Scott D. Rowley, Maher Albitar, Melissa F. Baker, Alaa Ali, Sukhdeep Kaur, Hyung C. Suh, Andre Goy and Michele L. Donato.
Simple Summary: Relapse of disease is a primary cause of treatment failure after allogeneic bone marrow transplantation. Patients may benefit from post-transplant consolidation therapy, but such therapy poses serious risks requiring careful balancing with the potential benefits. We performed a pilot study detecting disease-associated somatic mutations by measuring cell-free DNA (cfDNA) in the plasma after transplantation. We found that clearance or persistence of adverse-risk defining mutations tested as early as 28 days after transplantation identified patients at low or high risk of relapse. These data support the hypothesis that testing cfDNA early after transplantation will identify individual patients who may benefit from early modification of their treatment plans to reduce the risk of relapse. Testing for cfDNA may be also useful in the design and interpretation of clinical protocols testing various conditioning and GvHD regimens and post-transplant consolidation techniques in which disease relapse is a primary or secondary endpoint.
Abstract: Background: Disease relapse is a primary cause of treatment failure after hematopoietic stem cell transplantation in the treatment of malignancy. Consolidation therapy early after transplantation may reduce this risk, but it is difficult to administer in the setting of various post-transplant complications. We proposed that testing donor cell chimerism and for persistent minimal residual disease (MRD) with next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) early after transplantation would identify those patients at higher risk of relapse who would possibly benefit from consolidation therapy. Methods: We enrolled 20 subjects with known tumor-associated somatic mutations into this prospective pilot study, testing plasma samples before and at 28, 56, and 84 days after transplantation. Pre- and post-transplant bone marrow samples were also analyzed. All samples were subjected to an agnostic, commercially available panel covering 302 genes. Results: Significantly more mutations (p < 0.0001) were detected in the plasma cfDNA than in the bone marrow cells in pre-transplant testing (92 versus 61 mutations, respectively), most likely reflecting sampling variation when bone marrow was used. Two subjects were negative for MRD in staging studies immediately before transplants. Most (19/20) subjects had intermittent or sustained MRD detected in post-transplant plasma cfDNA testing, albeit with much lower average variant allele frequencies (VAFs). Six out of 20 subjects suffered relapses within 12 months after transplantation, and all 6 could be identified by adverse-risk driver mutations that persisted after transplantation. No patients who cleared the adverse-risk mutations relapsed. Donor chimerism using cfDNA fell for all relapsed patients and contributed to the identification of patients at early risk for relapse. Conclusions: These data demonstrate that testing plasma cfDNA for persistent leukemia-associated somatic mutations and donor chimerism as early as 28 days after transplantation will identify a subset of patients with high-risk mutations who are at high risk of relapse. This early assessment of relapse risk may facilitate modifications to the treatment plan, reducing the risk of treatment failure.
Keywords: cell-free DNA; next-generation sequencing; allogeneic hematopoietic cell transplantation; post-transplant relapse