Childhood B-cell Acute Lymphoblastic Leukemia Research Articles

Introduction Despite the emergence of effective novel immunotherapies, the outcome of relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains poor due to treatment-related mortality (TRM) and resistant disease. In response to accumulating evidence on the efficacy and low toxicity of blinatumomab in relapsed B-ALL and the availability of highly active CD19-targeted chimeric antigen receptor T-cell therapy (CART), we redesigned the United Kingdom (UK) relapse treatment pathway, based on two key guiding principles: 1) to reduce chemotherapy burden and associated toxicity through a move away from the highly intensive ALL R3 backbone towards increased reliance on blinatumomab to clear disease, and 2) to identify treatment failures early and direct them to CART, given the poor responses reported with hematopoietic stem cell transplant (HSCT) in this context. Methods Patients were treated with UKALL induction chemotherapy (<16yr: 3-drugs; >16yr: 4-drugs) until adequate blast clearance. Patients with blasts <5% at Day 15 progressed directly to blinatumomab; remaining patients continued to Day 28. Following reinduction, patients received up to 2 cycles of blinatumomab as a single agent. HR patients (early/very early relapses and/or HR cytogenetics) proceeded to HSCT once minimal residual disease (MRD) <0.01%. Those with high-risk (HR) isolated central nervous system (CNS) disease had the option to proceed directly to HSCT following CSF blast clearance without blinatumomab. All Standard risk (SR) patients continued on chemotherapy alone. Patients who were refractory after re-induction (>25% disease), blinatumomab (MRD >0.01%), or for whom there was no available donor were considered for CART. All patients were required to be discussed at a national tumour board, and data were subsequently collected every 3 months for analysis. Events were defined as death, relapse, and secondary cancer. Results Between September 2018 and July 2022, 111 patients were treated on the pathway; 63 (56.8%) were HR and 48 (43.2%) were SR. There were 26 patients >15yr, 3 Infant ALL, 2 Ph+ ALL and 4 with Down Syndrome. Induction therapy achieved disease reduction to <5% and CNS clearance in 98 patients (88%). Of the 90 patients with BM involvement, 52.2% required only 15 days of induction therapy. Induction failure (>25% blasts) occurred in 6.3%, comparable to the 7.1% using the R3 induction in the COG AALL1331 trial (p=1.00); 6/7 patients with induction failure successfully underwent CART infusion. The rate of end of induction MRD <0.01% in the HR group was also similar to COG AALL1331 (30% vs. 27.4%, p=0.669). Importantly, there were no cases of TRM with the reduced intensity induction, compared to 2.4-4% reported with the ALL R3 induction (p=0.06). Ninety patients received blinatumomab, of whom 87% achieved a complete MRD response, with grade 3 or 4 treatment-related toxicity in 11 patients (12.2%). Amongst HR patients, 86.8% underwent HSCT, significantly more than in the blinatumomab-treated IR/HR arm of COG AALL1331 (66%, p=0.02). With a median follow-up of 12 months (range 2-49), 19% of HR patients and 8.3% of SR patients have relapsed, comparable to results achieved in the blinatumomab-treated arm of the COG AALL1331 trial. There were no deaths in the SR group, and 12 deaths in the HR group (6 due to relapse/refractory disease, 6 due to post-HSCT TRM). Conclusions Our findings demonstrate that a reduced intensity reinduction can achieve equivalent disease control to the more intensive ALL R3 induction, with a substantial reduction in TRM. Although follow-up is short, consolidative blinatumomab achieved very high rates of MRD clearance, allowing a greater number of HR patients to reach potentially curative therapy with HSCT, the key predictor of outcome in the COG AALL1331 trial. We propose that our strategy represents a new standard of care for reinduction therapy in relapsed childhood B-ALL. DO and AV are joint senior authors Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

