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\begin{document}

\title{An exceptional case of durable remission achieved with reinfusion of
CD19-directed CAR-T despite failure to induce B-cell aplasia and review
of institutional experience with reinfusion of tisagenlecleucel}



\author[1]{Thomas Galletta}%
\author[2]{Jeremy  Rubinstein}%
\author[3]{Christa Krupski}%
\author[3]{Adam S. Nelson}%
\author[3]{Ruby Khoury}%
\author[3]{Christopher Dandoy}%
\author[3]{Stella Davies}%
\author[2]{Christine Phillips}%
\affil[1]{Cincinnati Children's Hospital Medical Center Cancer and Blood Diseases Institute}%
\affil[2]{Cincinnati Children's Hospital Medical Center}%
\affil[3]{University of Cincinnati Department of Pediatrics}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
CD19-directed chimeric antigen receptor T lymphocytes (CAR-T) have led
to durable remissions in children with refractory and/or multiply
relapsed B-lymphoblastic leukemia. For those who relapse or lose B-cell
aplasia post-CAR-T, the role of CAR-T reinfusion is unclear. We report a
case of durable remission with tisagenlecleucel reinfusion despite
failure to achieve B-cell aplasia and compare this case to seven
additional children who received multiple tisagenlecleucel infusions at
our institution. Our experience suggests that reinfusion is safe and may
be a definitive therapy for a small subset of patients. Reinfusion can
also reintroduce remission and/or B-cell aplasia, allowing for
subsequent therapies.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Chimeric antigen receptor T lymphocytes (CAR-T) targeting the CD19
surface antigen have led to durable remissions in children and young
adults with refractory and/or multiply relapsed B-lymphoblastic leukemia
(B-ALL).\textsuperscript{1-11} Pediatric trials of CD19-directed CAR-T
have shown complete response rates up to 89\% with one-year event-free
survival around 50\%.\textsuperscript{1-4,12} Historically,
consolidative allogeneic hematopoietic stem cell transplant (HSCT) has
been required to cure refractory and relapsed B-ALL, and CAR-T may be
used as a bridge to HSCT. However, CAR-T has resulted in long-term
remissions for some patients without the need for further therapy,
although the ability to predict response is
limited.\textsuperscript{4,5} CAR-T is an appealing option for heavily
pretreated patients unqualified for transplant, or patients at high risk
of transplant-related toxicities.\textsuperscript{13,14} Most post-CAR-T
relapses occur within the first year following infusion, and the role of
CAR-T reinfusion for the treatment of post-CAR-T relapse is
unclear.\textsuperscript{15} Here we report an unusual case of
reinfusions achieving durable remission despite failure to re-achieve
B-cell aplasia (BCA). For comparison, we briefly update the experience
of seven additional children with relapsed or refractory B-ALL, who were
reinfused with an additional dose of tisagenlecleucel, manufactured at
the same time as the original dose.

\textbf{Methods}

We performed a retrospective analysis of all patients who received
multiple infusions of a non-humanized CD19-directed 4-1BB CAR-T,
tisagenlecleucel, at Cincinnati Children's Hospital Medical Center
between January 2018 and December 2021. This study was approved by the
Cincinnati Children's Hospital Medical Center Institutional Review
Board. A comprehensive review of patient, disease, and product
characteristics, toxicities, and patient outcomes was performed.
Cytokine release syndrome (CRS) and immune effector cell-associated
neurotoxicity syndrome (ICANS) were graded according to the American
Society of Transplantation and Cellular Therapy consensus
guidelines.\textsuperscript{16} Remission status was tested via
multiparametric flow cytometry on bone marrow samples collected 28 days
following CAR-T infusion, as well as morphological cerebrospinal fluid
(CSF) analysis via lumbar puncture. BCA was monitored at least monthly
by peripheral blood analysis of lymphocyte subpopulations. Loss of BCA
was defined as \textgreater{}1\% CD19+ or 100 absolute CD19+ cells on
peripheral analysis, confirmed on a subsequent sample.

