Relapsed Chronic Lymphocytic Leukemia Research Articles

Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

ABSTRACTIntroduction: Ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK), is approved in many countries for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) and for previously untreated disease with a 17p deletion and, most recently, as a frontline therapy for CLL. In controlled trials in CLL, ibrutinib produced high response rates and improved survival in both the frontline and relapsed settings. While ibrutinib controls CLL with impressive efficacy, it only infrequently induces complete remissions, particularly of relapsed CLL, and does not eradicate minimal residual disease. Finally, ibrutinib is extremely expensive, has off-target toxicities, and requires indefinite therapy.Areas covered: In this article, we provide an overview of the CLL therapeutic landscape and discuss the pharmacokinetic and pharmacodynamic aspects of ibrutinib. Major clinical trials of ibrutinib in CLL are summarized, and its safety profile explored.Expert opinion: Ibrutinib represents a transformative advance in CLL management and has validated BTK as a therapeutic target in this disease, but has some limitations, leading to the emergence of other BTK inhibitors and mechanism-based combination strategies. Given complete BTK occupancy at lower doses of ibrutinib and declining levels of BTK on ibrutinib therapy, lower doses of ibrutinib in CLL are being explored.

A Quantitative Analysis of Subclonal and Clonal Gene Mutations before and after Therapy in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL)-associated gene mutations that influence CLL cell fitness and chemotherapy resistance should increase in clonal representation when measured before therapy and at relapse. To uncover mutations associated with CLL relapse, we have performed whole-exome sequencing in a discovery cohort of 61 relapsed CLL patients identifying 86 recurrently mutated genes. The variant allele fractions (VAF) of 19 genes with mutations in ≥3 of 61 cases were measured in 53 paired pre- and posttreatment CLL samples sorted to purity using panel-based deep resequencing or by droplet digital PCR. We identify mutations in TP53 as the dominant subclonal gene driver of relapsed CLL often demonstrating substantial increases in VAFs. Subclonal mutations in SAMHD1 also recurrently demonstrated increased VAFs at relapse. Mutations in ATP10A, FAT3, FAM50A, and MGA, although infrequent, demonstrated enrichment in ≥2 cases each. In contrast, mutations in NOTCH1, SF3B1, POT1, FBXW7, MYD88, NXF1, XPO1, ZMYM3, or CHD2 were predominantly already clonal prior to therapy indicative of a pretreatment pathogenetic driver role in CLL. Quantitative analyses of clonal dynamics uncover rising, stable, and falling clones and subclones without clear evidence that gene mutations other than in TP53 and possibly SAMHD1 are frequently selected for at CLL relapse. Data in aggregate support a provisional categorization of CLL-associated recurrently mutated genes into three classes (i) often subclonal before therapy and strongly enriched after therapy, or, (ii) mostly clonal before therapy or without further enrichments at relapse, or, (iii) subclonal before and after therapy and enriching only in sporadic cases. Clin Cancer Res; 22(17); 4525-35. ©2016 AACR.

Monoclonal Antibodies in Chronic Lymphocytic Leukemia

Monoclonal antibodies (MoAbs) play a pivotal role in the treatment of chronic lymphocytic leukemia (CLL). Rituximab, a MoAb against CD20, was initially used as a single agent in the treatment of CLL before being incorporated into newer combination regimens. Integration of rituximab into chemotherapy regimens has led to an improvement in the response rate and overall survival when used in frontline therapy. Despite this, CLL remains an incurable disease, and treatment of relapsed CLL, particularly after failure of purine analog-based regimens, remains challenging. Technological advances relating to development of chimeric and humanized MoAbs are supporting the role of antibody-based regimens for many diseases, including CLL. Currently, MoAbs represent an integral component of CLL therapy. The antitumor efficacy of many therapeutic MoAbs can be potentially improved upon by their use in combination with new targeted therapy agents.

An ultra-deep sequencing strategy to detect sub-clonal TP53 mutations in presentation chronic lymphocytic leukaemia cases using multiple polymerases.

Chronic lymphocytic leukaemia (CLL) is the most common clonal B-cell disorder characterized by clonal diversity, a relapsing and remitting course, and in its aggressive forms remains largely incurable. Current front-line regimes include agents such as fludarabine, which act primarily via the DNA damage response pathway. Key to this is the transcription factor p53. Mutations in the TP53 gene, altering p53 functionality, are associated with genetic instability, and are present in aggressive CLL. Furthermore, the emergence of clonal TP53 mutations in relapsed CLL, refractory to DNA-damaging therapy, suggests that accurate detection of sub-clonal TP53 mutations prior to and during treatment may be indicative of early relapse. In this study, we describe a novel deep sequencing workflow using multiple polymerases to generate sequencing libraries (MuPol-Seq), facilitating accurate detection of TP53 mutations at a frequency as low as 0.3%, in presentation CLL cases tested. As these mutations were mostly clustered within the regions of TP53 encoding DNA-binding domains, essential for DNA contact and structural architecture, they are likely to be of prognostic relevance in disease progression. The workflow described here has the potential to be implemented routinely to identify rare mutations across a range of diseases.

Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations

AbstractFludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.

