Rapid complete donor lymphoid chimerism and graft-versus-leukemia effect are important in early control of chronic lymphocytic leukemia

Abstract

Eradication of minimal residual disease (MRD) after allotransplantation in persons with chronic lymphocytic leukemia (CLL) is associated with lower rates of relapse. Rapid engraftment of donor lymphocyte elements can contribute to MRD control, but it remains unclear whether this strategy will benefit patients. In this study, we report the incidence of MRD eradication and graft-versus-host disease (GvHD) in persons with rapid versus later donor T lymphocyte engraftment after lymphodepleting chemotherapy and reduced intensity conditioning (RIC) allotransplantation. Twenty-seven subjects received lymphodepleting chemotherapy to facilitate donor engraftment followed by fludarabine and cyclophosphamide RIC and a blood cell allograft. MRD was monitored by multicolor flow cytometry after transplantation. Complete donor T lymphoid chimerism (TLC) and myeloid chimerism (MC) were achieved in 25 subjects at a median of 28 days (range, 14-60 days) and 21 days (range, 14-180 days), respectively. Achieving complete donor TLC by day 14 versus day 28 or later correlated with occurrence of grade 2 or higher acute GvHD (90% [95% confidence interval {CI}, 78-100%] versus 35% [95% CI, 16-54%]; p = 0.014) and better control of MRD in the bone marrow at day 100, median 0% (range, 0-0.1%) versus 8.5% (range, 0-92%; p = 0.016). Among 11 persons with early donor TLC, none had progressive disease, and seven died of treatment -related mortality (TRM). In persons with later development of TLC, 8 of 16 had progressive disease and 2 died of TRM. Time to donor myeloid chimerism had no effect on outcomes. Rapid establishment of donor TLC resulted in more complete eradication of early MRD, but greater incidence of acute GvHD and TRM in persons with CLL undergoing RIC allotransplantation.

Figure 1

Bar plot showing paired 25^th, median, and 75^th percentiles of selected lymphocyte subsets at study-entry (shaded) and after (open) EPOCH-F±R.

Figure 2

Degree of bone marrow involvement of CLL in subjects with day 14 (solid line) versus day ≥28 (dashed line) development of complete CD4+ T-lymphocyte donor chimerism. Bone marrow CLL cells were assessed by multi-color flow cytometry at study-entry (E) and days +28, +60, +100, +180 post transplantation.

Figure 3

Probability of progression of subjects with day 14 (dashed line) versus day ≥28 (solid line) development of complete CD4+ T-lymphocyte donor chimerism.

Figure 4

Overall survival.