Featured
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Article
| Open Access
Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial
In the final report of a phase 1/2 trial evaluating allogeneic CD19-specific CAR-NK cells armored with IL-15 in patients with CD19+ hematologic malignancies, the therapy was shown to be safe and efficacious with distinct cord blood features associated with response.
- David Marin
- , Ye Li
- & Katayoun Rezvani
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Article
| Open Access
Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
Analysis of the pivotal phase 3 ZUMA-7 trial identifies tumor gene expression signatures that are uniquely predictive of anti-CD19 CAR T cell response and event-free survival in second-line treatment for patients with relapsed or refractory large B cell lymphoma.
- Frederick L. Locke
- , Simone Filosto
- & Jérôme Galon
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Article
| Open Access
Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial
Treatment of patients with relapsed or refractory multiple myeloma with a combination of the BCMA-targeting antibody–drug conjugate belatamab mafodotin with dexamethasone and pomlidomide is safe and shows promising preliminary clinical efficacy.
- Suzanne Trudel
- , Arleigh McCurdy
- & Donna Reece
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Article
| Open Access
Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial
In an ongoing phase 1/2 trial, mosunetuzumab, a CD20xCD3 bispecific antibody, plus polatuzumab vedotin, an anti-CD79B antibody–drug conjugate, had an overall response rate of 59.2%, supporting the potential of this combination for second-line treatment of patients with transplant-ineligible or CAR-T-cell-ineligible relapsed or refractory large B cell lymphoma.
- Lihua E. Budde
- , Adam J. Olszewski
- & Julio C. Chavez
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Article
| Open Access
Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial
In a large single-arm phase 2 trial, the anti-PD-1 inhibitor tislelizumab combined with the next-generation BTK inhibitor zanubrutinib had an overall response rate of 58.3% and was well tolerated in patients with Richter’s transformation.
- Othman Al-Sawaf
- , Rudy Ligtvoet
- & Barbara Eichhorst
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Article
| Open Access
The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial
The bispecific molecule tebotelimab, which blocks both PD-1 and LAG-3, is well tolerated as a monotherapy and in combination with the anti-HER-2 antibody margetuximab and elicits encouraging clinical activity in solid tumors with high LAG-3 levels and/or expression of IFN-γ-regulated genes.
- Jason J. Luke
- , Manish R. Patel
- & Paul A. Moore
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Article
| Open Access
Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial
In the first-in-human trial of elranatamab, patients with refractory or relapsed multiple myeloma who received the bispecific antibody against BCMA and CD3 experienced no dose-limiting toxicities during dose escalation, and the agent showed promising clinical efficacy.
- Nizar J. Bahlis
- , Caitlin L. Costello
- & Alexander M. Lesokhin
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Article
| Open Access
Axicabtagene ciloleucel as second-line therapy in large B cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial
In the ALYCANTE trial, second-line treatment with axicabtagene ciloleucel, a CD19-targeting CAR T-cell therapy, resulted in high response rates and durable remissions in patients with high-risk large B-cell lymphoma deemed ineligible for autologous stem cell transplantation.
- Roch Houot
- , Emmanuel Bachy
- & François Lemonnier
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Research Briefing |
Decoding antigen escape and multiple myeloma relapse after targeted immunotherapy
By integrating genomic and in vitro functional analysis, this study uncovers tumor-intrinsic mechanisms of resistance to immunotherapies that target B cell maturation antigen (BCMA) or the orphan G-protein-coupled-receptor GPRC5D in multiple myeloma (MM), highlighting a pivotal role for mutations in the genes encoding BCMA and GPRC5D in driving clinical relapse. These insights provide crucial guidance for the selection of therapeutic strategies and the development of next-generation targeted immunotherapies in MM.
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Article
| Open Access
Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma
Tumor-intrinsic resistance mechanisms, including mutational events and immunoselection of mutant clones, were identified in 30 patients with multiple myeloma who experienced relapse after treatment with anti-BCMA CAR T cells and/or anti-BCMA bispecific T cell engagers (TCEs) or anti-GPRC5D TCE therapy.
- Holly Lee
- , Sungwoo Ahn
- & Nizar J. Bahlis
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Article
| Open Access
Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results
In a pivotal phase 2 trial, elranatamab, a bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, had a confirmed objective response rate of 61% in patients with relapsed or refractory multiple myeloma who had not previously received BCMA-directed therapy.
