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\begin{document}

\title{Immunotherapy beyond cellular therapy in Follicular Lymphoma: A case of
complete remission after failure of two CAR-T}



\author[1]{Adam Kase}%
\author[2]{Mohamed Kharfan Dabaja }%
\author[1]{Andrew Donaldson}%
\author[1]{Jamie Elliott}%
\author[1]{Taimur Sher}%
\affil[1]{Mayo Clinic in Florida}%
\affil[2]{Mayo Clinic Hospital Jacksonville}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Patients with relapsed follicular lymphoma who do not respond to CAR-T
have a poor outcome. We present a case of refractory follicular lymphoma
who relapsed after two CAR-T infusions and achieved a complete remission
after treatment with obinutuzumab and lenalidomide. This represents a
promising treatment option in the post-CAR-T setting.%
\end{abstract}%



\sloppy


Immunotherapy beyond cellular therapy in Follicular Lymphoma: A case of
complete remission after failure of two CAR-T

Adam M. Kase, M.D.\textsuperscript{1}, Mohamed A. Kharfan-Dabaja,
M.D.\textsuperscript{2}, Andrew Donaldson R.N.\textsuperscript{1}, Jamie
Elliott APRN, D.N.P.\textsuperscript{1}, Taimur Sher, M.B.B.S,
M.D.\textsuperscript{1}

\textsuperscript{1}Mayo Clinic Florida Division of Hematology Oncology

\textsuperscript{2}Mayo Clinic Florida Division of Hematology Oncology,
Blood and Marrow Transplantation and Cellular Therapies Program

Adam Kase: kase.adam@mayo.edu, Mohamed Kharfan-Dabaja:
kharfandabaja.mohamed@mayo.edu, Andrew Donaldson:
Donaldson.andrew@mayo.edu, Jamie Elliott: Elliott.jamie@mayo.edu, Taimur
Sher: sher.taimur@mayo.edu

Data Availability: The data that support the findings of this study are
not publicly available due to privacy or ethical restrictions.

The authors have no conflicts of interests.

Patient consent was obtained for the publication of this case report.

No funding was provided for this manuscript.

Introduction:

Follicular lymphoma is the most common indolent non-Hodgkin lymphoma
which is known for its relapsing-remitting disease course with 20\% of
patients developing progression of disease within 2 years of
chemoimmunotherapy.\textsuperscript{1} The treatment for relapsed
follicular lymphoma includes combinations of chemoimmunotherapy, immune
modulators and hematopoietic stem cell transplant. More recently
chimeric antigen receptor T-cell therapy (CAR-T) has demonstrated
impressive activity in the relapsed/refractory setting leading to the
FDA approval of axicabtagene ciloleucel in February 2021 for relapsed or
refractory follicular lymphoma.\textsuperscript{2} Patients not
responding to CAR-T or relapsing soon after treatment have a poor
outcome. \textsuperscript{3} The optimal treatment for such CAR-T
treatment failure remains unclear. Here we present a case of relapse
refractory follicular lymphoma who relapsed after multiple lines of
chemoimmunotherapy including two CAR-T infusions, who then achieved a
complete remission after treatment with obinutuzumab and lenalidomide.

Case Report:

The patient is a 73-year-old female who was diagnosed with stage IVA
follicular lymphoma in 2000. Over a period of 20 years, she received the
following treatments with variable responses (Table 1), including:
cyclophosphamide, vincristine and prednisone, followed by multiple
rounds of rituximab, targeted radiation, a clinical trial with
everolimus, single agent lenalidomide, an oral PI3K delta inhibitor on a
clinical trial and rituximab plus gemcitabine with oxaliplatin. Despite
all these therapies she continued to progress. She was enrolled in
ZUMA-5 clinical trial for treatment with axicabtagene ciloleucel CAR-T
and obtained a complete remission that lasted for approximately 1.5
years. At relapse, she underwent a second CD19 CAR-T in June 2020 and
had florid progression of disease just two months later in August 2020
(Figure 1A). She briefly enrolled on a clinical trial with a novel BCL-2
inhibitor but had rapid disease progression within few days. In October
2020, she was started on obinutuzumab and lenalidomide. The dose of
lenalidomide had to be reduced from 20 mg (days 1-21) to 5 mg (days
1-14) due to thrombocytopenia. A PET scan was obtained to assess
response to treatment after 2 months and revealed radiologic complete
remission. Ongoing surveillance PET scan (Figure 1B) in April 2021
showed continued remission, consistent with a 6-month durable radiologic
complete remission after 5 cycles of obinutuzumab and lenalidomide two
weeks on one week off.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1: (A) FDG-PET scan demonstrating extensive hypermetabolic soft
tissue activity involving the mediastinal bilateral hilar node chains
with extensive confluent mesenteric, retroperitoneal, pelvic and
inguinal lymph node disease. (B) Post treatment FDG-PET demonstrating
complete remission.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Treatment} & \textbf{Duration of Treatment} &
\textbf{Progression Free Survival (months)} & \textbf{Treatment
Response}\tabularnewline
\midrule
\endhead
\textbf{CVP} & 6 cycles & 16 & Partial response\tabularnewline
\textbf{Rituximab (start 8/9/2001)} & 8 cycles & 31 & Complete
response\tabularnewline
\textbf{Rituximab (start 4/2004)} & 5 cycles & 15 & Partial
response\tabularnewline
\textbf{Radiation Therapy} & 2000 cGy in 10 fractions & 1 & Stable
disease\tabularnewline
\textbf{Everolimus trial (start 1/2007)} & 12 months & 12 & Stable
disease\tabularnewline
\textbf{Lenalidomide start 9/27/2010)} & 5 months & 5 & Partial
response\tabularnewline
\textbf{Rituximab (start 2/2011)} & 8 cycles & 11 & Stable
disease\tabularnewline
\textbf{Lenalidomide (start 1/2012)} & 28 months & 28 & Complete
response\tabularnewline
\textbf{PI3K delta Inhibitor trial (6/2014)} & 6 months & 6 & Partial
response\tabularnewline
\textbf{Gemcitabine and Oxaliplatin (start 12/30/2014)} & 7 cycles & 19
& Partial response\tabularnewline
\textbf{Axicabtagene ciloleucel (9/2018)} & N/A & 20 & Complete
response\tabularnewline
\textbf{Axicabtagene ciloleucel (6/2020)} & N/A & 2 & Partial
response\tabularnewline
\textbf{BCL-2 inhibitor trial} & 2 weeks & 0 & No
response\tabularnewline
\textbf{Obinutuzumab and Lenalidomide} & 5 cycles & Ongoing
(\textgreater{}6) & Complete response\tabularnewline
\textbf{Lenalidomide maintenance} & Ongoing & Ongoing (\textgreater{}6)
& Complete response\tabularnewline
\bottomrule
\end{longtable}

