Publications by authors named "Ulrich Jaeger"

96 Publications

Influence of Mutation on Survival of Diffuse Large B-Cell Lymphoma in the CAR T-Cell Era.

Cancers (Basel) 2021 Nov 9;13(22). Epub 2021 Nov 9.

Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria.

Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) is associated with poor outcome. The clinical behavior and genetic landscape of DLBCL is heterogeneous and still not fully understood. mutations in DLBCL have been identified as markers of poor prognosis and are often associated with therapeutic resistance. Chimeric antigen receptor T-cell therapy is an innovative therapeutic concept and represents a game-changing therapeutic option by supporting the patient's own immune system to kill the tumor cells. We investigated the impact of mutations on the overall survival of refractory/relapsed DLBCL patients treated with comparable numbers of therapy lines. The minimum number of therapy lines was 2 (median 4), including either anti-CD19 CAR T-cell therapy or conventional salvage therapy. A total of 170 patients with DLBCL and high-grade B-cell lymphoma with and/or rearrangements (DHL/THL), diagnosed and treated in our hospital between 2000 and 2021, were included. Twenty-nine of them received CAR T-cell therapy. mutations were found in 10/29 (35%) and 31/141 (22%) of patients in the CAR T-cell and conventional groups, respectively. Among the 141 patients not treated with CAR T cells, mutation was an independent prognostic factor for overall survival (OS) (median 12 months with vs. not reached without mutation, < 0.005), but in the CAR T cell treated group, this significance could not be shown (median OS 30 vs. 120 months, = 0.263). The findings from this monocentric retrospective study indicate that mutation status does not seem to affect outcomes in DLBCL patients treated with CAR T-cell therapy. Detailed evaluation in large cohorts is warranted.
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http://dx.doi.org/10.3390/cancers13225592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616128PMC
November 2021

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematological Cancers and Identifies Exceptional Responders.

Cancer Discov 2021 Oct 11. Epub 2021 Oct 11.

Platform Austria for Chemical Biology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.

Personalized medicine aims to match the right drug with the right patient by utilizing specific features of the individual patients' tumor. However, current strategies of personalized therapy matching only provide treatment opportunities for less than 10% of cancer patients. A promising method may be drug profiling of patient biopsies with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival (PFS) compared to their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude, that therapy matching by scFPM is clinically feasible, and effective in advanced aggressive hematologic cancers.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0538DOI Listing
October 2021

Management of autoimmune complications in patients with lymphoid cancer.

Blood 2021 Sep 13. Epub 2021 Sep 13.

Medical University of Vienna, Vienna, Austria.

Autoimmune conditions can occur at any temporary relationship with malignant lymphomas. In many instances, treatment at diagnosis is not required, but symptomatic autoimmune conditions represent an indication for treatment particularly in chronic lymphoproliferative diseases. Treatment is selected depending on the predominant condition - autoimmune disease (immunosuppression) or lymphoma (anti-lymphoma therapy). Steroids as well as anti-CD20 antibodies are effective against both and may suppress the autoimmune complication for a prolonged period. Efficacy of B-cell receptor inhibitors has provided us with novel insights into the pathophysiology of antibody-producing B-cells. Screening for underlying autoimmune conditions is part of the lymphoma work-up since other drugs like immunomodulators or checkpoint inhibitors should be avoided or used with caution. Here we discuss diagnostic challenges and treatment approaches for different situations involving lymphomas and autoimmune cytopenias.
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http://dx.doi.org/10.1182/blood.2019003686DOI Listing
September 2021

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes.

Clin Lymphoma Myeloma Leuk 2021 Jul 22. Epub 2021 Jul 22.

Institute Jules Bordet, Brussels, Belgium.

Background: The SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor.

Patients And Methods: Data from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate.

Results: ORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels ≥ 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups.

Conclusions: Overall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin.
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http://dx.doi.org/10.1016/j.clml.2021.07.017DOI Listing
July 2021

Tisagenlecleucel Immunogenicity in Relapsed/Refractory Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma.

Blood Adv 2021 Aug 25. Epub 2021 Aug 25.

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.

Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; hence, we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from ELIANA (NCT02435849) and ENSIGN (NCT02228096) trials in r/r B-ALL (N=143) and the JULIET trial (NCT02445248) in r/r DLBCL (N=115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon gamma in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics including Cmax and persistence (r2<0.05), clinical response (day 28 response, duration of response, event-free survival), or safety. T-cell responses were consistent over time, with net responses <1% at baseline and posttreatment time points in the majority of patients with no effect on transgene expansion and persistence or outcomes. Presence of baseline and/or posttreatment anti-mCAR19 antibodies or T-cell responses did not alter the activity of tisagenlecleucel in patients with r/r B-ALL or r/r DLBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020003844DOI Listing
August 2021

Survival among patients with relapsed/refractory diffuse large B cell lymphoma treated with single-agent selinexor in the SADAL study.

J Hematol Oncol 2021 07 16;14(1):111. Epub 2021 Jul 16.

Karyopharm Therapeutics, Newton, USA.

Patients with RR DLBCL who have received ≥ 2 lines of therapy have limited treatment options and an expected overall survival (OS) of < 6 months. The SADAL study evaluated single-agent oral selinexor in patients with RR DLBCL and demonstrated an overall response rate (ORR) of 29.1% with median duration of response (DOR) of 9.3 months. The analyses described here evaluated a number of subpopulations in order to understand how response correlates with survival outcomes in order to identify patients who could most optimally benefit from selinexor treatment. Median age was 67 years; 44.8% of patients were ≥ 70 years of age. The median OS was 9.0 months (95% CI 6.2, 13.7) at a median follow-up of 14.8 months. The median OS was not reached in patients with a CR or PR, while patients who did not respond have a median OS of 4.9 months (p < 0.0001). Patients < 70 years had an OS of 11.1 months compared with 7.8 months in patients ≥ 70 years. Among patients with or without prior ASCT, the median OS was 10.9 and 7.8 months, respectively. Among patients with disease refractory to the most recent DLBCL treatment regimen, the median OS was 7.0 months compared with 11.1 months for disease not refractory to the most recent treatment. In a patient population in which survival is expected to be < 6 months, treatment with single-agent oral selinexor was associated with a median survival of 9 months. Increased median OS observed in patients responding to selinexor was consistent across subgroups regardless of age, prior ASCT therapy, or refractory status. Randomized studies of selinexor in combination with a variety of other anti-DLBCL agents are planned. This trial was registered at ClinicalTrials.gov (NCT02227251) on August 28, 2014. https://clinicaltrials.gov/ct2/show/NCT02227251 .
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http://dx.doi.org/10.1186/s13045-021-01122-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283921PMC
July 2021

[Measurement of Change with the Short Form of the OPD Structure Questionnaire (OPD-SQS)].

Psychother Psychosom Med Psychol 2021 Nov 29;71(11):456-463. Epub 2021 Apr 29.

Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie, Universitätsmedizin Rostock, Deutschland.

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.
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http://dx.doi.org/10.1055/a-1425-7618DOI Listing
November 2021

Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies for Hematological Cancers: Present and Future.

Hemasphere 2021 Feb 28;5(2):e524. Epub 2021 Jan 28.

Erasmus School of Health Policy and Management, Erasmus University, Rotterdam, The Netherlands.

Since 2018, 2 chimeric antigen receptor (CAR) T-cell therapies received approval from the European Medicine Agency, with list prices around 320 000 Euro (€) (EUR) per treatment. These high prices raise concerns for patient access and the sustainability of healthcare systems. We aimed to estimate the costs and budget impact associated with CAR T-cell therapies for current and future indications in hematological cancers from 2019 to 2029. We focused on the former France, Germany, Spain, Italy and the United Kingdom (EU-5) and the Netherlands. We conducted a review of list prices, health technology assessment reports, budget impact analysis dossiers, and published cost-effectiveness analyses. We forecasted the 10-year health expenditures on CAR T-cells for several hematological cancers in selected European Union countries. Nine cost-effectiveness studies were identified and list prices for CAR T-cell therapies ranged between 307 200 EUR and 350 000 EUR. Estimated additional costs for pre- and post-treatment were 50 359 EUR per patient, whereas the incremental costs of CAR T-cell therapy (when compared with care as usual) ranged between 276 086 EUR and 328 727 EUR. We estimated market entry of CAR T-cell therapies for chronic mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemia in 2021, 2022, 2022, 2022, and 2025, respectively. Cumulative expenditure estimates for existing and future indications from 2019 to 2029 were on average 28.5 billion EUR, 32.8 billion EUR, and 28.9 billion EUR when considering CAR T-cell therapy costs only, CAR T-cell therapy costs including pre- and post-treatment, and incremental CAR T-cell therapy costs, respectively. CAR T-cell therapies seem to be promising treatment options for hematological cancers but the financial burden on healthcare systems in the former EU-5 and the Netherlands will contribute to a substantial rise in healthcare expenditure in the field of hematology.
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http://dx.doi.org/10.1097/HS9.0000000000000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051992PMC
February 2021

