CML somatic mutation analysis linked to patient outcome

Blood 2016; Advance online publication

medwireNews: Researchers have identified six different patterns of somatic mutation acquisition, persistence, and clearance in patients with chronic myeloid leukemia (CML), with a significant link between these and tyrosine kinase inhibitor (TKI) therapy response.

The “diverse” patterns are “markedly distinct from other hematologic malignancies,” the team writes in Blood, recommending therefore that “clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.”

Hyeoung Joon Kim, from Chonnam National University in Hwasun, Korea, and co-workers present targeted deep sequencing results for 92 genes commonly mutated in myeloid malignancy in 300 serial samples taken from 100 CML patients.

The patients were treated with imatinib (n=78), nilotinib (n=11), dasatinib (n=8), or radotinib (n=3) and followed-up for a median of 55 months. The majority were responsive to treatment (n=74) but 18 were resistant and eight experienced disease progression.

While genetic analysis found no evidence of genetic variants associated with myeloid malignancy in 63 patients, 37 individuals had 63 different variants of 32 genes. Five genes were non-silently mutated in more than one patient, including ABL1 in six cases. Mutations occurred in ABL1 or genes related to chromatin modification or DNA methylation in 65% of cases, the researchers note.

All eight patients with disease progression had somatic mutations, falling to 61.1% of the patients with resistance and 24.3% of patients who responded to treatment, with a significant difference that demonstrated a “clear association of increasing mutation burden with poor TKI response and progression to advanced disease,” the researchers say.

Further analysis grouped the patients as having no somatic mutations except BCR–ABL fusion (pattern 0) or fitting within one of five patterns based on relative mutation burden at each of the three timepoints.

Specifically, pattern 1 consisted of seven patients who responded to treatment but did not clear their mutations after TKI therapy. The 16 genes altered in this group were not affected in any other patients; nine of the genes affected are involved with transcription and all but the mutation in ASXL1 are more common in myelodysplastic syndromes and acute myeloid leukemia than in CML.

“Since the mutations were not cleared in spite of significant reduction of BCR-ABL transcript level at the time of follow-up, they are likely to be indicative of a preleukemic [Philadelphia chromosome] Ph-negative clone that existed independent of Ph-positive clones,” the researchers hypothesize.

Pattern 2 consisted of nine patients who acquired 13 new somatic variants after TKI therapy; all nine were resistant to treatment or later experienced disease progression. Seven of the mutations occurred in ABL1; these are associated with TKI resistance and were unique to this pattern.

Fifteen patients were grouped in pattern 3, with 17 mutations occurring at a mean variant allele frequency (VAF) that was high at initial diagnosis and reduced or disappeared after TKI treatment. The majority (64.7%) of genes affected play a role in chromatin modification or DNA methylation.

Pattern 3 patients were more likely to have preleukemic mutations in their T cells than other patients (27 vs 7%), leading the authors to believe the mutations were likely to exist concurrently in both Ph-positive and Ph-negative clones. And clinical outcome varied in pattern 3 patients, with six good responses to TKI therapy and nine poor responses.

Patterns 4 and 5 occurred in just three and two patients, respectively, with five mutations in T-cell samples at high VAF, all occurring in genes associated with epigenetic regulation. “These mutations were likely early events that preceded CML leukemogenesis,” the researchers write, explaining that pattern 4 patients had persistent mutations at follow-up whereas pattern 5 patients had mutation clearance.

“The small number of patients exhibiting mutations with these patterns makes generalization difficult, however the presence of preleukemic mutations in the Ph-positive clone at least did not have an obvious effect on treatment outcomes,” they write, noting that three of the patients responded to TKI therapy and two had resistant disease.

Multivariate analysis showed that patients with mutations affecting epigenetic regulation at time of diagnosis had an increased risk of poor response to TKI therapy, regardless of other clinical features, with an odds ratio for cytogenetic response at 12 months of 0.20.

By Lynda Williams, Senior medwireNews Reporter

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