1,721,187 research outputs found
Three years of ibrutinib in CLL
No full textIn this issue of Blood, Byrd et al provide an important update on the prolonged efficacy and the limited and reducing toxicity of the single-agent Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma patients who are followed for a median time of 3 years from start of treatmen
Time for a new prognostic score in CLL?
No full textIn this issue of Blood, Langerbeins et al 1 evaluated the prognostic value of the current Chronic Lymphocytic Leukemia International Prognostic Index (CLL-IPI) using a pooled dataset of CLL-patients treated in first-line with targeted drugs (N=991) or chemoimmunotherapy (N=1,256).1 This work is timely, as all prognostic scores need re-evaluation as standard therapies change. The study was limited by a short median observation time (40.5 months), and the actual number of chemotherapy-free patients in the cohort receiving targeted drugs was 891 (100 patients in the targeted drug cohort had received bendamustine-debulking). Nevertheless, the authors were able to conclude that CLL-IPI retained prognostic value for progression-free survival (PFS), but with diminished discriminatory impact for the prediction of overall survival (OS).The “targeted drugs” treatments in the study by Langerbeins et al1 included combinations of anti-CD20 monoclonal antibodies with inhibitors of the B-cell receptor signaling-associated pathways (BCRi, mainly ibrutinib) and/or the BCL2 inhibitor (BCL2i) venetoclax, but only 26% of these patients had received venetoclax and ibrutinib in combination.1 The CLL-IPI score was originally generated by selecting 5 prognostic factors independently able to predict OS from 27 genetic, biochemical, and clinical parameters in patients with CLL treated in clinical trials with chemoimmunotherapy regimens in first-line between 1997 and 2010, at a time when targeted treatments were not available.2 The study describing the CLL-IPI was published in 2016 and the 5 factors were TP53 status (no abnormalities vs TP53 mutation or deletion or both), IGHV mutational status (mutated vs unmutated), serum β2-microglobulin concentration (≤3·5 mg/L vs >3·5 mg/L), clinical stage (Binet A or Rai 0 vs Binet B–C or Rai I–IV), and age (≤65 years vs >65 years). These factors were assigned a value (deleted/mutated TP53=4, unmutated IGHV=2, high β2-microglobulin =2, advanced clinical stage=1, advanced age=1) by approximating the hazard ratio (HR) value for OS risk, and a score was generated to discriminate four prognostic groups (low-risk score=0-1, intermediate=2-3, high=4-6, very-high=7-10).Langerbeins et al1 documented a significant improvement of PFS and OS in patients receiving targeted drugs compared to chemoimmunotherapy.1 The improved PFS gained using targeted treatments was observed in all CLL-IPI categories. However, the study by Langerbeins et al1 highlighted that only β2-microglobulin concentration (HR=1.7), IGHV status (HR=2.6), and TP53 status (HR=1.6) maintained prognostic value and that the relative weights of these 3 factors to PFS risk assessment were different from those calculated for OS in the 2016 study.2Langerbeins at al1 also demonstrated that the improvement gained using targeted drugs instead of chemoimmunotherapy on OS was particularly evident in the CLL-IPI high and very high-risk, but not in the low and intermediate risk groups. While there was a pair-wise significant difference between each risk group in the 2016 study,2 the current study documented a difference only between the intermediate and high-risk groups. Also, only Binet stage A vs C, β2-microglobulin, and TP53 status, but not Binet stage A vs B or B vs C and IGHV status, maintained their prognostic value for OS in the patients receiving targeted drugs with the current observation time. This suggested that, while an extension of the observation time was needed before making firm conclusions on the role of the CLL-IPI score in predicting OS, new parameters would need to be identified and weighted to predict PFS and OS in CLL in the context of targeted treatments. While there is always attention towards the role of genetic evolution,3 environmental factors explaining CLL resistance to novel treatments should also be sought.4,5 The better understanding of the main biological “drivers” of CLL, namely BCR and BCL2, and how to target them therapeutically has led to a significant improvement of the treatment strategies in CLL.6,7 The current most appealing strategies include those combining BCRi with BCL2i,8-10 which were given to only 26% of the patients in the trials considered by Langerbeins, or BCL2i with anti-CD20 antibodies.1 However, concepts are rapidly evolving and the period of observation of patients having received BCRi or BCL2i or their combinations remains short in a condition like CLL, where survivals can be measured in decades. Also, the new clinical trials with BCRi plus BCL2i combinations or BCL2i plus anti-CD20 antibody combinations will tell us if these therapeutic approaches may find a different indication for the CLL with unmutated IGHV (U-CLL) or mutated IGHV (M-CLL). U-CLL and M-CLL carry distinctive cellular origin, biology, epigenetics/genetics, and clinical behavior.6 Therefore prognostic algorithms may need to be generated separately in these 2 types of CLL. Only extended observation time and a better understanding of how to combine new targeted drugs will make it possible to identify the best prognostic factors of OS. In the interim, when combined with the outcome data in Langerbeins et al,1 the CLL-IPI remains a tool that assists prognostication for patients with CLL in the era of chemotherapy-free targeted regimens.References1. Langerbeins P, Giza A, Robrecht S, et al. Reassessing the Chronic Lymphocytic Leukemia International Prognostic Index in the era of targeted therapies. Blood. 