Publications by authors named "Barbara Eichhorst"

107 Publications

Vaccination against COVID-19: a challenge in CLL.

Blood 2021 06;137(23):3153-3154

University of Cologne; Center for Integrated Oncology Aachen, Bonn, Cologne, Duesseldorf.

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http://dx.doi.org/10.1182/blood.2021011935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192082PMC
June 2021

Durable Remissions Following Combined Targeted Therapy in Patients with CLL Harboring TP53 Deletions and/or Mutations.

Blood 2021 Jun 4. Epub 2021 Jun 4.

University Hospital, Cologne, Germany.

Fifty-one of 189 evaluable patients from three prospective phase-II trials evaluating a sequential targeted treatment (clinicaltrials.gov NCT02345863, NCT02401503, NCT02689141) had high-risk CLL with a deletion 17p, TP53 mutation or both. Twenty-seven patients started treatment with bendamustine debulking prior to the induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13 and venetoclax/obinutuzumab (AG) in 17 patients. The primary endpoint was the overall response rate after eight months of induction treatment, which were 81%, 100% and 94% for IO, IG and AG, respectively. Minimal residual disease (MRD) was undetectable in peripheral blood (uMRD; <10-4 by flow cytometry) in 0%, 23% and 82% of patients, respectively. Median progression free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to undetectable MRD, nine of them progressed and two died without progression (median PFS: 28 months after discontinuation of treatment), while six patients remained in remission after a median observation time of 46 (range 6-47) months after discontinuation of treatment. Thus, MRD-guided fix-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation.
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http://dx.doi.org/10.1182/blood.2020010484DOI Listing
June 2021

Health-related quality of life with fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Results from the randomized, phase 3 CLL14 trial.

Am J Hematol 2021 May 29. Epub 2021 May 29.

Department I of Internal Medicine and Center of Integrated Oncology Aachen, Bonn, Cologne, Duesseldorf; German CLL Study Group, University of Cologne, Cologne, Germany.

Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab compared to chlorambucil-obinutuzumab in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least 8 points at cycle 3, whereas improvement was delayed until cycle 8 with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ajh.26260DOI Listing
May 2021

Novel Agents in Chronic Lymphocytic Leukemia: New Combination Therapies and Strategies to Overcome Resistance.

Cancers (Basel) 2021 Mar 16;13(6). Epub 2021 Mar 16.

German CLL Study Group, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Department I of Internal Medicine, University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.

The approval of Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib and the Bcl-2 inhibitor venetoclax have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While these novel agents alone or in combination induce long lasting and deep remissions in most patients with CLL, their use may be associated with the development of clinical resistance. In this review, we elucidate the genetic basis of acquired resistance to BTK and Bcl-2 inhibition and present evidence on resistance mechanisms that are not linked to single genomic alterations affecting these target proteins. Strategies to prevent resistance to novel agents are discussed in this review with a special focus on new combination therapies.
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http://dx.doi.org/10.3390/cancers13061336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002361PMC
March 2021

MARCKS affects cell motility and response to BTK inhibitors in CLL.

Blood 2021 Mar 18. Epub 2021 Mar 18.

University of Cologne, Cologne, Germany.

BTK inhibitors are highly active drugs for the treatment of CLL. To understand the response to BTK inhibitors on a molecular level, we performed (phospho)proteomic analyses under ibrutinib treatment. We identified 3466 proteins and 9184 phosphopeptides (representing 2854 proteins) in CLL cells exhibiting a physiological ratio of phosphorylated serines, threonines and tyrosines (pS:pT:pY). Expression of 83 proteins differed between unmutated IGHV (UM)-CLL and mutated IGHV (M)-CLL. Strikingly, UM-CLL cells showed higher basal phosphorylation levels than M-CLL samples. Effects of ibrutinib on protein phosphorylation levels were stronger in UM-CLL, especially on phosphorylated tyrosines. The differentially regulated phosphopeptides and proteins clustered in pathways regulating cell migration, motility, cytoskeleton composition and survival. One protein, MARCKS, showed striking differences in expression and phosphorylation level in UM-CLL versus M-CLL. MARCKS sequesters PIP2, thereby affecting central signaling pathways and clustering of the B cell receptor. Genetically induced loss of MARCKSignificantly increased AKT signaling and the migratory capacity. CD40L stimulation increased expression of MARCKS. BCR stimulation induced phosphorylation of MARCKS, which was reduced by BTK inhibitiors. In line with our in vitro findings, low MARCKS expression is associated with significantly higher treatment-induced leukocytosis and more pronounced decrease of nodal disease in CLL patients treated with acalabrutinib.
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http://dx.doi.org/10.1182/blood.2020009165DOI Listing
March 2021

