RELEVANCE study: First line lenalidomide plus rituximab induces high molecular responses in patients with naïve follicular lymphoma

The standard treatment for patients with previously untreated follicular lymphoma (FL) and high tumor burden is often immunochemotherapy followed by maintenance. However, the phase III RELEVANCE trial (NCT01650701; previously reported on the Lymphoma Hub) demonstrated that the chemotherapy-free option of lenalidomide plus rituximab (R²) was as efficacious as immunochemotherapy (rituximab plus chemotherapy [R-Chemo]) in this subset of patients.¹

In the latest publication of the RELEVANCE trial in Blood Advances, Marie-Helene Delfau-Larue and colleagues performed a measurable residual disease (MRD) analysis to assess the ability of the chemotherapy-free regimen R² to induce molecular responses compared with R-Chemo. ¹

Study design and patient characteristics¹

• Peripheral blood (PB) and bone marrow (BM) samples from 222 patients (50% of patients from the RELEVANCE cohort) with a detectable BCL2-JH translocation at diagnosis were analyzed for MRD via quantitative polymerase chain reaction (qPCR) (≤ 10^-4 sensitivity)
  • R² cohort: n = 122
  • R-Chemo cohort: n = 100
• R² regimen consisted of 18 cycles of lenalidomide plus rituximab, followed by rituximab maintenance every 8 weeks for 12 cycles
• R-Chemo consisted of either of the following rituximab-based regimens, followed by maintenance with rituximab every 8 weeks for 12 cycles:
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
  • R-CVP (rituximab, cyclophosphamide, vincristine, prednisone)
  • R-B (rituximab, bendamustine)
• PB and BM samples were collected at screening and at the end of induction (Week 24)
• Primary endpoints were complete response (confirmed/unconfirmed complete response [CR/CRu]) at Week 120 and progression-free survival (PFS)
• Complete molecular response (CMR) was defined as MRD negativity in BM and/or PB with a sensitivity of ≤ 10^-4
• Baseline patient characteristics were well balanced between the two treatment arms and are shown below in Table 1

Table 1. Baseline patient characteristics per treatment arm¹

β2M, β2 microglobulin; BM, bone marrow; ECOG PS, Eastern Cooperative Oncology Group performance status; FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase; R2, lenalidomide plus rituximab; R-Chemo, rituximab plus chemotherapy; ULN, upper limit of normal
Characteristic	All (N = 222)	R2 (n = 122)	R-Chemo (n = 100)	p value
Median age (range), years	60 (30–89)	60 (33–78)	60 (30–89)	0.90
Male, %	54	53	55	0.89
ECOG PS, %				0.34
0	67	70	63
1	31	27	36
2	2	2	1
Not evaluated	0.5	0.8	0
Ann Arbor stage, %				0.47
I–II	4	2	5
III–IV	96	98	95
Nodal mass > 6 cm, %	50	47	52	0.59
FLIPI score, %				0.46
0–1	9	11	6
2	41	39	43
3–5	50	49	51
Missing data	0.5	0.8	0
FLIPI2 score, %				0.73
0–1	26	28	24
2	29	30	28
3–5	43	41	45
Missing data	2	0.8	3
Number of peripheral lymph nodes, %				0.23
≤ 4	47	43	52
> 4	53	57	48
β2M, %				0.67
< 3 mg/L	62	61	63
≥ 3 mg/L	35	37	33
Missing data	3	2	4
Elevated LDH (> ULN), %				0.77
No	71	70	73
Yes	28	30	27
Missing data	0.5	0.8	0
BM involvement, %				0.43
No	34	30	39
Yes	62	65	58
Unspecified	2	2	1
Not done	3	3	2

Results

• At Week 24, CMR was achieved in the PB of 97.5% of patients and in the BM of 77.5% of patients
• The only baseline characteristic that significantly differed between patients who achieved CMR compared with those who did not was FLIPI2 3–5 (66% vs 40%, respectively; p = 0.011)
• Molecular quantitative values (number of BCL2-JH copies/total cells analyzed) at diagnosis were significantly associated with positive MRD
  • The median value was 10 times higher in patients with positive MRD at Week 24 (PB = 0.056, BM = 0.16) compared with patients with negative MRD at Week 24 (PB = 0.0056, BM = 0.016; p = 0.03 and p = 0.02, respectively)
• Achievement of CMR had a significant impact on PFS, with a 3-year PFS of 84% vs 55% for MRD positive patients (HR, 2.6; 95% CI, 1.27–5.13; p = 0.015)
• Of those patients with positive MRD, 34% were clinically considered to be in CR/CRu at Week 24
• Of those patients with negative MRD (CMR), 35% were clinically considered to be in CR/CRu at Week 24; however, 39 patients were downgraded to partial response after central review due to missing or unspecified BM reassessment
• Multivariable analysis showed that only MRD positivity was significantly associated with shorter PFS (HR, 2.6; 95% CI, 1.3–5.2; p = 0.0076) after adjusting for clinical response (HR, 1.8; 95% CI, 0.9–3.6; p = 0.09 for patients with non-CR/CRu)
• Significantly more patients reached CMR at Week 24 in the R² arm (90%) compared with those in the R-Chemo arm (77%; p = 0.022); however, PFS was similar in both arms
• Persistence of molecular disease was associated with shorter PFS in both treatment arms (p = 0.31)

Conclusion

In agreement with the previously-reported clinical data of the RELEVANCE trial, these MRD analysis results indicate that the chemotherapy-free R² regimen can lead to high rates of CMR in terms of MRD negativity, as detected by quantitative BCL2-JH PCR in patients with naïve FL. This effect was seen as early as 6 months of treatment and was as effective as R-Chemo in this respect.

Limitations to this study include the possibility of the analyzed population to have had more severe disease than the entire RELEVANCE cohort, since the probability of detecting BCL2-JH increases with disease spread. However, the baseline characteristics were well balanced between the two arms and PFS was similar across the groups as reported in the original RELEVANCE analysis. A longer follow-up is required to better analyze the prognostic impact of MRD as a marker for treatment efficacy in this patient subset.