Venetoclax plus decitabine induced complete remission with molecular response in acute myeloid leukemia relapsed after hematopoietic stem cell transplantation
Authors: Giacomo Andreani, Matteo Dragani, Anna Serra, Paolo Nicoli, Marco De Gobbi, Daniela Cilloni
Journal: American Journal of Hematology (2018)

Recurrent mutations in the isocitrate dehydrogenase gene (IDH) have been identified in acute myeloid leukemia (AML), both in the cytosolic IDH1 enzyme and in its mitochondrial homolog, IDH2.1 Approximately 15%-20% of AML patients have mutations in IDH1 or IDH2.2 Normal counterparts of these enzymes play their role in the citric acid cycle, catalyzing the oxidative decarboxilation of isocitrate and producing alpha-ketoglutarate; mutant IDH1 and IDH2 gain the activity to convert the alpha-ketoglutarate into 2-hydroxyglutarate, an oncometabolite that leads to epigenetic changes that promote cellular transformation through deregulation of mitochondrial function increasing BCL-2 dependence (B-cell leukemia/lymphoma-2, an antiapoptotic protein) in AML cells.1 A subtle approach to face a malignancy with this molecular profile is to exploit the so called synthetic lethality, a strategy based on the concept of nononcogene addiction, wherein cells expressing an oncogenic mutation (ie, IDH1/2) exhibit dependence on subsets of nononcogenes (ie, BCL-2) for survival.1 Venetoclax is a small and orally available molecule that target specifically the BH3 domain of BCL-2 (hence the name BH3 mimetic) approved for the treatment of Chronic Lymphocytic Leukemia. Several studies on the use of venetoclax as single agent in relapsed/refractory AML (r/r AML) demonstrated clinical activity with tolerable and safe profile3; furthermore the addition of venetoclax to decitabine or azacitidine seems to sensitize AML cells to these hypomethylating agents (HMAs), in particular for patients with IDH mutations.4-6 Relapsed AML after allogeneic hematopoietic stem cell transplantation (HSCT) have poor prognosis despite numerous therapies available at the moment including standard chemotherapy and new allogeneic HSCT, donor lymphocyte infusion (DLI), HMA, different inhibitor molecules7; the possibility to integrate one of the above mentioned treatments with venetoclax is challenging.8 We report here the case of a 60-year-old man. In 2012 he was diagnosed with NPM1-mutated AML (FAB M2). He was treated with conventional chemotherapy following "3 + 7" scheme and 4 consolidation cycles with high dose cytarabine. He obtained a complete hematological and molecular remission with NPM1 negativity. In 2015 he relapsed with the same mutation of NPM1. He was treated with a reinduction chemotherapy following FLANG scheme (fludarabine 30 mg/die for 5 days, mitoxantrone 7 mg/m2 for 3 days, citarabine 2000 mg/die for 5 days, G-CSF from day −1) followed by 1 cycle of consolidation chemotherapy with high dose cytarabine and allogeneic HSCT from a matched unrelated donor with a reduced intensity conditioning regimen with fludarabine and busulphan. The molecular remission with NPM1 negativity was achieved before transplantation and maintained after HSCT. The follow up was regular for more than 2 years, complete hematological and molecular remission persisted with a picture of full chimerism. No signs of graft vs host disease were present. April 2018, the patient was hospitalized for fever and pancytopenia. Relapse of AML with 70% of blasts was confirmed by bone marrow analysis. Cytogenetic analysis documented a normal karyotype. Molecular analysis demonstrated the presence of NPM1-mutation, IDH1-mutation (not tested in 2012 and 2015), FLT3cod835-mutation; WT1 was overexpressed: 6016 copies/104 copies ABL (normal range 0-90); chimerism analysis confirmed the relapse with 46% of donor cells. Immunophenotype documented the loss HLA-DR (Human Leucocyte Antigen - DR isotype) expression on the myeloid clone. May 2018, the patient underwent a new chemotherapy induction following FLAG-IDA scheme: fludarabine 40 mg/die for 5 days, idarubicine 15 mg/die for 3 days, citarabine 2000 mg/die for 5 days, G-CSF from day −1. In parallel a new donor search was started since relapse occurred >2 years from the first transplant. Prolonged aplasia persisted after 33 days from chemotherapy therefore