Immune Dysfunction in Patients with Chronic Lymphocytic Leukemia and Challenges during COVID-19 Pandemic.

Acta Haematol 2021 Feb 25:1-11. Epub 2021 Feb 25.

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Cologne, Germany.

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been first described in December 2019 in Wuhan, China, and has led to a worldwide pandemic ever since. Initial clinical data imply that cancer patients are particularly at risk for a severe course of SARS-CoV-2. In patients with chronic lymphocytic leukemia (CLL), infections are a main contributor to morbidity and mortality driven by an impaired immune system. Treatment initiation is likely to induce immune modulation that further increases the risk for severe infections. This article aims to give an overview on pathogenesis and risk of infectious complications in patients with CLL. In this context, we discuss current data of SARS-CoV-2 infections in patients with CLL and how the pandemic impacts their management.
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http://dx.doi.org/10.1159/000514071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018219PMC
February 2021

EHA Endorsement of ESMO Clinical Practice Guidelines for Diagnosis, Treatment, and Follow-up of Chronic Lymphocytic Leukemia.

Hemasphere 2021 Jan 29;5(1):e520. Epub 2020 Dec 29.

Strategic Research Program on CLL, Division of Experimental Oncology, Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milano, Italy.

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http://dx.doi.org/10.1097/HS9.0000000000000520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773331PMC
January 2021

Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group (GCLLSG).

Haematologica 2020 11 1;105(11):2598-2607. Epub 2020 Nov 1.

Department of Internal Medicine III, Ulm University, Ulm, Germany.

Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.
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http://dx.doi.org/10.3324/haematol.2019.231027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604575PMC
November 2020

Venetoclax plus bendamustine-rituximab or bendamustine-obinutuzumab in chronic lymphocytic leukemia: final results of a phase 1b study (GO28440).

Haematologica 2020 10 29;Online ahead of print. Epub 2020 Oct 29.

Hospices Civils de Lyon, Université de Lyon, Pierre-Bénite, France.

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100-400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3-4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3-4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.
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http://dx.doi.org/10.3324/haematol.2020.261107DOI Listing
October 2020

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

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial.

Lancet Oncol 2020 09;21(9):1188-1200

Department I of Internal Medicine and Center of Integrated Oncology Cologne Aachen Cologne Bonn Duesseldorf, German CLL Study Group, University Hospital, University of Cologne, Germany.

Background: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia.

Methods: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942.

Findings: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma).

Interpretation: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia.

Funding: F Hoffmann-La Roche and AbbVie.
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http://dx.doi.org/10.1016/S1470-2045(20)30443-5DOI Listing
September 2020

[Current diagnosis and treatment of chronic lymphocytic leukaemia].

Dtsch Med Wochenschr 2020 08 13;145(16):1139-1144. Epub 2020 Aug 13.

Uniklink Köln, Klinik I für Innere Medizin, Deutsche CLL Studiengruppe; Kerpener Str. 62, 50937 Köln.

