ALADA Dose Optimization in the Computed Tomography of the Temporal Bone: The Diagnostic Potential of Different Low-Dose CT Protocols.

OBJECTIVE: Repeated computed tomography (CT) is essential for diagnosis, surgical planning and follow-up in patients with middle and inner ear pathology. Dose reduction to "as low as diagnostically acceptable" (ALADA) is preferable but challenging. We aimed to compare the diagnostic quality of images of subtle temporal bone structures produced with low doses (LD) and reference protocols (RP). METHODS: Two formalin-fixed human cadaver heads were scanned using a 64-slice CT scanner and cone-beam CT (CBCT). The protocols were: RP (120 kV, 250 mA, CTDIvol 83.72 mGy), LD1 (100 kV, 80 mA, CTDIvol 26.79 mGy), LD2 (100 kV, 35 mA, CTDIvol 7.66 mGy), LD3 (80 kV, 40 mA, CTDIvol 4.82 mGy), and CBCT standard protocol. Temporal bone structures were assessed using a 5-point scale. RESULTS: A median score of ≥2 was achieved with protocols such as the tendons of m. tensor tympani (RP/LD1/LD2/CBCT) and m. stapedius (CBCT), the incudostapedial joint (RP/LD1/CBCT), the incudomalleolar joint (RP/LD1/LD2/CBCT), the stapes feet (RP/LD1/CBCT), the stapes head (RP/LD1/LD2/CBCT), the tympanic membrane (RP/LD1/LD2/CBCT), the lamina spiralis ossea (none), the chorda tympani (RP/LD1/CBCT), and the modiolus (RP/LD1/LD2/CBCT). Adaptive statistical iterative reconstructions did not show advantages over the filtered back projection. CONCLUSIONS: LD protocols using a CTDIvol of 7.66 mGy may be sufficient for the identification of temporal bone structures.

Clonal dynamics in a composite chronic lymphocytic leukemia and hairy cell leukemia-variant.

Composite lymphoma is the rare simultaneous manifestation of two distinct lymphomas. Chronic lymphocytic leukemia (CLL) has a propensity for occurring in composite lymphomas, a phenomenon that remains to be elucidated. We applied cytogenetics, droplet digital polymerase chain reaction, and massively parallel sequencing to analyze longitudinally a patient with CLL, who 3 years later showed transformation to a hairy cell leukemia-variant (HCL-V). Outgrowth of the IGHV4-34-positive HCL-V clone at the expense of the initially dominant CLL clone with trisomy 12 and MED12 mutation started before CLL-guided treatment and was accompanied by a TP53 mutation, which was already detectable at diagnosis of CLL. Furthermore, deep sequencing of IGH showed a composite lymphoma with presence of both disease components at all analyzed timepoints (down to a minor clone: major clone ratio of ~1:1000). Overall, our analyses showed a disease course that resembled clonal dynamics reported for malignancies with intratumoral heterogeneity and illustrate the utility of deep sequencing of IGH to detect distinct clonal populations at diagnosis, monitor clonal response to therapy, and possibly improve clinical outcomes.

The prognostic value of additional copies of 1q21 in multiple myeloma depends on the primary genetic event.

Hyperdiploidy (HRD) and specific immunoglobulin heavy locus (IGH) translocations are primary chromosomal abnormalities (CA) in multiple myeloma (MM). In this retrospective study of 794 MM patients we aimed to investigate clinical features and common CA including gain(1q) in separate subgroups defined by primary CA. In the entire group, we confirmed that gain(1q) was associated with short time to next treatment and adverse overall survival (OS). The impact was worse for four or more copies of 1q21 as compared to three copies. However, in a subgroup of patients with clonal gain(11q) and without known primary IGH translocations (CG11q), already three copies of 1q21 were associated with a poor outcome; in the absence of gain(1q), patients in this subgroup had a remarkably long median OS of more than nine years. These cases were associated with HRD, coexpression of CD56 and CD117, male gender, and IgG subtype. In non-CG11q patients, four or more copies of 1q21 (but not three copies) had a significant adverse impact on outcome. Several associations with CA and clinical findings were observed for the defined subgroups. As an example, we found a predominance of early tetraploidy, plasma cell leukemia, and female gender in the t(14;16) subgroup. Our results underscore the importance of subgrouping in MM.

Magnetic resonance cholangiopancreatography with compressed sensing at 1.5 T: clinical application for the evaluation of branch duct IPMN of the pancreas.

