Pediatric Adrenocortical Carcinoma: The Nuts and Bolts of Diagnosis and Treatment and Avenues for Future Discovery.

Adrenocortical tumors (ACTs) are infrequent neoplasms in children and adolescents and are typically associated with clinical symptoms reflective of androgen overproduction. Pediatric ACTs typically occur in the context of a germline TP53 mutation, can be cured when diagnosed at an early stage, but are difficult to treat when advanced or associated with concurrent TP53 and ATRX alterations. Recent work has demonstrated DNA methylation patterns suggestive of prognostic significance. While current treatment standards rely heavily upon surgical resection, chemotherapy, and hormonal modulation, small cohort studies suggest promise for multi-tyrosine kinases targeting anti-angiogenic pathways or immunomodulatory therapies. Future work will focus on novel risk stratification algorithms and combination therapies intended to mitigate toxicity for patients with perceived low-risk disease while intensifying therapy or accelerating discoveries aimed at improving survival for patients with difficult-to-treat disease.

Outcomes in patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies.

Children with ETV6::RUNX1 or high-hyperdiploid B-acute lymphoblastic leukemia (B-ALL) have favorable outcomes. The St. Jude (SJ) classification considers these patients low-risk, regardless of their National Cancer Institute (NCI) risk, except when there is slow minimal residual disease (MRD) response or central nervous system/testicular involvement. We analyzed outcomes in children (aged 1-18.99 years) with these genotypes in the SJ Total XV and XVI studies (2000-2017). Patients with ETV6::RUNX1 (n = 222) or high-hyperdiploid (n = 296) B-ALL had 5-year event-free survival (EFS) of 97.7% ± 1.1% and 94.7% ± 1.4%, respectively. For ETV6::RUNX1, EFS was comparable for NCI standard-risk and high-risk patients (97.8% ± 1.2% and 97.5% ± 2.6%, respectively; P = 0.917) and for SJ low-risk and standard-risk patients (97.4% ± 1.2% and 100.0%; P = 0.360). Thirty-seven of 40 NCI high-risk patients who received SJ low-risk therapy had excellent EFS (97.3% ± 2.8%). For high-hyperdiploid B-ALL, EFS was worse for NCI high-risk patients than for standard-risk patients (87.6% ± 4.5% and 96.4% ± 1.3%; P = 0.016). EFS was similar for NCI standard-risk and high-risk patients classified as SJ low-risk (96.0% ± 1.5% and 96.9% ± 3.2%; P = 0.719); however, EFS was worse for NCI high-risk patients than for NCI standard-risk patients receiving SJ standard/high-risk therapy (77.4% ± 8.2% and 98.0% ± 2.2%; P = 0.004). NCI high-risk patients with ETV6::RUNX1 or high-hyperdiploid B-ALL who received SJ low-risk therapy had lower incidences of thrombosis (P = 0.013) and pancreatitis (P = 0.011) than those who received SJ standard/high-risk therapy. Contemporary MRD-directed therapy yielded excellent outcomes, except for NCI high-risk high-hyperdiploid B-ALL patients with slow MRD response, who require new treatment approaches. Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with high-hyperdiploid B-ALL experienced excellent outcomes with a low-intensity regimen. These trials were registered at www.clinicaltrials.gov as #NCT00137111 and #NCT00549848.

Integrated drug resistance and leukemic stemness gene-expression scores predict outcomes in large cohort of over 3500 AML patients from 10 trials.

