The study aims to limit the use of anthracyclines and to reduce the dose of ATRA. Another aim is to stratify treatment by risk group: standard risk - WBC <10 x 109/l : high risk - WBC >=10 x 109/l. Furthermore this study aims to…
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main endpoints will be:
•Achievement of molecular complete remission (CRm) and reasons for failure
•Duration of remission, rates of molecular and frank relapse and deaths in
first CR
•Overall survival
•Toxicity - hematological and non-hematological
•Supportive care requirements
Secondary outcome
To decrease long term effects of treatment such as cardiac toxicity
Background summary
Acute Promyelocytic Leukemia (APL), FAB classification M3 or M3v, represents
approximately 4-8% of pediatric AML but the incidence may be higher in children
of Hispanic and Mediterranean origin. The median age at presentation is
probably similar to that of other AML subtypes (7-9 years), but APL has rarely
been reported in the first year of life. It can arise de novo or be therapy
related (t-APL). The characteristics and outcome of t-APL appear similar to
those of de novo APL.
APL is characterized by chromosomal rearrangements of 17q21 involving the gene
encoding the Retinoic Acid Receptor Alpha (RAR*), which is most commonly fused
to the PML gene (ProMyelocytic Leukemia) as a result of the t(15;17)(q22;q21)
translocation. In a minority of cases (<5%), RAR* is fused to an alternative
partner, which in the pediatric setting is most commonly nucleophosmin (NPM1)
resulting from the t(5;17)(q35;q21) translocation. This subtype and that
involving NuMA as a result of t(11;17)(q13;q21) are sensitive to retinoic acid;
whereas APL involving PLZF and STAT5b as a result of t(11;17)(q23;q21) and
interstitial deletion of chromosome 17, respectively are resistant to ATRA.
While the outcome of APL patients with the PML-RAR* fusion treated with
extended courses of ATRA in combination with anthracycline-based chemotherapy
is generally favorable, pediatric patients appear to more commonly present with
hyperleukocytosis, as compared to their adult counterparts. Approximately
35-40% of children with APL fall within a high risk group defined by a
presenting WBC >=10 x 109/L, which is associated with M3v morphology, presence
of FLT3 length mutations and predicts for poorer outcome. This is due both to
an increased risk of induction death, particularly as a result of hemorrhage,
as well as a significantly higher rate of relapse. Using ATRA and anthracycline-
based chemotherapy protocols followed by maintenance with ATRA, 6-MP and
methotrexate, relapse rates for patients with a WBC <10 x 109/L at diagnosis
are typically 10% or less, while rates may exceed 20% for patients with a WBC
>=10 x 109/L.
The results from the Gimema-AIEOP-AIDA 93 trial demonstrate that the combined
use of ATRA and anthracyclines is well tolerated and highly effective in
children, therefore this ICC APL study will be based on this trial.
APL is a rare disease with each national group recruiting small numbers of
patients to their trials annually. Therefore this will be an international
study expecting to recruit 60-70 patients per annum and a total of 300 patients
in 5 years.
Study objective
The study aims to limit the use of anthracyclines and to reduce the dose of
ATRA. Another aim is to stratify treatment by risk group: standard risk - WBC
<10 x 109/l : high risk - WBC >=10 x 109/l. Furthermore this study aims to
monitor minimal residual disease by RQ-PCR for PML-RARα and adjust treatment
accordingly
Study design
The ICC APL Study 01 is a non-randomized multicenter study delivering risk
stratified treatment based on the Gimema -AIEOP/AIDA 93 protocol.
Intervention
1.All patients who enter the study must be PCR positive for the PML-RAR*
transcript (or have another retinoid sensitive subtype of APL, i.e. NPM-RAR* or
NuMA-RAR*). However, treatment and study entry should be based on suspicion of
M3 or M3v morphology. As APL is a hematological emergency, treatment should
not wait for cytogenetic and/or molecular confirmation, and ATRA should be
started as soon as the diagnosis is suspected.
2.Patients are risk-stratified at diagnosis by modified Sanz criteria; standard
risk (SR) - WBC < 10 x 109/l: high risk (HR) - WBC =/> 10 x 109/l.
3.ATRA is included in induction, consolidation and maintenance therapy.
4.Following one induction course of treatment standard risk patients have 2
consolidation blocks whilst high-risk patients have 3 consolidation blocks.
5.Intermediate Dose Ara-C (IDARAC) is given during consolidation.
6.Standard risk patients who are RQ-PCR+ for PML-RAR* transcript at the end of
the second consolidation block will receive a third consolidation block
identical to the high risk patients.
7.Patients who are RQ-PCR+ for PML-RAR* transcript after completion of the
third block of consolidation therapy will be candidates for the refractory
/relapsed strategy involving arsenic trioxide+/- GO+/-ATRA.
8.Refractory/ relapsed patients who remain RQ-PCR+ for PML-RAR* transcript
will be candidates for allo-BMT, whilst those who are RQ-PCR- for PML-RAR*
transcript will have individualised treatment with ongoing MRD monitoring.
9.Isolated CNS relapse will be treated with systemic and intrathecal
chemotherapy.
Study burden and risks
To get cured, children with APL must be treated. The extent of burden and risks
associated with this treatment are not different than other treatments used
untill now in the Netherlands. This treatment protocol has strict stopping
rules and safety guidelines.
Leyweg 299
den Haag 2545 CJ
NL
Leyweg 299
den Haag 2545 CJ
NL
Listed location countries
Age
Inclusion criteria
- Patients with a clinical diagnosis of initial APL and subsequently confirmed to have PML-RARα, NPM1-RARα or NUMA-RARα fusion. Whilst this study is only for ATRA-sensitive APL, APL is a hematological emergency and ATRA should be commenced as soon as the diagnosis is suspected. Study entry should not wait until the diagnosis of APL has been confirmed molecularly or cytogenetically
- Less than 21 years of age at initial diagnosis
- Considered suitable for anthracycline-based chemotherapy
- Written informed consent available
- Females of childbearing age must have a negative pregnancy test and subsequently must attempt to avoid pregnancy
Exclusion criteria
- Patients with a clinical diagnosis of APL but subsequently found to have PLZF-RARα fusion or lacking PML-RAR*, NPM-RAR* or NuMA-RAR* rearrangement should be withdrawn from the study and treated on an alternative protocol.
- Refractory/relapsed APL (the guidelines in this protocol for that subgroup are intended for patients treated from initial diagnosis according to this protocol)
- Concurrent active malignancy
- Pregnant or lactating
- Physician and patient/guardian think that intensive chemotherapy is not an appropriate treatment option
- Patients who have received alternative chemotherapy for 7 days or longer without ATRA for any reason (either APL not initially suspected or ATRA not available).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR200800231140-NL |
CCMO | NL31836.029.10 |