Toxic Leucoencephalopathy Due to CHOP Therapy in a Patient with NonHodgkin’s Lymphoma

Abstract Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.

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Phase II study of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) therapy for newly diagnosed patients with low- and low–intermediate risk, aggressive non-Hodgkin’s lymphoma: final results of the Japan Clinical Oncology Group Study, JCOG9508

International Journal of Hematology ◽

10.1007/s12185-012-1101-2 ◽

2012 ◽

Vol 96 (1) ◽

pp. 74-83 ◽

Cited By ~ 3

Author(s):

Yoshitoyo Kagami ◽

◽

Kuniaki Itoh ◽

Kensei Tobinai ◽

Haruhiko Fukuda ◽

...

Keyword(s):

Clinical Oncology ◽

Phase Ii ◽

Phase Ii Study ◽

Hodgkin's Lymphoma ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Oncology Group ◽

Japan Clinical Oncology Group ◽

Oncology Group Study ◽

Chop Therapy

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Toxic leucoencephalopathy after heroin inhalation

Australasian Radiology ◽

10.1046/j.1440-1673.2002.01066.x ◽

2002 ◽

Vol 46 (3) ◽

pp. 306-308 ◽

Cited By ~ 17

Author(s):

Kai Au-Yeung ◽

Chi Lai

Keyword(s):

Toxic Leucoencephalopathy

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CD5 expression is potentially predictive of poor outcome among biomarkers in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy

Annals of Oncology ◽

10.1093/annonc/mdn392 ◽

2008 ◽

Vol 19 (11) ◽

pp. 1921-1926 ◽

Cited By ~ 51

Author(s):

D. Ennishi ◽

K. Takeuchi ◽

M. Yokoyama ◽

H. Asai ◽

Y. Mishima ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Poor Outcome ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Chop Therapy

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Immunostimulation During and After R-CHOP Therapy for B-Cell Lymphoma

Journal of Clinical & Experimental Immunology ◽

10.33140/jcei.01.01.07 ◽

2016 ◽

Vol 01 (01) ◽

Keyword(s):

T Cells ◽

B Cell ◽

Tumor Immunity ◽

Cd8 T Cells ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Treg Cells ◽

T Cell Subsets ◽

T Helper ◽

Chop Therapy

Backgrounds: Many studies show an immune imbalance in the tumor environment; some reports show that the T helper 1 (Th1)/ T helper 2 (Th2) ratio, the number of regulatory T-cells (Treg cells) or CD8+T-cells, and the CD8+Tcell/Treg cell ratio are associated with tumor suppression and expansion. Additionally, chemotherapy was reported to affect the immunity of patients with malignancy. Patients and Methods: Using flow cytometry we measured peripheral blood lymphocytes including non T-cells, as well as T-cell subsets such as CD3+T-cells, CD4+T-cells, CD8+T-cells, Treg cells, Th1 cells and Th2 cells before treatment, at the fourth cycle, and at 1, 3, 6 and 12 months after treatment in 21 patients with B-cell lymphoma receiving R-CHOP therapy. We also analyzed the changes in three immune indexes that reflect anti-tumor immunity (the CD4/CD8 ratio, the CD8/Treg ratio and the Th1/Th2 ratio). Results: Compared to pre-treatment there were significant decreases in the CD4/CD8 ratio between 1 month and 12 months after treatment (p<0.001, for all time points). The CD8/Treg ratio gradually increased with treatment with significant increases observed at 6 months (p=0.009) and 12 months after treatment (p=0.002). The Th1/ Th2 ratio showed a significant increase only before 4 cycles of therapy (p=0.007). Conclusion: Based on the changes in these three immune indexes, we propose that anti-tumor immunity improved after R-CHOP therapy, which enhanced the efficacy of R-CHOP therapy for lymphoma as well as its direct cytotoxic activity

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Tumor necrosis could reflect advanced disease status in patients with diffuse large B cell lymphoma treated with R-CHOP therapy

Annals of Hematology ◽

10.1007/s00277-016-2822-8 ◽

2016 ◽

Vol 96 (1) ◽

pp. 17-23 ◽

Cited By ~ 8

Author(s):

Moo-Kon Song ◽

Joo-Seop Chung ◽

Dong-Yeop Shin ◽

Sung-Nam Lim ◽

Gyeong-won Lee ◽

...

Keyword(s):

B Cell ◽

Tumor Necrosis ◽

Advanced Disease ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Disease Status ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Chop Therapy

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Relative dose intensity of R‐CHOP therapy and patient outcomes in advanced follicular lymphoma

Hematological Oncology ◽

10.1002/hon.2614 ◽

2019 ◽

Vol 37 (3) ◽

pp. 303-307

Author(s):

Tatsuya Konishi ◽

Yusuke Kanemasa ◽

Yuki Sasaki ◽

Toshihiro Okuya ◽

Tsukasa Yamaguchi ◽

...

Keyword(s):

Follicular Lymphoma ◽

Patient Outcomes ◽

Dose Intensity ◽

Relative Dose Intensity ◽

Chop Therapy

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Diffuse large B-cell lymphoma in Southeast Asian cohort: expression patterns of B-cell receptor (BCR) repertoire and its linkage with molecular subtypes and response to R-CHOP therapy

Journal of Clinical Pathology ◽

10.1136/jclinpath-2019-205837 ◽

2019 ◽

Vol 72 (9) ◽

pp. 630-635 ◽

Cited By ~ 2

Author(s):

Noraidah Masir ◽

Ariz Akhter ◽

Tariq M Roshan ◽

Chandramaya Sabrina Florence ◽

Faridah Abdul-Rahman ◽

...

Keyword(s):

Southeast Asia ◽

B Cell ◽

Targeted Therapies ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Receptor ◽

B Cell Receptor ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Chop Therapy

AimsHeightened B-cell receptor (BCR) activity in diffuse large B-cell lymphoma (DLBCL) is well established, and a subset of patients with relapsed DLBCL can benefit from BCR-targeted therapies. Universal outreach of such emerging therapies mandates forming a global landscape of BCR molecular signalling in DLBCL, including Southeast Asia.Methods79 patients with DLBCL (nodal, 59% and extranodal, 41%) treated with rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy were selected. Expression levels of BCR and linked signalling pathway molecules were inter-related with Lymph2Cx-based cell of origin (COO) types and overall survival (OS).ResultsActivated B-cell (ABC) type DLBCL constituted 49% (39/79) compared with germinal centre B-cell (GCB) type DLBCL (29/79; 37%) and revealed poor prognosis (p=0.013). In ABC-DLBCL, high BTK expression exerted poor response to R-CHOP, while OS in ABC-DLBCL with low BTK expression was similar to GCB-DLBCL subtype (p=0.004). High LYN expression coupled with a poor OS for ABC-DLBCL as well as GCB-DLBCL subtypes (p=0.001). Furthermore, high coexpression of BTK/LYN (BTKhigh/LYNhigh) showed poor OS (p=0.019), which linked with upregulation of several genes associated with BCR repertoire and nuclear factor-kappa B pathway (p<0.01). In multivariate analysis, high BTK and LYN expression retained prognostic significance against established clinical predictive factors such as age, International Prognostic Index and COO (p<0.05).ConclusionsOur data provide a clear association between high BCR activity in DLBCL and response to therapy in a distinct population. Molecular data provided here will pave the pathway for the provision of promising novel-targeted therapies to patients with DLBCL in Southeast Asia.

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