In this study, we leveraged machine-learning tools by evaluating expression of genes of pharmacological relevance to standard-AML chemotherapy (ara-C/daunorubicin/etoposide) in a discovery-cohort of pediatric AML patients (N = 163; NCT00136084 ) and defined a 5-gene-drug resistance score (ADE-RS5) that was predictive of outcome (high MRD1 positivity p = 0.013; lower EFS p < 0.0001 and OS p < 0.0001). ADE-RS5 was integrated with a previously defined leukemic-stemness signature (pLSC6) to classify patients into four groups. ADE-RS5, pLSC6 and integrated-score was evaluated for association with outcome in one of the largest assembly of ~3600 AML patients from 10 independent cohorts (1861 pediatric and 1773 adult AML). Patients with high ADE-RS5 had poor outcome in validation cohorts and the previously reported pLSC6 maintained strong significant association in all validation cohorts. For pLSC6/ADE-RS5-integrated-score analysis, using Group-1 (low-scores for ADE-RS5 and pLSC6) as reference, Group-4 (high-scores for ADE-RS5 and pLSC6) showed worst outcome (EFS: p < 0.0001 and OS: p < 0.0001). Groups-2/3 (one high and one low-score) showed intermediate outcome (p < 0.001). Integrated score groups remained an independent predictor of outcome in multivariable-analysis after adjusting for established prognostic factors (EFS: Group 2 vs. 1, HR = 4.68, p < 0.001, Group 3 vs. 1, HR = 3.22, p = 0.01, and Group 4 vs. 1, HR = 7.26, p < 0.001). These results highlight the significant prognostic value of transcriptomics-based scores capturing disease aggressiveness through pLSC6 and drug resistance via ADE-RS5. The pLSC6 stemness score is a significant predictor of outcome and associates with high-risk group features, the ADE-RS5 drug resistance score adds further value, reflecting the clinical utility of simultaneous testing of both for optimizing treatment strategies.

Pharmacogenomic Score Effectively Personalizes Treatment of Acute Myeloid Leukemia.

PURPOSE: Cytarabine (also known as ara-C) has been the backbone of acute myeloid leukemia (AML) chemotherapy for more than five decades. Recent pharmacogenomics-based 10-SNP ara-C (ACS10) scores showed low ACS10 (≤0) to be associated with poor outcomes in patients with AML treated with standard chemotherapy. Here, we evaluated the ACS10 score in the context of three different induction I regimens in patients with pediatric AML. EXPERIMENTAL DESIGN: ACS10 score groups (low, ≤0, or high, >0) were evaluated for association with event-free survival (EFS) and overall survival (OS) by three randomized treatment arms in patients treated on the AML02 (NCT00136084) and AML08 (NCT00703820) clinical trials: AML02 low-dose ara-C (LDAC arm, n = 91), AML02 + AML08 high-dose ara-C (HDAC arm, n = 194), and AML08 clofarabine + ara-C (Clo/ara-C arm, n = 105) induction I regimens. RESULTS: Within the low-ACS10 score (≤0) group, significantly improved EFS and OS were observed among patients treated with Clo/ara-C as compared with LDAC (EFS, HR = 0.45; 95% CI, 0.23-0.88; P = 0.020; OS, HR = 0.44; 95% CI, 0.19-0.99; P = 0.048). In contrast, within the high-ACS10 score group (score >0), augmentation with Clo/ara-C was not favorable as compared with LDAC (Clo/ara-C vs. LDAC, EFS, HR = 1.95; 95% CI, 1.05-3.63; P = 0.035; OS, HR = 2.10; 95% CI, 0.96-4.59; P = 0.063). Personalization models predicted 9% improvement in the outcome in ACS10 score-based tailored induction (Clo/ara-C for low and LDAC for high-ACS10 score groups) as compared with nonpersonalized approaches (P < 0.002). CONCLUSIONS: Our findings suggest that tailoring induction regimens using ACS10 scores can significantly improve outcomes in patients with AML. Given the SNPs are germline, preemptive genotyping can accelerate matching the most effective remission induction regimen.

Pharmacogenomics, Race, and Treatment Outcome in Pediatric Acute Myeloid Leukemia.

