title: Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance.
abstract: There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens.
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Ezhilarasi
authors.initials: E
authors.lastname: Chendamarai
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Ansu Abu
authors.initials: AA
authors.lastname: Alex
authors.affiliation: Department of Transfusion Medicine and Immunohaematology, Christian Medical College, Vellore, India.
authors.forename: Vandana
authors.initials: V
authors.lastname: Kamath
authors.affiliation: Department of Transfusion Medicine and Immunohaematology, Christian Medical College, Vellore, India.
authors.forename: Sukesh C
authors.initials: SC
authors.lastname: Nair
authors.affiliation: Department of Biochemistry, Christian Medical College, Vellore, India.
authors.forename: Arun Jose
authors.initials: AJ
authors.lastname: Nellickal
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Nancy Beryl
authors.initials: NB
authors.lastname: Janet
authors.affiliation: Cytogenetics Unit, Christian Medical College, Vellore, India.
authors.forename: Vivi
authors.initials: V
authors.lastname: Srivastava
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Kavitha M
authors.initials: KM
authors.lastname: Lakshmi
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Auro
authors.initials: A
authors.lastname: Viswabandya
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Aby
authors.initials: A
authors.lastname: Abraham
authors.affiliation: Genotypic Technology, Bengaluru, India.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Aiyaz
authors.affiliation: Genotypic Technology, Bengaluru, India.
authors.forename: Nandita
authors.initials: N
authors.lastname: Mullapudi
authors.affiliation: Genotypic Technology, Bengaluru, India.
authors.forename: Raja
authors.initials: R
authors.lastname: Mugasimangalam
authors.affiliation: UMR 1131 Institut d'Hématologie, Hôpital Saint Louis, I avenue Claude Vellefaux, 75010 Paris, France.
authors.forename: Rose Ann
authors.initials: RA
authors.lastname: Padua
authors.affiliation: UMR 1131 Institut d'Hématologie, Hôpital Saint Louis, I avenue Claude Vellefaux, 75010 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Mammen
authors.initials: M
authors.lastname: Chandy
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Alok
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Biju
authors.initials: B
authors.lastname: George
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Poonkuzhali
authors.initials: P
authors.lastname: Balasubramanian
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Mathews
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000097:blood / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000097:blood / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D042381:Granulocyte Precursor Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010087:Oxides / Q000097:blood / Q000627:therapeutic use*; D000071156:Promyelocytic Leukemia Protein; D011446:Prospective Studies; D012008:Recurrence; D014157:Transcription Factors / Q000235:genetics; D014212:Tretinoin / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin; D000077237:Arsenic Trioxide
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