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Novel targeted treatment strategies for refractory chronic lymphocytic leukaemia.

ABSTRACT: Patients with refractory chronic lymphocytic leukaemia (CLL) still have an unfavourable prognosis and novel treatment strategies are necessary, preferably adjusted to the patient's individual situation. Refractoriness is no longer limited just to fludarabine (F) but extends to F-combinations with other chemotherapeutic agents (e.g. cyclophosphamide [C] and FC) and antibodies (e.g. rituximab [R], FR, and FCR). Also, refractoriness to alemtuzumab is an increasing problem. New pharmacological developments provide promising approaches. This review focuses on novel therapies such as monoclonal antibodies and small molecules aiming at specific targets of the CLL cell in the refractory situation. Approved therapeutic regimens will be presented as well as investigational approaches. An overview of completed and current clinical trials is offered.

SUBMITTER: Schnaiter A

PROVIDER: S-EPMC3573412 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Novel targeted treatment strategies for refractory chronic lymphocytic leukaemia.

Schnaiter Andrea A Stilgenbauer Stephan S

Therapeutic advances in hematology 20110801 4

Patients with refractory chronic lymphocytic leukaemia (CLL) still have an unfavourable prognosis and novel treatment strategies are necessary, preferably adjusted to the patient's individual situation. Refractoriness is no longer limited just to fludarabine (F) but extends to F-combinations with other chemotherapeutic agents (e.g. cyclophosphamide [C] and FC) and antibodies (e.g. rituximab [R], FR, and FCR). Also, refractoriness to alemtuzumab is an increasing problem. New pharmacological devel ...[more]

PMID: 23556093

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Refractory chronic lymphocytic leukemia--new therapeutic strategies.

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| S-EPMC3248129 | biostudies-literature

Chronic lymphocytic leukaemia.

Project description:Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.

| S-EPMC5336551 | biostudies-literature

Treatment Outcomes of Novel Targeted Agents in Relapse/Refractory Chronic Lymphocytic Leukemia: A Systematic Review and Network Meta-Analysis.

Project description:Most chronic lymphocytic leukemia patients experience a relapse or become refractory to treatment with conventional chemotherapeutic agents. The network meta-analysis assesses the relative efficacy of novel targeted agents for the treatment of a relapse or refractory chronic lymphocytic leukemia. A systematic literature search included seven phase III randomized controlled trials, including a total of 2512 patients treated with nine regimens. Data were extracted and evidence synthesized using network meta-analysis. All novel targeted therapies were significantly more effective than ofatumumab and demonstrated promising prolongation of progression free survival (PFS), with a hazard ratio (HR) ranging from 0.10 to 0.52. Two novel targeted agent regimens, venetoclax plus rituximab and ibrutinib monotherapy, resulted in greater overall survival (HR, 0.335 and 0.361, respectively). Venetoclax plus rituximab and ibrutinib monotherapy were most favorable based on (1) HR for PFS compared with ofatumumab (Ibrutinib: HR, 0.10; 95% CI, 0.07-0.14; Venetoclax plus rituximab: HR, 0.10; 95% CI, 0.05-0.21) and SUCRA value (probability of being best) (Ibrutinib SUCRA, 0.92; Venetoclax rituximab SUCRA, 0.90) (2) HR for overall survival compared with ofatumumab (Ibrutinib: HR, 0.361; 95% CI, 0.208-0.627; Venetoclax rituximab: HR, 0.335; 95% CI, 0.112-0.997) and SUCRA value (Ibrutinib SUCRA, 0.84; Venetoclax rituximab SUCRA, 0.85) Both treatments reduced the risk of progression or death by 90% versus conventional ofatumumab. Both ibrutinib monotherapy and venetoclax rituximab have a high probability of being the most effective treatments for a relapse or refractory chronic lymphocytic leukemia with respect to long-term progression-free survival and overall survival.

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Jumping translocations, a novel finding in chronic lymphocytic leukaemia.

