BJH: New advances in the treatment of recurrent/refractive invasive B cells in children and non-Hodgkin's lymphoma.

. Invasive B-cell non-Hodgkin's lymphoma (B-NHL) accounts for about 60% of the NHL for children/adolescents. The proportion of occurrences in different histological subgroups varies by age: burkitt lymphoma (BL) accounts for more than 80% of children under 15 years of age, diffuse large B-cell lymphoma (DLBCL) for 10-20%, and primary septum B-cell lymphoma (PMBCL) for only 2%. The incidence of DLBCL increases with age, reaching 30% in patients aged 15-19.

in children and adolescents, pmBCL is treated under the B-cell NHL Paediatric Program, and the EFS rate is lower than in adult PMBCL or other B-NHL hertological subtype children (Seidemann et al., 2003, 2013) regardless of the treatment option used. Currently all for PMBCL is rituximab combined with different chemotherapy regimens. The DA-EPOCH-R scheme showed excellent EFS rates (93%) in adult PMBCL. In children's PMBCL, the 2-3-year EFS rate of DA-EPOCH-R is also between 69% and 81%.

The results are encouraging in many new treatments for adult R/R B-NHL, most of which are in patients with diffuse large B-cell lymphoma (DLBCL). New drugs are difficult to test in the pediatric population for a variety of reasons. The invasive B-NHL treatment in children/adolescents has achieved excellent results, with very few patients experiencing relapse/difficult treatment (R/R), and only very little data has been reported in the literature. The prognosis of R/R B-NHL patients was poor, with a survival rate of between 10 and 36 percent in recent reports, and only those who were able to perform an autologous or allogeneic hematopoietic stem cell transplant (HSCT) had a higher survival chance. The poor results of R/R B-NHL have led to research into innovative therapies, which are particularly difficult to explore in the pediatric population due to the small number of patients and require special research design and logistical support. Differences in lymphoma biology in young patients limit the transfer of results from large adult DLBCL studies to pediatric B-NHL studies. In addition, clinical research on children has strict regulations.

this article will review the results of childhood R/R B-NHL treatments reported to date and briefly explore some of the current new treatment strategies and outcomes.

treatment outcomessince effective short-term intensive multidrug combination chemotherapy, only a small (5-15%) b-NHL children and adolescents have had difficulty or relapse. Reports in the literature since 1993 are shown in Table 1.

the number of patients in previous studies, ranging from 9 to 104. In a multicenter international study, the series reported varied in the following areas: disease conditions, some of which include incurable patients and others, and treatments that are heterogeneous. Philip et al. (1993) described the outcome of treatment for 27 patients. Recurrence after treatment with LMB84. Only four children, all of whom received hematopoietic stem cell transplants, survived four years later.
Atra et al. (2001) reported 26 cases of bl/B mature AL patients r/r to survive 4 years later. UKCCSG, UK Child Cancer Research Group, UKCcSG( 9003/9002 Agreement. Of these, only three (one late-stage, three-year, four-year and six-year-old, two relapsed and two self-transplant patients survived). The Austrian Cooperative Research Group reported on the results of the treatment of r/r NHL patients in the Berlin-Frankfurt-Minster (BFM) programme. Only 1 in 9 r/r B-NHL patients survived at 21 months. Fujita et al. (2008) reported that r/r B-NHL patients from different research groups in Japan had a four-year survival rate of 20-8%. More recent reports from the second group of UKCCSG queues (Anoop et al., 2012) and Korea Group (Kim et al., 2014) showed better results, with five-year survival rates of 27.3% and 31.6%, respectively.


. The French researchers focused on relapsed patients and reviewed 67 patients with relapsed B-NHL/B-AL who were enrolled in SFOP LMB89, FAB/LMB96 and LMB2001, with a total response rate (ORR) of 61% and a 5-year survival rate of 29.9% (Figure 1).


