Evaluation of Early Treatment Response Utilizing the MAS-ALL18 Adapted Management Guideline in Four "Mexico in Alliance with St. Jude" (MAS) Member Hospitals

Introduction: Acute lymphoblastic leukemia (ALL) represents approximately 50% of all childhood cancers in Latin America. Mexico is not the exception. The impact of ALL survival on overall childhood cancer survival is significant. According to government data, five-year survival is about 52%. Mexico in Alliance with St. Jude (MAS) is a multi-site, intersectoral collaboration. The collaborative network has explored and reported on factors associated with this suboptimal outcome and have identified challenges with ALL risk group classification as a leading cause. For example, as many as 82% of children diagnosed with ALL in Mexico receive high-risk treatment and the tendency for higher-risk group assignment often occurs in response to limited access to cytogenetic testing and minimal residual disease (MRD) testing. This leads to higher intensity treatment and may explain the high rate of treatment-related death (TRD) (12%) documented during the induction but also subsequently. In our previous case series, only 75% of patients were alive at the end of the first year of treatment. These findings, led MAS to develop a consensus-derived standardized diagnosis and treatment schema (MAS-ALL18), which takes into account clinical, cytogenetic, and MRD results. Diagnostic testing is performed in a centralized laboratory. Although centred on delivery of standard of care, this experience represents is the first prospective multi-site cooperative group effort in Mexico. We report on early treatment (first 90 days) clinical and implementation outcomes utilizing the MAS-ALL18 adapted management guideline (AMG) in four member hospitals of the MAS collaboration network. Results: From June 2019 to June 2020, 137 patients received treatment utilizing the MAS-ALL18 AMG in four publicly funded hospitals in Mexico. B-cell ALL represented 91.9% of the cases, 20.4% of patients were older than 9 years of age, 25.5% had a white blood cell count greater than 50,000 at diagnosis and 58.3% were male. Complete remission at the end of the induction was achieved in 90.6% of patients. TRD during the induction phase was 8%. MRD at Day 15 in 123 patients with B-cell ALL, 84.5% of them had MRD <1% and 7.3% had MRD ≥5%. MRD at Day 29 was assessed for the 10 patients diagnosed with T-cell ALL, 4 patients had MRD <0.01%, 2 had 0.02%, and 4 died during the induction phase. MRD was also assessed during consolidation (at Day 84) in 99 patients, 94.9% had MRD <0.01% and 5 patients MRD ≥0.01%, from which 3 had MRD at day 15 >1% and none registered an MRD result <0.5%. Utilizing the MAS-ALL18 risk group stratification, 50% of patients were assigned to a favorable risk group at the end of the consolidation. In 34 patients, the risk group was reclassified following the standardized algorithm; 30 reclassification events happened at the end of the induction and four at the end of the consolidation. Only two events were reassigned to a lower risk group, while the rest of the reclassifications were conducted to assign patients to a higher risk group due to unfavorable cytogenetics or an inadequate early response to treatment. High-risk treatment was ultimately assigned to 30% of patients using the MAS-ALL18 risk classification schema. Conclusion: It is feasible to implement a standardized multi-site adapted management guideline for ALL risk group stratification and treatment allocation in Mexico in the context of a collaborative network. TRD remains high during the induction phase, nevertheless, this number shows an improvement (8%) compared to the 2015 data report (12%). The ALL risk group classification is transitioning from a rigid scheme that placed 80% of patients in a high-risk group to a dynamic classification system that considers cytogenetic testing and MRD conducted in a centralized and externally validated laboratory that serves as reference for all the participating hospitals. The standardized MAS-ALL18 approach allowed us to classify 50% of patients in a favorable risk group during and at the end of the induction phase, which implies receiving a lower intensity treatment with a high probability of cure and a lower risk of TRD. The implementation of MAS-ALL18 risk classification scheme reduced the number of children requiring high-risk treatment in the participating hospitals. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations

Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using Molecular Inversion Probe sequencing and breakpoint-spanning PCR we reliably detected alterations below 1% allele frequency. We identified 660 genomic alterations in 285 diagnosis samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment.

ANALISIS KEANGGOTAAN PETANI DALAM KELOMPOK TANI : STUDI KASUS KELOMPOK PEMBUDIDAYA IKAN “ULAM SARI” DESA KALIKIDANG, SOKARAJA, BANYUMAS

Farmer groups become one of the agricultural institutions that have an important role in agricultural development. This study aims to analyze the effect of turnover, education level, length of business, and landholding on the membership of farmers in farmer groups and to analyze the variable that has the greatest effect on farmer membership. Stratified proportionate random sampling is used to select 34 farmers who join farmer group and 51 farmers who do not join farmer group. Stratification is based on landholding. The method used is logistic regression and Mann Whitney analysis using SPSS. The results show that turnover, education level, and landholding significantly influence farmer’s membership. Landholding has the biggest effect on the membership of farmers in farmer groups. Keywords: Agricultural institution, farmer group, farmer membership

Molecular genetic features of pediatric gliomas

Gliomas are the most common central nervous system tumors demonstrating an extremely broad range of clinical behavior. Over last few decades the understanding of molecular genetic mechanisms of tumor initiation and progression increased significantly. Furthermore, the identification of prognostic and predictive biomarkers aids the development of personalized and risk-adapted therapeutic approaches. In this review, we summarize the molecular findings in pediatric gliomas, both low and high grade (LGG and HGG), focusing on recurrent somatic mutations. There are nucleotide substitutions in BRAF, H3F3A, Hist1H3B/С, IDH1/2 genes, BRAF and NTRK1/2/3 fusions, and CDKN2A/B copy-number aberrations, known to be clinically relevant in the prognosis defining or predicting the efficacy of targeted therapy. We also describe how these findings could pave the way towards the novel genetic classification and risk-group stratification for pediatric patients with glial tumors.

Development and Implementation of Survivorship Tools to Enable Medical Follow-Up After Childhood Cancer Treatment in Southern Sweden

PURPOSE Survival rates after childhood cancer have increased from 20% to 80% since the 1970s. The increased number of survivors emphasizes the importance of late effects and their monitoring. Late effects may have a strong impact on quality of life in survivors. The purpose of this study was to make key data in a quality registry available for direct clinical use, enabling health care professionals to perform efficient and appropriate long-term medical follow-up after childhood cancer treatment. METHODS The population-based quality registry upon which this study is centered contains data on all individuals diagnosed with childhood cancer (diagnosed at 18 years of age or younger) in southern Sweden since January 1, 1970, and treatment data on 5-year survivors. Web tools, which were developed and implemented in a health care setting, generate a personalized treatment summary for each patient and enable risk group stratification of survivors. RESULTS Generation of a personalized treatment summary and risk group stratification of survivors led to identification of women at risk for developing breast cancer as a consequence of childhood cancer treatment. Three novel cases of previously undiagnosed breast cancer were identified. CONCLUSION The registry, together with the developed tools, enabled health care professionals to perform medical follow-up in this at-risk patient population.