Abstract
We conducted a cross-sectional study using a questionnaire to explore
the late effects in survivors of juvenile myelomonocytic leukemia
(JMML). The attending pediatric hematologist oncologists completed the
questionnaires. All survivors (N=30) had undergone allogeneic
hematopoietic stem cell transplantation. Approximately 83% survivors
showed more than one late effect. The identified late effects included
endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary,
neurocognitive, and cardiovascular dysfunction.
The prevalence of short stature
and cardiovascular and kidney dysfunction was significantly elevated
among survivors aged ≥18 years. Therefore, a multidisciplinary follow-up
system for survivors of JMML is crucial.
Introduction
Juvenile myelomonocytic leukemia (JMML) is a rare
myeloproliferative/myelodysplastic malignancy, typical in infancy and
early childhood, characterized by fever, hepatosplenomegaly, and organ
infiltration due to excessive production of monocytic and granulocytic
lineage cells.1,2 Approximately 90% patients with
JMML show either somatic or germline mutations in their leukemia cells
in the Ras pathway.3 Allogeneic
hematopoietic stem cell
transplantation (HSCT) is the only curative treatment for JMML, and a
myeloablative preparative regimen based on a combination of busulfan
with other cytotoxic agents is recommended.2,4 The
high prevalence of late effects among survivors treated with HSCT is a
major issue for hematologists devoted to long-term follow-up because the
median age for HSCT is 2–3 years.5,6 However, limited
studies have focused on data regarding the late effects in survivors of
JMML who underwent HSCT, particularly in those treated with
myeloablative regimens. We aimed
to elucidate these effects using a nationwide, retrospective analysis of
child and adolescent survivors who underwent HSCT.
Results
In this cross-sectional study, attending pediatric hemato-oncologists
completed a questionnaire. Eligible survivors were recruited from a
database of the myelodysplastic syndrome central review committee. All
survivors—first diagnosed between July 1999 and December 2016—were
alive at the time of the survey. The review board of each institution
approved this study. The
requirement for informed patient consent was waived because of the
nature of the study (chart review) and use of an opt-out method to
collect study data from the survivors or their guardians.
We evaluated demographic (age, sex, and social background) and medical
(treatment for JMML, conditioning regimen, and early morbidity)
variables after HSCT (Table 1). The late effects assessed were short
stature, underweight, and endocrine, cardiovascular, pulmonary,
neurocognitive, gastrointestinal, nephrological, dental,
musculoskeletal, ophthalmologic, and secondary neoplasm complications.
Hematologist oncologists rated each late effect according to the Common
Terminology Criteria for Adverse Events (CTCAE) version 4. We evaluated
the prevalence of each late effect before performing univariate analysis
between the late effects and demographic and medical variables.
Among the 43 eligible survivors, 30 (70%) were included. More than 80%
survivors had more than one late effect, and 10% had more than seven
late effects. The median number of late effects (CTCAE grades 1–5) was
3.3. The chi-square test of independence was performed by comparing the
number of late effects and age groups. Survivors aged ≥18 years showed a
significantly high number of late effects (chi-square: 11.1; df=3;
p<0.05).
A busulfan-based conditioning regimen was administered to 24 (80%)
survivors. Total body irradiation (TBI)-included conditioning was
conducted in four survivors for the first HSCT and in five survivors for
the second SCT. Ten survivors underwent a second HSCT. Chronic
graft-versus-host disease (GVHD) was observed in 33% survivors, and the
most common category of GVHD was skin lesions. Regarding social
background, 28 survivors were students, two were graduates, and two were
part-time workers.
The prevalence of late effects is illustrated in the descending order in
Supplemental Figure S1. The most common late effects were short stature
and underweight, which were found in 53% survivors. The third most
common late effect was dental problems such as permanent tooth loss.
