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Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofatumumab pharmacokinetics.Trial registrationwww.clinicaltrials.gov (NCT00410163).

The objective of this study was to evaluate the safety and efficacy of different lenalidomide starting doses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). CLL patients were randomized to receive lenalidomide at initial doses of 5, 10, or 15 mg/d (N = 103). Doses were escalated by 5 mg every 28-d up to a maximum of 25 mg/d; dose reductions in up to 5 mg decrements were permitted. The most common grade ≥3 adverse events (AEs) were neutropenia and thrombocytopenia. Ten patients died during therapy (four deaths considered as related to lenalidomide); 12 patients experienced second primary malignancies. The most common cause for treatment discontinuation was AEs. Overall response rates were similar across arms. Progression-free survival and overall survival rates were longer in patients who escalated treatment (to 15 or 20 mg/d) versus those who did not. Lower starting doses allowed subsequent dose escalation of lenalidomide while maintaining an acceptable tolerability profile in patients with relapsed/refractory CLL.

The SCHOLAR-2 retrospective study highlighted poor overall survival (OS) with standard of care (SOC) regimens among patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who failed a covalent Bruton tyrosine kinase inhibitor (BTKi). In the ZUMA-2 single-arm trial, brexucabtagene autoleucel (brexu-cel; autologous anti-CD19 CAR T-cell therapy) demonstrated high rates of durable responses in patients with R/R MCL who had previous BTKi exposure. Here, we compared OS in ZUMA-2 and SCHOLAR-2 using three different methods which adjusted for imbalances in prognostic factors between populations: inverse probability weighting (IPW), regression adjustment (RA), and doubly robust (DR). Brexu-cel was associated with improved OS compared to SOC across all unadjusted and adjusted comparisons. Hazard ratios (95% confidence intervals) were 0.38 (0.23, 0.61) for IPW, 0.45 (0.28, 0.74) for RA, and 0.37 (0.23, 0.59) for DR. These results suggest a substantial survival benefit with brexu-cel versus SOC in patients with R/R MCL after BTKi exposure. [ABSTRACT FROM AUTHOR]

Altogether twenty-seven patients with relapsed or refractory CLL were enrolled between December 2014 and December 2017 of which 10 patients received FCG and 17 patients received BG (Supplemental Digital Content (SDC) Figure 1). Before the introduction of targeted oral inhibitors to the treatment of chronic lymphocytic leukemia, chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) as well as bendamustine and rituximab (BR) was considered the standard treatment in fit patients. Patients were mainly treated with targeted substances, in particular ibrutinib [FCG 4 of 6 patients (67%), BG 8 of 8 patients (100%)], which was approved first of all by the EMA. [Extracted from the article]

Patients with diffuse large B-cell lymphoma (DLBCL) treated with the R-CHOP regime receive a high cumulative dose of prednisone. We used computer tomography-ascertained Hounsfield units (HU) as a surrogate parameter for bone mineral density (BMD) in three different locations of the L3 vertebral body at baseline and post-treatment. HU were measured in 50 patients with DLBCL of the previously published FLYER-trial which compared four cycles of R-CHOP + 2 × rituximab infusion to six cycles of R-CHOP in young, favorable DLBCL patients. In total, median loss was 26.8 HU in all patients over time. The median HU loss was significantly lower in the four cycles arm (21.3 HU vs. 41.3 HU, p = 0.023). In conclusion, young patients with DLBCL receiving R-CHOP have significant HU/BMD loss under treatment with R-CHOP. Patients receiving four cycles of R-CHOP had less HU/BMD loss than patients receiving six cycles. [ABSTRACT FROM AUTHOR]

