Am J Blood Res 2011;1(2):175-189
Review Article
Treatment of FLT3-ITD acute myeloid leukemia
Amir T. Fathi, Yi-Bin Chen
The Center for Leukemia and the Bone Marrow Transplant Unit, Division of Hematology/Oncology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA 02114, USA.
Received August 8, 2011; accepted August 27, 2011; Epub September 9, 2011; published September 30, 2011
Abstract: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A
FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients, imparts a particularly poor
prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher
propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive
induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years,
multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier
generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient
peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has
not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with
sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy.
Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand
levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and
potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in
the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3
inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues
which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first
complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to
further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical
investigation will lead to an optimization and improvement of outcomes for these patients. (AJBR1108003).
Keywords: AML, FLT3-ITD, tyrosine kinase inhibitor, allogeneic stem cell transplantation
Full Text PDF
Address all correspondence to:
Amir Fathi, MD
Zero Emerson Place, Suite 118
Massachusetts General Hospital
55 Fruit Street
Boston, MA 02114
Phone: 617-724-1124
Email: afathi@partners.org
Review Article
Treatment of FLT3-ITD acute myeloid leukemia
Amir T. Fathi, Yi-Bin Chen
The Center for Leukemia and the Bone Marrow Transplant Unit, Division of Hematology/Oncology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA 02114, USA.
Received August 8, 2011; accepted August 27, 2011; Epub September 9, 2011; published September 30, 2011
Abstract: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A
FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients, imparts a particularly poor
prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher
propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive
induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years,
multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier
generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient
peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has
not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with
sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy.
Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand
levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and
potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in
the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3
inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues
which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first
complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to
further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical
investigation will lead to an optimization and improvement of outcomes for these patients. (AJBR1108003).
Keywords: AML, FLT3-ITD, tyrosine kinase inhibitor, allogeneic stem cell transplantation
Full Text PDF
Address all correspondence to:
Amir Fathi, MD
Zero Emerson Place, Suite 118
Massachusetts General Hospital
55 Fruit Street
Boston, MA 02114
Phone: 617-724-1124
Email: afathi@partners.org
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