Allogeneic Stem Cell Transplantation (SCT) for children and adolescents with acute lymphoblastic Leukaemia (ALL)

Patients with high risk or relapsed acute lymphoblastic leukaemia (ALL) have a
poor prognosis. For these patients intensive therapy is required after they
have achieved remission with multimodal chemotherapy. Allogeneic hematopoietic
stem cell transplantation (HSCT) can effectively induce immunological
antileukaemic control in patients with ALL by means of the
graft-versus-leukaemia effect (GvL), but treatment related mortality (TRM),
morbidity and late effects remain serious problems of this treatment modality.
In the last decade the short term outcome of children with ALL who received
allogeneic HSCT has improved, due to the use of donors more closely matched by
Human leukocyte antigen (HLA) typing, resulting in less severe graft vs host
disease (GvHD) and better supportive care. However, the risk of life long
complications persists in all children.

In addition, the group of patients who do not identify a HLA compatible donor
is still faced with a HR for life threatening transplantation associated
complications. Therefore, this study attempts to explore the possibility,
whether children with an indication for an allogeneic HSCT can benefit from
omitting TBI and if children without a compatible donor could be successfully
rescued with stem cell from alternative donors.

Update 21-MAY-2019: Interim analysis of this study showed a superior EFS and OS
in the TBI/VP16 arm. Randomisation stopped. TB/VP16 is the standard treatment
in The NL after this interim analysis.

Total Body Irradiation (TBI): for decades TBI has been the most frequently
applied myeloablative and immunoablative procedure before HSCT in patients with
ALL. Most centres use fractionated TBI to reduce acute side effects, such as
nausea and vomiting, and late effects, such as cataracts. Lung shielding is
also widely used to prevent severe non infectious pneumonitis. In Europe, most
centres do not irradiate children below the age of 2 years due to the
deleterious effects on the developing brain. However, the biggest burdens for
children given TBI are the risks of secondary malignancies, growth retardation
(especially if irradiated below 10 years) and infertility (most common after
irradiation during or after puberty). To date, it has not been shown that TBI
in the conditioning regimen for childhood ALL can be replaced by chemotherapy.

Etoposide (VP16): For many groups the standard chemotherapy conditioning was
cyclophosphamide in combination with TBI. Dopfer et al. and the recent BFM- and
BFM international studies have shown better results with a conditioning regimen
consisting of TBI/VP16. Therefore, the comparator for the study questions
consists of a conditioning with TBI/VP16 for children above 4 years.

Intravenous Busulfan (ivBU) in children:
IvBu is licensed for use in children and is the most common myeloablative
chemoconditioning for paediatric HSCT in non malignant diseases. Since the
availability of ivBu, numerous studies have demonstrated the safety,
feasibility and engraftment efficacy in children with malignant and non
malignant disease. Sanz et al have published their experience of using a
combination of Bu, Flu and Thiotepa for patients with haematological
malignancy. The doses are the basis of those used in this protocol.

Fludarabine (Flu):
Fludarabine, a purine analogue with potent antitumor and immunosuppressive
activity, is a common component of conditioning regimens before allogeneic non
myeloablative HSCT in children. Its immunosuppressive properties promote
engraftment, development of donor chimerism and GvL effects.

Thiotepa
Thiotepa is a bialkylating highly lipid soluble agent with both myeloablative
and immunosuppressive activity in haematological malignant disease. Apart from
its use at high doses for patients with CNS tumours, it has been widely used as
an additional agent to promote engraftment in allogeneic transplantation for a
variety of non-malignant condition and also to promote the anti-leukaemic
efficacy in TBI-based regimens. Most recently, it* use has been reported in
combination with Bu and Flu for patients with malignancy (Sanz).

This study has been transitioned to CTIS with ID 2024-512657-24-00 check the CTIS register for the current data.

Stratum 1:
To show that a non total body irradiation (TBI) containing conditioning
(Flu/Thio/ivBu) results in a non inferior survival as compared to conditioning
with TBI/Etoposide in children older than 4 years after HSCT from a Human
leucocyte antigen (HLA) identical sibling donor (MSD) or a HLA matched donor
(MD).
Update 21-05-2019: randomisation related question was closed in December 2018;
patients are in active follow-up:

Update 21-05-2019:
Stratum 1 - MSD/MD: To explore the impact of risk factors on the
incidence of adverse events of special interest (AESIs) and on overall
survival and event free survival in the entire MSD/MD cohort (question 3
and 5) .

Stratum 2:
To explore event free survival (EFS) after HSCT from HLA mismatched donors
using mismatched unrelated donors (MMD), mismatched cord blood or HLA
haplo-identical family.

Update 21-05-2019: Randomisatie closed. Participants receive standard
treatment, registration of treatment, outcome, toxicity and late effects.

The ALL SCTped 2012 FORUM is a multinational, multi-centre, randomized,
controlled, prospective phase III study for the therapy and therapy
optimisation for children and adolescents with ALL in complete remission, who
have an indication for Allogeneic Hematopoietic Stem Cell Transplantation
(HSCT) with a myeloablative conditioning regimen.
The stratification and randomisation of patients in first and following
remission according to the individual transplantation modalities rests upon an
indication for allogeneic HSCT AND on the availability of a suitable donor
within the individual transplantation groups.

Randomisation will be performed in the web-based study database.
Eligibility for randomisation (to TBI or not) is as follows:
• Fullfills all study entry criteria, including signed informed consent for
randomisation
• Age 48 months or more (Less than 48 months - chemo arm only)
• Donor is MSD or MD donor (MMD -non-randomly allocated to chemo arm)
• Past cranial irradiation exposure is either:
18Gy or less if more than 24 months ago
12Gy or less if less than 24 months ago
• No active CNS disease
• No ALL with extramedullary involvement with indication for TBI
• No Trisomy 21

In case of refusal of the randomisation the patient is treated according to the
standard arm (i.e. TBI/VP16).

A conditioning regimen is mandatory in all cases; this protocol studies the way
of conditioning.

Acute and late side effects of TBI in combination with VP16 are manifold to the
growing organism and include severe organ dysfunction/failure due to toxicity.
Although transplant associated mortality was reduced after HSCT in the last
decade due to better HLA matching, infection prevention and control, the burden
of late complications is still a matter of concern. Growth retardation,
hormonal dysfunction, sterility and the risk of secondary cancer are the late
consequences of TBI in children. However, so far no prospective study has
demonstrated similar outcomes in paediatric ALL using chemo-conditioning
regimen before HSCT. Therefore, this study aims to explore the efficacy and
efficiency of a chemo-conditioning regimen (Flu/Thio with ivBu) in comparison
to the standard conditioning regimen (TBI/VP16). The potential benefit for
children and adolescent not receiving TBI are less severe acute organ toxicity
due to reduced inflammation processes, less severe gonadal damage and
especially a reduced risk for secondary malignancies. The potential risk for
patients not receiving TBI for a highly aggressive leukaemia is relapse after
HSCT. However, we anticipate an immunological disease control by the graft as
most of the patients will receive non T-cell depleted transplants. In addition,
there will be a chance for patients relapsing after a chemotherapy conditioning
to receive TBI prior to a second allograft. Although all components of the
chemoconditioning have been used for years in children undergoing HSCT, the
combination of Flu/Thio/ivBu have not been explored in larger trials for
paediatric ALL and side effects have to be carefully followed.