Project description:A jumping translocation (JT) is a rare cytogenetic aberration that can occur in haematological malignancy. It involves the translocation of the same fragment of donor chromosome onto two or more recipient chromosomes, typically in different cells. In this study, we describe the first series of chronic lymphocytic leukaemia (CLL) patients with JTs reported to date. Following a review of 878 CLL patient karyotypes, we identified 26 patients (3%) with 97 JTs. The most commonly occurring breakpoint in these translocations was 17p11.2. Loss of TP53 was identified prior to or at the same time as JT in 23 of 26 patients (88%). All patients eventually developed a complex karyotype. All but one patient has required treatment for CLL, with estimated median time to treatment of 11·5 months. This study establishes JTs as a recurrent abnormality found in CLL patients with aggressive disease. JTs contribute to complex karyotypes and, in many cases, are involved in chromosomal rearrangements that result in loss of the tumour suppressor gene TP53.

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Safety and efficacy of ofatumumab in patients with fludarabine and alemtuzumab refractory chronic lymphocytic leukaemia.

Project description:There are now many therapeutic CD20 monoclonal antibodies undergoing clinical trials for B-cell malignancy and autoimmune conditions; which is optimal for cancer therapy is not clear. The novel human IgG1 CD20 monoclonal antibody ofatumumab has shown significant activity in difficult to treat patients with chronic lymphocytic leukemia, namely those resistant or refractory to fludarabine and alemtuzumab and has now been licensed for this uncommon indication. This brief review summarizes the clinical data obtained with ofatumumab in CLL in terms of both efficacy and toxicity.

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Project description:Chronic lymphocytic leukaemia (CLL) is well known to generate impaired immune responses in the host, with the malignant clone residing in well-vascularized tissues and circulating in peripheral blood but also in close proximity to effector cells that are capable, if activated appropriately, of eliciting a cytotoxic response. These, combined with the fact that this is frequently a condition affecting older patients with co-morbidities often unfit for many "traditional" cytotoxic agents with their significant associated toxicities, make CLL an ideal candidate for the development of immunotherapy. The impressive results seen with the addition of a monoclonal antibody, rituximab, to a chemotherapy backbone, for example, is testament to how effective harnessing an immune-mediated response in CLL can be. This review serves to outline the available arsenal of immunotherapies-past and present-demonstrated to have potential in CLL with some perspectives on how the landscape in this disease may evolve in the future.

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Project description:Abstract This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness and safety of maintenance therapy in individuals with chronic lymphocytic leukaemia (CLL).

| S-EPMC6848968 | biostudies-literature

The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.

Project description:Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.

| S-EPMC7528953 | biostudies-literature

Zanubrutinib for treatment-naive and relapsed/refractory chronic lymphocytic leukaemia: long-term follow-up of the phase I/II AU-003 study.

Project description:The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.

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Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study.

Project description:Bendamustine + rituximab (BR) has demonstrated high response rates in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). However, progression-free survival (PFS) after BR is <18 months. This study was designed to determine if maintenance lenalidomide after BR induction could improve PFS in R/R CLL/SLL. Thirty-four patients with R/R CLL/SLL who had received 1-5 prior chemotherapy regimens were treated with 6 cycles of BR induction. Patients achieving at least a minor response received twelve 28-d cycles of lenalidomide 5-10 mg/d. The primary endpoint was PFS. The median age was 67 years, with a median of 2 prior therapies. Eleven patients had confirmed presence of 17p and/or 11q deletions. Twenty-five (74%) completed 6 cycles of induction BR (response rate 56%). Nineteen (56%) patients received maintenance lenalidomide; only 6 patients completed the intended 12 cycles, highlighting the limited feasibility of lenalidomide in this setting, primarily due to haematological and infectious toxicities. The observed median PFS of 18·3 months is not significantly different from that of BR induction in R/R CLL/SLL without maintenance therapy (15·2 months). It is possible that lenalidomide maintenance may be more feasible and effective in the front-line setting, which is being tested in an ongoing trial (NCT01754857).

| S-EPMC5923897 | biostudies-literature

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