- Alexander M. Lesokhin
- , Michael H. Tomasson
- & Mohamad Mohty
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Article
| Open Access
Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia
In children with relapsed or refractory B cell acute lymphoblastic leukemia and in complete remission after CD19 CAR-T cell therapy, long-lived CAR-T cells express a persistence gene signature that is also present in persistent CD19 CAR-T cells from adults with chronic lymphocytic leukemia.
- Nathaniel D. Anderson
- , Jack Birch
- & Sara Ghorashian
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Article |
CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results
Prophylactic subcutaneous administration of anakinra, an IL-1 receptor inhibitor, reduced severe immune effector cell-associated neurotoxicity syndrome incidence in patients with relapsed or refractory large B-cell and mantle cell lymphoma treated with anti-CD19 chimeric antigen receptor (CAR) T cells.
- Jae H. Park
- , Karthik Nath
- & Michel Sadelain
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Research Highlight |
Base-edited CAR T cells for pediatric leukemia
Researchers used base editing — a type of CRISPR technology — to create a cell-therapy product with potent activity in children with relapsed T-ALL.
- Karen O’Leary
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Article
| Open Access
Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial
The phase 3 GENESIS trial reports the superiority of the novel CXCR4 inhibitor motixafortide with G-CSF in mobilizing hematopoietic progenitor cells for autologous stem cell transplantation in multiple myeloma.
- Zachary D. Crees
- , Michael P. Rettig
- & John F. DiPersio
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Article
| Open Access
Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma
New experimental models provide much-needed tools for understanding how genetically diverse multiple myeloma progresses and evolves in response to therapy.
- Marta Larrayoz
- , Maria J. Garcia-Barchino
- & Jose A. Martinez-Climent
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Research Briefing |
Population screening for smoldering multiple myeloma reveals high prevalence
Smoldering multiple myeloma is an asymptomatic precursor condition to multiple myeloma, a cancer in the bone marrow. We conducted a population-based screening study — in which 51% of the population over 40 years of age in Iceland participated — and found that the prevalence of smoldering multiple myeloma was 0.5% in the study population.
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Article |
Prevalence of smoldering multiple myeloma based on nationwide screening
A nationwide screening program from the iStopMM study performed in Iceland to detect smoldering multiple myeloma reported a prevalence of 0.5% in individuals over 40 years of age, with increasing risks with age and in males.
- Sigrún Thorsteinsdóttir
- , Gauti K. Gíslason
- & Sigurður Y. Kristinsson
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Article |
Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results
In an interim phase 1 trial analysis, escalating doses of off-the-shelf allogeneic anti-BCMA CAR T cells, in combination with an anti-CD52 antibody-containing lymphodepletion regimen, were feasible to administer and exhibited an encouraging safety profile in patients with relapsed or refractory multiple myeloma
- Sham Mailankody
- , Jeffrey V. Matous
- & Shaji K. Kumar
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Article |
Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome
Integrative genomic and transcriptomic analyses reveal molecular events defining Richter transformation from CLL, and highlight the potential of cell-free DNA for early detection.
- Erin M. Parry
- , Ignaty Leshchiner
- & Catherine J. Wu
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Correspondence |
Unresolved questions in the second-line use of CAR-T cells for diffuse large B cell lymphoma
- Edward R. Scheffer Cliff
- , Reid W. Merryman
- & Caron A. Jacobson
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Article
| Open Access
A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma
Analysis of outcomes of over 800 patients with relapsed/refractory diffuse large B cell lymphoma, treated with commercially available CAR T cell therapy, supports higher efficacy and also a higher toxicity of axicabtagene ciloleucel compared to tisagenlecleucel as the third or more treatment line for this type of tumor.
- Emmanuel Bachy
- , Steven Le Gouill
- & Franck Morschhauser
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News & Views |
CAR Treg cells: prime suspects in therapeutic resistance
Using comprehensive single-cell profiling, two studies reveal the molecular phenotypes of CAR T cells associated with durable response in patients with lymphoma, and highlight the role of CAR regulatory T cells in mediating resistance.
