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Mixed chimerism (MC) and MRD strongly predict relapse in children with ALL after allo-SCT. Pre-emptive immunotherapy (IT), e.g. withdrawal of immunosuppression (WD-IS) or DLI can prevent impending relapse. In this study we retrospectively analysed chimerism and MRD monitoring and the effect of pre-emptive IT.
Patients:
Between January 2005 and July 2014, a total of 89 pts with ALL (pB-ALL, n=63; T-ALL, n=20; biphen. ALL, n=6) received allo-SCT in our institution. 47 pts were in CR1, 26 pts in CR2, 15 pts were CR3 and 1 pt CR4 at time of transplant. Donors were MSD (n=18), MUD (n=61) and haploidentical (n=10). Conditioning consisted of TBI (12 Gy) and ETO in pts with a matched donor and FLU, THIO, MEL in haplo pts.
Methods:
Chimerism was assessed weekly in peripheral blood until day 200 and monthly thereafter. Bone marrow analyses were done at days +30, +60, +90, +180 and +365 post-transplant. Thereby, MRD was assessed in 56 pts, whereas no diagnostic material was available in 33 pts.
Results:
64/89 pts (72%) showed complete chimerism (CC) in all follow-up analyses, and 25/89 pts (28%) developed MC. From 56 pts in whom MRD could be assessed, 40 pts remained MRD negative and 16 developed MRD positivity after transplantation. IT (WD-IS, n=12; DLI, n=14) was initiated based on chimerism analysis in 22/25 pts with MC, and was guided by MRD detection in 4 pts. For the total cohort of pts, pEFS and pOS were 0.67 and 0.77, respectively. Cumulative incidence (CI) of TRM and relapse (CI-R) were 0.11 and 0.24 for all pts.
Chimerism:
pEFS was 0.74 in CC-pts and 0.51 in MC-pts (p<0.032). 22/25 MC-pts received pre-emptive IT resulting in a pEFS of 0.58. Due to rapid progression IT was not initiated in 3/25 MC pts. All MC-pts without IT relapsed. While CI-TRM remained low (0.10 for CC resp. 0.12 for MC, p>0.68) in both groups, CI-R was 0.17 in CC- and 0.41 in MC-pts (p<0.021).
MRD:
Pts were grouped according to their highest MRD value post-transplant in MRD negative, low positive (<10E-4), and high positive (>10E-4) pts. pEFS and pOS were 0.82 and 0.95 in MRD negative (n=40), 0.56 and 0.88 in low level MRD (n=8), and 0.25 and 0.25 in high level MRD (n=8) positive pts (p<0.001). CI-R was 0.14 in MRD negative, 0.36 in MRD low, and 0.75 in MRD high positive pts (p<0.001), while CI-TRM between these groups remained low (0.05 for MRD negative, 0.13 for MRD low and 0.00 for MRD high, p>0.55).
Multivariate analysis:
Multivariate analysis for pEFS also indicated that MC and high level MRD were independent poor prognostic factors (MC, p<0.049, RR 3.16 and high level MRD, p<0.022, RR 3.99), while remission status before transplantation, ALL lineage, donor type, graft source, T cell depletion or sex showed no significant influence.
Conclusion:
Our results show that analysis of chimerism and MRD allow the prediction of impending relapse in virtually all pts with ALL and that pre-emptive IT can improve outcome in these pts.