Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab.

The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years' follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10-7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.

First impressions count: Therapists' impression on patients' motivation and helping alliance predicts psychotherapy dropout.

OBJECTIVE: With meta-analytically estimated rates of about 25%, dropout in psychotherapies is a major concern for individuals, clinicians, and the healthcare system at large. To be able to counteract dropout in psychotherapy, accurate insights about its predictors are needed. METHOD: We compared logistic regression models with two machine learning algorithms (elastic net regressions and gradient boosting machines) in the prediction of therapy dropout in two large inpatient samples (N = 1,691 and N = 12,473) using baseline and initial process variables reported by patients and therapists. RESULTS: Predictive accuracies of the two machine learning algorithms were similar and higher than for logistic regressions: Therapy dropout could be predicted with an AUC of .73 and .83 for Sample 1 and 2, respectively. The initial evaluation of patients' motivation and the therapeutic alliance rated by the respective therapist were the most important predictors of dropout. CONCLUSIONS: Therapy dropout in naturalistic inpatient settings can be predicted to a considerable degree by using baseline indicators and therapists' first impressions. Feature selection via regularization leads to higher predictive performances whereas non-linear or interaction effects are dispensable. The most promising point of intervention to reduce therapy dropouts seems to be patients' motivation and the therapeutic alliance.

miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors.

B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.

The impact of COVID-19 on cancer care of outpatients with low socioeconomic status.

Patients with low socioeconomic status (SES) are among the most underserved groups of people regarding cancer care. Analyzing the impact of the coronavirus-induced disease 2019 (COVID-19) pandemic on health care disparities and calling attention to inequalities in cancer care is crucial to justify and initiate adequate countermeasures. We aimed to determine whether the COVID-19 pandemic aggravated health care disparities of cancer outpatients related to their SES and analyzed patient data of the largest university center providing services for patients with hematologic and oncologic disorders in Austria from 2018 to 2021. SES was assessed using three indicators: monthly net household income, level of education and occupational prestige. In total, 1217 cancer outpatients (51.1% female) with a mean age of 59.4 years (SD = 14.2) participated. In the first year of the pandemic, the relative proportion of individuals with low income, low education level and low occupational prestige seeking cancer care at our outpatient center decreased significantly (P ≤ .015). The strongest indicator was income, with a consistent effect throughout the first pandemic year. Countermeasures and specific interventions to support cancer patients with low SES in their access to health care should be initiated and prioritized.

[Reliability and validity of the OPD-conflict-questionnaire in an inpatient treatment sample]. / Reliabilität und Validität des OPD-Konfliktfragebogens bei stationären Psychotherapiepatient*innen.

Reliability and validity of the OPD-conflict-questionnaire in an inpatient treatment sample Objectives: Unconscious conflicts are a major part of psychodynamic diagnostics. Benecke et al. (2018) developed the OPD-conflict-questionnaire (OPD-CQ) to assess unconscious conflicts according to the Operationalized Psychodynamic Diagnostics (OPD) via self-report. We inspected its reliability and validity in a large inpatient sample with a focus on correlations with symptomatic burden, interpersonal problems, and structural level. Methods: N = 2083 patients completed questionnaires at the beginning of their inpatient stay in the Fachklinikum Tiefenbrunn between 2017 and 2020. We calculated internal consistencies of the OPD-CQ scales and (partial-)correlations of the OPD-CQ scales with different instruments. Results: Internal consistencies were only partly satisfying (for eight of 13 scales). We found significant (partial-)correlations of the conflicts with symptom severity and interpersonal problems which were in line with expectations. However, structural level correlated with more conflicts than we expected. Conclusions: Due to the low internal consistencies of some scales, we recommend a revision of the OPD-CQ. Still, the found correlations show the potential of the OPD-CQ as a screening instrument for patients in inpatient treatment.

[Attachment predicts changes in the level of personality functioning after psychotherapeutic inpatient treatment]. / Bindung als Prädiktor von Strukturveränderungen im Verlauf von stationärer Psychotherapie.