- Neeraj Saini
- & Sattva S. Neelapu
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Article |
Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy
Single-cell proteomic profiling of circulating CAR T cells in patients treated with CD19-CAR shows that CD4+Helios+ CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity.
- Zinaida Good
- , Jay Y. Spiegel
- & Crystal L. Mackall
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Research Briefing |
The clonal evolution of Richter transformation cells uncovers therapeutic vulnerabilities
The commonly indolent chronic lymphocytic leukemia may evolve into Richter transformation (RT), a very aggressive large B cell lymphoma. We identified early seeding of RT cells decades before its final expansion, mapped the underlying (epi)genomic alterations driving this process, and validated in vitro potential actionable therapeutic pathways.
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Article
| Open Access
Detection of early seeding of Richter transformation in chronic lymphocytic leukemia
Single-cell genomic and transcriptomic analyses of longitudinal samples of patients with Richter syndrome reveal the presence and dynamics of clones driving transformation from chronic lymphocytic leukemia years before clinical manifestation
- Ferran Nadeu
- , Romina Royo
- & Elías Campo
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Article
| Open Access
Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects
An analysis of blood samples from longitudinal cohorts reveals insights on the dynamics of clonal hematopoiesis of indeterminate potential and proposes a model that could be used for individualized clone monitoring over time.
- Neil A. Robertson
- , Eric Latorre-Crespo
- & Tamir Chandra
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Article
| Open Access
In utero origin of myelofibrosis presenting in adult monozygotic twins
Lineage tracing analyses of cells from two monozygotic twins presenting with myelofibrosis in adulthood provide evidence of in utero transplacental transmission of the tumorigenic clone.
- Nikolaos Sousos
- , Máire Ní Leathlobhair
- & Adam J. Mead
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Article |
A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia
A novel gene expression classifier of AML heterogeneity captures patient-specific variation in leukemia cell composition and predicts clinical responses to treatment.
- Andy G. X. Zeng
- , Suraj Bansal
- & John E. Dick
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Review Article |
Engineered cellular immunotherapies in cancer and beyond
Oncology is trailblazing the field of engineered cellular therapeutics. This Review discusses the goals of cellular immunotherapy in cancer, key challenges facing the field and strategies to overcome them—paving the way for treatment of other diseases.
- Amanda V. Finck
- , Tatiana Blanchard
- & Carl H. June
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Article
| Open Access
Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial
In a phase 2 trial, first-line treatment with axicabtagene ciloleucel, an autologous CD19-targeting CAR T-cell therapy, exhibited a high complete response rate and a manageable safety profile in adults with high-risk large B-cell lymphoma.
- Sattva S. Neelapu
- , Michael Dickinson
- & Julio C. Chavez
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Research Briefing |
A distinct hematopoietic differentiation state characterizes aggressive infant leukemia
The developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) was identified by comparison of bulk and single-cell leukemia transcriptomes with those of a human fetal bone marrow reference. Unlike standard-risk childhood B-ALL, this aggressive leukemia was characterized by early lymphocyte precursor (ELP) differentiation. Moreover, in contrast to healthy ELPs, KMT2A-rearranged infant B-ALL cells had both myeloid and lymphoid features and expressed potentially targetable novel combinations of antigens.
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Article |
Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy
In an analysis of adult patients with hematologic malignancies who received anti-CD19 chimeric antigen receptor T cell therapy, baseline gut microbiome composition was correlated with clinical response and treatment with broad-spectrum antibiotics in the four weeks prior to infusion was associated with worse survival and increased neurotoxicity.
- Melody Smith
- , Anqi Dai
- & Marco Ruella
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Article
| Open Access
Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia
Single-cell transcriptomic and phylogenetic analyses reveal new insights into the developmental origin and potential therapeutic targets for a particularly aggressive form of B-cell acute lymphoblastic leukemia in infants.
- Eleonora Khabirova
- , Laura Jardine
- & Sam Behjati
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Article |
HLA-independent T cell receptors for targeting tumors with low antigen density
HLA-independent T cell receptors, in which the heavy and light chains of a chimeric antigen receptor are incorporated into the endogenous T cell receptor locus, are more effective than CD28-based chimeric antigen receptors at targeting tumors with low antigen expression.
