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\begin{document}

\title{Prolonged Remission in Multiple Relapsed MLL-rearranged Infant B-ALL
with Inotuzumab Ozogamicin}



\author[1]{Akhila Lattupally}%
\author[1]{Adonis Lorenzana}%
\author[2]{Grogory Yanik}%
\author[1]{Danielle Bell}%
\affil[1]{Ascension St John Hospital}%
\affil[2]{University of Michigan}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\textbf{Prolonged Remission in Multiple Relapsed MLL-rearranged Infant
B-ALL with Inotuzumab Ozogamicin}

Akhila Lattupally MD\textsuperscript{1}, Adonis Lorenzana
MD\textsuperscript{1}, Gregory Anthony Yanik MD\textsuperscript{2},
Danielle Bell MD\textsuperscript{1,3}

1. Ascension St. John Children's Hospital, Detroit, Michigan, United
States.

2. C.S. Mott Children's Hospital -- University of Michigan, Ann Arbor,
Michigan, United States.

3. Children's Hospital of Michigan, Detroit, Michigan, United States.

Corresponding Author: Akhila Lattupally MD

Address: 22101 Moross Rd, PB2, Suite 70, Detroit, Michigan 48236

Phone: 469-468-7978

Fax: 313-343-4756

Email:\emph{Akhila.Lattupally@ascension.org}

Word Count: Main text: 841 words

Number of Tables: 0 Number of Figures: 0 Number of Supporting
Information Files: 0

Running Title: Remission in Infant ALL with Inotuzumab Ozogamicin.

Keywords: Infant Leukemia, ALL Relapse, Immunotherapy

\textbf{Abbreviations}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
MLL & Mixed Lineage Leukemia\tabularnewline
\midrule
\endhead
MLL-r & Mixed Lineage Leukemia-rearranged\tabularnewline
ALL & Acute lymphoblastic leukemia\tabularnewline
InO & Inotuzumab Ozogamicin\tabularnewline
COG & Children's Oncology Group\tabularnewline
MRD & Minimal Residual disease\tabularnewline
CR1 & Clinical Remission 1\tabularnewline
CR2 & Clinical Remission 2\tabularnewline
CR3 & Clinical Remission 3\tabularnewline
CR4 & Clinical Remission 4\tabularnewline
CR5 & Clinical Remission 5\tabularnewline
CAR-T & Chimeric Antigen Receptor -- T Cell\tabularnewline
CNS & Central Nervous System\tabularnewline
CT & Computerized Tomography\tabularnewline
ANC & Absolute Neutrophil Count\tabularnewline
PTT & Partial Thromboplastin Time\tabularnewline
VOD & Vaso Occlusive Disease\tabularnewline
AST & Aspartate Transaminase\tabularnewline
ALT & Alanine Transaminase\tabularnewline
GGT & Gamma Glutamyl Transferase\tabularnewline
BID & Two times a day\tabularnewline
\bottomrule
\end{longtable}

Previously presented as a case report at ASPHO 2021, April 20-April 23
2021, Abstract published in the Pediatric Blood \& Cancer online
Journal.

\textbf{To The Editor}

MLL-rearranged (MLL-r) infant Acute lymphoblastic leukemia (ALL) is an
aggressive leukemia with poor prognosis. The 4-year event-free survival
is 47\%.\textsuperscript{1} Inotuzumab Ozogamicin (InO) is a
CD22-targeted antibody-drug conjugate approved to treat relapsed ALL.
There is limited data on InO in infant
leukemia.\textsuperscript{2,3}Here we present a case of MLL-rearranged
pre-B infant ALL with multiple relapses and eventual long-term response
to InO.

Our patient was diagnosed at 9-month-old of age with MLL-rearranged
pre-B ALL. He presented with leukemia cutis, leukocytosis and was CNS2.
He was enrolled in COG study AALL15P1.\textsuperscript{4} He had an
isolated bone marrow relapse 5 months into the treatment. He was then
enrolled on the COG relapse protocol AALL1331 and randomized to receive
chemotherapy with plans for bone marrow transplant. However, had a
second marrow relapse before he could receive a transplant.

Blinatumomab was then given as a bridging therapy while awaiting Car-T.
Ironically, on the day of admission for CAR-T therapy, he was found to
have CNS relapse and extra medullary disease. Thus, CAR-T was postponed
and at this time he was given InO along with triple intrathecal
chemotherapy for CNS 3 disease.

Our patient had an excellent response to InO. After two cycles of InO,
he was able to receive Car-T therapy. Unfortunately, while his marrow
remained MRD negative, his 28-day post-Car T evaluation showed CNS and
extramedullary relapse.

After having so many treatment failures within a span of 15 months, his
family chose to prioritize quality of life over the unlikelihood of
cure. InO was then resumed for palliative purposes. He was also treated
with triple intrathecal therapy followed by cranial radiation (1200Gy)
for his CNS disease. Surprisingly, our patient tolerated the InO well
and received 9 total cycles over the following year, his longest
treatment related remission, maintaining negative MRD. Dosing of Ino was
given weekly for 3 weeks/month for the first 5 cycles, then spaced
bi-weekly and then monthly for the remainder of the treatment.

