Preliminary exploration of lenalidomide in combination with obinutuzumab and CHOP in the treatment of treatment-naïve DLBCL

LO-CHOP scheme

The R-CHOP regimen is the standard first-line treatment for diffuse large B-cell lymphoma (DLBCL), and the addition of other drugs (R-CHOP+X) to it has been tried many times, but lenalidomide, ibrutinib, or bortezomib are not superior to R-CHOP, including the regimen of replacing R with obinutuzumab (O) has also failed
.

Ointarzumab is a sugar-engineered type II antibody targeting CD20 that improves antibody-dependent cytotoxicity, phagocytosis, and direct cell death compared with rituximab, and lenalidomide, an immunomodulator, activates interferon signaling, inhibits the NF-κβ pathway, and increases NK cell activity
.
Neither lenalidomide nor obinentuzumab are included in the first-line treatment of DLBCL, but their combined administration creates a synergistic effect, possibly by activating NK cell reversal and immature NK cell phenotype upon combined dosing
.

Professor Jason Westin of MD Anderson Cancer Center et al.
hypothesized that lenalidomide and obinutuzumab in combination with CHOP chemotherapy would exhibit high efficacy and tolerable toxicity profile, and conducted a Phase Ib/II single-center clinical trial (NCT02529852) of LO-CHOP for the treatment of patients with newly diagnosed DLBCL, which also included circulating tumor DNA (ctDNA) analysis to measure baseline tumor burden, molecular response, and molecular
。 The findings were recently published in Blood Advance
.

Study design

This study is a investigator-initiated, single-arm, phase Ib/II study, with the phase Ib part mainly looking at safety, and the phase II part mainly evaluating efficacy after LO-CHOP treatment (Lugano 2014 ORR and CR evaluated by PET/CT).

Patients were ≥ 18 years of age with newly diagnosed, untreated CD20+ DLBCL patients, measurable disease with a maximum diameter of ≥1.
5 cm on imaging, an ECOG PS score of ≤ 2 (or a previous PS of 0 to 1 but worsening due to lymphoma that can be reversed with treatment), and adequate
organ and bone marrow function.

Lenalidomide 15 mg orally daily on days 1-14 at 21 days/cycle, intravenous (IV) obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, plus standard CHOP (cyclophosphamide 750 mg/m², doxorubicin 50 mg^{/m 2}, vincristine 1.
4 mg/m 2 [up to^2.
0 from day 1 of all cycles mg], and prednisone 100 mg orally once daily on days 1-5).

All patients are planned to receive a total of 6 cycles of treatment
.
All patients are asked to receive granulocyte colony-stimulating factor, aspirin 81 mg (if not already on anticoagulation), and Pneumocystis jirovecii pneumonia prophylaxis
.
If the patient is at risk of CNS involvement due to risk factors, intrathecal chemotherapy
is allowed.

Circulating tumor DNA (ctDNA, PhasED-Seq assay) was also evaluated in this study, including baseline, after 2 cycles of treatment, and at the end of
treatment.

Study results

patient

A total of 53 patients were enrolled, including 6 cases in stage Ib and 47 patients in stage II
.
The median age was 62 years, 35 (66%) patients had stage III/IV, 26 (49%) had elevated lactate dehydrogenase (LDH), 12 (23%) had an international prognostic index (IPI) > 2,26 (49%) were germinal centers (GC), 22 (42%) were non-GC subtype, and 5 were unable to be subtyped
.
A detailed summary of baseline characteristics is shown in Table 1
.

security

Treatment-related adverse events occurred in all patients, of which 37 (70%) had ≥ one treatment related adverse event with no fatal AE.

Six patients with stage Ib did not develop dose-limiting toxicity
.
Common AEs of any grade include fatigue (96%), constipation (85%), nausea (72%), anaemia (62%), myalgia (59%), and dizziness (57%)
.
Common grade 3 to 4 AEs include neutropenia (38%), thrombocytopenia (17%), fatigue (13%), febrile neutropenia (13%), and infection (9%)
.
Grade 3 to 4 infections include cellulitis, urinary tract infection, pneumonia, and Clostridium difficile colitis
.
Thromboembolism
occurred in four (8%) patients.
The AE is shown in Table 2
.

Twenty-three (43%) patients discontinued lenalidomide(L) therapy due to AE (mainly due to mid-cycle neutropenia or thrombocytopenia), 11 (21%) required dose reduction, and 3 (6%) discontinued
.
One patient required a delay of the next cycle of LO-CHOP therapy for more than
7 days.

efficacy

Fifty-one patients underwent interim PET/CT evaluation after 2 LO-CHOP cycles (2 patients withdrew from the study and could not be evaluated, 1 due to AE and 1 due to patient selection).