\textbf{Case Descriptions}

An 8-year-old boy with trisomy 21 and high-risk B-ALL presented with
early marrow relapse fourteen months after initial diagnosis. He was
diagnosed at age 7 years with an initial WBC of 4,100 cells/\selectlanguage{greek}µ\selectlanguage{english}l and was
CNS 1. He did not have cytogenetic or molecular genetic alterations
besides his known constitutional trisomy 21. He underwent chemotherapy
per Children's Oncology Group (COG) AALL0932 with detectable minimal
residual disease (MRD) {[}0.022\% by flow cytometry{]} at the end of
induction. He received consolidation chemotherapy per COG AALL1131 but
was switched to treatment per COG AALL0232 due to significant
methotrexate toxicity during interim maintenance. He received CTL019
(tisagenlecleucel) on clinical trial (NCT02228096) due to the increased
risk of treatment-associated toxicity with trisomy 21 and poor prognosis
associated with HSCT in the setting of early relapse. He received CTL019
infusion following standard cyclophosphamide and fludarabine
lymphodepleting chemotherapy and developed grade 1 CRS without evidence
of ICANS. Bone marrow evaluation 28 days following CAR-T infusion was
MRD negative by flow cytometry.

Loss of BCA, indicating functional loss of CAR-T cells, occurred three
months post-CAR-T. CTL019 was undetectable on study-performed polymerase
chain reaction (PCR). Despite this, the patient remained in an
MRD-negative complete remission (CR) by flow cytometry. Since loss of
BCA prior to six months is highly predictive for subsequent
relapse\textsuperscript{15}, the following options were considered:
proceeding immediately with an unrelated donor HSCT while in remission,
proceeding with chemotherapy and HSCT if relapse occurred, or
administering a second CTL019 infusion through a single-patient
Investigational New Drug application to the Food and Drug
Administration. The patient received a second CTL019 infusion six months
after his original infusion. Parents declined preceding lymphodepleting
chemotherapy. Infusion was well tolerated without CRS. Before the second
CTL019 infusion bone marrow evaluation showed a tiny population of CD19+
blasts (0.0092\%), though the patient remained in a morphologic
remission. However, bone marrow evaluation 28 days following the second
CAR-T infusion was MRD-positive with 3\% blasts. CTL019 was absent by
PCR at that time. A third CTL019 infusion was given one month following
the second infusion, preceded by lymphodepleting chemotherapy. The
patient developed grade 1 CRS but otherwise tolerated treatment well.
His bone marrow evaluation 28 days after the third CAR-T infusion
demonstrated an MRD-negative remission by flow cytometry. Notably, he
failed to achieve BCA; however, he remains in an MRD-negative remission
seven years following his third CAR-T infusion.

Data for the other seven patients are summarized in Table 1. Patients
received initial tisagenlecleucel infusion for either refractory or
multiply relapsed B-ALL. Two patients had extramedullary isolated CNS
relapses. Two patients experienced grade 1 CRS, and no patients
experienced ICANS with initial infusion. No patients required
corticosteroid or anti-IL-6 treatment. All seven patients achieved an
MRD-negative CR and negative CNS status at evaluation 28 days
post-CAR-T.

Four of seven patients received reinfusion in disease remission for
early B cell recovery, as B cell recovery less than six months from
infusion is known to portend a higher risk of
relapse.\textsuperscript{15} Three patients received reinfusion for
frank disease relapse. Only one relapsed patient experienced CRS with
reinfusion, for which he required tocilizumab, and this same patient was
the only one to experience ICANS. Five of seven patients achieved an
MRD-negative CR following reinfusion, and one patient had 1.2\% residual
disease. The remaining patient achieved a marrow MRD-negative CR and had
biopsy-proven cutaneous B-ALL at assessment 28 days following CAR-T
reinfusion. Two patients who were MRD-negative failed to re-establish
BCA and required subsequent therapies. For one patient CAR-T reinfusion
was used as a direct bridge to HSCT, so the presence of BCA was not
monitored. CAR-T reinfusion remained the definitive therapy for one
patient, who experienced BCA for only two additional months and is alive
with no evidence of disease.

\textbf{Discussion}

We present an exceptional case of durable remission despite lacking
on-target loss of B cells following reinfusion, as well as a case series
of seven other pediatric patients who received tisagenlecleucel
reinfusion for treatment of post-CAR-T relapse or early loss of BCA.
Approximately 40-50\% of pediatric patients with B-ALL relapse
post-CAR-T, and consolidative HSCT is currently the standard of care.
The feasibility of reinfusion with the same product depends on the
availability of additional CAR-T cells, as well the presence of CD19+
blasts if in relapse.\textsuperscript{17,18} Our institutional
experience has suggested that tisagenlecleucel reinfusion has a limited,
albeit non-zero, likelihood of being a definitive therapy. There is a
subset of patients for whom it is successful, though the identification
of these patients remains unclear. For some, reinfusion can provide
temporary benefit with remission and/or BCA reintroduction.

