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 61^st 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 TET2, SRSF2, and IDH2. For emerging CH, the most common mutations have been observed in the following genes: JAK2, RUNX1, TET2, BRAF, BCOR, TP53, KDM6A, 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