Chimerism analysis within 6 months of allogeneic stem cell transplantation predicts relapse in acute myeloid leukemia

Abstract

The role of chimerism analysis as a prognostic indicator of relapse after hematopoietic stem cell transplantation (SCT) is controversial. We monitored chimerism status by short tandem repeat-based polymerase chain reaction (PCR) in T-and non-T-cell subsets and retrospectively evaluated clinical outcome in 96 patients with acute myeloid leukemia after myeloablative (MA) or reducedintensity conditioning SCT. Fifty-six percent of 80 patients in the MA group demonstrated complete donor chimerism (CC) at all time points, whereas 6% had decreasing mixed chimerism (MC), 8% stable MC, 25% increasing MC and 3% increasing and decreasing MC. In 16 RIC patients, these percentages were 12, 50, 6, 6 and 19, respectively, together with 6% nonengraftment. Fortythree out of 96 patients experienced relapse. The last chimerism evaluation before relapse revealed increasing MC in only eight patients. In samples taken between 1 and 6 months post SCT, CC/decreasing MC was significantly related with a lower risk of relapse (31 versus 83%, Po0.000) and mortality (38 versus 83%, Po0.000) than with MC/increasing MC. However, the development of relapse was very rapid. Only very frequent monitoring of chimerism status by highly sensitive methods might identify impending relapse and allow early immunological intervention.

Minimal residual disease diagnostics in myeloid malignancies in the post transplant period

“…In CML, quantitative measurement of the BCR-ABL-expression level was found to be more suitable for the planning of therapeutic interventions than chimerism. 60,124 In patients relapsing with AML after SCT it was shown that the NPM1 mutations precede the decrease of molecular chimerism and the increase of the FLT3-LM in doublemutated cases by intervals of 2-3 weeks, 28 but this has to be confirmed by additional studies and such comparisons are missing for other markers in myeloid malignancies. With respect to chimerism, the different levels of sensitivity as provided by different methods must be taken into account in the interpretation of studies.…”

“…At this time definite recommendations for the intervals between the diagnostic follow-ups are difficult to define, but the intervals of follow-up diagnostics should always consider the kinetics of relapse. In AML frequent monitoring of MRD and of chimerism is recommended 60 to plan immunological intervention as early as possible, 6,7,59 whereas in disorders with slower kinetics such as the CMPD longer intervals might be justified.…”

“…57,73 This approach is time-and labor intensive, but allows a two-log higher sensitivity and therefore can be helpful in unclear cases. 60,74 Following SCT with RIC, Mohty et al 75 found that patients with myeloid malignancies with delayed achievement of full donor CD3 þ T-cell chimerism at day 30 had a relapse risk of 40% in comparison to 0% in patients with full T-cell DC at this time point.…”

“…The introduction of RIC has further increased the clinical importance of chimerism as patients show more frequently mixed chimerism (MC) when compared to standard conditioning regimens. 60 Thus, the interpretation of chimerism results should always include consideration of the conditioning strategies. 61 Recent years showed a shift in the methods, as restriction fragment length polymorphisms now play a minor role.…”

“…66 The sensitivity of these approaches is 0.1-1%, but can be increased considerably by lineage-specific chimerism after fractionation of cells. 60,67 At this time, the most sensitive approaches are quantitative real-time PCR for genetic polymorphisms (10 À4 ) and for Y-specific sequences (10 À5 ). 29,31,61,[67][68][69] However, all assays are very much individualized between different centers, and the interpretation of findings should always include the different levels of sensitivity as achieved by the diverse methods.…”