Our institutional experience has shown mixed success. CAR-T reinfusion
remained the definitive therapy for 25\% of patients, who are alive
without evidence of disease. Prior studies have reported similar
experiences with CAR-T reinfusion for either loss of BCA or disease
relapse, where reinfusion was the definitive therapy for 20-25\% of
patients.\textsuperscript{6,19-22} Five of the remaining six patients
reinfused are alive, following additional therapy after tisagenlecleucel
reinfusion including HSCT, humanized CAR-T, and/or immunotherapy. In our
cohort CAR-T reinfusion was safe and generally well tolerated, with only
one patient requiring tocilizumab for CRS.

For our patient who remains in remission seven years following third
CAR-T infusion, his second CAR-T infusion, which was not preceded by
lymphodepleting chemotherapy, failed with disease progression 28 days
post-infusion. Gardner et al. reported a similar experience: of eight
patients reinfused for loss of CAR-T cells, only the two that received
lymphodepleting chemotherapy had CAR-T
re-expansion.\textsuperscript{2}For our patient we hypothesized that the
third infusion irradicated the remaining leukemic clone, as the lack of
BCA argues against the presence of persistent, active CAR-T cells for
surveillance against recurrence. While monitoring BCA allowed for the
early detection of MRD by flow cytometry prior to a morphologic relapse
following his initial CAR-T infusion, our current institutional practice
includes measuring MRD by next generation sequencing. This allows for
significantly higher sensitivity and earlier relapse detection but was
not commercially available when our patient was
treated.\textsuperscript{15}

Our experience suggests that tisagenlecleucel reinfusion is safe and can
induce remissions in patients with CD19+ relapse, possibly as an
alternative to HSCT or other therapies for post-CAR-T relapse. However,
the subset of patients for whom this is definitive therapy is small. Our
study is limited by sample size, and pooling experiences among pediatric
institutions is needed to make conclusions about tisagenlecleucel
reinfusion. Clinical trials of humanized CAR-T products may also offer a
pathway to durable remission.\textsuperscript{9} Other potential
strategies to deepen remission include increasing lymphodepleting
chemotherapy dosing, using PD-1 inhibitors to augment T cell response,
and empirically reinfusing as a ``boost'' while in remission with
ongoing BCA.\textsuperscript{23,24} CAR-T cell dose has been associated
with improved event-free and overall survival, and multiple CAR-T
infusions improved survival in preclinical mouse
studies.\textsuperscript{25,26} Such studies suggest that reinfusion may
reduce the rate of B cell recovery, allowing for prolonged CAR-T cell
persistence, and a pediatric phase II study of scheduled reinfusion is
ongoing (NCT05460533).\textsuperscript{27}

\textbf{Conflicts of Interest}

S.M.D. has received research support from Alexion Pharmaceuticals and
has had consultancies with Novartis, Rocket Pharma, CIRM, Allovir, and
Neurogene. C.L.P. has served on an advisory committee for Novartis. The
remaining authors declare no competing financial interests.