. Prognosis factorsalthough the number of patients and the variety of treatments saved, all the authors agree that the likelihood of a good prognosis is particularly low for patients with primary refractive refractive disorderors or patients who do not respond to treatment, as well as those who are not able to receive HSCT. The study analyzed a number of prognostic factors, including the initial characteristics and treatment of the disease, histological subtypes, the time and type of treatment failure, the response to the rescue treatment, and ultimately HSCT. In the single-factor analysis of different reports, primary refractive refractive diseases and early recurrence, high-risk characteristics/treatment groups at diagnosis, BL of histological diagnosis, multi-site recurrence, bone marrow recurrence and chemotherapy resistance were not positive for the prognosis. In multivariate analysis, only some of these factors have an effect on the prognosis (see Table 2).


. The rescue programme

studies assessed the efficacy of a single rescue programme for patients who were included or the survival rate of R/R patients treated with different programmes from different perspectives. The results of published studies are shown in Table 3.


. Central nervous system recurrencepediatric B-NHL central nervous system (CNS) recurrence accounted for 30-40% of recurrence, mainly occurred in BL, the relevant data are very small. The recommended treatment for CNS recurrence is to give high doses of methotrexate (one course of treatment every two weeks, methotrexate 8 or 12 g/m2 (24-hour infusion) and intrauterine treatment, followed by a rescue chemotherapy regimen and HSCT; Rigaud et al., 2019). Compared to all other patients, there was no significant decrease in the five-year survival rate of PATIENTs with RElapse (24% vs. 33.3%; P - 0.3).

the studies did not detail the patient's rescue treatment. Osumi et al. (2016) described 33 patients in a small case series, reported different results, and multivariate analysis confirmed a significant correlation between combined CNS recurrence and poor prognosis (no CNS: OS 54-5%; CNS: OS 0%, P - 0.001).

hematopoietic stem cell transplants

the isosome or allogeneic HSCT is considered the best choice for patients who respond. In the reported paediatric experience, the proportion of patients who were able to receive HSCT (treated with different rescue options) was 21% to 63% (Table 1). Table 4 summarizes the outcomes of R/R B-NHL children who received the epithelial or allogeneic HSCT reported in the literature. Even in stem cell transplants, the mortality rate is still high and there is no substantial difference between the body and the other skin transplant (34 percent and 31 percent).


.
new transplant
strategy

although an in-the-form or allogeneic hematopoietic stem cell transplant is currently the most effective treatment for R/R B-NHL patients, for transplant patients, disease-induced death remains the leading cause of treatment failure (-30%), which increases the need for strategies that may improve the effectiveness of transplants. One strategy is to perform the progenitor HSCT of myelin pretreatment (MAC) first, and then the heterogene HSCT for reduction in intensity pretreatment (RIC) for maximum reaction. This may reduce morbidity and mortality associated with conventional MAC allogeneic transplantation while maintaining its transplant anti-melanoma effect. In addition, radiation immunotherapy may further improve the efficacy of HSCT strategies.

radioimmune therapy can further improve the efficacy of hematopoietic stem cell transplantation strategy. Recently, at the sixth ISCAYANHL, among 13 children with r/r B-NHL in CAYA, ytrium-90 ibritumomab tiuxetan was added to the tandem hematopoietic stem cell transplant strategy--- the drug has been proven effective and safe (Coy-Qualter et al., 2007), with excellent efficacy (91% EFS, 2018).

the
of adolescents and young adults
in recent years, more and more attention has been paid to the assessment of the biological characteristics, clinical characteristics and results of malignant tumors in the hetle system from children to adolescents to young adults. Currently, adolescents and young adults (AYA) (15-39 years) are considered to be in different age groups with younger children and older adult lymphoma patients. AYA lymphoma patients showed significant differences in epidemiology, disease characteristics, tumor biology, and response to treatment.