Complications during InO treatment included moderate but persistent
pancytopenia, mucocutaneous bleeding, and one admission for localized
pseudomonas cellulitis.

As his mucocutaneous bleeding seemed out of proportion to the level of
thrombocytopenia (platelet count 40-50k), investigations were done to
identify other potential causes of bleeding. Coagulation studies, which
were normal at diagnosis, showed prolongation of PTT (45sec, ref
range:25-35), with no correction of mixing studies (42sec). Factor VIII,
IX, XI levels and Vitamin C, and K levels were normal. Workup for Von
Willebrand disease was negative. Dental evaluation was also normal.
Aminocaproic acid for persistent episodes of gingival bleeding was given
with some improvement, but the bleeding and bruising ultimately resolved
as InO dosing was spaced out.

Aside from thrombocytopenia, there are no previous reports of
coagulation abnormalities associated with InO.\textsuperscript{5,6} Due
to our patient's mucocutaneous bleeding, we suspect InO may have
precipitated some degree of platelet dysfunction. Platelet aggregation
studies were not done during this time period but would have been
helpful to better delineate this cause. Additionally, we did not test
for inhibitors which may have caused the prolonged PTT.

Due to the risk for VOD with InO, his hepatic function was monitored
closely. Bilirubin levels remained normal, and AST, ALT and GGT were
only mildly elevated (grade 1). He was treated with prophylactic
Actigall (10mg/kg) BID for liver protection.

Our patient had an excellent quality of life with few complications
during prolonged InO treatment. Because of his unexpected and prolonged
remission, after 1 year of therapy, his parents elected to pursue a
curative stem cell transplant with a haploidentical paternal donor. His
conditioning regimen for transplant included Fludarabine and
Cyclophosphamide with post-transplant Cyclophosphamide. Unfortunately,
one month after transplant, his bone marrow was found to have complete
autologous reconstitution. He remains in complete remission and MRD
negative with a detection level of 10\textsuperscript{-6.}(done by
CloneSeq), with recent bone marrow surveillance done 14 months after
stopping InO therapy.

After 4 prior relapses on conventional treatment protocols, our patient
has achieved a prolonged and ongoing remission with Inotuzumab. His
disease control can be attributed primarily to the prolonged treatment
of InO, as he has had disease recurrence after every other agent.
Although he was treated with Cytoxan and Fludarabine as a part of the
conditioning regimen for transplant it is unlikely this chemotherapy had
an impact on his disease as he was already in remission. Because he had
100\% autologous reconstitution after transplant, there is no graft vs.
leukemia to explain this prolonged response. Since InO has poor CNS
concentration, as it does not cross the blood-brain
barrier,\textsuperscript{7} intrathecal therapy as well as cranial
radiation was instrumental in maintaining our patient's excellent
response.

This is the first reported case of prolonged MRD negative remission
using Inotuzumab in a patient with heavily treated, multiple relapsed,
MLL-r infant ALL. InO was effective in maintaining disease control and
was well tolerated. Surprisingly, disease control has persisted even
after the cessation of InO. InO could be considered as an alternative
therapy for relapsed/refractory CD22+ infant ALL, either as a bridge to
curative therapy or as an option for life prolongation therapies.

\textbf{References}

1. Driessen EMC, De Lorenzo P, Campbell M, et al. Outcome of relapsed
infant acute lymphoblastic leukemia treated on the interfant-99
protocol. Leukemia 2016;30:1184-1187.

2. Bhojwani D, Sposto R, Shah NN, et al. Inotuzumab ozogamicin in
pediatric patients with relapsed/refractory acute lymphoblastic
leukemia. Leukemia 2019;33:884-892.

3. Brivio E, Chantrain CF, Gruber TA, et al. Inotuzumab ozogamicin in
infants and young children with relapsed or refractory acute
lymphoblastic leukemia: A case series. Br J Haematol 2021;193:1172-1177.

4. Pieters R, De Lorenzo P, Ancliffe P, et al. Outcome of infants
younger than 1 year with acute lymphoblastic leukemia treated with the
interfant-06 protocol: Results from an international phase III
randomized study. J Clin Oncol 2019;37:2246-2256.

5. Jabbour EJ, Deangelo DJ, Stelljes M, Stock W, Liedtke M. Efficacy and
safety analysis by age cohort of inotuzumab ozogamicin in patients with
relapsed or refractory acute lymphoblastic leukemia enrolled in
INO-VATE. Cancer 2018;124:1722-1732.

6. Stock W, G\selectlanguage{ngerman}ökbuget N, Brien SO, et al. Inotuzumab ozogamicin versus
standard therapy for acute lymphoblastic leukemia. N Engl J Med
2016;375:740-753.

7. McNeer JL, Rau RE, Gupta S, Maude SL, O'Brien MM. Cutting to the
front of the line: Immunotherapy for childhood acute lymphoblastic
leukemia. Am Soc Clin Oncol Educ B 2020;40:e132-e143.

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