RARE DISEASE
ALK-positive large B-cell lymphoma
ALK-positive large B-cell lymphoma
ALK-positive large B-cell lymphoma
Synonyms: ALK+ LBCL, ALK+ large B-cell lymphoma
Synonyms: ALK+ LBCL, ALK+ large B-cell lymphoma
Synonyms: ALK+ LBCL, ALK+ large B-cell lymphoma
Drug discovery
0
drugs
With orphan designations
Overview
ALK-positive large B-cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma characterized by ALK gene rearrangements (most commonly CLTC-ALK). It typically presents with nodal or extranodal involvement (e.g., mediastinum, nasopharynx) and exhibits plasmablastic morphology with CD20 negativity, CD138/EMA positivity, and ALK protein expression. Prognosis is generally poor, with resistance to standard chemotherapy regimens like CHOP and high relapse rates.
Therapies
Anthracycline-based chemotherapy (CHOP/CHOEP) remains initial therapy but yields low long-term remission rates [3][8].
ALK inhibitors (e.g., crizotinib, alectinib) show promise in relapsed/refractory cases [4][11][17].
Myeloma-like regimens (e.g., bortezomib + lenalidomide + dexamethasone) and stem cell transplantation (ASCT/allogeneic HSCT) are explored in refractory disease [11][14].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
104 drug discovery papers about ALK-positive large B-cell lymphoma. Recent publications:
104 drug discovery papers about ALK-positive large B-cell lymphoma. Recent publications:
categories:
Small molecules
small molecules
2026-07-02 | Alectinib shows promise for the treatment of refractory ALK-positive large B-cell lymphoma: a case report.
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is rare, accounts for <1% of DLBCL, and is characterized by ALK rearrangement. ALK+ LBCL is a very aggressive disease with a poor prognosis, a high risk of relapse and a poor response to standard chemotherapy treatment, with a median overall survival of approximately one year in advanced-stage disease. The activity of ALK inhibitors in the treatment of relapsed/refractory ALK+ LBCL is not well studied. Here, we report our experience with the use of alectinib in refractory ALK+ LBCL. A previously healthy 14-year-old Saudi Arabian girl presented with progressive chest, loin, and iliac crest pain over two months, without B symptoms. Imaging revealed a left supradiaphragmatic soft tissue mass with supra and infradiaphragmatic nodal masses, pancreatic mass and right iliac bone aggressive lesion. Core biopsy of a left pararenal mass confirmed ALK-positive large B-cell lymphoma (ALK+ LBCL). Immunohistochemistry showed positivity for CD138, MUM1, CD79a (subset), CD4, EMA, CD45, CD10 (weak), BCL6, c-MYC, BCL2, and cytoplasmic ALK1. CD20 and PAX5 were negative. ALK rearrangement was confirmed by FISH; the bone marrow was not involved. Initial treatment with CHOEP failed, followed by progression on salvage ESHAP and IGEV chemotherapy. Radiation was given for bulky disease. Crizotinib was initiated with partial response but discontinued due to hepatotoxicity and disease progression. Alectinib was then started, resulting in a complete metabolic response (CMR). This was consolidated with an allogeneic stem cell transplant from a matched sibling donor, leading to a sustained CMR for 4 years with good tolerance. The use of next-generation ALK inhibitors in this case demonstrated excellent tolerability and induced sustained responses. This report suggests that alectinib may be an effective bridging therapy for refractory ALK+ LBCL to enable allogeneic SCT in selected patients. Further prospective studies are warranted to explore and optimize therapeutic strategies for this rare disease.
2026-06-29 | ALK-positive large B-cell lymphoma presenting in the nasal cavity with CLTC::ALK fusion: a case report of alectinib-integrated therapy followed by autologous hematopoietic stem cell transplantation
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare and aggressive lymphoma for which no standard frontline treatment has been established. Presentation in the nasal cavity is particularly uncommon. We report the case of a 39-year-old man who presented with progressive left-sided nasal obstruction, epistaxis, and bilateral cervical lymphadenopathy. Imaging revealed a left sinonasal/nasopharyngeal mass, bilateral cervical lymphadenopathy, diffuse skeletal hypermetabolism, markedly elevated lactate dehydrogenase, and focal bone marrow involvement. Histopathologic examination showed a plasmablastic neoplasm with strong granular cytoplasmic ALK expression. The tumor cells were positive for CD138, MUM1, EMA, and kappa light chain, but negative for CD20, CD19, CD79a, CD3, CD30, CD56, and EBER. Fluorescence in situ hybridization confirmed ALK rearrangement, and RNA sequencing together with RT-PCR identified a CLTC::ALK fusion (CLTC exon 31::ALK exon 20). The patient was diagnosed with Ann Arbor stage IVB ALK+ LBCL. Disease progression after initial CVAD chemotherapy and persistent disease after CVAD-E prompted the addition of alectinib from cycle 3, with complete metabolic response on PET-CT after cycle 4. Consolidation with Hyper-CVAD plus concurrent alectinib was followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and post-transplant alectinib maintenance. The patient remains in complete remission 10 months after diagnosis. This case illustrates the diagnostic value of integrated morphologic and molecular assessment in CD20-negative plasmablastic lymphoid neoplasms and suggests that incorporating ALK inhibition into multimodal therapy may be a reasonable strategy for selected patients with ALK+ LBCL.
2026-03-09 | Anaplastic Lymphoma Kinase (ALK)-Positive Large B-cell Lymphoma in Children: A Case Report and Review of Literature.
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK⁺-LBCL) is an aggressive and rare B-cell lymphoma caused by the ALK gene mutation. It is exceptionally rare in children and typically presents at advanced stages. Due to morphological mimicry of other hematologic malignancies and conditions, diagnosis remains challenging. Moreover, prognosis is poor as there is a lack of standard therapy. We report the case of a 13-year-old Indonesian male who presented with abdominal pain, initially presumed to be appendicitis. Multiple abdominal masses were subsequently identified following surgery. Histopathological examination revealed diffuse sheets of large round cells with plasmablastic morphology and numerous mitotic figures. Immunohistochemical analysis demonstrated positive ALK expression with a granular cytoplasmic pattern, weak CD45 expression, strong positivity for CD38, MUM1, and EMA, a Ki-67 proliferation index of approximately 70%, and negativity for B- and T-cell markers. Staging confirmed ALK⁺-LBCL, stage IV, according to the Murphy and St. Jude Children's Research Hospital staging system, with both nodal and extranodal involvement. The patient was treated with CHOP chemotherapy, with alectinib added from the second cycle. A partial response was achieved after four cycles and was sustained for more than one year. Notably, neuron-specific enolase levels increased in parallel with disease progression. This case highlights diagnostic challenges related to an unusual clinical presentation and pathological overlap with other hematologic diseases.
2026-02-27 | Persistent lactic acidosis in ALK-positive anaplastic large cell lymphoma: a case report and literature review
Lactic acidosis is common in the ICU, but malignancy-associated type B lactic acidosis mediated by the clinical Warburg effect (CWE) is uncommon and easily missed when infection or organ dysfunction dominates the presentation. We report a 35-year-old man with a month of fever and progressive dyspnea who presented with persistent hyperlactatemia (peak 15.46 mmol/L) and markedly elevated LDH despite stable hemodynamics. Imaging revealed generalized lymphadenopathy, multifocal osteolytic lesions, and bilateral pleural effusions; infectious studies were unrevealing apart from chronic hepatitis B. Cervical node biopsy (CD30 + , ALK-L + , EMA + ; Ki-67 ~80%; EBER–; pan-B/T and epithelial markers negative) established ALK-positive anaplastic large-cell lymphoma. In the absence of shock or sustained hypoperfusion, CWE/type B lactic acidosis was diagnosed. An etoposide-containing CHOP variant (ECHOP/CHOEP, days 1–5) was initiated with parallel continuous renal replacement therapy (CVVHDF) to stabilize acid–base and electrolytes as a bridge to chemotherapy. Lactate declined from 13.30 mmol/L immediately before chemotherapy to 2.88 mmol/L by day 3, 1.33 mmol/L by day 8, and normalized (0.6 mmol/L) by day 17, closely tracking clinical improvement. The patient was extubated, CRRT discontinued, transferred out of the ICU, and discharged; chemotherapy-related myelosuppression and ICU-acquired weakness were managed with G-CSF, transfusions, and early rehabilitation, and a femoral deep-vein thrombosis was treated with anticoagulation. A focused review of 18 recent case reports (2021–2025) suggests that timely, standardized antitumor therapy is frequently followed by a rapid, time-locked fall in lactate, whereas the absence of definitive oncologic treatment portends uniformly poor short-term outcomes. This case underscores that, in hemodynamically stable patients with refractory hyperlactatemia, early consideration of CWE and prompt tumor-directed therapy—supported by targeted organ support such as CRRT—offer the most reliable path to metabolic reversal and recovery.
