Phase II study of lenalidomide and R-CHOP in patients with diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is recognized to be a molecularly heterogenous malignancy. Of the three main subtypes, the activated B-cell-like (ABC) subtype has the poorest prognosis historically. However, the ABC subtype has responded better than the germinal center B-cell-like (GCB) subtype to treatment with lenalidomide in previous studies.

Therefore, the phase II ECOG-ACRIN E1412 study (NCT01856192) was set up in the US to test how patients with DLBCL responded to treatment with R-CHOP compared with R-CHOP plus lenalidomide (R2CHOP). The results were recently published in the Journal of Clinical Oncology by Grzegorz Nowakowski and colleagues, and the impact on different DLBCL subtypes was analyzed.¹ 

Study design

A total of 280 patients were eligible for this study and were randomly assigned to each treatment arm. The treatment regimens for the two arms are shown in Figure 1.

R-CHOP: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m², and prednisone 100 mg/m²; R2CHOP, R-CHOP + lenalidomide.

Eligibility criteria:

• ≥ 18 years with newly diagnosed, untreated DLBCL that had been histologically assessed
• Stage II bulky to IV disease
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0−2
• International Prognostic Index of 2−5

Exclusion criteria:

• Known central nervous system lymphoma
• Deep vein thrombosis or emboli or thrombophilia history (unless willing to be on full anticoagulation treatment) if assigned to the R2CHOP arm
• Acquired immunodeficiency syndrome-related conditions

Key points

Baseline characteristics were similar between the two treatment groups. Most patients in this study had high-risk disease, with > 96% Stage III or IV, and over 60% with an ECOG PS of 1−2. The ABC subtype made up 40% of the 234 patients that were evaluated for cell of origin, and their characteristics are listed separately from the main cohort (Table 1).

Table 1. Patient baseline characteristics in the two treatment arms and for the ABC subtype¹

ABC, activated B-cell-like; DLBCL, diffuse large B-cell lymphoma; dx, diagnosis; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B-cell-like; IPI, International Prognostic Index; PS, performance status; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; rx, treatment. *Evaluable for 234 patients.
Characteristic	All (N = 280)		ABC-DLBCL (n = 94)
	R2CHOP (n =145)	R-CHOP (n = 135)	R2CHOP (n = 44)	R-CHOP (n = 50)
Age, years median (range)	67 (24−88)	66 (37−92)	67 (24−88)	67 (37−80)
Time dx to rx, days median (range)	21 (1−111)	19 (2−134)	21 (5−83)	19 (2−134)
Sex, male (%)	65	56	68	42
Stage III and/or IV (%)	97	96	100	97
Bulky disease ≥ 7 cm (%)	41	43	30	44
Extra nodal sites ≥ 2 (%)	45	47	40	32
ECOG PS (%)
0	39	35	41	34
1−2	61	65	59	66
IPI (%)
2	33	34	36	44
3	43	42	43	40
4−5	23	24	20	16
Cell of origin*, n
ABC	44	50
GCB	66	56
Unclassified	9	9
Unknown	26	20

Efficacy

With a median follow-up of 3 years, the overall response rates (ORR), and complete response rates (CR) were as follows:

ORR

• R2CHOP: 97%
• R-CHOP: 92% (p = 0.06)

CR

• R2CHOP: 73%
• R-CHOP: 68% (p = 0.43)

The primary endpoint of progression-free survival (PFS) was met in this study; PFS rates were as follows for R2CHOP versus R-CHOP:

• 1-year PFS: 84% vs 73%
• 2-year PFS: 76% vs 69%
• 3-year PFS: 73% vs 62%

Overall survival (OS) was increased in the R2CHOP group compared with the R-CHOP group, with a 3-year OS of 83% vs 75% (one-sided p = 0.05), respectively.

The R2CHOP group showed a 34% decrease in risk of death or progression vs the R-CHOP group (HR 0.66, one-sided 90% CI < 0.88; one-sided p = 0.03).

Analysis by cell of origin showed that R2CHOP improved outcomes in patients with an ABC subtype (n = 94; HR 0.64; one-sided 90% CI upper limit, 1.01; two-sided 95% CI, 0.31−1.29; one-sided p = 0.1). The HR in the GCB treatment group (n = 122) was not as reduced as in the ABC cohort at 0.82 (one-sided 90% CI upper limit, 1.27; two-sided 95% CI, 0.43−1.59).

Safety

In the R2CHOP arm there was one case of Grade V lung infection recorded. In the R-CHOP cohort four Grade V cases were recorded: one Grade V case of fatigue, two Grade V sepsis cases, and one Grade V lung infection.

The adverse events (AEs) experienced by patients were similar between groups, with anemia, neutropenia, and thrombocytopenia being the most frequently recorded Grade 3–4 AEs (Table 2).

Significant differences between R2CHOP and R-CHOP arms were found for the following Grade ≥ 3 AEs:

• anemia (29% vs 20%, p = 0.003)
• febrile neutropenia (25% vs 14%, p = 0.003)
• thrombocytopenia (34% vs 13%, p = 0.001)
• diarrhea (6% vs 1%, p = 0.005)
• electrolyte abnormalities (5% vs 2%, p = 0.06)

Table 2. Grade 3–4 adverse events for R2CHOP and R-CHOP treatment arms¹

R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. R2CHOP, lenalidomide + R-CHOP.
Adverse event (%)	R2CHOP (n = 166)		R-CHOP (n = 171)
	Grade 3	Grade 4	Grade 3	Grade 4
Anemia	25	4	18	2
Febrile neutropenia	20	5	11	1
Fatigue	10	—	6	—
Sepsis	—	7	—	4
Lung infection	5	1	4	—
Neutropenia	9	51	12	42
Thrombocytopenia	14	20	4	9
Hypokalemia	5	1	1	1
Hyponatremia	5	—	4	—
Hypophosphatemia	5	—	1	—
Generalized muscle weakness	5	—	2	—
Rash maculopapular	2	—	—	—
Thromboembolic event	3	1	2	—

The percentage of patients that completed six cycles of therapy was very similar between treatment arms (86% and 85% in the R2CHOP and R-CHOP arms, respectively). Treatment discontinuation occurred in 8% of patients receiving R2CHOP and 3% of patients receiving R-CHOP alone.

During the study there were nine treatment-related deaths, two in the R2CHOP arm (both due to lung infection) and seven in the R-CHOP arm (five due to sepsis or febrile neutropenia, one due to lung infection, and one due to adult respiratory distress syndrome).

Conclusions

The ECOG-ACRIN E1412 study demonstrated improved outcomes for patients with newly diagnosed DLBCL upon adding lenalidomide to R-CHOP, irrespective of the cell of origin subtype, although the superior OS and PFS observed for the R2CHOP group compared with the R-CHOP group was most notable for patients with ABC DLBCL. The safety profiles were similar between treatment groups and in line with what is expected for R-CHOP protocols. These results support further studies of lenalidomide in the frontline treatment of DLBCL.