Recent years have seen significant improvement in chronic lymphocytic leukemia (CLL) management. Targeting B-cell lymphoma (BCL-2) and Bruton's kinase (BTK) have become the main strategies to ...restrain CLL activity. These agents are generally well tolerated, but the discontinuation of these therapies happens due to resistance, adverse effects, and Richter's transformation. A growing population of patients who have previously used both BTK inhibitors and BCL2 suffer from the constriction of the following regimens. This review explores the resistance mechanisms for both ibrutinib and venetoclax. Moreover, we present innovative approaches evaluated for treating double-refractory CLL.
Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) ...signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion,
mutations, and unmutated status of the immunoglobulin heavy-chain variable region (
) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in
or phospholipase Cγ2 (
). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.
Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the ...development, differentiation and activation of B and T cells. Four isoforms are distinguished within class I (PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ). PI3Kδ expression is limited mainly to the B cells and their precursors, and blocking PI3K has been found to promote apoptosis of chronic lymphocytic leukemia (CLL) cells. Idelalisib, a selective PI3Kδ inhibitor, was the first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/
mutation, unmutated IGHV status and refractory/relapsed disease. However, its side effects, such as autoimmune-mediated pneumonitis and colitis, infections and skin changes, limited its widespread use. The dual PI3Kδ/γ inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3Kδ and casein kinase-1ε (CK1ε), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials.
Ibrutinib is the first Bruton's tyrosine kinase (BTK) inhibitor, which showed significant clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients ...regardless of cytogenetic risk factors. Recent results of phase III clinical trials in treatment-naïve CLL patients shift the importance of the agent to frontline therapy. Nevertheless, beside its clinical efficacy, ibrutinib possesses some off-target activity resulting in ibrutinib-characteristic adverse events including bleeding diathesis and arrhythmias. Furthermore, acquired and primary resistance to the drug have been described. As the use of ibrutinib in clinical practice increases, the problem of resistance is becoming apparent, and new methods of overcoming this clinical problem arise. In this review, we summarize the mechanisms of BTK inhibitors' resistance and discuss the post-ibrutinib treatment options.
Multiple myeloma (MM) is a plasma cell-derived malignancy that stands for around 1.5% of newly discovered cancer cases. Despite constantly improving treatment methods, the disease is incurable with ...over 13,000 deaths in the US and over 30,000 in Europe. Recent studies suggest that extracellular vesicles (EVs) might play a significant role in the pathogenesis and evolution of MM. Further investigation of their role could prove to be beneficial in establishing new therapies and hence, improve the prognosis of MM patients. What is more, EVs might serve as novel markers in diagnosing and monitoring the disease. Great advancements concerning the position of EVs in the pathophysiology of MM have recently been shown in research and in this review, we would like to delve into the still expanding state of knowledge.
Azacitidine (AZA) is recognized as a vital drug used in the therapy of myelodysplastic syndromes (MDS) due to its beneficial effect on survival and quality of life. Nevertheless, many patients fail ...to respond to AZA treatment, as prognostic factors still are not identified. The present retrospective analysis included 79 patients with MDS treated with AZA as first-line therapy in a real-life setting. The percentage of patients with good, intermediate, and poor cytogenetics was 46.8%, 11.4%, and 34.2%, respectively. The overall response rate (complete remission CR, partial remission PR, and hematological improvement HI) was 24%. The CR, PR, and HI rates were 13.9%, 2.5%, and 7.6%, respectively. Stable disease (SD) was documented in 40.5% of patients. The median overall survival (OS) and progression-free survival (PFS) were 17.6 and 14.96 months, respectively. Patients with ORR and SD had a significantly longer median OS (23.8 vs. 5.7 months,
= 0.0005) and PFS (19.8 vs. 3.5 months,
< 0.001) compared to patients who did not respond to AZA. In univariate analysis, only an unfavorable cytogenetic group was a prognostic factor of a lower response rate (
= 0.03). In a multivariate model, older age (
= 0.047), higher IPSS (International Prognostic Scoring System) risk (
= 0.014), and higher IPSS-R cytogenetic risk (
= 0.004) were independent factors of shorter OS. Independent prognostic factors for shorter PFS were age (
= 0.001), IPSS risk (
= 0.02), IPSS cytogenetic risk (
= 0.002), and serum ferritin level (
= 0.008). The safety profile of AZA was predictable and consistent with previous studies. In conclusion, our study confirms the efficacy and safety of AZA in a real-world population and identifies potential biomarkers for response and survival.
