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\begin{document}

\title{Outpatient Administration of Blinatumomab Infusion and Hematopoietic
Stem Cell Transplantation as Treatment for Patients with Refractory
Acute Lymphoblastic Leukemia in a Pediatric Oncologic Center in Mexico.}



\author[1]{Bernabé-Gaspar Luis Eduardo}%
\author[2]{Godoy-Fernández JF}%
\author[2]{María del Pilar Cubría-Juárez}%
\author[3]{Marta Margarita Zapata Tarrés}%
\author[2]{Taveras-Rodríguez Omageline}%
\author[2]{Briseño-Rebollar EV}%
\author[2]{* Bautista-Hernández}%
\author[2]{LOURDES VEGA-VEGA}%
\author[2]{Pérez-García M}%
\affil[1]{Benemerita Universidad Autonoma de Puebla Facultad de Medicina}%
\affil[2]{Hospital Infantil Teleton de Oncologia}%
\affil[3]{Fundacion IMSS AC}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer
and the most common subtype of pediatric leukemia, the high toxicity,
relapse and refractory disease of many patients require the development
of novel therapeutic approaches. New therapeutic approaches such as
targeted immunotherapy in combination with Hematopoietic Stem Cell
Transplantation (HSCT) must be taken in count to revolutionize the
management of numerous ALL subtypes, improve treatment outcomes and
maintain low toxicity without losing the effectiveness of the treatment.
We evaluated a novel therapeutic approach in Mexico, the outpatient
administration of blinatumomab infusion in patients with
relapsed/refractory acute lymphoblastic leukemia (R/R ALL).%
\end{abstract}%



\sloppy


\textbf{Outpatient Administration of Blinatumomab Infusion and
Hematopoietic Stem Cell Transplantation as Treatment for Patients with
Refractory Acute Lymphoblastic Leukemia in a Pediatric Oncologic Center
in Mexico.}

Godoy-Fern\selectlanguage{ngerman}ández JF\textsuperscript{1}, Pilar-Cubría
MP\textsuperscript{2}, Zapata-Tarrés M\textsuperscript{3},
Taveras-Rodríguez Omageline \textsuperscript{4}, Briseño-Rebollar
EV\textsuperscript{5}, Bautista-Hernández I\textsuperscript{6},
Vega-Vega L\textsuperscript{7},~Bernabé-Gaspar Luis
Eduardo\textsuperscript{8}, Pérez-García M\textsuperscript{9}.

1.Resident of the pediatric program for hematopoietic stem cell
transplantation, Hospital Infantil Teleton de Oncologia.
México.\emph{godoy@hospitalteleton.org.mx}

2. Chief of the Acute Lymphoblastic Leukemia Department, Hospital
Infantil Teleton de Oncologia.
México.\emph{cubria@hospitalteleton.org.mx}

3. Research Coordination, Mexican Institute of Social Services
Foundation, Fundación IMSS.
Mexico.\emph{marta.zapata@fundacionimss.org.mx}

4.Resident of the pediatric program for hematopoietic stem cell
transplantation, Hospital Infantil Teleton de Oncologia.
México.\emph{taveras@hospitalteleton.org.mx}

5. Department of hematopoietic stem cell transplantation, Hospital
Infantil Teleton de Oncologia.
México.\emph{briseno@hospitalteleton.org.mx}

6. Chief of the Oncologic Surgery Department, Hospital Infantil Teleton
de Oncologia. México.\emph{ibautista@hospitalteleton.org.mx}

7. Director, Hospital Infantil Teletón de Oncología.
México.\emph{vega@hospitalteleton.org.mx}

8. Faculty of Medicine, Benemérita Universidad Autónoma de
Puebla.\emph{luis.bernabe@alumno.buap.mx}

9. Chief of the hematopoietic cell stem transplantation Department,
Hospital Infantil Teleton de Oncologia.
México.\emph{mperezg@hospitalteleton.org.mx}

Corresponding Author: Martín Pérez García

Address: Anillo Vial Fray Junípero Serra 1999, Rancho Menchaca, 76140
Santiago de Querétaro, Querétaro. México.

Phone: +52 5514843680

email:\emph{mperezg@hospitalteleton.org.mx}

\textbf{Abstract~}

Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer
and the most common subtype of pediatric leukemia, the high toxicity,
relapse and refractory disease of many patients require the development
of novel therapeutic approaches. New therapeutic approaches such as
targeted immunotherapy in combination with Hematopoietic Stem Cell
Transplantation (HSCT) must be taken in count to revolutionize the
management of numerous ALL subtypes, improve treatment outcomes and
maintain low toxicity without losing the effectiveness of the treatment.