[Psychometric evaluation of the Experiences in Close Relationships Revised German 12-item version (ECR-RD 12) in a sample of psychotherapeutic inpatients].

Z Psychosom Med Psychother 2021 ;67(1):56-69

Klinik für Psychosomatische Medizin und Psychotherapie Universitätsmedizin Rostock Gehlsheimer Straße 20 18147 Rostock Deutschland https://kpm.med.uni-rostock.de/.

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. 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. 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. 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.
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http://dx.doi.org/10.13109/zptm.2021.67.1.56DOI Listing
February 2021

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

Blood 2021 05;137(18):2481-2494

Central European Institute of Technology, Masaryk University, Brno, Czech Republic.

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.
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http://dx.doi.org/10.1182/blood.2020005627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610744PMC
May 2021

Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study.

J Clin Oncol 2020 12 28;38(34):4042-4054. Epub 2020 Sep 28.

Royal Melbourne Hospital, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.

Purpose: In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics.

Patients And Methods: Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed.

Results: Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC ( = .042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with and mutations at EOCT and with , , , and mutations at EOT.

Conclusion: Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.
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http://dx.doi.org/10.1200/JCO.20.00948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768340PMC
December 2020

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.

Psychother Psychosom 2020 30;89(6):357-362. Epub 2020 Jul 30.

Department of Psychosomatics and Psychotherapy, University of Giessen, Giessen, Germany.

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.
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http://dx.doi.org/10.1159/000509213DOI Listing
August 2021

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial.

Lancet Haematol 2020 Jul;7(7):e511-e522

Karyopharm Therapeutics Inc, Newton, MA, USA.

Background: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit.

Methods: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling).

Findings: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor.

Interpretation: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting.

Funding: Karyopharm Therapeutics Inc.
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http://dx.doi.org/10.1016/S2352-3026(20)30120-4DOI Listing
July 2020

Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program.

Blood Adv 2020 03;4(6):997-1005

Division of Hematology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. We aimed to evaluate the safety and efficacy of long-term maintenance treatment with sutimlimab in patients with CAD. Seven CAD patients treated with sutimlimab as part of a phase 1B study were transitioned to a named patient program. After a loading dose, patients received biweekly (once every 2 weeks) infusions of sutimlimab at various doses. When a patient's laboratory data showed signs of breakthrough hemolysis, the dose of sutimlimab was increased. Three patients started with a dose of 45 mg/kg, another 3 with 60 mg/kg, and 1 with a fixed dose of 5.5 g every other week. All CAD patients responded to re-treatment, and sutimlimab increased hemoglobin from a median initial level of 7.7 g/dL to a median peak of 12.5 g/dL (P = .016). Patients maintained near normal hemoglobin levels except for a few breakthrough events that were related to underdosing and which resolved after the appropriate dose increase. Four of the patients included were eventually treated with a biweekly 5.5 g fixed-dose regimen of sutimlimab. None of them had any breakthrough hemolysis. All patients remained transfusion free while receiving sutimlimab. There were no treatment-related serious adverse events. Overlapping treatment with erythropoietin, rituximab, or ibrutinib in individual patients was safe and did not cause untoward drug interactions. Long-term maintenance treatment with sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels in re-exposed, previously transfusion-dependent CAD patients.
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http://dx.doi.org/10.1182/bloodadvances.2019001321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094024PMC
March 2020

Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma.

