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J.S. Vermaat et al.
3&5) and CD79B (exons 5&6). The minimum coverage threshold was 100 on-target reads with a minimum variant allele frequency of ≥10% of the reads. Variants were analyzed using Geneticist Assistant NGS Interpretative Workbench (v.1.4.15, SoftGenetics, State College). As described, identified variants were classified into five classes based on potential pathogenicity and only class 4 (possibly pathogenic) and class 5 variants (pathogenic) were reported.35
Statistical analysis
The correlation between the clinicopathologic parameters and biological aberrations was examined with the Chi-square test or ANOVA. The Kaplan-Meier method was applied to estimate 5- year OS and progression free survival (PFS). The starting point for time-to-event analysis was the date of the histological diagnosis. An event for OS was defined as death by any cause. An event for PFS was determined as relapse, disease progression, or death by any cause (whatever came first). If patients received palliative treatment and no remission evaluation was performed during the follow-up, an event for progression was defined at three weeks before patients succumbed to their disease. Observational inter- vals of patients without any event at the time of the last follow up or at 5 years after diagnosis were censored. The median follow up time for the whole cohort was determined by the use of reverse Kaplan-Meier.36 The log-rank test was performed to compare risk groups. The Cox proportional-hazards model was used to esti- mate hazard ratios (HR) including 95% confidence intervals (95%- CI). Adjusted HR were obtained in a multivariable Cox model. Competing risks analysis was used to estimate the cumulative incidences of relapse/progression, with non-relapse mortality con- sidered as competing risk. Gray’s test was performed to compare cumulative incidences, whereas a cause-specific Cox proportion- al-hazards model was used to estimate the impact of risk factors on them.37 The incremental prognostic value of MYD88 and/or CD79B was assessed by comparing Harrell’s cross-validated C sta- tistic for Cox models with and without MYD88 and/or CD79B.38 All statistical analyses were performed using SPSS software (ver- sion 23, IBM SPSS statistics) and RStudio (version 1.1442, RStudio, Inc. packages survival, prodlim, dynpred and cmprsk). P-values were two-sided and P<0.05 was considered statistically signifi- cant.
Results
Patient characteristics
Table 1 depicts the baseline characteristics of the 250 DLBCL patients (AUMC N=224 patients and LUMC N=26 cases). The median age at diagnosis was 61.4 years (range 18.6-89.6). A total of 38 DLBCL patients were immune-compromised, due to inherited conditions (severe combined immunodeficiency disorder, common variable immunodeficiency disorder), human immunode- ficiency virus (HIV) infection, or extended use of thera- peutic immunosuppression necessitated by organ trans- plantation or auto-immune disorders. Based on anatomi- cal locations, 75 patients (30.0%) had strictly nodal DLBCL and in 67 patients (26.8%) the lymphoma present- ed in IP sites: 33 patients with PTL and 35 patients with PCNSL of whom one patient had testicular and CNS loca- tions synchronously. The remaining 108 patients (43.2%) had extranodal disease in non-IP sites (with or without nodal involvement). With respect to staging, PCNSL was considered as advanced disease equivalent to Ann Arbor Stage IV for assignment of the IPI and subsequent statisti-
Table 1. Patient characteristics at time of diagnosis.
All patients
Gender Male Female
Median age in years (range)
History of immune deficiency
HIV
Organ transplantation with prolonged use of immune suppressive drugs
SCID/CVID
Othera
Anatomical lymphoma location
Nodal
Extranodalb (with or without nodal location) Immune-privileged
CNS locationc
Testis location
Ann Arbord I
II III IV
IPId 0 1 2 3 4 5
First line treatment
R-CHOP
CHOP
Other chemotherapye
Radiotherapy only
Surgery only
None /Palliative
High-dose methotrexate regimens (HD-MTX)f
Radiotherapy
With curative intent Palliative care only
Response to first line treatment
Complete response Partial response Stable disease Progressive disease Too early to call
(N=250)
168 (67.2 %) 82 (32.8 %) 61.4 (18.6-89.6) 38 (15.2 %) 16 (6.4 %)
7 (2.8 %)
3 (1.2 %)
13 (5.2 %)
75 (30.0 %) 108 (43.2 %) 67 (26.8 %) 35 (14.0 %) 32 (13.2 %) (N = 248) 51 (20.6 %) 32 (12.9 %) 26 (10.5 %) 139 (56.0 %) (N = 241) 20 (8.3 %) 41 (17.0 %) 90 (37.3 %) 58 (24.1 %) 24 (10.0 %) 8 (3.3 %)
160 (64.0 %) 25 (10.0 %) 5 (2.0 %) 1 (0.4 %) 2 (0.8 %) 34 (13.6 %) 23 (9.2 %)
77 (30.8 %) 60 (24.0 %) 17 (6.8 %)
166 (66.4 %) 14 (5.6 %) 2 (0.8 %) 67 (26.8 %) 1 (0.4 %)
HIV: humane immunodeficiency virus; SCID: severe combined immunodeficiency Disorder; CVID: common variable immunodeficiency disorder; CNS: central nervous system; IPI: international prognostic index; (R-)CHOP: (rituximab), cyclophos- phamide, doxorubicin, vincristine, prednisone. aOthers include inflammatory bowel disease, Sjögren, sarcoidosis, atopic dermatitis, and/or auto-immune haemolytic anaemia.bExtranodal comprised lung,liver,spleen,bone marrow,breast,soft tissue,thy- roid, bone, (ad)renal, orbital, stomach, skin, pancreas, bowel, bladder, ovary, and naso- /oropharynx locations. cOne patient experienced both CNS and testicular locations. dPCNSL were classified as advanced stage (Ann-Arbor stage IV) and subsequently received one risk point for IPI. e(R-)C(E)OP: (rituximab), cyclophosphamide, (etopo- side), vincristin, prednisone. fSpecific regimens include HD-MTX + cytarabine + car- mustine, HD-MTX + cytarabine, rituximab + HD-MTX + prednisone (RMP), cyclophos- phamide + doxorubicin + teniposide + prednisone + vincristine + bleomycin (CHVmP/BV), HD-MTX + procarbazin + lomustin, HD-MTX + cytarabine + thiotepa + rituximab (MATRiX), HD-MTX + teniposide + carmustin + prednisone (MBVP) (+ rit- uximab).
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