Search

Background In patients with presumed primary CNS lymphoma (PCNSL), a systemic manifestation is found only in a small minority. Although bone marrow biopsy (BMB) is recommended for staging, its diagnostic value is unclear. Methods A retrospective analysis of 392 patients with presumed PCNSL from 3 university hospitals and 33 patients with secondary CNS lymphoma (SCNSL) and initial CNS involvement from a multicenter Germany-wide prospective registry was performed. Results A BMB was performed and documented in 320/392 patients with presumed PCNSL; 23 had pathologic results. One harbored the same lymphoma in the brain and bone marrow (BM), 22 showed findings in BM discordant to the histology of brain lymphoma; n = 12 harbored a low-grade lymphoma in the BM, the other showed B-cell proliferation but no proof of lymphoma (n = 5), monoclonal B cells (n = 3), or abnormalities not B-cell-associated (n = 2). In the group of SCNSL with initial CNS manifestation, 32/33 patients underwent BMB; 7 were documented with bone marrow involvement (BMI); 1 had concordant results in the brain and BM with no other systemic manifestation. Six had additional systemic lymphoma manifestations apart from the brain and BM. Conclusions In only 2 out of 352 (0.6%) patients with CNS lymphoma (320 presumed PCNSL and 32 SCNSL), BMB had an impact on diagnosis and treatment. While collected in a selected cohort, these findings challenge the value of BMB as part of routine staging in presumed PCNSL.

Introduction: Integration of patient preferences into shared decision making improves disease-related outcomes, but such data from patients with advanced breast cancer (aBC) are limited. The objective of this study was to demonstrate the relative importance of overall survival (OS) and progression-free survival (PFS) in relation to quality of life (QoL) and therapy-associated side effects from the perspective of patients with aBC. Methods: Postmenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative aBC receiving first- or second-line treatment were recruited throughout Germany. Patient-relevant attributes for aBC therapy assessment were collected using a stepwise multimodal approach. A conjoint matrix was developed, resulting in 2 attributes for therapy goals (OS and PFS), 4 for QoL, and 6 for side effects. An online quantitative survey was then performed using adaptive choice-based conjoint (ACBC) methodology. Results: The quantitative survey included 104 patients: 67 (64.4%) receiving first-line treatment and 37 (35.6%) receiving second-line treatment. The QoL attribute “physical agility and mobility” received the highest utility score (19.4 of 100%), reflecting the greatest importance to patients, followed by treatment goals (OS [15.2%] and PFS [14.4%]). Therapy-related side effects were less important, with nausea/vomiting being the most important (9.3%), followed by infection (6.4%) and hair loss (5.0%). The McFadden pseudo R2 (0.805), the root likelihood (0.864), and the χ2 test (2,809.041; p < 0.0001) indicated a very good fit of the statistical model. Conclusion: Using ACBC analysis, it appears that QoL, OS, and PFS are most important to postmenopausal patients with aBC in relation to cancer treatment. Side effects seem to be less important if OS or PFS are prolonged and the QoL is maintained. Thus, QoL, OS, and PFS should be considered equally when making treatment decisions in aBC.

Objective: This study aimed to identify patient preferences in aBC related to cancer treatment characteristics, i.e. to determine the relevance of gained lifetime (OS) and time to progression (PFS) in relation to quality of life (QoL) and therapy-associated side effects. Methods: Post-menopausal women with HR+/HER2-aBC receiving 1st or 2nd line treatment were recruited throughout Germany. Patient relevant attributes to assess aBC therapies were collected in a stepwise multi-methodological approach, consisting of desk research, qualitative interviews with patients (n=12), caregivers (n=3) and aBC treating physicians (n=2) and iterative reviews of the empirical findings in a cross-functional team. A draft conjoint matrix was developed which was refined by means of two pre-tests with aBC patients (n=9). The final conjoint matrix consisted of two attributes for therapy goals (OS and PFS), four for QoL and six for side effects. It represented the basis of the subsequent quantitative survey using adaptive choice-based conjoint methodology. Results: In the qualitative phase, QoL emerged as a multidimensional concept, consisting of several factors such as ability to lead a ‘normal’ life, physical capability to do things like before, mobility, carefreeness (not continuously be reminded of the disease), having goals and being able to go for them, and spend quality time with family and friends. Factors limiting QoL were symptom burden, medical controls and side effects, which were considered particularly disturbing if long-lasting, affecting everyday life and when effective management was not available. The quantitative sample consisted of 104 patients (67% 50-64 yrs/33% >65 yrs). Time from aBC diagnosis to survey participation was ≤5 years and >5 years in 50% of patients each. At the time of the survey, 67 patients (64.4%) were receiving 1st line and 37 (35.6%) 2nd line treatment, i.e. regular oral intake in 80%, regular injections in 29% and regular infusions in 15% of patients; the start of the current treatment was ≤1 year in 43% and >1 year in 57% of patients. QoL parameters (physical mobility and flexibility) received the highest value (19.4%), followed by treatment goals (OS 15.2%, PFS 14.4%). Therapy-related side effects turned out to be less important overall with nausea/vomiting being the most relevant side effect (9.3%), followed by infection risk (6.4%), diarrhea (2.9%) and mucosal dryness (1.2%). No significant differences were found between 1st and 2nd line patients. A relation between having experienced a side effect in the past and a desire to avoid it was identified for nausea, vomiting, and dry mucosa. There was no relation between the desire to avoid a side effect and its severity in the past. McFadden pseudo R2 (0.805), Root-Likelihood (0.864) and Chi-square test (2809.041, highly significant (p Citation Format: Mattea Reinisch, Norbert Marschner, Thorsten Otto, Agnieszka Korfel, Clemens Stoffregen, Achim Wöckel. Patient preferences: Results of a German adaptive choice-based conjoint analysis study in patients on palliative treatment for advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-17-08.