Two major advances were made in the treatment of chronic lymphocytic leukaemia (CLL): the addition of the antibody rituximab to chemotherapy two decades ago and the introduction of the targeted agents during the last few years. Four targeted drugs with different mechanisms of action were added to the armamentarium of CLL treatment: the anti-CD20 antibody obinutuzumab, the two kinase inhibitors ibrutinib and idelalisib, which target the Bruton tyrosine kinase (BTK) and Phosphatidylinositiol-3-Kinase (PI3K) respectively in the B-cell receptor signalling pathway, as well as the Bcl2-antagonist venetoclax.Recently, the combination of venetoclax/obinutuzumab was approved for the first-line treatment of all CLL patients based on a phase-III trial in elderly unfit patients. This combination was shown to be clearly superior to chlorambucil/obinutuzumab and should become the preferred first-line treatment for the so called "slow-go" patients. Other options for these elderly, unfit patients are continuous ibrutinib or chlorambucil/obinutuzumab. Although data from phase-III studies are not yet available, venetoclax/obintuzumab may also be offered to younger, fit patients. Established therapeutic options for these so called "go go" patients are ibrutinib, fludarabin/cyclophosphamide/rituximab or bendemustine/rituximab (if > 65 years). Patients with the high-risk parameters deletion 17p or TP53mutation are known to poorly respond to chemo(immuno)therapy and should receive either ibrutinib or venetoclax/obinutuzumab.Thus, a choice has to be made between a continuous monotherapy with ibrutinib or a time-limited combination with either venetoclax/obinutuzumab (12 months) or chemoimmunotherapy (usually 6 months). In addition to disease-related factors (e. g. presence of deletion 17p/TP53 mutation, IgHV mutational status, prior therapies), comorbidities, co-medication and the specific side effects of the CLL therapies (myelosuppression, infections and secondary malignancies for chemoimmunotherapy; cardiac toxicity, bleeding and autoimmune disease for ibrutinib; tumour-lysis syndromes and infections for venetoclax) the patient's expectations need to be considered.
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http://dx.doi.org/10.1055/a-1039-8472DOI Listing
August 2020

COVID-19 complicated by parainfluenza co-infection in a patient with chronic lymphocytic leukemia.

Eur J Haematol 2020 Oct 10;105(4):508-511. Epub 2020 Jul 10.

Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, Germany.

The number of people suffering from the new coronavirus SARS-CoV-2 continues to rise. In SARS-CoV-2, superinfection with bacteria or fungi seems to be associated with increased mortality. The role of co-infections with respiratory viral pathogens has not yet been clarified. Here, we report the course of COVID-19 in a CLL patient with secondary immunodeficiency and viral co-infection with parainfluenza.
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http://dx.doi.org/10.1111/ejh.13475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361362PMC
October 2020

Invasive Aspergillosis in Patients Treated With Ibrutinib.

Hemasphere 2020 04 13;4(2):e309. Epub 2020 Feb 13.

Department I for Internal Medicine, Excellence Centre for Medical Mycology (ECMM), University Hospital Cologne, Cologne, Germany.

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http://dx.doi.org/10.1097/HS9.0000000000000309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162080PMC
April 2020

ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma.

Future Oncol 2020 Apr 24;16(10):517-523. Epub 2020 Mar 24.

Peter MacCallum Cancer Centre, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria 3000, Australia and University of Melbourne, Parkville, Victoria 3052, Australia.

Treatment standards for chronic lymphocytic leukemia (CLL) have been transformed with the advent of effective inhibitors of B-cell receptor signaling such as ibrutinib - a first-in-class inhibitor of BTK. Off-target kinase inhibitions by ibrutinib are thought to contribute to its adverse events. Zanubrutinib is a next-generation BTK inhibitor with minimal off-target effects, sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes from patients with B-cell malignancies and promising responses in patients with CLL. Described here is a head-to-head Phase III study comparing the efficacy and safety of zanubrutinib with those of ibrutinib in patients with CLL/small lymphocytic lymphoma in the relapsed/refractory setting.
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http://dx.doi.org/10.2217/fon-2019-0844DOI Listing
April 2020

Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax.

Blood 2020 06;135(26):2402-2412

Department of Internal Medicine 3, Ulm University, Ulm, Germany.

Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (IGHV) mutation status, common genomic aberrations, and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942), comparing obinutuzumab+chlorambucil (GClb) vs obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +12 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM, and BIRC3, none of these parameters reduced complete remission (CR) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV, and mutated TP53, BIRC3, and SF3B1 as independent prognostic factors for PFS with GClb, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis.
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http://dx.doi.org/10.1182/blood.2019004492DOI Listing
June 2020

Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicenter, open-label phase-II trial.