Spinocellular carcinoma of the skin was observed as a secondary neoplasm
in one survivor 10 years after receiving TBI-conditioned HSCT. The
correlation between the most recently measured height of survivors and
time lapsed from diagnosis to survey is plotted in Supplemental Figure
S2.
Table 2 showed the odds ratios and 95% confidence interval (CI) of the
late effects and risk factors associated with age and conditioning
regimen around HSCT. We found significantly greater pulmonary
complications in survivors who received HSCT at an age of ≤2 years, with
TBI as the conditioning regimen. Thyroid complications were observed in
survivors who received multiple HSCTs and those aged ≥18 years at the
time of the survey. Significantly high frequencies of heart and kidney
complications were observed in survivors ≥18 years. Underweight and
heart complications were observed in patients who received TBI as the
conditioning regimen.
Discussion
The present study focused on the late effects of survivors of JMML.
Strikingly, >80% survivors had at least one late effect,
and 10% had more than seven late effects. Our data suggested that older
survivors of JMML had more late effects. Allewelt7reported that 98% patients who underwent cord blood transplantation
with a busulfan-based conditioning regimen experienced at least one late
effect. A series of survivors transplanted with both TBI- and
busulfan-conditioning regimens showed a high incidence of late
effects.8 These reports highlight the necessity of
clinical care guidelines for
long-term follow-up.
In this study, growth impairment was the most frequent late effect, as
described in a series of reports on HSCT for younger children with
leukemia; Tomizawa9 revealed that 58.9% infantile
acute lymphoblastic leukemia survivors, most of whom received HSCT in
early infancy, showed short stature. We found a significant negative
correlation between the height of survivors and time lapse from
diagnosis to when this survey was conducted.
Giorgiani10 reported that survivors treated with
busulfan-conditioned regimens grew normally. The third most frequent
late effect was dental problems. HSCT in younger children is highly
related to dental problems, including microdontia, enamel hypoplasia,
and extensive caries. Although the prevalence was relatively low in this
study, we confirmed results reported previously.11,12
In this long-term follow-up study, univariable analysis revealed that
the prevalence of kidney, thyroid, and cardiovascular complications was
significantly higher in survivors aged ≥18 years than in those aged
<18 years. Künkele13 reported that 17%
acute leukemia survivors treated with HSCT showed renal
toxicity.13 While they found that TBI with high-dose
chemotherapy could be a risk factor, we found no significant correlation
between TBI and nephrotoxicity. This discrepancy may be due to the small
number of patients who received TBI in this study. Although
hypothyroidism is often reported after HSCT for various leukemias, it
has rarely been reported in studies of JMML alone.14Thyroid complications were significantly related to the number of HSCTs,
which in turn was related to the cumulative number of cytotoxic drugs or
irradiation. We found that heart complications were significantly
related to the time lapsed and TBI regimen. Future studies are needed to
explore heart function over a longer period after HSCT.
Lastly, pulmonary complications were significantly related to a younger
age at the time of HSCT- and TBI-regimen administration.
Hoffmeister15 reported that time lapse after HSCT,
single-fraction TBI, diseases such as chronic myeloid
leukemia/myelodysplastic syndrome/JMML, and chronic GVHD were
significant risk factors for pulmonary complications. Therefore, the
results of this study partly confirm those of previous research.
This study has several limitations. First, the number of participants
was small. Second, the study design was cross-sectional, preventing us
from drawing conclusions regarding causality. Third, in-depth medical
surveys were not conducted for all aspects of late effects because of
the retrospective hematologist oncologist-oriented survey.
In conclusion, this study revealed that growth, dental, endocrine, and
skin complications were common in survivors of JMML.
These findings suggest that
risk-based late effect follow-up is needed for survivors of JMML to
assess and treat potential outcomes.
Acknowledgements
The authors thank all of the attending physicians who provide the
information about survivors. This research was supported by AMED under
Grant Number 22ck0106611h0003. We would like to thank Editage
(www.editage.com) for English language editing.
Conflicts of Interest Statement: The authors declare no financial
interests.
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