Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KITD816V

Celalettin Ustun, Christopher L. Corless, Natasha Savage, Warren Fiskus, Elizabeth Manaloor, Michael C. Heinrich, Grant Lewis, Preetha Ramalingam, Ilana Kepten, Anand Jillella, Kapil Bhalla

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Dasatinib has been reported to potently inhibit juxtamembrane domain mutant KITD816V autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells. Additionally, dasatinib induced apoptosis in mast cell and leukemia cell lines expressing KITD816V. Here, we present the first case report of long-term hematologic and molecular remission achieved with combined treatment with chemotherapy and dasatinib in a patient with systemic mastocytosis (SM) and acute myeloid leukemia (AML) with mutant KITD816V expression. A 50-year-old male presented with pancytopenia, organomegaly, lymphadenopathy, and lytic bone lesions in the pelvis. The patient was found to have systemic mastocytosis (SM) and acute myelogeneous leukemia (AML) positive for KITD816V and therefore diagnosed with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Both primary CD34+ cells containing myeloblasts and CD34- cells containing mastocytes obtained from the diagnostic BM lost viability markedly by in vitro dasatinib treatment. In addition, dasatinib diminished activity of STAT5, STAT3, AKT and ERK and attenuated the levels of c-KIT. The patient achieved a hematologic complete remission (HCR) by two induction chemotherapies with residual mastocytes. Dasatinib (70 mg PO bid, days 1-4) was added to consolidation treatments composed of four cycles of high dose cytarabine and was then continued as maintenance therapy (50 mg PO bid). Periodic bone marrow (BM) aspirate/biopsies (eight over 18 months) were performed. The patient remained in HCR, and the mastocyte burden decreased by 50%. The bone lytic lesions improved. The KITD816Vmutation progressively decreased and became undetectable in the last three BM analyses. This result was confirmed by an independent laboratory showing a lack of c-KIT mutation in both CD34+ cells and CD34- cells in the last BM. No significant adverse effects of dasatinib occurred. Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KITD816V mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML.

Original languageEnglish (US)
Pages (from-to)735-741
Number of pages7
JournalLeukemia Research
Volume33
Issue number5
DOIs
StatePublished - May 1 2009
Externally publishedYes

Fingerprint

Systemic Mastocytosis
Acute Myeloid Leukemia
Drug Therapy
Bone Marrow
Mast-Cell Leukemia
Dasatinib
Remission Induction
Bone and Bones
Granulocyte Precursor Cells
Pancytopenia
Mutation
Induction Chemotherapy
Cytarabine
Stem Cell Transplantation
Cell Lineage
Therapeutics
Pelvis
Cell Survival
Leukemia
Apoptosis

Keywords

  • Acute myeloid leukemia
  • Asp816Val mutation
  • Dasatinib
  • KIT
  • Systemic mastocytosis
  • Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KITD816V. / Ustun, Celalettin; Corless, Christopher L.; Savage, Natasha; Fiskus, Warren; Manaloor, Elizabeth; Heinrich, Michael C.; Lewis, Grant; Ramalingam, Preetha; Kepten, Ilana; Jillella, Anand; Bhalla, Kapil.

In: Leukemia Research, Vol. 33, No. 5, 01.05.2009, p. 735-741.

Research output: Contribution to journalArticle

Ustun, Celalettin ; Corless, Christopher L. ; Savage, Natasha ; Fiskus, Warren ; Manaloor, Elizabeth ; Heinrich, Michael C. ; Lewis, Grant ; Ramalingam, Preetha ; Kepten, Ilana ; Jillella, Anand ; Bhalla, Kapil. / Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KITD816V. In: Leukemia Research. 2009 ; Vol. 33, No. 5. pp. 735-741.
@article{b6dafcf4040a435ab202d924b692024d,
title = "Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KITD816V",
abstract = "Dasatinib has been reported to potently inhibit juxtamembrane domain mutant KITD816V autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells. Additionally, dasatinib induced apoptosis in mast cell and leukemia cell lines expressing KITD816V. Here, we present the first case report of long-term hematologic and molecular remission achieved with combined treatment with chemotherapy and dasatinib in a patient with systemic mastocytosis (SM) and acute myeloid leukemia (AML) with mutant KITD816V expression. A 50-year-old male presented with pancytopenia, organomegaly, lymphadenopathy, and lytic bone lesions in the pelvis. The patient was found to have systemic mastocytosis (SM) and acute myelogeneous leukemia (AML) positive for KITD816V and therefore diagnosed with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Both primary CD34+ cells containing myeloblasts and CD34- cells containing mastocytes obtained from the diagnostic BM lost viability markedly by in vitro dasatinib treatment. In addition, dasatinib diminished activity of STAT5, STAT3, AKT and ERK and attenuated the levels of c-KIT. The patient achieved a hematologic complete remission (HCR) by two induction chemotherapies with residual mastocytes. Dasatinib (70 mg PO bid, days 1-4) was added to consolidation treatments composed of four cycles of high dose cytarabine and was then continued as maintenance therapy (50 mg PO bid). Periodic bone marrow (BM) aspirate/biopsies (eight over 18 months) were performed. The patient remained in HCR, and the mastocyte burden decreased by 50{\%}. The bone lytic lesions improved. The KITD816Vmutation progressively decreased and became undetectable in the last three BM analyses. This result was confirmed by an independent laboratory showing a lack of c-KIT mutation in both CD34+ cells and CD34- cells in the last BM. No significant adverse effects of dasatinib occurred. Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KITD816V mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML.",
keywords = "Acute myeloid leukemia, Asp816Val mutation, Dasatinib, KIT, Systemic mastocytosis, Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease, Tyrosine kinase inhibitor",
author = "Celalettin Ustun and Corless, {Christopher L.} and Natasha Savage and Warren Fiskus and Elizabeth Manaloor and Heinrich, {Michael C.} and Grant Lewis and Preetha Ramalingam and Ilana Kepten and Anand Jillella and Kapil Bhalla",
year = "2009",
month = "5",
day = "1",
doi = "10.1016/j.leukres.2008.09.027",
language = "English (US)",
volume = "33",
pages = "735--741",
journal = "Leukemia Research",
issn = "0145-2126",
publisher = "Elsevier Limited",
number = "5",

