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PRELIMINARY RESULTS OF THE FIRST PROSPECTIVE MULTI-INSTITUTIONAL TREATMENT STUDY IN CHILDREN WITH B-CELL NON-HODGKIN LYMPHOMA/LEUKEMIA (CCCG-BNHL-2015): A REPORT FROM THE CHINESE CHILDREN’S CANCER GROUP
Abstract
Background and Aims
The CCCG-BNHL-2015 study was the first prospective multi-institutional trial of the Chinese Children’s Cancer Group lymphoma subgroup. The primary objective was to test whether increasing the intensity of chemotherapy regimens and adding 4 doses of rituximab in advanced patients improve the EFS compared with the historical study. The second objective was to assess toxicity to ensure that the addition of rituximab to intensive chemotherapy would be practical in China.
Methods
Patients were stratified into 4 risk groups according to stage, resection status and serum LDH. Patients in group R1 received 3 therapy courses A-B-A. Patients in group R2 received 5 courses A-B-A-B-A. Patients in group R3 received 6 courses A-BB-AA-BB-AA-BB. For patients in group R4, rituximab was added to the chemotherapy backbone for patients in R3 (A-RBB-RAA-RBB-RAA-BB).
Results
From January 2015 to June 2019, 381 patients≤16 years of age with newly diagnosed B-NHL/B-AL from 8 centers were eligible for this analysis. The distribution of stages was stage I, II, III, IV, B-AL in 2.6%, 22.6%, 54.1%, 8.4%, and 12.1% of patients, respectively. The 3-year EFS for the entire group was 88.4±1.7% (76.0%±4.3% in the historical study). The median follow-up is 30.8 months. The EFS according to intention-to-treat principle was 100%, 98.6±1.4%, 93.2%±2.2%, and 78.6%±3.4% for patients treated according to group R1, R2, R3, and R4, respectively (P =0.000). Regarding the toxicities of rituximab: grade 3/4 mucositis and infection occurred 30.7% and 63.6% after courses R-BB compared to 18.4% and 47.4% after courses BB, respectively (P=0.006 and P=0.013); grade 3/4 neutropenia, thrombocytopenia and infection occurred 96.1%, 76.4% and 54.3% after courses RAA compared to 87.1%, 50.0% and 34.8% after courses of AA, respectively (P=0.013, P<0.05, and P=0.002).
Conclusions
EFS was significantly improved when compared with the historical data. The addition of rituximab to intensive chemotherapy is feasible in China.
COMPARISON OF EFFICACY AND SAFETY BETWEEN R-CHOP/CHOP AND MODIFIED NHL-BFM90/95 REGIMENS IN CHILDREN AND ADOLESCENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA
Abstract
Background and Aims
To compare the efficacy and safety between R-CHOP/CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90/95 (NHL-BFM90/95) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL).
Methods
Data on DLBCL patients aged ≤18 years old at diagnosis and treated with R-CHOP/CHOP or modified NHL-BFM-90/95 regimens from January 2001 to May 2019 were obtained. Survival outcomes and chemotherapy-related toxicities between the two groups were compared. Multivariable analysis was performed to assess the significant predictors of overall survival (OS) and event-free survival (EFS).
Results
With 76 patients in modified NHL-BFM90/95 regimen and 30 patients in R-CHOP/CHOP regimen, we enrolled 106 DLBCL patients. The clinical characteristics were mostly similar between the two regimens except age and stage. The 5-year OS and 5-year EFS between modified NHL-BFM90/95 and R-CHOP/CHOP regimen were 93.5% vs 86.1% (P=0.181) and 90% vs 62.7% (P=0.001). In patients with stage I-II (n=39), the 5-year OS and 5-year EFS between modified NHL-BFM90/95 and R-CHOP/CHOP regimen were both 100% and 95.7% vs 75% (P=0.064). In patients with stage III-IV (n=67), the 5-year OS and 5-year EFS between modified NHL-BFM90/95 and R-CHOP/CHOP regimen were 90.6% vs 70.1% (P=0.03) and 87.4% vs 49% (P=0.001). In multivariable analysis, R-CHOP/CHOP regimen and LDH>500U/L were independent risk factors of EFS in patients with stage III-IV. The accumulate dose of anthracycline in R-CHOP/CHOP regimen was obviously higher, though patients in modified NHL-BFM90/95 regimen had a significantly higher rate of grade 3 to 4 hematologic toxicities than that in R-CHOP/CHOP regimen (64.5% vs 36.7%, P=0.016).
Conclusions
Modified NHL-BFM90/95 regimen had better efficacy in children and adolescents with DLBCL, especially for advanced-stage DLBCL. And R-CHOP/CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical treatment decisions.
