Acute Myeloid Leukemia (AML) is a clonal malignant disorder which is characterized by the expansion of leukemic blasts in the bone marrow and the peripheral blood, which goes along with a suppression of normal hematopoiesis including granulopoiesis, erythropoiesis and thrombocytopoiesis. The prognosis is largely determined by cytogenetic and molecular risk factors, age, performance status and antecedent Myelodysplastic Syndrome (MDS).~With the exception of old and frail patients, most AML patients are eligible for intensive chemotherapy, which is given in curative intent consisting of induction and consolidation therapy. However, despite intensive therapy, the long-term outcome of AML patients remains poor, with less than 30% of patients achieving long lasting remission and even cure. This poor outcome is largely due to refractoriness to induction chemotherapy as well as relapses during and after completion of intensive induction and consolidation therapy. Regarding refractoriness, about 20-30% of AML patients under the age of 60 years and about 50% of older patients fail to attain complete remission (CR) following cytarabine plus anthracycline based standard induction therapy. Regarding relapses, even patients having achieved complete remission are at a high risk of relapse, particularly within the first two years after completion of chemotherapy.~In patients with blast persistence after induction therapy or relapse, allogeneic hematopoietic cell transplantation (allo-HCT) is currently the only treatment strategy to offer the prospect of cure. Outcome of allo-HCT is heavily influenced by the remission state before allo-HCT. With the aim to induce a complete remission (CR) before allo-HCT, salvage chemotherapy regimens are administered in refractory/relapsed patients. Typically, these salvage regimens are based on high dose cytarabine (HiDAC), which is frequently combined with either mitoxantrone (HAM regimen) or fludarabine plus idarubicin (idaFLA regimen). Currently, there is no commonly accepted standard salvage regime, but a large individual patient data meta-analysis and single arm phase-II studies suggest that combination chemotherapy including HiDAC and gemtuzumab ozogamicin, an antibody drug conjugate, are very effective. Since patients with refractory or relapsed AML are candidates for allo-HCT, the main purpose of the salvage regimen is to bridge patients to allo-HCT with induction of a CR before allo-HCT. Therapy resistance in cancer is still poorly understood. Beyond genetic aberrations epigenetic mechanisms are important components of resistance to cancer therapy. Recently, the investigators discovered an epigenetic therapy resistance mechanism in AML (Figure 1). This mechanism might be relevant in up to 50% of relapsed/refractory AML patients. This epigenetic mediated resistance can be successfully overcome in in vitro models by proteasome inhibition. Currently, relapsed and refractory r/r-AML still carries a dismal prognosis. In this multicentre, phase II trial the investigators will analyze efficacy of a novel therapy regimen for r/r-AML.~As detailed above, combination-chemotherapy including GO and HiDAC based chemotherapy is an effective regimen in r/r-AML.~Proteasome inhibitors can restore EZH2 protein levels in vitro and in vivo. The restoration of EZH2 significantly improved efficacy of anti-leukemic therapy. Based on the data mentioned above we combine the treatment efficacy of GO plus cytarabine based chemotherapy with the proteasome inhibitor bortezomib in the B-GA regimen. With such an approach the investigators believe that they can substantially improve treatment results in r/r-AML. Part of the study is a pre-specified biomarker analysis for EZH2 restoration after bortezomib exposure in vitro and in vivo. Accordingly, we will be able to determine whether EZH2 restoration after bortezomib exposure is associated with response and outcome. There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving bortezomib. In particular, 2 patients with r/r-AML given high-dose cytarabine (2 g/m²/day) by continuous infusion in combination with daunorubicin and bortezomib died of ARDS early in the course of therapy. However, in several trials evaluating the combination of bortezomib with standard and high-dose cytarabine in AML patients no toxicity signal was detected, especially with respect to ARDS.~Taken together, the rationale for this trial is based on the high unmet clinical need and strong in vitro evidence.
The long-term outcome of patients with acute myeloid leukemia (AML) remains poor, with less than 30% of patients achieving long lasting remission or cure. This poor outcome is largely due to refractoriness to induction chemotherapy as well as relapses during and after completion of intensive induction and consolidation therapy. In patients with refractory/relapsed AML hematopoietic cell transplantation (allo-HCT) is currently the only treatment option offering a prospect of cure but outcome is heavy influenced by the remission status before allo-HCT. Therefore, patients are typically treated with salvage regimens based on high dose cytarabine (HiDAC) combined with mitoxantrone, fludarabine or idarubicin. Nevertheless, the remission rates remain poor and currently there is no accepted standard salvage regimen. Recent studies indicate that combination chemotherapy including HiDAC and gemtuzumab ozogamicin (GO) at a dose of 3 mg/m² leads to improved response rates in refractory AML.~Proteasome inhibition with bortezomib appears to be a promising treatment strategy to restore chemo-sensitivity via EZH2 stabilisation.~This study aims at improving response rates in refractory/ relapsed AML by combining high dose cytarabine, gemtuzumab ozogamicin (GA) and bortezomib (B).~During this phase II study efficacy of B-GA is assessed in comparison to matched historical controls using the Matched Threshold Crossing (MTC)-approach. If results are promising, a subsequent randomized phase III study is intended to assess the efficacy of GA with or without bortezomib.