RESULTS
Study 1: symptomatic
ON
Characteristics of studied
cohort
Among 4973 childhood leukemia survivors included in the L.E.A cohort on
June 11, 2019, 129 (2.5%) had suffered from a symptomatic ON and all of
them were included in study 1. Among patients with symptomatic ON, 66
had MRI performed for the diagnosis of ON. In 39 patients this MRI was
available for central review at time of study n° 2. (Fig. 1).
The detailed characteristics of the 129 patients included in Study n°1
are described in Table 1. The median follow-up time for these patients
was 9.97 years and that of the entire cohort was 10.94 years.
ON population consisted of mainly patients with ALL (88%) with a
predominance of females (56.6%). Most patients were over 10 years old
with a median age of occurrence of 13.3 years. One third of the patients
received an allogeneic SCT prior to the onset of bone necrosis. Overall,
69% of patients had a multifocal involvement at ON diagnosis. The
median time to onset of ON was 1.8 years after AL diagnosis. Among
patients who received a SCT, necrosis was diagnosed on average 1.4 years
after the transplantation.
Risk factors for osteonecrosis and determinants for
multifocal
character
We analyzed our cohort, after excluding the 365 patients treated for AML
without SCT, since none of these patients had bone necrosis.
As a first step, we performed a comparative analysis of the 129 patients
with ON with the 4479 patients of the L.E.A cohort without ON in
univariate (Supplemental Table S1) and further in multivariate analysis
(Fig. 2). SCT was associated with a higher risk of ON in univariate
analysis (4.8% of ON for transplanted patients versus 2.3% for those
not, p < 0.001), but no longer in multivariate analysis (OR
1.29, 95%CI [0.82-2.05], p=0.269). In univariate analysis, BMI at
diagnosis (Z score) was also significantly associated with ON in the
group of ALL without SCT (p=0.008) but no longer in multivariate
analysis (OR 1.08, 95%CI [0.94-1.24], p=0.2). By contrast in
multivariate analysis (Fig. 2), we showed that the diagnosis of AL after
the age of 10 years was associated with a higher occurrence of ON (OR
22.46, 95%CI [13.8 -36.55] p <10-6).
Females were also more often affected by ON (OR 1.8, 95%CI
[1.23-2.58] p=0.002), but this predominance disappeared into the
group of transplanted patients (OR 1.49, 95%CI [0.7-3.13], p=0.29).
We finally highlighted that the presence of a relapse was associated
with a more frequent occurrence of bone necrosis (OR 1.80, 95%CI
[1.02-3.16], p=0.041).
In addition, we showed in the subgroup of patients who received a SCT
(Fig.2B) a higher incidence of ON in patients over 10 years of age and
who presented with chronic GVHD. We did not find any evidence of an
increased risk of ON according to irradiation use.
In a second step, we looked for risk factors for multifocal involvement
in our study population (Table 2). Multifocal involvement was not
associated with a particular patient profile, but it was the most
frequent presentation occurring in 89/129 (69%) patients suffering from
ON.
We were also able to demonstrate that patients who presented ON were
also those who were more likely to suffered from multiple sequelae
(p<10-6) (Supplemental Table S2)
Quality of life
First, we compared the last assessment of QoL of patients with
osteonecrosis with that of the general French population and of the
L.E.A cohort, separately for adults, according to the SF-36 score (Fig.
3A), then for adolescents, according to the parents VSP-A score (Fig.
3B).
We obtained a QoL assessment for 88.7% of L.E.A patients (4088/4608),
and for 118 of the 129 osteonecrosis patients. Data was collected from
VSP-A parents score for 2087 patients of L.E.A, and 15 patients with ON,
and from SF-36 for 1983 patients of L.E.A, and 103 patients with
osteonecrosis. In comparison with the general adult population, ON led
to a decrease in each parameter of the SF-36 score: physical (74.26 vs
94.76, p <10-6), social (73.14 vs 83.97,
p<0.001), and emotional well-being scores (67.51 vs 87, p
<10-6). Furthermore, this negative impact on
QoL is also shown when comparing with patients of the L.E.A cohort, for
most of parameters except mental health and emotional scores. (Fig. 3A)
These statements were also found when comparing adolescents with their
healthy peers, mainly through a physical (physical well-being 44.16 vs
69.97, p=0.002) and friendship impact (48.93 vs 66.86, p=0.005) (Fig.
3B)
Secondly, we looked for the evolution of the QoL of patients with
osteonecrosis during their lifetime. We therefore compared the results
for the 37 patients for who two assessments of SF-36 questionnaire were
available at two different times: first assessment after ON diagnosis
with the last available assessment (Fig. 3C). The median time between
these two evaluations was 45.6 months [11.6-127]. There was no
difference in QoL score with time from ON diagnosis suggesting that the
poor impact of ON on QoL occurred soon after ON and lasted.
Study 2: radiological description of
joint damage at diagnosis
Pain was the main symptom identified in medical records as a diagnostic
call point for ON, leading to the ordering of an initial standard
radiography sometimes followed by an MRI.
Fifty-one patients were excluded for lack of MRI performed. Most of
these suffered from osteonecrosis diagnosed before 2009 (40/51 =
72.5%), and for all before 2015. Twenty-seven MRI could not be read
even though they had been performed, in connection with default of
imaging storage since half of them were carried out before 2009, when a
storage tool was generalized in French hospitals. Finally, radiological
analysis could be performed for 39 patients, on 63 joints. Our
radiological results mainly concerned patients whose leukemia was
diagnosed after January 1, 2009: 32 patients out of 39 patients, which
corresponded to 69% (32/46) of all patients diagnosed during this
period. The characteristics of the 39 patients were not significantly
different from those of the 90 patients who had no initial imaging of
their necrosis, except for the delay between AL diagnosis and ON which
was shorter for the patients included in the study n°2. (Supplemental
Table S3).
For the 63 joints analyzed by MRI, we observed only 6 unconformities
between both radiologists, which corresponded to a good inter-observer
reproducibility with a kappa coefficient of 0.854. Radiological findings
per joints and per patients are available in Supplementals Tables S4A
and S4B.
The most often affected joints were the weight-bearing ones: knees and
hips, with radiological involvement of more than one joint from the time
of ON diagnosis in 56.4% of cases: 20 patients had bilateral
involvement and 2 patients had multiple joint osteonecrosis (illustrated
in supplemental fig.1).
Radiological severity was defined by the presence of V grade, i.e. joint
deformity according to Niinimäki’s classification 16.
Among the 14 patients with severe involvement, 8 had multifocal
involvement. The hips injuries were more often severe (p =0.003) at the
time of diagnosis of ON (Table 3). There was also a correlation between
radiological severity and surgical management since patients with grade
V disease, have more often benefited from joint replacement by
prosthesis. (57.14% vs 16%, p = 0.012)
MRI follow-up was performed for 11 patients (28%), with a median delay
of 10.9 months between the 2 imaging. There was a stage change for the
same articulation on the follow-up MRI for only 2 patients, in whom
stage IV worsened to stage V. Data are available in Supplemental Table
S5.