Clonal Hematopoiesis of Indeterminate Potential at time of ASCT associated with poor outcome and increased risk of Therapy-related Myeloid Neoplasm in patients with NHL

On 9^th January 2017, in the Journal of Clinical Oncology, Christopher J. Gibson of the Dana-Farber Cancer Institute, US, and colleagues published whole-exome sequencing and target sequencing data exploring the effect of Clonal Hematopoiesis of Indeterminate Potential (CHIP) at the time of ASCT on the following consequent outcomes in lymphoma patients: Therapy-related Myeloid Neoplasm (TMN) incidence, cause-specific mortality, and OS. Whole-exome sequencing used blood and bone marrow samples from lymphoma patients who developed TMN after ASCT and targeted sequencing used DNA purified from aliquots of mobilized stem cells collected from NHL patients before ASCT.

Key Highlights:

• Whole-exome sequencing (n = 12)
  • In TMN samples, 8/12 pts had ≥1 mutation in a known myeloid malignancy driver gene
  • At least one somatic mutation in TMN sample was also detected in pre-ASCT samples at a VAF of ≥0.02 in 6/8 pts
  • Genes mutated in both samples included TP53 (n = 3), PPM1D (n = 2), and TET2 (n = 2); one patient harbored two mutations
• Targeted sequencing of 86 genes (n = 401)
  • One or more pathogenic somatic mutation detected in 120/410 (29.9%) at time of ASCT
  • The most frequently mutated gene was PPM1D; 55 mutations in 48 pts
  • OS in PPM1D-mutated pts was worse compared to pts with other mutations (10-yr survival = 20.8% vs 9%, respectively; P = 0.02)
  • Median age of pts with CHIP at ASCT vs those without CHIP was 61 yrs and 57yrs, respectively (P < 0.001)
  • Cumulative incidence of TMN in pts with CHIP compared to pts without CHIP was 7.4% vs7% at 5 yrs, and 14.1% vs 4.3% at 10 yrs (P =0.002)
  • On multivariate analysis, receiving a nucleoside analog (Sub-distribution Hazard Ratio [SHR], 2.9; 95% CI, 1.1–7.3; P = 0.03), lifetime dose of cyclophosphamide >10 g/m² including mobilization (SHR, 4.6; range, 1.7–12.5; P = .003), and CHIP (SHR, 3.7; range, 1.4–9.9; P = 0.009) were significantly associated with risk of TMN
  • OS of pts with CHIP compared to pts without CHIP was 59.9% vs 4% at 5 yrs after ASCT, and 30.4% vs 60.9% at 10 yrs after ASCT (HR, 1.8; 95% CI, 1.4–2.8; P < 0.001)
  • Survival difference mainly due to increased risk of non-relapse mortality in pts with CHIP compared to pts without CHIP, at 10 yrs was 26.2% and 11.1%, respectively (P < 0.001)
  • The rate of death due to TMN was higher in pts with CHIP compared to pts without CHIP, with cumulative incidence of 2.6% vs 4% at 5 yrs, and 7.6% vs 0.4% at 10 yrs (P = 0.001)
  • Risk of death due to ischemic cardiovascular disease was higher in pts with CHIP (5 deaths) compared to pts without CHIP (2 deaths); cumulative incidence of 4.3% vs 3% (P = 0.03)

In this study of lymphoma patients undergoing ASCT, it was found that CHIP at the time of ASCT is associated with significantly poor survival outcomes, driven mainly by higher risk of non-relapse mortality including a higher risk of death from cardiovascular disease and TMN. The authors recommend that, based on this finding, prospective evaluation is required of CHIP in previously untreated patients, with a particular focus on how clonal expansion is affected by pre-ASCT therapy. The authors also stated that whole-exome sequencing suggests that, at the time of ASCT, CHIP is common in lymphoma patients who develop TMN, and their targeted sequencing data are consistent with others who found that CHIP is associated with older age. The authors recommend that clinical trials need to investigate alternative treatments other than ASCT for patients with CHIP and high-risk lymphoma, such as allogeneic transplantation or targeted therapies specific to mutated CHIP genes such as TP53 and PPM1D.

Abstract:

Purpose
Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes.

Methods
We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010. We assessed the effect of CHIP at the time of ASCT on subsequent outcomes, including TMN, cause-specific mortality, and overall survival.

Results
For six of 12 patients in the exome sequencing cohort, mutations found in the TMN specimen were also detectable in the pre-ASCT specimen. In the targeted sequencing cohort, 120 patients (29.9%) had CHIP at the time of ASCT, which was associated with an increased rate of TMN (10-year cumulative incidence, 14.1% v 4.3% for those with and without CHIP, respectively; P = .002). Patients with CHIP had significantly inferior overall survival compared with those without CHIP (10-year overall survival, 30.4% v 60.9%, respectively; P < .001), including increased risk of death from TMN and cardiovascular disease.

Conclusion
In patients undergoing ASCT for lymphoma, CHIP at the time of transplantation is associated with inferior survival and increased risk of TMN.