Publications by authors named "Wayne Tam"

100 Publications

Targeting the epichaperome as an effective precision medicine approach in a novel PML-SYK fusion acute myeloid leukemia.

NPJ Precis Oncol 2021 May 26;5(1):44. Epub 2021 May 26.

Department of Medicine, Division of Hematology/Oncology, Weill Cornell Medicine, New York, NY, USA.

The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.
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http://dx.doi.org/10.1038/s41698-021-00183-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155064PMC
May 2021

Myeloid/lymphoid neoplasms with FLT3 rearrangement.

Mod Pathol 2021 May 14. Epub 2021 May 14.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Myeloid/lymphoid neoplasms (M/LN) with 13q12/FLT3 rearrangement have been suggested as candidates for possible inclusion in the World Health Organization classification group of M/LN with eosinophilia (M/LN-eo). We report 12 patients with confirmed FLT3 rearrangement, six with t(12;13)/ETV6-FLT3; one with ins(13;22)/BCR-FLT3; and five with an unconfirmed partner gene located on chromosome bands 2p16, 3q27, 5q15, 5q35, and 7q36. Disease presentations were heterogeneous, including lymphoblastic leukemia/lymphoma, myeloid sarcoma, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. However, some common features were observed, such as extramedullary involvement (n = 7, 58%), associated eosinophilia in blood, bone marrow, or tissue (n = 8, 67%), multilineage involvement, either as biphasic myeloid/lymphoid neoplasms (n = 2) or mixed phenotype acute leukemia (n = 2). Mutations were detected in 4/8 (50%) patients by next-generation sequencing. None (0/10) had FLT3 or KIT mutations. Eleven patients received disease-based chemotherapy or hypomethylating agents, three received FLT3 inhibitors, and five patients proceeded to hematopoietic stem cell transplant. Together with a review of 16 cases published in the literature, it is apparent that M/LNs with FLT3 rearrangement show disease features reminiscent of members in the category of M/LN-eo with PDGFRA, PDGFRB, FGFR1, and PCM1/JAK2 rearrangement, characterized by a specific gene rearrangement, frequent eosinophilia, multi-lineage involvement and therapeutic benefit from kinase inhibitors.
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http://dx.doi.org/10.1038/s41379-021-00817-7DOI Listing
May 2021

In Vivo and Ex Vivo Patient-Derived Tumor Xenograft Models of Lymphoma for Drug Discovery.

Curr Protoc 2021 Apr;1(4):e96

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.

In the hemato-oncology field, remarkable scientific progress has been achieved, primarily propelled by the discovery of new technologies, improvement in genomics, and novel in vitro and in vivo models. The establishment of multiple cell line collections and the development of instrumental mouse models enhanced our ability to discover effective therapeutics. However, cancer models that faithfully mimic individual cancers are still imperfect. Patient-derived tumor xenografts (PDTXs) have emerged as a powerful tool for identifying the mechanisms which drive tumorigenesis and for testing potential therapeutic interventions. The recognition that PDTXs can maintain many of the donor samples' properties enabled the development of new strategies for discovering and implementing therapies. Described in this article are protocols for the generation and characterization of lymphoma PDTXs that may be used as the basis of shared procedures. Universal protocols will foster the model utilization, enable the integration of public and private repositories, and aid in the development of shared platforms. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Tissue handling and cryopreservation of primary and PDTX samples Basic Protocol 2: Performing tumor implant in immunocompromised mice PDTX models Alternate Protocol 1: Intra-medullary femoral injection Alternate Protocol 2: Intravenous injection Alternate Protocol 3: Intraperitoneal injection Support Protocol 1: Phenotypical characterization of PDTXs by flow cytometry Support Protocol 2: Biological and molecular characterization of PDTX tumors by PCR detection of IGK, IGH, and TCR rearrangements Basic Protocol 3: Harvesting PDTX-derived tumor cells for ex vivo experiments Basic Protocol 4: In vivo testing of multiple compounds in a PDTX mouse model.
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http://dx.doi.org/10.1002/cpz1.96DOI Listing
April 2021

The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.

Nat Cancer 2020 22;1:653-664. Epub 2020 Jun 22.

Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of cooperates with in lymphoma development; loss or inhibition of impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support -adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as and Together, our findings reveal that amplification of in cooperation with is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.
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http://dx.doi.org/10.1038/s43018-020-0080-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872152PMC
June 2020

Clinical, immunophenotypic and genomic findings of NK lymphoblastic leukemia: a study from the Bone Marrow Pathology Group.

Mod Pathol 2021 Jul 1;34(7):1358-1366. Epub 2021 Feb 1.