2025-12-08 | Flow Cytometry-Aided Early Diagnosis and Alectinib Response in Advanced ALK-Positive Large B-Cell Lymphoma: A Case Report
Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma (LBCL) is an exceptionally rare subtype of B-cell lymphoma that typically arises independent of immunosuppression. Patients with stage IV disease have a particularly poor prognosis, with a median overall survival of approximately 1 year (95% confidence interval [CI], 0.8–1.5) and a 5-year survival rate of 5% (95% CI, 0–18%). Early diagnosis is often difficult because its morphological features may mimic those of solid tumors. In addition, no standard therapeutic regimen has been established, and many patients present with advanced disease and poor performance status that limit treatment options.We describe an elderly patient with ALK + LBCL who developed the disease while receiving immunosuppressive therapy for rheumatoid arthritis and systemic lupus erythematosus. Flow cytometry-aided early diagnosis by characterizing the distinct immunophenotype of the tumor. To our knowledge, this is the first reported case of an elderly patient (> 60 years) with ALK + LBCL treated with alectinib. Despite relapsed/refractory disease, the patient achieved tumor control for 10 months, suggesting that alectinib may represent a promising therapeutic option for this rare lymphoma.
cell therapies
2026-04-03 | Abstract 5615: ALK-specific TCR-T cells showed potent and specific activity in ALK-positive anaplastic large cell lymphoma
Abstract Introduction: Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL) is a rare subtype of T-cell lymphoma driven by nucleophosmin 1 (NPM1)-ALK fusion protein. Treatment with standard chemotherapy or ALK tyrosine kinase inhibitor crizotinib is highly effective; however, a significant portion of patients still experience relapses or refractory disease, highlighting the need for innovative therapeutic options. Our group has recently identified two ALK-specific T cell receptors targeting the human ALK peptide RPRPSQPSSL presented by HLA-B*07:02 (B7) and demonstrated specific and robust anti-tumor activity of ALK.TCR-T cells (ALK.TCR-T) in ALK+ non-small cell lung cancer [Mecca et al, Cancer res, 2024]. In this work, we aimed to address the efficacy of ALK.TCR-T in multiple models of ALK+ ALCL. Methods: Two ALK-specific TCRs were retrovirally transduced into human CD3+ T cells to generate ALK.TCR-T1 and ALK.TCR-T2. The anti-tumor activity of ALK.TCR-T was tested both in vitro and in vivo against a panel of crizotinib-sensitive and crizotinib-resistant ALK+ ALCL models. The specificity of peptide-MHC recognition was evaluated by employing ALK+/B7+, ALK+/B7-, and ALK-/B7+ cells. For in vivo studies, NSG mice were injected intravenously with ALK+ ALCL cell lines, and, after engraftment, treated with ALK.TCR-T, alone or in combination with crizotinib. Mice received 50mg/kg crizotinib by oral gavage for 10 days. Tumor growth was evaluated weekly by bioluminescence imaging. Results: In vitro killing assays demonstrated that both ALK.TCR-T selectively recognize and eliminate 80-100% of ALK+/B7+ ALCL, while no killing occurred in ALK+/B7- or ALK-/B7+ models, confirming that ALK.TCR-T specifically target the ALK peptide RPRPSQPSSL presented by HLA-B*07:02. Moreover, ALK-TCR-T were equally effective in killing crizotinib-resistant ALCL cells, independently of the mechanism driving the resistance to crizotinib. Interestingly, the combination of ALK.TCR-T and crizotinib potentiated the killing of crizotinib-sensitive ALK+ ALCL even at unfavorable E:T ratios (1:5 and 1:10).A single treatment with ALK.TCR-T significantly slowed tumor growth in an ALK+/B7+ systemic tumor model and increased the survival of mice, compared to treatment with irrelevant TCR-T cells. The combined treatment with ALK.TCR-T and crizotinib resulted in a further enhancement of tumor regression and mouse survival, with 50% (5/10) mice with no evidence of tumor 40 days after ALK.TCR-T injection. Conclusions: We demonstrated that ALK.TCR-T show specific and potent anti-tumor activity against multiple ALK+ ALCL models both in vitro and in vivo. The combination of ALK.TCR-T and crizotinib further potentiate the ability of ALK.TCR-T to control tumor growth and extend the survival of mice. These results lay the basis for developing a novel immunotherapy strategy for patients with ALK+ ALCL. Citation Format: Simone Piane, Carmen Mecca, Nirmala Tilija Pun, Ana Azambuja, Luca Alessandri, Phuc Bao Nguyen, Elisa Bergaggio, Gabriele Saccu, Alessandro Gasparetto, Haley Ohlson, Claudia Voena, Marcos Simoes-Costa, Roberto Chiarle. ALK-specific TCR-T cells showed potent and specific activity in ALK-positive anaplastic large cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5615.
2025-05-28 | Comprehensive precise CAR-T bridging therapy for diffuse large B-cell lymphoma: A multicenter study from the Chinese Southwest Study Group.
7027 Background: Chimeric antigen receptor T-cell (CAR-T) therapy has showed substantial efficacy in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). However, over 50-60% of patients fail to respond or relapse following CAR T-cell treatment, underscoring the need for strategies to enhance its efficacy. Methods: We prospectively evaluated the efficacy of the Chinese Southwest Oncology Group (CSWOG) regimen, a precise bridging strategy, in patients with r/r DLBCL who received commercial CAR-T therapy. All patients underwent re-biopsy to assess the expression of biomarkers including CD19, CD20, CD22, CD30, CD38, CD79b, ALK, BCL2, PD-L1, and Ki-67 to identify potential treatment targets. Only patients with positive CD19 expression were eligible for inclusion. Patients received a precise salvage therapy consisting of non-cross-resistant chemotherapy and targeted immunotherapy guided by the re-biopsy results. Only those who responded to salvage therapy proceeded to leukapheresis and received an additional cycle of salvage immunochemotherapy. Non-responders were switched to an alternative precise regimen. Based on our previous findings that low-dose radiation enhances CAR-T cell recruitment and increases antigen exposure, all patients received involved-field low-dose radiation prior to CAR-T cell infusion. Patients treated with axicabtagene ciloleucel (axi-cel) in a real-world setting served as the control group. Results: Seventy-one patients with r/r DLBCL received the CSWOG bridging regimen, while 101 Chinese patients treated with axi-cel in a real-world setting served as the control group. In the CSWOG group, 63 patients (88.7%) responded to salvage precise immunochemotherapy, while 8 patients (11.3%) who did not respond were switched to alternative immunochemotherapy regimen. All patients in the CSWOG group received a median dose of 24.0 Gy involved-field radiation. After CAR-T infusion, the best overall response (BOR) rate was 84.5% in CSWOG group, with 74.6% achieving complete response (CR) and 9.9% partial response (PR). The BOR rate in control group was 83.2%, with 58.4% achieving CR and 24.8% achieving PR. After a median follow-up of 15.3 months, the 2 - year overall survival (OS) and progression-free survival (PFS) rates were 84.1% and 75.2%, respectively, in the CSWOG group, compared to 70.0% and 49.8% in the control group. Grade 3 or higher cytokine release syndrome occurred in 9.8% of the CSWOG group and 15.2% of the control group. Neurologic events of any grade were observed in 12.8% of the CSWOG group and 16.2% of the control group. Among the 4 CSWOG patients with neurologic events, all were managed with steroids and resolved; however, all 4 relapsed. Conclusions: Our results show that combining precise immunochemotherapy with low-dose radiation optimizes CAR-T therapy, supporting its global implementation. Clinical trial information: ChiCTR2100043613 .
