No Benefit of Rituximab in Primary Central Nervous System Lymphoma Patients: Results of the Randomised Phase III HOVON 105 / ALLG NHL 24 Intergroup Study

Abstract INTRODUCTION Lack of standard treatment of Primary Central Nervous System Lymphoma (PCNSL) was acknowledged in phase III intergroup study (HOVON 105/ALLG NHL 24). PCNSL incidence is increasing for unknown reasons, particularly among persons over 65 years. One of the major limitations of successful treatment of PCNSL is the blood-brain barrier (BBB), which prevents drug delivery into the brain. METHODS Polymer nanoconjugate based on biodegradable poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA) was used for treatment of BALB/C mice with intracranially inoculated murine A20 lymphoma. PHPMA-based nanoconjugates have defined synthesis strategy for BBB transcytosis, tumor targeting, and cancer cell killing. Nano immunodrug PHPMA/AP-2/Fab’/c-Myc inhibitor/H6 conjugate contains multiple AP-2 peptides for efficient delivery across the BBB and Fab’ fragments of αCD20 mouse Ab for CD20 receptor crosslinking on PCNSL cells. c-Myc inhibitor bound via a disulfide bond is transferred to the cytoplasm followed by cleavage. The therapeutic efficacy and survival were evaluated together with spectral flow cytometry and RNA-seq bioinformatic analysis of tumor tissues. RESULTS Nanoconjugates were able to penetrate BBB and accumulate in brain parenchyma. The best survival results were obtained for the group where nanoconjugate with αCD20 Fab’ causing tumor cell apoptosis and c-Myc antisense inhibitor was combined with αPD-1 checkpoint inhibitor. Survival compared to PBS-treated controls was significant (P=0.0006 by ANOVA). Ex vivo analysis of A20 brain lymphoma tissue after treatment with nanoconjugates demonstrated reduction of Tregs, associated with downregulation of IL-10 and IL-1β in plasma. Spectral flow cytometry revealed activation of tumor infiltrating T lymphocytes and M1 macrophages in lead nanodrug treated groups. RNA-seq data correlated with flow cytometry results indicating the activation of genes linked to IFN-γ pathway important for anti-tumor response and M1 macrophage activation. Immunostaining confirmed a marked increase of M1-specific iNOS expression in the nanodrug-treated tumors. Support: NIH grants: R01 CA188743, R01 CA206220, R01 CA209921

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Treatment of Primary Central Nervous System Lymphoma: From Chemotherapy to Small Molecules

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_200829 ◽

2018 ◽

pp. 604-615 ◽

Cited By ~ 6

Author(s):

Joe S. Mendez ◽

Christian Grommes

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Small Molecules ◽

Checkpoint Inhibitors ◽

Central Nervous System Lymphoma ◽

Phase Iii ◽

High Dose ◽

First Line ◽

The Past ◽

Systemic Spread

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that is typically confined to the brain, eyes, and cerebrospinal fluid (CSF) without evidence of systemic spread. PCNSL is an uncommon tumor, and only four randomized trials and one phase III trial have been completed so far, all in the first-line setting. The prognosis of patients with PCNSL has improved during the past few decades with the introduction of high-dose methotrexate (HD-MTX), which now serves as the backbone of all first-line treatment regimens. Despite recent progress, results after treatment are durable in half of patients, and therapy can be associated with late neurotoxicity. Novel insights into the pathophysiology of PCNSL have identified the B-cell receptor (BCR) pathway as a key mechanism in the pathogenesis of PCNSL. The use of novel agents targeting components of the BCR pathway, namely the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, and immunomodulatory drugs (IMIDs) like lenalidomide and pomalidomide, has so far been limited to patients who have recurrent/refractory PCNSL with promising high response rates. Within the past 5 years, there has been a peak in clinical trials investigating small molecules and novel reagents in the recurrent/refractory setting, including immune checkpoint inhibitors, IMIDs, and BTK and PI3K/AKT/mTOR inhibitors.

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Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study

Annals of Oncology ◽

10.1016/j.annonc.2020.04.014 ◽

2020 ◽

Vol 31 (8) ◽

pp. 1046-1055 ◽

Cited By ~ 1

Author(s):

M. van der Meulen ◽

K. Bakunina ◽

M. Nijland ◽

M.C. Minnema ◽

G. Cull ◽

...

Keyword(s):

Quality Of Life ◽

Central Nervous System ◽

Nervous System ◽

Central Nervous System Lymphoma ◽

Phase Iii ◽

Health Related Quality ◽

Related Quality ◽

Health Related ◽

Phase Iii Study

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NCOG-05. IMPACT OF ADDITIONAL RITUXIMAB TO STANDARD THERAPY ON COGNITIVE PERFORMANCES IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA PATIENTS

Neuro-Oncology ◽

10.1093/neuonc/noz175.666 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi159-vi159

Author(s):

Matthijs van der Meulen ◽

Linda Dirven ◽

Esther Habets ◽

Katerina Bakunina ◽

Martin Taphoorn ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Executive Functioning ◽

Cognitive Performance ◽

Low Dose ◽

Central Nervous System Lymphoma ◽

Phase Iii ◽

Motor Speed ◽

Over Time

Abstract BACKGROUND The goal of treatment of primary central nervous system lymphoma patients is to improve survival, without compromising neurocognitive functioning. The aim of this study was to analyze the effect of Rituximab and low-dose whole brain radiotherapy (WBRT) on cognition. METHODS 199 patients from a phase III trial (HOVON 105/ ALLG NHL 24), randomized to standard chemotherapy (and 30Gy WBRT for patients < 61 years-old only) with or without Rituximab, were asked to participate in a short neuropsychological evaluation (NPE) before and during treatment, and up to 2 years of follow-up or until progression. A difference in z-score, corrected for sex, age and education, of ≥ 1 point was considered as clinically relevant. The primary outcome was a difference over time between the arms in multiple cognitive domains, assessed by linear mixed models (LMM). Changes in cognitive performances between baseline and 24 months after treatment were assessed for both arms in cross-sectional analyses. Effect of WBRT was analyzed in irradiated patients only. RESULTS 105/199 patients completed at least one NPE; baseline characteristics were similar to the total trial population. Compliance was >60% at all evaluation points. No clinically relevant differences over time between the arms were seen in all domains in LMM analysis. Comparing changes from baseline to 24 months of follow-up, mean cognitive scores remained stable in both arms for attention, executive functioning (TMT B), and information processing speed. A clinically relevant improvement was seen in both arms for executive functioning (TMT A), memory and motor speed. In the irradiated patients (n=33) all scores remained stable after WBRT, up to 24 months of follow-up in all domains. CONCLUSION Cognitive performance remained stable or improved after treatment. Addition of Rituximab to standard treatment did not impact cognitive performance over time. After low-dose WBRT, cognition remained stable up to 2 years.

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