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\begin{document}

\title{Peripheral Blood Stem Cell Mobilisation with Pegylated Granulocyte
Colony Stimulating Factor in Children}



\author[1]{Dhwanee Thakkar}%
\author[1]{Aseem Tiwari}%
\author[1]{Swati Pabbi}%
\author[1]{Rohit Kapoor}%
\author[1]{Geet Aggarwal}%
\author[1]{Neha Rastogi}%
\author[1]{Satya Yadav}%
\affil[1]{Medanta The Medicity}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\begin{abstract}
Aim:We report here our experience of using pegylated granulocyte colony
stimulating factor (peg-GCSF) for peripheral blood stem cell (PBSC)
mobilisation in children. Methods: A total of 9 children suffering from
high-risk/relapsed solid tumors were mobilised with chemotherapy and
peg-GCSF (100 microgram/kg single dose). Mean age was 7.7years (range
2-15 years). Results:The mean time from peg-GCSF administration to PBSC
harvest was 9.7 days. Adequate stem cells (median dose 26.9 million/kg)
could be harvested in all children by a single apheresis procedure. No
major adverse events observed. Conclusion: It is feasible and safe to
mobilise PBSC with peg-GCSF in children with cancer.%
\end{abstract}%



\sloppy


\textbf{Introduction}

High dose chemotherapy followed by Autologous hematopoietic stem cell
transplant (HSCT) is a part of treatment regimens for many newly
diagnosed and relapsed malignancies in children (1,2). These autologous
HSCT are most commonly performed using peripheral blood stem cells
(PBSC) (2-5). Various methods are known to be effective for PBSC
mobilisation including chemotherapy combined with granulocyte-colony
stimulating factor (GCSF) for these patients (2,3,5,6). The conventional
recombinant human GCSF has a short half-life (\textasciitilde{}3.5
hours) and hence needs repeated administration which is quite painful
for the child and also requires multiple hospital visits. The pegylated
GCSF (Peg-GCSF) is a longer acting version of GCSF and has a half-life
ranging from 15 to 80 hours after a subcutaneous injection (7-9).

Peg-GCSF is a covalent conjugate between the N-terminal methionyl
residual of GCSF and mono-methoxy polyethylene glycol (Peg) moiety.
Addition of Peg moiety to GCSF increases its molecular weight and size
which results in decreased renal clearance by glomerular filtration.
With this, the primary mode of elimination of Peg-GCSF remains to be
neutrophil mediated clearance (7,8). Published studies have shown that a
sustained low level of GCSF is better than short pulse-like level to
mobilize PBSC. Hence, Peg-GCSF, might be superior to conventional GCSF
in PBSC harvest in this aspect (9).

Most of the experience with Peg-GCSF comes from its use for prophylaxis
and treatment of chemotherapy associated neutropenia in children and
adults as well as for PBSC mobilisation in adults (9-14). There is
paucity of literature of successful use of Peg-GCSF and its appropriate
dosing for PBSC mobilisation in children (1,6,15-17). We report our
experience of PBSC mobilisation with Peg-GCSF in 9 children.

\textbf{Methods}

We carried out a retrospective analysis of hospital records of children
who received Peg-GCSF for PBSC mobilization between May 2016 to
September 2020 in our unit. All children received single subcutaneous
dose of Peg-GCSF 100 microgram/kg 24-48 hours after completion of
mobilisation chemotherapy and proceeded to PBSC harvest once CD34 count
was \textgreater{}10/microliter in the peripheral blood. All PBSC
collection were performed on COMTEC (Fresenius Kabi, Germany) apheresis
machine. The product sample was taken at the end of PBSC collection from
the apheresis collection bag for enumerating CD34 count in the final
product. The stem cells were cryopreserved for autologous transplant.
Patients were monitored for possible adverse effects of Peg-GCSF viz.
bone pain, headache, skin rash, transient hypotension, splenic
enlargement, capillary leak syndrome characterized by puffiness,
difficulty in breathing, decreased urine output (1,6,13,15).