- Jorge Mansilla-Soto
- , Justin Eyquem
- & Michel Sadelain
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Article |
Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial
In a prespecified interim analysis of a pivotal phase 2 trial, tisagenlecleucel, an autologous CD19-targeting CAR-T cell therapy, produced a high rate of complete responses with a manageable safety profile in adults with relapsed or refractory follicular lymphoma
- Nathan Hale Fowler
- , Michael Dickinson
- & Catherine Thieblemont
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Brief Communication |
Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy
A progressive movement disorder in a patient with multiple myeloma treated with anti-BCMA CAR-T cells that might have been related to on-target activity in the brain supports prospective neurologic monitoring after BCMA-targeting therapies.
- Oliver Van Oekelen
- , Adolfo Aleman
- & Samir Parekh
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Article
| Open Access
Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial
In a phase 1 trial of patients with advanced systemic mastocytosis, avapritinib, a selective KIT inhibitor, was generally well tolerated, elicited durable clinical responses and led to reductions in mast cell disease burden.
- Daniel J. DeAngelo
- , Deepti H. Radia
- & Jason Gotlib
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Article
| Open Access
Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial
In a prespecified interim analysis of a pivotal phase 2 trial, avapritinib, a selective KIT inhibitor, elicited robust clinical and molecular responses, was generally well tolerated and led to improved patient-reported outcomes in patients with advanced systemic mastocytosis.
- Jason Gotlib
- , Andreas Reiter
- & Daniel J. DeAngelo
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Article |
Distinction of lymphoid and myeloid clonal hematopoiesis
Genomic analyses in the UK Biobank show that clonal hematopoiesis of indeterminate potential in the lymphoid lineage is associated with a higher risk of developing lymphoid malignancies
- Abhishek Niroula
- , Aswin Sekar
- & Benjamin L. Ebert
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Article
| Open Access
CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial
Bicistronic CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in pediatric and young adult patients with B cell acute lymphoblastic leukemia, with relapses associated with limited CAR T cell persistence.
- Shaun Cordoba
- , Shimobi Onuoha
- & Persis J. Amrolia
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Article
| Open Access
CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial
Bispecific CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in patients with large B cell lymphoma and B cell acute lymphoblastic leukemia, with relapses associated with loss of CD19 but not CD22.
- Jay Y. Spiegel
- , Shabnum Patel
- & David B. Miklos
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Article |
Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis
Analysis of single-nucleotide variants and copy number alterations gives a more complete picture of clonal hematopoiesis and its impact on hematological malignancy and cardiovascular disease.
- Ryunosuke Saiki
- , Yukihide Momozawa
- & Seishi Ogawa
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Article |
CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer
A study of hospitalized patients infected with SARS-CoV-2 and who have liquid or solid cancer suggests that hematologic malignancy is an independent risk factor for mortality and that CD8+ T cells might limit infection in this setting irrespective of humoral immunity.
- Erin M. Bange
- , Nicholas A. Han
- & Alexander C. Huang
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News & Views |
Context matters in CAR T cell tonic signaling
Unexpected clinical results unearth a new facet in CAR design that could facilitate the development of more-effective CAR T cell therapies.
- Kristen Hege
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Article |
Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells
A bedside-to-bench analysis identifies single-chain variable fragment linker length as an important component of chimeric antigen receptor (CAR) structure and suggests that, in contrast to CD28-based CAR T cells, tonic signaling can be beneficial for 4-1BB-based CAR T cell function.
- Nathan Singh
- , Noelle V. Frey
- & Marco Ruella
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News & Views |
Single-cell RNA sequencing: one step closer to the clinic
Single-cell RNA-sequencing can help in the prediction of drug resistance in patients with multiple myeloma.
- Romanos Sklavenitis-Pistofidis
- , Gad Getz
- & Irene Ghobrial
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Brief Communication |
Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma
Biallelic loss of BCMA caused a patient with multiple myeloma to relapse after anti-BCMA CAR T cell treatment. Baseline heterozygous BCMA deletions might be a risk factor for this form of resistance.
- Matteo C. Da Vià
- , Oliver Dietrich
- & Leo Rasche
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Letter |
Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial
A new bispecific CAR T cell product targeting the CD20 and CD19 antigens demonstrates an excellent safety profile and high clinical efficacy in patients with B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.
- Nirav N. Shah
- , Bryon D. Johnson
- & Parameswaran Hari
T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy