In this issue of Blood Advances, Cahil et al1 report results from an investigator-initiated, single-arm, phase 1/2 study that evaluated the addition of lenalidomide to dose-adjusted (DA) EPOCH-R (DA-EPOCH-R) in patients with double-hit (DHL) or double-expressor (DEL) large B-cell lymphomas. The study demonstrated encouraging response rates and survival outcomes in both cohorts with acceptable tolerability of treatment.
DHL is defined by chromosomal rearrangements that involve MYC and BCL2, identified by fluorescence in situ hybridization (FISH). These lymphomas, comprising ∼5% of large B-cell lymphomas, typically present as advanced-stage disease, with high International Prognostic Index scores, and tend to relapse within 12 months. Most DHLs are of germinal center origin and cluster molecularly within subgroups, namely EZB or BCL2-defined categories.2,3 The biology of DHL is driven by MYC-associated proliferation and BCL2-mediated apoptotic resistance, a combination that contributes to its poor prognosis.
In contrast, DEL is defined by the overexpression of MYC and BCL2 proteins, identified using immunohistochemistry, without rearrangement as determined by FISH. DELs represent a more genetically diverse group of lymphomas that are often of nongerminal center origin and activated B-cell (ABC) subtype. DELs have a more variable clinical course. Unlike DHL, DEL is not considered a distinct entity in the current World Health Organization or International Consensus Classification (ICC).2,3
Aggressive lymphomas that harbor a dark zone signature add further complexity, and although they are FISH-negative, they exhibit gene expression profiles and clinical behavior that resemble DHL.4
Standard frontline R-CHOP therapy is often insufficient in DHL, prompting many clinicians to favor intensified regimens, such as DA-EPOCH-R, R-HyperCVAD, or R-CODOX-M/IVAC. However, the rarity of DHL, evolving definitions, and enrollment biases have limited prospective data. Retrospective studies generally support intensification. For example, a multicenter observational study of 99 patients with confirmed DHL reported a 2-year overall survival (OS) of 70.7% with DA-EPOCH-R and 50% with R-CHOP.5 There is no evidence to support a consolidative autologous stem cell transplant in the first remission.6
Given DHL’s intrinsic chemoresistance and the advent of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory disease, a critical question arises. Should we pivot early to CAR T-cell therapy upon R-CHOP failure instead of initially escalating chemotherapy and exposing patients to additional toxicity? In ZUMA-7, a subset of patients with DHL (31 that received CAR T cells vs 25 that received standard of care) derived benefit in subgroup analyses.7 Patients with DEL also showed improved outcomes. The largest retrospective, multicenter analysis to date, spanning 13 academic centers, found no difference in the CAR T-cell response rates among DHL, DEL, and DLBCL, not otherwise specified (NOS), suggesting that CAR T cells may overcome the initial poor prognostic impact of DHL.8 However, patients with DHL who relapsed after CAR T-cell therapy had a dismal median OS of just 3 months, significantly worse than any other subgroup. This underscores the need to improve frontline therapy to achieve a durable first remission rather than relying on salvage CAR T cells.
Lenalidomide, an immunomodulatory agent with known efficacy in relapsed/refractory large B-cell lymphomas, may offer synergy in MYC-driven disease. However, its benefit in the frontline setting remains unproven. The ROBUST trial in which patients with ABC-subtype DLBCL were randomized to R-CHOP ± lenalidomide failed to demonstrate a significant progression-free survival (PFS) benefit and showed increased hematologic toxicity.9
In the current study, Cahil et al investigated the addition of lenalidomide to DA- EPOCH-R, followed by lenalidomide maintenance for 12 months. A dose of 15 mg on days 1-14 was selected based on previous dose escalation. A total of 55 patients (23 DHL and 32 DEL) were enrolled and treated. The outcomes were notable. The overall response rate was 90.9% with 1- and 2-year PFS rates of 85.2% and 78.2% and a 2-year OS of 83.6%. Although not statistically significant, patients with DEL had a higher 2-year PFS (84.4%) and OS (87.5%) rate than patients with DHL (69.6% and 78.3%, respectively), suggesting a possible enhanced benefit in patients who did not have DHL. The study is limited by its small sample size and the evolving biologic understanding of DHL and DEL that was not available at the time of trial design.
Hematologic toxicities were manageable and consistent with the expectations of intensified chemotherapy. However, a 20% incidence of venous thromboembolism was observed despite aspirin prophylaxis. Two cases of therapy-related acute myeloid leukemia were also reported, both were negative for TP53 mutations. Larger studies will be needed to clarify the long-term effects of lenalidomide, particularly when combined with intensified chemotherapy, on the myeloid compartment.
Although polatuzumab vedotin has recently improved the outcomes in certain large B-cell lymphoma subtypes, particularly ABC, its benefit in germinal center–derived large B-cell lymphomas remains uncertain.10 Before this, no frontline regimen had demonstrated consistent superiority over R-CHOP in DLBCL-NOS, let alone in DHL. Emerging strategies, including upfront CD20/CD3 bispecific antibodies in combination with chemotherapy and CD19-directed CAR T-cell therapy, are under active investigation and may redefine the standard of care in high-risk disease. Cahil et al provide compelling preliminary evidence that adding lenalidomide to an intensified chemotherapy backbone is feasible and potentially beneficial in both DHL and DEL. However, these results require validation in further randomized trials to determine lenalidomide’s definitive role in the frontline treatment of high-risk large B-cell lymphomas.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