2024-11-01 | 438 Development of ALK TCR-T therapy against ALK-positive human cancers
Although the development of ALK tyrosine kinase inhibitors (TKIs) has significantly improved clinical outcomes in patients with Anaplastic Lymphoma Kinase (ALK)-rearranged tumors, including non-small cell lung cancers (NSCLCs) and anaplastic large cell lymphoma (ALCL), acquired resistance inevitably develops within 2–3 years, limiting the survival of these patients. Here, we aimed to identify T cell receptor (TCR) clonotypes targeting two human ALK immunogenic peptides presented by the human HLA-B*07:02 that we previously identified by mass spectrometry in ALK-positive cell lines and a biopsy of a patient with NSCLCs1 and to develop TCR-T cell therapy for ALK-rearranged cancers. Transgenic mice expressing the human HLA-B*07:02 were vaccinated either with the human ALK peptide RPRPSQPSSL or IVRCIGVSL. Mice received two subcutis priming injections on days 0 and 14, followed by two boosters on days 28 and 56. On day 62 activated CD137(4-1BB)+/CD8+ T cells were sorted and subjected to single-cell sequencing. The expanded TCR clonotypes identified (VDJ count ≥ 4) were then cloned in a retroviral vector that was used to produce ALK TCR-T cells. We identified 353 and 742 unique TCR clonotypes from transgenic HLA-B*07:02 mice vaccinated with the human ALK peptides RPRPSQPSSL and IVRCIGVSL respectively. Single-cell RNA sequencing of the expanded clonotypes (TCR clonotype frequency ≥ 4) versus non-expanded clonotypes (TCR clonotype frequency < 4) revealed significant upregulation of Ccl3, Ccl4, Ccl1, Ifng, Xcl1 across mice vaccinated with RPRPSQPSSL and IVRCIGVSL (p < 0.05). Gene set enrichment analysis (GSEA) confirmed the upregulation of pathways of adaptive immune response, including T cell activation and proliferation, IFN-γ signaling, and cytokine release (adjusted p < 0.05). The in vitro functional validation of the expanded TCR clonotypes isolated from transgenic mice vaccinated with the RPRPSQPSSL peptide, revealed efficient binding to RPRPSQPSSL-dextramer (figure 1A). Clonotype 2.2, which showed 94% dextramer binding, did not kill tumor cells that were ALK-negative and HLA-B*07:02-positive, or tumor cells that were ALK-positive and HLA-B*07:02 negative. In contrast, we observed 95% killing activity against ALK-positive and HLA-B*07:02-positive lung and lymphoma human tumor cells (figure 1B). These data prove that clonotype 2.2 recognizes the ALK RPRPSQPSSL peptide specifically presented by HLA-B*07:02 on tumor cells, exerting robust anti-tumor activity. Here, we demonstrated that human HLA-B*07:02 restricted TCR-T identified via HLA-B*07:02 transgenic mice vaccination exerted potent anti-tumor activity in vitro. These findings pave the way for the development of ALK TCR-T cell therapy for patients with ALK-rearranged tumors. Mota I, Patrucco E, Mastini C, Mahadevan NR, Thai TC, Bergaggio E, Cheong TC, Leonardi G, Karaca-Atabay E, Campisi M, Poggio T, Menotti M, Ambrogio C, Longo DL, Klaeger S, Keshishian H, Sztupinszki ZM, Szallasi Z, Keskin DB, Duke-Cohan JS, Reinhold B, Carr SA, Wu CJ, Moynihan KD, Irvine DJ, Barbie DA, Reinherz EL, Voena C, Awad MM, Blasco EB, Chiarle R. ALK peptide vaccination restores the immunogenicity of ALK-rearranged non-small cell lung cancer. Nat Cancer 2023;4:1016–1035.
2022-09-01 | Real-World Evidence of Axicabtagene Ciloleucel for the Treatment of Large B Cell Lymphoma in the United States
Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) would have been ineligible for inclusion in the ZUMA-1 cohort. Efficacy and safety outcomes were described for the entire cohort and by ZUMA-1 eligibility. Their associations with age, Eastern Cooperative Oncology Group Performance Score, and comorbidities were evaluated using multivariable logistic and Cox regressions. At a median follow-up of 12.9 months, the overall response rate (ORR) was 73%, with a 56% complete response (CR) rate. Median overall survival (OS) and progression-free survival (PFS) were 21.8 months (95% confidence interval [CI], 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. Duration of response (DOR) was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients (62% by 1 year [95% CI, 57% to 66%] versus 67% [95% CI, 62% to 72%]). Patients age ≥65 years had favorable ORR (odds ratio [OR], 1.39; 95% CI, 1.05 to 1.83) despite having a higher risk of cytokine release syndrome (CRS) (OR, 1.41; 95% CI, 1.02 to 1.94) and immune effector cell-associated neurotoxicity syndrome (ICANS) (OR, 1.77; 95% CI, 1.39-2.26). Eastern Cooperative Oncology Group Performance Score ≥2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; 95% CI, 0.18-0.56; hazard ratio [HR] for OS, 3.27; 95% CI, 2.37 to 4.52) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93). The patients ineligible for ZUMA-1 still had a durable response with axi-cel. Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility.
2007-04-12 | CD4 T-helper responses to the anaplastic lymphoma kinase (ALK) protein in patients with ALK-positive anaplastic large-cell lymphoma.
We have previously shown both humoral and CTL responses to anaplastic lymphoma kinase (ALK) in patients with ALK-positive anaplastic large-cell lymphoma (ALCL). However, because CD4(+) T-helper (Th) cells also play a vital role in developing and maintaining tumor immunity, we investigated the presence of a CD4(+) Th response in ALK-positive ALCL. Using an IFN-gamma ELISPOT assay, we identified two ALK-derived DRB1-restricted 24-mer promiscuous peptides, ALK1(278-301) and ALK2(233-256), as being immunogenic in six ALK-positive ALCL patients but not in two ALK-negative ALCL patients or five normal subjects. A significant interleukin-4 response to the ALK peptides was detected in only one ALK-positive patient. CD4(+) Th cell lines lysed ALK-positive ALCL cell lines in a MHC class II-restricted manner. This first report of a CD4(+) Th response to ALK provides valuable information for developing future immunotherapeutic options for ALK-positive ALCL patients who fail to respond well to conventional therapies.