We evaluated a novel therapeutic approach in Mexico, the outpatient
administration of blinatumomab infusion in patients with
relapsed/refractory acute lymphoblastic leukemia (R/R ALL).

\textbf{Key words:} acute lymphoblastic leukemia, pediatric, advances,
blinatumomab, treatment, hematopoietic cell stem transplantation.

\textbf{Abbreviations}

ALL Acute Lymphoblastic Leukemia

HSCT Hematopoietic Stem Cell Transplantation

R/R ALL Relapsed/Refractory Acute Lymphoblastic Leukemia

MRD Minimal Residual Disease

HITO Hospital Infantil Teletón de Oncología

\textbf{Introduction}

Acute Lymphoblastic Leukemia (ALL) is the leading cause of cancer in the
pediatric population in Mexico.\textsuperscript{1,2} A significant
percentage of these patients drop out of treatment, being this and
relapses the most common cause of treatment failure. The intensification
of conventional chemotherapy has improved the survival of patients with
ALL; however, it involves a high rate of toxicity and
death.\textsuperscript{3} Significant advances in targeted immunotherapy
and molecular therapeutics, as well as in risk stratification for
therapy based on germline somatic genetic analysis and minimal residual
disease (MRD) monitoring, have enabled the development of targeted and
effective immunotherapies in its treatment, managing to reduce the
intensity and toxicity associated with conventional
chemotherapy.\textsuperscript{4,5,6} Blinatumomab is a low-toxicity
immunotherapy, but it does not maintain prolonged
remissions;\textsuperscript{7} while Hematopoietic Stem Cell
Transplantation is a cellular immunological treatment that allows more
prolonged remissions.\textsuperscript{8,9,10,11.}

The administration of Blinatumomab before HSCT reduces MRD, and has
favorable results in leukemia-free survival, toxicity, and overall
survival. It provides a complete response rate of up to 40\% in second
or third relapses and contributes substantially to long-term remission
of the disease, proving to be a useful treatment alternative in patients
with R/R ALL. \textsuperscript{12, 13, 14,15,16,17.}

\textbf{Aim}

To evaluate the use of Blinatumomab and HSCT as treatment in ambulatory
patients with refractory acute lymphoblastic leukemia in terms of
overall survival and disease-free survival in pediatric patients treated
at Hospital Infantil Teletón de Oncología (HITO).

\textbf{Materials and methods}

We conducted a retrospective, longitudinal, observational, descriptive
study where we considered variables such as: age, gender, percentage of
bone marrow blasts in relapse, extramedullary disease, and complete
remission prior to blinatumomab administration. The number of
blinatumomab cycles received and complications such as: infections,
cytokine release syndrome, overall survival rate, disease-free survival
rate, and cause of death. Pediatric patients between 0 and 18 years of
age with a diagnosis of ALL (R/R), treated with blinatumomab and HSCT
treated at HITO were included (Table 1). A multidisciplinary team
composed of physicians, nurses, and pharmacists was created to address
administration challenges associated with blinatumomab infusions.
Although blinatumomab requires a 28-day continuous infusion, it is not
necessary for patients to remain hospitalized for the entire cycle. To
ensure tolerability prior to discharge, patients are monitored closely
during the first 3 days of Cycle 1 for signs of cytokine release
syndrome and neurological toxicities. Once discharged to the shelter,
next to the hospital, the patients remain under supervision, where we
check them every 72 hours for infusion pump bag change.

The population was non-randomized, consecutively diagnosed with ALL
(R/R) according to hospital records from January 1\textsuperscript{st},
2015, to June 1\textsuperscript{st}, 2020. Statistical analysis was
performed using SPSS version 25.0 software. All transplants were
performed with informed consent signed by the responsible of the
patients under 18 years of age.

\textbf{Results~~}

Blinatumomab was administered as treatment for R/R ALL prior to HSCT in
9 patients (Table 1). The mean age at the time of administration was
10.1 years with a SD ±4.84. The distribution of cases by gender
corresponds to 66\% women (n= 5) and 44\% men (n=4). All patients had an
oncological diagnosis of ALL and 100\% of them presented refractoriness
and/or relapse. In the evaluation prior to the administration of
Blinatumomab, 88.8\% of the patients presented positive MRD (N=8) and
11.2\% of the negative cases (N=1). No patient had extramedullary
disease, the number of cycles of Blinatumomab received to achieve
complete remission and negative MRD were different; 4 patients received
1 cycle (44\%), 3 patients received 3 cycles (33\%), and 2 patients
received 2 cycles (22.2\%), 56\% of the cases achieved deep complete
remission at the end of treatment or at the last consultation, 12\%
achieved a first complete remission with one blinatumomab cycle and 88\%
required a second or third cycle to achieve it.