Objectives: The relationship between patients' attachment strategies and the effectiveness of psychotherapy is empirically well established. However, studies on outcome measures other than symptomatic change are mostly lacking. The present study investigates if attachment anxiety and avoidance predict changes in personality functioning at the end of inpatient psychotherapy. Method: In two independent samples (the first sample consisting of N = 967 diagnostically heterogeneous patients, Fachklinikum Tiefenbrunn, and the second sample comprising N = 344 patients with personality impairments, Rehaklinik Bad Grönenbach), personality functioning was assessed by means of the short version of the OPD structure questionnaire OPD-SQS (OPD-Strukturfragebogen 12-Item-Screeningversion, OPD-SFK) at admission and discharge in a naturalistic study design. Data on the Brief Symptom Inventory (BSI) and the Inventory of Interpersonal Problems (IIP-32) were evaluated as additional outcome measures in the first sample. Patients' attachment strategies were assessed at admission using the German short version of the Experiences in Close Relationships (ECR-RD 12). Results: Attachment avoidance at baseline was inversely associated with improvements in personality functioning, psychopathology, and interpersonal problems. In the sample of patients diagnosed with personality disorders (sample 2), we found a negative association between attachment anxiety and improvements in the ability to make contact with others. Conclusions: Considering the limitations, our results underline the relevance of attachment for the treatment outcome of inpatient psychotherapy. The assessment of patient's attachment strategy as part of standardized diagnostics can be helpful in clinical practice regarding prognosis, therapy planning as well as the adjustment of the therapeutic relationship while treating patients suffering from impairments in personality functioning.

Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia.

BACKGROUND: Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. METHODS: In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. RESULTS: After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients). CONCLUSIONS: Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).

Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course. With the advent of novel treatment options that will potentially change the management of patients with T-PLL, it has become necessary to produce consensus guidelines for the design and conduct of clinical trials. The T-PLL International Study group (TPLL-ISG) set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria will facilitate comparison of results from clinical trials in T-PLL, and will thus support clinical decision making, as well as the approval of new therapeutics by healthcare authorities.

Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab.

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS vs without these factors. Median duration of ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707.

[Measurement of Change with the Short Form of the OPD Structure Questionnaire (OPD-SQS)]. / Veränderungsmessung mit der Kurzform des OPD-Strukturfragebogens (OPD-SFK).

The transdiagnostic concept of personality structure plays a key role in psychodynamic nosology, since many mental and psychosocial disorders are considered mainfestations of structural vulnerabilities and deficits. Therefore, structural diagnostics is of particular importance, especially with respect to the planning of tailor-made psychotherapeutic interventions. Because changes in personality structure are increasingly being considered as a relevant therapeutic goal, any measures employed towards achieving this goal should be sensitive enough to capture these changes appropriately. Although the short form of the OPD Structure Questionnaire (OPD-SQS) can easily be administered and is therefore frequently used in clinical and research settings, its sensitivity to change has not yet been analyzed. Two large, independent and diagnostically heterogeneous samples of inpatient psychotherapy patients (n=1183 and n=967, respectively) completed the OPD-SQS both at admission and before discharge. Standardized Effect Size (SES), Standardized Response Mean (SRM) and Smallest Real Difference (SRD) were computed as indicators of the measure's ability to capture change. For the OPD-SQS and its subscales, low effect sizes were found in both samples (SES between 0.23 and 0.48; SRM between 0.27 and 0.53). Additionally, it was demonstrated that greater changes among patients with structural deficits were detectable with the OPD-SQS compared to those without structural deficits, and that these group differences were significant. By means of the SRD, we determined a proportion of about 22% of patients with significantly structurally improved changes in both samples. Despite some methodological issues, our findings suggest that the OPD-SQS is suitable for measuring changes in personality structure in inpatients between the beginning and the end of treatment. Since studies on the sensitivity to change of similar assessment tools are still pending, it is not yet possible to formulate any empirically validated recommendations as to which of the measure best captures therapeutically induced changes in personality structure.