OBJECTIVES: To evaluate magnetic resonance cholangiopancreatography (MRCP) with compressed sensing (CS) for the assessment of branch duct intraductal papillary mucinous neoplasm (BD-IPMN) of the pancreas. For this purpose, conventional navigator-triggered (NT) sampling perfection with application-optimized contrast using different flip angle evolutions (SPACE) MRCP was compared with various CS-SPACE-MRCP sequences in a clinical setting. METHODS: A total of 41 patients (14 male, 27 female, mean age 68 years) underwent 1.5-T MRCP for the evaluation of BD-IPMN. The MRCP protocol consisted of the following sequences: conventional NT-SPACE-MRCP, CS-SPACE-MRCP with long (BHL, 17 s) and short single breath-hold (BHS, 8 s), and NT-CS-SPACE-MRCP. Two board-certified radiologists evaluated image quality, duct sharpness, duct visualization, lesion conspicuity, confidence, and communication with the main pancreatic duct in consensus using a 5-point scale (1-5), with higher scores indicating better quality/delineation/confidence. Maximum intensity projection reconstructions and originally acquired data were used for evaluation. Wilcoxon signed-rank test was used to compare the intra-individual difference between sequences. RESULTS: BHS-CS-SPACE-MRCP had the highest scores for image quality (3.85 ± 0.79), duct sharpness (3.81 ± 1.05), and duct visualization (3.81 ± 1.01). There was a significant difference compared with NT-CS-SPACE-MRCP (p < 0.05) but no significant difference to the standard NT-SPACE-MRCP (p > 0.05). Concerning diagnostic quality, BHS-CS-SPACE-MRCP had the highest scores in lesion conspicuity (3.95 ± 0.92), confidence (4.12 ± 1.08), and communication (3.8 ± 1.06), significantly higher compared with NT-SPACE-MRCP, BHL-SPACE-MRCP, and NT-CS-SPACE-MRCP (p = <0.05). CONCLUSIONS: MRCP with CS 3D SPACE for the evaluation of BD-IPMN at 1.5 T provides the best results using a short breath-hold sequence. This approach is feasible and an excellent alternative to standard NT 3D MRCP sequences. KEY POINTS: • 1.5-T MRCP with compressed sensing for the evaluation of branch duct IPMN is a feasible method. • Short breath-hold sequences provide the best results for this purpose.

Five-year survival follow-up of a phase III randomised trial comparing ofatumumab versus physicians' choice for bulky fludarabine-refractory chronic lymphocytic leukaemia: a short report.

In 2014, an interim analysis of a phase 3 study was performed to evaluate the effectiveness of ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukaemia (BFR CLL) as compared to physician's choice. The five-year follow-up of this phase 3 trial showed that ofatumumab therapy resulted in a numerically but not significantly longer overall survival. As only few patients had the chance to receive a kinase inhibitor later, the study displays the survival of BFR CLL patients in the period prior to receiving small-molecule inhibitors. Ofatumumab is a well-tolerable treatment option in multiresistant advanced CLL.

Recommendations for ibrutinib treatment in patients with atrial fibrillation and/or elevated cardiovascular risk.

Ibrutinib is the first clinically approved inhibitor of Bruton's tyrosine kinase, an enzyme that is essential for survival and proliferation of B­cells by activating the B­cell receptor signalling pathway. Ibrutinib has been shown to be highly effective in B­cell malignancies in clinical trials and is recommended in current international guidelines as a first and/or second line treatment of chronic lymphocytic leukemia. The drug has a favorable tolerability and safety profile but the occurrence of specific side effects (e.g. atrial fibrillation, bleeding and hypertension) may complicate or be of concern for doctors and patients considering the use of this treatment. In many cases, however, it is not necessary to withhold this effective therapy. In contrast, ibrutinib treatment can be initiated or continued, if certain recommendations are followed. The possibilities of prevention, diagnosis and management of specific clinical situations are discussed in detail and recommendations are derived, which should facilitate ibrutinib use.

Cerebrospinal Fluid Drug Concentrations and Clinical Outcome of Patients with Neoplastic Meningitis Treated with Liposomal Cytarabine.

