In some patients with CLL, resistance to the BTK inhibitor ibrutinib develops. Two classes of resistance mutations have been found: the more common involves alteration of the drug-binding site to ...make binding reversible; the less common activates a downstream kinase that effectively bypasses BTK.
The development of B-cell–receptor antagonists has been a therapeutic advance in chronic lymphocytic leukemia (CLL). Although B-cell–receptor ligation in normal cells induces proliferation, apoptosis, or anergy,
1
pathway dysregulation in CLL results in the propagation of proliferative and prosurvival signals.
2
,
3
Several agents targeting the B-cell–receptor pathway are in development, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. Although
BTK
is not recurrently mutated in CLL,
4
,
5
it is up-regulated at the transcript level and is constitutively active.
6
,
7
Ibrutinib irreversibly binds BTK at the C481 residue, rendering it kinase-inactive, inducing modest CLL-cell apoptosis, and abolishing proliferation and B-cell–receptor signaling in . . .
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.
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.
Purpose of Review
Over the last years, targeted anticancer therapy with small molecule inhibitors and antibodies has much replaced chemoimmunotherapy, which has been the gold standard of care for ...patients with chronic lymphocytic leukemia (CLL). Here we give an overview of novel targeted agents used in therapy of chronic lymphocytic leukemia, as well as efforts to overcome resistance development, focusing on approved drugs since they gained high relevance in clinical practice.
Recent Findings
Novel agents moved to the forefront as a treatment strategy of CLL due to their outstanding efficacy, almost irrespectively of the underlying genetic features. Inhibition of Bruton’s tyrosine kinase (BTK), a key molecule in the B cell receptor pathway, achieved dramatic efficacy even in poor-risk and chemo-refractory patients. Further success was accomplished with venetoclax, which specifically inhibits anti-apoptotic BCL2 and induces apoptosis of CLL cells.
Summary
Inhibition of BTK or BCL2 is very effective and induces prolongation of progression-free and overall survival. Approved combination treatments such as venetoclax or ibrutinib with obinutuzumab show high responses rates and long remission durations. However, evolution and selection of subclones with continuous treatment leads to resistance towards these novel drugs and disease relapse. Hence, comparison of sequential treatment with combinations and discontinuation of therapy are important aspects which need to be investigated.
Obinutuzumab, a glycoengineered anti-CD20 antibody with increased killing capacity, outperformed rituximab when used in combination with chlorambucil in patients with chronic lymphocytic leukemia who ...had coexisting illnesses.
Chronic lymphocytic leukemia (CLL), which is characterized by a neoplastic accumulation of B lymphocytes,
1
is the most common leukemia in Western countries. The majority of patients with CLL are older than 70 years of age, and many present with coexisting conditions.
2
,
3
In the past, CLL was treated with chemotherapy without improving survival.
4
–
8
The addition of the monoclonal anti-CD20 antibody rituximab to fludarabine and cyclophosphamide has been shown to prolong overall survival in physically fit patients with previously untreated CLL.
9
–
11
However, randomized trials have not shown that targeting the CD20 antigen in patients with CLL and coexisting conditions . . .
Chronic lymphocytic leukemia is associated with a highly heterogeneous disease course in terms of clinical outcomes and responses to chemoimmunotherapy. This heterogeneity is partly due to genetic ...aberrations identified in chronic lymphocytic leukemia cells such as mutations of TP53 and/or deletions in chromosome 17p del(17p), resulting in loss of one TP53 allele. These aberrations are associated with markedly decreased survival and predict impaired response to chemoimmunotherapy thus being among the strongest predictive markers guiding treatment decisions in chronic lymphocytic leukemia. Clinical trials demonstrate the importance of accurately testing for TP53 aberrations both del(17p) and TP53 mutations before each line of treatment to allow for appropriate treatment decisions that can optimize patient outcomes. The current report reviews the diagnostic methods to better detect TP53 disruption, the role of TP53 aberrations in treatment decisions and current therapies available for patients with chronic lymphocytic leukemia carrying these abnormalities. The standardization in sequencing technologies for accurate identification of TP53 mutations and the importance of continued evaluation of TP53 aberrations throughout initial and subsequent lines of therapy remain unmet clinical needs as new therapeutic alternatives become available.
Summary Background Deletion of chromosome 17p (del17p) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral ...small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4–5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov , number NCT01889186 . Follow-up is ongoing, and patients are still receiving treatment. Findings Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1–14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5–86·6) of 107 patients. The most common grade 3–4 adverse events were neutropenia (43 40%), infection (21 20%), anaemia (19 18%), and thrombocytopenia (16 15%). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven 7% each), pneumonia (six 6%), and febrile neutropenia (five 5%). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding AbbVie and Genentech.
To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic ...leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.
•Patients with relapsed CLL achieving complete remission or undetectable MRD on venetoclax treatment have the most durable responses.•Less durable responses are associated with bulky adenopathy, TP53 aberrations, NOTCH1 mutations, and prior refractoriness to BCRis.
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Summary Background Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This ...international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab. Methods Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33–81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days or to intravenous bendamustine (90 mg/m2 per day) for the first 2 days of each cycle. Rituximab 375 mg/m2 was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m2 during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67·5% or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio (HR) based on the 90·4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov , number NCT%2000769522. Findings 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37·1 months (IQR 31·0–45·5) median progression-free survival was 41·7 months (95% CI 34·9–45·3) with bendamustine and rituximab and 55·2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1·643, 90·4% CI 1·308–2·064). As the upper limit of the 90·4% CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 84% of 279 vs 164 59% of 278, and 109 39% vs 69 25%, respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years. Interpretation The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects. Funding Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research.
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