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Natural killer (NK) cells are lymphocytes of the native immune system that play a pivotal role in host defense and immune surveillance. While the conceptual view of NK-neoplasms is evolving, little is known about the rare NK lymphoblastic leukemia (NK-LL), which remains as a provisional entity in the 2016 WHO Classification. The goal of this study is to characterize NK-LL cases and compare with other CD56 co-expressing acute leukemias. We identified 105 cases, diagnosed as NK-LL (6), CD56+ acute undifferentiated leukemia (AUL) (6), CD56+ T-lymphoblastic leukemia (T-LL) (51), and CD56+ acute myeloid leukemia (AML) (42). Compared to AUL patients, NK-LL patients were significantly younger (p = 0.021) and presented with higher white blood cell (WBC) (p = 0.037) and platelet counts (p = 0.041). Flow cytometry showed more frequent expression of cytoplasmic CD3 (cCD3, p = 0.064) and CD33, (p = 0.065), while HLA-DR was significantly absent from NK-LL (p = 0.035) compared to AUL. Compared to T-ALL, NK-LL cases showed less frequent cCD3 (p = 0.002), CD4 (p = 0.051), and CD10 expression (p = 0.06). The frequency of abnormal karyotypes was similar between NK-LL, AUL, and T-ALL. The mutational profile differed in four leukemia groups, with a significance enrichment of NOTCH1 (p = 0.002), ETV6 (p = 0.002) and JAK3 (p = 0.02) mutations in NK-LL as compared to AML. As compared to T-ALL, NK-LL cases showed a higher number of total mutations (p = 0.04) and significantly more frequent ETV6 mutations (p = 0.004). Clinical outcome data showed differences in overall survival between all four groups (p = 0.0175), but no difference in event free survival (p = 0.246). In this largest study to date, we find that that NK-LL shows clinical presentation, immunophenotypic and molecular characteristics distinct from AUL, T-ALL, and AML. Our findings suggest NK-LL is a distinct acute leukemia entity and should be considered in the clinical diagnosis of acute leukemias of ambiguous lineage.
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http://dx.doi.org/10.1038/s41379-021-00739-4DOI Listing
July 2021

Profiling of immune dysfunction in COVID-19 patients allows early prediction of disease progression.

Life Sci Alliance 2021 02 24;4(2). Epub 2020 Dec 24.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA

With a rising incidence of COVID-19-associated morbidity and mortality worldwide, it is critical to elucidate the innate and adaptive immune responses that drive disease severity. We performed longitudinal immune profiling of peripheral blood mononuclear cells from 45 patients and healthy donors. We observed a dynamic immune landscape of innate and adaptive immune cells in disease progression and absolute changes of lymphocyte and myeloid cells in severe versus mild cases or healthy controls. Intubation and death were coupled with selected natural killer cell KIR receptor usage and IgM+ B cells and associated with profound CD4 and CD8 T-cell exhaustion. Pseudo-temporal reconstruction of the hierarchy of disease progression revealed dynamic time changes in the global population recapitulating individual patients and the development of an eight-marker classifier of disease severity. Estimating the effect of clinical progression on the immune response and early assessment of disease progression risks may allow implementation of tailored therapies.
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http://dx.doi.org/10.26508/lsa.202000955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768198PMC
February 2021

GATA1 downregulation in prefibrotic and fibrotic stages of primary myelofibrosis and in the myelofibrotic progression of other myeloproliferative neoplasms.

Leuk Res 2021 01 15;100:106495. Epub 2020 Dec 15.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, NY, USA. Electronic address:

GATA binding protein 1 (GATA1) is a transcription factor essential for effective erythropoiesis and megakaryopoiesis. Two isoforms of GATA1 exist, derived from alternative splicing. "GATA1" is the full length and functionally active protein; "GATA1s" is the truncated isoform devoid of the activation domain, the function of which has not been fully elucidated. Reduced megakaryocytic expression of GATA1 has been linked to impaired hematopoiesis and bone marrow fibrosis in murine models and in vivo in patients affected by primary myelofibrosis (PMF). However, data is limited regarding GATA1 expression in other myeloproliferative neoplasms (MPN) such as pre-fibrotic PMF (pre-PMF), polycythemia vera (PV) and essential thrombocythemia (ET) and in their respective fibrotic progression. To assess whether an immunohistologic approach can be of help in separating different MPN, we have performed a comprehensive immunohistochemical evaluation of GATA1 expression in megakaryocytes within a cohort of BCR-ABL1 negative MPN. In order to highlight any potential differences between the two isoforms we tested two clones, one staining the sum of GATA1 and GATA1s ("clone 1"), the other staining GATA1 full length alone ("clone 2"). At the chronic phase, a significant reduction preferentially of GATA1 full length was seen in pre-fibrotic PMF, particularly compared to ET and PV; no significant differences were observed between PV and ET. The fibrotic progression of both PV and ET was associated with a significant reduction in GATA1, particularly affecting the GATA1 full length isoform. The fibrotic progression of pre-PMF to PMF was associated with a significant reduction of the overall GATA1 protein and a trend in reduction of GATA1s. Our findings support a role of GATA1 in the pathogenesis of BCR-ABL1 negative MPN, particularly in their fibrotic progression and suggest that the immunohistochemical evaluation of GATA1 may be of use in the differential diagnosis of these neoplasms.
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http://dx.doi.org/10.1016/j.leukres.2020.106495DOI Listing
January 2021