Complications: 33\% of the patients presented Cytokine Release Syndrome
(n=3), with 22\% being moderate grade and the most frequent (n=2) and
11\% mild (n=1). 2 were admitted to the Pediatric Intensive Care Unit.

A 3-year disease-free survival and overall survival of 55\% was
determined (Graph 1). Brown and cols conclude that the comparing high
and intermediate risk first relapse of B-ALL, post reinduction treatment
with blinatumomab compared with chemotherapy followed by transplant is
not statistically significant with disease free survival. Our series
includes only refractory ALL patients which represent a very positive
result. Adverse events are like the ones described in the literature.

\textbf{Discussion~}

Acute lymphoblastic leukemia is the most common type of cancer in
children and unfortunately, about 15\% of children with high-risk B-ALL
relapse after chemotherapy treatment, so there is a need for new
treatment options for these patients.\textsuperscript{18} Blinatumomab
is an adequate bridge therapy to consolidate with transplantation in
these patients, since it has been shown to be more effective and is
associated with a lower number of toxicities and less severe
complications, compared to intensive chemotherapy, allowing to obtain
favorable hematological conditions for the performance of a transplant
in terms of complete remission and residual disease, with satisfactory
clinical tolerance, however, it is a treatment of high cost and
difficult access for developing countries, such as Mexico. This series
of patient cases represents a clear example of this situation. HITO is
the unique specialized pediatric cancer hospital in Mexico. It was
inaugurated in 2013 and began offering the HSCT service in 2014. At the
beginning the number of HSCT procedures were approximately 4 to 5 per
year. Through the years, this has been changing for the better, growing
and improving the quality of care, allowing us to offer HSCT services to
more patients. In 2019, the opportunity arises to introduce blinatumomab
as a treatment in our institution. Nine patients were included in the
present study. Comparing our results with other series is difficult;
mainly because of the number of patients and because we do not randomize
them. However, comparing the overall survival of these patients with
those who do not have access to blinatumomab, as is the case with most
of the patients in developing countries, the use of blinatumomab gives
us a better prognosis and clearly a statistically better incentive for
our country and institution. Probably all patients with positive MRD
would have died. The international literature describes an overall
survival of 2 years with blinatumomab use of 71. 3\% versus 58.4\%
without the use of it.\textsuperscript{19}

\textbf{Conclusion}

Despite important advances in the treatment of ALL, HSCT remains the
therapy of choice for patients with failed induction in first remission,
relapsed, and refractory. Administering Blinatumomab prior to HSCT with
the goal of achieving a negative MRD, deep molecular remission provides
a favourable prognosis with better leukemia-free survival rates, overall
survival, and less toxicity. The highlights are that 100\% of the
patients went into remission after Blinatumomab infusion and there was
no mortality associated. Our results represent an innovation in Mexico
for pediatric patients with refractory ALL and a background to generate
experience in a medical group.

TABLE 1: Outpatient administration of Blinatumomab Infusion and
Hematopoietic Stem Cell Transplantation as Treatment for Patients with
Refractory Acute Lymphoblastic features. 2015-2020. Hospital Infantil
Teleton Oncologia.\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{No.}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{AGE}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{GENDER}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{MRD}\\
\textbf{IR / RR}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{MRD BLIN}\\
\textbf{Cycle 1}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{MRD BLIN}\\
\textbf{Cycle 2}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{MRD BLIN}\\
\textbf{Cycle 3}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{1}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
24.56\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{2}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6.12\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{3}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
18.6\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.21\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textless{}0.01\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{4}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.21\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{5}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
6.8\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textless{}0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textless{}0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textless{}0.01\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{6}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{7}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
21.4\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.85\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0,01\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{8}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.37\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.02\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.51\%\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0.01\%\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{9}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4.77\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}0.01\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

GRAPH 1: Outpatient administration of Blinatumomab Infusion and
Hematopoietic Stem Cell Transplantation as Treatment for Patients with
Refractory Acute Lymphoblastic overall survival at 3 years follow up.
2015-2020. Hospital Infantil Teleton Oncologia.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Conflicts of interest~}

None of the authors have a conflict of interest to disclose.

\textbf{Acknowledgments}

None.

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