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

In contrast to findings from previously conducted retrospective single-centerstudies, results of a study of a large population-based cohort of patients withlymphoma undergoing autologous hematopoietic stem cell (HSC) harvesting showedno independent association between the general presence of clonal hematopoiesisof indeterminate origin (CHIP) and overall survival. These findings werepublished in Leukemia.1

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

Although CHIP can occur in individuals without a known hematologicmalignancy, previous retrospective studies of patients with cancer conducted atsingle centers with varying amounts of follow-up have shown worse clinicaloutcomes in those with CHIP compared with patients without this condition.

This large population-based study included data for 565 adult patientsfrom 5 independent national stem cell harvest registries from Denmark whounderwent 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 andclinical follow-up were performed prospectively. The main aims of this studywas to evaluate the impact of CHIP on survival, as well as the tolerability ofautologous-HSC transplantation (ASCT).

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

In the patient subgroup for which immediateHSCT was planned, at least 1 CHIP mutation of any type or DNA repair pathway-relatedCHIP 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 ofDNA repair (ie, PPM1D, TP53, RAD21,BRCC3). Other types of CHIP mutations were mostcommonly identified in DNMT3Aand TET2.

At a median follow-up of 9.1 years, the overall group had a 15-yearoverall survival of 40.2%. Although OS was worse in the subgroup with CHIP,these patients were significantly older than thosewithout this condition (P <.0001).No significant difference in OS was found following multivariate analysesadjusting for age and aggressiveness of lymphoma subtype.

Incontrast, median OS was 2.2 years and 9.0 years in inthe subgroup of patients with CHIP mutations in DNA pathway-associated genescompared with those without these CHIP mutations. Multivariateanalyses showed significantly worse late but not early OS for those with these typesof CHIP mutations versus not (P =.00067). However, OS was not significantly different for thosewith common CHIP mutation in nonDNA repair-associated genes compared withthose without CHIP mutations.

Anotherinteresting finding of this study was that patients with CHIP mutations in DNArepair genes had a significantly higher risk of being admitted to an intensivecare unit compared with those without these mutations (P =.035 on multivariate analysis). Furthermore, this finding wasnot observed when the overall subgroups of those with and without any CHIPmutations 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.


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

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