Sex-Based Differences in Risk of Therapy-Related Myeloid Neoplasms

Abstract

Purpose: Therapy-related myeloid neoplasm (t-MN) is a life-threatening complication of autologous peripheral blood stem cell (PBSC) transplantation for non-Hodgkin lymphoma (NHL). Previous studies report an association between clonal hematopoiesis (CH) in PBSC and risk of t-MN, but small samples precluded examination of risk within specific subpopulations.

Methods: Targeted DNA sequencing was performed to identify CH mutations in PBSC from a retrospective cohort of 984 patients with NHL (median age at transplant, 57 years; range, 18-78). Fine-Gray proportional subdistribution hazard regression models estimated association between number of CH mutations and t-MN, adjusting for demographic, clinical, and therapeutic variables. Secondary analyses evaluated the association between CH and t-MN among males and females.

Results: CH was identified in PBSC from 366 patients (37.2%). t-MN developed in 60 patients after a median follow-up of 5 years. Presence of ≥2 mutations conferred increased t-MN risk (adjusted hazard ratio [aHR], 2.10; 95% CI [1.08 to 4.11]; P = .029). CH was associated with increased t-MN risk among males (aHR, 1.83 [95% CI, 1.01 to 3.31]) but not females (aHR, 0.56 [95% CI, 0.15 to 2.09]). Although the prevalence and type of CH mutations in PBSC were comparable, the 8-year cumulative incidence of t-MN was higher among males vs. females with CH (12.4% v 3.6%) but was similar between males and females without CH (4.9% v 3.9%). Expansion of CH clones from PBSC to t-MN was seen only among males.

Conclusion: presence of CH mutations in PBSC confers increased risk of t-MN after autologous transplantation in male but not female patients with NHL. Factors underlying sex-based differences in risk of CH progression to t-MN merit further investigation.

Figure 1.. Clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Cumulative incidence of therapy-related myeloid neoplasms (t-MN) among patients receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). B. Cumulative incidence of t-MN by presence of clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product.

Figure 1.. Clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Cumulative incidence of therapy-related myeloid neoplasms (t-MN) among patients receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). B. Cumulative incidence of t-MN by presence of clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product.

Figure 1.. Clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Cumulative incidence of therapy-related myeloid neoplasms (t-MN) among patients receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). B. Cumulative incidence of t-MN by presence of clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product.

Figure 1.. Clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Cumulative incidence of therapy-related myeloid neoplasms (t-MN) among patients receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). B. Cumulative incidence of t-MN by presence of clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product.

Figure 2.. Association between clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma by sex.

A. Proportion of males and females with clonal hematopoiesis (CH) in the peripheral blood stem cell (PBSC) product and subsequent therapy-related myeloid neoplasm (t-MN). B. Cumulative incidence of t-MN among males and females receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product among males and females with NHL. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product among males and females with NHL.

Figure 2.. Association between clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma by sex.

A. Proportion of males and females with clonal hematopoiesis (CH) in the peripheral blood stem cell (PBSC) product and subsequent therapy-related myeloid neoplasm (t-MN). B. Cumulative incidence of t-MN among males and females receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product among males and females with NHL. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product among males and females with NHL.

Figure 2.. Association between clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma by sex.

A. Proportion of males and females with clonal hematopoiesis (CH) in the peripheral blood stem cell (PBSC) product and subsequent therapy-related myeloid neoplasm (t-MN). B. Cumulative incidence of t-MN among males and females receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product among males and females with NHL. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product among males and females with NHL.

Figure 2.. Association between clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma by sex.

A. Proportion of males and females with clonal hematopoiesis (CH) in the peripheral blood stem cell (PBSC) product and subsequent therapy-related myeloid neoplasm (t-MN). B. Cumulative incidence of t-MN among males and females receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product among males and females with NHL. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product among males and females with NHL.

Figure 2.. Association between clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma by sex.

A. Proportion of males and females with clonal hematopoiesis (CH) in the peripheral blood stem cell (PBSC) product and subsequent therapy-related myeloid neoplasm (t-MN). B. Cumulative incidence of t-MN among males and females receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product among males and females with NHL. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product among males and females with NHL.

Figure 2.. Association between clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma by sex.

A. Proportion of males and females with clonal hematopoiesis (CH) in the peripheral blood stem cell (PBSC) product and subsequent therapy-related myeloid neoplasm (t-MN). B. Cumulative incidence of t-MN among males and females receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product among males and females with NHL. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product among males and females with NHL.