Clinical Laboratory Validation and Implementation of Quantitative, Real-Time PCR-based Detection of NPM1 Type A Mutation.

Clin Lab 2020 Dec;66(12)

Background: NPM1 mutations have prognostic significance in acute myeloid leukemia (AML) and monitoring mutant NPM1 levels during and after therapy has been described to predict relapse and survival. Despite the published significance of this molecular biomarker, routine monitoring for mutant NPM1 levels has not been widely adopted in academic clinical laboratories. Therefore, our objective was to validate a quantitative, reverse transcription-PCR assay for the detection of NPM1 Type A mutant transcripts for use in the clinical laboratory.

Methods: A quantitative, real-time, reverse-transcription PCR-based method for the detection of NPM1 Type A mutant transcripts was validated for use in routine clinical practice. Results from this assay were compared to results from orthogonal methods, including next generation sequencing and digital droplet PCR.

Results: This real-time, reverse-transcription PCR-based method is sensitive (limit of detection: 0.0150% NCN and reproducible (≤ 0.5 log10-fold variation). We summarize the rigorous validation results and share observations that will help other clinical laboratories that may wish to implement this testing. We show the superior sensitivity of this assay compared to other assays (e.g., 45 gene Myeloid Next Generation Sequencing panel) and present a representative case which highlights the assay's utility in the pathologic assessment of cases with borderline morphologic or flow cytometric findings.

Conclusions: As molecular testing for residual disease in AML continues to expand, this sensitive and reproducible method will be an appropriate testing option for the detection of NPM1 Type A mutant transcripts in clinical practice.
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http://dx.doi.org/10.7754/Clin.Lab.2020.200104DOI Listing
December 2020

T-cell neoplasms in the spleen.

Semin Diagn Pathol 2021 Mar 9;38(2):135-143. Epub 2020 Oct 9.

Weill Cornell Medicine, Department of Pathology and Laboratory Medicine, 525 E 68th Street, Starr Pavilion 715, New York, NY 10065, United States.

Hematopoietic neoplasms involving the spleen are uncommon, but T cell neoplasms involving the spleen are extremely rare. The rarity of splenic involvement by T cell neoplasms has resulted in a limited body of literature describing their splenic characteristics. As a result, our purpose in this review article is to provide and summarize some of the characteristics seen by different T cell neoplasms that may involve the spleen.
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http://dx.doi.org/10.1053/j.semdp.2020.10.001DOI Listing
March 2021

Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.

Mol Cancer Res 2021 02 5;19(2):249-260. Epub 2020 Nov 5.

Duke University Medical Center, Division of Hematopathology and Department of Pathology, Durham, North Carolina.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with / double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether mutation synergizes with MYC abnormalities ( rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2-targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-/-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of // status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. IMPLICATIONS: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092941PMC
February 2021

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53.

J Hematol Oncol 2020 11 4;13(1):148. Epub 2020 Nov 4.

Division of Hematopathology, Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1 observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.
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http://dx.doi.org/10.1186/s13045-020-00982-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641823PMC
November 2020

Myeloproliferative and lymphoproliferative malignancies occurring in the same patient: a nationwide discovery cohort.

Haematologica 2020 10 1;105(10):2432-2439. Epub 2020 Oct 1.

Aarhus University Hospital and Aarhus University, Aarhus, Denmark.