Haematologica 2021 02 1;106(2):543-554. Epub 2021 Feb 1.

University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany.

The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias, anaemia, infusion-related reactions, and diarrhoea. This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with minimal residual disease negativity. However, ibrutinib should still be used as a single agent outside clinical trials. Clinicaltrials.gov number: NCT02689141.
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http://dx.doi.org/10.3324/haematol.2019.223693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849583PMC
February 2021

Long Term Follow-up Data and Health-Related Quality of Life in Frontline Therapy of Fit Patients Treated With FCR Versus BR (CLL10 Trial of the GCLLSG).

Hemasphere 2020 Feb 27;4(1):e336. Epub 2020 Jan 27.

Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf and German CLL Study Group, University of Cologne, Germany.

Fludarabine, cyclophosphamide and rituximab (FCR) was compared to bendamustine and rituximab (BR) in an international, randomized, open label, phase 3 trial in 561 previously untreated, fit patients with chronic lymphocytic leukemia (CLL) without del (17p). Primary endpoint was progression free survival (PFS). The final primary endpoint analysis after 37.1 months median follow up failed to show the non-inferiority of BR as compared with FCR. With extended median follow up of 58.2 months, median PFS was 42.3 months in BR-treated patients versus 57.6 months for FCR-treated patients (Hazard Ratio [HR] 1.593; 95% CI 1.271-1.996; p < 0.0001). For patients > 65 years, median PFS was 48.5 months with BR versus 57.9 months with FCR without reaching statistical significance (HR 1.352; 95% CI 0.912-2.006; p = 0.134). Median OS was not reached for both arms with 5-year OS rates of 80.1% vs 80.9%, respectively (HR 1.108; 95% CI 0.755-1.627; p = 0.599). No statistically significant difference was found in the time to secondary malignancy between the 2 groups (at 5 years, 86.6% free from secondary malignancies in the BR group vs 83.8% in the FCR group [HR 0.801; 95% CI 0.507-1.267; p = 0.344]). In patients >65 years secondary neoplasia occurred more frequently after FCR treatment [28 of 86 (32.6%) patients] as compared with BR [18 of 107 (16.8%) patients; p = 0.011]. Health-related quality of life was similar in both treatments. Despite the improved PFS for FCR, OS did not differ. These results also suggest an increase in secondary neoplasia associated with FCR in elderly fit CLL patients.
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http://dx.doi.org/10.1097/HS9.0000000000000336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000471PMC
February 2020

Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial.

Leukemia 2020 08 18;34(8):2038-2050. Epub 2020 Feb 18.

Unite de Recherche Clinique, Hopital Avicenne, Bobigny, France.

We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0-99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p < 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care "watch and wait" for these patients.
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http://dx.doi.org/10.1038/s41375-020-0747-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387319PMC
August 2020

[Chronic lymphocytic leukemia].

Internist (Berl) 2020 Mar;61(3):277-287

Klinik I für Innere Medizin, Centrum für Integrierte Onkologie Aachen Bonn Köln Düsseldorf, Deutsche CLL-Studiengruppe, Universität zu Köln, Kerpener Straße 62, 50937, Köln, Deutschland.

Chronic lymphocytic leukemia (CLL) is one of the most common hematological neoplasms and is the most common leukemia in western industrial nations. According to the World Health Organization classification, CLL is an indolent B‑cell non-Hodgkin's lymphoma (NHL). Diagnosis requires an increase of B‑lymphocytes to more than 5.0 G/l as well as detection of CD5- and CD19-positive B‑lymphocytes. Symptoms can be B symptoms, fatigue or frequent infections. Therapy is only required if there are pronounced symptoms or changes in the blood count, such as a relevant drop in hemoglobin and/or platelets. The prognosis strongly depends on the individual molecular and cytogenetic risk factors. For a long time, the first-line treatment was characterized by chemotherapy in combination with CD20 antibodies. In recent years, the approval of new targeted drugs has changed the treatment landscape significantly and has led to a shift towards chemotherapy-free regimens.
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http://dx.doi.org/10.1007/s00108-019-00733-8DOI Listing
March 2020

Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group.