Importance: Disparities in outcomes exist between Black and White patients with acute myeloid leukemia (AML), with Black patients experiencing poorer prognosis compared with their White counterparts. Objective: To assess whether varying intensity of induction therapy to treat pediatric AML is associated with reduced disparities in treatment outcome by race. Design, Setting, and Participants: A comparative effectiveness analysis was conducted of 86 Black and 359 White patients with newly diagnosed AML who were enrolled in the AML02 trial from 2002 to 2008 or the AML08 trial from 2008 to 2017. Statistical analysis was conducted from July 2023 through January 2024. Interventions: Patients in AML02 were randomly assigned to receive standard low-dose cytarabine-based induction therapy or augmented high-dose cytarabine-based induction therapy, whereas patients in AML08 received high-dose cytarabine-based therapy. Main Outcomes and Measures: Cytarabine pharmacogenomic 10-single-nucleotide variant (ACS10) scores were evaluated for association with outcome according to race and treatment arm. Results: This analysis included 86 Black patients (mean [SD] age, 8.8 [6.5] years; 54 boys [62.8%]; mean [SD] leukocyte count, 52 600 [74 000] cells/µL) and 359 White patients (mean [SD] age, 9.1 [6.2] years; 189 boys [52.6%]; mean [SD] leukocyte count, 54 500 [91 800] cells/µL); 70 individuals with other or unknown racial and ethnic backgrounds were not included. Among all patients without core binding factor AML who received standard induction therapy, Black patients had significantly worse outcomes compared with White patients (5-year event-free survival rate, 25% [95% CI, 9%-67%] compared with 56% [95% CI, 46%-70%]; P = .03). By contrast, among all patients who received augmented induction therapy, there were no differences in outcome according to race (5-year event-free survival rate, Black patients, 50% [95% CI, 38%-67%]; White patients, 48% [95% CI, 42%-55%]; P = .78). Among patients who received standard induction therapy, those with low ACS10 scores had a significantly worse 5-year event-free survival rate compared with those with high scores (42.4% [95% CI, 25.6%-59.3%] and 70.0% [95% CI, 56.6%-83.1%]; P = .004); however, among patients who received augmented induction therapy, there were no differences in 5-year event-free survival rates according to ACS10 score (low score, 60.6% [95% CI, 50.9%-70.2%] and high score, 54.8% [95% CI, 47.1%-62.5%]; P = .43). Conclusions and Relevance: In this comparative effectiveness study of pediatric patients with AML treated in 2 consecutive clinical trials, Black patients had worse outcomes compared with White patients after treatment with standard induction therapy, but this disparity was eliminated by treatment with augmented induction therapy. When accounting for ACS10 scores, no outcome disparities were seen between Black and White patients. Our results suggest that using pharmacogenomics parameters to tailor induction regimens for both Black and White patients may narrow the racial disparity gap in patients with AML.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

COVID-19 in Pediatric Patients With Acute Lymphoblastic Leukemia or Lymphoma.

Importance: COVID-19 in pediatric patients with acute lymphoblastic leukemia or lymphoma (ALL/LLy) has not been described in detail and may affect chemotherapy administration and long-term outcomes. Objective: To describe the clinical presentation of COVID-19 and chemotherapy modifications in pediatric patients with ALL/LLy. Design, Setting, and Participants: This is a retrospective case series of patients at St Jude Children's Research Hospital and its affiliate sites with newly diagnosed ALL/LLy who were treated on the Total XVII protocol (NCT03117751) between March 30, 2020, and June 20, 2022. Participants included patients aged 1 to 18 years who were receiving protocol chemotherapy. Acute symptoms and chemotherapy modifications were evaluated for 60 days after the COVID-19 diagnosis, and viral clearance, adverse events, and second SARS-CoV-2 infections were followed up during the 27-month study period. Exposures: SARS-CoV-2; all patients were screened at least weekly and at symptom onset and/or after known exposure to SARS-CoV-2. Main Outcomes and Measures: Description of the spectrum of COVID-19 illness and chemotherapy modifications. Results: Of 308 pediatric patients, 110 (36%) developed COVID-19 at a median age of 8.2 (IQR, 5.3-14.5) years. Sixty-eight patients (62%) were male. Most patients were in the continuation/maintenance phase of chemotherapy (101 [92%]). Severe disease was rare (7 [6%]) but was associated with older age, higher white blood cell counts at ALL/LLy diagnosis, lower absolute lymphocyte counts at COVID-19 diagnosis, abnormal chest imaging findings, and SARS-CoV-2 reinfection. Rare but serious thrombotic events included pulmonary embolism and cerebral venous sinus thrombosis (n = 1 for each). No multisystem inflammatory syndrome in children or death was seen. SARS-CoV-2 reinfection occurred in 11 patients (10%) and was associated with older age and with receiving standard or high-risk vs low-risk ALL/LLy therapy. Chemotherapy interruptions occurred in 96 patients (87%) and were longer for patients with severe disease, SARS-CoV-2 reinfection, and/or a COVID-19 diagnosis during the pre-Omicron variant period vs the post-Omicron period (after December 27, 2021). Conclusions and Relevance: In this case series of COVID-19 in pediatric patients with ALL/LLy, severe COVID-19 was rare, but chemotherapy administration was affected in most patients. Long-term studies are needed to establish the outcomes of COVID-19 in this population.

Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility.

The germline TP53 p.R337H mutation is reported as the most common germline TP53 variant. It exists at a remarkably high frequency in the population of southeast Brazil as founder mutation in two distinct haplotypes with the most frequent co-segregating with the p.E134∗ variant of the XAF1 tumor suppressor and an increased cancer risk. Founder mutations demonstrate linkage disequilibrium with neighboring genetic polymorphic markers that can be used to identify the founder variant in different geographic regions and diverse populations. We report here a shared haplotype among Brazilian, Portuguese, and Spanish families and the existence of three additional distinct TP53 p.R337H alleles. Mitochondrial DNA sequencing and Y-STR profiling of Brazilian carriers of the founder TP53 p.R337H allele reveal an excess of Native American haplogroups in maternal lineages and exclusively European haplogroups in paternal lineages, consistent with communities established through male European settlers with extensive intermarriage with Indigenous women. The identification of founder and independent TP53 p.R337H alleles underlines the importance for considering the haplotype as a functional unit and the additive effects of constitutive polymorphisms and associated variants in modifier genes that can influence the cancer phenotype.

Rituximab administration in pediatric patients with newly diagnosed acute lymphoblastic leukemia.

Polyethylene glycol (PEG)-asparaginase (pegaspargase) is a key agent in chemotherapy for acute lymphoblastic leukemia (ALL), but recipients frequently experience allergic reactions. We hypothesized that by decreasing antibody-producing CD20-positive B cells, rituximab may reduce these reactions. Children and adolescents (aged 1-18 years) with newly diagnosed B-ALL treated on the St. Jude Total XVII study were randomized to induction therapy with or without rituximab on day 3 (cohort 1) or on days 6 and 24 (cohort 2). Patient clinical demographics, CD20 expression, minimal residual disease (MRD), rituximab reactions, pegaspargase allergy, anti-pegaspargase antibodies, and pancreatitis were evaluated. Thirty-five patients received rituximab and 37 did not. Among the 35 recipients, 16 (45.7%) experienced a grade 2 or higher reaction to rituximab. There were no differences between recipients and non-recipients in the incidence of pegaspargase reactions (P > 0.999), anti-pegaspargase antibodies (P = 0.327), or pancreatitis (P = 0.480). CD20 expression on day 8 was significantly lower in rituximab recipients (P < 0.001), but there were no differences in MRD levels on day 8, 15, or at the end of induction. Rituximab administration during induction in pediatric patients with B-ALL was associated with a high incidence of infusion reactions with no significant decrease in pegaspargase allergies, anti-pegaspargase antibodies, or MRD.

Childhood Leukemia Survival in the US-Mexico Border: Building Sustainable Leukemia Care Using Health Systems Strengthening Models.

