/STAT pathway inhibition, and checkpoint blockade. This review summarizes the diagnostic, biologic, and therapeutic challenges affecting young patients with ALK-negative ALCL and the healthcare teams that care for them. We highlight the need for further collaborative and multidisciplinary work, systematic molecular profiling, and consideration of this group in future clinical trials to ultimately advance care for this group of pediatric and adolescent cancer patients.
2026-08-01 | Intravenous pharmacologic ascorbate as a redox modulator and chemosensitizer in targeted Cancer therapies.
Intravenous pharmacologic ascorbate represents a re-emerging oncologic adjunct that exploits concentration-dependent pro-oxidant effects to selectively induce oxidative stress in malignant cells while preserving normal tissue. Supported by recent clinical data in metastatic pancreatic ductal adenocarcinoma, where high-dose ascorbate combined with gemcitabine and nab-paclitaxel has improved survival outcomes, this review proposes a broader therapeutic paradigm. This paper presents a hypothesis-driven translational perspective that synthesises current mechanistic evidence with a novel therapeutic proposal. Using Brentuximab Vedotin-based therapy for CD30-positive lymphomas as a representative model, we delineate the multi-mechanistic potential of intravenous pharmacologic ascorbate to enhance targeted treatment regimens. Intravenous pharmacologic ascorbate may act as both a redox disruptor and chemosensitizer-amplifying antibody-drug conjugate cytotoxicity through oxidative stress potentiation, apoptotic enhancement, and tumour microenvironment modulation. While preclinical evidence from related chemotherapy contexts suggests potential for synergistic interactions, direct evidence for this specific combination is currently lacking, and the mechanisms discussed remain hypothetical until validated in appropriate models. Notably, the redox-modulating properties of intravenous pharmacologic ascorbate could theoretically address common resistance pathways in cancer, such as the upregulation of endogenous antioxidant defences. Furthermore, emerging data suggests intravenous pharmacologic ascorbate may also influence epigenetic regulation in cancer cells through modulation of α-ketoglutarate-dependent dioxygenases, including ten-eleven translocation enzymes and histone demethylases, potentially reversing hypermethylation-associated silencing of tumour suppressor genes. This paper advocates for preclinical validation followed by well-designed phase II clinical trials to evaluate the safety, efficacy, and pharmacodynamics of intravenous pharmacologic ascorbate combined with targeted therapies. If the hypothesised benefits are confirmed, this approach could position intravenous pharmacologic ascorbate as an accessible, low-toxicity adjunct capable of improving long-term outcomes and quality of life for patients with aggressive malignancies.
2026-07-31 | Breast implant associated anaplastic large cell lymphoma is a heterogeneous T cell disease with active pro-tumour cross-talk and immune suppression.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T cell lymphoma in women with textured implants. Little is known about the cell of origin (COO) and whether the tumour immune microenvironment (TIME) is critical for BIA-ALCL survival. Single-cell RNA sequencing revealed BIA-ALCL cells were heterogeneous with unique gene profiles per patient and signature genes BATF3, SERPINS, TNFSFR8, and IL2RA. The COO is a CD4+ or CD8+ memory T cell identified through rearranged TCR and gene expression. The BIA-ALCL TIME included distinct myeloid clusters, dendritic cells (DCs), and monocytes, which may support lymphoma cells. Cytokines IL-13, IL-10, TNF and secretory PDL1 were increased in BIA-ALCL seroma, indicating an immunosuppressive TIME. Interactome analysis revealed a complex network among lymphoma cells, dominated by IL-13, IL-10, and TNF members. Endogenous CD8+ T cells exhibit higher checkpoint expression than benign seromas. No clonal relationship exists between BIA-ALCL and endogenous T cells. Tissue-archetype and gene-expression analysis revealed T-cell exclusion and immunosuppressive TIME in invasive disease. In summary, BIA-ALCL cells are diverse with markedly different TIME across stages. The TIME provides immunosuppressive signals to activated/exhausted T cells and homeostatic signals that promote BIA-ALCL proliferation. These new findings may offer novel therapeutic targets for advanced disease patients.
2026-07-31 | Arsenic trioxide promotes a glue‑like interaction to drive STUB1-mediated NPM-ALK degradation in ALK+ ALCL.
