Table 2: Response rates and outcomes for the treatment of relapsed or
refractory follicular lymphoma.
†CHOP, CNOP, CVP, FCM, MCP. ‡ Includes multiple subtypes of lymphoma
including DLBCL, primary B-cell lymphoma, transformed follicular. mPFS,
median progression free survival; HR, hazard ratio; mTTP, time to
progression; DOR, duration of response; n/a, not available.
The recent approval of axicabtagene ciloleucel for the treatment of
relapsed or refractory follicular lymphoma after two prior lines of
therapy was based on the results of a ZUMA-5 which demonstrated 80%
complete response rate and 12 month durable response of
72%.2 This offers an effective treatment option for
patients who develop refractory disease. However, treatment after
disease progression following CAR-T is unclear and provides an
opportunity for further investigation. With the CAR-T FDA approval
occurring after two lines of treatment, patients with relapsed
follicular lymphoma will be receiving this therapeutic modality earlier
in their disease course which opens the door for re-treatment with
previous used regimens or unused combinations guided by mechanisms of
treatment failure. The mechanisms of CAR-T treatment failure have been
divided into three categories including tumor intrinsic factors (i.e.
loss of CD19 epitope), other host factors (i.e. negative regulatory
pathways, high tumor burden) and inadequacies of the CAR-T
cell.15 Clinical trials are ongoing to overcome these
mechanisms of treatment failures including targeting programmed
death-ligand 1/programmed cell death protein 1. A phase I/II trial is
underway using pembrolizumab in patients failing to respond to CD19
CAR-T or relapse after CAR-T.13 Of the 11 patients, 2
patients had partial response and 1 CR suggesting benefit that could be
the result of altering CAR T-cell exhaustion, or immunosuppressive tumor
microenvironment.
Lenalidomide has been investigated for the treatment of lymphoma based
on its direct antineoplastic effects on malignant B-cells, and
cytotoxicity mediated by T cells and NK cells.16 The
malignant B-cell effects of lenalidomide are shown through its ability
to regulate cyclin dependent kinases decreasing cellular proliferation,
down regulation of programmed death ligand-1, and AKT inhibition all
resulting in antineoplastic and antiproliferation. Lenalidomide combats
cancers ability to evade the immune system, a key defensive mechanism.
While lymphoma cells induce impaired immune synapse formation and
effector function impacting antigen presentation, lenalidomide has been
shown to repair this immune synapse formation in an Ex vivo
model,17 thereby enhancing T cell mediated
cytotoxicity. Additional improvement in cellular cytotoxicity can be
seen with lenalidomide’s impact on NK cell activity. In patients treated
with lenalidomide, NK cell number and activity were increased resulting
in enhanced antibody dependent cellular cytotoxicity (ADCC) and NK cell
induced cytotoxicity.18 With understanding the
mechanisms of action, lenalidomide has been combined with other agents
to achieve synergistic activity. When the anti-CD20 monoclonal antibody,
rituximab, is used as an antineoplastic agent it results in the direct
induction of apoptosis and ADCC. When lenalidomide is combined with
rituximab it results in enhanced apoptosis via upregulation of c-Jun
N-terminal protein kinase phosphorylation and activating the
mitochondrial derived apoptotic pathway.19 This
combined therapy was performed in mantle cell lymphoma mouse models and
resulted in synergistic activity causing decrease tumor burden by two
fold and improved survival time compared to single
agents.19
Lenalidomide success in the post-CAR-T setting has been demonstrated in
a small cohort of patients presented at the 2020 American Society of
Hematology by Dr. Thieblemont et al. Eleven patients with varying
lymphoma subtypes who progressed within 15 days post-CD19 CAR-T infusion
were treated with lenalidomide with or without rituximab or with
obinutuzumab.14 An ORR of 63.6% was observed with a
CR of 36.4%. Response rates with lenalidomide were also seen in
patients who progressed/relapsed after 15 days from CAR-T infusion with
an ORR of 18.8% and CR of 10.4%. In addition to response, patient’s
receiving lenalidomide also had a higher CAR-T expansion in the blood.
These results with lenalidomide are promising based on its antitumor
response and immunomodulatory impact, mechanisms which are necessary as
patient’s progress after CAR-T. The response rate in this cohort as well
as our case presented here is likely the combined result of the
synergistic activity of lenalidomide plus anti-CD20 monoclonal antibody
in addition to lenalidomides immune modulatory effects which aid in
cellular cytotoxicity and achieving a durable response.
Conclusion:
The complete remission seen in this patient suggests the use of
lenalidomide with obinutuzumab could be used in follicular lymphoma in
the post-CAR-T setting, analogous to published data with other lymphoma
subtypes. With CAR-T being an approved third line option for follicular
lymphoma, further research is warranted to determine appropriate
sequencing of agents leading up to CAR-T and post-CAR-T failure in order
to optimize survival outcomes. With lenalidomide’s T-cell and antitumor
effects, begs the question of where this agent should be in the sequence
of treatments? Whether it is included as therapy pre-CAR-T, maintenance
post CAR-T, or salvage post CAR-T, still requires further investigation.
While confirmation in a large clinical trial is needed, lenalidomide
plus obinutuzumab could be considered as a treatment option in patients
with follicular lymphoma who progress/relapse post CAR-T.
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