Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06

Abstract

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).

Figure 1.

CONSORT diagram illustrating patient selection. ICE: idarubicin, cytarabine, etoposide; sHD: sequential high-dose chemotherapy; TKI: tyrosine-kinase inhibitors; AML: acute myeloid leukemia; tAML: therapy-related AML; sAML: secondary AML; CS-AML: de novo AML carrying chromatin-spliceosome mutations; MDS: myelodysplastic syndrome; WHO: World Health Orginization; NGS: next-generation squencing.

Figure 2.

Cytogenetic and molecular characteristics of acute myeloid leukemia categories. For each acute myeloid leukemia (AML) category, pie charts depict the distribution of chromosomal abnormalities, while histograms show the frequency of individual mutations. (A and B) CS-AML (de novo AML carrying chromatin-spliceosome mutations), (C and D) secondary AML (sAML) and (E and F) de novo AML. The label “other” includes: for the CS-AML category, abnormalities of chromosome 11 [(other than t(v;11q23.3) and del(11q)] and +8; for the sAML category, del(11q), +8, del(12p), t(5q;12p), t(1p;3q), t(3q;5q) and -Y; for the de novo AML category, +8, del(9q), +21, monosomy 21, +13, t(8q;11q), inv(3), monosomy X, -Y, del(16q), add(4q), add(6p), t(13p;17p).

Figure 3.

Mutational profile of acute myeloid leukemia patients carrying the chromatin-spliceosome mutation. Each column represents an individual acute myeloid leukemia patient carrying a chromatin-spliceosome mutation (CS-AML patient), while each row represents a single gene mutation out of the list at the left. Colored bars indicate the presence of one or more mutations of each gene. Variant types are specified according to the legend at the bottom of the figure.

Figure 4.

Patterns of co-occurrence and mutual exclusivity of gene mutations among 55 CS-AML patients. In the lower triangle are shown pairwise associations between gene mutations. For each pair, odds ratios indicate an in-creased (>1) or decreased (<1) probability of co-occurrence between the two mutations as assessed by the Fisher exact test for statistical significance. The odds ratio of the association is color coded and the significance level is indicated by the number of asterisks in each colored square as reported in the legend at the right of the figure. The upper triangle illustrates the absolute number of occurrences of each molecular pair, shown in green gradient and divided in intervals as reported in the legend. The analysis was performed on the whole study cohort (n=413), excluding mutations occurring in less than six patients and not defining AML categories.

Figure 5.

Kaplan-Meier survival analysis according to acute meloid leukemia category. Survival estimates were calculated at 5 years and not censored at allogeneic transplant. (A) Overall survival; CS-AML vs. de novo AML, P<0.0001; sAML vs. de novo AML, P<0.0001; CS-AML vs. sAML, P=0.02. (B) Disease free survival; CSAML vs. de novo AML, P=0.0009; sAML vs. de novo AML, P<0.0001; CS-AML vs. sAML, P=0.32. CS: chromatin-spliceosome; AML: acute myeloid leukemia; sAML: secondary AML; CS-AML: de novo AML carrying the CS mutations.

Figure 6.

Simon-Makuch plots of overall survival according to allogeneic hematopoietic stem cell transplant. Transplant was considered as a timedependent event. Survival estimates were calculated at 5 years from the date of complete remission (CR) after induction chemotherapy. (A) CS-AML, (B) sAML and (C) de novo AML. CS: chromatin-spliceosome; AML: acute myeloid leukemia; sAML: secondary AML; CS-AML: de novo AML carrying the CS mutations.