Blood Adv 2020 02;4(4):629-637

Peter MacCallum Cancer Centre, St Vincent's Hospital and University of Melbourne, Melbourne, VIC, Australia.

The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the HRQoL assessments at baseline, including 57 patients who eventually achieved CR or partial response (PR). Further, 30 and 21 patients in clinical response who completed assessments at baseline also completed assessments at months 12 and 18, respectively. Patients who achieved CR or PR sustained HRQoL improvement in all FACT scores at all time points. SF-36 instruments showed improvement above the minimal clinically important differences on 5 of 8 subscales. Long-term follow-up in the phase 2 JULIET study demonstrated that patients with r/r DLBCL who respond to tisagenlecleucel therapy had sustained, clinically meaningful improvements in HRQoL. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
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http://dx.doi.org/10.1182/bloodadvances.2019001026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042998PMC
February 2020

RECIL versus Lugano for Treatment Response Assessment in FDG-Avid Non-Hodgkin Lymphomas: A Head-to-Head Comparison in 54 Patients.

Cancers (Basel) 2019 Dec 18;12(1). Epub 2019 Dec 18.

Department of Biomedical Imaging and Image-guided Therapy, Division of General and Pediatric Radiology, Medical University of Vienna, 1090 Vienna, Austria.

The response evaluation criteria in lymphoma (RECIL) classification for lymphoma treatment response assessment was introduced in 2017, but it has not yet been compared to the established Lugano classification. Also, the value of the provisional "minor response" (MiR) category of RECIL is unclear. In 54 patients with FDG-avid non-Hodgkin lymphomas (41 diffuse large B-cell lymphomas (DLBCL) and 13 follicular lymphomas), [F]FDG-PET/CT-based response according to RECIL and Lugano was determined at interim and end-of-treatment (EOT) restaging. Rates of agreement and Cohen's kappa (κ) coefficients were calculated. The relationship between RECIL and Lugano responses and 2-year complete remission (CR) status of DLBCL patients was determined. At interim restaging, MiR was observed in 14.8%, and at EOT, in 5.6% of patients. When MiR was recoded as partial remission, agreement between RECIL and Lugano was 83.3% at interim restaging (κ = 0.69), and 90.7% at EOT (κ = 0.79). 85.4%, of DLBCL patients with responding disease at interim restaging according to both RECIL and Lugano achieved 2-year CR status; whereas, at EOT, 82.9% of patients with responding disease according to Lugano, and 85.4% of patients with responding disease according to RECIL, achieved 2-year CR status. Thus, RECIL and Lugano classifications show comparable performance for treatment response assessment, and a similar association with 2-year CR status in FDG-avid lymphomas.
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http://dx.doi.org/10.3390/cancers12010009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016710PMC
December 2019

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

Psychooncology 2019 12 3;28(12):2382-2388. Epub 2019 Nov 3.

Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

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.
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http://dx.doi.org/10.1002/pon.5239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916606PMC
December 2019

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.

Am J Hematol 2019 12 13;94(12):1353-1363. Epub 2019 Oct 13.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

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).
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http://dx.doi.org/10.1002/ajh.25638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899718PMC
December 2019

Long-Term Studies Assessing Outcomes of Ibrutinib Therapy in Patients With Del(11q) Chronic Lymphocytic Leukemia.

Clin Lymphoma Myeloma Leuk 2019 11 15;19(11):715-722.e6. Epub 2019 Jul 15.

Department of Internal Medicine and German CLL Study Group, University of Cologne, Cologne, Germany.

Background: Certain genomic features, such as del(11q), expression of unmutated immunoglobulin heavy-chain variable region (IGHV) gene, or complex karyotype, predict poorer outcomes to chemotherapy in patients with chronic lymphocytic leukemia (CLL).

Patients And Methods: We examined the pooled long-term follow-up data from PCYC-1115 (RESONATE-2), PCYC-1112 (RESONATE), and CLL3001 (HELIOS), comprising a total of 1238 subjects, to determine the prognostic significance of these markers in patients treated with ibrutinib.

