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Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.

ABSTRACT: Background:Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial. Patients and methods:The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged??18?years with bulky stage I-IV DLBCL (n?=?1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated. Results:177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n?=?163, intravenous (IV) MTX n?=?2, prophylaxis type unknown n?=?11 and IT MTX and cytarabine n?=?1). At a median follow-up of 6.5?years, 21 cases of CNS relapse (isolated n?=?11, with systemic relapse n?=?10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI,?>1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively. Conclusion:Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence. ClinicalTrials.gov:ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.

SUBMITTER: Gleeson M

PROVIDER: S-EPMC5834096 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.

Gleeson M M Counsell N N Cunningham D D Chadwick N N Lawrie A A Hawkes E A EA McMillan A A Ardeshna K M KM Jack A A Smith P P Mouncey P P Pocock C C Radford J A JA Davies J J Turner D D Kruger A A Johnson P P Gambell J J Linch D D

Annals of oncology : official journal of the European Society for Medical Oncology 20171001 10

<h4>Background</h4>Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial.<h4>Patients and methods</h4>The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years ...[more]

PMID: 28961838

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Project description:BACKGROUND:The introduction of rituximab (R) to conventional CHOP chemotherapy for newly diagnosed diffuse large B-cell lymphoma (DLBCL) led to an unequivocal improvement in survival, establishing RCHOP as the standard of care. Still, nearly 40% of DLBCL patients will eventually die of relapsed disease. Efforts to improve outcomes by addition of new biologic agents (X) to the RCHOP backbone are underway. In this era of R(X)CHOP, it is imperative to develop prognostic and predictive markers, not only to identify patients who will suffer a particularly aggressive course, but also to accurately select patients for clinical trials from which they will most benefit. DESIGN:The following review was undertaken to describe prognostic factors in DLBCL, with emphasis on markers that are accurate, relatively available, and clinically applicable in 2014. RESULTS:The International Prognostic Index retains its validity in the era of RCHOP, although with limited ability to predict those with <50% chance of long-term survival. Gene expression profiling has provided novel insights into the biology of DLBCL and led to the development of immunohistochemistry (IHC) algorithms that are in routine practice. Identification of a 'double-hit' (DH) lymphoma by fluorescent in situ hybridization with aberrations involving MYC and/or BCL2 and BCL6 genes has important implications due to its extremely dismal prognosis with RCHOP. Other markers such as the absolute lymphocyte count (ALC), serum immunoglobulin free light chains, vitamin D levels, serum cytokines/chemokines, and imaging with positron emission tomography (PET) have all shown promise as future predictive/prognostic tests. CONCLUSIONS:The future for new treatment options in DLBCL is promising with current clinical trials testing novel targeted agents such as bortezomib, lenalidomide, and ibrutinib as the 'X' in R(X)CHOP. Predictive factors are required to select and randomize patients appropriately for these trials. We envision the day when 'X' will be chosen based on the biological characteristics of the tumor.

Project description:Background:There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients??60 years treated on the R-CHOP14v21 trial with extended follow-up. Patients and methods:Six hundred and four R-CHOP14v21 patients??60 years were included in this subgroup analysis, with a median follow-up of 77.7?months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N?=?217) and RICOVER-60 (N?=?204) trials. Results:Elderly DLBCL patients received high dose intensities with median total doses of??98% for all agents. Toxicities were similar in both arms with the exception of more grade??3 neutropenia (P?<?0.0001) and fewer grade??3 thrombocytopenia (P?=?0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR?=?1.96; 95% CI: 1.22-3.16; P?=?0.01) and DHL (HR?=?2.21; 95% CI: 1.18-4.11; P?=?0.01) on OS in the combined trial cohorts, independent of other prognostic factors. Conclusions:Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. Trial numbers:ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Dataset Information

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.

Publications

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial.

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