antibodies
2026-01-23 | Case Report: Durable response to PD-1 blockade after failure of ALK-targeted therapy and chemoimmunotherapy in ALK-positive large B-cell lymphoma
Background Anaplastic lymphoma kinase–positive large B-cell lymphoma (ALK+ LBCL) is an exceedingly rare and aggressive subtype of B-cell non-Hodgkin lymphoma, comprising less than 1% of all LBCL cases. These tumors often exhibit resistance to standard chemoimmunotherapy and targeted approaches, resulting in poor clinical outcomes and a median overall survival of approximately 20 months. Despite the identification of ALK rearrangements and activating mutations, effective treatment strategies remain elusive. Case presentation We report a case of an adult diagnosed with stage IV ALK+ LBCL, confirmed via lymph node biopsy and fluorescence in situ hybridization (FISH) demonstrating ALK rearrangement in 91% of nuclei. The patient progressed through four lines of therapy, including R-CHOP, alectinib, lorlatinib with involved-field radiation, and brentuximab vedotin plus bendamustine. Comprehensive genomic profiling revealed a CLTC-ALK fusion and two ALK gain-of-function mutations (p.L1196M and p.G1202R), which are typically sensitive to lorlatinib, suggesting ALK-independent resistance mechanisms. Repeat biopsy demonstrated 20%–30% PD-L1 expression in tumor cells. With no standard options remaining, the patient elected to receive off-label nivolumab. Remarkably, despite an initial disease flare, a rapid clinical and radiological response was observed after just two cycles. As of the latest follow-up after 16 cycles, the patient remains on treatment with sustained clinical benefit and no adverse events reported. Discussion This case highlights the therapeutic challenges of ALK+ LBCL, including its refractoriness to both standard chemotherapy and ALK inhibitors, even in the presence of targetable mutations. The exceptional response to PD-1 blockade, possibly facilitated by acquired PD-L1 expression and an inflammatory tumor microenvironment, suggests an immunologically active tumor niche. Comparison with prior cases supports the hypothesis that PD-L1 expression, even at moderate levels, may predict responsiveness to immune checkpoint inhibitors in this rare lymphoma subtype. Conclusion This case underscores the potential of immune checkpoint inhibition in ALK+ LBCL, particularly in patients with relapsed or refractory disease. PD-L1 testing and repeat biopsy at progression may offer critical insights for guiding therapy. Prospective studies are warranted to explore checkpoint blockade alone or in combination with targeted agents in this aggressive lymphoma.
2025-01-23 | AntiCD30-Conjugated Antibody Plus Standard BEAM as Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Systemic Anaplastic Large Cell Lymphoma.
Background/objectives: The outcome of refractory/relapsed systemic Anaplastic Large Cell Lymphoma (R/R-sALCL), especially for anaplastic lymphoma kinase-1 (ALK-1)-negative disease, remains dismal even after autologous hematopoietic stem cell transplantation (AHSCT). The intensification of both salvage and conditioning regimens, without increasing the toxicity, could improve the outcome of AHSCT in R/R-sALCL. Methods: Based on the successful experience of the incorporation of antiD20 monoclonal antibodies in the treatment of B-Cell Lymphomas, we designed a salvage and conditioning regimen incorporating the antiCD30-conjugated antibody (Brentuximab Vedotin, BV) to standard chemotherapy regimens, and we describe herein the clinical course of a patient with AKL-ve, R/R-sALCL, who received salvage regimen BV + DHAP, followed by AHSCT with preparative regimen consisted of BV plus standard BEAM. Results: The novel regimen was well tolerated, and no severe adverse effects were noticed. The engraftment was prompt and successful. The patient remained in complete metabolic remission for almost 12 months post-transplant. Conclusions: The proposed treatment approach, which combines antiCD30-conjugated antibody with standard salvage and conditioning regimens, demonstrated a completely acceptable toxicity with promising efficacy.
2025-01-15 | Synchronous clonally related anaplastic large cell lymphoma and malignant histiocytosis.
Synchronous malignant histiocytoses are rare conditions that occur concurrently with another hematologic neoplasm. Most reported cases are associated with B-cell lymphoproliferative disorders, while associations with T-cell hemopathies are less common. These two diseases may share mutations and/or cytogenetic anomalies, which can lead to malignant proliferations. In such cases, the term "secondary malignant histiocytosis" can be applied. A 26-year-old patient was diagnosed with anaplastic lymphoma kinase negative anaplastic large cell lymphoma [ALK-ALCL] associated with synchronous malignant histiocytosis. Neoplastic cells were distinguished by the exclusivity of the rearrangement of TCR genes within the lymphoma cells, whereas mutations in the KRAS and TP53 genes affected mono-histiocytic cells. However, these two cells populations shared common chromosomal abnormalities. First line treatment protocol included Brentuximab vedotin, cyclophosphamide, doxorubicin, and methylprednisolone. Despite a partial clinical and biological response after cycle 1 of treatment, the patient was refractory at the end of cycle 2. Patient died in the intensive care unit from a multiple-organ failure related to lymphohistiocytic hemophagocytosis. This case represents the first documented instance of synchronous malignant histiocytosis associated with anaplastic large cell lymphoma. Notably, the uniqueness of this case lies in the absence of TCR rearrangement in the histiocytic cells, despite the presence of shared chromosomal abnormalities with the lymphomatous cells indicating a common origin for both neoplastic proliferations. Considering the rarity of such occurrences, the use of histiocytosis targeted therapy alongside conventional lymphoma treatment warrants consideration in such a context.
2023-07-31 | Aberrant expression of GOLM1 protects ALK+ anaplastic large cell lymphoma from apoptosis by enhancing BCL-XL stability.
Golgi membrane protein 1 (GOLM1) is aberrantly expressed in many types of solid tumors and contributes to cancer development; however, its role in hematopoietic and lymphoid neoplasms remains unknown. Here, we report that GOLM1 was significantly upregulated in anaplastic large cell lymphoma (ALCL), particularly in anaplastic lymphoma kinase-positive (ALK+) ALCL. Mechanistically, the expression of GOLM1 was induced by nucleophosmin-ALK in both ALK-transformed T cells and ALCL cell lines through AKT/mTOR pathway. Knockdown of GOLM1 expression led to a reduction in the growth and viability of ALCL cells with increased spontaneous apoptosis, whereas ectopic expression of GOLM1 protected ALCL cells from apoptosis induced by staurosporine treatment. Moreover, GOLM1 directly interacted with B-cell lymphoma-extra large protein (a crucial anti-apoptosis regulator) and significantly prolonged its stability. Introduction of GOLM1 promoted ALK+ ALCL cells colony formation in vitro and tumor growth in a murine xenograft model. Taken together, our findings demonstrate, to our knowledge, for the first time that GOLM1 plays a critical role in suppressing apoptosis and promoting the progression of ALK+ ALCL and provide evidence that GOLM1 is a potential biomarker and therapeutic target in ALK-induced hematological malignancies.
2020-12-21 | PD-1/PD-L1 Pathway and Its Blockade in Patients with Classic Hodgkin Lymphoma and Non-Hodgkin Large-Cell Lymphomas.
Programmed cell death protein-1 (PD-1) is currently the most extensively studied inhibitory checkpoint molecule. Many malignant neoplasms express the PD-1 ligands, PD-L1, and/or PD-L2, which bind to PD-1 on T cells and induce T cell "exhaustion." By doing so, the malignant cells escape from an antitumor immune response (immune evasion). Blockade of the PD-1/PD-L1 pathway releases T cells from the inhibitory effects exerted by tumor cells and restores a T cell-mediated antitumor immune response. Here, we focus on understanding the immune biology of the PD-1/PD-L1 pathway in large-cell lymphomas, including classic Hodgkin lymphoma (CHL), diffuse large B cell lymphoma (DLBCL), and anaplastic large-cell lymphoma (ALCL), and the current status of PD-1 blockade immunotherapy in treating patients with these lymphomas. PD-1/PD-L1 pathway and PD-1 inhibitors have been widely tested in patients with a variety of lymphomas. Nivolumab and pembrolizumab have been approved by the U.S. Food and Drug Administration for treating patients with some types of relapsed or refractory (R/R) lymphomas. The highest response rate has been achieved in patients with CHL, due to a high frequency of genetic alterations of 9p24.1 and high expression of PD-1 ligands. The frequency of alterations of chromosome 9p24.1 and expression of PD-L1/PD-L1 in DLBCL (except some specific subtypes) is low; therefore, it is not recommended to treat unselected DLBCL patients with PD-1 inhibitors. Studies have shown a high frequency of PD-L1 expression in ALCL, especially in anaplastic lymphoma kinase (ALK)+ type. Several cases reports have described a dramatic and durable response to PD-1 blockade in patients with R/R ALCL, suggesting that patients with R/R ALCL may be potential candidates for PD-1 blockade immunotherapy. Understanding the immune biology of lymphoid neoplasms has helped us identify the specific lymphoma types that are vulnerable to PD-1 inhibitors, such as CHL, and specific subtypes of DLBCL. However, our knowledge of many other lymphomas, including ALCL, in this area is still very limited and the future of PD-1 inhibitors in treating those lymphomas remains unclear.
small molecules
2026-07-02 | Alectinib shows promise for the treatment of refractory ALK-positive large B-cell lymphoma: a case report.
