Therapy-Related Myeloid Neoplasms with Balanced Chromosome Rearrangements Frequently Arise from Pre-Existing Clonal Haematopoiesis

Medientyp: E-Artikel
Titel: Therapy-Related Myeloid Neoplasms with Balanced Chromosome Rearrangements Frequently Arise from Pre-Existing Clonal Haematopoiesis
Beteiligte: Dillon, Richard; Jovanovic, Jelena; Potter, Nicola; Foot, Nicola; Ahearne, Matthew J; Jayne, Sandrine; Dennis, Michael; Hunter, Ann E.; Dyer, Martin J.S.; Vyas, Paresh; Quek, Lynn; Russell, Nigel H.; Hills, Robert K.; Solomon, Ellen; Grimwade, David
Erschienen: American Society of Hematology, 2018
Erschienen in: Blood
Sprache: Englisch
DOI: 10.1182/blood-2018-99-114233
ISSN: 0006-4971; 1528-0020
Schlagwörter: Cell Biology ; Hematology ; Immunology ; Biochemistry
Entstehung:
Anmerkungen:
Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Introduction</jats:p> <jats:p>Therapy-related myeloid neoplasms (tMN) are an increasing healthcare problem resulting from rising long-term survival from primary cancers. Approximately 80% of cases are associated with an adverse karyotype and have a dismal prognosis; pre-existing clonal haematopoiesis (CH) appears to be a predisposing factor and mutations in genes including TP53, PPM1D and DNMT3A have been detected prior to chemo- or radiotherapy exposure. In contrast ~20% of tMN are characterised by balanced chromosome rearrangements and have a relatively favourable outcome; chemotherapy agents targeting topoisomerase II have been implicated in generating these rearrangements however the involvement of CH has not previously been described.</jats:p> <jats:p>Methods and results</jats:p> <jats:p>We performed whole exome sequencing (WES) of samples taken at diagnosis (D) and molecular complete remission (mCR) followed by targeted capture and error-corrected deep sequencing (ECS) on ≥2 mCR samples for 11 patients with therapy-related acute promyelocytic leukemia (tAPL) and 20 patients with de novo APL (dnAPL). All patients had t(15;17) / PML-RARA at diagnosis with no additional cytogenetic abnormality.</jats:p> <jats:p>The median age of patients with tAPL was 46.7y (range 30-78); primary cancer types were breast (4), colorectal (2), lymphoma (3), CNS (1) and testicular (1). Ten patients had received chemotherapy and 4 radiotherapy. The median latency between primary cancer treatment and tAPL diagnosis was 3.9y (range 2.2-6.1). Patients received a mixture of chemotherapy- and arsenic-based treatments.</jats:p> <jats:p>The median age of patients with dnAPL was 40.3y (range 18-69); all patients were treated with the AIDA regimen and none developed tMN subsequently.</jats:p> <jats:p>There were no significant differences between the number or type of mutations between dnAPL and tAPL however disease associated somatic mutations were detectable in mCR samples by ECS in 4/11 tAPL samples compared to 0/20 dnAPL samples (p=0.04).</jats:p> <jats:p>Mutations detected in mCR were UPN1: PPM1D exon (e) 6 1bp deletion (del, variant allele fraction, VAF, D 32% mCR 11.3%); UPN2: DNMT3A e8 1bp del (VAF D 40.2% mCR 0.48%); UPN3: DNMT3A e10 1bp del (VAF D 35.4% mCR 2.9%); UPN4: MYCN e3 6bp insertion (ins, VAF D 38% mCR 0.37%).</jats:p> <jats:p>We screened samples from these patients and a further 39 dnAPL patients for a panel of genes with known CH associated mutations (CH-M) using ECS and detected additional mutations in 2 tAPL patients (UPN4, DNMT3A G104R, VAF D 0% mCR 3% and UPN5 DNMT3A R693H VAF D 2% mCR 25%, who subsequently developed tMN with complex karyotype). We did not detect CH-M in diagnostic samples from any patient with dnAPL and publicly available NGS datasets encompassing 220 patients only showed 1 APL case with a CH-M (DNMT3A e8 ins, prior cytotoxic exposure unknown). We detected treatment-emergent CH clones in mCR by ECS in 6/59 dnAPL patients treated with AIDA (DNMT3A n=3, PPM1D n=2, TP53 n=1, SF3B1 n=1).</jats:p> <jats:p>Applying the same techniques to six patients with therapy-related core-binding factor AML, we identified a persistent CH-M in mCR in one (DNMT3A e15 del, VAF D 38%, mCR 11.8%).</jats:p> <jats:p>DNA samples taken at the time of primary cancer diagnosis were available from UPN 1-3. In UPN1 we detected the PPM1D mutation in a lymph node (LN) involved with T-cell lymphoma (LN) (VAF 2.1%) and an uninvolved staging bone marrow (VAF 3.3%). In UPN3 the DNMT3A mutation was detected in a breast biopsy (VAF 0.7%) and LN involved with carcinoma (VAF 0.9%). In UPN2 the DNMT3A mutation was not detected in the LN biopsy diagnostic for Hodgkin lymphoma.</jats:p> <jats:p>We used FACS to isolate T, B, monocyte, granulocyte and CD34+ cells from complete remission samples from UPN1-4 with >99% purity and detected the persistent mutations in each cell compartment e.g. UPN3 VAF: T cell 1.3%, B cell 8.6%, monocyte 4%, granulocyte 3.7%, CD34+ 3.9%.</jats:p> <jats:p>Diagnostic material from UPN1 and 4 was injected into irradiated NSG mice. After 12 weeks we detected multilineage human engraftment in both samples by FACS in 1/3 mice from UPN1 and 2/3 mice from UPN4. We detected the PPM1D and MYCN mutations respectively in bone marrow samples from each engrafting mouse.</jats:p> <jats:p>Conclusions</jats:p> <jats:p>Together these findings indicate that tMN with balanced chromosome rearrangements can occur on a background of non-malignant CH. Using ECS we observed this phenomenon in 5/17 (29%) patients with therapy-related APL or CBF AML. This has important implications for planning curative therapy, notably for tAPL where effective cytotoxic-free regimens are available.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Russell: Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau; Daiichi Sankyo: Consultancy. Hills:Daiichi Sankyo: Consultancy, Honoraria.</jats:p> </jats:sec>
Zugangsstatus: Freier Zugang

Nur in Feld suchen:

Zuletzt gesuchte Begriffe: