Colleen Timlin

Optimal Sequencing of Ibrutinib, Idelalisib, and Venetoclax in Chronic Lymphocytic Leukemia: Results from a Multi-Center Study of 683 Patients.

Background Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.BACKGROUND Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the US. However, there is no guidance as to their optimal sequence. PATIENTS AND METHODS We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). RESULTS A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81% respectively. With a median follow up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (vs. idelalisib) as first KI had a significantly better PFS in all settings; front-line (HR 2.8, CI1.3-6.3 p=.01), relapsed-refractory (HR 2.8, CI 1.9-4.1 p<.001), del17p (HR 2.0, CI 1.2-3.4 p=.008), and complex karyotype (HR 2.5, CI 1.2-5.2 p=.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS as compared to chemoimmunotherapy (CIT). Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, p=.06). CONCLUSIONS In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Further, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to CIT combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Toxicities and outcomes of 621 ibrutinib-treated chronic lymphocytic leukemia patients in the United States: a real-world analysis

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Comparable outcomes in chronic lymphocytic leukaemia (CLL) patients treated with reduced-dose ibrutinib: results from a multi-centre study

Additional Supporting Information may be found in the online version of this article: Data S1. Supplementary methods. Fig S1. Computed tomography, macroscopic, and loupe images. Table S1. Abberations common to both the malignant phyllodes tumour and myeloid sarcoma components detected by array comparative genomic hybridization. Table S2. Variants common to both the malignant phyllodes tumour and myeloid sarcoma components detected by whole-exome sequencing. Table S3. Variants only in the myeloid sarcoma component detected by whole-exome sequencing. Table S4. Antibodies used for immunohistochemistry and results. Table S5. Primer sequences.

Evidence for and Against Green Tea and Turmeric in the Management of Chronic Lymphocytic Leukemia

Abstract Complementary and alternative medicine (CAM) is a diverse group of medical and health care systems, practices, and products that are not generally considered part of conventional medicine. Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in the western hemisphere, and 16.5% to 66% of patients have reported using CAM. Most patients use spiritual/mind–body techniques and high doses of vitamins and herbs (most commonly polyphenols, including teas). We have reviewed the reported data on green tea and turmeric use in CLL patients.