Current Treatment of Chronic Lymphocytic Leukemia Jamroziak, Krzysztof; Puła, Bartosz; Walewski, Jan
Current Treatment Options in Oncology,
2017/1, Letnik:
18, Številka:
1
Journal Article, Book Review
Recenzirano
Opinion statement
A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, ...phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions. Ibrutinib was proven as a primary choice for patients with the
TP53
gene deletion/mutation, who otherwise have no active treatment available. Idelalisib with rituximab is also an active therapy, but due to increased risk of serious infections, its use in first-line treatment is limited to patients for whom ibrutinib is not an option. A new indication for ibrutinib was recently approved for older patients with comorbidities, as an alternative to the already existing indication for chlorambucil with obinutuzumab. The use of kinase inhibitors is already well established in recurrent/refractory disease. Immunochemotherapy with fludarabine, cyclophosphamide, rituximab (FCR) remains a major first-line option for many CLL patients without the
TP53
gene deletion/mutation, and who have no significant comorbidities or history of infections, and is particularly effective in patients with favorable features including mutated IGHV status. There are a number of issues regarding novel therapies for CLL that need further investigation such as optimum duration of treatment with kinase inhibitors, appropriate sequencing of novel agents, mechanisms of resistance to inhibitors and response to class switching after treatment failure, along with the potential role of combinations of targeted agents.
Lenalidomide is a cornerstone of maintenance therapy in patients with newly diagnosed multiple myeloma after autologous stem-cell transplantation. We aimed to compare the efficacy and safety of ...maintenance therapy with carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone in this patient population.
This study is an interim analysis of ATLAS, which is an investigator-initiated, multicentre, open-label, randomised, phase 3 trial in 12 academic and clinical centres in the USA and Poland. Participants were aged 18 years or older with newly diagnosed multiple myeloma, completed any type of induction and had stable disease or better, autologous stem-cell transplantation within 100 days, initiated induction 12 months before enrolment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) using permuted blocks of sizes 4 and 6 and a web-based system to receive up to 36 cycles of carfilzomib, lenalidomide, and dexamethasone (28-day cycles of carfilzomib 20 mg/m2 administered intravenously in cycle one on days 1 and 2 then 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles one to four and 36 mg/m2 on days 1, 2, 15, and 16 from cycle five up to 36 per protocol; lenalidomide 25 mg administered orally on days 1–21; and dexamethasone 20 mg administered orally on days 1, 8, 15, and 22) or lenalidomide alone (10 mg administered orally for the first three cycles and then at the best tolerated dose ≤15 mg for 28 days in 28-day cycles) until disease progression or unacceptable toxicity as maintenance therapy. After 36 cycles, patients in both treatment groups received lenalidomide maintenance. Randomisation was stratified by response to previous treatment, cytogenetic risk factors, and country. Investigators and patients were not masked to treatment allocation. Patients in the carfilzomib, lenalidomide, and dexamethasone group with no detectable minimal residual disease after cycle six (as per International Myeloma Working Group criteria) and standard-risk cytogenetics were switched to lenalidomide maintenance as of cycle nine. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all randomly assigned patients). Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. This unplanned interim analysis was triggered by the occurrence of 59 (61%) of the expected 96 events for the primary analysis and the results are considered preliminary. This trial is registered with ClinicalTrials.gov, NCT02659293 (active, not recruiting) and EudraCT, 2015–002380–42.
Between June 10, 2016, and Oct 21, 2020, 180 patients were randomly assigned to receive either carfilzomib, lenalidomide, and dexamethasone (n=93) or lenalidomide alone (n=87; intention-to-treat population). The median age of patients was 59·0 years (IQR 49·0–63·0); 84 (47%) patients were female and 96 (53%) were male. With a median follow-up of 33·8 months (IQR 20·9–42·9), median progression-free survival was 59·1 months (95% CI 54·8–not estimable) in the carfilzomib, lenalidomide, and dexamethasone group versus 41·4 months (33·2–65·4) in the lenalidomide group (hazard ratio 0·51 95% CI 0·31–0·86; p=0·012). The most common grade 3 and 4 adverse events were neutropenia (44 48% in the carfilzomib, lenalidomide, and dexamethasone group vs 52 60% in the lenalidomide group), thrombocytopenia (12 13% vs six 7%), and lower respiratory tract infections (seven 8% vs one 1%). Serious adverse events were reported in 28 (30%) patients in the carfilzomib, lenalidomide, and dexamethasone group and 19 (22%) in the lenalidomide group. One treatment-related adverse event led to death (respiratory failure due to severe pneumonia) in the carfilzomib, lenalidomide, and dexamethasone group.
This interim analysis provides support for considering carfilzomib, lenalidomide, and dexamethasone therapy in patients with newly diagnosed multiple myeloma who completed any induction regimen followed by autologous stem-cell transplantation, which requires confirmation after longer follow-up of this ongoing phase 3 trial.
Amgen and Celgene (Bristol Myers Squibb).
The hematopoietic stem cell transplantation (HSCT) procedure is considered a cardiovascular burden. This is due to the potentially cardiotoxic cytostatic agents used before and the risks associated ...with peri-transplant procedures. We designed a pilot study to determine the clinical utility of the new ST2 marker; furthermore, we routinely assessed cardiac parameters in HSCT recipients. Based on previous cardio-oncology experience in lung and prostate cancer, we can confirm the prognostic and predictive value of classic cardiac biomarkers and modern echocardiography parameters such as global longitudinal strain of the left and right ventricle. After conducting this pilot study we can create a predictive and prognostic model for patients undergoing HSCT. This will greatly enrich our clinical practice, especially in treating older people.
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