randomized trial in adult de novo ph positive all with chemotherapy, imatinib or ponatinib, blinatumomab and sct

Conditions: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Summary: the current standard of care (soc) in younger patients with ph+ all is imatinib in combination with low-dose chemotherapy, change of tki in case of persistent mrd above 10-3 after consolidation i and indication for stem cell transplantation. the evolve trial aims to answer three questions challenging the current soc: use of ponatinib compared to imatinib both in combination with low-dose chemotherapy and consolidation i (randomization i). in mrd good responders: omit end of therapy in primary care and indication for sct but continue therapy with tki, chemotherapy and blinatumomab as additional antileukemic compound (randomization ii). in mrd poor responders: omit indication for tki change but give instead blinatumomab followed by end of therapy in primary care and indication for sct (non-randomized).


Eligibility criteria:
inclusion criteria: * male or female patients \>= 18 years, \<=65 years * philadelphia chromosome or bcr-abl1 positive all * not previously treated except with corticosteroids ≤ 7 days, standard gmall prephase with dexamethasone and cyclophosphamide including intrathecal therapy, hydroxyurea, a single dose vincristine or other cytostatic drugs and start of standard induction for ph-positive all (1 dose vincristine, 1 dose of rituximab, 2 doses dexamethasone and up to 5 days imatinib) * ecog performance status ≤2 * signed written inform consent * molecular evaluation for bcr-abl1 performed * negative pregnancy test in women of childbearing potential * woman of childbearing potential willing to use 2 highly effective methods of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment (pearl-index \<1%). male who has a female partner of childbearing potential willing to use 2 highly effective forms of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment (pearl-index \<1%). * normal serum levels \> lln (lower limit of normal) of potassium and magnesium, or corrected to within normal limits with supplements, prior to the first dose of study medication * serum lipase ≤ 1.5 x uln. for serum lipase \> uln - ≤ 1.5 x uln, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis * normal qtcf interval ≤450 ms for males and ≤470 ms for females * signed and dated written informed consent is available * participation in the registry of the german multicenter study group for adult all (gmall) exclusion criteria: * history of malignancy other than all diagnosed within 5 years (yrs) prior to start of protocol-specified therapy with defined exceptions * contraindications against the use of imatinib, ponatinib, chemotherapy or blinatumomab * patient previously treated with tyrosine kinase inhibitors * nursing women * known impaired cardiac function, including any of the following: as detailed in protocol * symptomatic peripheral vascular disease * any history of ischemic stroke or transient ischemic attacks (tias) * uncontrolled hypertriglyceridaemia * history or presence of clinically relevant cns pathology as detailed in protocol * history or active relevant autoimmune disease * known hypersensitivity to immunoglobulins or to any other component of the study drug formulation * known diagnosis of human immunodeficiency virus (hiv) infection (hiv testing is not mandatory) or active infection with hepatitis b or c * history of pancreatitis within 6 months previous to start of treatment within the trial * treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study * inadequate hepatic functions defined as asat or alat \> 2,5 times the institutional upper limit of normal or \> 5 times uln if considered due to leukemia * total bilirubin \> 1.5-fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to m. gilbert / m. meulengracht * concurrent severe diseases which exclude the administration of therapy e.g. severe, uncontrolled acute or chronic infections * inability to understand and/or unwillingness to sign a written informed consent

Keywords: philadelphia chromosome positive acute lymphoblastic leukemia tyrosinekinase inhibitors blinatumomab