Utilization of next generation sequencing identifies potentially actionable mutations in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is characterized by extensive genetic heterogeneity. Mutations in TP53 are associated with refractoriness to chemoimmunotherapy. Although new therapies have improved clinical outcomes in this group of patients, many patients eventually relapse. Several studies using high throughput sequencing have identified novel genetic mutations with prognostic significance in CLL (Wang et al, 2011). However, there has not been a systematic effort to identify high priority, targetable mutations for which pharmaceuticals already exist for other indications, or for which pharmaceuticals are already in development. We performed a retrospective analysis of CLL patients who underwent next generation sequencing (NGS) of tumour samples obtained from peripheral blood and bone marrow sources. We describe our findings in which we identify potentially targetable somatic mutations that may inform future clinical trial design. In particular, our results highlight the occurrence of mutations in BRAF as a potential target in CLL management. A total of 122 sequential patients with CLL who underwent NGS were identified from our clinical database. NGS was performed on an Illumina MiSeq (Illumina, Inc., San Diego, CA, USA) using a custom 68-gene amplicon-based panel developed at our centre with a detection limit of 5% allele frequency and a minimum depth of coverage of 2509. We used a custom bioinformatics pipeline, combining open source tools and custom algorithms for analysis (Daber et al, 2013; Sehgal et al, 2015). All mutational events in the coding regions were classified as pathogenic, benign polymorphisms or variants of uncertain significance. We defined pathogenic mutations as those that alter protein function in a way that drives tumourigenesis with functional evidence showing that the mutation is associated with disease. Benign polymorphisms are defined as those that have an allele frequency >0.1% in the general population as reported in the Exome Variant Server (EVS) and Exome Aggregation Consortium (ExAC) databases (http:// evs.gs.washington.edu/EVS/; http://exac.broadinstitute.org/). Variants of uncertain significance were defined as those mutational events that did not meet the definition of pathogenic or benign polymorphism. Seventy-two patients (59%) had at least one pathogenic mutation (range of 1–8 mutations). Pathogenic mutations were found in 27 genes, with the top five (TP53, SF3B1, ATM, NOTCH1 and BRAF) affecting 62 patients and these represented 64% of the pathogenic mutational events. Sixty-two patients were found to have pathogenic mutations in genes for which targeted therapeutic agents exist, i.e. those having shown efficacy, either in preclinical in vivo models or in the clinical setting. Pathogenic mutations in NOTCH1, ATM, BRAF and XPO1 were the most frequently implicated targetable mutations in our cohort (Fig 1). Among the most common mutations found in our cohort, mutations in BRAF are the most readily targeted given currently available pharmaceuticals. In contrast to the limited experience in targeting malignancies with NOTCH1, ATM and XPO1 mutations, BRAF inhibition has not only transformed the treatment of BRAF-mutated melanoma, but has also been successfully employed in other malignancies. Both the frequency of its occurrence in CLL, and efficacy in different malignancies supports the rationale for clinical trial design in BRAF inhibition in CLL. Among the seven patients affected, four different amino acid changes were identified in BRAF: V600E, K601E, D594G and D594N. The BRAF V600E mutation is well documented to have oncogenic activity in papillary thyroid cancers, melanomas and hairy cell leukaemia (Li et al, 2009; Wellbrock & Hurlstone, 2010), and it results in the constitutive activation of BRAF kinase activity. BRAF V600E is found in nearly all cases of hairy cell leukaemia (HCL), and the BRAF inhibitor vemurafenib has already been shown to be clinically active in relapsed-refractory HCL (Dietrich et al, 2012; Samuel et al, 2014). The BRAF K601E mutation, like V600E, is also an activating mutation associated with the RAF/MEK/Erk pathway. Preclinical and clinical evidence suggest that BRAF inhibition with vemurafenib and MEK inhibition with trametinib can block downstream signalling induced by the K601E mutation (Dahlman et al, 2012; Kim et al, 2013). The remaining BRAF mutations are both D594 inactivating mutations, against which BRAF inhibitors are not expected to be effective. The mechanism through which BRAF D594 inactivating mutations may contribute to oncogenesis has been elucidated (Heidorn et al, 2010). In the presence of activated RAS, inactivated BRAF can form a complex with CRAF, resulting in the hyperactivation of MEK. Choosing Correspondence

Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract

Steroid-refractory (SR) acute gastrointestinal (GI) graft-versus-host disease (GVHD) is associated with significant mortality in allogeneic hematopoietic cell transplantation recipients. We retrospectively evaluated the efficacy of tocilizumab for the treatment of SR biopsy-proven acute lower GI GVHD in 16 consecutive adult transplant recipients between October 2015 and July 2016. Tocilizumab 8 mg/kg was administered every 2 weeks until achievement of complete response, defined as resolution of all manifestations of GI GVHD, or until patients had progression or initiation of other therapy. Ten of 16 patients (62.5%; 95% CI, 0.39–82) achieved a complete response after a median time of 11 days (range, 2–28 days) from tocilizumab initiation. The median time to response onset (improvement in stage by at least 1) was 1 day (range, 1–4 days). Tocilizumab was administered at a median of 9 days (range, 3–75 days) from GVHD diagnosis and 10 days (range, 3–75 days) from initiation of high-dose steroids. At a median follow-up of 7.6 months (range, 0.8–27.7 months) from initiation of tocilizumab, 6/16 (37.5%) patients are alive and free of their underlying hematologic malignancy. Tocilizumab appears to be a highly active agent for the treatment of severe SR lower GI acute GVHD.