Page 153 - 2019_11 Resto del Mondo-web
P. 153

dysfunction (including 17p deletion and/or TP53 muta- tion), advanced stage disease, disease burden, and thera- peutic regimen.1,6,7
Chronic lymphocytic leukemia generally exhibits low levels of 18-F-fluorodeoxyglucose (FDG) uptake on positron emission tomography-computed tomography (PET-CT), compared to aggressive lymphomas and trans- formed lymphomas.8,9 This difference suggests that PET- CT would be a useful tool for distinguishing aggressive versus indolent lymphomas and for selection of nodes for transformation confirmation biopsy. Various studies examining CLL and RT provide a considerable amount of data to inform the use of PET-CT imaging as a tool for dis- tinguishing RT from CLL after chemoimmunotherapy, including standardized uptake value (SUVmax) cutoff thresholds.3,9,10 Recent studies have emphasized the unfa- vorable prognosis for patients with RT following treat- ment with targeted agents, such as the B-cell receptor sig- naling pathway inhibitors (BCRi) ibrutinib or idelalisib.11,12 Patients who progress after BCRi therapy often demon- strate highly proliferative CLL, even in the absence of a RT, possibly relating to biological differences required for rapid disease progression after BCRi, and thus requiring re-evaluation of PET-CT SUVmax cutoffs for distinguish- ing RT from CLL.
Venetoclax is a selective, orally bioavailable small-mole- cule BCL-2 inhibitor that has been approved for patients with previously-treated CLL del(17)(p13.1) and for those without del(17)(p13.1) or TP53 mutation who have not responded to chemoimmunotherapy and BCR-inhibitor therapy.13,14 Given the promising efficacy of venetoclax across a broad range of patients with relapsed/refractory CLL,15,16 an open-label, phase II study was conducted to evaluate venetoclax monotherapy in patients with CLL refractory to or progressed after discontinuation of ibruti- nib or idelalisib. Per protocol, all consenting patients were required to undergo PET-CT imaging at screening, with FDG-avid lymph node biopsy in patients with a suspicion of RT. Here we describe a post hoc analysis to determine if PET-CT and/or patient characteristics were able to differ- entiate RT versus CLL progression for patients who discon- tinued BCRi. We also report on the incidence of RT on venetoclax in these patients and how pre-venetoclax PET- CT SUVmax may predict clinical outcomes.
Methods
Study design and overview
Data from a phase II, open-label, multicenter trial (clinicaltrials.gov identifier: 02141282) of venetoclax monotherapy enrolled patients with CLL relapsed/refractory following ibrutinib or idelalisib were analyzed post hoc.17 At each participating site, the institutional review board approved the study protocol and amendments. Study activities were conducted in accordance with ethical principles established in the Declaration of Helsinki and the International Conference on Harmonization Guideline for Good Clinical Practice. All patients provided written informed consent.
Patients
Adults with CLL refractory to or progressed after discontinua- tion of ibrutinib or idelalisib who required therapy according to 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria18 were eligible. Included patients had Eastern
Identifying Richter’s after BCRi Therapy
Cooperative Oncology Group performance score of ≤ 2, adequate bone marrow function (absolute neutrophil count ≥1x109/L, platelet count ≥30x109/L, hemoglobin ≥8 g/dL), and creatinine clearance ≥50 mL/minute. Patients were excluded if RT was con- firmed on biopsy (see details below), and if they had active and uncontrolled autoimmune cytopenias, unresolved toxicities from prior therapy, or allogeneic stem cell transplantation within one year of study entry.17
Venetoclax treatment
Venetoclax was administered orally once daily beginning no sooner than three days after the last prior therapy. Patients received 20 mg daily for one week, followed by a weekly dose increase to reach the final dose of 400 mg daily by week 5.17
Assessments
Screening - patients who signed informed consent, had at least one screening assessment; in case of failed screening they did not proceed on the study. PET-CT imaging within 28 days prior to venetoclax administration was performed on all patients; results were locally reviewed and the node with highest SUV that met protocol criteria was chosen to have either excisional or core biop- sy. Based on published literature,3,9,19 and as per the study protocol, biopsy of the suspicious area was mandatory if FDG uptake on PET-CT scan was above SUVmax ≥10, or for patients with CD38 positive, ZAP-70 positive, TP53 disrupted or IGHV unmutated CLL with SUVmax 4-10 with at least one of the following: B- symptoms, lymph node >5 cm, and/or lactate dehydrogenase (LDH) elevation. Additional screening procedures and on-study assessments are described in the Online Supplementary Appendix.
Statistical analysis
Using June 30th 2017 as the data cutoff, this post hoc analysis was conducted to evaluate PET-CT characteristics (lymph node SUVmax ≥5 and SUVmax ≥10) and patients' clinical features that may differentiate RT from CLL progression for patients who were screening for this study following discontinuation of prior BCRi therapy.3,9 Descriptive statistics were used to describe PET-CT test characteristics and patients' clinical features. Logistic regression analyses were performed to evaluate if biopsy following PET-CT could differentiate RT post-BCRi therapy during screening. Additional available data on clinical/laboratory parameters for CD38, ZAP70, TP53 and IGHV mutation status, LDH, beta-2 (β2)- microglobulin, and tumor size by logistic regression were also evaluated to determine if any of these patient features may distin- guish RT from CLL in this patient population. Based on statistical experience, the small sample size, and uniform direction for all analyses for clinical applicability, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operator characteristic (ROC) curve were calcu- lated. The following definitions were used.
Sensitivity: number of patients with true positive divided by observed positive;
Specificity: number of patients with true negative divided by observed negative;
PPV: number of patients with true positive divided by estimated positive;
NPV: number of patients with true negative divided by estimat- ed negative.
Statistical analyses were evaluated for all patients who enrolled and received at least one dose of venetoclax. Overall response rate (ORR) was calculated with a 95% confidence interval based on binomial distribution. Kaplan-Meier methods were used for time- to-event analyses. Differences in outcomes on venetoclax were stratified based on screening SUVmax cutoff of 10. SAS software
haematologica | 2019; 104(11)
2259


































































































   151   152   153   154   155