Health-Related Quality of Life and Patient-Reported Outcomes in Patients Receiving Ofatumumab in Combination with Fludarabine and Cyclophosphamide (FC) Versus FC Alone in the Complement 2 Trial

Introduction: The randomized COMPLEMENT 2 study demonstrated a statistically significant improvement in independent reviewer committee-assessed median progression-free survival (PFS) in patients with relapsed chronic lymphocytic leukemia (CLL) who were treated with ofatumumab plus fludarabine and cyclophosphamide (OFC) compared with fludarabine and cyclophosphamide (FC) alone (28.9 vs. 18.8 months, p=0.0032) and that the addition of O was well tolerated (Robak T, et al. Haematologica 2015;100:abstract LB219). Moreover, the median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (p=0.1410) with a median follow-up of 34 months. In addition to the PFS benefit, it is important to consider the impact of adding O to FC on health-related quality of life (HRQoL) and patient-reported symptoms.Methods: In the COMPLEMENT 2 trial, patients with relapsed CLL (N=365) were randomized to either OFC or FC. F and C were administered as intravenous infusions (F: 25 mg/m2, Days 1-3 every 28 days for 6 cycles; C: 250 mg/m2, Days 1-3 every 28 days for 6 cycles). O was also administered intravenously (Cycle 1: 300 mg Day 1 and 1000 mg Day 8, subsequent cycles: 1000 mg Day 1). During the trial, the EORTC QLQ-C30 v3.0 and the QLQ-CLL16 questionnaires were administered at baseline, during Cycle 4 of 6 and throughout follow-up. Specified patient-reported endpoints were HRQoL as reported by the global health status/QoL domain of the QLQ-C30 questionnaire and a B symptom index including patient-reported symptoms of fatigue, night sweats, temperature changes, and weight loss as reported by certain items of the QLQ-C30 and QLQ-CLL16 questionnaires.Results: The least square mean change in HRQoL, measured on a scale scored from 0 (worse) to 100 (best), improved between baseline and Cycle 4 by 8.3 points in the OFC arm vs. 4.8 points in the FC arm. Although there was no significant difference between the least square mean changes in the two arms (p=0.09), the OFC arm surpassed the 5-point difference defined as being a clinically relevant change (Osoba D, et al. J Clin Oncol 1998;16;139-144). The least square mean change in B symptom index, measured on a scale of 0-100 with 0 meaning no symptoms, improved from baseline to Cycle 4 by 5.6 points and 4.5 points in the OFC and FC arms, respectively, with no significant difference between the arms (p=0.49). Patients who achieved a complete or partial response to therapy showed a larger mean improvement in B symptoms (OFC 6.5 improvement, FC 7.5 improvement) than those who did not respond (OFC 4.3 improvement, FC 3.5 worsening of symptoms) but these differences between the arms were not significant (p=0.51 and p=0.22, respectively). During follow-up, patients who did not progress maintained a consistent level of HRQoL in both arms (Figure).Conclusion: This study demonstrates durable improvements in both HRQoL and patient-reported B symptoms for patients being treated for relapsed CLL. Although there are no significant differences observed between the OFC and FC treatment arms in terms of the least square mean change in HRQoL or B symptom scores, the improvement in PFS in the OFC arm reported previously (Robak T, et al. Haematologica 2015;100:abstract LB219) suggests that these patients may enjoy HRQoL and symptom improvements for a longer duration. [Display omitted] DisclosuresRobak:GlaxoSmithKline: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Off Label Use: Ofatumumab (Arzerra) is approved in the frontline and refractory CLL setting but not in relapsed CLL. This Abstract presents the Health related quality of life and patient reported outcomes in patients receiving ofatumumab in combination with fludarabine and cyclophosphamide (FC) versus FC alone. Kryachok:GlaxoSmithKline: Honoraria, Other: Investigator for Study. Homenda:GlaxoSmithKline: Honoraria, Other: Intestigator in Clinical Trial - OMB110913 (COMPLEMENT 2). Blonski:GlaxoSmithKline: Research Funding. McKeown:GlaxoSmithKline: Equity Ownership; Novartis: Employment, Equity Ownership. Chang:GlaxoSmithKline: Equity Ownership; Novartis: Employment, Equity Ownership. Manson:GlaxoSmithKline: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Lisby:Genmab: Employment. Gupta:Novartis: Employment, Equity Ownership; GlaxoSmithKline: Equity Ownership.

Modulation of the Clonal Composition in Relapsed CLL: A Study Based on Targeted Deep-Sequencing of ATM, BIRC3, NOTCH1, POT1, SF3B1, SAMHD1 and TP53

