The impact of acute and chronic graft-versus-host disease on normal and malignant B-lymphoid precursors after allogeneic stem cell transplantation for B-lineage acute lymphoblastic leukemia

Abstract

BACKGROUND AND OBJECTIVES: The development of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT) for B-lineage acute lymphoblastic leukemia (B-ALL) is associated with a lower probability of leukemia relapse. However, mechanisms by which this GVHD-associated graft-versus-leukemia effect is exerted are poorly understood. In this study, we simultaneously traced the kinetics of normal donor-derived and leukemic recipient-derived B-lymphopoiesis comparing patients with or without GVHD. DESIGN AND METHODS: We used multiparameter flow-cytometry to quantify pro-B (CD19+CD10+CD34+), pre-B (CD19+CD10+CD34-) precursors and malignant lymphoblasts identified by leukemia-associated markers in 161 prospective marrow samples from 39 consecutive B-ALL patients after allogeneic SCT. Chimerism analysis was performed by quantitative real-time polymerase chain reaction of null alleles and insertion/deletion (indel) polymorphisms. RESULTS: Acute GVHD of grades II-IV is associated with a strong inhibition of normal donor-derived pro-B and pre-B precursors at days +30 and +60 post-SCT. Patients who develop chronic GVHD have lower percentages of marrow B-cell precursors during the first year after SCT. Likewise, recipient-derived leukemia B cells were absent at days +30 and +60 in patients with acute GVHD grades II-IV and were less likely to be detected in patients with chronic GVHD. Induction of GVHD as treatment of increasing amounts of leukemia cells causes inhibition of both normal and malignant B compartments even in the absence of steroid therapy. INTERPRETATION AND CONCLUSIONS: We conclude that the development of GVHD after allogeneic SCT is associated with a non-specific inhibition of B-lymphopoiesis.