Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly ...diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN-AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22-86) and 73 (61-81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13,
= 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (
= 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN-AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN-AZA is a promising treatment for ND AML and for selected R/R AML patients.
AML relapse is often associated with a clonal evolution at the cytogenetic and molecular level and therefore represents a challenge for the treatment. Targeted sequencing is now usually done at ...diagnosis in AML, as only a small core group of genes is frequently mutated in AML and MDS. This approach, contrary to Whole Genome Sequencing, is cheaper and allows the detection of variant allele fractions as low as 2% with a rapid turnover and high sequencing coverage and depths.
In this study we analyzed the karyotype and the mutations occuring in a panel of genes in 31 AML patients at diagnosis and at the relapse.
The Illumina TruSight Myeloid Sequencing Panel® was used that covers all exons of 15 genes and hotspots of 39 additionnal genes involved in myeloid malignancies. Three different pipelines were used for data analysis including GATK, Picard, Samtools, VarScan reference tools. We tried to assess the clonality and the clonal evolution patterns at relapse. Five different clonal evolution patterns including cytogenetic and molecular analyses were observed: (1) Stability, defined by absence of clonal change, (2) Gain, strictly defined by acquisition of additional variations (mutations or cytogenetic alterations), (3) Loss, strictly defined by loss of variants or regression, (4) Gain and Loss, indicating the combination of both “Gain” and “Loss” patterns, (5) Emergence, defined by the emergence of alterations that is unrelated to those found at diagnosis.
The cohort included 20 men and 11 women with a median age of 59 years old for which frozen DNA was available both at diagnosis and relapse that were referred in a single center. The elapsed time between the first remission and relapse (TTR) was 1.6 to 113.8 months. Almost all patients relapsed prematurely (less than 12 months). The overall survival and the survival after relapse were respectively 23.7 months and 9.1 months.
The cytogenetic evolution patterns observed at relapse were the following: Stability (40%), Gain (27%), Loss (31%), Gain and Loss (4%), Emergence (<1%). The mutation evolution patterns observed at relapse were the following: Stability (26%), Gain (23%), Loss (32%), Gain and Loss (16%), Emergence (3%) . No correlation between cytogenetic and mutation pattern was observed.
Patients without change at relapse (“Stability” pattern) had less mutated genes at diagnosis than in the other patterns (p=0.009). Whereas patients with the “Gain and Loss” pattern had more mutated genes at diagnosis than the other patients (≥4 mutated genes, p=0.001). Thirty five percent of the alterations acquired at relapse (“Gain” and “Gain and Loss” patterns) were found in tumor suppressor genes: TP53 was mutated in 60% of these patients, but mutations were also observed in signaling genes (25% of the patients). Thirty eight percent of the alterations lost at relapse (“Loss” and “Gain and Loss” patterns) are found in signaling genes (i.e FLT3, KIT, KRAS, NRAS ) and 23% in myeloid transcription factors (i.e CEBPA, RUNX1, GATA2 ). It was also been observed that 47% of mutations thatwere observed in each group at diagnosis and relapse were localized in DNA methylation and chromatin modification genes (i.e DNMT3A, IDH1/2, TET2, ASXL1, EZH2 ).
Interestingly, at diagnosis, mutations of DNA methylation and spliceosome complex genes were preferentially observed in the “Gain” pattern group (p=0.040). In contrast, mutations of signaling genes were preferentially mutated at diagnosis in the “Loss” group (p=0.020).
Even if not statistically significant, we observed that evolution and prognosis seemed to be different among the different patterns. The “Gain” pattern tends to have shorter overall survival (median 14.7 months vs 22.9 months in Stability group) whereas in the “Loss” group, overall survival appeared longer (median 34.1 months). Moreover, patients in the “Gain” group were significantly older (p=0.017), and were classified as AML with myelodysplasia-related changes in most of the cases.
To our knowledge, our work is the first reporting multiplex targeted NGS sequencing in AML at diagnosis and relapse. The comparison of clonal landscape between diagnosis and relapse allowed us to define 5 evolution patterns that differed in terms of mutation landscape and evolution.
Even if these data must be confirmed on a larger cohort, our study shows the feasibility of clonal analysis using targeted NGS at diagnosis and relapse in AML and its potential prognosis interest in clinical routine.
No relevant conflicts of interest to declare.
Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic ...impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact.
•SRSF2 mutations predict worse OS and LFS in ND-AML patients treated with VEN-AZA.•This persists when taking into account prior HMAs treatment or pre-AML conditions.•Prior HMAs treatment and TET2 mutation are associated with lower response rates.
B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with ...B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC t(MYC) (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.
•B-PLL is tightly linked to MYC aberrations (translocation or gain) and 17p (TP53) deletion.•Cases of B-PLL with MYC aberration and 17p (TP53) deletion have the worst prognosis.
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