A phase 1/2 study of lenalidomide and obinutuzumab with CHOP for newly diagnosed DLBCL

Abstract

Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy (R-CHOP), but a third of patients experience refractory or relapsed disease after frontline R-CHOP. Randomized studies comparing R-CHOP with modified regimens replacing R with obinutuzumab (O) or adding lenalidomide (L) to R-CHOP have not resulted in improved outcomes, but the combination of L and O may enhance NK-cell mediated antibody dependent cellular toxicity when paired with CHOP. Here, we report on long term outcomes of a phase Ib/II study (NCT02529852) where 53 patients with newly diagnosed DLBCL received 6 cycles of LO-CHOP. End of treatment overall and complete response rates in the 50 evaluable patients were 98% and 90%, respectively. After a median follow up of 4.5 years, 4-year progression free and overall survival rates were 87.4% and 91.3%. Grade 3-4 adverse events were experienced by 70% of patients and included neutropenia (38%), thrombocytopenia (17%), fatigue (13%), neutropenic fever (13%), and infection (9%). Of 33 patients profiled with circulating tumor DNA (ctDNA) sequencing, 31 (94%) had detectable pre-treatment ctDNA with CAPP-Seq, 24/31 (77%) were classifiable by LymphGen classifier, and 15/20 (75%) and 12/17 (71%) patients achieved early and major molecular responses after 1 and 2 cycles, respectively. Using PhasED-Seq, 16/18 evaluable patients (89%) had no detectable ctDNA after at least 5 cycles of LO-CHOP. LO-CHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA by end of therapy. This trial is registered at www.clinicaltrials.gov as NCT02529852.

Liquid biopsy‐based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results

“…In DLBCL and other B‐cell lymphomas, tools such as “Lymphopanel” that employ tissue‐based NGS to detect targetable mutations in genes like EZH2 , MYD88 , and XPO1 were informative and may serve as a marker of residual disease 18 . However, a limitation of these platforms is the need for sufficient DNA at the pretreatment timepoint, predominantly still requiring tissue sequencing 19 . Again, LBx represents a promising complementary tool.…”

“…18 However, a limitation of these platforms is the need for sufficient DNA at the pretreatment timepoint, predominantly still requiring tissue sequencing. 19 Again, LBx represents a promising complementary tool. A recent prospective study of 30 patients with DLBCL leveraged cfDNA sequencing, demonstrating substantial correlation between positron emission tomography (PET) scan findings of bulky tumour with levels of cfDNA.…”