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is rare, accounts for <1% of DLBCL, and is characterized by ALK rearrangement. ALK+ LBCL is a very aggressive disease with a poor prognosis, a high risk of relapse and a poor response to standard chemotherapy treatment, with a median overall survival of approximately one year in advanced-stage disease. The activity of ALK inhibitors in the treatment of relapsed/refractory ALK+ LBCL is not well studied. Here, we report our experience with the use of alectinib in refractory ALK+ LBCL. A previously healthy 14-year-old Saudi Arabian girl presented with progressive chest, loin, and iliac crest pain over two months, without B symptoms. Imaging revealed a left supradiaphragmatic soft tissue mass with supra and infradiaphragmatic nodal masses, pancreatic mass and right iliac bone aggressive lesion. Core biopsy of a left pararenal mass confirmed ALK-positive large B-cell lymphoma (ALK+ LBCL). Immunohistochemistry showed positivity for CD138, MUM1, CD79a (subset), CD4, EMA, CD45, CD10 (weak), BCL6, c-MYC, BCL2, and cytoplasmic ALK1. CD20 and PAX5 were negative. ALK rearrangement was confirmed by FISH; the bone marrow was not involved. Initial treatment with CHOEP failed, followed by progression on salvage ESHAP and IGEV chemotherapy. Radiation was given for bulky disease. Crizotinib was initiated with partial response but discontinued due to hepatotoxicity and disease progression. Alectinib was then started, resulting in a complete metabolic response (CMR). This was consolidated with an allogeneic stem cell transplant from a matched sibling donor, leading to a sustained CMR for 4 years with good tolerance. The use of next-generation ALK inhibitors in this case demonstrated excellent tolerability and induced sustained responses. This report suggests that alectinib may be an effective bridging therapy for refractory ALK+ LBCL to enable allogeneic SCT in selected patients. Further prospective studies are warranted to explore and optimize therapeutic strategies for this rare disease.
2026-06-29 | ALK-positive large B-cell lymphoma presenting in the nasal cavity with CLTC::ALK fusion: a case report of alectinib-integrated therapy followed by autologous hematopoietic stem cell transplantation
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare and aggressive lymphoma for which no standard frontline treatment has been established. Presentation in the nasal cavity is particularly uncommon. We report the case of a 39-year-old man who presented with progressive left-sided nasal obstruction, epistaxis, and bilateral cervical lymphadenopathy. Imaging revealed a left sinonasal/nasopharyngeal mass, bilateral cervical lymphadenopathy, diffuse skeletal hypermetabolism, markedly elevated lactate dehydrogenase, and focal bone marrow involvement. Histopathologic examination showed a plasmablastic neoplasm with strong granular cytoplasmic ALK expression. The tumor cells were positive for CD138, MUM1, EMA, and kappa light chain, but negative for CD20, CD19, CD79a, CD3, CD30, CD56, and EBER. Fluorescence in situ hybridization confirmed ALK rearrangement, and RNA sequencing together with RT-PCR identified a CLTC::ALK fusion (CLTC exon 31::ALK exon 20). The patient was diagnosed with Ann Arbor stage IVB ALK+ LBCL. Disease progression after initial CVAD chemotherapy and persistent disease after CVAD-E prompted the addition of alectinib from cycle 3, with complete metabolic response on PET-CT after cycle 4. Consolidation with Hyper-CVAD plus concurrent alectinib was followed by autologous hematopoietic stem cell transplantation (auto-HSCT) and post-transplant alectinib maintenance. The patient remains in complete remission 10 months after diagnosis. This case illustrates the diagnostic value of integrated morphologic and molecular assessment in CD20-negative plasmablastic lymphoid neoplasms and suggests that incorporating ALK inhibition into multimodal therapy may be a reasonable strategy for selected patients with ALK+ LBCL.
2026-03-09 | Anaplastic Lymphoma Kinase (ALK)-Positive Large B-cell Lymphoma in Children: A Case Report and Review of Literature.
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK⁺-LBCL) is an aggressive and rare B-cell lymphoma caused by the ALK gene mutation. It is exceptionally rare in children and typically presents at advanced stages. Due to morphological mimicry of other hematologic malignancies and conditions, diagnosis remains challenging. Moreover, prognosis is poor as there is a lack of standard therapy. We report the case of a 13-year-old Indonesian male who presented with abdominal pain, initially presumed to be appendicitis. Multiple abdominal masses were subsequently identified following surgery. Histopathological examination revealed diffuse sheets of large round cells with plasmablastic morphology and numerous mitotic figures. Immunohistochemical analysis demonstrated positive ALK expression with a granular cytoplasmic pattern, weak CD45 expression, strong positivity for CD38, MUM1, and EMA, a Ki-67 proliferation index of approximately 70%, and negativity for B- and T-cell markers. Staging confirmed ALK⁺-LBCL, stage IV, according to the Murphy and St. Jude Children's Research Hospital staging system, with both nodal and extranodal involvement. The patient was treated with CHOP chemotherapy, with alectinib added from the second cycle. A partial response was achieved after four cycles and was sustained for more than one year. Notably, neuron-specific enolase levels increased in parallel with disease progression. This case highlights diagnostic challenges related to an unusual clinical presentation and pathological overlap with other hematologic diseases.
2026-02-27 | Persistent lactic acidosis in ALK-positive anaplastic large cell lymphoma: a case report and literature review
Lactic acidosis is common in the ICU, but malignancy-associated type B lactic acidosis mediated by the clinical Warburg effect (CWE) is uncommon and easily missed when infection or organ dysfunction dominates the presentation. We report a 35-year-old man with a month of fever and progressive dyspnea who presented with persistent hyperlactatemia (peak 15.46 mmol/L) and markedly elevated LDH despite stable hemodynamics. Imaging revealed generalized lymphadenopathy, multifocal osteolytic lesions, and bilateral pleural effusions; infectious studies were unrevealing apart from chronic hepatitis B. Cervical node biopsy (CD30 + , ALK-L + , EMA + ; Ki-67 ~80%; EBER–; pan-B/T and epithelial markers negative) established ALK-positive anaplastic large-cell lymphoma. In the absence of shock or sustained hypoperfusion, CWE/type B lactic acidosis was diagnosed. An etoposide-containing CHOP variant (ECHOP/CHOEP, days 1–5) was initiated with parallel continuous renal replacement therapy (CVVHDF) to stabilize acid–base and electrolytes as a bridge to chemotherapy. Lactate declined from 13.30 mmol/L immediately before chemotherapy to 2.88 mmol/L by day 3, 1.33 mmol/L by day 8, and normalized (0.6 mmol/L) by day 17, closely tracking clinical improvement. The patient was extubated, CRRT discontinued, transferred out of the ICU, and discharged; chemotherapy-related myelosuppression and ICU-acquired weakness were managed with G-CSF, transfusions, and early rehabilitation, and a femoral deep-vein thrombosis was treated with anticoagulation. A focused review of 18 recent case reports (2021–2025) suggests that timely, standardized antitumor therapy is frequently followed by a rapid, time-locked fall in lactate, whereas the absence of definitive oncologic treatment portends uniformly poor short-term outcomes. This case underscores that, in hemodynamically stable patients with refractory hyperlactatemia, early consideration of CWE and prompt tumor-directed therapy—supported by targeted organ support such as CRRT—offer the most reliable path to metabolic reversal and recovery.