[Psychometric evaluation of the Experiences in Close Relationships Revised German 12-item version (ECR-RD 12) in a sample of psychotherapeutic inpatients]. / Evaluation der deutschsprachigen Kurzform des Experiences in Close Relationships Questionnaire (ECR-RD 12) im stationären Psychotherapiesetting.

Psychometric evaluation of the Experiences in Close Relationships Revised German 12-item version (ECR-RD 12) in a sample of psychotherapeutic inpatients Objectives: The ECR-R assesses the self-description of adult attachment strategies in romantic relationships. The present study evaluates the psychometric properties of the German 12-item short version ECR-RD 12 in a large sample of patients in psychotherapeutic inpatient treatment. Method: Inpatients in psychotherapeutic treatment (N = 2231) were assessed using the ECR-RD 12 and other clinical questionnaires. Its psychometric properties and factor structure of were evaluated. Results: The psychometric properties of the short form measure were in line with the German full length version (ECR-RD). In contrast to theoretical assumptions, factor analysis suggested a three factor solution in the present sample. Discussion: The ECR-RD 12 can be recommended as a screening measure for assessing attachment styles in inpatient psychotherapeutic settings. Further studies are required to investigate the factor structure of the measure in clinical samples.

CD44 is a RAS/STAT5-regulated invasion receptor that triggers disease expansion in advanced mastocytosis.

The Hermes receptor CD44 is a multifunctional adhesion molecule that plays an essential role in the homing and invasion of neoplastic stem cells in various myeloid malignancies. Although mast cells (MCs) reportedly express CD44, little is known about the regulation and function of this receptor in neoplastic cells in systemic mastocytosis (SM). We found that clonal CD34+/CD38- stem cells, CD34+/CD38+ progenitor cells, and CD117++/CD34- MCs invariably express CD44 in patients with indolent SM (ISM), SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia (MCL). In addition, all human MCL-like cell lines examined (HMC-1, ROSA, and MCPV-1) displayed cytoplasmic and cell-surface CD44. We also found that expression of CD44 in neoplastic MCs depends on RAS-MEK and STAT5 signaling and increases with the aggressiveness of SM. Correspondingly, higher levels of soluble CD44 were measured in the sera of patients with advanced SM compared with ISM or cutaneous mastocytosis and were found to correlate with overall and progression-free survival. To investigate the functional role of CD44, a xenotransplantation model was employed using severe combined immunodeficient (SCID) mice, HMC-1.2 cells, and a short hairpin RNA (shRNA) against CD44. In this model, the shRNA-mediated knockdown of CD44 resulted in reduced MC expansion and tumor formation and prolonged survival in SCID mice compared with HMC-1.2 cells transduced with control shRNA. Together, our data show that CD44 is a RAS-MEK/STAT5-driven MC invasion receptor that correlates with the aggressiveness of SM. Whether CD44 can serve as therapeutic target in advanced SM remains to be determined in forthcoming studies.

The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL.

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy.

Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1-/- mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.

To Be or Not to Be Improved: Patients' Perception of Symptom Improvement - Linking the SCL-90-R to Patient-Rated Global Improvement in a Large Real-World Treatment Sample.

INTRODUCTION: From both a clinical and research perspective, it is important to determine what constitutes a perceivable change in commonly used outcome measures. OBJECTIVE: We aimed to do so for the Symptom Checklist-90-Revised (SCL-90-R). METHODS: Patients from a large real-world sample treated with inpatient psychotherapy (n = 4,791) rated improvements in symptoms on a global 5-point Likert scale at discharge. These ratings were related to pre-post changes in the Global Severity Index (GSI) of the SCL-90-R by use of equipercentile linking. RESULTS: A patient rating of 5 ("clearly improved") was found to be equivalent to an absolute pre-post difference in the GSI of 0.67 or to a percentage improvement of 54%, with the latter corresponding to the common definition of response as a 50% reduction in symptoms. A rating of 1 ("clearly worse") was equivalent to an increase in the GSI >0.50 and to a percentage worsening >55%. "Slightly improved" or "slightly worse" (ratings of 4 or 2) corresponded to pre-post changes in the GSI of 0.07 and 0.50. For severely disordered patients, larger changes were required for ratings of improvement, and for less severely disordered patients, larger changes were required for ratings of worsening. Results for depressive, anxiety, and personality disorders were widely consistent with those of the total sample. CONCLUSIONS: This study is the first to link patient ratings of improvement or worsening to changes in the SCL-90-R. Results are relevant to both the interpretation of changes in individual patients and of effect sizes in outcome research. Results require replication.

Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis.

Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.

Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL.

Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ∼9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/or TP53 status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing ≥8 consecutive days of ibrutinib had a shorter median PFS vs those missing <8 days (10.9 months vs not reached). These results support sustained adherence to once-daily ibrutinib dosing at 420 mg as clinically feasible to achieve optimal outcomes in patients with previously treated CLL. The trial was registered at www.clinicaltrials.gov as #NCT01578707.

Screening for post-traumatic stress disorders in 1017 cancer patients and correlation with anxiety, depression, and distress.

OBJECTIVE: Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder, which might develop after a traumatic event, like cancer diagnosis, and threatens the patient's psychological and/or physiological integrity. Anxiety, depression, and mental distress are known to be common in cancer patients; however, the frequency of PTSD was not investigated thoroughly in this patient group so far. Here, we aim to screen cancer patients for PTSD symptoms and determine a possible correlation with anxiety, depression, and distress. METHODS: The study was performed at the Divisions of Hematology and Oncology of the Medical University of Vienna from 2010 to 2018. Following written consent, patients were asked to fill out the validated self-assessment questionnaire for PTSS-10 and HADS. The study was approved by the institutional ethics committee of the Medical University of Vienna (EC Nr: 2255/2016). RESULTS: A total of 1017 adult cancer patients (513 male, 504 female) were included in a cross-sectional single-center study. Mean age was 57.6 years (SD 14.4 years); 31.7%, 14.6%, 13.2%, and 27.4% of patients outscored the predefined thresholds for self-assessed cases of PTSD, anxiety, depression, and distress, respectively. Compared with men, women showed a higher prevalence of symptoms for PTSD (38.9% vs 24.5%; P < .001) and anxiety (20.4% vs 8.6%; P < .001). The scores of HADS-A, HADS-D, and the combined HADS score (distress) were significantly correlated with PTSS-10 scores (P < .01). No differences in age were observed among the different score groups. CONCLUSION: The study shows a significant prevalence as well as a correlation of PTSD symptoms with anxiety, depression, and distress among cancer patients. Findings underscore the necessity of a serious screening for psychiatric disorders, especially in female patients. In order to enable multidisciplinary care for cancer patients and to reduce the burden for psychiatric disorders, interdisciplinary screening and treatment concepts, which take into account gender aspects, are urged.

Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

Increasing use of immunotherapy and prolonged survival among younger patients with primary CNS lymphoma: a population-based study.

Background: Primary CNS lymphoma is a highly aggressive and rare type of extranodal non-Hodgkin lymphoma. Although, new therapeutic approaches have led to improved survival, the management of the disease poses a challenge, practice patterns vary across institutions and countries, and remain ill-defined for vulnerable patient subgroups. Material and Methods: Using information from the Austrian Brain Tumor Registry we followed a population-based cohort of 189 patients newly diagnosed from 2005 to 2010 through various lines of treatment until death or last follow-up (12-31-2016). Prognostic factors and treatment-related data were integrated in a comprehensive survival analysis including conditional survival estimates. Results: We find variable patterns of first-line treatment with increasing use of rituximab and high-dose methotrexate (HDMTX)-based poly-chemotherapy after 2007, paralleled by an increase in median overall survival restricted to patients aged below 70 years. In the entire cohort, 5-year overall survival was 24.4% while 5-year conditional survival increased with every year postdiagnosis. Conclusion: In conclusion, we show that the use of poly-chemotherapy and immunotherapy has disseminated to community practice to a fair extent and survival has increased over time at least in younger patients. Annually increasing conditional survival rates provide clinicians with an adequate and encouraging prognostic measure.