Jones et al. have given us an excellent guide for the management of
symptomatic osteonecrosis in children and young adults with ALL. (1) I
would like to present our 10 year retrospective concurrent control
evaluation of pamidronate for reducing the incidence of symptomatic
osteonecrosis which may be of interest.
Patients aged 10-28 years at time of ALL diagnosis were given
intravenous pamidronate (1 mg/kg IV over 2 hours) monthly for one year
at the discretion of the primary oncologist, starting as early as
possible after diagnosis.
Concurrent controls age 10-28 did not receive pamidronate. All were
treated according to the concurrent COG protocols with intermittent
dexamethasone during delayed intensification.(2) Imaging was performed
if osteonecrosis was suspected based on symptoms. Patients with BCR-ABL
ALL were excluded, as dasatinib may increase the risk of osteonecrosis.
(3,4)
Patients were diagnosed between January 2010 and March 2018. They were
censored at relapse (n=4; 2 controls) bone marrow transplant (n=4; 3
controls) or at last follow up. Data was analyzed 6/1/2020. The median
follow up is 3.3 years from diagnosis to event or censoring. This
retrospective study was approved by Children’s Minnesota IRB. Data was
entered into excel and transferred to SPSS version 23 for analysis.
There were 65 patients, 38 males, 27 females, of which 49 had B-lineage
and 16 T-lineage ALL. Pamidronate was started during induction in 63%
of patients, and before delayed intensification in 85%. The mean,
median and interquartile range for the number of pamidronate doses was
11.6, 12, 10.8 to 12. Pamidronate was used in 26 patients, with four
subsequently developing symptomatic osteonecrosis. There were 39
concurrent controls who did not receive pamidronate with 14 developing
osteonecrosis. Five from this group have since received joint
replacements. There were no short or long term side-effects from
pamidronate infusions including osteonecrosis of the jaw or
hypocalcemia.
The incidence of symptomatic osteonecrosis by Kaplan-Meier analysis with
was 16% with pamidronate vs. 39% in controls (figure 1). P-value is
significant at 0.043 (Breslow Generalized Wilcoxan). There was no
significant difference in the leukemia lineage, gender distribution or
Body Mass Index (BMI) at diagnosis between groups. For all patients the
mean, median, and interquartile range for BMI was 25.8; 22.0; 14.2 to
28.8 Kg/m2.
The age at diagnosis was significantly greater in the pamidronate group
with a mean, median and Interquartile range 18.4; 18.6; 13.8 to 23.4
years for pamidronate patients vs. 15.6; 15.7; 11.5 to 19.9 in
concurrent controls (independent means t-test p = 0.01). Age was not
significant for osteonecrosis in Cox Proportional Hazard analysis
(p=0.10).
Study limitations include small numbers of patients from a single
institution and lack of a randomized control group. Strengths of the
study are the long duration of followup, as most of the patients are
beyond the peak risk time for osteonecrosis. We hope these results even
with its limitations would spark interest in a randomized trial of
pamidronate in patients at high risk of symptomatic osteonecrosis.
Author Contributions and Disclosures: Bruce Bostrom was the
sole contributor to this submission and has no conflict-of-interest to
disclose. Jack Knutson assisted with data collection as part of a high
school senior mentor connection project. Char Bostrom provided
invaluable editorial assistance.
Figure 1 legend : Incidence of symptomatic osteonecrosis from
time of ALL diagnosis in patients who received prophylactic pamidronate
and concurrent controls.