Blinatumomab + ponatinib for relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia in adults

Abstract We retrospectively examined the results of a new chemo-free approach combining blinatumomab with ponatinib (blina/pona) in 26 relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients. All but one achieved complete morphologic remission, and 23 achieved a complete molecular response. With a median follow-up of 34.4 months, the median overall (OS) and event-free (EFS) survivals were 20 and 15.3 months, respectively. After blina/pona, 8 patients underwent an allotransplant (allo), while among the 18 non-transplanted cases, 15 received ponatinib in maintenance. Fifteen relapse/progressions occurred with a significant difference between allo and non allo cases (12.5% vs 82.3%, p = 0.003). However, OS and EFS were similar between both groups. Finally, blina/pona was well tolerated with eight reversible neurologic events and three cytokine release syndromes. Prospective studies are needed to properly assess the safety, tolerability and efficacy of the combination therapy.

[1]  S. Mercadal,et al.  Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group , 2019, Cancer.

[2]  R. Foà,et al.  S1617 A DASATINIB-BLINATUMOMAB COMBINATION FOR THE FRONT-LINE TREATMENT OF ADULT PH+ ALL PATIENTS. PRELIMINARY RESULTS OF THE GIMEMA LAL2116 D-ALBA TRIAL; ON BEHALF OF GIMEMA ACUTE LEUKEMIA WORKING PARTY , 2019, HemaSphere.

[3]  M. Geyer,et al.  Blinatumomab administered concurrently with oral tyrosine kinase inhibitor therapy is a well-tolerated consolidation strategy and eradicates measurable residual disease in adults with Philadelphia chromosome positive acute lymphoblastic leukemia. , 2018, Leukemia research.

[4]  H. Dombret,et al.  Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. , 2018, Blood.

[5]  Mithat Gonen,et al.  Long‐Term Follow‐up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia , 2018, The New England journal of medicine.

[6]  M. Konopleva,et al.  Safety and Efficacy of Blinatumomab in Combination With a Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome‐positive Leukemia , 2017, Clinical lymphoma, myeloma & leukemia.

[7]  P. Chevallier,et al.  Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  W. Klapper,et al.  Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia , 2017, The New England journal of medicine.

[9]  M. Konopleva,et al.  Hyper‐CVAD plus ponatinib versus hyper‐CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia: A propensity score analysis , 2016, Cancer.

[10]  H. Dombret,et al.  Acute lymphoblastic leukemia relapsing after first-line pediatric-inspired therapy: a retrospective GRAALL study , 2016, Blood Cancer Journal.

[11]  J. Esteve,et al.  Use of tyrosine kinase inhibitors to prevent relapse after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia: A position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transpl , 2016, Cancer.

[12]  J. Cayuela,et al.  Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. , 2016, Blood.

[13]  M. Liedtke,et al.  Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. , 2016, The New England journal of medicine.

[14]  M. Konopleva,et al.  Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. , 2015, The Lancet. Oncology.

[15]  J. Cayuela,et al.  Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. , 2015, Blood.

[16]  J. Esteve,et al.  Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia , 2015, Haematologica.

[17]  M. Tallman,et al.  UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. , 2014, Blood.

[18]  T. Clackson,et al.  A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. , 2013, The New England journal of medicine.

[19]  J. Cayuela,et al.  Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. , 2013, Biology of Blood and Marrow Transplantation.

[20]  N. Cross,et al.  Standardized definitions of molecular response in chronic myeloid leukemia , 2012, Leukemia.

[21]  A. Fielding.  Current treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. , 2011, Hematology. American Society of Hematology. Education Program.

[22]  A. Fielding.  Philadelphia-positive acute lymphoblastic leukemia--is bone marrow transplant still necessary? , 2011, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[23]  H. Nakasone,et al.  Dasatinib followed by second allogeneic hematopoietic stem cell transplantation for relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia after the first transplantation , 2010, International journal of hematology.

[24]  E. Thiel,et al.  Patients' age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group. , 2008, Blood.

[25]  H. Dombret,et al.  Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial , 2007, Leukemia.

[26]  R. Foà,et al.  Gruppo Italiano Malattie Ematologiche dell ' Adulto ( GIMEMA ) acute lymphoblastic leukemia without additional chemotherapy : results survival in elderly Philadelphia chromosome – positive patients with Imatinib plus steroids induces complete remissions and prolonged , 2007 .

[27]  J. Cayuela,et al.  Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome – positive acute lymphoblastic leukemia : results of the GRAAPH-2003 study , 2006 .

[28]  G. Lenz,et al.  Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph^+ALL) , 2006 .

[29]  Ping Chen,et al.  Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor , 2004, Science.

[30]  Steven M Kornblau,et al.  Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. , 2004, Blood.

[31]  C. Bloomfield,et al.  Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  J. Kuriyan,et al.  Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. , 2002, Cancer cell.

[33]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.

[34]  X. Thomas,et al.  Philadelphia chromosome positive adult acute lymphoblastic leukemia: characteristics, prognostic factors and treatment outcome. , 1998, Hematology and cell therapy.