Relapsed Acute Promyelocytic Leukemia Clinical Trial
Official title:
Treatment of Relapsed Acute Promyelocytic Leukemia With Arsenic Trioxide (Phase IV Study)
Summary
Acute promyelocytic leukemia is defined by a characteristic morphology (AML FAB M3/M3v), by
the specific translocation t(15;17) and its molecular correlates (PML/RARa and RARa/PML).
Thereby it can be separated from all other forms of acute leukemia.
By all-trans retinoic acid in combination with chemotherapy cure rates of 70 to 80% can be
reached. On average, about 10% of patients still die in the early phase of the treatment and
about 20 to 30% relapse. Molecular monitoring of the minimal residual disease (MRD) by
qualitative nested RT-PCR and quantitative REAL-time PCR of PML/RARa allows to follow the
individual kinetics of MRD and to identify patients with an imminent hematological relapse.
A standardized treatment for patients with relapsed APL has not yet been established. With
arsenic trioxide (ATO) monotherapy remission rates over 80% were achieved and long-lasting
molecular remissions are described. The drug was mostly well tolerated. ATO exerts a dose
dependent dual effect on APL blasts, apoptosis in higher and partial differentiation in
lower concentrations. ATO was also successfully administered before allogeneic and
autologous transplantation. ATO is approved for the treatment of relapsed and refractory APL
in Europe and in the USA.
In the present protocol, ATO is given for remission induction:
1. in patients with hematological or molecular first or subsequent relapse of APL and
2. in patients who do not reach a hematological or molecular remission after first line
therapy.
Induction therapy with ATO is the mandatory part of the protocol.
After remission induction, there are several options for postremission therapy. Factors
which have influence on the treatment decision in the individual case are:
1. the eligibility for allogeneic transplantation
2. the eligibility for autologous transplantation
3. the presence or absence of contraindications against intensive chemotherapy
4. the PCR status after induction and during follow up (RT-PCR of PML/RARa, sensitivity
10-4)
A mandatory form of post-remission therapy is not defined in the protocol. Data and outcomes
of any post-remission therapy should be documented in order to collect data of treatment
after ATO.
The following stratification of post-remission therapy can be performed according to the
decision of the treating physician:
Patients with a HLA-compatible donor who are suitable for allogeneic stem cell
transplantation should be transplanted. In patients with a positive PCR one cycle of
intensive chemotherapy (HAM) before transplantation should be considered and patients with a
negative result are immediately transplanted without preceding chemotherapy. In patients who
do not qualify for allogeneic, but for autologous transplantation, the intensity of the
chemotherapy (Ara-C dose of the HAM cycle) is scheduled according to the PCR status after
ATO and to the patient's age. In patients under 60 years, the recommended single Ara-C dose
is scheduled to 3 g/m² in case of a positive PCR result and to 1 g/m² in case of a negative
PCR result after ATO. In all patients aged over 60 years, the Ara-C dose should be uniformly
reduced to 1 g/m² independent of the PCR status. Patients who are not eligible for
allogeneic or autologous transplantation (too old, no stem cells collected, PCR positive
stem cell transplant, contraindications against intensive chemotherapy) receive three
further cycles with ATO and ATRA. The group of patients not qualifying for autologous
transplantation, but without contraindications against intensive chemotherapy should receive
an age adapted HAM, whenever a positive PCR persists or reappears after the three
maintenance cycles of ATO. A close monitoring of the PCR of PML/RARa after each treatment
cycle is part of the protocol.
The main objective of the protocol is to take advantage of the expected low toxicity of ATO
and to keep the part of chemotherapy as low as possible.
Synopsis
Title of study
Treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO). A phase-IV
study to assess the effectiveness and toxicity of ATO as well as the kinetics of minimal
residual disease (MRD) in patients with first and subsequent hematological or molecular
relapse of APL.
Study coordination: Priv.-Doz. Dr. Eva Lengfelder
Protocol committee: German AMLCG and German AML-Intergroup (open for other participating
groups)
Study duration: Time of recruitment 3 years, individual follow up scheduled for 3 years
Objectives of the study
Primary objectives
Assessment of:
1. the rate of hematological remission
2. the rate of molecular remission
3. the kinetics of the MRD of PML/RARa during and after ATO
Secondary objectives
Assessment of:
1. the side effects of ATO
2. percentage of transplantable patients in comparison to the historical results after
chemotherapy
3. the overall survival
4. duration of the hematological and molecular remission
Study characteristics: Open-label multicenter controlled phase-IV study
Number of patients: 30 patients
Inclusion criteria
* Patients in first or subsequent hematological or molecular relapse of APL
* Persistence of a positive PCR or no hematological CR after first line therapy
* No complete hematological remission after first line therapy
* Age over 18 years
* No upper age limit
* Informed consent of the patient
Exclusion criteria
* Absolute QTc-interval prolonged over 460 msec before therapy (normal electrolytes, no
other drugs prolonging the QT-interval )
* Heart failure NYHA grade III and IV
* Renal or hepatic failure WHO grade >= III
* Pneumonia with hypoxemia
* Uncontrolled sepsis
* Pregnancy and lactation period
- Secondary malignancy, which will have major influence on the prognosis
- Expected noncompliance
- No informed consent of the patient
Diagnostic measures:
Confirmation of relapse by RT-PCR of PML/RARa and by cytogenetics. Follow up PCRs with
quantitative nested RT-PCR and qualitative REAL-time PCR of PML/RARa.
Treatment plan
Induction therapy:
- 3 cycles of ATO with the aim to induce a hematological or a molecular remission.
Options for postremission therapy:
· Allogeneic transplantation (PBSCT) in suitable patients with a related or unrelated
donor.
The administration of chemotherapy preceding allogeneic transplantation is stratified
according to the PCR status after ATO. Chemotherapy (HAM) should be considered in PCR
positive patients according to the individual situation.
No chemotherapy is given in PCR negative patients.
· Autologous PBSCT in patients without a donor qualifying for autologous
transplantation.
The intensity of chemotherapy (HAM with either 3 or 1 g/m²) is proposed according to
the PCR status of PML/RARa (sensitivity 10-4) after ATO and to patient's age.
· 3 maintenance cycles of ATO. This is followed by HAM in patients with persistence or
reappearance of a positive PCR.
Patients not eligible for allogeneic or autologous transplantation, but without
contraindications against intensive chemotherapy. · 3 maintenance cycles of ATO in
patients not eligible for allogeneic or autologous transplantation (no suitable donor,
too old, no stem cells collected, positive stem cell transplant) and with
contraindications against intensive chemotherapy.
Monitoring of MRD is mandatory after each ATO cycle and further treatment step.
(Details of the treatment plan are shown in the overview of the study design, Paragraph
2.2).
Criteria for evaluation
The effectiveness of the therapy is assessed by the evaluation of the rate of
hematological and molecular remission and of the duration of remission according to the
commonly used definitions.
The safety of the therapy is assessed by a close study monitoring using the criteria of
toxicity according to WHO.
;
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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