。 The RRR for the interim assessment was 100% (51/51), CRR was 84% (43/51), and the PR was 16% (8/51); After 6 cycles of LO-CHOP treatment, 50 patients with PET/CT were assessable (and one patient withdrew from the study due to AE), with an ORR of 98% (49/50) at the end of treatment, and CR, PR, and PD of 90% (45/50), 8% (n=4), and 2% (n=1),
respectively.

At a median follow-up of 4.
5 years, disease progression or recurrence occurred in 6 patients, death occurred in 4 patients (causes: lymphoma progression, translational MDS, cerebrovascular accident and unknown), median PFS and OS were not achieved, and 4-year PFS and OS rates were 87.
4% and 91.
3%, respectively (Figure 1A-B).

Circulating tumor DNA

ctDNA was successfully evaluated in a total of 24/33 (73%) patients, with molecular subtypes including other (9,38%), EZB (5,21%), ST2 (5,21%), MCD (4,17%), and A53 (1,4%) (Figure 2A); Two patients had composite subtypes (EZB/ST2 and EZB/A53), which were classified here as EZB
.
As expected, all 5 patients with EZB and 4/5 ST2 were classified as GC subtypes, while only 2/4 of patients with MCD were non-GC, and manual review of the genotype of the remaining 2 patients with MCD was deemed appropriate
based on the presence of typical hotspot mutations suggesting that these cases may be misclassified as COO by IHC.
The incidence of COO subgroups within each genotype is shown
in Figure 2B.

Of the 24 eligible patients, 20 and 17 were able to assess samples from EMR (early molecular response, defined as 2 logarithms of ctDNA decline after 1 treatment cycle) and MMR (major molecular response, defined as 2.
5 logarithms of ctDNA decline after 2 cycles of treatment
).
The EMR and MMR rates were 75% (15/20) and 71% (12/17), respectively (Figure 3A-B).

Of the 15 patients evaluated on both EMR and MMR, the agreement between the two endpoints was 87% (13/15).

The fold change in ctDNA levels at all time points is shown
in Figure 3C.
A total of 18 patients were eligible for ctDNA evaluation after at least 5 treatment cycles, of which 16 (89%) ctDNA was undetectable and 2 patients had ctDNA
detected at this advanced time point.

No ctDNA signatures (including late time-point MRD for molecular subtypes, EMR, MMR, or PhasED-Seq) were found and correlated
with significant differences in patient response rates, PFS, or OS.

conclusion

In this phase Ib/II study, lenalidomide and obinentuzumab in combination with CHOP chemotherapy (LO-CHOP) were highly effective in the treatment of newly diagnosed DLBCL, with ORR and CR of 98% and 90% at the end of treatment, and 4-year PFS and OS rates of 87% and 91%,
respectively.
LO-CHOP is equally effective in high-risk patient subpopulations, including high IPI, non-GCB COO, high ctDNA levels prior to treatment, and MCD and EZB molecular subtypes
.
Early and major molecular response rates after 1 or 2 cycles of LO-CHOP treatment were 75% and 71%, respectively, with high agreement
between the two endpoints.
It is also encouraging that the negative MRD rate assessed by PhasED-Seq at the end of treatment is as high as 89%; This study also demonstrates that ctDNA sequencing can be used for non-invasive molecular classification
of patients receiving genoisotyping in prospective clinical trials.

The safety profile of LO-CHOP did not show any unexpected toxicity; Grade 3 to 4 AEs (e.
g.
, neutropenia, thrombocytopenia, and febrile neutropenia) are more common than reported
in LR-CHOP and O-CHOP with mandatory growth factor support.
In addition, the incidence of thromboembolism of any grade may be higher than in ROBUST studies, but it is difficult to draw conclusions with
a small number of patients.
Higher than expected incidence of any grade of AE (e.
g.
, fatigue, nausea, and constipation) but no dose-limiting toxicity, lower incidence of treatment discontinuation or delay, and similar incidence of cytopenias compared with other studies, suggesting that this difference may be related to reported differences rather than R-CHOP or LR-CHOP
.

Overall, LO-CHOP, as a modified first-line regimen for DLBCL in this single-arm phase Ib/II study, had high radiographic and molecular response rates, durable responses with long-term follow-up, and expected safety profiles, but this study could not be directly compared
with R-CHOP.
In addition, the study design methods included in this study, including novel combinations and ctDNA-based assessments, may also be critical
for further improvement of first-line treatment for DLBCL.

References

Chern HJ,et al.
A phase I/II study of lenalidomide and obinutuzumab with CHOP for newly diagnosed diffuse large B-cell lymphoma.
Blood Adv .
2022 Nov 14; bloodadvances.
2022008174.
doi: 10.
1182/bloodadvances.
2022008174

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