Educational theme | R-miniCHOP plus lenalidomide for elderly patients with DLBCL: Results from the phase III SENIOR trial

Although approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) are aged ≥70 years, elderly patients are notoriously underrepresented in clinical trials and have a worse prognosis compared with younger patients in the same setting. This article is one in a series addressing the treatment of lymphoma in elderly patients as an educational theme.

Elderly patients often present with comorbidities, which can limit the use of intensive chemotherapy. With this in mind, attenuated-dose CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), known as miniCHOP, in combination with rituximab (R-miniCHOP) has been employed in two clinical trials as part of a LYSA study. R-miniCHOP is now considered a suitable option for patients over 80 years old for whom intensive therapy is not an option.^1,2

It has been suggested that the addition of lenalidomide to the R-miniCHOP regimen (R2-miniCHOP) may enhance its efficacy, without posing additional toxicity. The phase III SENIOR trial was designed to investigate R2-miniCHOP exclusively in patients ≥80 years, representing the first trial designated to older patients in the DLBCL setting. The Lymphoma Hub is happy to provide a summary of the results here.¹

Study design

• Multicenter, open-label, phase III study whereby patients aged ≥80 years with CD20⁺ DLBCL were randomized 1:1 to receive six cycles of R-miniCHOP (n = 127) or R2-miniCHOP (n = 122).
• In Cycle 1, rituximab was delivered intravenously on Day 1. In Cycles 2–6, rituximab was administered subcutaneously on Day 1 to determine the safety and feasibility of this route of administration in the elderly population.
• In the R2-miniCHOP cohort, lenalidomide (10 mg/day) was given on Days 1–14 of each cycle.
• Primary endpoint: overall survival (OS).
• Secondary endpoints: progression-free survival, event-free survival, duration of response, complete response and unconfirmed complete response, and overall response rate.

Results

Baseline characteristics of the 249 patients enrolled in the SENIOR trial are presented in Table 1.

Table 1. Patient characteristics*

ABC, activated B cell-like; ECOG PS, Eastern Cooperative Oncology Group performance status; GCB, germinal center B cell-like; IPI, International Prognostic Index; R-miniCHOP, rituximab plus attenuated-dose cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-miniCHOP, R-miniCHOP plus lenalidomide. *Adapted from Oberic et al.1 †Immunohistochemistry. ‡Hans algorithm. §Data missing for 24 and 13 patients in the R-miniCHOP and R2-miniCHOP groups, respectively. ‖Lymph2CX. ¶Data missing for 50 and 45 patients in the R-miniCHOP and R2-miniCHOP groups, respectively.
Characteristic, %	R-miniCHOP (n = 127)	R2-miniCHOP (n = 122)	Total (N = 249)
Male sex	44	46	45
Age, years               80–85               >85	75 25	76 24	75.5 24.5
Ann Arbor Stage III–IV	83	87	85
ECOG PS               0–1               2	72 28	78 22	75 25
IPI 3–5	75	72	73.5
CD10 positive†	38	35	36.5
Phenotype‡§               GCB               Non-GCB	40 60	50 50	45 55
Phenotype‖¶               GCB or unclassified               ABC	50 50	58 42	54 46

Efficacy

• At a median follow-up of 25.1 months, the intention to treat analysis revealed no significant difference in OS between patients who received R-miniCHOP (66%; 95% confidence interval [CI], 56.4–74.0) or R2-miniCHOP (65.7%; 95% CI, 55.6–74.1).
• Progression-free survival, event-free survival, overall response rate, duration of response, and rates of complete response and unconfirmed complete response were also not significantly different between treatment arms (Table 2).
• Of the patients treated with R-miniCHOP and R2-miniCHOP, deaths were reported in 34% and 37%, respectively. The majority of deaths occurred as a result of lymphoma progression.

Table 2. Efficacy of R-miniCHOP and R2-miniCHOP in patients enrolled in the SENIOR trial*

CI, confidence interval; CR/CRu, complete response and unconfirmed complete response; EFS, event-free survival; NA, not applicable, NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R-miniCHOP, rituximab plus attenuated-dose cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-miniCHOP, R-miniCHOP plus lenalidomide. *Adapted from Oberic et al.1
Patient outcomes	R-miniCHOP (n = 127)	R2-miniCHOP (n = 122)
2-year outcomes, % (95% CI)               OS               PFS               EFS	66 (56.4–74.0) 56.2 (46.2–65.1) 50.7 (40.8–59.8)	65.7 (55.6–74.1) 54.8 (44.6–63.9) 53.1 (43–62.2)
ORR, % (95% CI)	73 (64.6–80.7)	82 (75–89)
DoR, months (95% CI)	NR (40.1–NA)	36 (26.3–NA)
CR/CRu, %	53	58

Safety

• The safety population comprised 241 patients (R-mini-CHOP, n = 124; R2-miniCHOP, n = 117).
• Of the patients in the R-miniCHOP and R2-miniCHOP cohorts, 70% and 86% experienced ≥1 adverse event (AE) of any grade, respectively.
• R2-miniCHOP was associated with an increased likelihood of experiencing ≥1 Grade 3–4 AE, when compared with conventional R-miniCHOP.
• Notably, rates of Grade 3 or 4 neutropenia were significantly higher in patients who received R2-miniCHOP compared with R-miniCHOP (p = 0.01).
• Table 3 outlines the most common Grade 3–4 AEs and the incidence of fatal AEs observed in both treatment cohorts.

Table 3. Grade 3–4 AEs observed in patients enrolled in the SENIOR trial*

AE, adverse event; DVT, deep vein thrombosis; PE, pulmonary embolism; R-miniCHOP, rituximab plus attenuated-dose cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-miniCHOP, R-miniCHOP plus lenalidomide. *Adapted from Oberic et al.1
AE, %	R-miniCHOP (n = 124)	R2-miniCHOP (n = 117)
Grade 3–4               Neutropenia               Anemia               Thrombocytopenia               Febrile neutropenia               Infections               DVT               PE               Vascular disorders (arterial)	18 5 0.8 0.8 8 0 0.8 1.5	35 9 7.6 3.4 13.5 5 6 5
Grade 5 (fatal)	5.6	6.8

Prognostic factors

• Univariate analysis identified the following factors to be prognostic for improved survival:
  • International Prognostic Index score
  • stage
  • serum albumin
  • lymphocyte count
• Univariate analysis identified the following geriatric assessment scores to be predictive of shorter survival:
  • instrumental activities of daily living score <4
  • mini-nutritional assessment score <12
• Multivariate analysis only identified albuminemia <35 g/L as being prognostic of OS.

Conclusion

The SENIOR trial is the first randomized phase III trial to solely enrol patients with DLBCL aged ≥80 years and demonstrated the feasibility for large prospective studies in this setting. R2-miniCHOP did not provide a survival benefit over R-miniCHOP and resulted in higher incidences of AEs.

The study showed that rituximab could be administered safely subcutaneously in elderly patients with DLBCL. Across three studies, R-miniCHOP has induced 2-year OS rates of 59% to 66% in patients aged >80 years with DLBCL, highlighting the need for novel therapeutic approaches in the elderly DLBCL population.