J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website http://www.thejh.org

Review

Volume 6, Number 2-3, September 2017, pages 33-43

Rituximab-Based Therapy in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: Individualized Risk-Adapted Therapy Approach Using Molecular Subtypes

**Table 1.** Clinical Trials of DLBCL Treatment Evaluating Role of Specific Biomarkers
Reference	Biomarker	Study/patient population	Intervention	Main results
BCL: B-cell leukemia/lymphoma; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone; DA-EPOCH: dose-adjusted etoposide, prednisone, oncovin (vincristine), cyclophosphamide, and hydroxydaunorubicin (doxorubicin); DLBCL: diffuse large B-cell lymphoma; GCB: germinal center B-cell; PRDM1: positive regulatory domain 1; R: rituximab.
Mounier et al, 2003[35]	BCL2	Patients aged between 60-80 years with DLBCL Stage II or higher	R-CHOP versus CHOP	Rituximab can prevent chemotherapy failure in patients with BCL2 protein overexpression.
Wilson et al, 2008 [36]	BCL2	Patients aged ≥ 18 years with untreated DLBCL of stage II or higher	DA-EPOCH-R versus DA-EPOCH	Addition of rituximab only benefited patients with BCL2 positive tumors.
Winter et al, 2006 [37]	BCL6	DLBCL patients aged ≥ 60 years included in E4494, C9793, S4494 trial and with adequate pathology sample	R-CHOP versus CHOP	The addition of R to CHOP reduced treatment failures and death in BCL6-DLBCL cases only. BCL2 protein expression was not predictive of outcome in both groups.
Wilson et al, 2008 [36]	BCL6	Patients aged ≥ 18 years with untreated DLBCL of stage II or higher	DA-EPOCH-R versus DA-EPOCH	BCL6 expression was associated with higher PFS.
Winter et al, 2010 [38]	p21	DLBCL patients aged ≥ 18 years included in E4494 trial and with adequate pathology sample trial	R-CHOP versus CHOP	p21 expression was a favorable independent prognostic indicator in patients treated with R-CHOP but not with CHOP alone. The addition of R to CHOP selectively benefited the p21 positive patients.
Liu et al, 2007 [39]	PRDM1: PRDM1α and PRDM1β	DLBCL patients aged ≥ 18 years with adequate pathology sample	R-CHOP versus CHOP	In the non-GCB patients, PRDM1β gene expression was correlated with short survival time in CHOP versus R-CHOP.

Table 1. Clinical Trials of DLBCL Treatment Evaluating Role of Specific Biomarkers

Reference

Biomarker

Study/patient population

Intervention

Main results

BCL: B-cell leukemia/lymphoma; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone; DA-EPOCH: dose-adjusted etoposide, prednisone, oncovin (vincristine), cyclophosphamide, and hydroxydaunorubicin (doxorubicin); DLBCL: diffuse large B-cell lymphoma; GCB: germinal center B-cell; PRDM1: positive regulatory domain 1; R: rituximab.

Mounier et al, 2003[35]

BCL2

Patients aged between 60-80 years with DLBCL Stage II or higher

R-CHOP versus CHOP

Rituximab can prevent chemotherapy failure in patients with BCL2 protein overexpression.

Wilson et al, 2008 [36]

BCL2

Patients aged ≥ 18 years with untreated DLBCL of stage II or higher

DA-EPOCH-R versus DA-EPOCH

Addition of rituximab only benefited patients with BCL2 positive tumors.

Winter et al, 2006 [37]

BCL6

DLBCL patients aged ≥ 60 years included in E4494, C9793, S4494 trial and with adequate pathology sample

R-CHOP versus CHOP

The addition of R to CHOP reduced treatment failures and death in BCL6-DLBCL cases only. BCL2 protein expression was not predictive of outcome in both groups.

Wilson et al, 2008 [36]

BCL6

Patients aged ≥ 18 years with untreated DLBCL of stage II or higher

DA-EPOCH-R versus DA-EPOCH

BCL6 expression was associated with higher PFS.

Winter et al, 2010 [38]

p21

DLBCL patients aged ≥ 18 years included in E4494 trial and with adequate pathology sample trial

R-CHOP versus CHOP

p21 expression was a favorable independent prognostic indicator in patients treated with R-CHOP but not with CHOP alone. The addition of R to CHOP selectively benefited the p21 positive patients.