\textbf{Acknowledgments}

The authors thank the staff of the Regenerative Medicine and Cellular
Therapies Division at Hoxworth Blood Center for their critical aid in
managing cellular products. The authors also gratefully acknowledge the
patients treated and their families, as well as the CAR-T and
Immunotherapy team within the Cancer and Blood Diseases Institute of
Cincinnati Children's Hospital Medical Center.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et
  al. Tisagenlecleucel in Children and Young Adults with B-Cell
  Lymphoblastic Leukemia.~\emph{N Engl J Med} . 2018;378(5):439-448.
  doi:10.1056/NEJMoa1709866
\item
  Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al.
  Intent-to-treat leukemia remission by CD19 CAR T cells of defined
  formulation and dose in children and young adults.~\emph{Blood} .
  2017;129(25):3322-3331. doi:10.1182/blood-2017-02-769208
\item
  Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, et al.
  Real-world evidence of tisagenlecleucel for pediatric acute
  lymphoblastic leukemia and non-Hodgkin lymphoma {[}published
  correction appears in Blood Adv. 2021 Feb 23;5(4):1136{]} {[}published
  correction appears in Blood Adv. 2022 Mar 22;6(6):1731{]}.~\emph{Blood
  Adv} . 2020;4(21):5414-5424. doi:10.1182/bloodadvances.2020003092
\item
  Rives S, Maude SL, Hiramatsu, H, Baruchel A, Bader P, Bittencourt H,
  et al. S112: Tisagenlecleucel in Pediatric and Young Adult Patients
  (Pts) with Relapsed/Refractory (R/R) B-cell Acute Lymphoblastic
  Leukemia (B-ALL): Final Analyses from the ELIANA
  Study.\emph{HemaSphere} . 2022;6:13-14.
\item
  Grupp SA, Maude SL, Rives S, Baruchel A, Boyer M, Bittencourt H, et
  al. Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in
  Pediatric and Young Adult Patients with Relapsed/Refractory (r/r)
  Acute Lymphoblastic Leukemia.~\emph{Blood} ~2018; 132 (Supplement 1):
  895. doi:10.1182/blood-2018-99-112599
\item
  Maude SL, Teachey DT, Rheingold SR, Shaw PA, Aplenc R, Barrett DM, et
  al. Sustained remissions with CD19-specific chimeric antigen receptor
  (CAR)-modified T cells in children with relapsed/refractory
  ALL.\emph{J Clin Oncol} . 2016;34(Supplement 15): 3011.
\item
  Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al.
  Chimeric antigen receptor T cells for sustained remissions in leukemia
  {[}published correction appears in N Engl J Med. 2016 Mar
  10;374(10):998{]}.~\emph{N Engl J Med} . 2014;371(16):1507-1517.
  doi:10.1056/NEJMoa1407222
\item
  Park JH, Rivi\selectlanguage{ngerman}ère I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al.
  Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic
  Leukemia.~\emph{N Engl J Med} . 2018;378(5):449-459.
  doi:10.1056/NEJMoa1709919
\item
  Myers RM, Li Y, Barz Leahy A, Barrett DM, Teachey DT, Callahan C, et
  al. Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in
  CAR-Naive and CAR-Exposed Children and Young Adults with Relapsed or
  Refractory Acute Lymphoblastic Leukemia.~\emph{J Clin Oncol} .
  2021;39(27):3044-3055. doi:10.1200/JCO.20.03458
\item
  Shah NN, Lee DW, Yates B, Yuan C, Shalabi H, Martin S, et al.
  Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young
  Adults With B-ALL.~\emph{J Clin Oncol} . 2021;39(15):1650-1659.
  doi:10.1200/JCO.20.02262
\item
  Zhang X, Lu XA, Yang J, Zhang G, Li J, Song L, et al. Efficacy and
  safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell
  acute lymphoblastic leukemia with high-risk features.~\emph{Blood Adv}
  . 2020;4(10):2325-2338. doi:10.1182/bloodadvances.2020001466
\item
  Schultz LM, Baggott C, Prabhu S, Pacenta HL, Phillips CL, Rossoff J,
  et al. Disease Burden Affects Outcomes in Pediatric and Young Adult
  B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A
  Pediatric Real-World Chimeric Antigen Receptor Consortium
  Report.~\emph{J Clin Oncol} . 2022;40(9):945-955.
  doi:10.1200/JCO.20.03585
\item
  Laetsch TW, Maude SL, Balduzzi A, Rives S, Bittencourt H, Boyer MW, et
  al. Tisagenlecleucel in pediatric and young adult patients with Down
  syndrome-associated relapsed/refractory acute lymphoblastic
  leukemia.~\emph{Leukemia} . 2022;36(6):1508-1515.
  doi:10.1038/s41375-022-01550-z
\item