The advent of novel B-cell receptor pathway targeting agents like ibrutinib dramatically changed management of B-cell malignancies. However, with concomitant anticoagulation (AC) and antiplatelet (AP) therapy, ibrutinib is associated with increased bleeding. This post hoc analysis aimed to determine the role of AC/AP therapy in patients with idelalisib-treated B-cell malignancies and to establish if it contributes to increased bleeding events. Data from two idelalisib trials (rituximab ± idelalisib in chronic lymphocytic leukemia [CLL] and idelalisib monotherapy in indolent non-Hodgkin lymphoma [iNHL]) were analyzed. Antithrombotic therapy was common (36%–63%), with comparable bleeding incidence across treatment groups (14%–19%; p = 0.56). Bleeding events of grade ≥3 occurred in 0.9% and 3.2% of the idelalisib-treated CLL and iNHL cohorts, respectively. Our findings demonstrate no increase in bleeding events with simultaneous AC/AP treatment and idelalisib use. Hemorrhagic risk is prevalent in these patients and an important consideration when evaluating available treatment options. ClinicalTrials.gov identifiers: NCT01539512 and NCT01282424 [ABSTRACT FROM AUTHOR]

Clinical trials in T-cell prolymphocytic leukemia (T-PLL) are scarce. Based on a precursor study testing fludarabine, mitoxantrone, and cyclophosphamide followed by alemtuzumab (FMC-A), we aimed to improve this regimen by upfront combining subcutaneous (s.c.) alemtuzumab with FMC for four cycles followed by an alemtuzumab-maintenance (FMCA + A). This prospective multicenter phase-II trial assessed response, survival, and toxicity of that regimen administered to pretreated (n = 4) and treatment-naïve (n = 12) T-PLL patients. The best overall response rate after FMCA was 68.8% (n = 11) including five CRs (31.3%) and six PRs (37.5%). Six patients entered the alemtuzumab-maintenance. Median overall and progression-free survival was 16.7 and 11.2 months, respectively. Hematologic toxicities were the most frequent grade 3/4 side effects. A reduced incidence of CMV-reactivations was attributed to the prophylactic administration of valganciclovir. Overall, FMCA + A did not improve the efficacy of the FMC-A-regimen or of single i.v. alemtuzumab. It suggests that a chemotherapy backbone prevents efficient alemtuzumab dosing and confirms that intravenous alemtuzumab is to be preferred over its s.c. route in T-PLL. ClinicalTrials.gov identifier: NCT01186640. [ABSTRACT FROM AUTHOR]

Telomere length in chronic lymphocytic leukemia (CLL) is described as an independent prognostic factor based largely on previously untreated patients from chemotherapy based trials. Here, we studied telomere length associations in high-risk, relapsed/refractory CLL treated with alemtuzumab in the CLL2O study (n = 110) of German and French CLL study groups. Telomere length (median 3.28 kb, range 2.52-7.24 kb) was relatively short, since 84.4% of patients had 17p- which is generally associated with short telomeres. Median telomere length was used for dichotomization into short and long telomere subgroups. Telomere length was associated with s-TK (p = .025) and TP53 mutations (p = .050) in untreated patients, while no association with clinical/biological characteristics was observed in relapsed/refractory CLL. Short telomeres had significant association with shorter PFS (p = .018) only in refractory CLL. Presence of short telomeres, loss of genes maintaining genomic integrity (SMC5) and increased incidence of chromothripsis, indicated the prevalence of genomic instability in this high-risk cohort (clinicaltrials.gov: NCT01392079). [ABSTRACT FROM AUTHOR]

Multidimensional geriatric assessment (GA) has been demonstrated to predict outcomes in older patients with cancer. This study evaluated GA in a cohort of older patients with chronic lymphocytic leukemia (CLL). Seventy-five of 97 subjects with CLL who were enrolled in a clinical trial of the German CLL Study Group underwent GA prior to the start of study treatment (low-dose chemotherapy with fludarabine). GA included cumulative illness rating scale (CIRS), timed-up-and-go (TUG) test, dementia detection (DEMTECT) test and instrumental activities of daily living (IADL) index. There was little correlation between CIRS, TUG, DEMTECT or IADL results and treatment toxicity, feasibility or efficacy in this study. CIRS and IADL had no statistically significant impact on overall prognosis. However, under-performance in TUG or DEMTECT test was strongly associated with poor survival. The latter findings provide a rationale to further investigate geriatric assessment in CLL and in the context with other CLL treatments. [ABSTRACT FROM AUTHOR]

