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Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy. In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282. Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8–18) for all 91 patients, 19 months (9–27) for the main cohort, and 12 months (8–15) for the expansion cohort. 59 (65%, 95% CI 53–74) of 91 patients had an overall response, including 30 (70%, 54–83) of 43 patients in the main cohort and 29 (60%, 43–72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred. The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019. AbbVie, Genentech.

The TP53 gene, encoding tumour suppressor protein p53, is located on the short arm of chromosome 17 (17p). Patients with 17p deletion (del17p) chronic lymphocytic leukaemia have poor responses and survival after chemoimmunotherapy. We assessed the activity and safety of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, in relapsed or refractory patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma. We did a multicentre, international, open-label, single-arm study at 40 sites in the USA, Canada, Europe, Australia, and New Zealand. Patients (age ≥18 years) with previously treated del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was overall response in the all-treated population per International Workshop on Chronic Lymphocytic Leukaemia 2008 response criteria modified for treatment-related lymphocytosis. Preplanned exploratory analyses were progression-free survival, overall survival, sustained haematological improvement, and immunological improvement. Patient enrolment is complete, but follow-up is ongoing. Treatment discontinuation owing to adverse events, unacceptable toxicity, or death were collected as a single combined category. This study is registered with ClinicalTrials.gov, number NCT01744691. Between Jan 29, 2013, and June 19, 2013, 145 patients were enrolled. The all-treated population consisted of 144 patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma who received at least one dose of study drug, with a median age of 64 years (IQR 57–72) and a median of two previous treatments (IQR 1–3). At the prespecified primary analysis after a median follow-up of 11·5 months (IQR 11·1–13·8), 92 (64%, 95% CI 56–71) of 144 patients had an overall response according to independent review committee assessment; 119 patients (83%, 95% CI 76–88) had an overall response according to investigator assessment. In an extended analysis with median follow-up of 27·6 months (IQR 14·6–27·7), the investigator-assessed overall response was reported in 120 patients (83%, 95% CI 76–89). 24-month progression-free survival was 63% (95% CI 54–70) and 24-month overall survival was 75% (67–81). Sustained haematological improvement was noted in 72 (79%) of 91 patients with any baseline cytopenia. No clinically relevant changes were noted from baseline to 6 months or 24 months in IgA (median 0·4 g/L at baseline, 0·6 g/L at 6 months, and 0·7 g/L at 24 months), IgG (5·0 g/L, 5·3 g/L, and 4·9 g/L), or IgM (0·3 g/L at each timepoint) concentrations. Common reasons for treatment discontinuation were progressive disease in 34 (24%) patients and adverse events, unacceptable toxicity, or death in 24 (17%) patients. Major bleeding occurred in 13 (9%) patients (11 [8%] grade 3–4). Grade 3 or worse infections occurred in 43 (30%) patients, including pneumonia in 19 (13%) patients. In the extended analysis, 38 patients died, 18 as a result of adverse events (four pneumonia, three chronic lymphocytic leukaemia, two Richter's syndrome, two sepsis, and one each of acute myocardial infarction, septic shock, encephalopathy, general deterioration in physical health, abnormal hepatic function, myocardial infarction, and renal infarction). A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable, providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. Ibrutinib represents a clinical advance in the treatment of patients with del17p chronic lymphocytic leukaemia and has been incorporated into treatment algorithms as a primary treatment for these patients. Pharmacyclics LLC, an AbbVie Company.

Treatment of B-cell malignancies with the PI3K inhibitor (PI3Ki) idelalisib often results in high toxicity and resistance, with limited treatment alternatives for relapsed/refractory patients since idelalisib is recommended as a later or last line therapy. To investigate resistance mechanisms and identify alternative treatments, we studied functional phenotypes of idelalisib-resistant B-cell malignancy models. The idelalisib-resistant KARPAS1718 model remained sensitive to Bcl-2 inhibitors (Bcl-2i), whereas the resistant VL51 model showed reduced sensitivity compared to parental cells. Sensitivity correlated with phosphorylation and expression of the Bcl-2 family members Bcl-2 and Bim. Target addiction scoring revealed high dependence on the proteasome, and proteasome inhibitors (PI) were effective across models and in primary chronic lymphocytic leukemia (CLL) cells, independently of their PI3Ki- or Bcl-2i-sensitivities. PI treatment consistently upregulated Bim and Mcl-1, while Bcl-2 increased in KARPAS1718 and CLL cells. Bcl-2i plus PI combinations led to an additive effect in these models. A multi-refractory CLL patient in the IMPRESS-Norway trial (NCT04817956) treated with Bcl-2i plus PI showed initial clinical improvement but relapsed within four months. Treatment induced Bim and Mcl-1 upregulation and reduced cytotoxic CD8 + T-cell and CD56 dim NK-cell populations. Our findings suggest that PIs may overcome resistance to targeted therapies, and warrant further studies to optimize clinical responses.