Background Despite beguiling responses to initial therapy in many patients, PCNSL remains a therapeutic challenge. Relapse is common, cures are elusive for most patients, and overall response are disappointing compared to other diffuse large B-cell lymphomas. High-dose methotrexate-based therapies have become the standard of care, with many variations, but there is no consensus, and very little data regarding the role of ITC in the initial treatment of patients with PCNSL. Material and Methods We collected study-level and where possible, patient-level data from three independent clinical trials comparing adults with newly diagnosed PCNSL treated with regimens that differed based on the use of ITC. Patient characteristics, overall (OS) and progression-free survival (PFS), and characteristics of relapse were examined. The frequency of lymphomatous meningitis at diagnosis based on the location of CSF sampling - ventricular vs. lumbar - was also investigated. Complete data retrieval for this updated analysis has allowed us to combine data from the three studies and calculate summary statistics using a random effects model and inverse variance technique. In addition, predictors of OS and PFS were modeled using a Cox proportional hazards technique. Results The three cohorts were treated with: HD MTX/rituximab/ifosfamide followed by either HD MTX/cytarabine/ifosfamide (group Ia), or cytarabine/thiotepa and autologous stem cell transplant (group Ib) (n=80); HDMTX/vinca alkaloids/ifosfamide/cytarabine (group II) (n=83); or HD MTX/rituximab (group III) (n=49). ITC consisted of MTX/cytarabine/prednisolone (group Ia only, n=43); MTX/cytarabine/prednisolone (group II, n=65); or liposomal cytarabine (group III, n=21). One- and two-year OS was better in the ITC chemotherapy compared to the no-ITC group (RR 1.25 [1.16-1.34] and 1.20 [1.14-1.26] respectively, p< 0.001 for both comparisons). One-year PFS was also improved in the ITC group (RR 1.12 [1.01-1.25], p=0.031). Two-year PFS was not statistically different between groups (RR 1.20 [0.90-1.59], p=0.220). Relapse involving the CSF was more frequent in the non-IT chemotherapy group (RR 2.31 [2.03-2.62], p< 0.001). CSF cytology was positive in 81% of ventricular specimens vs 14.3% of lumbar specimens (p< 0.001). Conclusion This analysis of three independent cohorts of adults with newly diagnosed PCNSL suggests (when ventricular rather than lumbar CSF is sampled) that lymphomatous meningitis is dramatically more frequent, and perhaps universal. Including ITC as part of the initial treatment regimen increased both OS and PFS substantially. A randomized controlled trial is urgently required.

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the genomic and transcriptional landscape of PCNSL, we here performed whole-genome and transcriptome sequencing and integrative analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL and matched controls. The results were compared to an independent validation cohort of 31 FFPE CNSL specimens (PCNSL, n = 19; SCNSL, n = 9; EBV+ CNSL, n = 3) as well as 39 FL and 36 systemic DLBCL cases outside the CNS. Somatic genomic alterations in PCNSL mainly affect the JAK-STAT, NFkB, and B-cell receptor signaling pathways, with hallmark recurrent mutations including MYD88 L265P (67%) and CD79B (63%), CDKN2A deletions (83%) and also non-coding RNA genes such as MALAT1 (70%), NEAT (60%), and MIR142 (80%). Kataegis events, which affected 15 of 50 identified driver genes and 21 of the top 50 mutated ncRNAs, played a decisive role in shaping the mutational repertoire of PCNSL. Compared to systemic DLBCL, PCNSLs exhibited significantly more focal deletions in 6p21 targeting the HLA-D locus that encodes for MHC class II molecules as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis (SBS1, ID1 and ID2) were significantly enriched in PCNSL (SBS1: p = 0.0027, ID1/ID2: p < 1×10−4). Furthermore, TERT gene expression was significantly higher in PCNSL compared to ABC-DLBCL (p = 0.027). Although PCNSL share many genetic alterations with systemic ABC-DLBCL in the same signaling pathways, transcriptome analysis clearly distinguished both into distinct molecular subtypes. EBV+ CNSL cases may be distinguished by lack of recurrent mutational hotspots apart from IG and HLA-DRB loci.