Myeloid and lymphoid malignancies are postulated to have distinct pathogenetic mechanisms. The recent observation that patients with a myeloproliferative neoplasm have an increased risk of developing lymphoproliferative malignancy has challenged this assumption. We collected a nationwide cohort of patients with both malignancies. Patients diagnosed in 1990-2015 were identified through the national Danish Pathology Registry. We identified 599 patients with myeloproliferative neoplasm and a concomitant or subsequent diagnosis of lymphoma. Histopathological review of the diagnostic samples from each patient led to a final cohort of 97 individuals with confirmed dual diagnoses of myeloproliferative neoplasm and lymphoma. The age range at diagnosis was 19-94 years (median: 71 years). To avoid the inclusion of cases of therapy-induced myeloproliferative neoplasm occurring in patients previously treated for lymphoma, only patients with myeloproliferative neoplasm diagnosed unequivocally before the development of lymphoma were included. The average time interval between the diagnoses of the two malignancies was 1.5 years. In the majority of patients (90%) both diagnoses were established within 5 years from each other. Among the lymphoma entities, the frequency of peripheral T-cell lymphomas was markedly increased. Interestingly, all but one of the T-cell lymphomas were of angioimmunoblastic type. These findings suggest that myeloproliferative neoplasm and lymphoproliferative malignancy developing in the same patient may have common pathogenetic events, possibly already at progenitor level. We believe that the molecular characterization of the newly developed biorepository will help to highlight the mechanisms driving the genesis and clonal evolution of these hematopoietic malignancies.
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http://dx.doi.org/10.3324/haematol.2019.225839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556673PMC
October 2020

Myeloid, mast cell, histiocytic and dendritic cell neoplasms and proliferations involving the spleen.

Semin Diagn Pathol 2021 Mar 31;38(2):144-153. Epub 2020 Jul 31.

Weill Cornell Medicine, Department of Pathology and Laboratory Medicine, 525 E 68th Street, Starr Pavilion 715, New York, NY 10065, United States.

Splenic involvement and consequent splenomegaly are usually seen as part of systemic involvement by myeloid neoplasms as well as mast cell and histiocytic neoplasms. Primary splenic involvement by these neoplasms is rare. Splenectomy is usually not performed for establishing a diagnosis of these entities. However, in rare instances, the pathologist may need to evaluate the spleen secondary to splenic rupture or palliative splenectomy to alleviate symptoms related to splenomegaly. This review article describes the clinicopathologic features of a broad group of myeloid, mastocytic, and histiocytic proliferative and neoplastic disorders.
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http://dx.doi.org/10.1053/j.semdp.2020.07.003DOI Listing
March 2021

Longitudinal immune profiling of mild and severe COVID-19 reveals innate and adaptive immune dysfunction and provides an early prediction tool for clinical progression.

medRxiv 2020 Sep 9. Epub 2020 Sep 9.

With a rising incidence of COVID-19-associated morbidity and mortality worldwide, it is critical to elucidate the innate and adaptive immune responses that drive disease severity. We performed longitudinal immune profiling of peripheral blood mononuclear cells from 45 patients and healthy donors. We observed a dynamic immune landscape of innate and adaptive immune cells in disease progression and absolute changes of lymphocyte and myeloid cells in severe versus mild cases or healthy controls. Intubation and death were coupled with selected natural killer cell KIR receptor usage and IgM+ B cells and associated with profound CD4 and CD8 T cell exhaustion. Pseudo-temporal reconstruction of the hierarchy of disease progression revealed dynamic time changes in the global population recapitulating individual patients and the development of an eight-marker classifier of disease severity. Estimating the effect of clinical progression on the immune response and early assessment of disease progression risks may allow implementation of tailored therapies.
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http://dx.doi.org/10.1101/2020.09.08.20189092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491529PMC
September 2020

Mutation landscape, clonal evolution pattern, and potential pathogenic pathways in B-lymphoblastic transformation of follicular lymphoma.

Leukemia 2021 04 12;35(4):1203-1208. Epub 2020 Aug 12.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.

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http://dx.doi.org/10.1038/s41375-020-01014-2DOI Listing
April 2021

Selective dysregulation of ROCK2 activity promotes aberrant transcriptional networks in ABC diffuse large B-cell lymphoma.

Sci Rep 2020 08 4;10(1):13094. Epub 2020 Aug 4.

Autoimmunity and Inflammation Program, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA.

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive subtype of lymphoma usually associated with inferior outcomes. ABC-DLBCL exhibits plasmablastic features and is characterized by aberrancies in the molecular networks controlled by IRF4. The signaling pathways that are dysregulated in ABC-DLBCL are, however, not fully understood. ROCK2 is a serine-threonine kinase whose role in lymphomagenesis is unknown. Here we show that ROCK2 activity is constitutively dysregulated in ABC-DLBCL but not in GCB-DLBCL and BL. We furthermore show that ROCK2 phosphorylates IRF4 and that the ROCK2-mediated phosphorylation of IRF4 modulates its ability to regulate a subset of target genes. In addition to its effects on IRF4, ROCK2 also controls the expression of MYC in ABC-DLBCL by regulating MYC protein levels. ROCK inhibition furthermore selectively decreases the proliferation and survival of ABC-DLBCL in vitro and inhibits ABC-DLBCL growth in xenograft models. Thus, dysregulated ROCK2 activity contributes to the aberrant molecular program of ABC-DLBCL via its dual ability to modulate both IRF4- and MYC-controlled gene networks and ROCK inhibition could represent an attractive therapeutic target for the treatment of ABC-DLBCL.
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http://dx.doi.org/10.1038/s41598-020-69884-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403583PMC
August 2020

A refined cell-of-origin classifier with targeted NGS and artificial intelligence shows robust predictive value in DLBCL.