SAFETY ANALYSIS OF HIGH-DOSE METHOTREXATE IN PEDIATRIC PATIENTS WITH NON-HODGKIN LYMPHOMAS
Abstract
Background and Aims
Approximately 85% of children and adolescents with non-Hodgkin lymphoma (NHL) can expect long-term survival in the United States. In equatorial Sub-Saharan Africa (SSA), NHL occurs more frequently (30 – 50% of children with cancer) and the chance of cure is low. Contemporary protocols in high-income countries incorporate high-dose methotrexate (HDMTX) with rigorous supportive care. Unfortunately, a similar approach is challenging in SSA. Recently published data support the notion that a HDMTX-containing regimen may be feasible and effective in children with B-NHL in Africa. We describe the safety and tolerability of HDMTX in patients with NHL treated at Texas Children’s Hospital, with the goal of informing practice at our partner sites in SSA.
Methods
This was a retrospective cohort study of patients with NHL who received HDMTX (3 gm/m2 over 3 hours) at Texas Children’s Hospital over a 9-year period. Descriptive statistics describe the incidence and characteristics of delayed MTX clearance and associated complications.
Results
Forty-two patients received 185 infusions of HDMTX. Most infusions cleared on time by hour 48 (76.2%). Forty-four infusions (24.3%) did not meet the target level for discontinuation of IV fluids and leucovorin at hour 48. The median time to clearance for these infusions was 72 hours (range: 60 to 256 hours). Six patients (14%) were prescribed leucovorin at a higher frequency (i.e., every 3 hours). Grade 3 or 4 mucositis developed in 16 patients (23 cycles). Twenty five infusions (13.5%) were associated with a >25% increase in serum creatinine. No patient required glucarpidase.
Conclusions
More than half of pediatric patients with NHL in a US tertiary care children’s hospital experienced at least one episode of delayed HDMTX clearance, and some develop serious toxicities such as Grade 3 or 4 mucositis. These results may be used to inform safe HDMTX approaches in Sub-Saharan Africa.
NEW CLINICAL PATTERNS OF CHILDHOOD NON-HODGKIN LYMPHOMA IN SUB-SAHARAN AFRICA
- Irene M. Nzamu, Uganda
- Joseph Ssenyondwa, Uganda
- Ronald Naitala, Uganda
- Peter Wasswa, United States of America
- Ruth Namazzi, Uganda
- Phillip Kasirye, Uganda
- Deogratius Munube, Uganda
- Susan Nabbadda, Uganda
- Ernest Naturinda, Uganda
- Deogratius Bakulumpagi, Uganda
- Anne Akullo, Uganda
- Siyadora Ankunda, Uganda
- Heronima J. Kashaigili, Uganda
- Nana J. Nakiddu, Uganda
- Deborah Omeddo, Uganda
- Joseph Lubega, United States of America
Abstract
Background and Aims
Burkitt lymphoma (BL) is considered the most common pediatric cancer in sub-Saharan Africa (SSA) with a classical presentation of jaw tumor. Recent improvements in access to pathology have enabled more specific diagnoses of pediatric cancers including immunophenotyping of non-Hodgkin lymphoma (NHL). We aimed to study the clinical patterns of childhood NHL at a pediatric cancer center with gold standard pathology.
Methods
We analyzed the frequency of cancer histological subtypes and clinical outcomes of a cohort of children with NHL at Global HOPE-Mulago National Referral Hospital, Kampala (Uganda). All children had a biopsy, morphology, flow cytometry or immunohistochemistry, and cytogenetics where applicable. Descriptive and survival analysis were done using Stata v.12.1.
Results
From February 2019 to March 2020, 293 children were diagnosed with cancer; of these, 34(11.6%) had NHL with mean age 8.7(SD 4.1) years and male to female ratio 1.85:1. The distribution of immunophenotypes of NHL were: Mature B-Cell NHL 7.8%(23/293) (which included BL 6%(18/293) and Diffuse Large B-cell lymphoma 2%(5/293)); lymphoblastic lymphoma 3%(8/293) and Mature T-Cell NHL 1%(3/293). The commonest sites of Mature B-Cell NHL were abdomen 61%(14/23), jaw 26%(6/23) and others 13%(3/23). Most patients with Mature B NHL presented with Murphy Stage III/IV 91%(21/23). The 1-year overall survival was 60.1%;95%CI(38.1–82.1) with event free survival of 25.8%;95%CI(0.0–53.8). The other cancers were acute leukemia (30%), non-hematological solid tumors (42%), brain tumors (10%), and Hodgkin lymphoma (6.4%).
Conclusions
With improved diagnostics, we found lower BL rates and predominance of abdominal disease than is historically reported in SSA. This pattern may be due to change in epidemiological risk factors for classical African BL or referral bias; although similar patterns have been reported in other recent single center series. The outcomes of Mature B-Cell NHL, of which BL is most prevalent, remain poor in our setting.