BACKGROUND AND OBJECTIVE: Liposomal cytarabine is a slow-release formulation for intrathecal application in patients with neoplastic meningitis. Although standard dosing intervals range from 2 to 4 weeks, it is unclear whether sustained cytotoxic cerebrospinal fluid (CSF) concentrations can be achieved beyond 14 days from drug injection. The objective of this study was to assess CSF and plasma concentrations of liposomal cytarabine more than 2 weeks after lumbar drug administration and to correlate those findings with clinical outcome. METHODS: 66 matched CSF and plasma drug concentrations were analyzed by a validated liquid chromatography-tandem mass spectrometry method starting at day 13 from lumbar drug injection in 19 patients with neoplastic meningitis treated with liposomal cytarabine. CSF drug concentrations were correlated with clinical outcome. RESULTS: Overall response rate was 63.2% (12/19). 100% (9/9) of patients with positive CSF cytology at diagnosis achieved cytological complete remission, and none of the patients (0/19) experienced on-drug disease progression. In responding patients with controlled systemic disease, CNS-specific progression-free survival was 14 months (n = 4; range 5-25 months). The median CSF concentration of free cytarabine was 156 ng/ml (range 5-4581 ng/ml) and 146 ng/ml (range 5-353 ng/ml) in samples withdrawn at days 13-16 and at days 25-29 after intrathecal drug injection, respectively. Free cytarabine concentrations > 100 ng/ml were detected in 58.8% (20/34) and 53.3% (7/13) of the CSF samples obtained at days 13-16 and days 25-29, respectively. CSF drug concentrations did not differ significantly between responding and nonresponding patients. CONCLUSION: Liposomal cytarabine permits prolonged CSF drug exposure, with cytotoxic cytarabine concentrations that are detectable for 4 weeks in the majority of patients. The preserved clinical activity seen in patients with inferior CSF drug concentrations (< 100 ng/ml) suggests that maintaining lower cytarabine concentrations for a longer period of time may be similarly effective as using short peak concentrations.

Complementing clinical cancer registry data with patient reported outcomes: A feasibility study on routine electronic patient-reported outcome assessment for the Austrian Myelome Registry.

OBJECTIVES: Routinely assessed patient-reported outcomes (PROs), such as quality of life (QOL), are important to supplement clinical cancer data but requires rigorous implementation. This study aims at depicting the implementation procedure and evaluating the feasibility of routine electronic PRO monitoring (ePRO) for collecting data supplementing the Austrian Myeloma Registry (AMR). METHODS: Integration of ePRO monitoring into clinical routine was planned according to the Replicating Effective Programs framework. QOL data were assessed regularly during treatment and aftercare at the hematooncological outpatient unit at the Medical University of Innsbruck with the EORTC QLQ-C30/ +MY20 and the EQ-5D-5L. Feasibility and usability testing were performed via a multimethod approach. RESULTS: Within the first year, 94.4% of the MM patients (N = 142, mean age 65.4, SD 11.8, 60% male) provided 748 PRO assessment time points overall. Patients and clinicians were satisfied with ePRO monitoring and indicated no to little disruption in clinical routine. Patient preference on assessment time points and completion frequency became evident. CONCLUSIONS: Complementing the AMR with ePRO data proved to be feasible. Our findings provide useful insights for healthcare providers considering introducing ePRO monitoring to their units for informing clinical registries as well as individualised feedback to patients alike.

Olaptesed pegol (NOX-A12) with bendamustine and rituximab: a phase IIa study in patients with relapsed/refractory chronic lymphocytic leukemia.

Olaptesed pegol (NOX-A12) is a pegylated structured L-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine tightly regulating the life cycle of chronic lymphocytic leukemia cells. The resulting inhibition of CXCR4 and CXCR7 signaling reduces the protective activity of the bone marrow and lymph node microenvironment. CXCL12 inhibition mobilizes chronic lymphocytic leukemia cells into the circulation and prevents their homing into the protective niches. In this phase I/II study, 28 patients with relapsed/refractory chronic lymphocytic leukemia were treated with olaptesed pegol in combination with bendamustine and rituximab. Combination treatment was preceded by single escalating pilot doses of olaptesed pegol in the first ten patients for evaluation of safety and pharmacokinetics. Peak concentrations and systemic exposure of olaptesed pegol were dose-linear; plasma elimination was monophasic with a 53.2 h half-life. A rapid increase in circulating chronic lymphocytic leukemia cells was observed already 1 h after administration of olaptesed pegol and lasted for at least 72 h. Single-agent treatment was well tolerated and no dose-limiting toxicity was observed. The combination regimen yielded an overall response rate of 86%, with 11% of patients achieving a complete response and 75% a partial response. Notably, all ten high-risk patients, including four with a 17p deletion, responded to treatment. The median progression-free survival was 15.4 (95% confidence interval: 12.2, 26.2) months while the median overall survival was not reached with >80% of patients alive after a median follow-up of 28 months. Olaptesed pegol was well tolerated and did not result in additional toxicity when combined with bendamustine and rituximab (ClinicalTrials.gov identifier: NCT01486797). Further clinical development of this novel CXCL12 inhibitor is thus warranted.

Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL-8a mabtenance trial.

