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. 2021 Nov 4;138(18):1733-1739.
doi: 10.1182/blood.2020010483.

Clonal dynamics and clinical implications of postremission clonal hematopoiesis in acute myeloid leukemia

Tomoyuki Tanaka  1 , Kiyomi Morita  1 , Sanam Loghavi  2 , Feng Wang  3 , Ken Furudate  1   4 , Yuya Sasaki  1 , Latasha Little  3 , Curtis Gumbs  3 , Jairo Matthews  1 , Naval Daver  1 , Naveen Pemmaraju  1 , Courtney D DiNardo  1 , Koji Sasaki  1 , Musa Yilmaz  1 , Tapan M Kadia  1 , Farhad Ravandi  1 , Marina Y Konopleva  1 , Hagop M Kantarjian  1 , Richard E Champlin  5 , Gheath Al-Atrash  5 , Guillermo Garcia-Manero  1 , Sa A Wang  2 , P Andrew Futreal  3 , Koichi Takahashi  1   3
Affiliations

Clonal dynamics and clinical implications of postremission clonal hematopoiesis in acute myeloid leukemia

Tomoyuki Tanaka et al. Blood. .

Abstract

Although clonal hematopoiesis (CH) can precede the development of acute myeloid leukemia (AML), it can also persist after achieving remission. Long-term clonal dynamics and clinical implications of persistent CH are not well understood. Here, we studied the prevalence, dynamics, and clinical implications of postremission CH in 164 AML patients who attained complete remission after induction chemotherapies. Postremission CH was identified in 79 (48%) patients. Postremission CH persisted long term in 91% of the trackable patients despite treatment with various types of consolidation and maintenance therapies. Postremission CH was eradicated in 20 out of 21 (95%) patients who underwent allogeneic stem cell transplant. Although patients with postremission CH as a group had comparable hematopoiesis with those without it, patients with persistent TET2 mutations showed significant neutropenia long term. Postremission CH had little impact on relapse risk, nonrelapse mortality, and incidence of atherosclerotic cardiovascular disease, although the clinical impact of post-CR CH was heterogeneous among different mutations. These data suggest that although residual clonal hematopoietic stem cells are generally resistant to consolidation and maintenance therapies, they retain the ability to maintain normal hematopoiesis and have little impact on clinical outcomes. Larger study is needed to dissect the gene-specific heterogeneity.

