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Forconi, Francesco; Cencini, Emanuele; Rossi, Davide; Bomben, Riccardo; Sozzi, Elisa; Coscia, Marta; Massaia, Massimo; Veronese, Silvio; Tedeschi, Alessandra; Montillo, Marco; Fazzi, Rita; Petrini, Mario; Ciolli, Stefania; Bosi, Alberto; Dottori, Roberto; Pirrotta, Maria Teresa; Caremani, Alessandra; Poeta, Giovanni Del; Giudice, Ilaria Del; Santangelo, Simona; Laurenti, Luca; Efremov, Dimitar G; Trentin, Livio; Arcaini, Luca; [...]

Unmutated IGHV1-69/D3-16/J3 Stereotyped HCDR3 Rearrangements (Subset 6) Are Associated with Indolent Disease Course and Have Outcome Independent of Mutational Status In Early Stage CLL (Rai 0)

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  • Medientyp: E-Artikel
  • Titel: Unmutated IGHV1-69/D3-16/J3 Stereotyped HCDR3 Rearrangements (Subset 6) Are Associated with Indolent Disease Course and Have Outcome Independent of Mutational Status In Early Stage CLL (Rai 0)
  • Beteiligte: Forconi, Francesco; Cencini, Emanuele; Rossi, Davide; Bomben, Riccardo; Sozzi, Elisa; Coscia, Marta; Massaia, Massimo; Veronese, Silvio; Tedeschi, Alessandra; Montillo, Marco; Fazzi, Rita; Petrini, Mario; Ciolli, Stefania; Bosi, Alberto; Dottori, Roberto; Pirrotta, Maria Teresa; Caremani, Alessandra; Poeta, Giovanni Del; Giudice, Ilaria Del; Santangelo, Simona; Laurenti, Luca; Efremov, Dimitar G; Trentin, Livio; Arcaini, Luca; [...]
  • Erschienen: American Society of Hematology, 2010
  • Erschienen in: Blood
  • Sprache: Englisch
  • DOI: 10.1182/blood.v116.21.1371.1371
  • ISSN: 0006-4971; 1528-0020
  • Schlagwörter: Cell Biology ; Hematology ; Immunology ; Biochemistry
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Abstract 1371</jats:p> <jats:sec> <jats:title>Background:</jats:title> <jats:p>IGHV1-69 gene identifies the most frequent IGHV gene in chronic lymphocytic leukemia (CLL) and identifies the paradigm of unmutated CLL (U-CLL), being used in roughly 1/3 U-CLL. It is often rearranged to form subsets of stereotyped HCDR3 patterns, likely selected and transformed from the natural naïve B-cell repertoire (Blood. 2010; 115:71-7). Being unmutated, IGHV1-69 CLL are hypothetically expected to have competent tumor B-cell receptors (BCR) and to progress more rapidly. However, it has not been investigated if progression occurs similarly in all the subsets.</jats:p> </jats:sec> <jats:sec> <jats:title>Aims:</jats:title> <jats:p>we aimed to investigate the prognostic significance of mutational status and of stereotypic B-cell receptors in IGHV1-69+ CLL.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Nucleotide sequences of the tumor IGHV1-69/D/J rearrangement, clinical and molecular prognostic parameters at diagnosis and clinical status at follow-up of 294 IGHV1-69+ CLL patients were obtained from 22 hematological Institutions in Italy. CLL B-cell derived IGHV1-69 rearrangements were scanned for HCDR3 stereotypic patterns and assigned to subsets according to the criteria by Murray et al (Blood. 2008; 111: 1524–1533). Enpoint of outcome was time to progression requiring first treatment according to NCI criteria (TTFT) in Rai stage 0 CLL.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Of 294 IGHV1-69+ CLL, 264 (89,8%) were unmutated, 168 (57,1%) were assigned to subsets, of which subsets 7 (n=23, 7,8%), 6 (17, 5,8%), 3 (13, 4,4%), 5 (10, 3,4%) and 9 (10, 3,4%) were the most frequent. CD38, ZAP70, normal or sole del13, +12, del11 and del17p scored positive in 109/264 (58,7%), 139/245 (56,7%), 128/248 (50,5%), 51/248 (20,6%), 43/248 (17,3%) and 34/248 (13,7%). CLLs were reclassified as 18 (6,1%) clinical MBL, 101 (34,4%) Rai 0, 155 (52,7%) Rai I-II and 20 (6,8%) Rai III-IV CLL. Subset 6 was also UM in 16/17 (94,1%) cases. Prevalence of CD38 (p&lt;.001), ZAP70 (p=.016), normal or sole del13 (p&lt;.001), +12 (p=.026), del11 (p=.011), and clinical high risk CLL (p=.025) were lower in IGHV1-69 M-CLL than in IGHV1-69 U-CLL. TTFT was significantly shorter in stage 0 IGHV1-69 U-CLL than in IGHV1-69 M-CLL (49 vs 144 months, p&lt;.001, while it was not different between CLL assigned or not to subsets (65 vs 55 months, p=.346). However, specific analysis of individual subsets revealed differential outcomes (p=.005). Among all, it emerged that subset 6 had a TTFT equivalent to IGHV1-69 M-CLL (p=.29) and significantly longer than stage 0 IGHV1-69 U-CLL (median not reached vs 48 months, p=.017).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>our analysis documents and confirms that unmutated status of IGHV, and not stereotypy, is a relevant prognosticator of outcome (TTFT) in CLL. In the IGHV1-69 CLL it exclude a role of IGHV gene use for CLL progression. However, the good prognosis of Rai 0 U-CLL assigned to subset 6 suggests a differential clinical benign course of this particular subset, irrelevant of unmutated status. One possibility is that the IGHV1-69/D3-16/J3 rearrangements of subset 6 produce a tumor-specific BCR with stereotypic HCDR3 patterns that are anergized by antigen while circulating in the peripheral blood in early stage (Rai 0) CLL.</jats:p> </jats:sec> <jats:sec> <jats:title>Disclosures:</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>
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