2025-12-08 | Flow Cytometry-Aided Early Diagnosis and Alectinib Response in Advanced ALK-Positive Large B-Cell Lymphoma: A Case Report
Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma (LBCL) is an exceptionally rare subtype of B-cell lymphoma that typically arises independent of immunosuppression. Patients with stage IV disease have a particularly poor prognosis, with a median overall survival of approximately 1 year (95% confidence interval [CI], 0.8–1.5) and a 5-year survival rate of 5% (95% CI, 0–18%). Early diagnosis is often difficult because its morphological features may mimic those of solid tumors. In addition, no standard therapeutic regimen has been established, and many patients present with advanced disease and poor performance status that limit treatment options.We describe an elderly patient with ALK + LBCL who developed the disease while receiving immunosuppressive therapy for rheumatoid arthritis and systemic lupus erythematosus. Flow cytometry-aided early diagnosis by characterizing the distinct immunophenotype of the tumor. To our knowledge, this is the first reported case of an elderly patient (> 60 years) with ALK + LBCL treated with alectinib. Despite relapsed/refractory disease, the patient achieved tumor control for 10 months, suggesting that alectinib may represent a promising therapeutic option for this rare lymphoma.
cell therapies
2026-04-03 | Abstract 5615: ALK-specific TCR-T cells showed potent and specific activity in ALK-positive anaplastic large cell lymphoma
Abstract Introduction: Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL) is a rare subtype of T-cell lymphoma driven by nucleophosmin 1 (NPM1)-ALK fusion protein. Treatment with standard chemotherapy or ALK tyrosine kinase inhibitor crizotinib is highly effective; however, a significant portion of patients still experience relapses or refractory disease, highlighting the need for innovative therapeutic options. Our group has recently identified two ALK-specific T cell receptors targeting the human ALK peptide RPRPSQPSSL presented by HLA-B*07:02 (B7) and demonstrated specific and robust anti-tumor activity of ALK.TCR-T cells (ALK.TCR-T) in ALK+ non-small cell lung cancer [Mecca et al, Cancer res, 2024]. In this work, we aimed to address the efficacy of ALK.TCR-T in multiple models of ALK+ ALCL. Methods: Two ALK-specific TCRs were retrovirally transduced into human CD3+ T cells to generate ALK.TCR-T1 and ALK.TCR-T2. The anti-tumor activity of ALK.TCR-T was tested both in vitro and in vivo against a panel of crizotinib-sensitive and crizotinib-resistant ALK+ ALCL models. The specificity of peptide-MHC recognition was evaluated by employing ALK+/B7+, ALK+/B7-, and ALK-/B7+ cells. For in vivo studies, NSG mice were injected intravenously with ALK+ ALCL cell lines, and, after engraftment, treated with ALK.TCR-T, alone or in combination with crizotinib. Mice received 50mg/kg crizotinib by oral gavage for 10 days. Tumor growth was evaluated weekly by bioluminescence imaging. Results: In vitro killing assays demonstrated that both ALK.TCR-T selectively recognize and eliminate 80-100% of ALK+/B7+ ALCL, while no killing occurred in ALK+/B7- or ALK-/B7+ models, confirming that ALK.TCR-T specifically target the ALK peptide RPRPSQPSSL presented by HLA-B*07:02. Moreover, ALK-TCR-T were equally effective in killing crizotinib-resistant ALCL cells, independently of the mechanism driving the resistance to crizotinib. Interestingly, the combination of ALK.TCR-T and crizotinib potentiated the killing of crizotinib-sensitive ALK+ ALCL even at unfavorable E:T ratios (1:5 and 1:10).A single treatment with ALK.TCR-T significantly slowed tumor growth in an ALK+/B7+ systemic tumor model and increased the survival of mice, compared to treatment with irrelevant TCR-T cells. The combined treatment with ALK.TCR-T and crizotinib resulted in a further enhancement of tumor regression and mouse survival, with 50% (5/10) mice with no evidence of tumor 40 days after ALK.TCR-T injection. Conclusions: We demonstrated that ALK.TCR-T show specific and potent anti-tumor activity against multiple ALK+ ALCL models both in vitro and in vivo. The combination of ALK.TCR-T and crizotinib further potentiate the ability of ALK.TCR-T to control tumor growth and extend the survival of mice. These results lay the basis for developing a novel immunotherapy strategy for patients with ALK+ ALCL. Citation Format: Simone Piane, Carmen Mecca, Nirmala Tilija Pun, Ana Azambuja, Luca Alessandri, Phuc Bao Nguyen, Elisa Bergaggio, Gabriele Saccu, Alessandro Gasparetto, Haley Ohlson, Claudia Voena, Marcos Simoes-Costa, Roberto Chiarle. ALK-specific TCR-T cells showed potent and specific activity in ALK-positive anaplastic large cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5615.
2025-05-28 | Comprehensive precise CAR-T bridging therapy for diffuse large B-cell lymphoma: A multicenter study from the Chinese Southwest Study Group.
7027 Background: Chimeric antigen receptor T-cell (CAR-T) therapy has showed substantial efficacy in relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). However, over 50-60% of patients fail to respond or relapse following CAR T-cell treatment, underscoring the need for strategies to enhance its efficacy. Methods: We prospectively evaluated the efficacy of the Chinese Southwest Oncology Group (CSWOG) regimen, a precise bridging strategy, in patients with r/r DLBCL who received commercial CAR-T therapy. All patients underwent re-biopsy to assess the expression of biomarkers including CD19, CD20, CD22, CD30, CD38, CD79b, ALK, BCL2, PD-L1, and Ki-67 to identify potential treatment targets. Only patients with positive CD19 expression were eligible for inclusion. Patients received a precise salvage therapy consisting of non-cross-resistant chemotherapy and targeted immunotherapy guided by the re-biopsy results. Only those who responded to salvage therapy proceeded to leukapheresis and received an additional cycle of salvage immunochemotherapy. Non-responders were switched to an alternative precise regimen. Based on our previous findings that low-dose radiation enhances CAR-T cell recruitment and increases antigen exposure, all patients received involved-field low-dose radiation prior to CAR-T cell infusion. Patients treated with axicabtagene ciloleucel (axi-cel) in a real-world setting served as the control group. Results: Seventy-one patients with r/r DLBCL received the CSWOG bridging regimen, while 101 Chinese patients treated with axi-cel in a real-world setting served as the control group. In the CSWOG group, 63 patients (88.7%) responded to salvage precise immunochemotherapy, while 8 patients (11.3%) who did not respond were switched to alternative immunochemotherapy regimen. All patients in the CSWOG group received a median dose of 24.0 Gy involved-field radiation. After CAR-T infusion, the best overall response (BOR) rate was 84.5% in CSWOG group, with 74.6% achieving complete response (CR) and 9.9% partial response (PR). The BOR rate in control group was 83.2%, with 58.4% achieving CR and 24.8% achieving PR. After a median follow-up of 15.3 months, the 2 - year overall survival (OS) and progression-free survival (PFS) rates were 84.1% and 75.2%, respectively, in the CSWOG group, compared to 70.0% and 49.8% in the control group. Grade 3 or higher cytokine release syndrome occurred in 9.8% of the CSWOG group and 15.2% of the control group. Neurologic events of any grade were observed in 12.8% of the CSWOG group and 16.2% of the control group. Among the 4 CSWOG patients with neurologic events, all were managed with steroids and resolved; however, all 4 relapsed. Conclusions: Our results show that combining precise immunochemotherapy with low-dose radiation optimizes CAR-T therapy, supporting its global implementation. Clinical trial information: ChiCTR2100043613 .
