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\begin{document}

\title{Combining Brentuximab Vedotin with dexamethasone, high-dose cytarabine,
and cisplatin (BV-DHAP) as salvage treatment in paediatric relapsed or
refractory classical Hodgkin lymphoma: two case reports.}



\author[1]{Carmen Sinisi}%
\author[2]{Paola Muggeo}%
\author[2]{Rosa Angarano}%
\author[2]{Rosa Maria Daniele}%
\author[2]{Massimo Grassi}%
\author[2]{Nicola Santoro}%
\affil[1]{Universita degli Studi di Bari Aldo Moro Scuola di Medicina}%
\affil[2]{Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\selectlanguage{english}
\begin{abstract}
Hodgkin Lymphoma (HL) is a common malignancy in adolescents. For
relapsed/refractory disease many regimens have been proposed and novel
agents are increasingly used. Brentuximab Vedotin (BV) is an antiCD30
antibody-drug conjugate used as single agent or in combination with
classical regimens mainly in adults, while limited is the experience in
paediatrics. We report here on two boys with aggressive and high-risk
relapsed HL, successfully treated with the BV plus DHAP regimen as
induction salvage treatment. Our experience provides initial real-world
evidence on the use of BV-DHAP as first-line salvage therapy for
high-risk relapsed/refractory HL and expands the current therapeutic
choices.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Hodgkin Lymphoma (HL) is one of the most commonly occurring malignancies
in adolescents and young adults, curable in the majority of cases.
Unfortunately, a subgroup of patients do not enter remission with front
line therapy or relapse after initial response to therapy (R/R cHL). In
such cases, treatment options are different regimens of chemotherapy,
radiotherapy, high-dose chemotherapy plus autologous stem cell
transplantation (HDCT/ASCT), and immunotherapy\textsuperscript{1,2}.
Many regimens have been proposed\textsuperscript{1} and recently novel
agents are increasingly involved in order to achieve a better response
without increasing the toxicity burden. Brentuximab Vedotin (BV) is an
antibody-drug conjugate combining the anti-CD30 monoclonal antibody with
the monomethyl auristatin-E. Studies are evaluating the combination of
BV with classical regimens mainly in adults, while limited is the
experience in paediatrics.

Recently a phase II study\textsuperscript{3} investigated for the first
time BV plus the DHAP regimen as salvage therapy in adults, with
encouraging results. The experience with this regimen in children or
adolescent has not been described so far.

\textbf{Results}

We report here on two boys with high-risk relapsed HL, successfully
treated with the BV-DHAP regimen as induction salvage treatment.

\textbf{Case Description n.1}

A 15-year-old boy presented classical-HL, advanced stage (IVB) and
started treatment according to the EuroNet-PHL-C2 protocol, TL-3. After
two OEPA cycles, the PET/CT scan for the early response assessment (ERA)
showed partial metabolic response (pMR) with Deauville Score (DS) 5. He
went on with 4 DECOPDAC-21 cycles. Late response assessment (LRA) PET/CT
scan showed slight residual uptake in the mediastinum, requiring
mediastinal residual node radiotherapy (28.8 Gy). The three-month
follow-up CT scan showed pulmonary nodules (19mm diameter); the PET/CT
revealed high metabolic uptake in the lungs and in multiple
supra-diaphragmatic adenopathies. After repeated biopsies, insufficient
to confirm the suspect of relapsed disease, the pulmonary biopsy
confirmed the diagnosis of R/R cHL. According to the EuroNet-PHL
recommendations\textsuperscript{1}, this patient was candidate to
HDCT/ASCT. Considering published data in adults\textsuperscript{3}, we
decided to take a chance on salvage induction chemotherapy regimen
adopting the BV plus DHAP regimen (figure 1) followed by HDCT/ASCT. The
boy collected successfully hematopoietic stem cells after one cycle.
After 2 cycles, the interim PET/CT revealed complete metabolic response
(cMR), DS2. After 4 BV-DHAP the PET/TC showed no pathological uptake.
The patient then proceeded to HDCT/ASCT. Hematological toxicity grade
3-4 was reported without any particular adverse event (AE) during the
BV-DHAP administration. Considering the high\textbf{-} risk disease, BV
consolidation program (12 doses) was added. The boy is in complete
remission and good clinical conditions at 36-month follow-up.

