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The New England Journal of Medicine Jul 2014In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.
METHODS
In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.
RESULTS
At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.
CONCLUSIONS
Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).
Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cough; Diarrhea; Disease-Free Survival; Fatigue; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recurrence; Survival Rate
PubMed: 24881631
DOI: 10.1056/NEJMoa1400376 -
Blood Reviews Jul 2023Large Granular Lymphocyte (LGL) Leukemia is a rare, heterogeneous even more that once thought, chronic lymphoproliferative disorder characterized by the clonal expansion... (Review)
Review
Large Granular Lymphocyte (LGL) Leukemia is a rare, heterogeneous even more that once thought, chronic lymphoproliferative disorder characterized by the clonal expansion of T- or NK-LGLs that requires appropriate immunophenotypic and molecular characterization. As in many other hematological conditions, genomic features are taking research efforts one step further and are also becoming instrumental in refining discrete subsets of LGL disorders. In particular, STAT3 and STAT5B mutations may be harbored in leukemic cells and their presence has been linked to diagnosis of LGL disorders. On clinical grounds, a correlation has been established in CD8+ T-LGLL patients between STAT3 mutations and clinical features, in particular neutropenia that favors the onset of severe infections. Revisiting biological aspects, clinical features as well as current and predictable emerging treatments of these disorders, we will herein discuss why appropriate dissection of different disease variants is needed to better manage patients with LGL disorders.
Topics: Humans; Leukemia, Large Granular Lymphocytic; Killer Cells, Natural; Mutation; Leukemia; Neutropenia
PubMed: 36870881
DOI: 10.1016/j.blre.2023.101058 -
BMJ Case Reports Jan 2016A man in his 60s was brought to the emergency department, with airway compromise and dysarthria due to a grossly enlarged tongue. As he was on a current course of...
A man in his 60s was brought to the emergency department, with airway compromise and dysarthria due to a grossly enlarged tongue. As he was on a current course of antibiotics, he was treated for a likely antibiotic-associated allergic reaction. However, as he failed to improve with intramuscular and nebulised epinephrine, another cause of his symptoms was sought. Further discussion revealed a history of chronic lymphocytic leukaemia (CLL), which had recently relapsed. Investigations were ordered to confirm that the symptoms were due to acquired angioedema, and the patient was managed for this diagnosis based on the presence of an undetectable C4 level. This diagnosis was later confirmed when the results of specialist tests became available. The patient was treated for his relapsed CLL with good effect, and has had no further episodes of angioedema and an improvement in the level of his C1 esterase protein level and function.
Topics: Airway Obstruction; Angioedema; Complement C1 Inactivator Proteins; Epinephrine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Recurrence
PubMed: 26823364
DOI: 10.1136/bcr-2015-213880 -
Molecular Medicine (Cambridge, Mass.) Mar 2018Chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in western countries, is characterized by the progressive accumulation in blood, bone marrow and... (Review)
Review
Chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in western countries, is characterized by the progressive accumulation in blood, bone marrow and lymphoid tissues of monoclonal B lymphocytes with a characteristic immunophenotype. Despite advances in therapy and improved outcome, in most instances CLL is an incurable disorder. Signaling via the B-cell receptor (BCR), the upregulation of anti-apoptotic proteins, and the cross-talk between CLL cells and microenvironment constitute key factors in the pathogenesis of CLL. Currently, inhibitors of kinases like BTK or PI3K blocking BCR signaling, and molecules that mimic the BH3 domain to compete with BCL-2 are established tools in the treatment of CLL. As the complex biology of CLL is rapidly unfolding, the number of small molecules targeting CLL molecular pathways is increasing and it is likely that they will further improve the outcome of patients with this form of leukemia.