Blood Adv 2020 07;4(14):3391-3404

Division of Hematopathology and Department of Pathology, Duke University Medical Center, Durham, NC.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of B-cell lymphoma. Cell-of-origin (COO) classification of DLBCL is required in routine practice by the World Health Organization classification for biological and therapeutic insights. Genetic subtypes uncovered recently are based on distinct genetic alterations in DLBCL, which are different from the COO subtypes defined by gene expression signatures of normal B cells retained in DLBCL. We hypothesize that classifiers incorporating both genome-wide gene-expression and pathogenetic variables can improve the therapeutic significance of DLBCL classification. To develop such refined classifiers, we performed targeted RNA sequencing (RNA-Seq) with a commercially available next-generation sequencing (NGS) platform in a large cohort of 418 DLBCLs. Genetic and transcriptional data obtained by RNA-Seq in a single run were explored by state-of-the-art artificial intelligence (AI) to develop a NGS-COO classifier for COO assignment and NGS survival models for clinical outcome prediction. The NGS-COO model built through applying AI in the training set was robust, showing high concordance with COO classification by either Affymetrix GeneChip microarray or the NanoString Lymph2Cx assay in 2 validation sets. Although the NGS-COO model was not trained for clinical outcome, the activated B-cell-like compared with the germinal-center B-cell-like subtype had significantly poorer survival. The NGS survival models stratified 30% high-risk patients in the validation set with poor survival as in the training set. These results demonstrate that targeted RNA-Seq coupled with AI deep learning techniques provides reproducible, efficient, and affordable assays for clinical application. The clinical grade assays and NGS models integrating both genetic and transcriptional factors developed in this study may eventually support precision medicine in DLBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020001949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391158PMC
July 2020

Chronic myeloid neoplasms harboring concomitant mutations in myeloproliferative neoplasm driver genes (JAK2/MPL/CALR) and SF3B1.

Mod Pathol 2021 01 21;34(1):20-31. Epub 2020 Jul 21.

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

JAK2, CALR, and MPL are myeloproliferative neoplasm (MPN)-driver mutations, whereas SF3B1 is strongly associated with ring sideroblasts (RS) in myelodysplastic syndrome (MDS). Concomitant mutations of SF3B1 and MPN-driver mutations out of the context of MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) are not well-studied. From the cases (<5% blasts) tested by NGS panels interrogating at least 42 myeloid neoplasm-related genes, we identified 18 MDS/MPN-RS-T, 42 MPN, 10 MDS, and 6 MDS/MPN-U cases with an SF3B1 and an MPN-driver mutation. Using a 10% VAF difference to define "SF3B1-dominant," "MPN-mutation dominant," and "no dominance," the majority of MDS/MPN-RS-T clustered in "SF3B1-dominant" and "no dominance" regions. Aside from parameters as thrombocytosis and ≥15% RS required for RS-T, MDS also differed in frequent neutropenia, multilineage dysplasia, and notably more cases with <10% VAF of MPN-driver mutations (60%, p = 0.0346); MPN differed in more frequent splenomegaly, myelofibrosis, and higher VAF of "MPN-driver mutations." "Gray zone" cases with features overlapping MDS/MPN-RS-T were observed in over one-thirds of non-RS-T cases. This study shows that concomitant SF3B1 and MPN-driver mutations can be observed in MDS, MPN, and MDS/MPN-U, each showing overlapping but also distinctively different clinicopathological features. Clonal hierarchy, cytogenetic abnormalities, and additional somatic mutations may in part contribute to different disease phenotypes, which may help in the classification of "gray zone" cases.
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http://dx.doi.org/10.1038/s41379-020-0624-yDOI Listing
January 2021

A Novel JAK1 Mutant Breast Implant-Associated Anaplastic Large Cell Lymphoma Patient-Derived Xenograft Fostering Pre-Clinical Discoveries.

Cancers (Basel) 2020 Jun 17;12(6). Epub 2020 Jun 17.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.