Background: Relapse or refractory disease is a challenging clinical problem in the majority of chronic lymphocytic leukemia (CLL) patients. Treatment influences the clonal composition by selection and eventually induction of additional genetic abnormalities.Aim: To characterize the clonal evolution in relapsed CLL patients by deep-sequencing analysis of mutations in ATM, BIRC3, NOTCH1, POT1, SF3B1, SAMHD1 and TP53.Patients and Methods: Sequential samples of 20 relapsed CLL patients at three time-points were evaluated: A: at diagnosis (n=16) or in untreated state (n=4), B: at first relapse (n=20) and C: at second relapse (n=2). Patients were treated with diverse treatment schemes and had temporarily achieved either complete or partial remission during the course of the disease. The median time from diagnosis to first-line treatment was 13 months (1 - 169 months). All geneswere sequenced by a deep sequencing approach (Illumina, San Diego, CA). IGHV mutational status was determined by direct Sanger sequencing at time-point A. Chromosome banding analysis (CBA) and FISH data on del(17p), del(11q), trisomy 12 (+12), and del(13q) were available in 33/42 and 36/42 samples, respectively.Results: Initially, samples at first relapse were sequenced. Mutations in SF3B1 (6/20, 30%), TP53 (5/20, 25%), ATM (5/20, 25%), NOTCH1 (4/20, 20%), and SAMHD1 (3/20, 15%) were detected at high frequencies. No mutations were detected in BIRC3 and POT1. In total, 75% of cases presented with at least one mutation (Figure 1): 8 (40%) cases had one, 6 (30%) cases had two and one patient had three genes concomitantly mutated (mut). Patients were also analyzed for IGHV mutational status at diagnosis and presented with unmutated status at a frequency of 85% (17/20).Subsequently, samples from cases with mutations were analyzed at time-point A. In 12/15 (80%) cases the mutations at relapse were already detectable at time-point A with a similar load indicating presence of the main clone before and after chemotherapy. However, in 7/15 (47%) patients new gene mutations were acquired either additionally to existing mutations (n=4) or in previously wild-type cases (n=3). In 5/7 (71%) cases mutations were located in TP53. TP53 mut were the only mutations that were not detected in samples before treatment (sensitivity of 3%). Thus, TP53 mutations might have been initiated by chemotherapy or exist in a minor subclone subsequently selected by chemotherapy. Furthermore, only 4 cases had low-level mutations (3-6% mutation load) at diagnosis in either SAMHD1 or SF3B1 that eventually increased in their burden during disease course.Of note, in two patients a multibranching clonal evolution could be identified (#2, #9). For patient #2 three time-points were analyzed. At diagnosis 2 ATM mutations were detected with mutation loads of about 20%, each. In the course of the disease these mutations were lost, whereas SF3B1 mut showed a stable mutation load in all three time-points of about 40%. In contrast, mutation load of SAMHD1 increased over time from 4% to 87%. CBA was performed at diagnosis and detected independent clones with del(11q) and del(13q). Accordingly, del(11q) detected by FISH at diagnosis was lost and the percentage of cells with del(13q) increased from diagnosis to time-point C. Therefore, patient #2 shows different genetic subclones in parallel that were eradicated or selected by chemotherapy. In patient #9 two SF3B1 mutations were initially detected with the same mutation load of 10%. After treatment one mutation was lost, whereas the load of the second mutation increased indicating at least two different subclones with only one of them being sensitive to chemotherapy. This might be due to different additional aberrations. Indeed, CBA identified two clones: one with +12 alone and one in combination with del(13q). FISH revealed unchanged percentage of +12 at time-point B, whereas del(13q) positive cells were diminished.Conclusions: In 75% of relapsed CLL cases mutations in SF3B1, TP53, ATM, NOTCH1, and SAMHD1 are present at high frequencies. 80% of these mutations are already detectable before treatment initiation representing the main clone. Remarkably, TP53 mutations were the only mutations that were not detected before but only after chemotherapy. [Display omitted] DisclosuresJeromin:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schabath:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Ibrutinib Enhances the Activity of Anti-CD20 Antibodies in an MCL Mouse Model: Effect of Drug at Clinically Relevant Concentrations on ADCC and ADCP