Results: With a median follow-up of 47 months, ibrutinib-treated patients had longer progression-free survival (PFS) than patients treated in the comparator arm, regardless of genomic risk factors. Among patients treated with ibrutinib, we found that high-risk genomic features were not associated with shorter PFS (63-75% across all subgroups at 42 months) or overall survival (79-83% across all subgroups at 42 months). Surprisingly, we observed that ibrutinib-treated patients with del(11q) actually had a significantly longer PFS than ibrutinib-treated patients without del(11q) (42-month PFS rate 70% vs. 65%, P = .02).

Conclusion: These analyses not only demonstrate that genomic risk factors previously associated with poor outcomes lose their adverse prognostic significance but also that del(11q) can be associated with a superior PFS with ibrutinib therapy.
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http://dx.doi.org/10.1016/j.clml.2019.07.004DOI Listing
November 2019

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

Blood 2019 10 10;134(14):1132-1143. Epub 2019 Jul 10.

The Royal Marsden Hospital, NHS Foundation Trust, London, United Kingdom.

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.
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http://dx.doi.org/10.1182/blood.2019000402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042666PMC
October 2019

Changes in Personality Functioning After Inpatient Psychodynamic Therapy: A Dimensional Approach to Personality Disorders.

Psychodyn Psychiatry 2019 ;47(2):183-196

Asklepios Clinic Tiefenbrunn, Germany.

Objective: Patients with mental disorders do not only show specific symptoms but also impairments in personality functioning, especially those with personality disorders. Recent developments in and ICD-11 suggest a dimensional approach to personality disorders. Few studies, however, have examined changes in personality functioning.

Methods: In a large sample of 2,596 patients treated by inpatient psychodynamic therapy, changes in personality functioning were studied. Two patient groups were examined, one with ( = 1152, BPO) and one without a presumptive diagnosis of a borderline personality organization ( = 1444, NBPO). For the assessment of personality functioning, the Borderline-Personality Inventory (BPI) was used. The BPI taps personality functioning as defined by Kernberg's structural criteria of personality organization. Symptom distress and interpersonal problems were examined with the Symptom Checklist SCL-90-R and the Inventory of Interpersonal Problems (IIP). Patients were assessed at admission and discharge.

Results: In the BPO sample significant and substantial pre-post effect sizes in overall personality functioning, identity integration, and defense mechanisms/object relations were found ( = 0.68, 0.60, 0.78). In addition, large improvements in symptoms (SCL-90-R) were achieved ( = 0.97). For interpersonal problems effect sizes were medium (0.56). At discharge 36% of the BPO patients scored below the BPI-Cut-Off score for a BPO (remission). Pre-post effect sizes in the NPBO sample ( = 1444) were significant but small for changes in personality functioning ( = 0.31-0.46) and substantial for improvements in symptoms ( = 0.77).

Conclusions: Both personality functioning and symptom distress can be substantially improved by inpatient psychodynamic therapy. Future research is recommended to study both improvements in symptoms and personality functioning.
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http://dx.doi.org/10.1521/pdps.2019.47.2.183DOI Listing
February 2020

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

Acta Oncol 2019 Jul 17;58(7):967-976. Epub 2019 Apr 17.

b Comprehensive Cancer Center , Medical University of Vienna , Vienna , Austria.

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. 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. 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. 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.
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http://dx.doi.org/10.1080/0284186X.2019.1599137DOI Listing
July 2019

Integrating structure and dynamics in personality assessment: First steps toward the development and validation of a personality dynamics diary.

Psychol Assess 2019 Apr 14;31(4):516-531. Epub 2019 Mar 14.

Department of Psychology.