. AYA B-NHL patients have traditionally been included in pediatric and adult clinical trials in different phased approaches. In addition, disease subtypes and tumor biology change gradually with age, and their different incidences limit the interpretation of the results. The limited number of Patients with R/R B-NHL, and the particular challenge of clarifying the differences in b-cell lymphoma biology and receptor signaling in this population and other age groups, are under development of a research program for B-NHL treatment in the AYA population, which is critical to the development of targeted treatment strategies for that age group.

primary isolation B-cell lymphoma

primary isolation B-cell lymphoma (PMBCL) is unique clinical and biological characteristics, with the highest incidence among AYA populations. PMBCL differs from other B-NHL subtypes and has characteristics that overlap with classic Hodgkin's lymphoma, including biological similarities such as immunoescape, component activation of the JAK-STAT and NF-kB pathways. In children and adults, R/R PMBCL's second-line treatment strategy is similar to that used in R/R B-NHL, including the use of non-cross-resistant drugs such as rituximatomatic combined ICE or DHAP or less toxic R-GDP, and then consolidation therapy with high doses of drugs and an isologoh HSCT.

in adult PMBCL, the response rate after treatment was low, especially in patients with primary and primary incurability. However, for adult patients with a reaction, the pmBCL and DLBCL's ego HSCT results were similar, with a PFS rate of about 50%. In children and adolescents, 7 to 31% of patients experience relapse/difficulty. Data on the outcome of R/R PMBCL in children and adolescents are scarce. In a large retrospective study of 646 NHL patients under the age of 18, Burkhardt et al. (2018) found that 41 PMBCL patients had 58 percent OS. Targeted therapy that inhibits different signaling pathways, such as immunocheckpoint inhibitors, has been used in adult patients and has achieved encouraging results. Since PMBCL occurs primarily in the AYA population, collaboration between children and adults, as well as intergroup trial designs, including in children and adult patients, will be very beneficial.

. R/R B-NHL's new therapy

B cell receptor signaling pathway inhibitors

Abnormal activation of B cell receptor (BCR) signaling pathways is related to the pathogenesis and progression of multiple B-cell malignancies. BTK is a regulator for normal B cell development and is activated after BCR is stimulated. Ibtinib is a selective small molecule BTK inhibitor that irreversibly inhibits the enzyme activity of BTK and blocks the transmission of cell survival signals in B cells. Studies have shown that ibtinib can be used as a single drug or in conjunction with the R-ICE program for the treatment of patients with R/R ABC type DLBCL. Ibtinib showed significant activity in preclinical burkitt lymphoma (BL) models. An ongoing R/R B-NHL international study in children, adolescents, and young people (CAYA) is evaluating the efficacy of ibtinib's combined libtoxiic monobifytreatment (R-ICE or R-VICI).

immunocheckpoint inhibitors

immunocheckpoint inhibitors block receptors that protect tumors from T-cell identification and immune damage. Activation of the signals of procedural death ligands 1 and 2 (PD-L1/2) is a way for tumor cells to avoid antigen-specific T-cell immune response. PD-1 inhibitor Paboli satag binds PD-1 and blocks the interaction of PD-1 with ligand PD-L1/2. Due to the expression of PD-L1/2 in primary cell cell lymphoma (PMBCL) cells and its known efficacy in classic Hodgkin lymphoma, a clinical trial of Paboli zuma in adult patients with R/R PMBCL has been conducted. Based on the results of the study of Keynote 013 and Keynote 170 in Stage I clinical, the ORR results reached 48% and 45%, respectively. Based on the results of these two clinical studies, Paboli Zuma has also recently been approved by the FDA for the treatment of pediatric R/R PMBCL.

the next generation of monoclonal antibodies

has developed the next generation of monoclonal antibodies to enhance antibody-dependent cytotoxicity. Obinotuzumab (Ottozumab) is an anti-CD20 monoclonal antibody that enhances the affinity of the Fc receptor and shows efficacy in cell lines that are sensitive/resistant to rituximab. The current Phase II clinical trial (NCT02393157) is studying the efficacy of Ottozumab in CAYA patients in R/R B-NHL patients and has obtained initial results.