bone marrow aspirate was repeated demonstrating the persistence of 45% of blasts in the bone marrow. The patient was discharged with persistence of cytopenia. June 2018, the patient started therapy with venetoclax (ramp-up from 50 mg to 400 mg/die in 4 weeks) plus decitabine 20 mg/m2 per day (5-days dosing). The blood cell count was as follow: WBC 3120/μL (Neutrophils 20/μL), Hb 7.6 g/dL, Platelets 2000/μL. Transfusions of red blood cells and platelets were needed. In the meantime a new hospitalization occurred due to infection of central venous catheter. Antibiotic therapy was started and after resolution of the infection the patient was discharged. Venetoclax administration was never stopped but the second cycle of decitabine was delayed. August 2018, before the second administration of decitabine, a bone marrow revaluation was done. Surprisingly, no more blast cells were detected at the bone marrow and all the molecular markers (NPM1, IDH1, and FLT3cod835) were negative. WT1 expression returned within the normal range (19 copies/104 copies ABL); donor hematopoiesis re-emerged with 90% of donor cells. The blood cell count was: WBC 590/μL (Neutrophils 380/μL), Hb 8.7 g/dL, Platelets 36 000/μL. After the second cycle of decitabine the patient was hospitalized again for a new episode of sepsis. Venetoclax was not interrupted during hospitalization but the third cycle of decitabine was postponed. September 2018, a new bone marrow aspiration after 2 cycles of decitabine and 93 days of venetoclax was done: no blast cells in the bone marrow were documented, molecular markers persisted negative, chimerism improved to 95% of donor cells. The blood cell count was: WBC 2680/μL (Neutrophils 780/μL), Hb 11.7 g/dL, Platelets 219 000/μL. No more transfusions of blood components were necessary. At the moment we are writing the patient is asymptomatic in good clinical conditions, he is able to carry on all the activities with a good performance status. Molecular remission with incomplete hematologic recovery persists (Figure 1). A fourth cycle of decitabine is planned and the administration of venetoclax 400 mg/die is going on. We describe the case of an AML patient relapsed after allogeneic HSCT and refractory to a new re-induction chemotherapy who responded to combined treatment of venetoclax plus decitabine with molecular remission. At our knowledge this is the first report of molecular response after this combined therapy in a r/r AML patient. A retrospective study analyzed response rate after treatment with venetoclax plus HMA among 33 r/r AML (13 of them had prior allogeneic HSCT); 15 patients reached complete remission or complete remission with incomplete hematologic recovery, 8 of them were MRD negative by flow cytometry but no molecular data after therapy were reported.5 Chyla et al.9 reported 10 AML cases with IDH1/2 mutations treated with venetoclax as monotherapy who remained positive for the mutation by next generation sequencing. How to consider the molecular remission in a patient relapsed after allogeneic HSCT remains an open question: how long the remission will last? Which is the best treatment now? If we have a curative intention we can propose to the patient standard chemotherapy followed by new allogeneic HSCT; this could be an option but we should consider that the blast clone do not express the HLA-DR on surface anymore, therefore the rationale for an allogeneic HSCT is, at least partially, lost. We could try to exploit the properties of DLI with the aim to induce remission using graft vs leukemia effect, but this is not the case for the aforementioned reasons. Otherwise in patients ineligible for intensive treatment the utilization of HMA can be a chance to improve the quality of life but without modifying the natural history of the disease. At present, the reported data on the use of venetoclax and decitabine are very few and too immature to help us with clinical decisions. For sure, the idea to use this synergistic therapy with a good profile of tolerability in patients who are not eligible for standard chemotherapy or as a bridge to allogeneic HSCT is both promising and exciting. Based on the excellent reported results, larger clinical trials with this association therapy are advisable. Nothing to report.