# Therapy-related leukemia following autologous transplantation for lymphoma

> **NIH NIH P50** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $638,056

## Abstract

PROJECT SUMMARY
Therapy-related myelodysplasia/acute myeloid leukemia (t-MDS/AML) is a lethal complication of autologous
hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma NHL). The
10-year cumulative incidence of t-MDS/AML is ~6% to 8%. Post-aHCT t-MDS/AML is associated with older age
at aHCT, pre-aHCT exposure to alkylators, etoposide and radiation, peripheral blood stem cell (PBSC)
mobilization with etoposide, and conditioning with total body irradiation (TBI). t-MDS/AML is characterized by
poor response to conventional chemotherapy, and median survival of <10 months. t-MDS/AML is the leading
cause of non-relapse mortality among aHCT recipients for HL/NHL. It is generally believed that hematopoietic
stem cells (HSCs) exposed to cytotoxic therapy suffer genomic damage leading to malignant transformation.
However, high inter-individual variation in t-MDS/AML risk suggests a potential role for genetic susceptibility.
Previous reports (using a candidate gene approach) suggest an association between germline single nucleotide
polymorphisms (SNPs) and t-MDS/AML risk. We are conducting a genome-wide association study (GWAS:
Illumina® HumanOmni5-Quad BeadChip platform; 303 cases; 606 controls) to identify germline variants
associated with t-MDS/AML; top SNPs will contribute to creation of genetic profile. Somatic mutations in
leukemia-associated genes DNMT3A, ASXL1, and TET2 seen in peripheral blood in ~10% of older healthy
population, are associated with >10-fold increase in risk for subsequent leukemia; targeted next-generation
sequencing will be used to identify driver mutations. We observed altered gene expression in PBSC samples
from patients who subsequently developed t-MDS/AML when compared with patients who did not. This
information was used to develop a 38-gene PBSC classifier in an independent test set; this classifier will also
contribute to the genomic profile. The elevated risk of t-MDS/AML after aHCT, coupled with the poor prognosis,
present an unmet need for pre-aHCT identification of patients at increased risk for post-aHCT t-MDS/AML to
guide use of alternative therapeutic options for HL/NHL management. We hypothesize that a combined clinical
and genetic risk prediction model applied prior to aHCT will allow identification of HL/NHL patients at increased
risk for post-aHCT t-MDS/AML. The City of Hope cohort with the available PBSC products will serve as the
Discovery cohort (n=1,915). aHCT recipients for HL/NHL with PBSC product at the University of Nebraska or
University of Minnesota will be utilized as an independent Validation cohort (n=2,036). The two cohorts will be
used to develop a prediction model that includes clinical predictors (therapeutic exposures, conditioning, stem
cell mobilization and CD34+ cell dose) and genetic factors (SNPs, gene expression profile and clonal somatic
mutations) to optimize pre-aHCT identification of HL/NHL patients at highest risk for t-MDS/AML after aHCT.
...

## Key facts

- **NIH application ID:** 9998908
- **Project number:** 5P50CA107399-13
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Smita Bhatia
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $638,056
- **Award type:** 5
- **Project period:** 2004-09-02 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998908

## Citation

> US National Institutes of Health, RePORTER application 9998908, Therapy-related leukemia following autologous transplantation for lymphoma (5P50CA107399-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998908. Licensed CC0.

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