IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: Clinical evidence for leukemogenic collaboration with JAK2V617F

Ayalew Tefferi, T. Jimma, N. H. Sulai, T. L. Lasho, C. M. Finke, R. A. Knudson, R. F. McClure, Animesh D Pardanani

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50%) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6%) patients displayed only MPL and 164 (54.3%) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95% confidence interval (95% CI) 0.2-0.75), 0.50 (95% CI 0.27-0.95) and 0.53 (95% CI 0.23-1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F.

Original languageEnglish (US)
Pages (from-to)475-480
Number of pages6
JournalLeukemia
Volume26
Issue number3
DOIs
StatePublished - Mar 2012

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Isocitrate Dehydrogenase
Primary Myelofibrosis
Mutation
Survival
Blast Crisis
Confidence Intervals
Leukemia

Keywords

  • cytogenetics
  • IDH1
  • IDH2
  • myeloproliferative
  • prognosis

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival : Clinical evidence for leukemogenic collaboration with JAK2V617F. / Tefferi, Ayalew; Jimma, T.; Sulai, N. H.; Lasho, T. L.; Finke, C. M.; Knudson, R. A.; McClure, R. F.; Pardanani, Animesh D.

In: Leukemia, Vol. 26, No. 3, 03.2012, p. 475-480.

Research output: Contribution to journalArticle

Tefferi, Ayalew ; Jimma, T. ; Sulai, N. H. ; Lasho, T. L. ; Finke, C. M. ; Knudson, R. A. ; McClure, R. F. ; Pardanani, Animesh D. / IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival : Clinical evidence for leukemogenic collaboration with JAK2V617F. In: Leukemia. 2012 ; Vol. 26, No. 3. pp. 475-480.
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abstract = "Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4{\%}): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50{\%}) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6{\%}) patients displayed only MPL and 164 (54.3{\%}) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95{\%} confidence interval (95{\%} CI) 0.2-0.75), 0.50 (95{\%} CI 0.27-0.95) and 0.53 (95{\%} CI 0.23-1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F.",
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AU - Lasho, T. L.

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