Both theories and cutting-edge research highlight the dynamic nature of personality and personality pathology, thereby posing significant challenges for an exclusively between-person, trait-based approach to personality assessment. In a series of 3 studies, we explored the viability of integrating within-person, dynamic aspects into clinical personality assessment by means of daily dairy methods. In the 1st study, 314 students filled out a 73-item questionnaire capturing daily behaviors and situation experiences across 7-10 consecutive days. We used multilevel exploratory factor analyses to construct a shortened version, the Personality Dynamics Diary (PDD). In the 2nd study, the PDD was applied in a sample of 77 psychotherapy inpatients across 40 days, on average. In the 3rd study, 35 psychotherapy outpatients as well as their therapists judged the clinical utility of a smartphone version of the PDD. Taken together, we were able to construct a relatively brief self-report measure that assesses major dimensions of within- and between-person differences of situations and behaviors in daily life with acceptable reliability. Application in clinical samples provided further evidence for the reliability, validity, and clinical utility of the PDD but also highlighted possible obstacles in clinical practice as well as the need for further replication and refinement. We conclude that daily diary methods have the potential to integrate within- and between-person approaches to personality assessment. By applying measures like the PDD, clinicians may gain insight into the psychological mechanisms that give rise to, and maintain, a person's maladaptive dispositions and ultimately find individualized leverage points for targeted therapeutic interventions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0000625DOI Listing
April 2019

[Psychotherapy Inpatients With Illusory Mental Health - An Explorative Approach].

Psychother Psychosom Med Psychol 2019 Oct 13;69(11):445-452. Epub 2019 Mar 13.

Klinik für Konsiliarpsychiatrie und Psychosomatik, Universitätsspital Zürich, Zürich, Switzerland.

There is no systematic knowledge about patients in psychotherapy, who score in the healthy range of symptom-related self-report questionnaires, and thus are termed patients with illusory mental health. 4088 psychotherapy inpatients were exploratively analysed with regard to their frequency, their impairment as judged by the therapists, and clinical indicators for deficits in personality structure. About 14% of the entire sample classified themselves as mentally healthy by means of the GSI of the SCL-90-R. In contrast, therapists rated only 6% as clini-cally unimpaired, and the agreement between patients and therapists was low (κ=0,12). The personality structure of patients with illusory mental health was only moderately compro-mised. Our findings do not allow any clear conclusions about possible explanations of illusory mental health. Rather, these patients seem to represent a very heterogenous group.
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http://dx.doi.org/10.1055/a-0853-1762DOI Listing
October 2019

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

Blood 2019 05 6;133(19):2031-2042. Epub 2019 Mar 6.

CLL Center, Dana-Farber Cancer Institute, Boston, MA.

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 or 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.
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http://dx.doi.org/10.1182/blood-2018-08-870238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509542PMC
May 2019

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

Br J Haematol 2019 02 2;184(4):558-569. Epub 2018 Dec 2.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.
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http://dx.doi.org/10.1111/bjh.15690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587776PMC
February 2019

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

Blood 2018 12 4;132(23):2446-2455. Epub 2018 Oct 4.

Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany; and.

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; < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or mutations (HR = 0.40; = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; < .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.
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http://dx.doi.org/10.1182/blood-2018-05-850461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284216PMC
December 2018

Improvement in Parameters of Hematologic and Immunologic Function and Patient Well-being in the Phase III RESONATE Study of Ibrutinib Versus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Clin Lymphoma Myeloma Leuk 2018 12 18;18(12):803-813.e7. Epub 2018 Aug 18.

The Leeds Teaching Hospitals, St. James University Hospital, Leeds, United Kingdom.

Background: Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Patients And Methods: Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization.

Results: With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P < .0001). Higher rates of clinically meaningful improvement were demonstrated with ibrutinib versus ofatumumab for FACIT-F and EORTC global health. Greater improvement was observed in disease-related weight loss, fatigue, night sweats, and abdominal discomfort with ibrutinib versus ofatumumab. Hospitalizations in the first 30 days occurred less frequently with ibrutinib than ofatumumab (0.087 vs. 0.184 events/patient; P = .0198). New-onset diarrhea was infrequent with ibrutinib after the first 6 months (47% at ≤6 months vs. 5% at 12-18 months). With ibrutinib, grade ≥ 3 hypertension occurred in 6%, grade ≥ 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients.

Conclusion: Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.
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http://dx.doi.org/10.1016/j.clml.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527106PMC
December 2018

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

Blood 2018 11 17;132(18):1936-1950. Epub 2018 Jul 17.

Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

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.
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http://dx.doi.org/10.1182/blood-2018-02-833582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382065PMC
November 2018
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