Breast implant-associated lymphoma (BIA-ALCL) has recently been recognized as an independent peripheral T-cell lymphoma (PTCL) entity. In this study, we generated the first BIA-ALCL patient-derived tumor xenograft (PDTX) model (IL89) and a matching continuous cell line (IL89_CL#3488) to discover potential vulnerabilities and druggable targets. We characterized IL89 and IL89_CL#3488, both phenotypically and genotypically, and demonstrated that they closely resemble the matching human primary lymphoma. The tumor content underwent significant enrichment along passages, as confirmed by the increased variant allele frequency (VAF) of mutations. Known aberrations (JAK1 and KMT2C) were identified, together with novel hits, including PDGFB, PDGFRA, and SETBP1. A deep sequencing approach allowed the detection of mutations below the Whole Exome Sequencing (WES) sensitivity threshold, including JAK1G1097D, in the primary sample. RNA sequencing confirmed the expression of a signature of differentially expressed genes in BIA-ALCL. Next, we tested IL89's sensitivity to the JAK inhibitor ruxolitinib and observed a potent anti-tumor effect, both in vitro and in vivo. We also implemented a high-throughput drug screening approach to identify compounds associated with increased responses in the presence of ruxolitinib. In conclusion, these new IL89 BIA-ALCL models closely recapitulate the primary correspondent lymphoma and represent an informative platform for dissecting the molecular features of BIA-ALCL and performing pre-clinical drug discovery studies, fostering the development of new precision medicine approaches.
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http://dx.doi.org/10.3390/cancers12061603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352499PMC
June 2020

Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.

J Immunother Cancer 2019 10 22;7(1):272. Epub 2019 Oct 22.

Hematopathology Division, Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.

Background: Diffuse large B-cell lymphoma (DLBCL) harbors somatic hypermutation (SHM) in the immunoglobulin heavy chain and light chain variable region genes, IGHV and IGK/LV. Recent studies have revealed that IGV SHM creates neoantigens that activate T-cell responses against B-cell lymphoma.

Methods: To determine the clinical relevance of IGV SHM in DLBCL treated with standard immunochemotherapy, we performed next-generation sequencing of the immunoglobulin variable regions and complementarity determining region 3 (CDR3) for 378 patients with de novo DLBCL. The prognostic effects of IGV SHM and ongoing SHM or intra-clonal heterogeneity were analyzed in the training (192 patients), validation (186 patients), and overall DLBCL cohorts. To gain mechanistic insight, we analyzed the predicted IG-derived neoantigens' immunogenicity potential, determined by the major histocompatibility complex-binding affinity and the frequency-of-occurrence of T cell-exposed motifs (TCEMs) in a TCEM repertoire derived from human proteome, microbiome, and pathogen databases. Furthermore, IGV SHM was correlated with molecular characteristics of DLBCL and PD-1/L1 expression in the tumor microenvironment assessed by fluorescent multiplex immunohistochemistry.

Results: SHM was commonly found in IGHV and less frequently in IGK/LV. High levels of clonal IGHV SHM (SHM) were associated with prolonged overall survival in DLBCL patients, particularly those without BCL2 or MYC translocation. In contrast, long heavy chain CDR3 length, the presence of IGHV ongoing SHM in DLBCL, and high clonal IGK/LV SHM in germinal center B-cell-like (GCB)-DLBCL were associated with poor prognosis. These prognostic effects were significant in both the training and validation sets. By prediction, the SHM groups harbored more potentially immune-stimulatory neoantigens with high binding affinity and rare TCEMs. PD-1/L1 expression in CD8 T cells was significantly lower in IGHV SHM than in SHM patients with activated B-cell-like DLBCL, whereas PD-1 expression in CD4 T cells and PD-L1 expression in natural killer cells were higher in IGK/LV SHM than in SHM patients with GCB-DLBCL. PD-L1/L2 (9p24.1) amplification was associated with high IGHV SHM and ongoing SHM.

Conclusions: These results show for the first time that IGV SHM and ongoing SHM have prognostic effects in DLBCL and potential implications for PD-1/PD-L1 blockade and neoantigen-based immunotherapies.
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http://dx.doi.org/10.1186/s40425-019-0730-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806565PMC
October 2019

Myeloid neoplasms with isolated del(5q) and V617F mutation: a "grey zone" combination of myelodysplastic and myeloproliferative features?

Haematologica 2020 06 26;105(6):e276-e279. Epub 2019 Sep 26.

Department of Pathology and Laboratory Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA.

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http://dx.doi.org/10.3324/haematol.2019.227686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271604PMC
June 2020

Somatic mutations and cell identity linked by Genotyping of Transcriptomes.

Nature 2019 07 3;571(7765):355-360. Epub 2019 Jul 3.

New York Genome Center, New York, NY, USA.