\textbf{Case Description n.2}

A 13-year-old boy was diagnosed with cHL stage IIBE, bulky disease,
extranodal involvement of pleura and enrolled in the EuroNet-PHL-C2
study, TL-3. The ERA-PET, after 2 OEPA, showed pMR with DS-5. Four
DECOPDAC-21 cycles were performed and the LRA-PET showed the complete
disappearance of the pathological uptake. One month later, the patient
presented Covid-19 and, shortly after, enlargement of left axillary
lymphnodes. The excisional biopsy showed no evidence of the disease.
However, because of the persistence of the axillary lymphadenopathy,
high fever and deteriorated clinical conditions, a new biopsy confirmed
relapsed cHL, stage IVB (bone marrow involvement). Based on our previous
experience, considering the high risk of the disease, the patient
started with BV-DHAP as salvage therapy. The clinical conditions
recovered. The interim PET/CT evaluation showed pMR, DS-3; the BM
trephine confirmed absence of HL, and stem cell apheresis was
successfully performed. The patient proceeded with two further cycles of
BV-DHAP. At this moment the disease assessment showed persistent pMR.
With the aim to obtain complete metabolic response before HDCT/ASCT, and
taking into account the good clinical conditions of the patient, 2
cycles of BV-Bendamustine\textsuperscript{4} regimen were delivered.
Haematological toxicity grade 3-4 without any particular adverse event
was reported. The pre-ASCT PET/TC scan evaluation showed a cMR and the
boy proceeded to HDCT/ASCT. Considering the features of high-risk
disease, the patient started consolidation treatment with 12 doses of
BV. At the time of this writing, after 12-month follow-up, the boy is in
good clinical conditions free of disease.

\textbf{Discussion}

The standard of care, both in adults and paediatric patients, for risk
R/R cHL is the HDCT/ASCT\textsuperscript{1}. Achieving cMR before the
HDCT/ASCT has been demonstrated as the most impactful factor affecting
DFS and OS\textsuperscript{5,6,7,8,9}. For this reason, identifying the
best rescue therapy represents the most important challenge. There is no
``gold standard'' chemotherapy regimen because no randomized trials have
been done on children or adolescent; the overall response rates (ORR) of
salvage regimens vary between 70\% and 90\%\textsuperscript{1,10}.

The DHAP regimen has been extensively studied as rescue therapy in
high-risk Hodgkin and non-Hodgkin lymphomas with optimal relationship
between efficacy and toxicity, in particular ORR of 88\% (21\% CR, 67\%
PR) in R/R cHL has been reported\textsuperscript{11,12,13}. Novel agents
like BV have gained an increasing role in R/R cHL. The use of BV as
single agent for the salvage therapy is reported in adults with ORR of
75\%, CR 34\%, with manageable toxicity\textsuperscript{14}. Better
results have been achieved combining classical chemotherapy regimens and
BV\textsuperscript{1}. Despite the widespread use of BV in adults and
the large number of prospective and retrospective studies, there are few
data on efficacy and safety in paediatrics. The initial experience of BV
in pediatric patients with R/R cHL showed 47\% ORR\textsuperscript{15}.
A retrospective multicentric italian real-life study on 66 young
patients demonstrated the efficacy of BV single agent or combined with
chemotherapy in R/R cHL with manageable toxicity\textsuperscript{16}.
Recently the combination regimen of BV-bendamustine in pediatric
patients reported ORR of 81\%\textsuperscript{17}. In adults the phase
II HOVON/LLPC Transplant BRaVE study investigated the combination BV
plus DHAP achieving cMR in 42/52 (81\%) evaluable patients and pMR in 5
(10\%), with ORR of 90\%. After a median follow-up of 27 months, the
2-year PFS by intention-to-treat was 73.5\%, and the 2-year OS was
94.9\%\textsuperscript{3}. This combination has not been investigated in
the pediatric setting, so far. In our experience the BV-DHAP regimen
resulted highly effective. The patients we reported on were both
characterized by rapid progression and high burden of disease leading to
a stage IVB bulky disease in about a two-month lapse. Considering the
high-risk disease, our previous experience with DHAP and the encouraging
data of BV-DHAP in adults we decided to adopt this regimen. We gained
disease control and cMR before the HDCT/ASCT. Furthermore, monitoring
haematological toxicity, liver and renal function, ototoxicity and
neurotoxicity we found a lower rate of AEs than reported in adults. Both
patients did not experience any important AE, exception for a grade
II/III neutropenia, and a mild hepatotoxicity. None of these events was
likely to cause treatment discontinuation. We then decided to start
maintenance with BV following the results of the AETHERA
trial\textsuperscript{18}. This choice was also possible because of the
low degree of toxicity shown during the previous cycles.

