Trial Information

Treatment of Relapsed Acute Promyelocytic Leukemia With Arsenic Trioxide (Phase IV Study)

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.