allogeneic hematopoietic stem cells transplantation

Impact of molecular genetic and cytogenetic characteristics on outcomes of allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia

BONE MARROW TRANSPLANTATION , , ,

A.V. Gorbunova, T.L. Gindina, E V. Morozova, I.M. Barkhatov, N.N. Mamayev, and B.V. Afanasyev

R.M. Gorbacheva Institute of Pediatric Oncology, Hematology and Transplantology, I.P. Pavlov State Medical University, Saint Petersburg, Russian Federation

ABSTRACT

Point mutations in the BCR-ABL kinase domain, BCR-ABL and EVI1 gene expression alterations, and additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are strongly associated with resistance to tyrosine kinase inhibitors (TKIs) and disease progression, but their effect on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is uncertain. This retrospective study included 35 CML patients with resistance to TKI therapy who received a related or unrelated HSCT. Additional chromosomal aberrations were associated with the decreased rate of the complete molecular response (CMR) after allo-HSCT. EVI1 expression level was associated with a decreased disease-free survival (DFS). BCR-ABL kinase domain mutations showed no influence on CMR, OS, and DFS in this patient cohort. 9 out of 10 patients with T315I mutation achieved CMR. EVI1-directed stratification of patients during the post-transplantation period may improve outcome of HSCT.

Keywords: chronic myeloid leukemia, CML, allogeneic hematopoietic stem cells transplantation, allo-HSCT, BCR-ABL, EVI1.

Read in PDF (RUS)pdficon

Refernces

  1. Oyekunle A., Klyuchnikov E., Ocheni S. et al. Challenges for allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia in the era of tyrosine kinase inhibitors. Acta Haematol. 2011; 126(1): 30–9.
  2. Baccarani M., Cortes J., Pane F. et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. Clin. Oncol. 2009; 27(35): 6041–51.
  3. Soverini S., Hochhaus A., Nicolini F.E. et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011; 118(5): 1208–15.
  4. Cortes J.E., Kantarjian H., Shah N.P. et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. Engl. J. Med. 2012; 367(22): 2075–88.
  5. Hochhaus A., Kreil S., Corbin A.S. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16: 2190–6.
  6. Wang Y., Cai D., Brendel C. et al. Adaptive secretion of granulocytemacrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood 2007; 109: 2147–55.
  7. Chu S., Holtz M., Gupta M. et al. BCR/ABL kinase inhibition by imatinib mesylate enhances MAP kinase activity in chronic myelogenous leukemia CD34+ cells. Blood 2004; 103: 3167–74.
  8. Burchert A., Wang Y., Cai D. et al. Compensatory PI3-kinase/Akt/mTOR activation regulates imatinib resistance development. Leukemia 2005; 19: 1774–82.
  9. Daghistani M., Marin D., Khorashad J.S. et al. EVI-1 oncogene expression predicts survival in chronic-phase CML patients resistant to imatinib treated with second-generation tyrosine kinase inhibitors. Blood 2010; 116(26): 6014–7.
  10. Мамаев Н.Н., Горбунова А.В., Гиндина Т.Л. и др. Лейкозы и миело- диспластические синдромы с экспрессией гена EVI1: теоретические и клинические аспекты. Клин. онкогематол. 2012; 5(4): 361–4. [Mamayev N.N., Gorbunova A.V., Gindina T.L. i dr. Leykozy i miyelodis_ plasticheskiye sindromy s vysokoy ekspressiyey gena EVI1: teoreticheskiye i klinicheskiye aspekty (Leukemias and myelodisplastic syndromes with high EVI1 gene expression: theoretical and clinical aspects. In: Clin. oncohematol.). Klin. onkogematol. 2012; 5(4): 361–4.]
  11. Groschel S., Lugthart S., Schlenk R.F. et al. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. Clin. Oncol. 2010; 28(12): 2101–7.