\textbf{Results}

Out of all the patients in our unit who underwent PBSC mobilization and
autologous stem cell harvest, 9 received chemotherapy followed by
Peg-GCSF. Male: Female ratio was 3.5:1 and the mean age was 7.7years
(range 2-15 years). There were 3 cases of stage 4 Neuroblastoma and one
each of metastatic Ewing's sarcoma, metastatic Germ cell tumor of ovary,
recurrent anaplastic Ependymoma, relapsed Wilms tumor, relapsed
Osteosarcoma and relapsed Medulloblastoma. The data on demographic
profile, diagnosis, mobilisation chemotherapy, harvest details is shown
in Table I. The mean time from Peg-GCSF administration to PBSC harvest
was 9.7 days (range 8-12 days) and from start of mobilization
chemotherapy to PBSC harvest was 12.2 days (range 10-15 days). 2
patients required one dose of GCSF boost the day before harvest. All 9
patients harvested with single apheresis procedure. The median CD34
count at the start of harvest was 203/microliter (range
30-490/microliter). The median CD34 hematopoietic stem cell count
collected was 26.9 million/kg (range 4.1-60 million/kg) recipient
body-weight. The mean product volume collected was 152ml (range
70-250ml). None of the patients had any major adverse events. The median
duration of follow-up for these patient's post-harvest was 6 months
(range 4-38 months).

With regard to the outcome data, 1 patient couldn't reach autologous
HSCT due to progression of disease. Remaining children engrafted after
autologous hematopoietic stem cell infusion and all had a brisk
engraftment. Neutrophil engraftment occurred at a median of 9.5 days
(range 8-12 days) post autologous HSCT; Platelet engraftment occurred at
a median of 11.5 days (range 10-23 days) post autologous HSCT.
Transplant related mortality was nil. Two children relapsed after
autologous HSCT.

\textbf{Discussion}

The Peg-GCSF has a longer half-life requiring a one-time administration
as compared to conventional recombinant human GCSF which has a short
half-life and hence requiring daily administration. This makes it more
tolerable and acceptable for children (7-9). Peg-GCSF also provides a
sustained drug level as compared to pulse like levels with GCSF which is
more effective for PBSC mobilization (9).

Most of the experience with Peg-GCSF comes from its use for prophylaxis
and treatment of chemotherapy associated neutropenia in children and
adults as well as for PBSC mobilization in adults. There is paucity of
literature of successful use of Peg-GCSF and its appropriate dosing for
PBSC mobilization in children. From the meagre published data, we can
draw conclusion that it is non-inferior to conventional GCSF with regard
to efficacy and safety (1,6,15,16). We have described here our
experience of PBSC mobilization with Peg-GCSF in 9 children. Our
patients received chemotherapy followed by Peg-GCSF and we found in our
cohort a fairly uniform and predictable time to CD34 peak from start of
chemotherapy and from the administration of Peg-GCSF. Also, we were able
to harvest the desired CD34 stem cell dose in single harvest procedure
for all our patients including the ones with relapsed malignancies who
were heavily pretreated and hence deemed poor mobilisers. None of our
patients had any major adverse event. All our patients who received
autologous HSCT had a brisk and robust engraftment.

Fritsch et al. have reported a similar successful and safe harvest
experience among their patient cohort which comprised of first time
diagnosed solid tumor patients as well as relapsed cases. Also, no other
adverse events except leukocytosis had been observed in all their
patients (1). The side effect of leukocytosis was lower in those who
received Peg-GCSF because Peg-GCSF has a predominant neutrophil mediated
elimination and hence its clearance is self-regulating (1,7). Dallorso
et al found a success rate of \textasciitilde{}77\% for PBSC
mobilization with single dose of 100mcg/kg of Peg-GCSF. They also found
that CD34 cell levels more than 20/microliter were first observed in the
peripheral blood at a median of 6 days after Peg-GCSF administration and
they remained sustained above 20/microliter for a median of 6 days. This
points to another appealing aspect of Peg-GCSF that it provides a wider
temporal window for planning harvest in case the peak is apparently
likely to coincide with a holiday (15). Merlin et al reported a success
of 60\% with peg-GCSF. Target dose of 5 million/kg stem cells could be
collected with a single apheresis procedure in only 16 out of 26
children despite using higher dose of peg-GCSF 300 microgram/kg (16). In
our cohort, PBSC could be harvested successfully in 100\% of patients
with a single apheresis procedure. We used lower dose of peg-GCSF 100
microgram/kg in all our patients. Lowest dose of stem cell collected in
our cohort was 4 million/kg.

Peg-GCSF can circumvent the concerns of daily painful GCSF injections
thereby improving the compliance and making the entire experience of
autologous hematopoietic stem cell harvest more tolerable for children.
Our experience highlights that its feasible and safe to mobilise PBSC
with peg-GCSF in children with cancer.

\textbf{Disclosure} -- All authors have nothing to declare. All authors
have contributed to this manuscript. DT wrote manuscript, AT collected
data, SP-Collected data, GA-collected data, RK-reviewed literature, NR-
reviewed literature, SY-wrote manuscript

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