NIVOLUMAB IN COMBINATION THERAPY FOR PEDIATRIC HODGKIN'S LYMPHOMA
- Andrey Kozlov, Russian Federation
- Tatiana Iukhta, Russian Federation
- Asmik Gevorgian, Russian Federation
- Ilya Kazantzev, Russian Federation
- Polina Tolkunova, Russian Federation
- Lubov A. Tsvetkova, Russian Federation
- Elena Morozova, Russian Federation
- Kirill Lepik, Russian Federation
- Natalia Mikhailova, Russian Federation
- Ludmila Zubarovskaya, Russian Federation
- Boris Afanasyev, Russian Federation
Abstract
Background and Aims
Discovery and clinical success of checkpoint inhibitors (CIs) produced revolution in oncology. At 2018 Nobel prizes were awarded to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". CIs demonstrated substantial efficiency in classical Hodgkin's lymphoma (cHL). There are limited data on safety and efficiency of CIs in children. Despite impressive progress in oncology children with refractory or resistant (R-R) cHL still demonstrate suboptimal prognosis if ≥ 3 lines of therapies have to be used. This group of patients needs new approaches in management and CIs are among the most promising.
Methods
Eight children with R-R cHL received nivolumab (nivo) as part of combination therapy in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of Saint Petersburg. Median age was 14 years (9-16). Median number of previous therapy lines was 4 (2-6). Prior to nivo 6 children (75%) had progression and 2 (25%) stabilization according to Lugano criteria. Combinations of nivo with following drugs were used: brentuximab vedotin 1,8 mg/kg triweekly (n=4) with median of 5 cycles (4-7), bendamustine 180 mg/m2 triweekly (n=3) with median of 5 cycles (5-7) and gemcitabine 1000 mg/m2 №5 weekly (n=1). Median number of nivo cycles was 7.5 (2-28). Response to treatment based on LYRIC criteria.
Results
Overall response was registered in 6 patients (75%) with complete response in 4 (50%), partial response in 2 (25%) and indeterminate response in 2 (25%). Seven children (88%) are alive with median follow-up of 373 days (range 65– 902). Among them 5 patients (63%) remain in remission. Two patients (25%) developed transient cytopenias that could not be attributed solely to nivo and were probably associated with chemotherapy.
Conclusions
Combinations of nivo with chemotherapy or immunotherapy are effective and safe in children with R-R cHL.
CELL-SPECIFIC GENE EXPRESSION PROFILING OF CHILDHOOD HODGKIN LYMPHOMA
- Jennifer Agrusa, United States of America
- Elmoataz Abdel Fattah, United States of America
- Howard Lin, United States of America
- Brooks Scull, United States of America
- Harshal Abhyankar, United States of America
- Nmazuo W. Ozuah, United States of America
- Olive Eckstein, United States of America
- Nitya Gulati, United States of America
- Terzah Horton, United States of America
- Kala Kamdar, United States of America
- Kenneth McClain, United States of America
- Chris Man, United States of America
- Rikhia Chakraborty, United States of America
- Carl E. Allen, United States of America
Abstract
Background and Aims
Studies characterizing Hodgkin Reed-Sternberg (HRS) cell gene expression have been limited in these rare, malignant Hodgkin lymphoma (HL) cells, and the majority of existing data has focused on adult HL. To inform underlying mechanisms of HL pathogenesis and identify cell-specific clinical biomarkers, we isolated viable cells from pediatric HL tumors to define the transcriptomes of HRS cells and infiltrating lymphocytes.
Methods
Multi-parameter flow cytometry was used to sort HRS cells, CD4+/CD8+ T-cells, and CD20+/30+ B-cells from pediatric subjects’ HL lesions and control tonsils. Gene expression profiles (GEPs) for all sorted cell types and HL cell lines were assessed using Affymetrix GeneChip HTA 2.0. Unsupervised hierarchical clustering and principal component analysis (PCA) determined relatedness, and Cibersort confirmed the phenotype of the sorted cell types. GEPs of HL cells were compared to respective controls using a univariate t-test. Significance was determined using a multivariate permutation test to estimate false discovery. DEGs were analyzed through gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA).
Results
GEPs were compared for HL samples: HRS vs. control CD20+/CD30+ (1934/3846 DEGs), HL CD4+ vs. control CD4+ (635 DEGs), HL CD8+ vs. control CD8+ (2 DEGs). HRS cells demonstrated a heterogeneous phenotype (Cibersort) that may reflect aberrant differentiation, and they over-expressed genes associated with T-cell pathways while clustering separately from T-cells, which may reflect an innate T-cell signature rather than T-cell rosetting and contamination. Comparing HRS vs. control CD30+ cells using transcriptome analysis revealed a 2-fold downregulation of telomere maintenance/packaging genes (P<.001), association with genes involved in cellular senescence, and increased expression of genes associated with EBV status and therapy response.
Conclusions
Candidate clinical biomarkers were identified within this small cohort. This supports prospective collection of biological specimens in an expanded validation cohort and eventual incorporation of these biomarkers into risk stratification strategies of prospective clinical trials.