Liu et al, 2007 [39]

PRDM1: PRDM1α and PRDM1β

DLBCL patients aged ≥ 18 years with adequate pathology sample

R-CHOP versus CHOP

In the non-GCB patients, PRDM1β gene expression was correlated with short survival time in CHOP versus R-CHOP.

**Table 2.** Efficacy and Safety of XR-CHOP in ABC DLBCL in Clinical Trials
Trial	Intervention	Patients	Efficacy	Safety
ABC: activated B-cell; AE: adverse event; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone; CR: complete response; DLBCL: diffuse large B-cell lymphoma; EFS: event-free survival; GCB: germinal center B-cell; HR: hazard ratio; OR: odds ratio; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; R: rituximab; V: bortezomib; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.
Bortezomib
LYM-2034, NCT01040871 [51]	VR-CAP versus R-CHOP	Previously untreated non-GCB DLBCL patients (identified by Hans method)	No significant differences between VR-CAP and R-CHOP. VR-CAP did not improve efficacy versus R-CHOP in non-GCB DLBCL: CR rate (64.5%, 66.2%; OR, 0.91; P = 0.80); ORR, (93.4%, 98.6%; OR, 0.21; P = 0.11); PFS: HR, 1.12; P = 0.76); OS: HR, 0.89; P = 0.75).	Rates of AEs were similar with VR-CAP and R-CHOP: AEs with grade ≥ 3 (88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%). Grade ≥ 3 peripheral neuropathy rates were 6% and 3%, respectively.
PYRAMID, NCT00931918 [52]	R-CHOP versus VR-CHOP	Non-GCB DLBCL patients (identified by Hans method)	VR-CHOP did not have significant efficacy advantage over R-CHOP in previously untreated non-GCB DLBCL patients. Two-year PFS (R-CHOP versus VR-CHOP) was 77% versus 82% (HR: 0.77; 90% CI: 0.45-1.30; P = 0.70). At data cut-off, 15% and 11% of patients in the R-CHOP and VR-CHOP arms had died (HR: 0.65; 90% CI: 0.32 - 1.29); 2-year OS rates were 80% versus 82%. In 86 R-CHOP and 90 VR-CHOP response-evaluable patients, ORRs were 98% versus 92% and CRs were 52% versus 54%.	In the R-CHOP (n = 100) versus VR-CHOP (n = 101) safety populations, the proportion of AEs was as follows: Grade ≥ 3 AE: 71% versus 79%; serious AEs: 31% versus 34%; drug-related AEs with grade ≥ 3: 55% versus 68%, the most common being neutropenia (34% versus 28%) and thrombocytopenia (8% versus 20%). Peripheral neuropathies grade ≥ 3 were 1% versus 5%.
REMoDL-B, NCT01324596 [32, 61]	R-CHOP versus VR-CHOP	Newly diagnosed ABC subtype DLBCL defined by central GEP assay	No difference in PFS of ABC versus GCB subtype patients (2-year PFS: 71%)
Lenalidomide
NCT00670358 [55]	Lenalidomide plus R-CHOP	Adults with newly diagnosed untreated stages II-IV CD20-positive DLBCL. Non-GCB versus GCB analyses were conducted.	Of 64 enrolled patients, 60 were evaluable for response. The ORR was 98% with 80% CR. EFS and OS at 24 months were 59% (95% CI: 48-74%) and 78% (95% CI: 68-90%), respectively. In contemporary cohort of non-GCB versus GCB DLBCL patients treated with R-CHOP, 24-month PFS and OS were 28% versus 64% (P < 0.001) and 46% versus 78% (P < 0.001), respectively. Contrastingly, there was no difference in 24-month PFS or OS for the study patients on the basis of non-GCB and GCB subtype (60% versus 59% (P = 0.83) and 83% versus 75% (P = 0.61) at 2 years, respectively).	Following toxicities were seen in the patients: grade ≥ 3 non-hematologic toxicities, 25%; grade ≥ 3 hematologic toxicities, 94%; grade 4 hematologic toxicities, 77%; grade 3 neutropenia, 13%; grade 4 neutropenia, 75%; grade 3 febrile neutropenia, 9%; grade 3 thrombocytopenia, 27%; grade 4 thrombocytopenia, 17%; and thrombocytopenia leading to bleeding complications, 1.6%.