  Laetsch TW, Maude SL, Grupp SA, Boyer MW, Harris AC, Qayed M, et al.
  CTL019 Therapy Appears Safe and Effective in Pediatric Patients with
  Down Syndrome with Relapsed/ Refractory (r/r) Acute Lymphoblastic
  Leukemia.~\emph{Blood} ~2017; 130 (Supplement 1): 1280.
  doi:10.1182/blood.V130.Suppl\_1.1280.1280
\item
  Pulsipher MA, Han X, Maude SL, Laetsch TW, Qayed M, Rives S, et al.
  Next-Generation Sequencing of Minimal Residual Disease for Predicting
  Relapse after Tisagenlecleucel in Children and Young Adults with Acute
  Lymphoblastic Leukemia.~\emph{Blood Cancer Discov} . 2022;3(1):66-81.
  doi:10.1158/2643-3230.BCD-21-0095
\item
  Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et
  al. ASTCT Consensus Grading for Cytokine Release Syndrome and
  Neurologic Toxicity Associated with Immune Effector Cells.~\emph{Biol
  Blood Marrow Transplant} . 2019;25(4):625-638.
  doi:10.1016/j.bbmt.2018.12.758
\item
  Orlando EJ, Han X, Tribouley C, Wood PA, Leary RJ, Riester M, et al.
  Genetic mechanisms of target antigen loss in CAR19 therapy of acute
  lymphoblastic leukemia.~\emph{Nat Med} . 2018;24(10):1504-1506.
  doi:10.1038/s41591-018-0146-z
\item
  Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al.
  Convergence of Acquired Mutations and Alternative Splicing of CD19
  Enables Resistance to CART-19 Immunotherapy.~\emph{Cancer Discov} .
  2015;5(12):1282-1295. doi:10.1158/2159-8290.CD-15-1020
\item
  Gauthier J, Bezerra ED, Hirayama AV, Fiorenza S, Sheih A, Chou CK, et
  al. Factors associated with outcomes after a second CD19-targeted CAR
  T-cell infusion for refractory B-cell malignancies.~\emph{Blood} .
  2021;137(3):323-335. doi:10.1182/blood.2020006770
\item
  Myers RM, Devine K, Li Y, Lawrence S, Leahy AB, Liu H, et al. Outcomes
  after Reinfusion of CD19-Specific Chimeric Antigen Receptor
  (CAR)-Modified T Cells in Children and Young Adults with
  Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia.~\emph{Blood}
  ~2021; 138 (Supplement 1): 474. doi:10.1182/blood-2021-147299
\item
  Boyer MW, Chaudhury S, Davis KL, Triscoll TA, Grupp SA, Hermiston M,
  et al. HESTER: A Phase II Study Evaluating Efficacy and Safety of
  Tisagenlecleucel Reinfusion in Pediatric and Young Adult Patients with
  Acute Lymphoblastic Leukemia Experiencing Loss of B-Cell
  Aplasia.~\emph{Blood} ~2020; 136 (Supplement 1): 23--24.
  doi:10.1182/blood-2020-136340
\item
  Holland EM, Molina JC, Dede K, Moyer D, Zhou T, Yuan CM, et al.
  Efficacy of second CAR-T (CART2) infusion limited by poor CART
  expansion and antigen modulation.~\emph{J Immunother Cancer} .
  2022;10(5):e004483. doi:10.1136/jitc-2021-004483
\item
  Fabrizio VA, Boelens JJ, Mauguen A, Baggott C, Prabhu S, Egeler E, et
  al. Optimal fludarabine lymphodepletion is associated with improved
  outcomes after CAR T-cell therapy.~\emph{Blood Adv} .
  2022;6(7):1961-1968. doi:10.1182/bloodadvances.2021006418
\item
  Li AM, Hucks GE, Dinofia AM, Seif AE, Teachey DT, Baniewicz D, et al.
  Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor
  (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic
  Leukemia.~\emph{Blood} ~2018; 132 (Supplement 1): 556.
  doi:10.1182/blood-2018-99-112572
\item
  Stefanski H, Eaton A, Baggott C, Rossoff J, Verneris MR, Keating AK,
  et al. Higher doses of tisagenlecleucel associate with improved
  outcomes: a report from the pediatric real-world CAR consortium
  {[}published online ahead of print, 2022 Aug 8{]}. \emph{Blood Adv} .
  2022;bloodadvances.2022007246. doi:10.1182/bloodadvances.2022007246
\item
  Brentjens RJ, Santos E, Nikhamin Y, Yeh R, Matsushita M, La Perle K,
  et al. Genetically targeted T cells eradicate systemic acute
  lymphoblastic leukemia xenografts. \emph{Clin Cancer Res} . 2007;13(18
  Pt 1):5426-5435. doi:10.1158/1078-0432.CCR-07-0674
\end{enumerate}

\textbf{Hosted file}

\verb`CART reinfusion Table 12.20.22.docx`  available at \url{https://authorea.com/users/453372/articles/614197-an-exceptional-case-of-durable-remission-achieved-with-reinfusion-of-cd19-directed-car-t-despite-failure-to-induce-b-cell-aplasia-and-review-of-institutional-experience-with-reinfusion-of-tisagenlecleucel}

\selectlanguage{english}
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