General AML

Long-term clonal dynamics of post-remission clonal hematopoiesis in patients with acute myeloid leukemia (AML)

Clonal hematopoiesis (CH) can precede the development of AML, but can also persist after complete remission (CR).1 In rare cases, non-leukemic CH can emerge after remission.2 Patients with AML that have post-CR CH have delayed platelet and neutrophil recovery.3 Unfortunately, the long-term clonal dynamics of post-CR CH in patients with AML during consolidation or maintenance therapies are not well understood.

At the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Tomoyuki Tanaka, Department of Leukemia, MD Anderson Cancer Center, Houston, US, discussed the results from a study analyzing the clonal behavior of post-CR CH during consolidation and maintenance therapies, in samples from patients with AML after remission.4

Study design4

  • Bone marrow samples were collected from 176 AML patients who attained CR after either intensive induction therapy (n= 135) or low intensity chemotherapy (n= 41). Of these samples, paired bone marrow samples from 164 patients were analyzed by targeted deep sequencing of 295 genes. Among these patients, 79 were post-CR CH positive and 85 were post-CR CH negative
  • Patients who were post-CR CH positive were defined as:
    • Persistent CH, when patients had mutations that were originally detected in AML and persisted after CR with variant allele frequency > 2.5%
    • Emerging CH, when patients had new mutations arising after CR
  • Patients who were included had received different types of therapies:
    • High-dose chemotherapy, such as clofarabine, idarubicin, and cytarabine
    • Immunomodulating agents such as lenalidomide or nivolumab
    • Experimental drugs such as SGI-110, SL-401, PRI-724
    • Allogeneic hematopoietic stem cell transplantation (allo-SCT)
    • Hypomethylating agents (HMA) or low-dose cytarabine +/- venetoclax or gemtuzumab ozogamicin

Results4

  • Patients with post-CR CH were:
    • Significantly older than patients that did not have post-CR CH (58 years [range; 23–85] vs 47 years [range; 17–81], respectively; p< 0.001)
    • Treated with low intensity therapy (35% vs 12%, respectively) which included low dose cytarabine-based or HMA-based agents
  • The most commonly mutated genes for persistent CH were DNMT3A, followed by TET2SRSF2, and IDH2. For emerging CH, the most common mutations have been observed in the following genes: JAK2RUNX1TET2BRAFBCORTP53KDM6A, and NRAS
  • Among 48 patients with post-CR CH, consolidation/maintenance chemotherapy had very little impact on the clonal size of post-CR CH, with post-CR CH cleared in only two patients
  • In patients with persistent post-CR CH who underwent allo-SCT (n= 23), post-CR CH was eradicated in 19 patients
  • No significant differences were observed in long-term blood counts (neutrophil, hemoglobin, lymphocyte, monocyte and platelet counts) between post-CR CH positive and no CR CH
  • Post-CR CH did not impact the cumulative risk of relapse, in contrast, patients with post-CR CH had significantly worse overall survival (p= 0.0227), however, this result was confounded by other clinical factors such as age groups and prior therapies

Conclusion4

  • Post-CR CH does often persist long-term in AML patients
  • Consolidation or maintenance therapies do not reduce post-remission CH
  • The majority of patients who undergo allo-SCT were able to achieve post-CR CH clearance
  • Post-CR CH does not affect long-term blood counts and the risk of relapse
References
  1. Jongen-Lavrencic M. et al., Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018 Mar 29;378(13):1189-1199. DOI: 10.1056/NEJMoa1716863
  2. Wong T.N. et al., Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood. 2016 Feb 18;127(7):893-7. DOI: 10.1182/blood-2015-10-677021
  3. Murphy T. et al., Impact of preleukemic mutations and their persistence on hematologic recovery after induction chemotherapy for AML. Blood Adv. 2019 Aug 13;3(15):2307-2311. DOI: 10.1182/bloodadvances.2019000306
  4. Tanaka T. et al., Clonal dynamics and clinical implications of post-remission clonal hematopoiesis in acute myeloid leukemia (AML). Oral Abstracts #17. 2019 Dec 8. 61st American Society of Hematology (ASH) Annual Meeting & Exposition, Orlando, FL
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