2024-11-01 | 438 Development of ALK TCR-T therapy against ALK-positive human cancers
Although the development of ALK tyrosine kinase inhibitors (TKIs) has significantly improved clinical outcomes in patients with Anaplastic Lymphoma Kinase (ALK)-rearranged tumors, including non-small cell lung cancers (NSCLCs) and anaplastic large cell lymphoma (ALCL), acquired resistance inevitably develops within 2–3 years, limiting the survival of these patients. Here, we aimed to identify T cell receptor (TCR) clonotypes targeting two human ALK immunogenic peptides presented by the human HLA-B*07:02 that we previously identified by mass spectrometry in ALK-positive cell lines and a biopsy of a patient with NSCLCs1 and to develop TCR-T cell therapy for ALK-rearranged cancers. Transgenic mice expressing the human HLA-B*07:02 were vaccinated either with the human ALK peptide RPRPSQPSSL or IVRCIGVSL. Mice received two subcutis priming injections on days 0 and 14, followed by two boosters on days 28 and 56. On day 62 activated CD137(4-1BB)+/CD8+ T cells were sorted and subjected to single-cell sequencing. The expanded TCR clonotypes identified (VDJ count ≥ 4) were then cloned in a retroviral vector that was used to produce ALK TCR-T cells. We identified 353 and 742 unique TCR clonotypes from transgenic HLA-B*07:02 mice vaccinated with the human ALK peptides RPRPSQPSSL and IVRCIGVSL respectively. Single-cell RNA sequencing of the expanded clonotypes (TCR clonotype frequency ≥ 4) versus non-expanded clonotypes (TCR clonotype frequency < 4) revealed significant upregulation of Ccl3, Ccl4, Ccl1, Ifng, Xcl1 across mice vaccinated with RPRPSQPSSL and IVRCIGVSL (p < 0.05). Gene set enrichment analysis (GSEA) confirmed the upregulation of pathways of adaptive immune response, including T cell activation and proliferation, IFN-γ signaling, and cytokine release (adjusted p < 0.05). The in vitro functional validation of the expanded TCR clonotypes isolated from transgenic mice vaccinated with the RPRPSQPSSL peptide, revealed efficient binding to RPRPSQPSSL-dextramer (figure 1A). Clonotype 2.2, which showed 94% dextramer binding, did not kill tumor cells that were ALK-negative and HLA-B*07:02-positive, or tumor cells that were ALK-positive and HLA-B*07:02 negative. In contrast, we observed 95% killing activity against ALK-positive and HLA-B*07:02-positive lung and lymphoma human tumor cells (figure 1B). These data prove that clonotype 2.2 recognizes the ALK RPRPSQPSSL peptide specifically presented by HLA-B*07:02 on tumor cells, exerting robust anti-tumor activity. Here, we demonstrated that human HLA-B*07:02 restricted TCR-T identified via HLA-B*07:02 transgenic mice vaccination exerted potent anti-tumor activity in vitro. These findings pave the way for the development of ALK TCR-T cell therapy for patients with ALK-rearranged tumors. Mota I, Patrucco E, Mastini C, Mahadevan NR, Thai TC, Bergaggio E, Cheong TC, Leonardi G, Karaca-Atabay E, Campisi M, Poggio T, Menotti M, Ambrogio C, Longo DL, Klaeger S, Keshishian H, Sztupinszki ZM, Szallasi Z, Keskin DB, Duke-Cohan JS, Reinhold B, Carr SA, Wu CJ, Moynihan KD, Irvine DJ, Barbie DA, Reinherz EL, Voena C, Awad MM, Blasco EB, Chiarle R. ALK peptide vaccination restores the immunogenicity of ALK-rearranged non-small cell lung cancer. Nat Cancer 2023;4:1016–1035.
2022-09-01 | Real-World Evidence of Axicabtagene Ciloleucel for the Treatment of Large B Cell Lymphoma in the United States
Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) would have been ineligible for inclusion in the ZUMA-1 cohort. Efficacy and safety outcomes were described for the entire cohort and by ZUMA-1 eligibility. Their associations with age, Eastern Cooperative Oncology Group Performance Score, and comorbidities were evaluated using multivariable logistic and Cox regressions. At a median follow-up of 12.9 months, the overall response rate (ORR) was 73%, with a 56% complete response (CR) rate. Median overall survival (OS) and progression-free survival (PFS) were 21.8 months (95% confidence interval [CI], 17.4 to 28.8 months) and 8.6 months (95% CI, 6.5 to 12.1 months), respectively. Duration of response (DOR) was comparable in the ZUMA-1 ineligible patients and ZUMA-1 eligible patients (62% by 1 year [95% CI, 57% to 66%] versus 67% [95% CI, 62% to 72%]). Patients age ≥65 years had favorable ORR (odds ratio [OR], 1.39; 95% CI, 1.05 to 1.83) despite having a higher risk of cytokine release syndrome (CRS) (OR, 1.41; 95% CI, 1.02 to 1.94) and immune effector cell-associated neurotoxicity syndrome (ICANS) (OR, 1.77; 95% CI, 1.39-2.26). Eastern Cooperative Oncology Group Performance Score ≥2 was associated with inferior efficacy outcomes (OR for ORR, 0.32; 95% CI, 0.18-0.56; hazard ratio [HR] for OS, 3.27; 95% CI, 2.37 to 4.52) and higher incidence of ICANS (OR, 2.63; 95% CI, 1.40 to 4.93). The patients ineligible for ZUMA-1 still had a durable response with axi-cel. Elderly patients had favorable efficacy outcomes despite higher rates of CRS and ICANS. Patient selection for standard-of-care axi-cel should consider comorbidities and risk-to-benefit ratio rather than be based strictly on ZUMA-1 eligibility.
2007-04-12 | CD4 T-helper responses to the anaplastic lymphoma kinase (ALK) protein in patients with ALK-positive anaplastic large-cell lymphoma.
We have previously shown both humoral and CTL responses to anaplastic lymphoma kinase (ALK) in patients with ALK-positive anaplastic large-cell lymphoma (ALCL). However, because CD4(+) T-helper (Th) cells also play a vital role in developing and maintaining tumor immunity, we investigated the presence of a CD4(+) Th response in ALK-positive ALCL. Using an IFN-gamma ELISPOT assay, we identified two ALK-derived DRB1-restricted 24-mer promiscuous peptides, ALK1(278-301) and ALK2(233-256), as being immunogenic in six ALK-positive ALCL patients but not in two ALK-negative ALCL patients or five normal subjects. A significant interleukin-4 response to the ALK peptides was detected in only one ALK-positive patient. CD4(+) Th cell lines lysed ALK-positive ALCL cell lines in a MHC class II-restricted manner. This first report of a CD4(+) Th response to ALK provides valuable information for developing future immunotherapeutic options for ALK-positive ALCL patients who fail to respond well to conventional therapies.
antibodies
2026-01-23 | Case Report: Durable response to PD-1 blockade after failure of ALK-targeted therapy and chemoimmunotherapy in ALK-positive large B-cell lymphoma
Background Anaplastic lymphoma kinase–positive large B-cell lymphoma (ALK+ LBCL) is an exceedingly rare and aggressive subtype of B-cell non-Hodgkin lymphoma, comprising less than 1% of all LBCL cases. These tumors often exhibit resistance to standard chemoimmunotherapy and targeted approaches, resulting in poor clinical outcomes and a median overall survival of approximately 20 months. Despite the identification of ALK rearrangements and activating mutations, effective treatment strategies remain elusive. Case presentation We report a case of an adult diagnosed with stage IV ALK+ LBCL, confirmed via lymph node biopsy and fluorescence in situ hybridization (FISH) demonstrating ALK rearrangement in 91% of nuclei. The patient progressed through four lines of therapy, including R-CHOP, alectinib, lorlatinib with involved-field radiation, and brentuximab vedotin plus bendamustine. Comprehensive genomic profiling revealed a CLTC-ALK fusion and two ALK gain-of-function mutations (p.L1196M and p.G1202R), which are typically sensitive to lorlatinib, suggesting ALK-independent resistance mechanisms. Repeat biopsy demonstrated 20%–30% PD-L1 expression in tumor cells. With no standard options remaining, the patient elected to receive off-label nivolumab. Remarkably, despite an initial disease flare, a rapid clinical and radiological response was observed after just two cycles. As of the latest follow-up after 16 cycles, the patient remains on treatment with sustained clinical benefit and no adverse events reported. Discussion This case highlights the therapeutic challenges of ALK+ LBCL, including its refractoriness to both standard chemotherapy and ALK inhibitors, even in the presence of targetable mutations. The exceptional response to PD-1 blockade, possibly facilitated by acquired PD-L1 expression and an inflammatory tumor microenvironment, suggests an immunologically active tumor niche. Comparison with prior cases supports the hypothesis that PD-L1 expression, even at moderate levels, may predict responsiveness to immune checkpoint inhibitors in this rare lymphoma subtype. Conclusion This case underscores the potential of immune checkpoint inhibition in ALK+ LBCL, particularly in patients with relapsed or refractory disease. PD-L1 testing and repeat biopsy at progression may offer critical insights for guiding therapy. Prospective studies are warranted to explore checkpoint blockade alone or in combination with targeted agents in this aggressive lymphoma.