Topics: Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors
PubMed: 30134797
DOI: 10.1186/s10020-018-0001-1 -
Blood Cancer Journal Oct 2018The treatment landscape for patients with chronic lymphocytic leukemia (CLL) has changed considerably with the introduction of very effective oral targeted therapies... (Review)
Review
The treatment landscape for patients with chronic lymphocytic leukemia (CLL) has changed considerably with the introduction of very effective oral targeted therapies (such as ibrutinib, idelalisib, and venetoclax), and next-generation anti-CD20 monoclonal antibodies (such as obinutuzumab). These agents lead to improved outcomes in CLL, even among patients with high-risk features, such as del17p13 or TP53 mutation and unmutated immunoglobulin heavy chain (IGHV) genes. Each of these treatments is associated with a unique toxicity profile; in the absence of randomized data, the choice of one type of treatment over another depends on the co-morbidities of the patient. Chemoimmunotherapy still plays an important role in the management of previously untreated CLL patients, particularly among young fit patients who have standard risk FISH profile and mutated IGHV genes. Richter's transformation of CLL remains a difficult complication to treat, although therapy with programmed death 1 inhibitors such as pembrolizumab and nivolumab has shown impressive responses in a subset of patients. Our ability to risk stratify CLL patients continues to evolve; the CLL-International Prognostic Index (CLL-IPI) is the best validated tool in predicting time to first therapy among previously untreated patients. This review summarizes the current approach to risk stratification and management of CLL patients.
Topics: Algorithms; Biomarkers, Tumor; Combined Modality Therapy; Disease Management; Disease Progression; Disease Susceptibility; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Practice Guidelines as Topic; Prognosis; Recurrence; Treatment Outcome
PubMed: 30283014
DOI: 10.1038/s41408-018-0131-2 -
Frontiers in Immunology 2018The NOTCH signaling pathway is a conserved signaling cascade that regulates many aspects of development and homeostasis in multiple organ systems. Aberrant activity of... (Comparative Study)
Comparative Study Review
The NOTCH signaling pathway is a conserved signaling cascade that regulates many aspects of development and homeostasis in multiple organ systems. Aberrant activity of this signaling pathway is linked to the initiation and progression of several hematological malignancies, exemplified by T-cell acute lymphoblastic leukemia (T-ALL). Interestingly, frequent non-mutational activation of NOTCH1 signaling has recently been demonstrated in B-cell chronic lymphocytic leukemia (B-CLL), significantly extending the pathogenic significance of this pathway in B-CLL. Leukemia patients often present with high-blood cell counts, diffuse disease with infiltration of the bone marrow, secondary lymphoid organs, and diffusion to the central nervous system (CNS). Chemokines are chemotactic cytokines that regulate migration of cells between tissues and the positioning and interactions of cells within tissue. Homeostatic chemokines and their receptors have been implicated in regulating organ-specific infiltration, but may also directly and indirectly modulate tumor growth. Recently, oncogenic NOTCH1 has been shown to regulate infiltration of leukemic cells into the CNS hijacking the CC-chemokine ligand 19/CC-chemokine receptor 7 chemokine axis. In addition, a crucial role for the homing receptor axis CXC-chemokine ligand 12/CXC-chemokine receptor 4 has been demonstrated in leukemia maintenance and progression. Moreover, the CCL25/CCR9 axis has been implicated in the homing of leukemic cells into the gut, particularly in the presence of phosphatase and tensin homolog tumor suppressor loss. In this review, we summarize the latest developments regarding the role of NOTCH signaling in regulating the chemotactic microenvironmental cues involved in the generation and progression of T-ALL and compare these findings to B-CLL.
Topics: Animals; Carcinogenesis; Cell Movement; Central Nervous System; Chemokines; Chemotaxis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Receptor, Notch1; Signal Transduction; Tumor Microenvironment
PubMed: 29666622
DOI: 10.3389/fimmu.2018.00633 -
Blood May 2018Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are 2 well-defined entities that diverge in their basic pathogenic mechanisms and clinical evolution... (Review)
Review
Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are 2 well-defined entities that diverge in their basic pathogenic mechanisms and clinical evolution but they share epidemiological characteristics, cells of origin, molecular alterations, and clinical features that differ from other lymphoid neoplasms. CLL and MCL are classically considered indolent and aggressive neoplasms, respectively. However, the clinical evolution of both tumors is very heterogeneous, with subsets of patients having stable disease for a long time whereas others require immediate intervention. Both CLL and MCL include 2 major molecular subtypes that seem to derive from antigen-experienced CD5 B cells that retain a naive or memory-like epigenetic signature and carry a variable load of immunoglobulin heavy-chain variable region somatic mutations from truly unmutated to highly mutated, respectively. These 2 subtypes of tumors differ in their molecular pathways, genomic alterations, and clinical behavior, being more aggressive in naive-like than memory-like-derived tumors in both CLL and MCL. The pathogenesis of the 2 entities integrates the relevant influence of B-cell receptor signaling, tumor cell microenvironment interactions, genomic alterations, and epigenome modifications that configure the evolution of the tumors and offer new possibilities for therapeutic intervention. This review will focus on the similarities and differences of these 2 tumors based on recent studies that are enhancing the understanding of their pathogenesis and creating solid bases for new management strategies.
Topics: Biomarkers; Clonal Evolution; Disease Susceptibility; Genetic Predisposition to Disease; Genetic Variation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Signal Transduction; Tumor Microenvironment
PubMed: 29666114
DOI: 10.1182/blood-2017-10-764373 -
Experimental Hematology Jul 2020Non-random chromosomal translocations involving the putative transcription factor Mixed Lineage Leukemia Translocated to 10 (MLLT10, also known as AF10) are commonly... (Review)
Review
Non-random chromosomal translocations involving the putative transcription factor Mixed Lineage Leukemia Translocated to 10 (MLLT10, also known as AF10) are commonly observed in both acute myeloid and lymphoid leukemias and are indicative of a poor prognosis. Despite the well-described actions of oncogenic MLLT10 fusion proteins, the role of wild-type MLLT10 in hematopoiesis is not well characterized. The protein structure and several interacting partners have been described and provide indications as to the potential functions of MLLT10. This review examines these aspects of MLLT10, contextualizing its function in benign and malignant hematopoiesis.
Topics: Animals; Hematopoiesis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasm Proteins; Transcription Factors
PubMed: 32569758
DOI: 10.1016/j.exphem.2020.06.002 -
Blood Advances Aug 2023Chronic lymphocytic leukemia (CLL) is an immunosuppressive disease characterized by increased infectious morbidity and inferior antitumor activity of immunotherapies....
Chronic lymphocytic leukemia (CLL) is an immunosuppressive disease characterized by increased infectious morbidity and inferior antitumor activity of immunotherapies. Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKis) or the Bcl-2 inhibitor venetoclax has profoundly improved treatment outcomes in CLL. To overcome or prevent drug resistance and extend the duration of response after a time-limited therapy, combination regimens are tested. Anti-CD20 antibodies that recruit cell- and complement-mediated effector functions are commonly used. Epcoritamab (GEN3013), an anti-CD3×CD20 bispecific antibody that recruits T-cell effector functions, has demonstrated potent clinical activity in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma. Development of CLL therapy is ongoing. To characterize epcoritamab-mediated cytotoxicity against primary CLL cells, peripheral blood mononuclear cells from treatment-naive and BTKi-treated patients, including patients progressing on therapy, were cultured with epcoritamab alone or in combination with venetoclax. Ongoing treatment with BTKi and high effector-to-target ratios were associated with superior in vitro cytotoxicity. Cytotoxic activity was independent of CD20 expression on CLL cells and observed in samples from patients whose condition progressed while receiving BTKi. Epcoritamab induced significant T-cell expansion, activation, and differentiation into Th1 and effector memory cells in all patient samples. In patient-derived xenografts, epcoritamab reduced the blood and spleen disease burden compared with that in mice receiving a nontargeting control. In vitro, the combination of venetoclax with epcoritamab induced superior killing of CLL cells than either agent alone. These data support the investigation of epcoritamab in combination with BTKis or venetoclax to consolidate responses and target emergent drug-resistant subclones.
Topics: Humans; Mice; Animals; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Antineoplastic Agents; Proto-Oncogene Proteins c-bcl-2; Antibodies, Bispecific
PubMed: 37219524
DOI: 10.1182/bloodadvances.2022009517 -
Experimental Hematology Feb 2022The CD99 gene encodes a transmembrane protein that is involved in cell differentiation, adhesion, migration, and protein trafficking. CD99 is differentially expressed on... (Review)
Review
The CD99 gene encodes a transmembrane protein that is involved in cell differentiation, adhesion, migration, and protein trafficking. CD99 is differentially expressed on the surface of hematopoietic cells both in the myeloid and lymphoid lineages. CD99 has two isoforms, the long and short isoforms that play different roles depending on the cellular context. There has been extensive evidence supporting the role of CD99 in myeloid and lymphoblastic leukemias. Here we review research findings related to the CD99 in malignant hematopoiesis. We also summarize the significance of CD99 as a therapeutic target in hematological malignancies.
Topics: 12E7 Antigen; Animals; Gene Expression Regulation, Leukemic; Hematopoiesis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34920053
DOI: 10.1016/j.exphem.2021.12.363