Bruton’s tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and acalabrutinib. All FDA-approved covalent BTK inhibitors rely on binding to the cysteine 481 (C481) amino acid within the active site of BTK, thus rendering it inert. While covalent BTK inhibitors have been very successful in multiple B-cell malignancies, improving both overall survival and progression-free survival relative to chemoimmunotherapy in phase 3 trials, they can be limited by intolerance and disease progression. Pirtobrutinib is a novel, highly selective, and non-covalent BTK inhibitor that binds independently of C481, and in a recent, first-in-human phase 1/2 clinical trial was shown to be extremely well tolerated and lead to remissions in relapsed/refractory patients with multiple B-cell malignancies. Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies.

Among 38 patients with refractory diffuse large B-cell lymphoma or follicular lymphoma, 28 were able to receive CAR T cells; 16 had complete remission, and none of those who had had a complete response at 6 months had a relapse at 28 months of follow-up.

In patients previously treated with covalent, irreversible BTK inhibitors, pirtobrutinib (a noncovalent, reversible BTK inhibitor) induced responses in 73%, with a median progression-free survival of nearly 20 months.

In this review, we examine the literature supporting treatment decision making in the front-line and relapsed/refractory settings for patients with chronic lymphocytic leukemia (CLL). In the front-line setting, novel-agent-based approaches, including continuous Bruton tyrosine kinase (BTK) inhibitor-based therapy and time-limited venetoclax with obinutuzumab, have demonstrated survival benefit over chemoimmunotherapy. While novel-agent-based front-line approaches are appropriate for most patients, fludarabine, cyclophosphamide, and rituximab (FCR) remains a consideration for a selected population of young patients with immunoglobulin heavy chain variable region gene ( IGHV )-mutated disease because of the possibility of a prolonged remission following FCR. As front-line novel-agent-based approaches have not been compared directly, decision making regarding which novel-agent-based approach to use in the front-line setting is often based on comorbidities and shared decision making. In the relapsed/refractory setting, BTK inhibitors, venetoclax-based therapy, and phosphoinositide 3-kinase (PI3K) inhibitors have demonstrated survival benefit when compared with chemoimmunotherapy regimens. Data to support various treatment sequences are limited, which highlights the need for prospective data to examine the optimal treatment sequence. Finally, we examine therapies with combinations of novel agents, and novel agents in development, including covalent and noncovalent BTK inhibitors, PI3K inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, immunotherapies, and cellular therapies. With effective approved options and new agents in development, the role of chemoimmunotherapy in the management of CLL has diminished.

Recently, the treatment landscape for chronic lymphocytic leukemia (CLL) has changed dramatically due to the development of drugs targeting proteins in the B cell antigen receptor (BCR) pathway. Acalabrutinib, a second-generation Bruton's tyrosine kinase (BTK) inhibitor, was recently FDA approved for treatment of treatment naïve and relapsed refractory CLL. Acalabrutinib was designed as a more selective BTK inhibitor as compared to ibrutinib in an attempt to mitigate some of the treatment limiting toxicities seen with ibrutinib such as atrial fibrillation and bleeding. In preclinical studies, acalabrutinib was demonstrated to have efficacy in CLL in both patient blood samples and murine models. A multinational phase 1/2 study demonstrated the efficacy and safety of acalabrutinib monotherapy in treatment naïve, relapsed refractory and ibrutinib-intolerant CLL patients. Subsequent phase 3 studies, ASCEND and ELEVATE-TN, compared acalabrutinib monotherapy or combination acalabrutinib and obinutuzumab to standard of care treatments and demonstrated acalabrutinib's improved efficacy and tolerability. Currently, a phase 3 study is ongoing to compare acalabrutinib to ibrutinib monotherapy (NCT02477696). In the setting of recent FDA approval, real-world evidence will help to elucidate the optimal use of acalabrutinib in the treatment of CLL.