e22508 Background: The proportion of Acute Myeloid Leukemia (AML) among childhood leukemias is putatively higher in Sub-Sahara Africa (SSA) compared to Western experiences. However, the treatment of childhood AML is challenging in SSA settings because of inadequate facilities for supportive care to deliver intensive AML regimens and, hence, high treatment-related mortality (TRM). Many pediatric oncology centers in SSA treat childhood AML with a palliative intent, with or without chemotherapy. At the Mulago National Referral Hospital (MNRH)/Global HOPE Center in Uganda, we treat AML with a curative intent. We distinguish Acute Promyelocytic Leukemia (APL) and AML with Down Syndrome (AML-DS) from other subtypes of AML. We treat APL with Children’s Oncology Group (COG) AAML1331 and AML-DS and other AML with modified reduced intensity regimens. We hereby share our experience of anti-cancer and supportive treatment, TRM, remission rates, and short-term overall survival (OS). Methods: We performed a retrospective cohort analysis of children diagnosed with AML between March 2019 and February 2020. The diagnosis of AML was established by bone marrow or peripheral blood morphology and immunophenotyping by flow cytometry according to WHO criteria. All cases of APL were confirmed by cytogenetics for t(15;17). Children without DS or APL received 2 cycles of Cytarabine 100mg/m2 12 hourly Days 1-10, Daunorubicin 50mg/m2 Days 1,3,5 and a single triple intrathecal chemotherapy for induction and 2 cycles of high dose Cytarabine 3000mg/m2 for consolidation. Supportive care comprised warm saline oral rinses, antiseptic baths, antimicrobial prophylaxis with cotrimoxazole, ciprofloxacin and itraconazole, and blood product support. Results: Of the 74 children diagnosed with leukemia 23 (31%) were AML; 4/23 (17%) of AML were APL and 3/23 (13%) were AML-DS. The mean age at diagnosis of AML was 6.1 (SD 4.3) years and 16/23 (70%) were males. For the 4 cases of APL, TRM 1/4 (25%) due to differentiation syndrome, remission rate 2/4 (50%), 1-year OS 75%; 95% CI 32.5-100. For the 3 cases of AML-DS, TRM 1/3 due to severe sepsis with respiratory failure, remission rate 1/3, and 1 was referred to another treatment center. For the other AML, TRM 2/16 (12.5%) due to severe sepsis, remission rate 9/16 (56%) and 1-year OS 78.6%; 95% CI 57.1-100. Conclusions: It is feasible to treat, manage TRM, and achieve remission in childhood AML in the SSA setting. Although there were several TRMs, a remission rate of 56% in the non-APL non-AML-DS is a promising outcome.
ObjectivesHIV and sickle cell disease (SCD) are significant causes of morbidity and mortality in sub‐Saharan Africa. Given their separate roles in immune dysregulation, our objective was to characterise the impact that SCD has on the presentation and progression of paediatric HIV.MethodsThe study was a retrospective cohort study (study period 2004–2018). Cases of HIV + and SCD‐afflicted patients (HIV+/SCD+) were obtained via electronic chart review from a paediatric HIV clinic in Kampala, Uganda and matched 1:3 with HIV + controls without SCD (HIV+/SCD‐).ResultsThirty‐five HIV+/SCD + subjects and 95 HIV+/SCD‐ controls were analysed (39% female (51/130), age 3.6 years (SD3.9)). At baseline, WHO clinical stage (64% total cohort Stage III/IV) and nutritional status (9.4% severe acute malnutrition) were similar for both groups, whereas HIV+/SCD + had higher though non‐significant baseline CD4 count (1036 (SD713) vs 849 (SD638) cells/microlitre, P = 0.20, two‐tailed t‐test). There were 19 deaths, 6 (17%) HIV+/SCD + and 13 (14%) HIV+/SCD‐, with unadjusted/adjusted models showing no significant difference. Nutritional progression and clinical stage progression showed no significant differences between groups. Kaplan–Meier analysis showed a slower rate of treatment failures in the HIV+/SCD + cohort (P = 0.11, log‐rank survival test). Trajectory analysis showed that in the time period analysed, the HIV+/SCD + cohort showed a more rapid rise and higher total CD4 count (P = 0.012, regression analysis).ConclusionThe study suggests that SCD does not adversely affect the progression of HIV in patients on ART. Further, HIV+/SCD + achieved higher CD4 counts and fewer HIV treatment failures, suggesting physiological effects due to SCD might mitigate HIV progression.
