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Phase II Study on Gemtuzumab Ozogamicin in Combination With All-trans-Retinoic Acid, High-dose Cytarabine and Mitoxantrone in Patients With Primary Refractory Acute Myeloid Leukemia

Phase 2
18 Years
60 Years
Not Enrolling
Leukemia, Myeloid, Acute

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Trial Information

Phase II Study on Gemtuzumab Ozogamicin in Combination With All-trans-Retinoic Acid, High-dose Cytarabine and Mitoxantrone in Patients With Primary Refractory Acute Myeloid Leukemia

Primary refractory AML is associated with an extremely poor prognosis [1,2]. In the AMLHD93
trial conducted by the AMLSG ULM, patients refractory to the first induction therapy with
ICE (idarubicin, cytarabine, etoposide) had an overall survival of 12% after 5 years [1].
All patients alive in this cohort had received allogeneic transplantation. Therefore, we
assigned allogeneic transplantation in our consecutive trial, AMLHD98A, to all primary
refractory patients [3]. However, the main problem in this patient group remains achieving a
partial (PR) or complete (CR) remission to a salvage therapy. Additionally, the
pre-transplant disease status is an important prognostic factor in most studies of
allogeneic transplantation, regardless dose intensified or dose reduced conditioning
regimens are used [4,5,6]. Since 1993, in all studies of the German-Austrian-AMLSG
response-adapted treatment strategies had been used. Within the AMLHD93 trial, refractory
patients were assigned to an intensified second induction regimen with S-HAM (age<55 years)
[7] or HAM (age 55 to 60 years) [1], and in the AMLHD98A trial, with A-HAM [3]. The
incorporation of all-trans-retinoic acid was based on in vitro data [8-13] and by our
randomised AMLHD98B study for elderly AML-patients showing a benefit in primary response and
survival for patients assigned to standard induction therapy in combination with ATRA [14].

To compare the different salvage therapy strategies, we performed an as-treated analysis in
primary refractory patients of the different cohorts. Although refractory to the first
induction therapy with ICE, nine patients received a second cycle ICE. The results
summarized in table 1 showed an improved response rate (CR and PR) for patients treated with
the A-HAM protocol and thus leading to a higher proportion of patients receiving an
allogeneic transplantation. Survival analysis showed so far no difference between the 4
different groups. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 conjugated to
Calicheamicin. The efficacy and the toxicity profile has been evaluated in several studies,
so far the substance is approved for the monotherapy in relapsed AML-patients in a dose of
9mg/m² q 14d [15]. However, used as a single agent the efficacy is limited and not durable.
Therefore, several trials have evaluated GO in combination with conventional chemotherapy
[16,17]. In the MRC study a dose of 6 mg/m² given once at day 1 was associated with an
increased liver toxicity and therefore the study continues with a dose of 3 mg/m² once at
day 1 of induction therapy [17]. In summary, the available data for combination therapy
showed efficacy of GO in phase II trials. The dose limiting toxicity was defined in the MRC
trial at 6 mg/m². Therefore we consider GO in combination with A-HAM for primary refractory
adult AML patients. Because all primary refractory patients are candidates for an allogeneic
transplantation special considerations have to be taken with respect to the development of
VOD after allogeneic transplantation. One recent report suggests a substantial risk for VOD
for patients receiving an allogeneic transplantation after a therapy with GO [18]. In this
report the odds ratio for VOD after a therapy with GO within 3.5 months before allogeneic
transplantation was 21.6 (95%-confidence interval 4.2-112.2%). However, this report is based
on 62 patients and the dosage of GO used was 6mg/m² and 9mg/m². Therefore, holding in mind
the risk of VOD after GO exposure and the extremely poor prognosis of primary refractory
patients the treatment approach combining A-HAM with GO with a dose of 3mg/m² is justified.

Inclusion Criteria:

- Acute myeloid leukemia defined according the WHO classification not responding to
first induction therapy

- Age 18-60 years

- Written informed consent

Exclusion Criteria:

- Acute promyelocytic leukemia

- Uncontrolled infection

- Transfusion-refractory thrombocytopenia

- Pregnancy, breast-feeding, insufficient contraception

- Organ insufficiency: kidneys, liver, lungs, heart

- Severe neurological and psychiatrical interfering with informed consent

- No consent for the registration, storage and processing of data concerning the
characteristics of the AML and the individual course

- Performance status > grad 2 according the WHO classification

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

CR-rate after therapy with GO-A-HAM

Outcome Time Frame:

day 30

Safety Issue:


Principal Investigator

Richard F Schlenk, Dr. med.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Ulm / Department of Internal Medicine III


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

June 2004

Completion Date:

June 2009

Related Keywords:

  • Leukemia, Myeloid, Acute
  • Acute myeloid leukemia
  • gemtuzumab ozogamicin
  • refractory disease
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid