Submission type: Correspondence and Letters
Azacitidine as a bridge to allogeneic stem cell transplantation in a
patient with juvenile myelomonocytic leukemia: a case report
Akira Takebayashi, MD1, Tsukasa Hori, MD,
PhD1, Masaki Yamamoto, MD, PhD1,
Takeshi Tsugawa, MD, PhD1, Keita Igarashi,
MD1, Kotoe Iesato, MD, PhD1, Ryo
Hamada, MD1, Hideki Muramatsu, MD,
PhD2, Yukihiko Kawasaki, MD, PhD1
1Departments of Pediatrics, Sapporo Medical University
School of Medicine, Sapporo, Japan
2Department of Pediatrics, Nagoya University Graduate
School of Medicine, Nagoya, Japan
Corresponding author : Akira Takebayashi, MD, 291, South-1,
West-16, Chuo-ku, Sapporo 060-8543, Japan. Phone: +81-11-611-2111; Fax:
+81-11-611-0352; E-mail: take884akir@gmail.com
Key Words : JMML, juvenile myelomonocytic leukemia, azacitidine,
bridge, bridging therapy, stem cell transplantation
Running title : Azacitidine as a bridging therapy to JMML
Words count : 488 words, 1 table.
Conflict of interest statement: The authors have no conflict of
interest to declare.
To the Editor:
Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic
/myeloproliferative neoplasm in infants and toddlers. Allogeneic
hematopoietic stem cell transplantation (HSCT) is the only curative
therapy for most patients, but no appropriate pre-HSCT bridging therapy
has been established. Since Furlan1 reported the
effectiveness of azacitidine in pre-HSCT JMML, several reports have been
published. Here we report a case of JMML treated with azacitidine.
A 6-month-old male presented with hepatosplenomegaly and
thrombocytopenia. Laboratory examinations revealed monocytosis (8.5 ×
109 /L), mild anemia (hemoglobin: 10.2 g/dL),
thrombocytopenia (17 × 109/L), and 11.7% hemoglobin
F. Myeloblasts were peripheral blood: 2.0%; bone marrow: 8.2%.
Fluorescence in situ hybridization detected monosomy-7 cells. Molecular
analysis found a somatic KRAS p.G13D mutation, and he was
diagnosed with JMML.
We planned an unrelated bone marrow transplantation (UR-BMT) because an
HLA-matched related donor was unavailable, and used 6-mercaptoprine
(6-MP) as a bridging therapy. However, he still needed frequent
transfusions and his hepatosplenomegaly was exacerbated (TABLE 1). We
therefore changed the bridging therapy from 6-MP to azacitidine (2.5
mg/kg, over 1 hour intravenously on 7 consecutive days, every 28 days;
TABLE 1). Platelet transfusion frequency decreased and he became
transfusion-independent after azacitidine Cycle 6. Peripheral blood
myeloblasts disappeared after Cycle 6, and the hepatosplenomegaly had
completely improved after Cycle 8. Monosomy-7 cells significantly
decreased, but did not disappear until his UR-BMT. He maintained
clinical partial remission and genetic stable disease after Cycle 1,
evaluated with response criteria defined by C. M. Niemeyer et al.
Adverse effects of azacitidine included febrile neutropenia after Cycle
1 and exacerbated thrombocytopenia during Cycles 1 and 2. However, he
suffered no adverse effects after Cycle 3.
UR-BMT from an HLA 7/8 matched donor was performed after azacitidine
Cycle 8, when the patient was in partial remission. His conditioning
regimen included busulfan, fludarabine and melphalan; a short course of
methotrexate and tacrolimus was used as prophylaxis against for
graft-versus-host disease. He remains in complete remission with
complete donor chimerism at 27 months after UR-BMT.
Azacitidine is a DNA-hypomethylating agent used for myelodysplastic
syndrome in adults, but is not generally used for JMML. Cseh reported
twelve patients with JMML treated with azacitidine,3of whom nine patients were treated with azacitidine before HSCT and five
achieved partial or complete remission. The remaining four received HSCT
during progressive disease after 1–4 cycles of azacitidine therapy.
Although the optimal number of azacitidine cycles is unknown, continuing
azacitidine therapy for six to eight cycles might be valuable if the
patient can tolerate it.
Another infant with JMML, somatic KRAS mutation and monosomy-7
who achieved sustained remission following azacitidine monotherapy had
been reported,4 but identifying patients who can
sustain remission without HSCT is not currently possible. Reportedly,
DNA methylation patterns in JMML can be predictive for
prognosis,5,6 but whether they can predict response to
hypomethylating agents or not is unclear. Although azacitidine bridging
therapy is effective for JMML patients, further studies are needed to
clarify several questions about JMML treatment.