4 ︳ DISCUSSION
C-MYC has been described as a proto-oncogene that is involved in the
pathogenesis of many cancers, including leukemia and lymphoma.
Physiologically, c-MYC plays an important role in B-cell differentiation
and proliferation. During the maturation of B cell, c-MYC base levels
are maintained and its transient downregulation is required at some
specific point to promote the proliferation of
B-cell10, 11. The most common c-MYC rearrangement is
reciprocal chromosomal translocation between 8q24 and 14q32, followed by
8q24 with t(8;22)(q24;q11), and t(2;8)(p12;q24)12. The
translocation places the c-MYC gene under direct regulation of the
enhancer of the IGH (or IGK/IGL genes), causing overexpression of c-MYC
gene13.
Although it is mainly observed in mature B-cell neoplasms, c-MYC gene
rearrangement can occasionally detected in patients with BCP-ALL
immunophenotype. Previous published researches have shown that pre-BLL
is a rare subtype comprising 0.1% (5/5280) of BCP-ALL in the Pediatric
Oncology Group (POG) and 0.2% (10/4043) in a nationwide study in
Japan14, 15. Our data also indicates that pre-BLL is
rarely detected in clinic, and comprising ~0.5% of all
the B-NHL and BCP-ALL.
Kimiyoshi Sakaguchi et al. had conducted the literature survey to
further shed light on the clinical and immunological features of pre-BLL
compared to BCP-ALL15. Compared to his research, we
failed to observe a relatively older median age (6.8y) and a higher UA
level (6.93mg/dl) of our patients, but we could observe an elevated
level of LDH (median >5,700 IU/l), which was consistent
with other researches. The blast immunophenotypes reported in other
researches were similar to that of our patients.
With the improvement in standard chemotherapy and supportive care, the
outcome for pediatric BL and BCP-ALL has improved with a 5-year overall
survival (OS) rates achieve 90%16, 17. Despite with
the immunophenotype of BCP-ALL and the genetic characteristic of BL, the
biological characteristics and treatment of pre-BLL are still
controversial. By using
next
generation sequencing (NGS), Wagener et al. have uncovered that pre-BLL
shows similar molecular features of BCP-ALL rather than BL, with
recurrent NRAS/KRAS mutations, lack of functional B-cell receptor and
c-MYC translocation due to aberrant VDJ recombination, instead of class
switch or somatic hypermutation like mature B-cell
neoplasms18, 19. Whereas protocols for BL consist of
short-course and high-intensity pulsed chemotherapeutic regimen,
protocols for BCP-ALL are characterized by continuous treatment regimen
with a long-term maintenance therapy of low intensity. Based on the
literature survey and several cases, Herbrueggen et al. encouraged
treatment of pre-BLL according to protocols for mature B-cell NHL rather
than BCP-ALL3. In this study, five patients were
treated with mature B-cell neoplasm protocols and one (1/5) relapsed in
a short time (5 months). Among the other four patients who was treated
with BCP-ALL protocols, two (2/4) relapsed before termination of
treatment. It is suggested that the outcomes of pre-BLL patients appear
to be favorable when treated with protocols used for mature B-cell
neoplasm. Sakaguchi et al. have suggested that high-risk ALL-type
treatment might be adequate for the treatment of
pre-BLL15, but there is still inconclusive how
intensive the chemotherapy should be.
Although with a molecular similarity to BCP-ALL, the presence of the
c-MYC warrants intensive treatment due to the highly proliferate nature
of pre-BLL. However, the intensity of chemotherapy, the value of the
supplemented of targeted drug like rituximab and the necessity of
maintenance therapy are still unknown. Some patients relapsed even when
treated with high-intensity regimen, suggesting further genetic studies
should be performed. In view of the rarity of pre-BLL, international
collaborative efforts are encouraged to further elucidate the biological
and clinical characteristics of pre-BLL and finally establish a
consensual treatment approach.