Therapy-induced Ph1 suppression in chronic myeloid leukemia: molecular and cytogenetic studies in patients treated with alpha-2b IFN, high-dose chemotherapy and autologous stem cell infusion.

Abstract

In this study, cytogenetic and molecular analyses were employed to assess the response to therapy in 29 chronic myeloid leukemia patients undergoing high dose chemotherapy followed by autologous stem cell infusion. Of these, 11 had previously achieved hematologic remission and cytogenetic improvement after alpha-2b interferon (IFN) treatment, whereas 18 underwent autografting in an early phase of the disease. In each case bone marrow samples were examined pre-treatment and at +2, +6 and +12 months in order to verify the degree of Ph1 suppression. In addition, the position of the breakpoint within the BCR region was mapped with multiple restriction enzymes. In 17 cases (59%) a significant Ph1 reduction was observed at +60 days (0-57% residual Ph1+ cells). In three of these cases, a complete cytogenetic response was confirmed at the DNA level by Southern blotting, but specific amplification of the BCR/ABL junction by the polymerase chain reaction (PCR), performed in two cases, still showed residual disease. The remaining 12 patients (41%) revealed a substantial persistence of Ph1+ metaphases (90-100%). Nine of 17 responding patients (53%) showed an increase of Ph1+ cells at 6 months, and five of 20 evaluated had a further increase at 12 months. With the exception of the results seen by PCR, comparison of molecular and cytogenetic techniques did not show significant differences. The variable degrees of Ph1 suppression observed did not appear to be associated with the position of BCR breakpoints. The factors predicting cytogenetic response to IFN and stem cell autograft and long-term durability of cytoconversion should be elucidated in further studies and with longer follow-up.

• Authors: F Lo Coco, F Mandelli, D Diverio, G Alimena, P De Fabritiis, G Meloni, M Cedrone, M Frontani, A Guerrasio, G Saglio
• Journal: Bone marrow transplantation (Bone Marrow Transplant) Vol. 6 Issue 4 Pg. 253-8 (Oct 1990) ISSN: 0268-3369 [Print] England
• PMID: 2085700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon alpha-2
• Interferon-alpha
• Proto-Oncogene Proteins
• RNA, Messenger
• Recombinant Proteins
• Protein-Tyrosine Kinases
• BCR protein, human
• Proto-Oncogene Proteins c-bcr

Topics

• Base Sequence
• Blotting, Southern
• Bone Marrow Transplantation (pathology)
• Dose-Response Relationship, Drug
• Hematopoietic Stem Cells (pathology)
• Humans
• Interferon alpha-2
• Interferon-alpha (therapeutic use)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, pathology)
• Molecular Sequence Data
• Polymerase Chain Reaction
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins c-bcr
• RNA, Messenger (genetics)
• Recombinant Proteins
• Suppression, Genetic (drug effects, genetics)