HR, hazards ratio; CI, confidence interval; WBC, white blood cell; SCT,
stem cell transplantation; CR, complete remission; GO, gemtuzumab
ozogamicin; EMI, extramedullary infiltration; OS, overall survival; EFS,
event-free survival.
Discussion
In the current study, we assessed the clinical and prognostic
characteristics of pediatric AML patients who exhibited EMI at different
time points. Out of the 713 pediatric AML patients, 123 (17.3%) were
diagnosed with EMI at initial diagnosis, which is consistent with
previous reported4. However, certain patients with EMI
may remain asymptomatic or lack bone marrow involvement, and the routine
use of lumbar puncture, incorporation of flow cytometry as a part of
cerebrospinal fluid assessment, and variations in the type and frequency
of imaging examinations could impact the detection rate of
EMI12,19-21.
In this cohort, patients with EMI, both at diagnosis and at relapse,
were more commonly found to be ≤2 years old and M5 morphology.
Conversely, only patients with EMI at relapse exhibited a higher
prevalence of WBC count ≥100×109/L. These factors have
also been demonstrated to be correlated with EMI in previous
studies8-11,22,23. Donna L. Johnston et al. conducted
a study involving 886 pediatric patients and observed that individuals
experiencing CNS relapse exhibited a higher prevalence of age
<2 years, FAB-M5 subtype, and higher white blood cell (WBC)
counts24. In the realm of cytogenetics and molecular
biology, a comprehensive investigation involving 315 children
participating in the NOPHO-AML 2004 trial revealed an association
between extramedullary infiltration (EMI) and 11q23/MLL(KMT2A ) rearrangements, which corroborated our own
findings11. Another study, comprising 240 cases
registered with the Japanese Childhood AML Cooperative Study Group,
identified a higher prevalence of inv16 and 11q23 abnormalities among
patients with EMI10. Chromosome 11 abnormalities were
also found to be related to CNS relapse in pediatric AML
patients24. In the context of pediatric low-risk AML,
Guan-hua Hu et al. observed that abnormalities such as t(8;21), t(1;11),
and c-KIT mutation were linked to EMI25. Our
investigation indicated that patients presenting with EMI, both at
diagnosis and at relapse, exhibited a higher incidence of KMT2Arearrangements and a lower incidence of normal karyotype. NPM1and FLT3-ITD mutation was found to be associated with EMI in
adult AML patients while CEBPA mutation decreased the occurrence
of EMI5,14. In this cohort, the mutation of theCEBPA showed unrelated to the presence of EMI. Intriguingly, we
observed that patients with EMI at the initial diagnosis presented a
lower frequency of FLT3 ITD-/NPM1+ , whereas EMI relapse patients
displayed a lower frequency of FLT3-ITD mutation. Further
research is needed to explore the cytogenetic and molecular biological
characteristics in pediatric AML patients with extramedullary
infiltration.
Although EMI is typically considered a presentation of advanced disease,
there is still no consensus on the prognosis of EMI in pediatric
patients. In the cohort, patients with EMI at initial diagnosis had a
low rate of CR1 and a higher rate of relapse. For initially diagnosed
patients, EMI appeared to independently predict both shorter OS and EFS.
Sorts of researches insisted our results. In the NOPHO-AML 2004 trial,
pediatric patients with EMI at diagnosis had significantly lower 5-year
OS (64% vs. 73%, p=0.04) but not 5-year EFS (54% vs. 45%, p=0.57)
and a higher risk of induction death (8% vs. 1%,
p=0.002)11.
Xiaoli
Xin et al. also found that EMI at initial diagnosis [HR 3.313, 95%
CI 1.748-13.664, p <0.001] was an independent risk factors
affecting the prognosis14. The appearance of EMI at
diagnosis was also proven to be a significant adverse factor in
pediatric RUNX1-RUNX1T1 (+) AML by
Jae
Wook Lee et al.15. Guanhua Hu et al. found myeloid
sarcoma instead of CNS leukemia was a predictor of adverse prognosis for
RFS and OS in low-risk pediatric AML25. However, sorts
of clinical trials have described no significant association between
extramedullary infiltration and outcome in pediatric AML
patients9,10. When analyzing the outcomes of different
subgroups of EMI, Donna L. Johnston et al. collected data from patients
who participated in CCG trials 2861, 2891, 2941 and 2961 and found
patients with orbital-MS and CNS-MS experienced better survival compared
to patients with other types of EMI, or without EMI16.
