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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3074-3080
Prognostic Implication of FLT3 and N-RAS Gene
Mutations in Acute Myeloid Leukemia
Hitoshi Kiyoi,
Tomoki Naoe,
Yasuyuki Nakano,
Shohei Yokota,
Saburo Minami,
Shuichi Miyawaki,
Norio Asou,
Kazutaka Kuriyama,
Itsuro Jinnai,
Chihiro Shimazaki,
Hideki Akiyama,
Kenji Saito,
Hakumei Oh,
Toshiko Motoji,
Eijiro Omoto,
Hidehiko Saito,
Ryuzo Ohno, and
Ryuzo Ueda
From the Department of Infectious Diseases, Nagoya University School
of Medicine, Nagoya; the Third Department of Medicine and the Second
Department of Medicine Kyoto Prefectural University of Medicine, Kyoto;
the Department of Medicine, Japanese Red Cross Nagoya First Hospital,
Nagoya; the Department of Medicine, Saiseikai Maebashi Hospital,
Maebashi; the Second Department of Internal Medicine, Kumamoto
University School of Medicine, Kumamoto; the Department of Hematology,
Atomic Disease Institute Nagasaki University School of Medicine; the
First Department of Internal Medicine, Saitama Medical School, Saitama;
the Department of Hematology, Tokyo Metropolitan Komagome Hospital,
Tokyo; the Third Department of Internal Medicine, Dokkyo University
School of Medicine, Tochigi; the Second Department of Internal
Medicine, Chiba University School of Medicine, Chiba; the Department of
Hematology, Tokyo Women's Medical College, Tokyo; the Department of
Medicine, Okayama University Medical School, Okayama; the Department of
Medicine III, Hamamatsu University School of Medicine, Hamamatsu; and
the Second Department of Internal Medicine, Nagoya City University
School of Medicine, Nagoya, Japan.
Internal tandem duplication of the FLT3 gene and point
mutations of the N-RAS gene are the most frequent somatic
mutations causing aberrant signal-transduction in acute myeloid
leukemia (AML). However, their prognostic importance is unclear. In
this study, their prognostic significance was analyzed in 201 newly diagnosed patients with de novo AML except acute promyelocytic leukemia. Three patients had mutations in both genes, 43 had only the
FLT3 gene mutation, 25 had only the N-RAS gene
mutation, and 130 had neither. These mutations seemed to occur
independently. Both mutations were related to high peripheral white
blood cell counts, and the FLT3 gene mutation was infrequently
observed in the French-American-British (FAB)-M2 type. AML cases with
wild FLT3/mutant N-RAS had a lower complete remission
(CR) rate than those with wild FLT3/wild N-RAS, whereas
the presence of mutant FLT3 did not affect the CR rate.
Univariate analysis showed that unfavorable prognostic factors for
overall survival were age 60 years or older (P = .0002),
cytogenetic data (P = .002), FAB types other than M2
(P = .002), leukocytosis over 100 ± 109/L
(P = .003), and the FLT3 gene mutation
(P = .004). However, the N-RAS gene mutation was
only a marginal prognostic factor (P = .06). For the
subjects under 60 years old, multivariate analysis showed that the
FLT3 gene mutation was the strongest prognostic factor
(P = .008) for overall survival. The FLT3 gene
mutation, whose presence is detectable only by genomic polymerase chain reaction amplification and gel electrophoresis, might serve as an
important molecular marker to predict the prognosis of patients with AML.
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