Figure 2.. Association between clonal hematopoiesis and incidence of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma by sex.

A. Proportion of males and females with clonal hematopoiesis (CH) in the peripheral blood stem cell (PBSC) product and subsequent therapy-related myeloid neoplasm (t-MN). B. Cumulative incidence of t-MN among males and females receiving autologous peripheral blood stem cell transplantation (aPBSCT) for non-Hodgkin lymphoma (NHL). C. Cumulative incidence of t-MN by number of CH mutations in the PBSC product among males and females with NHL. D. Cumulative incidence of t-MN by variant allele frequency (VAF) of CH mutations in the PBSC product among males and females with NHL.

Figure 3.. Sex-related difference in common clonal hematopoiesis mutations and risk of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Proportion of male and female patients with common clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. B. Proportion of male and female patients with common CH mutations in the PBSC product among males and females who subsequently develop t-MN. C. Distribution of variant allele frequency (VAF) of commonly mutated CH genes in the PBSC product among males and females and by subsequent development of t-MN. D. Adjusted hazard of t-MN by presence of CH mutations in PBSC among males. E. Adjusted hazard of t-MN by presence of CH mutations in PBSC among females. F. CH mutations in the PBSC product and at time of t-MN and associated cytogenetic abnormalities, organized by presence and absence of CH in PBSC and by male and female sex. TP53: presence of TP53 mutation (with or without additional CH mutations); PPM1D: presence of PPM1D mutation without co-occurring TP53 mutation; DNMT3A: presence of DNMT3A mutation without co-occurring TP53 or PPM1D mutation; Other CH: CH mutations other than TP53, PPM1D and TP53 mutations; No CH: no mutation detected; Del 5/Del 7: deletion chromosome 5/5q and/or deletion chromosome 7/7q; Translocation: rearrangements of chromosomes 11q23, 21q22 and BCR-ABL rearrangement; Other CH: includes deletions of chromosome 20, 13 and trisomy 8; Normal: no cytogenetic abnormality.

Figure 3.. Sex-related difference in common clonal hematopoiesis mutations and risk of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Proportion of male and female patients with common clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. B. Proportion of male and female patients with common CH mutations in the PBSC product among males and females who subsequently develop t-MN. C. Distribution of variant allele frequency (VAF) of commonly mutated CH genes in the PBSC product among males and females and by subsequent development of t-MN. D. Adjusted hazard of t-MN by presence of CH mutations in PBSC among males. E. Adjusted hazard of t-MN by presence of CH mutations in PBSC among females. F. CH mutations in the PBSC product and at time of t-MN and associated cytogenetic abnormalities, organized by presence and absence of CH in PBSC and by male and female sex. TP53: presence of TP53 mutation (with or without additional CH mutations); PPM1D: presence of PPM1D mutation without co-occurring TP53 mutation; DNMT3A: presence of DNMT3A mutation without co-occurring TP53 or PPM1D mutation; Other CH: CH mutations other than TP53, PPM1D and TP53 mutations; No CH: no mutation detected; Del 5/Del 7: deletion chromosome 5/5q and/or deletion chromosome 7/7q; Translocation: rearrangements of chromosomes 11q23, 21q22 and BCR-ABL rearrangement; Other CH: includes deletions of chromosome 20, 13 and trisomy 8; Normal: no cytogenetic abnormality.

Figure 3.. Sex-related difference in common clonal hematopoiesis mutations and risk of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Proportion of male and female patients with common clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. B. Proportion of male and female patients with common CH mutations in the PBSC product among males and females who subsequently develop t-MN. C. Distribution of variant allele frequency (VAF) of commonly mutated CH genes in the PBSC product among males and females and by subsequent development of t-MN. D. Adjusted hazard of t-MN by presence of CH mutations in PBSC among males. E. Adjusted hazard of t-MN by presence of CH mutations in PBSC among females. F. CH mutations in the PBSC product and at time of t-MN and associated cytogenetic abnormalities, organized by presence and absence of CH in PBSC and by male and female sex. TP53: presence of TP53 mutation (with or without additional CH mutations); PPM1D: presence of PPM1D mutation without co-occurring TP53 mutation; DNMT3A: presence of DNMT3A mutation without co-occurring TP53 or PPM1D mutation; Other CH: CH mutations other than TP53, PPM1D and TP53 mutations; No CH: no mutation detected; Del 5/Del 7: deletion chromosome 5/5q and/or deletion chromosome 7/7q; Translocation: rearrangements of chromosomes 11q23, 21q22 and BCR-ABL rearrangement; Other CH: includes deletions of chromosome 20, 13 and trisomy 8; Normal: no cytogenetic abnormality.

