Molecular Complete Remission Following Ivosidenib in a Patient With an Acute Undifferentiated Leukemia

et al. 2020

Preprint

Background Acute leukemia with ambiguous lineage (ALAL) is a rare and heterogeneous group of highly aggressive malignancy with poor clinical outcome, limited molecular characterization and lack of general therapeutic recommendations. Results In this study, we retrospectively analyzed 1635 acute leukemia cases in our center from January 2012 to June 2018.The diagnose of ALAL was based on either EGIL or 2016 WHO criteria. Totally, 39 patients were included in this study and 30 patients satisfied the WHO criteria. Four patients diagnosed as acute undifferentiated leukemia (AUL) by both classification systems. Genetic analysis showed that mutations detected in bi-phenotypic acute leukemia enriched in genes related to genomic stability and transcriptional regulation; while AUL cases frequently mutated in genes involved in signaling pathway. Survival analysis of all patients included suggested that the prognosis of ALAL was independent of immunophenotype, chromosome karyotype, treatment, but significantly associated with the mutation complexity, also termed numbers of the mutations carried by each patient (Log rank p = 0.009 for progression-free survival [PFS] and Log rank p = 0.047 for overall survival [OS], respectively). Similar results were obtained when the WHO diagnostic system were applied. Among these patients, those excluded by WHO criteria had even worse clinical outcome than the patients included (Log rank p = 0.023 for PFS and Log rank p = 0.031 for OS). Conclusions Collectively, the complexity of genomic mutation of ALAL patients seems significantly related to the clinical outcomes. The rationality and clinical applicability of the diagnostic criteria of WHO system need to be evaluated by more large-scale clinical studies.

Section: Resultsmentioning

confidence: 99%

The complexity of genomic mutation dictates the prognosis of acute leukemia with ambiguous lineage

et al. 2020

Preprint

“…There is a proof that a patient with IDH1-mutated AUL achieved molecular complete remission following ivosidenib 19 . This might be a promising step to open the door for targeted therapy in IDH-mutated ALAL 20 .…”

Section: Discussionmentioning

confidence: 99%

The complexity of genomic mutation dictates the prognosis of acute leukemia with ambiguous lineage

et al. 2021

Preprint

Acute leukemia with ambiguous lineage (ALAL) is a rare and highly aggressive malignancy with limited molecular characterization and therapeutic recommendations. In this study, we retrospectively analyzed 1635 acute leukemia cases in our center from January 2012 to June 2018.The diagnose of ALAL was based on either EGIL or 2016 WHO criteria, a total of 39 patients were included. Four patients diagnosed as acute undifferentiated leukemia (AUL) by both classification systems. The mutations detected in bi-phenotypic acute leukemia enriched in genes related to genomic stability and transcriptional regulation; while AUL cases frequently mutated in genes involved in signaling pathway. Survival analysis of all patients suggested that the prognosis of ALAL was independent of immunophenotype, chromosome karyotype, treatment, but significantly associated with the mutation complexity, also termed numbers of the mutations carried by each patient (Log rank p = 0.009 for progression-free survival [PFS] and Log rank p = 0.047 for overall survival [OS], respectively). Similar results were obtained when the WHO diagnostic system were applied (Log rank p < 0.001 for both PFS and OS). Among these patients, those excluded by WHO criteria had even worse clinical outcome than the patients included (Log rank p = 0.023 for PFS and Log rank p = 0.031 for OS). Collectively, the complexity of genomic mutation of ALAL patients is significantly associated with the clinical outcomes. The rationality and clinical applicability of the diagnostic criteria of WHO system need to be evaluated by more large-scale clinical studies.

“…Recently, novel selective inhibitors of IDH1/2 mutations, ivosidenib and enasidenib, have been approved for patients with relapsed or refractory IDH1/2-mutated AML 22 . There is a proof that a patient with IDH1-mutated AUL achieved molecular complete remission following ivosidenib 23 . This might be a promising step to open the door for targeted therapy in IDH-mutated ALAL 24 .…”

Section: Discussionmentioning

confidence: 99%

The association of complex genetic background with the prognosis of acute leukemia with ambiguous lineage

et al. 2021

Sci Rep

Acute leukemia with ambiguous lineage (ALAL) is a rare and highly aggressive malignancy with limited molecular characterization and therapeutic recommendations. In this study, we retrospectively analyzed 1635 acute leukemia cases in our center from January 2012 to June 2018. The diagnose of ALAL was based on either EGIL or 2016 WHO criteria, a total of 39 patients were included. Four patients diagnosed as acute undifferentiated leukemia (AUL) by both classification systems. Among the patients underwent high-throughput sequencing, 89.5% were detected at least one mutation and the median number of gene mutation was 3 (0–8) per sample. The most frequently mutated genes were NRAS (4, 21%), CEBPA (4, 21%), JAK3 (3, 16%), RUNX1 (3, 16%). The mutations detected in mixed-phenotype acute leukemia (MPAL) enriched in genes related to genomic stability and transcriptional regulation; while AUL cases frequently mutated in genes involved in signaling pathway. The survival analysis strongly suggested that mutation burden may play important roles to predict the clinical outcomes of ALAL. In addition, the patients excluded by WHO criteria had even worse clinical outcome than those included. The association of the genetic complexity of blast cells with the clinical outcomes and rationality of the diagnostic criteria of WHO system need to be evaluated by more large-scale prospective clinical studies.