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Figures

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Graphical abstract
Figure 1.
Figure 1.
Characteristics, dynamics, and clinical significance of postremission CH in AML. (A) CONSORT diagram for the study cohort. (B) Violin plot showing the distribution of the number of gene mutations detected as post-CR CH. (C) Violin plots showing VAFs of post-CR CH mutations in all patients and based on the mutated genes. (D) Bar graph showing the number of mutations detected as persistent preleukemic CH (red bar) or emerging CH (blue bar). (E) Box plots comparing the age of patients with or without post-CR CH (*P < .001). (F-G) Representative cases with clonal dynamics of persistent preleukemic CH (F), emerging CH (G), and post-CR CH cleared by allo-SCT (H). (I) The summary of the clonal trajectories of post-CR CH in the 43 patients in whom we were able to track the long-term clonal dynamics. (J-K) The long-term trend of peripheral blood counts in patients with (red line) and without post-CR CH (black line). Patients with post-CR CH had significantly lower absolute neutrophil counts (ANC) and platelets (PLT) at the beginning (day 0 corresponds to the first attainment of CR), but later the difference became insignificant. *P < .001. (L) Cumulative incidence of relapse in post-CR CH-patients (black line) and in post-CR CH+ patients (red line). (M) Nonrelapse mortality in post-CR CH−patients (black line) and in post-CR CH+ patients (red line). Data were censored at the time of allo-SCT in first CR. BM, bone marrow; CLIA, cladribine, idarubicin, and cytarabine; FAI, fludarabine, idarubicin, and cytarabine.
Figure 1.
Figure 1.
Characteristics, dynamics, and clinical significance of postremission CH in AML. (A) CONSORT diagram for the study cohort. (B) Violin plot showing the distribution of the number of gene mutations detected as post-CR CH. (C) Violin plots showing VAFs of post-CR CH mutations in all patients and based on the mutated genes. (D) Bar graph showing the number of mutations detected as persistent preleukemic CH (red bar) or emerging CH (blue bar). (E) Box plots comparing the age of patients with or without post-CR CH (*P < .001). (F-G) Representative cases with clonal dynamics of persistent preleukemic CH (F), emerging CH (G), and post-CR CH cleared by allo-SCT (H). (I) The summary of the clonal trajectories of post-CR CH in the 43 patients in whom we were able to track the long-term clonal dynamics. (J-K) The long-term trend of peripheral blood counts in patients with (red line) and without post-CR CH (black line). Patients with post-CR CH had significantly lower absolute neutrophil counts (ANC) and platelets (PLT) at the beginning (day 0 corresponds to the first attainment of CR), but later the difference became insignificant. *P < .001. (L) Cumulative incidence of relapse in post-CR CH-patients (black line) and in post-CR CH+ patients (red line). (M) Nonrelapse mortality in post-CR CH−patients (black line) and in post-CR CH+ patients (red line). Data were censored at the time of allo-SCT in first CR. BM, bone marrow; CLIA, cladribine, idarubicin, and cytarabine; FAI, fludarabine, idarubicin, and cytarabine.
Figure 1.
Figure 1.
Characteristics, dynamics, and clinical significance of postremission CH in AML. (A) CONSORT diagram for the study cohort. (B) Violin plot showing the distribution of the number of gene mutations detected as post-CR CH. (C) Violin plots showing VAFs of post-CR CH mutations in all patients and based on the mutated genes. (D) Bar graph showing the number of mutations detected as persistent preleukemic CH (red bar) or emerging CH (blue bar). (E) Box plots comparing the age of patients with or without post-CR CH (*P < .001). (F-G) Representative cases with clonal dynamics of persistent preleukemic CH (F), emerging CH (G), and post-CR CH cleared by allo-SCT (H). (I) The summary of the clonal trajectories of post-CR CH in the 43 patients in whom we were able to track the long-term clonal dynamics. (J-K) The long-term trend of peripheral blood counts in patients with (red line) and without post-CR CH (black line). Patients with post-CR CH had significantly lower absolute neutrophil counts (ANC) and platelets (PLT) at the beginning (day 0 corresponds to the first attainment of CR), but later the difference became insignificant. *P < .001. (L) Cumulative incidence of relapse in post-CR CH-patients (black line) and in post-CR CH+ patients (red line). (M) Nonrelapse mortality in post-CR CH−patients (black line) and in post-CR CH+ patients (red line). Data were censored at the time of allo-SCT in first CR. BM, bone marrow; CLIA, cladribine, idarubicin, and cytarabine; FAI, fludarabine, idarubicin, and cytarabine.
Figure 1.
Figure 1.
Characteristics, dynamics, and clinical significance of postremission CH in AML. (A) CONSORT diagram for the study cohort. (B) Violin plot showing the distribution of the number of gene mutations detected as post-CR CH. (C) Violin plots showing VAFs of post-CR CH mutations in all patients and based on the mutated genes. (D) Bar graph showing the number of mutations detected as persistent preleukemic CH (red bar) or emerging CH (blue bar). (E) Box plots comparing the age of patients with or without post-CR CH (*P < .001). (F-G) Representative cases with clonal dynamics of persistent preleukemic CH (F), emerging CH (G), and post-CR CH cleared by allo-SCT (H). (I) The summary of the clonal trajectories of post-CR CH in the 43 patients in whom we were able to track the long-term clonal dynamics. (J-K) The long-term trend of peripheral blood counts in patients with (red line) and without post-CR CH (black line). Patients with post-CR CH had significantly lower absolute neutrophil counts (ANC) and platelets (PLT) at the beginning (day 0 corresponds to the first attainment of CR), but later the difference became insignificant. *P < .001. (L) Cumulative incidence of relapse in post-CR CH-patients (black line) and in post-CR CH+ patients (red line). (M) Nonrelapse mortality in post-CR CH−patients (black line) and in post-CR CH+ patients (red line). Data were censored at the time of allo-SCT in first CR. BM, bone marrow; CLIA, cladribine, idarubicin, and cytarabine; FAI, fludarabine, idarubicin, and cytarabine.
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