The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) fusion constitutively activates ALK tyrosine kinase, driving oncogenesis in anaplastic large cell lymphoma (ALCL). While arsenic trioxide (ATO) exhibits therapeutic potential, its precise mechanism remains elusive, limiting clinical application. Here, we used a combined approach of E3 ligase library screening, ATO chemical proteomics, and NPM-ALK immunoprecipitation-mass spectrometry to reveal that ATO regulates NPM-ALK stability via the E3 ligase STUB1. Clinically, high STUB1 expression correlates with improved survival, identifying it as a candidate favorable prognostic biomarker in NPM-ALK+ ALCL. Mechanistically, ATO promotes a glue‑like interaction that stabilizes the ternary complex of STUB1 and NPM-ALK, promoting ubiquitination at K174 and subsequent proteasomal degradation. Furthermore, structural modeling, domain mapping, and point mutations support a proposed arsenic-dependent interaction model involving STUB1 Cys83, Cys103, and NPM-ALK Cys599, which may modulate the STUB1-NPM-ALK interface and enhance their interaction, thereby promoting ubiquitin-mediated degradation. Crucially, we demonstrate that STUB1 overexpression or pharmacological activation using the FDA-approved cardiac glycoside Deslanoside synergizes profoundly with ATO to inhibit tumor growth both in vitro and in vivo. These findings provide novel mechanistic insight into ATO's action in NPM-ALK+ ALCL and reveal new therapeutic strategies and candidate prognostic biomarkers for patient management.
2026-07-28 | CD4+ T cells orchestrate the immune response to ALK-positive T-cell lymphoma.
Immunotherapy has revolutionized the treatment of solid cancers in recent years. However, T-cell lymphomas (T-NHLs) originate from immune cells themselves and are biologically heterogeneous, rendering investigations of immune checkpoint inhibitor (ICI) mechanisms of action complex. While case reports and individual Anaplastic Large Cell Lymphoma (ALCL) cases enrolled in T-NHL trials demonstrated favourable responses to ICI, hyperprogression was observed in other T-NHL subtypes. We therefore utilized a syngeneic mouse model of ALK+ ALCL to investigate immune surveillance and ICI-induced immune response. Transplantation experiments combined with depletion of relevant immune axes revealed that ALCL immune surveillance is mediated by CD4+ T cells and NK cells. Innate and adaptive immune cell infiltration was confirmed on a large series of primary human ALK+ ALCL samples. ICI monotherapy demonstrated robust efficacy in murine ALCL, inducing complete remissions in approximately 50% of treated animals. Mechanistically, PD-L1 blockade reversed Treg-mediated immunosuppression and increased the frequency of circulating effector CD8+ T lymphocytes, thereby prolonging survival significantly. Importantly, CD4+ T cells proved indispensable for driving and sustaining immunotherapy-induced anti-tumour responses in murine ALCL. CD4+ T cells of non-responder animals exhibited an exhausted phenotype and a transcriptomic Th22-like signature, implicating persistent T-cell exhaustion and polarization as a meaningful immune-evasion mechanism. Our findings uncover CD4+ T cells as key players in spontaneous and immunotherapy-mediated anti T-cell lymphoma immunity, which demonstrates the critically needed preclinical proof-of-concept for the safe and effective use of immunotherapy for ALCL.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
8 orphan drug designations for Anaplastic large cell lymphoma, including 2 approved therapies.
8 orphan drug designations for Anaplastic large cell lymphoma, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
CD30-Targeted Genetically-modified Autologous T-cell immunotherapy | cell therapies | FDA | 2024-01-29 | — | Wu Han Bio-raid Biotech Co., Ltd. |
Belinostat | small molecules | EMA | 2012-10-10 | — | Onxeo DK, Filial af Onxeo S.A., Frankrig |
crizotinib [Xalkori] | small molecules | FDA | 2012-09-28 | 2021-01-14 | Pfizer, Inc. |
Mogamulizumab | antibodies | EMA | 2012-01-11 | — | Kyowa Kirin Holdings B.V. |
mogamulizumab | antibodies | FDA | 2010-11-02 | — | Kyowa Kirin Pharmaceutical Development, Inc. |
Darinaparsin | small molecules | FDA | 2010-09-13 | — | Solasia Pharma K.K. |
Brentuximab vedotin [Adcetris] | antibodies | EMA | 2009-01-15 | — | Takeda Pharma A/S |
brentuximab vedotin [Adcetris] | antibodies | FDA | 2008-10-23 | 2011-08-19 | Seagen Inc. |
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