In a recent report in Nature Cell Biology (2022. 24:242–52) Zhang and coworkers discuss comparative genetic and biochemical features of leukemia cells from children with B-cell acute lymphoblastic leukemia (ALL) obtained at diagnosis, in remission, and at relapse.1 The authors analyzed large numbers of single-cell transcriptomes looking for dynamic changes and simultaneously, B-cell receptor sequences. They report that in contrast to leukemia cells at diagnosis, those at relapse shifted to a poorly-differentiated state. Changes in residual leukemia cells in remission were more complicated. Differential functional analyses highlighted activation of the hypoxia pathway in residual leukemia cells which correlated with drug resistance which was reversible with appropriate drug interventions in in vitro and in vivo models. The authors suggest this might be a therapy approach to eradicating measurable residual disease (MRD) in childhood B-cell ALL. This is a data dense article which requires understanding a machine learning algorithm. I suggest putting aside at least 5 hours to read and understand the text and supplement. I had to read it twice. This is not something to breeze through while texting on WeChat if you really want to understand the authors’ message and to critique it appropriately. First, a word on nomenclature. The authors use the term minimal residual disease. As John Goldman and I discussed several years ago the correct term is measurable residual disease.2Minimal is a subjective term; minimal to 1 person is not necessarily minimal to another. What we are considering is what can and cannot be measured in someone in complete histological remission. (Another source of confusion; remissions are histological, not morphological. Morphology comes from the Greek μ&z.omicr;ρϕ which means form, structure or shape, not appearance). As an aside Morpheus was the Greek God of sleep and is the root of the drug name morphine. Lest you think I’m getting lost in semantics please recall the comment from George Orwell: Slovenliness of our language makes it easier for us to have foolish thoughts.3 For MRD to be meaningful we need to know what technique is used to detect residual leukemia cell, its sensitivity and specificity, accuracy and precision, false-positive and -negative rate, and other parameters. We discuss these issues in considerable detail in two recent articles.3–6 The key point in the context of the article by Zhang and coworkers is our MRD tests do not distinguish between residual leukemia cells able or not to cause relapse. For example, in chronic myeloid leukemia (CML) tyrosine kinase-inhibitor-therapy does not eradicate the CML stem cell but some people with CML achieving a sustained deep molecular response can stop therapy without leukemia recurrence, a situation referred to as operational cure.7,8 Back to the article by Zhang and coworkers. My purpose is not to discuss the elegant experiments they did which would take considerable space and is best done by studying their article in detail. Rather, my purpose is to try to put their interesting and important findings in context. To know if becoming hypoxic is really how residual leukemia cells escape eradication (or if chemotherapy selects for emergence of hypoxic cells) we would need a prospective study showing a correlation. This article does not provide such data but perhaps the authors have this as their next task. This would be a difficult study to do since we fortunately cure most children with B-cell ALL. Another difficult challenge would be to prove anti-hypoxemic drugs improve therapy outcomes. Another interesting question is how we cure children with B-cell ALL. Most children achieving a histological remission with conventional therapy with corticosteroids, vincristine, cytarabine, doxorubicin, L-asparaginase, and etoposide then receive 2 to 3 years of so-called maintenance therapy with 6-mercaptopurine and methotrexate. But what exactly does maintenance therapy do? It is most unlikely these drugs typically given at low doses kill ALL stem cells. More likely, B-cells, normal and leukemia, are fated to die and maintenance therapy simply delays leukemia relapse sufficiently so these cells commit suicide.9 I was especially interested in the authors’ use of a machine learning algorithm to classify stages of B-cell development (described in METHODS). For those unfamiliar with this technique this is a supervised approach where there are learning and validation cohorts. Reproducibility was high but correct attribution accuracy always depends on accuracy of labeling of the training dataset. In summary, I recommend a careful reading of this important study. Much of the methods will be beyond the comfort zone of most hematologists. As such, struggling through and trying to understand the techniques may be as or more important than the conclusion. If you are going to print the article out (a good idea for reading on the high speed train) be sure to use a color printer or you will be lost. Finally, this article is a striking example of the increasingly high quality of biomedical research in China. I congratulate the authors. I wish they had submitted it to Leukemia. ACKNOWLEDGMENT RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Childhood B-cell Acute Lymphoblastic Leukemia Research Articles

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CircRNAome of Childhood Acute Lymphoblastic Leukemia: Deciphering Subtype-Specific Expression Profiles and Involvement in TCF3::PBX1 ALL.

Association between genetic variants of membrane transporters and the risk of high-grade hematologic adverse events in a cohort of Mexican children with B-cell acute lymphoblastic leukemia.

Chromosomal instability in aneuploid acute lymphoblastic leukemia associates with disease progression

Genomic Determinants of Therapy Response in ETV6::RUNX1 Leukemia

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Flow cytometric assessment of leukemia-associated monocytes in childhood B-cell acute lymphoblastic leukemia outcome.

Cytokine network imbalance in children with B-cell acute lymphoblastic leukemia at diagnosis

DNMT3A low-expression is correlated to poor prognosis in childhood B-ALL and confers resistance to daunorubicin on leukemic cells

Significance of CEBPE Gene Promoter Polymorphism (Rs2239630 G > A ) Assessment in Childhood B-cell Acute Lymphoblastic Leukemia.

Whole genome sequencing provides comprehensive genetic testing in childhood B-cell acute lymphoblastic leukaemia

The Landscape of Secondary Genetic Rearrangements in Pediatric Patients with B-Cell Acute Lymphoblastic Leukemia with t(12;21)

The prognostic significance of hematogones in childhood B-cell acute lymphoblastic leukemia.

B-Cell Acute Lymphoblastic Leukemia with iAMP21 in a Patient with Constitutional Ring Chromosome 21

Reduced Intensity Reinduction Followed By Blinatumomab Achieves Excellent MRD Clearance with Reduced Toxicity and Facilitates Timely Transplant in Children and Young People with Relapsed B-Precursor Acute Lymphoblastic Leukemia

Integrating RNA-seq and scRNA-seq to explore the biological significance of NAD + metabolism-related genes in the initial diagnosis and relapse of childhood B-cell acute lymphoblastic leukemia.

The kinetics of blast clearance are associated with copy number alterations in childhood B-cell acute lymphoblastic leukemia

Measurable residual disease in childhood B-cell acute lymphoblastic leukemia.

Prognostic significance of CNSL at diagnosis of childhood B-cell acute lymphoblastic leukemia: A report from the South China Children's Leukemia Group.

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