In conclusion, in our experience in two adolescent patients with R/R
cHL, the BV-DHAP regimen resulted highly effective to obtain mCR prior
to HDC/ASCT in very high risk and aggressive disease. Patients should be
closely monitored for toxicity, especially hematological toxicity. Our
experience provides initial practical and real-world evidence in favour
of the use of BV-DHAP as first-line salvage therapy for high-risk
relapsed/refractory HL. This regimen expands the currently existing
therapeutic choices making BV-DHAP a suitable salvage therapy.

\textbf{Conflict of interest}

None of the authors has any conflicts of interest to declare.

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\textbf{LegendsFigure 1} Schematic overview of the BV-DHAP regimen.
Drugs with their dosage are indicated on the left. Cycles were delivered
every 21 days

\textbf{Table 1} Clinical characteristics of the two patients\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{FIGURE 1} Schematic overview of the BV-DHAP regimen. Drugs with
their dosage are

indicated on the left. Cycles were delivered every 21 days.

Note: Granulocyte colony-stimulating factor (G-CSF) was given at a dose
of 5\selectlanguage{greek}µ\selectlanguage{english}g/kg from day 4 until day 13 to respect the dose-intensity.

\textbf{TABLE 1} Clinical characteristics of the two patients\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& \textbf{Patient 1} & \textbf{Patient 2}\tabularnewline
\midrule
\endhead
\textbf{Ann Arbor stage at diagnosis} & IVB & IIBE\tabularnewline
\textbf{Prior therapies} & 2 OEPA+4 DECOPDAC-21 and RT & 2 OEPA+ 4
DECOPDAC-21\tabularnewline
\textbf{Time to relapse} & 4 months & 4 months\tabularnewline
\textbf{Ann Arbor stage at relapse} & IVB & IVB\tabularnewline
\textbf{Risk factors at relapse*} & Early relapse after more than 4
cycles of first line chemotherapy; Stage IV relapse & Early relapse
after more than 4 cycles of first line chemotherapy; Stage IV
relapse\tabularnewline
\textbf{Salvage treatment} & 4 BV-DHAP followed by HDCT/ASCT & 4
BV-DHAP+ 2 B-BV followed by HDCT/ASCT\tabularnewline
\textbf{Medium time of delivering (days) of chemotherapy**} & 21-23 &
21\tabularnewline
\textbf{Best response at salvage treatment} & CR & CR\tabularnewline
\textbf{Follow up (DFS)} & 36 months & 15 months\tabularnewline
\bottomrule
\end{longtable}

*Risk factors according to the EuroNet-PHL criteria

** According to hematological recovery (Absolute neutrophil count
\textgreater{}1x10\textsuperscript{9}/L and platelets count
\textgreater{} 1x10\textsuperscript{9}/L)

\selectlanguage{english}
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