Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia

Mrinal M Patnaik, Daniela Barraco, Terra L. Lasho, Christy M. Finke, Kaaren Reichard, Katherine P. Hoversten, Rhett P. Ketterling, Naseema Gangat, Ayalew Tefferi

Research output: Contribution to journalArticle

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Abstract

Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8%, and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (P =.02), low hemoglobin (P =.01), red blood cell transfusion dependence (P =.03), high white blood cell count (P =.02), TET2 (P =.03), NRAS (P =.04), PTPN11 (P =.02) mutations and the presence of ≥3 gene mutations (P =.006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (P =.003) [age >67: HR 10.1, 95% CI 1.3-119], low hemoglobin (P =.008) [HB< 10 gm/dL: HR 8.2, 95% CI 1.6-23.2] and TET2 mutations (P =.01) [HR 8.8, 95% CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dL and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months, respectively.

Original languageEnglish (US)
Pages (from-to)542-548
Number of pages7
JournalAmerican Journal of Hematology
Volume92
Issue number6
DOIs
StatePublished - Jun 1 2017

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Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Mutation
Survival
Erythrocyte Transfusion
Myelodysplastic Syndromes
Leukocytosis
Leukocyte Count
Chromosome Aberrations
Genes
Neoplasms
Hemoglobins

ASJC Scopus subject areas

  • Hematology

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Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia. / Patnaik, Mrinal M; Barraco, Daniela; Lasho, Terra L.; Finke, Christy M.; Reichard, Kaaren; Hoversten, Katherine P.; Ketterling, Rhett P.; Gangat, Naseema; Tefferi, Ayalew.

In: American Journal of Hematology, Vol. 92, No. 6, 01.06.2017, p. 542-548.

Research output: Contribution to journalArticle

Patnaik, Mrinal M ; Barraco, Daniela ; Lasho, Terra L. ; Finke, Christy M. ; Reichard, Kaaren ; Hoversten, Katherine P. ; Ketterling, Rhett P. ; Gangat, Naseema ; Tefferi, Ayalew. / Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia. In: American Journal of Hematology. 2017 ; Vol. 92, No. 6. pp. 542-548.
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abstract = "Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84{\%} males. Cytogenetic abnormalities were seen in 36{\%} and gene mutations in 100{\%}. Mutational frequencies were, ASXL1 28{\%}, TET2 16{\%}, NRAS 16{\%}, SETBP1 12{\%}, RUNX1 12{\%}, ETNK1 8{\%}, and PTPN11 4{\%}. Fifteen patients (60{\%}) had >1 mutation, while 9 (36{\%}) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68{\%}) deaths and 2 (8{\%}) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (P =.02), low hemoglobin (P =.01), red blood cell transfusion dependence (P =.03), high white blood cell count (P =.02), TET2 (P =.03), NRAS (P =.04), PTPN11 (P =.02) mutations and the presence of ≥3 gene mutations (P =.006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (P =.003) [age >67: HR 10.1, 95{\%} CI 1.3-119], low hemoglobin (P =.008) [HB< 10 gm/dL: HR 8.2, 95{\%} CI 1.6-23.2] and TET2 mutations (P =.01) [HR 8.8, 95{\%} CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dL and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months, respectively.",
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AU - Patnaik, Mrinal M

AU - Barraco, Daniela

AU - Lasho, Terra L.

AU - Finke, Christy M.

AU - Reichard, Kaaren

AU - Hoversten, Katherine P.

AU - Ketterling, Rhett P.

AU - Gangat, Naseema

AU - Tefferi, Ayalew

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N2 - Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8%, and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (P =.02), low hemoglobin (P =.01), red blood cell transfusion dependence (P =.03), high white blood cell count (P =.02), TET2 (P =.03), NRAS (P =.04), PTPN11 (P =.02) mutations and the presence of ≥3 gene mutations (P =.006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (P =.003) [age >67: HR 10.1, 95% CI 1.3-119], low hemoglobin (P =.008) [HB< 10 gm/dL: HR 8.2, 95% CI 1.6-23.2] and TET2 mutations (P =.01) [HR 8.8, 95% CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dL and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months, respectively.

AB - Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8%, and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (P =.02), low hemoglobin (P =.01), red blood cell transfusion dependence (P =.03), high white blood cell count (P =.02), TET2 (P =.03), NRAS (P =.04), PTPN11 (P =.02) mutations and the presence of ≥3 gene mutations (P =.006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (P =.003) [age >67: HR 10.1, 95% CI 1.3-119], low hemoglobin (P =.008) [HB< 10 gm/dL: HR 8.2, 95% CI 1.6-23.2] and TET2 mutations (P =.01) [HR 8.8, 95% CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dL and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months, respectively.

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