Patients with primary central nervous system lymphoma (PCNSL) not fulfilling inclusion criteria for clinical trials represent an underreported population. Thirty-four consecutive PCNSL patients seen at our center between 2005 and 2019 with exclusion criteria for therapeutic trials were analyzed (non-study patients) and compared with patients from the G-PCNSL-SG-1 (German PCNSL Study Group 1) study (study patients), the largest prospective multicenter trial on PCNSL, comprising 551 patients. Median follow up was 68 months (range 1–141) in non-study patients and 51 months (1–105) in study patients. Twenty-seven/34 (79.4%) non-study patients received high dose methotrexate (HDMTX), while seven/34 (20.6%) with a glomerular filtration rate (GFR) < 50 mL/min did not. Median overall survival (OS) was six months (95% confidence interval [CI] 0–21 months) in those 34 non-study patients. The 27 non-study patients treated with HDMTX were compared with 526/551 G-PCNSL-SG-1 study patients who had received HDMTX as well. Median OS was 20 months (95% CI 0–45)/21 months (95% CI 18–25) in 27 non-study/526 study patients (\(\it p\) = 0.766). Favorable prognostic factors in non-study patients were young age, application of HDMTX and early response on magnet resonance imaging (MRI). If HDMTX-based chemotherapy can be applied, long-term disease control is possible even in patients not qualifying for clinical trials. Initial response on early MRI might be useful for decision on treatment continuation.

Patients with primary central nervous system lymphoma (PCNSL) not fulfilling inclusion criteria for clinical trials represent an underreported population. Thirty-four consecutive PCNSL patients seen at our center between 2005 and 2019 with exclusion criteria for therapeutic trials were analyzed (non-study patients) and compared with patients from the G-PCNSL-SG-1 (German PCNSL Study Group 1) study (study patients), the largest prospective multicenter trial on PCNSL, comprising 551 patients. Median follow up was 68 months (range 1–141) in non-study patients and 51 months (1–105) in study patients. Twenty-seven/34 (79.4%) non-study patients received high dose methotrexate (HDMTX), while seven/34 (20.6%) with a glomerular filtration rate (GFR) &lt, 50 mL/min did not. Median overall survival (OS) was six months (95% confidence interval [CI] 0–21 months) in those 34 non-study patients. The 27 non-study patients treated with HDMTX were compared with 526/551 G-PCNSL-SG-1 study patients who had received HDMTX as well. Median OS was 20 months (95% CI 0–45)/21 months (95% CI 18–25) in 27 non-study/526 study patients (p = 0.766). Favorable prognostic factors in non-study patients were young age, application of HDMTX and early response on magnet resonance imaging (MRI). If HDMTX-based chemotherapy can be applied, long-term disease control is possible even in patients not qualifying for clinical trials. Initial response on early MRI might be useful for decision on treatment continuation.

In primary central nervous system lymphomas (PCNSL), optimal therapy remains to be established, and the role of whole-brain radiotherapy (WBRT) is a matter of debate. With radiation alone, transient responses and clinical improvement are frequent, but long-term disease control is exceptional. WBRT has been considered possible consolidation therapy after high-dose methotrexate (HDMTX)-based initial chemotherapy. This strategy has been questioned due to a high risk of delayed neurotoxicity after combined treatment. This review analyses the current role of WBRT in PCNSL.Neither in retrospective analyses nor in randomized trials, an overall survival benefit with WBRT in addition to HDMTX-based initial chemotherapy could be found. On the other hand, a recent randomized trial did not show superiority of consolidation with high-dose chemotherapy followed by autologous stem-cell transplantation to consolidation WBRT after initial HDMTX-based polychemotherapy. This finding, however, is probably due to an intense initial therapy and to a small number of patients having reached consolidation and randomization to WBRT vs. high-dose chemotherapy followed by autologous stem-cell transplantation.The current role of WBRT in PCNSL is confined to patients who cannot tolerate chemotherapy or have failed it. WBRT should not routinely be used for consolidation of HDMTX-based chemotherapy due to lack of evidence of efficacy as additional treatment and due to a high risk of neurotoxicity.