Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory ...(R/R) chronic lymphocytic leukemia (CLL).
Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status score, and number of prior lines of therapy. Patients received acalabrutinib monotherapy or investigator's choice (idelalisib plus rituximab I-R or bendamustine plus rituximab B-R). The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC) in the intent-to-treat population. Key secondary end points included IRC-assessed overall response rate, overall survival, and safety.
From February 21, 2017, to January 17, 2018, a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator's choice (n = 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1-10). After a median follow-up of 16.1 months (range, 0.03-22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator's choice (16.5 months 95% CI, 14.0 to 17.1 months; hazard ratio, 0.31 95% CI, 0.20 to 0.49;
< .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator's choice. Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients receiving acalabrutinib monotherapy, I-R, and B-R, respectively.
Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL.
Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat ...is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concentrations required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between October 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, respectively. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses observed in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large B-cell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less dose-intense week-on-week-off schedule is warranted. (
).
Hodgkin's lymphoma is a lymphoid malignancy of the immune system. The pathognomonic Hodgkin and Reed-Sternberg cells (HRS) are derived mainly from monoclonal, preapoptotic B cells, and they carry ...rearranged, somatically mutated immunoglobulin heavy chains. In an appropriate microenvironment, HRS cells escape from apoptosis by several mechanisms, including single mutations, aberrant signaling pathways. Eventually, weakened immune surveillance leads to uncontrolled, disproportional B cell proliferation. This review summarizes the latest findings on the pathogenesis of Hodgkin lymphoma, with a special emphasis on immunologic processes, and depicts current and future immunotherapeutic regimens, which improve treatment outcomes and reduce late toxicities.
Since the introduction of tyrosine kinase inhibitors, the overall survival of patients with chronic myeloid leukemia has markedly improved. However long term use of these drugs results in various ...adverse events. Treatment with second generation dasatinib is often complicated by hemorrhagic events. Previous lumi-aggregometry studies have shown impaired platelet function in patients on dasatinib therapy. Dual agonist activated platelets (coated-platelets) are also sensitive indicators of platelet function. We hypothesized that dual activation with convulxin and thrombin of platelets in a flow cytometric assay could be a more sensitive method for detecting platelet dysfunction as compared to single agonist studies used in lumi-aggregometer. Platelets of healthy volunteers incubated with dasatinib as well as platelets from patients on dasatinib therapy were investigated. Low therapeutic plasma level dasatinib concentrations at which a considerable reduction in coated-platelet generation was observed in vitro, did not cause detectable change in platelet aggregation response. Coated-platelet assay and lumi-aggregometry were also investigated at 0, 1 and 4 hours after drug administration in dasatinib treated CML patients. Significant decrease was observed at 1 hour in maximal aggregation by collagen. Although the aggregation curves became normalized by 4 hours, coated-platelet generation was still inhibited in dasatinib treated patients. Nilotinib, another second generation tyrosine kinase inhibitor, had no effect on aggregation and on coated-platelet formation neither in vitro nor in ex vivo samples. At therapeutic plasma levels coated-platelet assay is more sensitive than lumi-aggregometry studies for the demonstration of the inhibitory effect of dasatinib on platelet function.
Overall and disease-free survival of Hodgkin lymphoma patients has improved significantly since the 2000s. This is due to the use of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ...polychemotherapy and modern radiotherapy. In recent years, further diagnostic and therapeutic changes have been made, which further improve patients' survival. The most significant role in this is the improvement of diagnostics, such as the 18FDG-PET/CT, which is now routinely used repeatedly during treatment, and the response-adapted treatment(s) based on it. The main role of ABVD treatment in first-line treatment is still clear, but the combination of anti-CD30 monoclonal antibody (brentuximab vedotin) and AVD (adriamycin, vinblastine, dacarbazine) is already available as a targeted treatment for patients at higher risk. The role of autologous hematopoietic stem cell transplantation in the treatment of high-risk, relapsing/refractory patients is still clear, but the new, targeted innovative drugs (brentuximab vedotin, pembrolizumab) can already be used in the previous salvage treatments. New therapeutic options have new side effects, which must be taken into account during treatment (and after it). In our summary, we present these new diagnostic and therapeutic approaches, based on our own practice and experience. Orv Hetil. 2023; 164(11): 403-410.