Another study adopted CCG AML trials 213 or 213P, 2861 and 2891 revealed
that the non-skin EML group had the best outcome compared to the skin
EML group and the no EML group12. In the cohort,
patients with myeloid sarcoma at diagnosis showed similar EFS and OS
compared to those with exclusive CNS involvement at diagnosis. Due to
the limitation of available data, we were unable to further explore the
impact of myeloid sarcoma at different site on prognosis.
Bone marrow is the most common site for relapse, while extramedullary
relapse also accounts for a considerable proportion26.
Without the limitation of age, the prognosis of extramedullary relapse
in AML patients is controversial. Most previous studies have indicated
that the survival of patients who developed extramedullary relapse was
slightly better than that of patients who developed bone marrow
relapse26-28. There is a notable lack of studies
focusing on pediatric patients. A retrospective study enrolled 1527
acute leukemia patients (983 ALL and 544 AML) by Volkan Hazar et al. and
found that post-HSCT patients with isolated extramedullary relapse
(without bone marrow involvement) remained poor prognosis but had
slightly better survival than those who developed bone marrow
relapse7. According to our results, patients with EMI
at relapse had similar overall survival compared to those without EMI.
This result indicated that the presence of EMI may not contribute to a
worse prognosis in patients experiencing relapse. However, when further
analyzed the prognosis of different types of EMI, we observed that
relapse patients with MS showed a significant shorter OS than those with
exclusive CNS involvement. Further studies requiring more cases of EMI
relapse are essential to validate the findings and investigate whether
the difference in prognosis is associated with special clinical
characteristics.
HSCT is a pivotal and widely utilized treatment modality in the context
of pediatric AML, but it also carries the risk of additional
treatment-related mortality due to graft-versus-host disease, infection,
and organ toxicity. Identifying the specific patient population that
will derive benefits from HSCT is of paramount
importance29,30. There is limited research exploring
the mutual prognostic significance of stem cell transplantation and EMI
in AML patients, especially in pediatric patients. A report of 51
patients (both children and adults were adopted) from the SFGM-TC
registry showed that allo-HSCT is a potentially efficient therapy for
myeloid sarcoma, with a notable proportion of patients achieving
long-term remission31. On contrast, a retrospective
study enrolled multi-center clinical trials showed that allo-HSCT did
not improved the survival5. A previous study by
Lu‑Hong Xu et al. also used data from the TAGART dataset and found that
stem cell transplantation did not improve either OS or EFS in patients
with myeloid sarcoma32. Our studies included patients
with myeloid sarcoma as well as those with CNS involvement, and we
obtained similar results. Given the limitations in the number of
EMI-positive patients who had also underwent SCT, further investigation
is needed to assess the prognostic association of between EMI and SCT.
Gemtuzumab Ozogamicin is an
antibody-drug conjugate (ADC) composed of an anti-CD33 monoclonal
antibody and a cytotoxic agent N-acetyl gamma
calicheamicin33. The incorporation of GO in the
induction treatment was proven to improve the RFS and EFS in
AML34. Taofeek Owonikoko et al. reported a case
involving GO therapy for a 19-year-old AML patient with isolated
extramedullary relapse after HSCT35. This patient
experienced extramedullary relapse at multiple sites, and radiation
therapy showed no discernible effect. However, extramedullary remission
was achieved after GO treatment. Regarding patients with EMI at initial
diagnosis, we evaluated the prognosis between those who underwent GO
treatment or not and found possibly significant difference in OS. The
immunohistochemical stains in myeloid sarcoma reveled a positivity rate
of CD33 ranging from 55% to 94%36,37. GO emerges a
potential treatment for extramedullary AML, particularly in cases with
CD33 positive upon biopsy.
Conclusion
In conclusion, EMI at diagnosis
independently predicts a worse prognosis. While for patients
experiencing relapse, the presence of EMI does not significantly impact
survival. Moreover, SCT does not lead to a prognosis improvement for
patients with EMI at initial diagnosis, whereas GO treatment has the
potential to prolong overall survival. This study enhances our
comprehension of EMI in pediatric AML patients and
demonstrates the potential
significance of GO treatment for AML with EMI. With the advancement of
flow cytometry and imaging techniques, the diagnostic rate of EMI is
expected to increase, and further exploration of treatment approaches is
needed to improve the survival of EMI patients.