PURPOSE: Pediatric leukemia outcomes are poor in most low- and middle-income countries (LMICs) and exacerbated by health care systems ill equipped to manage cancer. Effective leukemia management in LMICs involves curating epidemiologic data; providing health care workforce specialty training; developing evidence-based treatments and supportive care programs; safeguarding access to medications and equipment; providing patient and family psychosocial, financial, and nutritional support; partnering with nongovernmental organizations, and ensuring treatment adherence. METHODS: In 2013, through a partnership between North-American and Mexican institutions, we used the WHO Framework for Action, a health systems strengthening model to implement a leukemia care sustainable program aimed at improving acute lymphoblastic leukemia (ALL) outcomes at a public hospital in Mexico. We prospectively assessed clinical features, risk classification, and survival outcomes in children with ALL at Hospital General-Tijuana from 2008 to 2012 (preimplementation) and from 2013 to 2017 (postimplementation). We also evaluated program sustainability indicators. RESULTS: Our approach led to a fully-staffed leukemia service, sustainable training programs, evidence-based and data-driven projects to improve clinical outcomes, and funding for medications, supplies, and personnel through local partnerships. Preimplementation and postimplementation 5-year overall survival for the entire cohort of children with ALL, children with standard-risk ALL, and children with high-risk ALL improved from 59% to 65% (P = .023), 73% to 100% (P < .001), and 48% to 55% (P = .031), respectively. All sustainability indicators improved between 2013 and 2017. CONCLUSION: Using the health systems strengthening WHO Framework for Action model, we improved leukemia care and survival in a public hospital in Mexico across the US-Mexico border. We provide a model for the development of similar programs in LMICs to sustainably improve leukemia and other cancer outcomes.

Clinical impact of minimal residual disease in blood and bone marrow of children with acute myeloid leukemia.

The prognostic significance of bone marrow minimal residual disease (MRD) in pediatric patients with acute myeloid leukemia (AML) is well characterized, but the impact of blood MRD is not known. We, therefore, used flow cytometric assessment of leukemia-specific immunophenotypes to measure levels of MRD in both the blood and bone marrow of patients treated in the AML08 (NCT00703820) clinical trial. Blood samples were obtained on days 8 and 22 of therapy, whereas bone marrow samples were obtained on day 22. Among patients who tested as having MRD-negative bone marrow on day 22, neither day-8 nor day-22 blood MRD was significantly associated with the outcome. However, day-8 blood MRD was highly predictive of the outcome among patients who tested as having MRD-positive bone marrow on day 22. Although the measurement of blood MRD on day 8 cannot be used to identify patients who have day-22 MRD-negative bone marrow who are likely to relapse, our findings suggest that day-8 blood MRD results can identify patients with MRD-positive bone marrow who have a dismal prognosis and may be candidates for the early use of experimental therapy.

Clinical characteristics and outcomes of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis managed with different cytoreductive methods.

BACKGROUND: Hyperleukocytosis in patients with acute myeloid leukemia (AML) has been associated with worse outcomes. For cytoreduction, leukapheresis has been used but its clinical utility is unknown, and low-dose cytarabine (LD-cytarabine) is used as an alternative method. METHODS: Children with newly diagnosed AML treated between 1997 and 2017 in institutional protocols were studied. Hyperleukocytosis was defined as a leukocyte count of ≥100 × 109 /L at diagnosis. Clinical characteristics, early complications, survival data, and effects of cytoreductive methods were reviewed. Among 324 children with newly diagnosed AML, 49 (15.1%) presented with hyperleukocytosis. Initial management of hyperleukocytosis included leukapheresis or exchange transfusion (n = 16, considered as one group), LD-cytarabine (n = 18), hydroxyurea (n = 1), and no leukoreduction (n = 14). RESULTS: Compared with patients who received leukapheresis, the percentage decrease in leukocyte counts following intervention was greater among those who received LD-cytarabine (48% vs. 75%; p = .02), with longer median time from diagnosis to initiation of protocol therapy (28.1 vs. 95.2 hours; p < .001). The incidence of infection was higher in patients (38%) who had leukapheresis than those who receive LD-cytarabine (0%) or leukoreduction with protocol therapy (14%) (p = .008). No differences were noted in the outcomes among the intervention groups. Although patients with hyperleukocytosis had higher incidences of pulmonary and metabolic complications than did those without, no early deaths occurred, and the complete remission, event-free survival, overall survival rates, and outcomes of both groups were similar. CONCLUSION: LD-cytarabine treatment appears to be a safe and effective means of cytoreduction for children with AML and hyperleukocytosis.

