Myeloid Mixed Chimerism and Relapse in Myelofibrosis after Allogeneic Stem Cell Transplant

Background:Allogeneic stem cell transplant (SCT) remains the only potential curative treatment for myelofibrosis (MF). However, relapse after transplant is one of the leading causes of death. The role of mixed myeloid chimerism (MMC) in predicting post-transplant molecular and morphologic relapse is not well studied.

Methods: Using a large single-center database, all consecutive patients with primary or secondary MF who underwent first allogeneic SCT in the period 2005-2015 were included in the study. Patients were defined to have MMC if they were found to have less than 95% of donor myeloid cells at any point over the duration of their follow up. Peripheral blood chimerism analysis was performed using 8 highly polymorphic microsatellite markers (Integrated DNA Technologies, Coralville, IA) in a multiplex PCR assay. The primary end point was to assess the correlation of MMC with any evidence of morphologic and/or molecular relapse.

Results: A total of 85 patients (47 males, 38 females) were identified with a median age at transplant of 57 years (27-74). Among patients with molecular data (n=80), 60% had positive pre-transplant molecular markers. A total of 36 (43%) patients with full chimerism data (n=83) had MMC. All patients with MMC developed morphologic and/or molecular relapse, except for two; the first patient converted to full donor chimerism after immunosuppression reduction and the second patient had progressive myeloid chimerism and graft failure. Among patients with positive molecular testing and available chimerism data (n=46), 22 patients had MMC, of which 95% (n=21) had molecular relapse. Similarly, for patients with available chimerism data and negative pre-transplant molecular testing (n=32), 93% (n=14) of the 15 patients with MMC experienced eventual morphologic relapse. On the other hand, none of the patients with full donor myeloid chimerism (n=47) progressed during the study period, except for one patient with mixed T-Cell chimerism. With a median follow up of 49 months, the 5-year PFS was 7% for those with MMC vs 62% for patients with full donor myeloid chimerism (p<0.0001).

Conclusion: Given the high sensitivity of chimera PCR DNA testing and its strong association with molecular and morphologic relapse, we speculate that myeloid chimerism testing, alone or combined with clonal molecular testing, would serve as one of the earliest and best markers to predict MRD and relapse in myelofibrosis post-transplant.