The ATM-p53 DNA damage response pathway plays a crucial role in chemoresistance in chronic lymphocytic leukemia, as indicated by the adverse prognostic impact of deletions of 17p (locus of TP53) and 11q (locus of ATM) detected by fluorescence in situ hybridization (FISH) analysis. In addition to deletions, mutations in these respective genes are also associated with chemoresistance, and add to the prognostic information provided by FISH. In order to explore the possibility that dysfunction of the ATM-p53 pathway might also result from mechanisms other than ATM/ TP53 deletion/mutation, assays have been developed that probe the functional integrity of the ATM-p53 pathway. Currently, four different p53 function assays have been developed that are based on the measurement of p53 and p53-dependent genes at the RNA (real-time polymerase chain reaction [RT-PCR] p21; RT-PCR miR34a; reverse transcription-multiplex ligation-dependent probe amplification assay [RT-MLPA] p21, bax, puma and CD95) or protein (fluorescence activated cell sorting [FACS]p53-p21) level in untreated cells or following irradiation or drug treatment. Here we provide an overview of these assays based on the available literature. [ABSTRACT FROM AUTHOR]

BRAF mutations have been shown to occur at a high frequency in melanoma and thyroid cancer, but also at lower frequencies in hematological malignancies. To assess the potential role of BRAF, we have sequenced exons 11 and 15 of BRAF in 138 cases with chronic lymphocytic leukemia (CLL) and 32 cases of B-cell prolymphocytic leukemia (B-PLL). We found an incidence of BRAF mutations of 2.8% in CLL (4/138), while no cases with B-PLL showed BRAF mutations. The analysis of a cohort of patients with fludarabine-refractory disease ( n = 87) showed no increase in the mutation incidence, suggesting that this mutation is not selected for during the disease progression. A limited analysis of the effect of BRAF inhibition in primary CLL cells showed no cell death induction in CLL samples with and without BRAF mutations. Our analysis suggests that BRAF mutations occur at a low frequency in CLL. The pharmacological inhibition of MEK/ERK signaling using the mutant BRAF inhibitor PLX4720 showed no effect on viability in vitro in CLL cases. [ABSTRACT FROM AUTHOR]

AbstractIn chronic lymphocytic leukemia (CLL), TP53 mutations or deletions on chromosome 17p lead to adverse prognosis and reduced levels of miR-34a, which targets NOTCH1. Also, hyperactivated NOTCH1 signaling is crucial for CLL progression. Here we explored the interaction between p53, miR-34a, and NOTCH1 in CLL. We investigated the effect of p53 and miR-34a on NOTCH1 signaling and expression in CLL cells with altered TP53. Our results indicate that miR-34a reduces NOTCH1 3’ UTR activity but might not be a mediator between p53 signaling and NOTCH1. p53 activation increases miR-34a expression and NOTCH1 protein levels, correlating with decreased NOTCH1 and miR-34a levels in primary CLL cells with TP53 alterations. Some samples with high NOTCH1 levels presented increased BCL-2, suggesting an anti-apoptotic mechanism of a potentially direct p53-NOTCH1 relation in CLL. This study deepens the understanding of the p53-miR-34a-NOTCH1 signaling network, providing insights that could guide future therapeutic strategies for CLL. [ABSTRACT FROM AUTHOR]

The article presents a commentary on the rapid detection of mutations in TP53 and ATM genes as a tool for diagnosing chronic lympocytic leukemia (CLL). It describes the outcome of the evaluation of the functionality of the genes using reverse-transcription polymerase chain reaction (RT-PCR). Also discussed is the use of flow cytometry to conduct functional analysis of the ATM and p53 pathway in primary CLL cells.

The article presents author's view on the prognostic factors in chronic lymphocytic leukemia (CLL) with reference to an article within this issue. He describes CLL as a disease of failed apoptosis. He discusses the prognostic factor armentarium which has been established for CLL by studying the expression of transferring cell receptor CD71. The authors developed a BCL-2/CD71 based stratification which added to their models, with poorest outcome for patients with high expression of both.