}

TY - JOUR

T1 - Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KITD816V

AU - Ustun, Celalettin

AU - Corless, Christopher L.

AU - Savage, Natasha

AU - Fiskus, Warren

AU - Manaloor, Elizabeth

AU - Heinrich, Michael C.

AU - Lewis, Grant

AU - Ramalingam, Preetha

AU - Kepten, Ilana

AU - Jillella, Anand

AU - Bhalla, Kapil

PY - 2009/5/1

Y1 - 2009/5/1

N2 - Dasatinib has been reported to potently inhibit juxtamembrane domain mutant KITD816V autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells. Additionally, dasatinib induced apoptosis in mast cell and leukemia cell lines expressing KITD816V. Here, we present the first case report of long-term hematologic and molecular remission achieved with combined treatment with chemotherapy and dasatinib in a patient with systemic mastocytosis (SM) and acute myeloid leukemia (AML) with mutant KITD816V expression. A 50-year-old male presented with pancytopenia, organomegaly, lymphadenopathy, and lytic bone lesions in the pelvis. The patient was found to have systemic mastocytosis (SM) and acute myelogeneous leukemia (AML) positive for KITD816V and therefore diagnosed with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Both primary CD34+ cells containing myeloblasts and CD34- cells containing mastocytes obtained from the diagnostic BM lost viability markedly by in vitro dasatinib treatment. In addition, dasatinib diminished activity of STAT5, STAT3, AKT and ERK and attenuated the levels of c-KIT. The patient achieved a hematologic complete remission (HCR) by two induction chemotherapies with residual mastocytes. Dasatinib (70 mg PO bid, days 1-4) was added to consolidation treatments composed of four cycles of high dose cytarabine and was then continued as maintenance therapy (50 mg PO bid). Periodic bone marrow (BM) aspirate/biopsies (eight over 18 months) were performed. The patient remained in HCR, and the mastocyte burden decreased by 50%. The bone lytic lesions improved. The KITD816Vmutation progressively decreased and became undetectable in the last three BM analyses. This result was confirmed by an independent laboratory showing a lack of c-KIT mutation in both CD34+ cells and CD34- cells in the last BM. No significant adverse effects of dasatinib occurred. Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KITD816V mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML.

AB - Dasatinib has been reported to potently inhibit juxtamembrane domain mutant KITD816V autophosphorylation and KIT-dependent activation of down stream signaling important for cell growth and survival of neoplastic cells. Additionally, dasatinib induced apoptosis in mast cell and leukemia cell lines expressing KITD816V. Here, we present the first case report of long-term hematologic and molecular remission achieved with combined treatment with chemotherapy and dasatinib in a patient with systemic mastocytosis (SM) and acute myeloid leukemia (AML) with mutant KITD816V expression. A 50-year-old male presented with pancytopenia, organomegaly, lymphadenopathy, and lytic bone lesions in the pelvis. The patient was found to have systemic mastocytosis (SM) and acute myelogeneous leukemia (AML) positive for KITD816V and therefore diagnosed with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Both primary CD34+ cells containing myeloblasts and CD34- cells containing mastocytes obtained from the diagnostic BM lost viability markedly by in vitro dasatinib treatment. In addition, dasatinib diminished activity of STAT5, STAT3, AKT and ERK and attenuated the levels of c-KIT. The patient achieved a hematologic complete remission (HCR) by two induction chemotherapies with residual mastocytes. Dasatinib (70 mg PO bid, days 1-4) was added to consolidation treatments composed of four cycles of high dose cytarabine and was then continued as maintenance therapy (50 mg PO bid). Periodic bone marrow (BM) aspirate/biopsies (eight over 18 months) were performed. The patient remained in HCR, and the mastocyte burden decreased by 50%. The bone lytic lesions improved. The KITD816Vmutation progressively decreased and became undetectable in the last three BM analyses. This result was confirmed by an independent laboratory showing a lack of c-KIT mutation in both CD34+ cells and CD34- cells in the last BM. No significant adverse effects of dasatinib occurred. Dasatinib has in vitro and in vivo efficacy in SM-AML patients with KITD816V mutation. Along with chemotherapy, dasatinib should be considered in these patients particularly if they cannot undergo allogeneic stem cell transplantation for this poor prognostic AML.

KW - Acute myeloid leukemia

KW - Asp816Val mutation

KW - Dasatinib

KW - KIT

KW - Systemic mastocytosis

KW - Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease

KW - Tyrosine kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=61449256026&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=61449256026&partnerID=8YFLogxK

U2 - 10.1016/j.leukres.2008.09.027

DO - 10.1016/j.leukres.2008.09.027

M3 - Article

C2 - 18986703

AN - SCOPUS:61449256026

VL - 33

SP - 735

EP - 741

JO - Leukemia Research

JF - Leukemia Research

SN - 0145-2126

IS - 5

ER -