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Treating classical Hodgkin lymphoma: Spotlight on targeted therapies
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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
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.
Figure 1. Study treatment schedule: 1 cycle of a 6-cycle schedule1
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:
Exclusion criteria:
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
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 |
|
|
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. |
With a median follow-up of 3 years, the overall response rates (ORR), and complete response rates (CR) were as follows:
ORR
CR
The primary endpoint of progression-free survival (PFS) was met in this study; PFS rates were as follows for R2CHOP versus R-CHOP:
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).
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:
Table 2. Grade 3–4 adverse events for R2CHOP and R-CHOP treatment arms1
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 |
— |
R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. R2CHOP, lenalidomide + R-CHOP. |
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).
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.
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