Clonal Architecture of Donor-Derived Myeloid Neoplasms after Allogeneic Hematopoietic Stem Cell Transplant

• Published in: Transplantation and cellular therapy 2024-02, Vol.30 (2), p.S350-S351
• Main Authors: Wechalekar, Gauri, Cibich, Ms. Alia, Shanmuganathan, Naranie, Kutyna, Monika, Sekaran, Usha Chandra, Singhal, Deepak, Beligaswatte, Ashanka, Purins, Leanne, Hahn, Christopher Norman, Yeung, David T, Bardy, Peter, Purtill, Duncan, Bajel, Ashish, Branford, Susan, Hiwase, Devendra
• Format: Article
• Language: English
• ISSN: 2666-6367; 2666-6367
• DOI: 10.1016/j.jtct.2023.12.490

Donor derived leukemia (DDL) is observed in 0.12% to 5% (Dietz et al. BJH 2014) of allogenic HCT (alloHCT), with estimated mortality rate of 47% (Wang et al. AMCP 2011). However, insight into kinetics of clonal hematopoiesis (CH) is limited. Here we characterize burden of unexplained persistent cytopenia and donor derived clonal hematopoiesis following alloHCT. Persistent unexplained cytopenia was screened in 282 alloHCT performed at the Royal Adelaide Hospital between 01 Jan 2015 and 31 Dec 2021. CH was assessed by next-generation sequencing (NGS) using a myeloid gene panel. Persistent unexplained cytopenia was detected in 9% (n=9) of alloHCT alive >1-year without relapse and moderate/severe CGVHD (Figure 1). Of the 9 cases, 4 were evaluated by NGS and confirmed to have DDL. The remaining 5 are pending evaluation by NGS. Figure 2 provides comprehensive summary of 12 DDL cases including an additional 8 cases who had alloHCT before 2015 (n=5) at our institute or were diagnosed at other institutes (n=3). Key findings include: (i) unexplained persistent cytopenia in 9% of alloHCT survivors without moderate/severe cGVHD; (ii) DNMT3Amut and TET2mut were detected in 75% (9/12) of DDL cases; (iii) 71% (5/7) of DNMT3Amut DDL had single DNMT3Amut while both TET2mut DDL had either multiple TET2mut or other co-mutations; (iv) shorter latency of DNMT3Amut DDL (26 months, IQR 10,42 months) compared to TET2mut DDL (299 and 343 months) following alloHCT (Figure 3a); (v) different kinetics of individual clones: in RAH001, TET2mut (p.Cys1378Tyr) variant allele frequency (VAF) progressively increased from 0% to 40% across 25 years, whilst SRSF2 (p. Pro95His) was not detected until 23 years post-alloHCT, presenting with a significant VAF of 36% (Figure 3b); (vi) kinetics of CH expansion was highly different in recipient and donor: in RAH002, DNMT3A (p. Gly543Cys) VAF increased from 12.5% to 47% over 53 months since alloHCT (Figure 3ci), whilst the VAF of the clone was only 12.65% after 60 months of stem cell donation (Figure 3cii); (vii) DDL can be due to in vivo CH in engrafted donor cells: RAH004 was diagnosed with myelodysplastic syndrome with three distinct TET2mut, 29 years after alloHCT in the setting of complete donor chimerism (Figure 2). Surprisingly, none of these clones were detected in donor sample collected 29-years post donation. However, different TET2mut (p.Ser82LysfsTer2) was detected at VAF of 6%. Persistent unexplained cytopenia was detected in 9% of long-