Little response to zoledronic acid in a child of juvenile myelomonocytic leukemia (JMML) harboring the PTPN11 mutation

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative disorder with a high mortality rate. Dysregulation of the RAS pathway has been implicated in the pathogenesis. A targeting therapy against the RAS pathway, therefore, can be an important therapeutic option. Zoledronic acid, a third-generation bisphosphonate that is capable of inhibiting the activation of small GTPases, was recently shown in vitro to have antiproliferative potency against JMML cells [1Go]. Here we report the first case of JMML to undergo zoledronic acid therapy.

The patient was a 3-year-old Japanese boy who was diagnosed as having JMML at the age of 4 months. As described previously, his JMML cells harbored the PTPN11 mutation, which may increase activation of the RAS pathway [2Go]. A diagnosis of JMML relapse was made after the second hematopoietic stem cell transplantation (HSCT). 6-mercaptopurine, cytarabine and interferon-{alpha} were administered consecutively, while white blood cell count (WBC) increased to 13.7 x 109/l on day 215 (Figure 1). The patient was expected to benefit from the anti-leukemic effects of zoledronic acid [1Go, 3Go]. Written informed consent was obtained from patients, and zoledronic acid therapy was approved by the institutional review board. The initial dose was determined based on experience treating adult cases with acute panmyelosis with myelofibrosis [3Go]. Serum levels of albumin-corrected calcium (Ca), inorganic phosphorus (IP), creatinine and vitamin D were normal. On day 215, a single dose of zoledronic acid (2.5 mg/m2) was administered by intravenous infusion over 45 min. The patient developed no post-infusion flu-like illness. WBC increased steadily as before the therapy (Figure 1). Since the patient tolerated zoledronic acid well, the increased doses were sequentially administered 7 days (5 mg/m2) and 14 days (6.25 mg/m2) after the first infusion. However, WBC increased rapidly and the progressive splenomegaly was uncontrollable. Four days after the third infusion, the patient died of respiratory failure caused by deterioration in JMML. Asymptomatic hypocalcemia and hypophosphatemia were the only side effects of zoledronic acid. After the second infusion, the patient was treated with an oral calcium supplement and vitamin D, while serum Ca and IP levels decreased rapidly to 5.6 mg/dl and 1.8 mg/dl at their nadirs, respectively (Figure 1). No renal side-effects were observed during the three consecutive infusions in the present case in contrast to the adult cases who have been reported to develop renal deterioration frequently [4Go].



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Figure 1. Serum Ca and IP levels and WBC before and during therapy with zoledronic acid. Ca, albumin-corrected calcium; IP, inorganic phosphorus; WBC, white blood cell count; CBT, cord blood stem cell transplantation.

 
The patient showed little response to zoledronic acid despite being administered the higher-dose compared with the recommended dose for children with malignancy-induced hypercalcemia [5Go]. Unfavorable outcome may be attributable to several factors; the rapidly expanding population of resistant JMML cells could have been independent on the RAS pathway. Since zoledronic acid preferentially binds to bone surfaces, the JMML cells forming splenomegaly may not be exposed to an effective level. The effects of zoledronic acid on JMML may be expected for a group of patients who are in remission or in the very early phase of relapse after HSCT. Further clinical studies are certainly required to evaluate the efficacy of zoledronic acid in the target therapy of JMML.

H. Shimada*, H. Shima, N. Shimasaki, H. Yoshihara, T. Mori and T. Takahashi

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

* Email: hshimada{at}1992.jukuin.keio.ac.jp

References

1. Ohtsuka Y, Manabe A, Kawasaki H et al. Bisphosphonate zoledronic acid (ZOL) inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia (JMML) cells. Blood 2004; 104: 265b (Abstr).

2. Shimada H, Mori T, Shimasaki N et al. Somatic PTPN11 mutation with a heterogeneous clonal origin in children with juvenile myelomonocytic leukemia. Leukemia 2004; 18: 1142–1144.[CrossRef][ISI][Medline]

3. Espanol I, Romagosa V, Berlanga J et al. Zoledronate-induced remission of acute panmyelosis with myelofibrosis. Eur J Haematol 2004; 73: 215–218.[CrossRef][ISI][Medline]

4. Chang JT, Green L, Beitz J, Renal failure with the use of zoledronic acid. N Engl J Med 2003; 349: 1676–1679.[Free Full Text]

5. Hogler W, Yap F, Little D et al. Short-term safety assessment in the use of intravenous zoledronic acid in children. J Pediatr 2004; 145: 701–704.[CrossRef][ISI][Medline]





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