Introduction: Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase (BTK), is clinically established as an effective treatment for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Further, recent trials reported that ibrutinib combined with anti-CD20 monoclonal antibodies (CD20 mAbs) led to overall response rates (ORRs) of 95% and 100% in relapsed CLL patients (Burger et al Lancet Oncol 2014, Jaglowski et al Blood 2015), and an ORR of 87% in relapsed MCL patients (Wang et al ASH 2014), indicating complementary therapeutic effects from the 2 drugs. However, some preclinical studies showed that ibrutinib inhibited antibody-dependent cell-mediated cytotoxicity and phagocytosis (ADCC and ADCP). This discrepancy may be due to differences between experimental conditions (eg, drugs used at micromolar concentrations for sustained periods of time) relative to the pharmacokinetics (PK) of ibrutinib, which has a typical peak plasma concentration (Cmax) of ~200 nM 2 hours (tmax) after oral administration of 420-560 mg, and is cleared rapidly from circulation (Davis et al ASH 2014; Advani et al J Clin Oncol 2013). Using clinical PK as a basis, we designed in vitro and in vivo studies to re-evaluate the impact of ibrutinib on ADCC and ADCP.Methods: To model the effect of covalent inhibition by ibrutinib long after tmax, peripheral blood mononuclear cells (PBMC) from multiple healthy donors were incubated for 2 hrs with 200 nM ibrutinib, washed, and rested for 12 hours to represent a time halfway to the next daily dose. Natural killer (NK) cells purified from these PBMC were cultured with JeKo-1 (MCL line) or primary CLL cells opsonized with the CD20 mAbs rituximab (RTX), ofatumumab (OFA), or obinutuzumab (OBZ; washout protocol). To assess the effect of ibrutinib at tmax, treated PBMC, without being washed or rested, were used to purify NK cells for an ADCC assay in the presence of 200 nM ibrutinib (no wash protocol). Dead target tumor cells were counted by flow cytometry and presented as % maximum killing by NK cells from PBMC treated with vehicle. In ADCP assays, % PBMC-derived macrophages that had phagocytosed target cells are shown. In a xenograft model of MCL, SCID mice (10/group) bearing subcutaneous Mino tumors were treated with CD20 mAbs with or without daily oral dosing with ibrutinib at 12 mg/kg. Tumor size was recorded twice weekly. Plasma concentration of ibrutinib was measured using LC-MS. BTK occupancy in tumor cells by ibrutinib was determined as described previously (Dubovsky et al Blood 2013).Results: The ADCC activity of NK cells treated with ibrutinib rebounded significantly after the washout procedure. Killing of RTX-opsonized JeKo-1 and primary CLL cells rose from 36% and 21% (no wash) to 77% and 71% (wash), respectively. Similar results were obtained using OFA. The killing of OBZ-opsonized JeKo-1 cells was not substantially affected with or without washouts (Fig 1A). Phagocytosis was not affected in the presence of 200 nM ibrutinib (Fig 1B). In tumor-bearing mice, ibrutinib administered at 12 mg/kg by oral gavage resulted in a Cmax of 338 ng/mL (767 nM), exceeding the Cmax observed in patients receiving up to 560 mg a day. However, total drug exposure over time (AUC0-last = 391 ng·h/mL) was within range (Advani et al J Clin Oncol 2013, de Jong et al Cancer Chem Pharmacol 2015). In contrast to previous preclinical study results, ibrutinib significantly enhanced the therapeutic effect of CD20 mAbs (Fig 2). At study termination, we confirmed 98.4 ± 0.3% BTK occupancy in tumor cells.Conclusions: We recommend ibrutinib concentrations used in cellular assays and in vivo models reflect pharmacologic levels of ibrutinib in patients administered 420-560 mg once daily. The optimal dose in animal studies can be determined by PK/PD measurements. Our data indicate that NK-mediated ADCC recovers significantly 12 hours after ibrutinib has been removed, which may be attributed to turnover of ITK, or other signaling components of ADCC that are targets of ibrutinib during the rest period. ADCP activity of macrophages was not affected by 200 nM ibrutinib. These data suggest that the 2 major effector cell types for tumor-targeting antibodies are not as inhibited by clinically relevant concentrations of ibrutinib as have been described previously. This is supported by the present in vivo study data showing that ibrutinib did not inhibit, but augmented the therapeutic effect of CD20 mAbs. [Display omitted] [Display omitted] DisclosuresNg:Pharmacyclics LLC, an AbbVie Company: Employment. Lu:Pharmacyclics LLC, an AbbVie Company: Employment. Sukbuntherng:Pharmacyclics LLC, an AbbVie Company: Employment. Neuenburg:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment.

Targeting BTK By a microRNA Mechanism in Chronic Lymphocytic Leukemia

The B-Cell Receptor (BCR) pathway is overactive and plays a crucial role in the survival, proliferation and trafficking of chronic lymphocytic leukemia (CLL), the most common leukemia in adults. Brutons agammaglobulenemia tyrosine kinase (BTK) is a key downstream component of the BCR pathway and targeting BTK with ibrutinib, an orally bioavailable irreversible inhibitor of BTK has had remarkable success in relapsed CLL including in patients with high risk genetic features. However, therapy-induced point mutations affecting BTK p.C481, which convert ibrutinib from an irreversible inhibitor to a less potent reversible inhibitor, have emerged in a subset of patients with high risk genomic factors. Alternative strategies are therefore needed to prevent and treat ibrutinib-resistant disease for these high risk patients. Micro-RNAs (miRNAs) are small non coding RNAs that are aberrantly expressed in many cancers including CLL. We have previously shown that epigenetic silencing, due to the overexpression of HDACs in CLL, was responsible for the low expression of specific miRNAs in CLL.In this study we identified a key set of microRNA (miR147b, miR-210, miR425, miR1253, miR4267 and miR4667-3p) that targeted BTK. Ectopic expression of each individual miRNA reduced BTK expression by 30-50% whereas a pool of these miRNA reduced BTK by 80%. When the expression of the BTK targeting microRNAs was compared in the CLL cells from 80 patients with a pool of healthy B-cells (5 donors) we found that CLL cells expressed lower levels of the BTK targeting microRNA compared to healthy B cells. Chromatin immunoprecipitation followed by deep sequencing as well as real time-PCR experiments identified that a gene repressive complex, consisting of HDAC1, HDAC2 and KDM1, became recruited to the promoters of these microRNA to silence their expression. Consequently, targeting the HDACs with the novel 2nd generation HDAC inhibitor Abexinostat induced the expression of BTK targeting miRNAs by 5-200 fold with reciprocal decreases in the levels of BTK protein. Similarly RNAi against HDAC1 induced the BTK targeting miRNA as well as decreased BTK in primary CLL cells as well as in Mec2, a CLL cell line. We then demonstrated that HDAC inhibition with Abexinostat synergized with ibrutinib to dually target BTK (where abexinostat decreased total BTK protein and ibrutinib inhibits kinase activity of remaining BTK to achieve a more complete inhibition of BTK signaling and synergistic cytotoxicity. Importantly, we also demonstrated that HDAC inhibitors retain the ability to induce the BTK targeting microRNA and reduce BTK protein in ibrutinib-resistant CLL cells that developed the mutant p.C481S BTK.Together, our results show that the over-expression of HDACs in CLL causes epigenetic silencing of BTK targeting miRNAs leading to a higher expression of BTK in these patients. HDAC inhibition restores the expression of these miRNAs which in turn target BTK effecting a quantitative reduction. Since Abex is well toleratd in phase 1 clinical trials for heme malignancies, it makes an attractive therapeutic strategy to target BTK as part of a combination therapy as well as in Ibrutinib resistant patients. DisclosuresByrd:Acerta Pharma BV: Research Funding.

Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.

Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients

Nurse-like cells mediate ibrutinib resistance in chronic lymphocytic leukemia patients

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Idelalisib: A Novel PI3Kδ Inhibitor for Chronic Lymphocytic Leukemia.

To review and summarize data on idelalisib, which was approved by the Food and Drug Administration (FDA) in July 2014 for use in combination with rituximab for relapsed chronic lymphocytic leukemia (CLL). A literature search using PubMed was conducted from January 2011 through May 2015 using the terms idelalisib, GS-101, CAL-101, PI3Kδ, and CLL. Data were also obtained through the FDA briefing documents, American Society of Clinical Oncology, and American Society of Hematology abstracts. The literature search was limited to human studies published in English. Priority was placed on trials of idelalisib in CLL. Idelalisib is a potent, first-in-class selective inhibitor of phosphatidylinositol-3-kinaseδ (PI3Kδ) approved by the FDA in July 2014 for the treatment of relapsed CLL, in combination with rituximab, in patients for whom rituximab monotherapy would be considered appropriate due to other comorbidities. PI3Kδ is hyperactivated in B-cell malignancies and plays a vital role in the B-cell receptor pathway, a key oncogenic driver in various B-cell malignancies, including CLL. Several phase I/II studies have demonstrated clinical activity of idelalisib in CLL, particularly in the setting of relapsed/refractory disease, with overall response rate ranging from 70% to 82%. The FDA approval was based on a phase III, randomized trial of rituximab monotherapy (n = 110) or idelalisib in combination with rituximab (n = 110) in heavily, pre-treated patients (median of 3 prior therapies) with relapsed CLL. Idelalisib was administered as 150 mg orally twice daily. Idelalisib plus rituximab was associated with an overall response rate of 81% and overall survival of 91% at 12 months. The median progression-free survival was not reached in the idelalisib arm at the time of the first interim analysis. The incidence of grade 3 or higher adverse events in the idelalisib plus rituximab arm was as follows: neutropenia (34%), thrombocytopenia (10%), anemia (5%), elevation in transaminases (5%), and diarrhea (4%). Idelalisib in combination with rituximab is a safe and effective new treatment option for patients with relapsed CLL, including those with poor prognostic factors. As the results from various ongoing studies become available, the role of idelalisib will likely continue to expand.

Systematic review of rash in cancer patients receiving ibrutinib and idelalisib.

e12655 Background: Ibrutinib is a BTK inhibitor approved for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and Waldenstrom’s macroglobulinemia....

Ibrutinib Treatment of Relapsed CLL Following Allogeneic Transplantation: Sustained Disease Response and Promising Donor Immune Modulation