Background: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and is characterised by hy- perproliferation of malignant lymphocytes in the bone marrow. Rarely, ALL may be preceded by a period of pancytopenia and bone marrow hypoplasia which spontaneously recovers. This phenomenon, which has not before been described in T-cell ALL, is referred to as transient bone marrow hypoplasia. Case presentation: A 5-year-old boy who presented with high-grade fever and generalised lymphadenopathy, was found to have pancytopenia on peripheral blood count and bone marrow hypoplasia. He was observed over a one-month period during which his bone marrow and peripheral blood counts recovered spontaneously. Symptoms recurred after 4 months and he was found to have blast infiltration of the bone marrow and diagnosed with T-cell ALL. Conclusion: Cases of transient bone marrow hypoplasia or overt aplastic anemia with spontaneous recovery and then followed by B-cell ALL or Acute Myeloid Leukemia have been described previously in the medical literature. This is the first case of transient bone marrow hypoplasia resulting into ALL of T-cell immunophenotype. While marrow hypoplasia preceding ALL remains poorly understood, it suggests an antecedent environmental insult to lymphoid progenitors or a germline abnormality that predisposes to lymphoid dysplasia. This may provide clues to the hitherto unknown pathophysi- ological process and etiological factors that precede the majority of childhood ALL cases. This case enlightens pediatricians about the existence of such rare cases so as to periodically follow up children with pancytopenia and/or bone marrow hy- poplasia for prolonged periods even after apparent recovery. Keywords: Pancytopenia, hypoplasia; aplastic anemia; T-cell acute lymphoblastic leukemia; case report.
Introduction Burkitt Lymphoma (BL) is a highly aggressive hematological malignancy that originates from germinal center B-cells, is characterized by IG/MYC translocation, and affects both children and adults. Clinical and biological differences have been noted between endemic BL, which occurs in equatorial Africa and is virtually always associated with Epstein-Barr virus (EBV) infection, and sporadic BL that is infrequently associated with EBV. BL is highly curable using an aggressive chemotherapy regimen, but the intensive supportive care required to manage the toxicities of this treatment precludes its use for most patients with endemic BL, resulting in poorer survival for those patients. Although previous genetic studies have identified recurrent mutations in BL (including alterations in ID3 and its downstream targets TCF3 and CCND3), endemic BL has not been as well characterized and the extent of differences between sporadic and endemic BL (and their potential relation to pathogenesis and response to therapy) is not yet clear. Therefore, more extensive genomic characterization of both sporadic and endemic BL is needed to provide insight into tumor biology and to identify novel therapeutic targets that can be utilized to provide less toxic treatments. Methods We interrogated frozen tumor and matched normal blood samples from a cohort of 30 pediatric BL cases, 12 of which were collected from Uganda and 18 from Texas Children's Cancer Center (Houston, TX). Whole exome sequencing (WES) and copy number analysis were performed on the Illumina platform using the OmniExpress array and VCrome 2.1 WES capture reagent and analyzed utilizing the Baylor College of Medicine Human Genome Sequencing Center bioinformatic pipeline. A median of 135x average coverage and >97% of targeted bases with at least 20x coverage was observed for WES. Results WES revealed a median of 46 nonsilent somatic mutations per case for endemic BL (range 19-207), and 32 per case for sporadic BL (range 13-119). Evidence of the EBV genome was detected in all endemic BL samples and 3/18 (17%) of sporadic BL cases. Mutations were found in genes known to be frequently mutated in BL, including MYC in 7/12 (58%) of endemic cases and 12/18 (67%) of sporadic cases and TP53 in 5/12 (42%) and 9/18 (50%), respectively. Of note, mutations in DDX3X (7/12 [58%] endemic, 9/18 [50%] sporadic) and FOXO1 (5/12 [42%] endemic, 7/18 [39%] sporadic) were identified frequently in our cohort. As previously described, the ID3 pathway was more frequently targeted by mutations in sporadic BL: ID3 in 8/18 (44%) sporadic cases vs 3/12 (25%) endemic, TCF3 in 3/18 (17%) vs. 1/12 (8%), and CCND3 in 7/18 (39%) vs 2/12 (17%), respectively. Mutations in the SWI/SNF chromatin-remodeling genes ARID1A and SMARCA4 have been reported to occur in BL in a mutually exclusive fashion. In our cohort, mutations in SMARCA4 were exclusive to sporadic cases (9/18, 50%) and not found in endemic tumors (P = 0.01). Conversely, ARID1A mutations were much more frequent in endemic cases (7/12, 58%) as compared to sporadic ones (3/18, 17%) (P < 0.05). Only one sporadic case was found to have both genes mutated. Copy number analysis did not reveal recurrent focal copy number deletions. Amplification of 13q31.2 - q32.2 was detected in sporadic cases (4/18, 22%) but not in endemic cases, while focal amplification of 7p14.1 (3/10, 30%) and 14q11.2 (4/10, 40%) were exclusive to endemic tumors. Conclusions These findings provide novel insight into the landscapes of genomic alterations in pediatric endemic and sporadic BL. Our data confirm the recurrence of mutated genes previously associated with BL and highlight differences between endemic and sporadic BL, most notably, the exclusivity of SMARCA4 mutations in sporadic BL cases in this cohort. The recurrence of mutations in ARID1A and SMARCA4 emphasizes the critical role of these SWI/SNF proteins in BL. More extensive molecular studies (whole genome and transcriptome sequencing) of this cohort are ongoing and may reveal additional differences between endemic and sporadic BL. Additional studies will be required to more precisely assess the frequency of these alterations in BL and their link to clinical features of the disease, as well as the biological relevance of the BL genes identified through these genomic analyses. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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