No data are available regarding obesity and outcome in Chronic Lymphocytic Leukemia (CLL). We analyzed 263 patients from the AGMT CLL-8a Mabtenance trial for the impact of obesity. The trial included patients after rituximab-containing induction treatment in first or second line that had achieved at least a PR. A randomization to rituximab maintenance treatment (375 mg/m2 q3 months for 2 years) vs observation was performed. In this cohort 22% of the patients (58/263) were classified as obese. The baseline response to induction treatment was inferior in obese patients with a lower CR rate (43.1% vs 60.5% in obese vs non-obese, P = 0.018) and with a lower rate of patients achieving MRD negativity after chemoimmunotherapy induction treatment (19.6% vs 35.8%, P = 0.02). The PFS outcome of obese patients was significantly worse in the observation group of the trial (24 vs 39 months median PFS, P = 0.03). However, in the rituximab maintenance group the outcome for obese vs non-obese was not different (P = 0.4). In summary, obesity was overall associated with a worse outcome of chemoimmunotherapy induction. However, rituximab maintenance treatment seems to be able to overcome this negative effect.

Current and evolving treatment strategies in adult immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune phenomenon resulting in low platelet count and increased bleeding risk. Goals of upfront management include prompt control of severe bleeding-which is rare-as well as induction and maintenance of a hemostatic platelet count. Thus, optimal management of ITP patients is often challenging and requires a highly individualized approach. Many patients may not suffer significant bleeding despite severe thrombocytopenia and the risk of toxicity associated with treatment may outweigh its benefit. Most patients treated with standard first-line regimen of glucocorticoids achieve an initial response. However, the rate of long-term remission remains low and multiple lines of therapy are often required. Current investigations aim at defining the subgroup of patients at risk of relapse and providing intensified risk-balanced induction regimens to improve long-term disease control. This short review summarizes current and emerging treatment strategies in adult ITP.

Chronic lymphocytic leukemia at ASH 2017.

At ASH (American Society of Hematology) 2017 three out of a plethora of trials showed remarkable and promising results. The combinations of venetoclax with rituximab and ibrutinib with venetoclax convinced with striking efficacy together with a manageable safety profile in relapsed/refractory setting as well as in first line therapy of high-risk disease. These two combinations are potential new standard treatment options in chronic lymphocytic leukemia.

Correction to: Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study.

The original version of this article contained a mistake. The name of Tanja Nicole Hartman should have been Tanja Nicole Hartmann. The original article has been corrected.

Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study.

Despite recent advances, chemoimmunotherapy remains a standard for fit previously untreated chronic lymphocytic leukaemia patients. Lenalidomide had activity in early monotherapy trials, but tumour lysis and flare proved major obstacles in its development. We combined lenalidomide in increasing doses with six cycles of fludarabine and rituximab (FR), followed by lenalidomide/rituximab maintenance. In 45 chemo-naive patients, included in this trial, individual tolerability of the combination was highly divergent and no systematic toxicity determining a maximum tolerated dose was found. Grade 3/4 neutropenia (71%) was high, but only 7% experienced grade 3 infections. No tumour lysis or flare > grade 2 was observed, but skin toxicity proved dose-limiting in nine patients (20%). Overall and complete response rates after induction were 89 and 44% by intention-to-treat, respectively. At a median follow-up of 78.7 months, median progression-free survival (PFS) was 60.3 months. Minimal residual disease and immunoglobulin variable region heavy chain mutation state predicted PFS and TP53 mutation most strongly predicted OS. Baseline clinical factors did not predict tolerance to the immunomodulatory drug lenalidomide, but pretreatment immunophenotypes of T cells showed exhausted memory CD4 cells to predict early dose-limiting non-haematologic events. Overall, combining lenalidomide with FR was feasible and effective, but individual changes in the immune system seemed associated with limiting side effects. clinicaltrials.gov (NCT00738829) and EU Clinical Trials Register ( www.clinicaltrialsregister.eu , 2008-001430-27).

Impact of white blood cells on thrombotic risk in patients with optimized platelet count in essential thrombocythemia.

OBJECTIVES: Risk of thrombosis is significantly enhanced by both elevated platelet (PLT) and white blood cell (WBC) counts according to a retrospective analysis of a large anagrelide registry in thrombocythemic MPN patients. We were interested in the impact of elevated WBC counts on thrombosis risk in patients where PLT counts were reduced below the calculated cutoff of 574.5 G/L by treatment with anagrelide. METHODS: Cox regression analysis and Kaplan-Meier plot were applied on all patients in the registry with optimized PLT counts. RESULTS: Using the calculated cutoff of 9.66 G/L for WBC, Cox regression analysis revealed a clear influence of elevated WBC counts on the occurrence of a major thrombotic event (P = .012). A Kaplan-Meier plot revealed a markedly shorter time to a major thrombotic event for patients with WBC counts above the cutoff (P = .001). CONCLUSIONS: These data suggest that additional correction of elevated WBC counts is mandatory in patients with optimally managed PLT counts to reduce thrombotic risk. This study is the first investigation in a prospectively observed large patient cohort which was treated homogenously allowing for evaluation of single parameters for an effect on thrombophilia.