Navigating preemptive and therapeutic donor lymphocyte infusions in advanced myeloid malignancies by high-sensitivity chimerism analysis

Michael Stadler; Letizia Venturini; Ivonne Bünting; Elke Dammann; Eva M Weissinger; Adrian Schwarzer; Christian Schultze-Florey; Steve Ehrlich; Dominik Markel; Catherina Lueck; Alexandra Gladysz; Tabea Fröhlich; Nouraldin Damrah; Gernot Beutel; Matthias Eder; Arnold Ganser; Lothar Hambach

doi:10.3389/fonc.2022.867356

Navigating preemptive and therapeutic donor lymphocyte infusions in advanced myeloid malignancies by high-sensitivity chimerism analysis

Front Oncol. 2022 Aug 17:12:867356. doi: 10.3389/fonc.2022.867356. eCollection 2022.

Authors

Michael Stadler¹, Letizia Venturini¹, Ivonne Bünting¹, Elke Dammann¹, Eva M Weissinger¹, Adrian Schwarzer¹, Christian Schultze-Florey¹, Steve Ehrlich¹, Dominik Markel¹, Catherina Lueck¹, Alexandra Gladysz¹, Tabea Fröhlich¹, Nouraldin Damrah¹, Gernot Beutel¹, Matthias Eder¹, Arnold Ganser¹, Lothar Hambach¹

Affiliation

¹ Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Abstract

Preemptive and therapeutic donor lymphocyte infusions (preDLI and tDLI) are widely used in relapsing and relapsed hematopoietic malignancies after allogeneic stem cell transplantation (alloSCT) to enhance the graft-versus-malignancy effect. However, in advanced myeloid malignancies, long-term survival after preDLI and tDLI remains low, reflecting our inability to master the double-edged sword of alloreactivity, balancing anti-neoplastic activity versus graft-versus-host disease (GvHD). We previously evaluated a quantitative PCR-based high-sensitivity chimerism (hs-chimerism) based on insertion/deletion polymorphisms instead of short tandem repeats, where increasing host chimerism in peripheral blood predicts relapse more than a month before clinical diagnosis, and declining host chimerism signals anti-host alloreactivity. Here we report 32 consecutive patients with advanced myeloid malignancies receiving preDLI or tDLI "navigated" by hs-chimerism ("navigated DLI"). We compared them to a historical cohort of 110 consecutive preDLI or tDLI recipients, prior to implementation of hs-chimerism at our institution ("controls"). Both groups were comparable regarding age, gender, conditioning, donor type, and time to DLI. With longer median follow-up of the navigated DLI group (8.5 versus 5 months), their landmark overall (64%) and disease-free survival (62%) at 2 years from first DLI compared favorably with controls (23% and 21%, respectively). Improved survival of navigated DLI was due to both reduced relapse incidence (38% versus 60%) and non-relapse mortality (17% versus 44%) at 2 years. Early relapse prediction by hs-chimerism allowed a preemptive approach in 28% of navigated DLI versus 7% in controls. Our results confirm hs-chimerism as a highly valuable tool for monitoring and steering immune interventions after alloSCT.

Keywords: Donor lymphocyte infusion; allogeneic stem cell transplantation; alloreactivity; chimerism; graft-versus-host; graft-versus-leukemia.