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.