DNA Repair Gene-Related CHIP Is a Marker for Worse Outcomes in Patients With Lymphoma

In contrast to findings from previously conducted retrospective single-center studies, results of a study of a large population-based cohort of patients with lymphoma undergoing autologous hematopoietic stem cell (HSC) harvesting showed no independent association between the general presence of clonal hematopoiesis of indeterminate origin (CHIP) and overall survival. These findings were published in Leukemia.¹

In normal hematopoiesis, a single type of HSC accounts for only a very low percentage of the overall HSCs present. However, in the case of CHIP, a single HSC clone can expand to comprise 10% or more of the overall HSC population.² Specifically, CHIP has often been defined as the presence of somatic mutations in HSCs at a variant gene frequency of 2% or higher.³  

Although CHIP can occur in individuals without a known hematologic malignancy, previous retrospective studies of patients with cancer conducted at single centers with varying amounts of follow-up have shown worse clinical outcomes in those with CHIP compared with patients without this condition.

This large population-based study included data for 565 adult patients from 5 independent national stem cell harvest registries from Denmark who underwent autologous HSC harvesting between January 1, 2000, and July 1, 2012, followed by high-throughput DNA sequencing of HSC specimens.

Although this was a retrospective analysis, specimen collection and clinical follow-up were performed prospectively. The main aims of this study was to evaluate the impact of CHIP on survival, as well as the tolerability of autologous-HSC transplantation (ASCT).

Immediate HSCT was planned for 440 of these patients, and only this subgroup was included in the survival analysis. The percentages of lymphoma subtypes represented in this subgroup were as follows: diffuse large B-cell lymphoma (DLBCL; 37%), follicular lymphoma (8%), Hodgkin lymphoma (15%), mantle cell lymphoma (19%), peripheral T-cell lymphoma (PTCL; 17%) and other lymphoma subtypes (4%).

In the patient subgroup for which immediate HSCT was planned, at least 1 CHIP mutation of any type or DNA repair pathway-related CHIP mutation was present in 112 (26%) and 40 patients (9.1%), respectively. Specifically, of the 143 total CHIP mutations identified, 48 (34%) encoded for a regulator of DNA repair (ie, PPM1D, TP53, RAD21, BRCC3). Other types of CHIP mutations were most commonly identified in DNMT3A and TET2.

At a median follow-up of 9.1 years, the overall group had a 15-year overall survival of 40.2%. Although OS was worse in the subgroup with CHIP, these patients were significantly older than those without this condition (P <.0001). No significant difference in OS was found following multivariate analyses adjusting for age and aggressiveness of lymphoma subtype.

In contrast, median OS was 2.2 years and 9.0 years in in the subgroup of patients with CHIP mutations in DNA pathway-associated genes compared with those without these CHIP mutations. Multivariate analyses showed significantly worse late but not early OS for those with these types of CHIP mutations versus not (P = .00067). However, OS was not significantly different for those with common CHIP mutation in non–DNA repair-associated genes compared with those without CHIP mutations.

Another interesting finding of this study was that patients with CHIP mutations in DNA repair genes had a significantly higher risk of being admitted to an intensive care unit compared with those without these mutations (P =.035 on multivariate analysis). Furthermore, this finding was not observed when the overall subgroups of those with and without any CHIP mutations were compared.

In their concluding remarks, the study authors commented that “this information could aid [in] the identification of patients with lymphoma who are susceptible to adverse outcomes after ASCT.”

References

1. Husby S, Favero F, Nielsen C, et al. Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study [published online March 20, 2020]. Leukemia. doi: 10.1038/s41375-020-0795-z
2. Steensma, DP. Up-to-Date. Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis. Accessed April 6, 2020.
3. Steensma DP, Bejar R, Jaiswal S, et al Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndrome. Blood. 2015;126:9-16.