Abstract Background: Treatment of relapsed chronic lymphocytic leukemia (CLL) with ibrutinib results in high rates of progression-free and overall survival. Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), is FDA-approved for use in relapsed CLL. Ibrutinib may also modulate donor T cell alloimmunity via inhibition of interleukin-2-inducible kinase (ITK). Here we report the effects of ibrutinib salvage therapy in 5 CLL patients who relapsed following allogeneic hematopoietic cell transplantation (allo-HCT). In addition to minimal residual disease (MRD) response measurements, we also assessed donor T cell chimerism and donor B cell immune reconstitution following ibrutinib therapy. Methods: Five patients with high-risk CLL relapsed 1-8.5 yrs following allo-HCT. Four patients had never achieved donor CD3 T cell chimerism >95% following reduced-intensity transplant. Ibrutinib 420mg daily was started 1 mo-2 yrs after clinical relapse. Four of the 5 patients remain on ibrutinib with treatment courses ranging from 3-17 mos. CLL MRD was measured by IgH high-throughput sequencing (HTS) using the ClonoSIGHTTM test (Sequenta, Inc.), which has the sensitivity to detect 1 CLL clone per million leukocytes. Lymph node (LN) size was assessed by CT scan and reported as the sum of the products of the LN diameters (SPD). Donor B cell reconstitution was determined by IgH HTS quantification of total IgH molecules and unique IgH clonotypes. Results: Lymphocytosis was observed in all 5 patients following initiation of ibrutinib treatment, consistent with previous reports. In 2 patients who received >1 yr of ibrutinib treatment, lymphocytosis peaked at 3 wks and 8 wks after initiation of treatment and slowly declined thereafter, fully resolving within 1 yr (Fig 1A). All 4 patients with pathologic lymphadenopathy prior to treatment experienced dramatic LN reduction (Fig 1B; 68% average reduction in LN size after 3 mos on ibrutinib). The longest duration of follow-up is reported for patient SPN 3975, who had a 17p deletion and received ibrutinib for 39 mos. Treatment was discontinued after CLL MRD became undetectable by ClonoSIGHT (Fig 1C). Evidence of donor T cell immune modulation included achievement of full donor CD3 chimerism after 1 yr and resolution of oral and skin chronic graft-versus-host disease (GVHD) after 6 mos. Although this patient has been off ibrutinib for >8 mos, full donor chimerism persists and CLL MRD remains undetectable (Fig 1C). Before ibrutinib treatment, donor B cells (excluding the patient’s CLL clone) accounted for 1% of PBMC (Fig 1D). Furthermore, recovering B cells have diverse, low frequency IgH clonotypes (Fig 1E). Together, our findings show rapid, sustained, and diverse immune reconstitution without CLL recurrence following ibrutinib discontinuation. Conclusions: Ibrutinib provides effective salvage therapy for CLL relapse following allo-HCT. Post-transplant CLL relapse is often extra-nodal and our experience shows ibrutinib is effective in clearing both nodal and extra-nodal disease. Here we present one patient who stopped therapy after achieving MRD negativity and maintains undetectable disease 8 mos following ibrutinib discontinuation. Ibrutinib treatment demonstrates promising donor immune modulation by promoting full donor chimerism and resolution of chronic GVHD. Our five patient experience supports using ibrutinib in relapsed CLL patients following allo-HCT. Clinical trials are needed to determine the best duration of ibrutinib therapy following post-allo-HCT relapse, chronic GVHD treatment efficacy, and the role of ibrutinib maintenance following allo-HCT. Download : Download high-res image (120KB) Download : Download full-size image Figure 1 . (A) Percent change in absolute lymphocytic count (ALC) for 2 patients who received ibrutinib treatment for >1 yr. SPN = Stanford Patient Number. (B) Percent reduction in LN size, as reported by the sum of the product of LN diameters (SPD) for 4 patients following initiation of ibrutinib. (C) CLL MRD (reported as a percentage of WBCs) and blood donor CD3 T cell levels shown for patient SPN 3975. (D) B cells (excluding the CLL clone) as percent of total PBMC for patient SPN 3975 as measured by IgH HTS. (E) Total IgH molecules and unique IgH clone counts for patient SPN 3975 at different time points (D=day) post allo-HCT. Disclosures Kong: Sequenta, Inc.: Employment, Equity Ownership. Klinger: Sequenta, Inc.: Employment, Equity Ownership. Faham: Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Coutre: Pharmacyclics, Inc.: Consultancy, Research Funding. Miklos: Sequenta, Inc.: Research Funding.

Idelalisib: a review of its use in chronic lymphocytic leukaemia and indolent non-Hodgkin's lymphoma.

Idelalisib (Zydelig®) is a first-in-class, orally administered, phosphatidylinositol 3-kinase-δ inhibitor that was recently approved for the treatment of relapsed chronic lymphocytic leukaemia (CLL), relapsed follicular B-cell non-Hodgkin's lymphoma (NHL) and relapsed small lymphocytic lymphoma (SLL) in the USA and for the treatment of CLL and refractory follicular lymphoma in the EU. In a pivotal phase III trial in patients with relapsed CLL who were not able to receive cytotoxic agents, recipients of idelalisib plus rituximab had significantly improved progression-free survival, overall survival, overall response and lymph node response, compared with recipients of placebo plus rituximab. In a pivotal phase II trial, idelalisib monotherapy was effective in patients with relapsed indolent NHL who were refractory to rituximab and an alkylating agent, including in the subgroups of patients with follicular lymphoma or SLL. Oral idelalisib had a generally manageable adverse event profile, although episodes of serious/fatal diarrhoea or colitis, hepatotoxicity, pneumonitis and intestinal perforation were reported. In conclusion, idelalisib represents an important advance in the treatment of relapsed CLL and relapsed indolent NHL.

Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors

BACKGROUND: There is high unmet need in frail pts with relapsed CLL, particularly in those characterized by adverse prognostic factors such as presence of del(17p) and/or TP53 mutations. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kd recently approved for the treatment of relapsed CLL in combination with R. This report describes results from the 2nd interim analysis (IA) of a Phase 3 study evaluating IDELA in combination with R in relapsed CLL with focus on various risk subgroups of pts.METHODS: A Phase 3 study evaluated IDELA+R vs placebo (PBO)+R in pts with CLL requiring therapy after progression <24 mos since last therapy and considered unfit to receive cytotoxic therapy. Pts were randomized to receive IDELA at 150 BID (n=110) or PBO (n=110) in combination with R at 375 mg/m2 [1st dose] and then 500 mg/m2 q2 wks x 4, followed by q4 wks x 3 [8 doses total]). After progression, pts could enroll into a blinded extension study to receive IDELA at 150 mg BID (prior PBO+R) or 300 mg BID (prior IDELA+R). Primary endpoint PFS was assessed by an IRC using standard criteria (Hallek 2008/2012, Cheson 2012). The first IA (Furman, NEJM 2014) led to an early stop due to overwhelming efficacy. The 2nd IA was conducted at end of the blinded phase according to protocol (data cut-off Oct 9, 2013 with 63% of total PFS events) (Coutre, ASCO 2014). Samples for genetic analyses were analyzed by a central lab.RESULTS: 220 pts (110/group) with median age of 71 yrs (78% ≥65 yrs), median time since diagnosis of 8.5 yrs, and median number of 3 prior therapies (range: 1-12) were randomized. 43% had del(17p)/TP53 mutation and 84% had unmutated IGHV.At the time of data cut-off, the median (range) exposure was 5 (0-17) mos on IDELA+R and 4 (0-15) mos on PBO+R. 76% of pts on IDELA+R and 46% of pts on PBO+R were continuing on study.Median PFS was not reached for pts on IDELA+R and was 5.5 mos for pts on the comparator arm. At 12 months, the PFS rates for pts on IDELA treatment was 66% compared to 13% for pts on PBO+R. PFS strongly favored IDELA+R in all risk-subgroups, including those with genetic risk factors such as del(17p)/TP53 mutations, del(11q) (FIGURE 1) or unmutated IGHV as well as with disease-related risk factors like advance Rai stage or high levels of β2-microglobulin.Adverse events (any Gr/Gr ≥3) occurring in ≥20% of pts on IDELA treatment were: pyrexia (IDELA+R 35%/3%; PBO+R 17%/1%), fatigue (IDELA+R 28%/3%; PBO+R 27%/2%), nausea (IDELA+R 26%/0%; PBO+R 21/0%), chills (IDELA+R 21%/2%; PBO+R 16%/0%), diarrhea/colitis (IDELA+R 21%/5%; PBO+R 15%/0%). ALT/AST elevation (any Gr/Gr ≥3) occurred in 40%/8% of pts on IDELA+R and in 20%/1% of pts on PBO+R. At the time of this analysis, 19 total deaths had occurred on the primary study: 6 on IDELA+R and 13 on PBO+R. [Display omitted] a) Number of patients on both arms evaluable at the time of analysisb) Number of patients on both arms with respective test result. Note: Distribution of risk features on both arms was balanced.c) Includes 16 preferred terms [Display omitted] CONCLUSIONS: IDELA+R demonstrated statistically significant improvement over PBO+R in PFS, ORR, and OS with an acceptable safety profile in these frail pts with relapsed CLL. These results confirm the 1st interim analysis of comparable efficacy of IDELA+R across all risk groups, including those with high-risk genomic markers like del(17p), TP53 mutations, and del(11q). DisclosuresSharman:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Furman:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. O’Brien:Gilead Sciences: Research Funding. Tausch:Gilead Sciences: Research Funding. Kreuzer:Gilead Sciences: Research Funding. Jiang:Gilead Sciences: Employment, Equity Ownership. Lazarov:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Science: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Stilgenbauer:Gilead Sciences: Research Funding.

Ibrutinib Treatment of Relapsed CLL Following Allogeneic Transplantation: Sustained Disease Response and Promising Donor Immune Modulation

Background: Treatment of relapsed chronic lymphocytic leukemia (CLL) with ibrutinib results in high rates of progression-free and overall survival. Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), is FDA-approved for use in relapsed CLL. Ibrutinib may also modulate donor T cell alloimmunity via inhibition of interleukin-2-inducible kinase (ITK). Here we report the effects of ibrutinib salvage therapy in 5 CLL patients who relapsed following allogeneic hematopoietic cell transplantation (allo-HCT). In addition to minimal residual disease (MRD) response measurements, we also assessed donor T cell chimerism and donor B cell immune reconstitution following ibrutinib therapy.Methods: Five patients with high-risk CLL relapsed 1-8.5 yrs following allo-HCT. Four patients had never achieved donor CD3 T cell chimerism >95% following reduced-intensity transplant. Ibrutinib 420mg daily was started 1 mo-2 yrs after clinical relapse. Four of the 5 patients remain on ibrutinib with treatment courses ranging from 3-17 mos. CLL MRD was measured by IgH high-throughput sequencing (HTS) using the ClonoSIGHTTM test (Sequenta, Inc.), which has the sensitivity to detect 1 CLL clone per million leukocytes. Lymph node (LN) size was assessed by CT scan and reported as the sum of the products of the LN diameters (SPD). Donor B cell reconstitution was determined by IgH HTS quantification of total IgH molecules and unique IgH clonotypes.Results: Lymphocytosis was observed in all 5 patients following initiation of ibrutinib treatment, consistent with previous reports. In 2 patients who received >1 yr of ibrutinib treatment, lymphocytosis peaked at 3 wks and 8 wks after initiation of treatment and slowly declined thereafter, fully resolving within 1 yr (Fig 1A). All 4 patients with pathologic lymphadenopathy prior to treatment experienced dramatic LN reduction (Fig 1B; 68% average reduction in LN size after 3 mos on ibrutinib). The longest duration of follow-up is reported for patient SPN 3975, who had a 17p deletion and received ibrutinib for 39 mos. Treatment was discontinued after CLL MRD became undetectable by ClonoSIGHT (Fig 1C). Evidence of donor T cell immune modulation included achievement of full donor CD3 chimerism after 1 yr and resolution of oral and skin chronic graft-versus-host disease (GVHD) after 6 mos. Although this patient has been off ibrutinib for >8 mos, full donor chimerism persists and CLL MRD remains undetectable (Fig 1C). Before ibrutinib treatment, donor B cells (excluding the patient’s CLL clone) accounted for <0.2% of total PBMC as determined by IgH HTS. Following discontinuation of ibrutinib, the percentage of donor B cells increased within 6 months, and now comprises >1% of PBMC (Fig 1D). Furthermore, recovering B cells have diverse, low frequency IgH clonotypes (Fig 1E). Together, our findings show rapid, sustained, and diverse immune reconstitution without CLL recurrence following ibrutinib discontinuation.Conclusions: Ibrutinib provides effective salvage therapy for CLL relapse following allo-HCT. Post-transplant CLL relapse is often extra-nodal and our experience shows ibrutinib is effective in clearing both nodal and extra-nodal disease. Here we present one patient who stopped therapy after achieving MRD negativity and maintains undetectable disease 8 mos following ibrutinib discontinuation. Ibrutinib treatment demonstrates promising donor immune modulation by promoting full donor chimerism and resolution of chronic GVHD. Our five patient experience supports using ibrutinib in relapsed CLL patients following allo-HCT. Clinical trials are needed to determine the best duration of ibrutinib therapy following post-allo-HCT relapse, chronic GVHD treatment efficacy, and the role of ibrutinib maintenance following allo-HCT. [Display omitted] DisclosuresKong:Sequenta, Inc.: Employment, Equity Ownership. Klinger:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Coutre:Pharmacyclics, Inc.: Consultancy, Research Funding. Miklos:Sequenta, Inc.: Research Funding.