Table 1: Treatment history demonstrating duration of treatment,
progression free survival and best treatment response.

Discussion:

Relapsed follicular lymphoma can be treated with a variety of modalities
including chemoimmunotherapy, immune modulators, hematopoietic stem cell
transplant and CAR-T (Table 2). Rituximab has been studied in heavily
pretreated and in patients who had previously responded to rituximab and
resulted in overall response rate (ORR) 40\% and complete response (CR)
in 11\% of patients.\textsuperscript{4} Chemotherapy can also be added
to monoclonal antibodies in patients with untreated and relapsed
follicular lymphoma to achieve an improved overall survival compared to
patients with chemotherapy alone.\textsuperscript{5} In the GADOLIN
trial, rituximab refractory indolent non-Hodgkin lymphoma was treated
with obinutuzumab plus bendamustine. In the intention-to-treat group the
median progression-free survival was 25.8 months and 14.1 months, in the
combination and monotherapy arms
respectively.\textsuperscript{6}Combination was given for 6 cycles
followed by maintenance obinutuzumab every 2 months for 2 years until
progression. Immune modulators have also been incorporated into these
regimens. Lenalidomide can be combined with rituximab or obinutuzumab
for early or late relapse. In the AUGMENT trial, patients received
lenalidomide or placebo for 12 cycles plus rituximab
weekly.\textsuperscript{7} The median PFS was improved from 14 months to
39 months. Obinutuzumab was combined with lenalidomide after
rituximab-containing therapy in a phase Ib trial with 63\% of patients
achieving a response, as seen in this patient.\textsuperscript{8} While
these regimens have a higher toxicity profile, combining these agents in
patients with a good performance status appears to be beneficial.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Regimen}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Overview}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Overall Response Rate}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Survival Outcomes}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Single agent Rituximab\textsuperscript{4}}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Low tumor burden, poor performance status, slowly progressive\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
66\% (initial) 40\% (re-treatment)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
mPFS: 21 months (initial) mPFS: 18 months (re-treatment)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Rituximab + Chemo+\textsuperscript{5}}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
First relapse, or late relapse\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
RR 1.28 favoring R-chemo\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
HR for mortality: 0.63 2y OS: 90\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Obinutuzumab+Bendamustine\textsuperscript{6}}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Rituximab refractory\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
57\%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
mPFS: 25.8 months\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Anti-CD20 + lenalidomide\textsuperscript{7,9}}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Late or early relapse\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
65-77\%\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
mPFS: 39 months mTTP: 24 months\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Lenalidomide\textsuperscript{9}}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Late or early relapse\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
53\%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
mTTP: 13.2 months\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Idelalisib\textsuperscript{10}}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
After two prior therapies\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
57\%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
mPFS: 11 months\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Tazemetostat\textsuperscript{11}}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
EZH2 mutation in first relapse\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
69\%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
mPFS: 11 months\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Autologous HSCT\textsuperscript{12}}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Early treatment failure\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
78\%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5y OS 73\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Axicabtagene ciloleucel\textsuperscript{2}}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
After two prior therapies\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
95\%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12 month DOR: 71.7\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Pembrolizumab}++\textsuperscript{\textbf{13}}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
After failed CAR-T\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27\%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
n/a\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Lenalidomide +/-anti-CD20}++\textsuperscript{\textbf{14}}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
After failed CAR-T\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
63.6\% (within 15 days of CAR-T infusion) 18.8\% (15 days after CAR-T
infusion)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
n/a\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

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\%.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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,\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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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