Leukemia 2020 04 10;34(4):1038-1051. Epub 2020 Feb 10.

Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany.

The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin >3.5 mg/dL, lymphocyte doubling time (LDT) <12 months, and age >60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0-1.5), low (2-4), high (4.5-6.5), and very high-risk (7-14) scores, respectively (P < 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.
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http://dx.doi.org/10.1038/s41375-020-0727-yDOI Listing
April 2020

Minimal Residual Disease Assessment in CLL: Ready for Use in Clinical Routine?

Hemasphere 2019 Oct 9;3(5):e287. Epub 2019 Aug 9.

Department I of Internal Medicine and Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, German CLL Study Group, University Hospital Cologne, Cologne, Germany.

The introduction of chemoimmunotherapy and more recently the implementation of novel agents into first-line and relapse treatment have substantially improved treatment outcomes in patients with chronic lymphocytic leukaemia (CLL). With longer progression-free survival and more frequently observed deep remissions there is an emerging need for sensitive methods quantitating residual disease after therapy. Over the last decade, assessment of minimal residual disease (MRD) has increasingly been implemented in CLL trials. The predictive value of MRD status on survival outcomes has repeatedly been proven in the context of chemoimmunotherapy and cellular therapies. Recent data suggests a similar correlation for Bcl-2 inhibitor-based therapy. While the relevance of MRD assessment as a surrogate endpoint in clinical trials is largely undisputed, its role in routine clinical practice has not yet been well defined. This review outlines current methods of MRD detection in CLL and summarizes MRD data from relevant trials. The significance of MRD testing in clinical studies and in routine patient care is assessed and new MRD-guided treatment strategies are discussed.
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http://dx.doi.org/10.1097/HS9.0000000000000287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919470PMC
October 2019

First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy.

Cancer Manag Res 2019 13;11:10463-10476. Epub 2019 Dec 13.

Sarah Cannon Research Institute, Drug Development Unit, Tennessee Oncology, Nashville, TN, USA.

Purpose: This first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase.

Patients And Methods: Patients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy.

Results: Forty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission >4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD.

Conclusion: CC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment.

Clinical Trial Registration: NCT01353625.
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http://dx.doi.org/10.2147/CMAR.S208720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916675PMC
December 2019

Relapsed disease and aspects of undetectable MRD and treatment discontinuation.

Hematology Am Soc Hematol Educ Program 2019 12;2019(1):482-489

Department I for Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Duesseldorf; and.

Continuous treatment vs fixed duration of monotherapies and combinations of targeted agents are treatment options in relapsed chronic lymphocytic leukemia. The optimal choice of relapse treatment is dependent on the prior frontline therapy, duration of remission after frontline, genetic markers, and patients' condition, including age and comorbidities. Combination therapies may result in deep responses with undetectable minimal residual disease (uMRD). Although uMRD is an excellent predictive marker for disease progression, it is rarely used in clinical practice and needs additional evaluation in clinical trials before discontinuation of therapy should be guided according to uMRD.
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http://dx.doi.org/10.1182/hematology.2019000070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913464PMC
December 2019

Sequential and combination treatments with novel agents in chronic lymphocytic leukemia.

Haematologica 2019 11 4;104(11):2144-2154. Epub 2019 Oct 4.

University of Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University Hospital Cologne

Chemoimmunotherapy has been the standard of care for patients with chronic lymphocytic leukemia for a long time. However, over the last few years, novel agents have produced unprecedented outcomes in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia. With the advent of these targeted agents, treatment options have diversified very considerably and new questions have emerged. For example, it is unclear whether these novel agents should be used as sequential monotherapies until disease progression or whether they should preferably be combined in time-limited treatment regimens aimed at achieving deep and durable remissions. While both approaches yield high response rates and long progression-free and overall survival, it remains challenging to identify patients individually for the optimal concept. This review provides guidance in this decision process by presenting evidence on sequential and combined use of novel agents and discussing the advantages and drawbacks of these two approaches.
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http://dx.doi.org/10.3324/haematol.2018.208603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821614PMC
November 2019