Acute Lymphoblastic Leukaemia in Johannesburg, South Africa: The State-Sector Experience

Abstract

IntroductionLymphoblastic leukemia (ALL) is a neoplasm of immature lymphoid cells of either B- or T-cell lineage. B-ALL is the more common (particularly in childhood), and has a number of described recurrent genetic abnormalities with distinct clinic-pathological associations. T-ALL comprises a larger proportion of adult ALL (18-23%) than childhood cases (7-15%) in high income countries, and is genetically heterogeneous without clear prognostic associations with genetic subtypes. The frequency of T-ALL and the genetic landscape of B-ALL show regional variation. T-ALL is common among African American children (~25%), but seen infrequently in Asia (~7% of childhood cases). In B-ALL, the translocation t(12;21) and hyperdiploidy predominate among children in Europe and the USA, while KMT2A rearrangement and the translocation t(9;22) are relatively more common in Asia. There is a paucity of literature regarding ALL in Africa; the distribution of its subtypes (B vs T), its genetic composition and outcomes are not known. This study aimed to characterize ALL diagnosed in the state-sector hospitals of Johannesburg, South Africa (SA).MethodsCases diagnosed with ALL in the flow cytometry laboratory at Charlotte Maxeke Johannesburg Academic Hospital (which provides diagnostic immunophenotyping services to all state-sector hospitals of the southern Gauteng region of SA) between 2016-2019 (42 months) were identified and recorded in a database. Pertinent information was documented from the laboratory information system.ResultsALL was diagnosed in 181 patients over the time period; pertinent clinical information is reported in Table 1. T-ALL was substantially more common than reported elsewhere, comprising 31.5% and 35.2% of childhood and adult ALL, respectively. Differences were evident in the cytogenetic patterns seen in both B- and T-ALL as compared to other parts of the world. In B-ALL the translocation t(1;19) (which occurs in <10% of cases elsewhere) was the most common recurrent genetic abnormality (23.7%), and the t(9;22) had a relatively high frequency in children <13 years (8.8%) (Figure 1). In T-ALL, karyotypic abnormalities were more common than typical (seen in 80.0% of cases vs 50-70% elsewhere), with derangements of chromosome 6q being the most frequent (19%). The translocation t(10;11) (PICALM-MLLT10) and abnormalities involving the TLX1 (HOX11) and TLX3 (HOX 11L2) genes (which are among the more frequent genetic abnormalities reported internationally) were all uncommon, each occurring in only 2.4% of the cases.Disease outcomes were substantially poorer compared to those reported in high income countries, where survival rates in childhood T-ALL range from 60-80% and exceed 90% in B-ALL. At a median follow-up time of 36 months, only 68.2% (B-ALL) and 27.8% (T-ALL) of children <10 years were alive, while mortality rates among adults exceeded 80% in both T- (86.7%) and B-ALL (83.3%). Survival in patients with T-ALL did not differ between those with high vs low risk clinical features (age >10 years, white cell count >100 x10 9/L), and was significantly worse as compared to those with B-ALL (p = 0.01). Relapse was the dominant cause of death in children <10 years (more so in those with T-ALL), while death due to chemotherapy-related neutropenic sepsis was more common in older patients (particularly those with B-ALL) (Figure 2). Factors associated with disease relapse in B-ALL included KMT2A rearrangement and measurable residual disease (MRD) after induction chemotherapy (as defined by non-quantitative, non-allele specific PCR of IgH/T-cell receptor gene rearrangement status and 4 color flow cytometry (both with sensitivities >0.1%)). Notably, the high risk of relapse associated with MRD was not seen in patients with t(9;22), likely due to the use of targeted molecular therapy in these cases. No significant predictors of survival were identified in T-ALL, but the presence of MRD post-induction was associated with early death due to relapse (<12 months).ConclusionALL in SA shows distinct differences in the cytogenetic landscape, disease patterns and outcomes. The cause of the poor survival rates likely includes differences in tumour/host biology, late presentation, restricted access to haemopoietic stem cell transplantation in the SA state-sector, and suboptimal neutropenic support. Although rudimentary, available MRD testing is a valuable risk predictor in both B- and T-ALL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.