Defining the transcriptomic identity of malignant cells is challenging in the absence of surface markers that distinguish cancer clones from one another, or from admixed non-neoplastic cells. To address this challenge, here we developed Genotyping of Transcriptomes (GoT), a method to integrate genotyping with high-throughput droplet-based single-cell RNA sequencing. We apply GoT to profile 38,290 CD34 cells from patients with CALR-mutated myeloproliferative neoplasms to study how somatic mutations corrupt the complex process of human haematopoiesis. High-resolution mapping of malignant versus normal haematopoietic progenitors revealed an increasing fitness advantage with myeloid differentiation of cells with mutated CALR. We identified the unfolded protein response as a predominant outcome of CALR mutations, with a considerable dependency on cell identity, as well as upregulation of the NF-κB pathway specifically in uncommitted stem cells. We further extended the GoT toolkit to genotype multiple targets and loci that are distant from transcript ends. Together, these findings reveal that the transcriptional output of somatic mutations in myeloproliferative neoplasms is dependent on the native cell identity.
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http://dx.doi.org/10.1038/s41586-019-1367-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782071PMC
July 2019

Histiocytic Sarcoma Following B-Lymphoblastic Leukemia/Lymphoma.

Am J Clin Pathol 2019 09;152(4):486-494

Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY.

Objectives: Rare cases of clonally related histiocytic sarcoma (HS) following B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) have been reported to date.

Methods: We present a patient with HS, which appeared as a breast mass 12 months after the initial diagnosis of B-ALL.

Results: Both HS and the B-ALL shared IGH-MYC and IGK gene rearrangements. Next-generation sequencing and whole-exome sequencing (WES) studies detected 35 common mutations, as well as mutations unique to B-ALL (16) and HS (15), including BRAF D594G. The patient achieved complete remission of B-ALL, but HS failed to respond to many cycles of intensive chemotherapy regimens. A partial response was achieved with sorafenib, a BRAF-targeted therapy.

Conclusions: To our knowledge, this is the first study to demonstrate by WES that clonally related B-ALL and HS arise through divergent evolution from a common precursor. We present our findings together with a discussion of the previously reported cases of HS in patients with B-ALL.
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http://dx.doi.org/10.1093/ajcp/aqz056DOI Listing
September 2019

Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.

Cancer Immunol Res 2019 04 11;7(4):644-657. Epub 2019 Feb 11.

Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8 T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1CD20 cells proximal (indicates interaction) to PD-1 CD8 T cells in patients with low PD-1 percentage of CD8 T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1/PD-L1 patients with unfavorable prognosis and implication of /, and upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab-CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0439DOI Listing
April 2019

PD-1/PD-L1 expression and interaction by automated quantitative immunofluorescent analysis show adverse prognostic impact in patients with diffuse large B-cell lymphoma having T-cell infiltration: a study from the International DLBCL Consortium Program.

Mod Pathol 2019 06 21;32(6):741-754. Epub 2019 Jan 21.

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Programmed cell death protein 1/programmed cell death protein ligand1 (PD-1/PD-L1) interaction is an important immune checkpoint targeted by anti-PD-1/PD-L1 immunotherapies. However, the observed prognostic significance of PD-1/PD-L1 expression in diffuse large B-cell lymphoma treated with the standard of care has been inconsistent and even contradictory. To clarify the prognostic role of PD-1/PD-L1 expression and interaction in diffuse large B-cell lymphoma, in this study we used 3-marker fluorescent multiplex immunohistochemistry and Automated Quantitative Analysis Technology to assess the CD3, PD-L1, and PD-1CD3 expression in diagnostic samples and PD-1/PD-L1 interaction as indicated by presence of PD-1CD3 cells in the vicinity of PD-L1 cells, analyzed their prognostic effects in 414 patients with de novo diffuse large B-cell lymphoma, and examined whether PD-1/PD-L1 interaction is required for the prognostic role of PD-1/PD-L1 expression. We found that low T-cell tissue cellularity, tissue PD-L1 expression (irrespective of cell types), PD-1CD3 expression, and PD-1/PD-L1 interaction showed hierarchical adverse prognostic effects in the study cohort. PD-1/PD-L1 interaction showed higher sensitivity and specificity than PD-1 and PD-L1 expression in predicting inferior prognosis in patients with high CD3 tissue cellularity ("hot"/inflammatory tumors). However, both PD-1 and PD-L1 expression showed adverse prognostic effects independent of PD-1/PD-L1 interaction, and PD-1/PD-L1 interaction showed favorable prognostic effect in PD-L1 patients without high CD3 tissue cellularity. Macrophage function and tumor-cell MYC expression may contribute to the PD-1-independent adverse prognostic effect of PD-L1 expression. In summary, low T-cell tissue cellularity has unfavorable prognostic impact in diffuse large B-cell lymphoma, and tissue PD-L1 expression and T-cell-derived PD-1 expression have significant adverse impact only in patients with high T-cell infiltration. PD-1/PD-L1 interaction in tissue is essential but not always responsible for the inhibitory effect of PD-L1/PD-1 expression. These results suggest the benefit of PD-1/PD-L1 blockade therapies only in patients with sufficient T-cell infiltration, and the potential of immunofluorescent assays and Automated Quantitative Analysis in the clinical assessment of PD-1/PD-L1 expression and interaction.
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http://dx.doi.org/10.1038/s41379-018-0193-5DOI Listing
June 2019

Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study.

