Post-Allogeneic Monitoring with Molecular Markers Detected by Pre-Transplant Next Generation Sequencing (NGS) Predicts Clinical Relapse in Patients with Chronic Myelomonocytic Leukemia (CMML)

Abstract 4212

Allogeneic stem cell transplantation remains the only curative treatment approach for chronic myelomonocytic leukemia (CMML), but relapse is the major cause of treatment failure. Here, we evaluated the impact of molecular mutations on outcome and the value of molecular monitoring post transplantation in patients with CMML. We screened 45 patients with a median age of 57 years (range: 24–73 years) who underwent allogeneic SCT pre transplant for molecular markers including a sensitive next-generation sequencing (NGS) technique. Of those, 7 were transformed to secondary acute myeloid leukemia, 5 were classified as MDS/MPN overlap and one patient as atypical CML. In 36 patients sufficient DNA was available for molecular analyses for ASXL1, CBL, NRAS and TET2, mutations. In particular, TET2 and CBL mutations were screened applying amplicon deep-sequencing (454 Life Sciences, Branford, CT).

In 32 patients (89%) at least one mutation could be detected: ASXL1: n=18: 50%; CBL: n=7: 19%; TET2: n=15:42%; NRAS: n= 11: 32%. Allogeneic SCT was performed after reduced intensity (66%) or standard myeloablative (33%) conditioning from related (22%) or unrelated donors (78%). The overall survival at 5 years was 46% (95% CI 28–64%) and the cumulative incidence of relapse at 2 year was 35%. Neither TET2, ASXL1, CBL nor NRAS mutations influenced overall survival significantly.

In 21 surviving patients with at least one positive marker pre transplantation, the corresponding marker was subsequently tested in peripheral blood after a median of 6 months (range 3–9 months) after transplantation.

In 6 (33%) of the patients one of the molecular markers was still detectable: ASXL1: n=3; CBL: n= 3; TET2: n=2, NRAS: n=3) and in 66% the markers were undetectable. In patients who became negative for any molecular marker the cumulative incidence of relapse at 1 year was significantly lower than in the positive tested patients. (15% versus 50%, p = 0.04).

In conclusion, this study shows that molecular monitoring post transplant with molecular markers detected also by NGS pre-transplant can help to predict the risk of relapse and may be used to guide post transplant immune-modulating therapies to prevent clinical relapse. In larger studies sequential monitoring of molecular markers after stem cell transplantation are mandatory to determine optimal timing for predicting relapse and for therapeutic intervention.