Table 2. Efficacy and Safety of XR-CHOP in ABC DLBCL in Clinical Trials

Trial

Intervention

Patients

Efficacy

Safety

ABC: activated B-cell; AE: adverse event; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone; CR: complete response; DLBCL: diffuse large B-cell lymphoma; EFS: event-free survival; GCB: germinal center B-cell; HR: hazard ratio; OR: odds ratio; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; R: rituximab; V: bortezomib; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.

Bortezomib

LYM-2034, NCT01040871 [51]

VR-CAP versus R-CHOP

Previously untreated non-GCB DLBCL patients (identified by Hans method)

No significant differences between VR-CAP and R-CHOP. VR-CAP did not improve efficacy versus R-CHOP in non-GCB DLBCL: CR rate (64.5%, 66.2%; OR, 0.91; P = 0.80); ORR, (93.4%, 98.6%; OR, 0.21; P = 0.11); PFS: HR, 1.12; P = 0.76); OS: HR, 0.89; P = 0.75).

Rates of AEs were similar with VR-CAP and R-CHOP: AEs with grade ≥ 3 (88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%). Grade ≥ 3 peripheral neuropathy rates were 6% and 3%, respectively.

PYRAMID, NCT00931918 [52]

R-CHOP versus VR-CHOP

Non-GCB DLBCL patients (identified by Hans method)

VR-CHOP did not have significant efficacy advantage over R-CHOP in previously untreated non-GCB DLBCL patients. Two-year PFS (R-CHOP versus VR-CHOP) was 77% versus 82% (HR: 0.77; 90% CI: 0.45-1.30; P = 0.70). At data cut-off, 15% and 11% of patients in the R-CHOP and VR-CHOP arms had died (HR: 0.65; 90% CI: 0.32 - 1.29); 2-year OS rates were 80% versus 82%. In 86 R-CHOP and 90 VR-CHOP response-evaluable patients, ORRs were 98% versus 92% and CRs were 52% versus 54%.

In the R-CHOP (n = 100) versus VR-CHOP (n = 101) safety populations, the proportion of AEs was as follows: Grade ≥ 3 AE: 71% versus 79%; serious AEs: 31% versus 34%; drug-related AEs with grade ≥ 3: 55% versus 68%, the most common being neutropenia (34% versus 28%) and thrombocytopenia (8% versus 20%). Peripheral neuropathies grade ≥ 3 were 1% versus 5%.

REMoDL-B, NCT01324596 [32, 61]

R-CHOP versus VR-CHOP

Newly diagnosed ABC subtype DLBCL defined by central GEP assay

No difference in PFS of ABC versus GCB subtype patients (2-year PFS: 71%)

Lenalidomide

NCT00670358 [55]

Lenalidomide plus R-CHOP

Adults with newly diagnosed untreated stages II-IV CD20-positive DLBCL. Non-GCB versus GCB analyses were conducted.

Of 64 enrolled patients, 60 were evaluable for response. The ORR was 98% with 80% CR. EFS and OS at 24 months were 59% (95% CI: 48-74%) and 78% (95% CI: 68-90%), respectively. In contemporary cohort of non-GCB versus GCB DLBCL patients treated with R-CHOP, 24-month PFS and OS were 28% versus 64% (P < 0.001) and 46% versus 78% (P < 0.001), respectively. Contrastingly, there was no difference in 24-month PFS or OS for the study patients on the basis of non-GCB and GCB subtype (60% versus 59% (P = 0.83) and 83% versus 75% (P = 0.61) at 2 years, respectively).

Following toxicities were seen in the patients: grade ≥ 3 non-hematologic toxicities, 25%; grade ≥ 3 hematologic toxicities, 94%; grade 4 hematologic toxicities, 77%; grade 3 neutropenia, 13%; grade 4 neutropenia, 75%; grade 3 febrile neutropenia, 9%; grade 3 thrombocytopenia, 27%; grade 4 thrombocytopenia, 17%; and thrombocytopenia leading to bleeding complications, 1.6%.