Gemtuzumab Ozogamicin in Combination With A-HAM in Refractory AML (GO-A-HAM)
Condition: Leukemia, Myeloid, Acute
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 2

Summary: 
      GO-A-HAM:

      Gemtuzumab Ozogamicin 3g/m² day 1 Cytarabine 3g/m² bid days 1-3 Mitoxantrone 12mg/m² days 2,3
      All-trans Retinoic acid 45mg/m² days 4-6 and 15 mg/m² days 7-28
    

Detailed description: 
      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.
    

Intervention name(s): Cytarabine; Mitoxantrone; Gemtuzumab Ozogamicin; All-trans-Retinoid Acid
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 3 g/m2 bid. i.v day 1-3; 12 mg/m2 i.v. day 2 and 3; 3mg/m² i.v. day 1; 45 mg/m2 p.o. day 4-6 15 mg/m2 p.o. day 7-28
Intervention MeSH terms: Cytarabine; Mitoxantrone; Gemtuzumab
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute myeloid leukemia; gemtuzumab ozogamicin; refractory disease