Treatment of Relapsed Acute Promyelocytic Leukemia With Arsenic Trioxide (Phase IV Study)
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
Study duration: Time of recruitment 3 years, individual follow up scheduled for 3 years
Objectives of the study
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
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
* 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
* 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
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.
- 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
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
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
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
the rate of hematological remission
Eva Lengfelder, MD, PhD
Germany: Federal Institute for Drugs and Medical Devices