Treating relapsed and refractory diffuse large B-cell lymphoma is still challenging for clinicians, but the available CAR-T and bispecific antibodies have revolutionized therapy. Autologous stem cell ...transplantation was the most effective treatment modality previously. The authors reported data from a single center over ten years. The retrospective study included 116 patients, with 53 relapsed cases, 39 primary refractory cases, 19 who had CNS involvement, and 5 who had received primary consolidation transplants. The median duration of follow-up was 46 months. The median event-free survival was 75 months, and the median overall survival was 105 months for all cases. Five-year overall survival was 59%, and event-free survival was 54%. Pretreatment prognostic factors at diagnosis had no effect on the outcome of transplantation. The authors found no difference between survival in relapsed or refractory cases, and the number of salvage lines or the germinal center/activated B-cell type also did not influence the results. Complete metabolic response before transplantation confirmed by
FDG PET/CT strongly affected survival. The pre-transplant creatinine and CRP levels significantly influenced the long-term outcome. The number of stem cells infused did not affect survival, but engraftment within nine days did result in a longer survival. These data support the finding that the response to salvage therapy did facilitate the identification of a better prognostic group who may still benefit from autologous transplantation.
The scenario of immune pathomechanism-based first- and second-line therapies of immune thrombocytopenia (i.e., immunosuppression, splenectomy) substantially changed approximately more than 20 years ...ago, giving place and important role for thrombopoietin analogs in steroid refractory cases, positioning splenectomy as third-line intervention. Although this approach became dominant and powerful, refractory cases urged the search for further medications. More recently, the traditional immunological approach received more attention again, and new targets were determined: (1) shortening selectively IgG life span and clearance, (2) modifying complement system in an effort to reduce antibody binding to platelet surface, (3) cell signaling pathway modification efforts to reduce antiplatelet phagocytic events, mainly spleen tyrosine kinase and Bruton tyrosine kinase inhibitory compounds. These new agents seem to be capable alone and probably in different combinations and sequence of increasing platelet count even in thrombopoietin analog refractory adult chronic thrombocytopenic purpura cases. These promising approaches probably will bring new treatment schedules in the adult chronic thrombocytopenic purpura field quite soon, and the scenario moves back to the refreshed immunological basis rewriting many elements of the therapeutic algorithm of thrombocytopenic purpura.
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.
Treating patients with DLBCL remains a challenge, as the response to first-line immunochemotherapy is somewhat unpredictable. The International Prognostic Index (IPI) is one of the most widely used ...methods for assessing prognosis. Interim PET/CT (iPET/CT) can play an important role in the early identification of ‘non-responder’ patients before the end of treatment examination. In this study, we retrospectively analyzed 104 newly diagnosed DLBCL patients treated with R-CHOP-like regimens who underwent iPET/CT imaging during therapy. There was a significant difference in 2-year OS between patients with negative iPET/CT and those with positive iPET/CT. Patients who had positive iPET/CT showed inferior 2-year PFS compared to those with negative iPET/CT. According to IPI, there was a statistically significant difference in 2-year OS and PFS between patients in the lower and higher risk groups. However, these patients can be further subdivided according to iPET/CT. The iPET/CT results in the present study clearly separate good- and poor-prognosis patients according to differences in 2-year OS, both in the lower and higher IPI risk groups. These results are in agreement with those of previous studies that demonstrated that iPET/CT has high negative predictive value, clearly identifying good-prognosis patients even within the poor-prognosis IPI group.
PDF