Figure 3.. Sex-related difference in common clonal hematopoiesis mutations and risk of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Proportion of male and female patients with common clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. B. Proportion of male and female patients with common CH mutations in the PBSC product among males and females who subsequently develop t-MN. C. Distribution of variant allele frequency (VAF) of commonly mutated CH genes in the PBSC product among males and females and by subsequent development of t-MN. D. Adjusted hazard of t-MN by presence of CH mutations in PBSC among males. E. Adjusted hazard of t-MN by presence of CH mutations in PBSC among females. F. CH mutations in the PBSC product and at time of t-MN and associated cytogenetic abnormalities, organized by presence and absence of CH in PBSC and by male and female sex. TP53: presence of TP53 mutation (with or without additional CH mutations); PPM1D: presence of PPM1D mutation without co-occurring TP53 mutation; DNMT3A: presence of DNMT3A mutation without co-occurring TP53 or PPM1D mutation; Other CH: CH mutations other than TP53, PPM1D and TP53 mutations; No CH: no mutation detected; Del 5/Del 7: deletion chromosome 5/5q and/or deletion chromosome 7/7q; Translocation: rearrangements of chromosomes 11q23, 21q22 and BCR-ABL rearrangement; Other CH: includes deletions of chromosome 20, 13 and trisomy 8; Normal: no cytogenetic abnormality.

Figure 3.. Sex-related difference in common clonal hematopoiesis mutations and risk of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Proportion of male and female patients with common clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. B. Proportion of male and female patients with common CH mutations in the PBSC product among males and females who subsequently develop t-MN. C. Distribution of variant allele frequency (VAF) of commonly mutated CH genes in the PBSC product among males and females and by subsequent development of t-MN. D. Adjusted hazard of t-MN by presence of CH mutations in PBSC among males. E. Adjusted hazard of t-MN by presence of CH mutations in PBSC among females. F. CH mutations in the PBSC product and at time of t-MN and associated cytogenetic abnormalities, organized by presence and absence of CH in PBSC and by male and female sex. TP53: presence of TP53 mutation (with or without additional CH mutations); PPM1D: presence of PPM1D mutation without co-occurring TP53 mutation; DNMT3A: presence of DNMT3A mutation without co-occurring TP53 or PPM1D mutation; Other CH: CH mutations other than TP53, PPM1D and TP53 mutations; No CH: no mutation detected; Del 5/Del 7: deletion chromosome 5/5q and/or deletion chromosome 7/7q; Translocation: rearrangements of chromosomes 11q23, 21q22 and BCR-ABL rearrangement; Other CH: includes deletions of chromosome 20, 13 and trisomy 8; Normal: no cytogenetic abnormality.

Figure 3.. Sex-related difference in common clonal hematopoiesis mutations and risk of therapy-related myeloid neoplasms following autologous peripheral blood stem cell transplantation for non-Hodgkin lymphoma.

A. Proportion of male and female patients with common clonal hematopoiesis (CH) mutations in the peripheral blood stem cell (PBSC) product. B. Proportion of male and female patients with common CH mutations in the PBSC product among males and females who subsequently develop t-MN. C. Distribution of variant allele frequency (VAF) of commonly mutated CH genes in the PBSC product among males and females and by subsequent development of t-MN. D. Adjusted hazard of t-MN by presence of CH mutations in PBSC among males. E. Adjusted hazard of t-MN by presence of CH mutations in PBSC among females. F. CH mutations in the PBSC product and at time of t-MN and associated cytogenetic abnormalities, organized by presence and absence of CH in PBSC and by male and female sex. TP53: presence of TP53 mutation (with or without additional CH mutations); PPM1D: presence of PPM1D mutation without co-occurring TP53 mutation; DNMT3A: presence of DNMT3A mutation without co-occurring TP53 or PPM1D mutation; Other CH: CH mutations other than TP53, PPM1D and TP53 mutations; No CH: no mutation detected; Del 5/Del 7: deletion chromosome 5/5q and/or deletion chromosome 7/7q; Translocation: rearrangements of chromosomes 11q23, 21q22 and BCR-ABL rearrangement; Other CH: includes deletions of chromosome 20, 13 and trisomy 8; Normal: no cytogenetic abnormality.