2025-01-23 | AntiCD30-Conjugated Antibody Plus Standard BEAM as Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Systemic Anaplastic Large Cell Lymphoma.
Background/objectives: The outcome of refractory/relapsed systemic Anaplastic Large Cell Lymphoma (R/R-sALCL), especially for anaplastic lymphoma kinase-1 (ALK-1)-negative disease, remains dismal even after autologous hematopoietic stem cell transplantation (AHSCT). The intensification of both salvage and conditioning regimens, without increasing the toxicity, could improve the outcome of AHSCT in R/R-sALCL. Methods: Based on the successful experience of the incorporation of antiD20 monoclonal antibodies in the treatment of B-Cell Lymphomas, we designed a salvage and conditioning regimen incorporating the antiCD30-conjugated antibody (Brentuximab Vedotin, BV) to standard chemotherapy regimens, and we describe herein the clinical course of a patient with AKL-ve, R/R-sALCL, who received salvage regimen BV + DHAP, followed by AHSCT with preparative regimen consisted of BV plus standard BEAM. Results: The novel regimen was well tolerated, and no severe adverse effects were noticed. The engraftment was prompt and successful. The patient remained in complete metabolic remission for almost 12 months post-transplant. Conclusions: The proposed treatment approach, which combines antiCD30-conjugated antibody with standard salvage and conditioning regimens, demonstrated a completely acceptable toxicity with promising efficacy.
2025-01-15 | Synchronous clonally related anaplastic large cell lymphoma and malignant histiocytosis.
Synchronous malignant histiocytoses are rare conditions that occur concurrently with another hematologic neoplasm. Most reported cases are associated with B-cell lymphoproliferative disorders, while associations with T-cell hemopathies are less common. These two diseases may share mutations and/or cytogenetic anomalies, which can lead to malignant proliferations. In such cases, the term "secondary malignant histiocytosis" can be applied. A 26-year-old patient was diagnosed with anaplastic lymphoma kinase negative anaplastic large cell lymphoma [ALK-ALCL] associated with synchronous malignant histiocytosis. Neoplastic cells were distinguished by the exclusivity of the rearrangement of TCR genes within the lymphoma cells, whereas mutations in the KRAS and TP53 genes affected mono-histiocytic cells. However, these two cells populations shared common chromosomal abnormalities. First line treatment protocol included Brentuximab vedotin, cyclophosphamide, doxorubicin, and methylprednisolone. Despite a partial clinical and biological response after cycle 1 of treatment, the patient was refractory at the end of cycle 2. Patient died in the intensive care unit from a multiple-organ failure related to lymphohistiocytic hemophagocytosis. This case represents the first documented instance of synchronous malignant histiocytosis associated with anaplastic large cell lymphoma. Notably, the uniqueness of this case lies in the absence of TCR rearrangement in the histiocytic cells, despite the presence of shared chromosomal abnormalities with the lymphomatous cells indicating a common origin for both neoplastic proliferations. Considering the rarity of such occurrences, the use of histiocytosis targeted therapy alongside conventional lymphoma treatment warrants consideration in such a context.
2023-07-31 | Aberrant expression of GOLM1 protects ALK+ anaplastic large cell lymphoma from apoptosis by enhancing BCL-XL stability.
Golgi membrane protein 1 (GOLM1) is aberrantly expressed in many types of solid tumors and contributes to cancer development; however, its role in hematopoietic and lymphoid neoplasms remains unknown. Here, we report that GOLM1 was significantly upregulated in anaplastic large cell lymphoma (ALCL), particularly in anaplastic lymphoma kinase-positive (ALK+) ALCL. Mechanistically, the expression of GOLM1 was induced by nucleophosmin-ALK in both ALK-transformed T cells and ALCL cell lines through AKT/mTOR pathway. Knockdown of GOLM1 expression led to a reduction in the growth and viability of ALCL cells with increased spontaneous apoptosis, whereas ectopic expression of GOLM1 protected ALCL cells from apoptosis induced by staurosporine treatment. Moreover, GOLM1 directly interacted with B-cell lymphoma-extra large protein (a crucial anti-apoptosis regulator) and significantly prolonged its stability. Introduction of GOLM1 promoted ALK+ ALCL cells colony formation in vitro and tumor growth in a murine xenograft model. Taken together, our findings demonstrate, to our knowledge, for the first time that GOLM1 plays a critical role in suppressing apoptosis and promoting the progression of ALK+ ALCL and provide evidence that GOLM1 is a potential biomarker and therapeutic target in ALK-induced hematological malignancies.
2020-12-21 | PD-1/PD-L1 Pathway and Its Blockade in Patients with Classic Hodgkin Lymphoma and Non-Hodgkin Large-Cell Lymphomas.
Programmed cell death protein-1 (PD-1) is currently the most extensively studied inhibitory checkpoint molecule. Many malignant neoplasms express the PD-1 ligands, PD-L1, and/or PD-L2, which bind to PD-1 on T cells and induce T cell "exhaustion." By doing so, the malignant cells escape from an antitumor immune response (immune evasion). Blockade of the PD-1/PD-L1 pathway releases T cells from the inhibitory effects exerted by tumor cells and restores a T cell-mediated antitumor immune response. Here, we focus on understanding the immune biology of the PD-1/PD-L1 pathway in large-cell lymphomas, including classic Hodgkin lymphoma (CHL), diffuse large B cell lymphoma (DLBCL), and anaplastic large-cell lymphoma (ALCL), and the current status of PD-1 blockade immunotherapy in treating patients with these lymphomas. PD-1/PD-L1 pathway and PD-1 inhibitors have been widely tested in patients with a variety of lymphomas. Nivolumab and pembrolizumab have been approved by the U.S. Food and Drug Administration for treating patients with some types of relapsed or refractory (R/R) lymphomas. The highest response rate has been achieved in patients with CHL, due to a high frequency of genetic alterations of 9p24.1 and high expression of PD-1 ligands. The frequency of alterations of chromosome 9p24.1 and expression of PD-L1/PD-L1 in DLBCL (except some specific subtypes) is low; therefore, it is not recommended to treat unselected DLBCL patients with PD-1 inhibitors. Studies have shown a high frequency of PD-L1 expression in ALCL, especially in anaplastic lymphoma kinase (ALK)+ type. Several cases reports have described a dramatic and durable response to PD-1 blockade in patients with R/R ALCL, suggesting that patients with R/R ALCL may be potential candidates for PD-1 blockade immunotherapy. Understanding the immune biology of lymphoid neoplasms has helped us identify the specific lymphoma types that are vulnerable to PD-1 inhibitors, such as CHL, and specific subtypes of DLBCL. However, our knowledge of many other lymphomas, including ALCL, in this area is still very limited and the future of PD-1 inhibitors in treating those lymphomas remains unclear.
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