Bortezomib is a dipeptidyl boronic acid that selectively inhibits the ubiquitin proteasome pathway, which plays a role in the degradation of many intracellular proteins. It is the first-in-class ...selective and reversible inhibitor of the 26S proteasome, with antiproliferative and antitumor activity. It exerts its anti-neoplastic action mainly via the inhibition of the nuclear factor-κB pathway components associated with cell proliferation, apoptosis, and angiogenesis. The drug has revolutionized the treatment of multiple myeloma and, more recently, mantle cell lymphoma. In 2003, bortezomib received accelerated approval from the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma and in 2008 for patients with previously untreated multiple myeloma. In 2006, bortezomib was approved for the treatment of refractory/relapsed mantle cell lymphoma and, in 2014, for previously untreated mantle cell lymphoma. Bortezomib has also demonstrated clinical efficacy both as a single drug and in combination with other agents in light chain amyloidosis, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, and peripheral T-cell lymphomas. Furthermore, continued clinical studies are required to confirm its value for patients with indolent and aggressive B-cell non-Hodgkin lymphomas and acute leukemias.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The substitution of bortezomib for vincristine in R-CHOP resulted in higher rates of complete response and nearly a doubling in progression-free survival among patients with advanced mantle-cell ...lymphoma not eligible for stem-cell transplantation.
Mantle-cell lymphoma is an incurable, aggressive hematologic cancer with a poor prognosis (median survival, 4 to 5 years).
1
,
2
It comprises 5 to 6% of all non-Hodgkin's lymphomas, including approximately 5000 cases per year in the United States.
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For previously untreated patients who are either ineligible or not considered for intensive chemotherapy and stem-cell transplantation, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is a standard of care
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–
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and produces complete response rates of up to 48%. However, progression-free survival is limited (median, 16.6 months).
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The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma in . . .
The use of Bruton's tyrosine kinase (BTK) inhibitors has changed the management of patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects B-cell antigen receptor ...(BCR) signaling. BTK inhibitors (BTKis) are classified into three categories, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors. Ibrutinib is the first covalent, irreversible BTK inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other covalent, irreversible, second-generation BTKis, acalabrutinib and zanubrutinib, have been developed for lymphoid malignancies to reduce the ibrutinib-mediated adverse effects. More recently, irreversible and reversible BTKis have been under development for immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, and chronic spontaneous urticaria, among others. This review article summarizes the preclinical and clinical evidence supporting the role of BTKis in various autoimmune, allergic, and inflammatory conditions.
Hairy cell leukemia (HCL) is a rare type of chronic lymphoid leukemia originating from a mature B lymphocyte. A diagnosis of HCL is based on cytology, confirmed by multiparametric flow cytometry ...(MFC) studies using anti-B-cell monoclonal antibodies, together with a panel of antibodies more specific to HCL, such as CD11c, CD25, CD103 and CD123. Recently, the
BRAF
V600E mutation has been described as a disease-defining genetic event. Measurable residual disease (MRD) is defined as the lowest level of HCL cells that can be detected accurately and reproducibly using validated methods; as MRD negativity is associated with high rates of durable complete response, by clearing MRD, the long-term outcome may be improved in patients with advanced HCL. MRD is typically detected using bone marrow, and in some cases, peripheral blood; however, in HCL, discrepancies frequently exist between MRD results obtained from blood, bone marrow aspirate and core biopsy. Among the methods used for MRD detection, MFC appears to be a more sensitive technique than immunohistochemistry. Molecular tests are also used, such as real-time quantitative PCR for unique immunoglobulin heavy chain (IgH) gene rearrangements and PCR techniques with clone specificity for
BRAF
V600E. Clone-specific PCR (spPCR) is able to detect one HCL cell in 10
6
normal cells, and is particularly suitable for patients found to be negative for MRD by MFC. Recently, the Hairy Cell Leukemia Consortium created a platform to work on a definition for MRD, and establish the optimal time point, tissue type and method for measuring MRD. This
RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 ...to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR 95% CI: 0.146 0.098-0.218; OS estimates at 5 years: 83% vs 68%; HR 95% CI: 0.450 0.266-0.761). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR 95% CI: 0.083 0.047-0.145; OS: HR 95% CI: 0.366 0.181-0.736). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators ...caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion–based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.
In a trial involving patients with relapsed or refractory chronic lymphocytic leukemia, the BCL2 inhibitor venetoclax in combination with rituximab resulted in a higher 2-year rate of ...progression-free survival than bendamustine in combination with rituximab (85% vs. 36%).
Skin changes in hairy cell leukemia Robak, Ewa; Jesionek-Kupnicka, Dorota; Robak, Tadeusz
Annals of hematology,
03/2021, Letnik:
100, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Skin lesions have been reported in about 10–12% of hairy cell leukemia (HCL) patients. Most are etiologically related to autoimmune or infectious processes, although secondary cutaneous neoplasms and ...drug-induced lesions are also reported. However, leukemia cutis with the direct infiltration of the skin by leukemic cells is extremely rare in HCL patients. This paper reviews the epidemiology, pathogenesis, clinical symptoms, diagnosis, and approach to treating skin lesions in HCL. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skin lesions, leukemia cutis, adverse events, infectious, cutaneous, drug reactions, neutrophilic dermatoses, secondary neoplasms, and vasculitis was conducted via PubMed. Publications from January 1980 to September 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.
Zanubrutinib (BGB-3111, Brukinsa
, BeiGene) is a next-generation irreversible inhibitor of Bruton's tyrosine kinase (BTK), developed by BeiGene in 2012 for the treatment of B-cell malignancies. It ...was designed to minimize off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib is more selective than ibrutinib for BTK versus EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. In addition, compared to ibrutinib, zanubrutinib has improved oral absorption and better target occupancy. Zanubrutinib demonstrated a lower incidence of off-target toxicities and reduced severity than ibrutinib. Moreover, zanubrutinib is similar to acalabrutinib, with less activity against TEC and ITK. The preliminary phase 1 results suggest that zanubrutinib has clinical activity and the drug is well tolerated in patients with B-cell lymphoid malignancies. Recent clinical trials have found it to demonstrate excellent efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM) and mantle cell lymphoma (MCL). In recent phase 3 studies, zanubrutinib was compared with ibrutinib in patients with relapsed/refractory (R/R) MW and RR CLL. In both trials, zanubrutinib was found to demonstrate clinically meaningful advantages in safety and tolerability over ibrutinib; in particular, it was associated with a lower risk of atrial fibrillation/flutter and major bleeding events. In the recent SEQUOIA study, comparing zanubrutinib with bendamustine and rituximab (BR) in patients with previously untreated CLL, zanubrutinib significantly improved progression-free survival versus BR, with an acceptable safety profile consistent with previous studies. Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the efficacy and safety of the combination of zanubrutinib with obinutuzumab venetoclax and other drugs are ongoing. This review summarizes the clinical efficacy and safety of zanubrutinib in lymphoid malignancies.
Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, ...randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).
Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS).
Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4%
16.0%;
= .02); among other selected secondary end points, grade 3 or higher infections (30.8%
30.0%) and Richter transformations (3.8%
4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients.
In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.
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