SAMHD1 single nucleotide polymorphisms impact outcome in children with newly diagnosed acute myeloid leukemia.

Cytarabine arabinoside (Ara-C) has been the cornerstone of acute myeloid leukemia (AML) chemotherapy for decades. After cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway has been shown to affect intracellular abundance of Ara-CTP and, thus, its therapeutic benefit. Recently, SAMHD1 (SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1) has emerged to play a role in Ara-CTP inactivation, development of drug resistance, and, consequently, clinical response in AML. Despite this, the impact of genetic variations in SAMHD1 on outcome in AML has not been investigated in depth. In this study, we evaluated 25 single nucleotide polymorphisms (SNPs) within the SAMHD1 gene for association with clinical outcome in 400 pediatric patients with newly diagnosed AML from 2 clinical trials, AML02 and AML08. Three SNPs, rs1291128, rs1291141, and rs7265241 located in the 3' region of SAMHD1 were significantly associated with at least 1 clinical outcome: minimal residual disease after induction I, event-free survival (EFS), or overall survival (OS) in the 2 cohorts. In an independent cohort of patients from the COG-AAML1031 trial (n = 854), rs7265241 A>G remained significantly associated with EFS and OS. In multivariable analysis, all the SNPs remained independent predictors of clinical outcome. These results highlight the relevance of the SAMHD1 pharmacogenomics in context of response to Ara-C in AML and warrants the need for further validation in expanded patient cohorts.

Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia.

Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.

Characterisation of children and adolescents with acute lymphoblastic leukaemia who presented without peripheral blood blasts at diagnosis.

Of 1003 children with acute lymphoblastic leukaemia (ALL), 147 (14.7%) presented without peripheral blood blasts (PBB). While absence of PBB was not independently associated with survival outcomes when compared to those with PBB, patients without PBB had distinct genetic and clinical characteristics. Notably, we identified a novel genotype-phenotype relationship, in that the patients without PBB had a significantly higher incidence of hyperdiploid B-ALL, accounting for almost half of all patients without PBB (46.9% vs. 22.7%, p < 0.001). Further, absence of PBB was associated with decreased rates of leukaemia involvement of the central nervous system (p < 0.001).

SIOP PODC adapted risk stratification and treatment guidelines: Recommendations for acute myeloid leukemia in resource-limited settings.

In low- and middle-income countries (LMICs), limited resources, suboptimal risk stratification, and disproportionate patient-to-infrastructure ratio result in low survival of patients with acute myeloid leukemia (AML). A high incidence of relapse, inherent to the biology, renders management arduous. The challenge of treating AML in LMICs is of balancing the intensity of myelosuppressive chemotherapy, which appears necessary for cure, with available supportive care, which influences treatment-related mortality. The recommendations outlined in this paper are based on published evidence and expert opinion. The principle of this adapted protocol is to tailor treatment to available resources, reduce preventable toxic death, and direct limited resources toward those children who are most likely to be cured.

PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia.

Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genome-wide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of CD58 as a top driver for resistance, in addition to CD19. Screening 1639 transcription factor genes, we then identified PAX5 as the key activator of CD58. ALL with the PAX5 P80R mutation also expressed the lowest level of CD58 among 20 ALL molecular subtypes in 1988 patients. Genome editing confirmed the effects of this mutation on CD58 expression and blinatumomab sensitivity in B-ALL, with validation in patient leukemic blasts. We described a PAX5-driven enhancer at the CD58 locus, which was disrupted by PAX5 P80R, and the loss of CD58 abolished blinatumomab-induced T cell activation with global changes in transcriptomic/epigenomic program. In conclusion, we identified previously unidentified genetic mechanisms of blinatumomab resistance in B-ALL, suggesting strategies for genomics-guided treatment individualization.