2024.2. International CLLIPIwg. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790.3. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294.4. Chiodin G, Drennan S, Martino EA, et al. High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL. Blood Adv. 2022;6(18):5494-5504.5. Bonfiglio S, Sutton LA, Ljungstrom V, et al. BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib. Blood Adv. 2023;7(12):2794-2806.6. Stevenson FK, Forconi F, Kipps TJ. Exploring the pathways to chronic lymphocytic leukemia. Blood. 2021;138(10):827-835.7. Forconi F, Lanham SA, Chiodin G. Biological and Clinical Insight from Analysis of the Tumor B-Cell Receptor Structure and Function in Chronic Lymphocytic Leukemia. Cancers. 2022;14(3):663.8. Munir T, Cairns DA, Bloor A, et al. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024;390(4):326-337.9. Jain N, Keating M, Thompson P, et al. Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med. 2019;380(22):2095-2103.10. Niemann CU, Munir T, Moreno C, et al. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(12):1423-1433.<br/
Five years of ibrutinib in CLL
No full textThe study by Ahn et al in this issue of Blood is an important clinical update with a 5-year follow-up on efficacy and toxicity of single-agent ibrutinib, an inhibitor of B-cell receptor (BCR) pathway–associated Bruton tyrosine kinase (BTK), in patients with chronic lymphocytic leukemia (CLL).</p
Hedgehog activation in CLL
No full textIn this issue of Blood, Ghia et al observe that a proportion of patients with chronic lymphocytic leukemia (CLL) harbor mutations in genes involved in the Hedgehog (Hh) pathway resulting in expression of glioma-associated oncogene homolog 1 (GLI1). They also find that GLI1 is expressed in CLL cells without evidence of Hh mutations and that the high GLI1 levels correlate with disease progression.</p
Development of DNA vaccines against B-cell neoplasms
No full textAvailable from British Library Document Supply Centre-DSC:DXN053898 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo
Hairy cell leukaemia: biological and clinical overview from immunogenetic insights
No full textHairy cell leukaemia (HCL) is a rare neoplasm of peripheral B cells which represents a paradox in oncology. Despite its largely unknown origin and behaviour, HCL is one of the few example of dramatic success in the treatment of a malignancy. The recent steps forward to understanding the biology of HCL from immunogenetic and genomic studies have recently provided new insight into diagnosis and prognosis. Several data from immunoglobulin gene (IG) analysis have provided hints regarding the cell of origin and the ongoing selective interactions of the tumour BCR with environmental stimuli. It has also recently emerged that an unmutated status of the HCL IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome and aggressive disease. These observations suggest a central role of the tumour B-cell receptor in defining the outcome of HCL and that that IG gene analysis may have biological and prognostic relevance. Hopefully, IG analysis will help tailor treatment strategies for the most aggressive cases
Emerging drugs in chronic myelogenous leukaemia
No full textChronic myelogenous leukaemia (CML) is characterised by a t(9;22)(q34;q11) translocation, which produces a fusion BCR-ABL protein with constitutive tyrosine kinase activity that is central to the pathogenesis of CML representing an ideal target for therapeutic intervention. Targeting BCR-ABL by imatinib has revolutionised the clinical course of CML. All patients in early chronic phase treated with imatinib achieve a complete haematological response, with 80-90% achieving a complete cytogenetic response. However, BCR-ABL transcripts remain detectable in the great majority of them, and approximately 16% chronic phase CML patients are resistant to or relapse after imatinib treatment, mainly through pre-existing or acquired point mutations in the binding pocket. Thus, other targeted approaches are being developed to overcome imatinib resistance. These include two novel tyrosine kinase inhibitors (nilotinib and dasatinib) that are producing clinical responses in different clinical settings, while other similar compounds are under evaluation in preclinical studies. Furthermore, additive immunotherapeutic strategies are emerging to synergise with imatinib in the elimination of molecular residual disease. This paper reviews the current details regarding these approaches and their developments
Erratum: Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation (Blood (2012) 119:1 (192-195))
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