Long-Term Follow-up of a Phase 1 Trial of Idelalisib (ZYDELIG®) in Combination with Bendamustine (B), Bendamustine/Rituximab (BR), Fludarabine (F), Chlorambucil (Chl), or Chlorambucil/Rituximab (ChlR) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

BACKGROUND: PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ with considerable activity as monotherapy and in combination with R in patients with relapsed/refractory CLL, and was recently approved for the treatment of relapsed CLL in combination with R. This report summarizes the long-term follow-up of the Phase 1 combination experience of idelalisib with chemo- and immuno-chemotherapies.METHODS: 74 subjects were sequentially enrolled into one of 5 regimens of idelalisib combined with either B (70 or 90 mg/m2 IV on D1,2 of cycles 1-6, N=18, enrolled Apr 2011-Nov 2011), BR (B: 70 mg/m2 IV on D1,2 of cycles 1-6; R: 375 mg/m2 IV on D1 of cycles 1-6, N=15, enrolled Apr 2011-Aug 2011), F (40 mg/m2 po D1-5 of cycles 1-6, N=12, enrolled Apr 2011-Aug 2011), Chl (10 mg/m2 po D1-7 x 3(min)-12(max) cycles, N=15, enrolled Mar 2012-Aug 2012), or ChlR (N=14, enrolled Mar 2012-Jul 2012). Idelalisib was administered at 100 (4 of the pts receiving B) or 150 mg po BID (all other patients) continuously.Patients on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical responses were evaluated according to published criteria (Hallek 2008; Cheson 2012).RESULTS: Of 74 subjects enrolled, 66% were male. Median age was 65 years, and median time since diagnosis was 8 years with a median of 3 (range 1-9) prior regimens. Overall, prior therapies included R (97%), F (78%), B (45%), and Chl (14%), and 55% of patients were refractory to last therapy. 65% of patients had Rai stage III/IV disease at enrollment. Adverse prognostic factors included del(17p) and/or TP53 mutation (30%), IGHV unmutated status (82%), NOTCH1 mutation (28%).As of 7/15/2014, the median idelalisib exposure for patients of all cohorts was 12.8 (range 1-48) months. 41 (55%) of patients completed the 48 weeks of the primary study, and 20 subjects (27%) were still on treatment on the extension study at the time of analysis.The most common reasons for discontinuation reported by investigators were adverse events (AEs) (15, 20%) or progressive disease (PD) (12, 16%). There were 13 deaths reported on study; 4 patients experienced PD before death.Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (51%/18%), pyrexia (47%/5%), fatigue (35%/7%), cough (35%/0%), nausea (31%/1%), pneumonia (23%/14%), rash (22%/7%), dyspnea (19%/3%), and pneumonitis (3%/3%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 37%/14%. Of those, only 1 patient discontinued the study because of (recurrent) TA elevation. Richter’s transformation as category of progressive disease was reported in 1 patient (3%).The ORR was 82% for all 74 patients with a CR rate of 10%. 4 of 74 patients (5%) were not evaluable because of missing follow-up assessments. Among 69 subjects with genetic data available, the ORR in the 22 subjects with either del(17p) and/or TP53 mutation was 68% vs. 87% among 47 subjects with neither aberration. The overall median PFS was not reached at the time of analysis (Figure 1); KM estimate of PFS was 57% [43-72%, 95% CI] at 24 months. Overall median time to response was 1.9 months, and overall median DOR was not yet reached.CONCLUSIONS: These preliminary results in patients with relapsed or refractory disease and multiple prior therapies suggest that idelalisib can be combined with B, BR, F, Chl, and ChlR with acceptable safety and that these combinations have substantial clinical activity. A Phase 3 study evaluating the combination of idelalisib with BR in relapsed CLL is ongoing (NCT01732926). [Display omitted] DisclosuresBarrientos:Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Coutre:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment, Equity Ownership. Viggiano:Gilead Sciences: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Furman:Gilead Sciences: Research Funding.

Long-Term Follow-up of a Phase 1 Study of Idelalisib (ZYDELIG®) in Combination with Anti-CD20 Antibodies (Rituximab [R] or Ofatumumab [O]) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Long-Term Follow-up of a Phase 1 Study of Idelalisib (ZYDELIG®) in Combination with Anti-CD20 Antibodies (Rituximab [R] or Ofatumumab [O]) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)