Mod Pathol 2019 04 6;32(4):490-498. Epub 2018 Nov 6.

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

The purpose of this study is to examine hematopoietic neoplasms with 9p24/JAK2 rearrangement including neoplasms associated with t(8;9)(p22;p24)/PCM1-JAK2 fusion neoplasm as well as cases with translocations involving 9p24/JAK2 and other partner genes. From seven large medical centers, we identified ten patients with t(8;9)(p22;p24) /PCM1-JAK2 and 3 with t(9p24;v)/JAK2 at diagnosis. Majority of the cases showed myeloproliferative neoplasm (MPN) associated features (n = 7) characterized by variable degrees of eosinophilia, myelofibrosis, frequent proliferations of early erythroblasts in bone marrow and extramedullary sites, and infrequent/absent somatic mutations. Other less common presentations included myelodysplastic syndromes (MDS) or MDS/MPN (one each). Four patients presented with B-lymphoblastic leukemia (B-ALL), and of them, two patients with t(8;9)(p22;p24.1) were proven to be B-lymphoblastic crisis of MPN; and the other two cases with t(9p24;v) both were de novo B-ALL, BCR-ABL1-like (Ph-like). We show that the hematopoietic neoplasms with 9p24/JAK2 rearrangement are extremely rare, and most of them are associated with t(8;9)(p22;p24)/PCM1-JAK2, a recent provisional World Health Organization entity under "myeloid/lymphoid neoplasm with a specific gene rearrangement". Cases of t(8;9)(p22;p24)/PCM1-JAK2, though heterogeneous, do exhibit some common clinicopathological characteristic features. Cases with t(9p24;v)/JAK2 are extremely rare; while such cases with a MPN presentation may resemble t(8;9)(p22;p24.1)/PCM1-JAK2, B-ALL cases presenting de novo B-ALL might belong to Ph-like B-ALL.
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http://dx.doi.org/10.1038/s41379-018-0165-9DOI Listing
April 2019

TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis.

Cancer Discov 2018 12 1;8(12):1632-1653. Epub 2018 Oct 1.

INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

somatic mutations occur in ∼10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in -mutant DLBCLs. Accordingly, mutation in patients yields a -mutant gene-expression signature, and mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies somatic mutation. These results advocate for sequencing in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors...
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http://dx.doi.org/10.1158/2159-8290.CD-18-0657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279514PMC
December 2018

Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma.

Blood 2018 11 4;132(19):2016-2025. Epub 2018 Sep 4.

Division of Hematology and Medical Oncology.

We report 5-year follow-up of a multicenter phase 2 study of lenalidomide plus rituximab (LR) as initial treatment of mantle cell lymphoma (MCL). The regimen includes induction and maintenance with the LR doublet. Treatment was continuous until progression, with optional discontinuation after 3 years. The median age of the 38 participants was 65 years, with MCL international prognostic index scores balanced among low, intermediate, and high risk (34%, 34%, and 32%, respectively). Twenty-seven (75%) of the 36 evaluable patients completed ≥3 years of study treatment. At a median follow-up of 64 months (range, 21-78), the 3-year progression-free survival (PFS) and overall survival (OS) were 80% and 90%, respectively, with 5-year estimated PFS and OS of 64% and 77%, respectively. During maintenance, hematologic adverse events (AEs) included asymptomatic grade 3 or 4 cytopenias (42% neutropenia, 5% thrombocytopenia, 3% anemia) and mostly grade 1 or 2 infections managed in the outpatient setting (45% upper respiratory infection, 21% urinary tract infection, 13% sinusitis, 11% cellulitis, 8% pneumonia). Nonhematologic AEs, such as constitutional and inflammatory symptoms, occurred at reduced frequency and intensity compared with induction. A peripheral blood minimal residual disease (MRD) assay (clonoSEQ) showed MRD-negative complete remission in 8 of 10 subjects who had completed ≥3 years of treatment and with available samples for analysis. With longer follow-up, LR continues to demonstrate durable responses and manageable safety as initial induction and maintenance therapy for MCL (ClinicalTrials.gov NCT01472562).
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http://dx.doi.org/10.1182/blood-2018-07-859769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634960PMC
November 2018
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