Biology of childhood acute lymphoblastic leukemia (ALL) in low/middle‐income countries—A case for using age at diagnosis for defining low‐risk ALL

I n this issue of the journal, Fadoo et al. (PBC 2015) describe the epidemiologic features of and outcome in childhood acute lymphoblastic leukemia in Pakistan. [1] The findings stem from a multi-institutional collaborative study from the city of Karachi, the largest in Pakistan and involves two government/charity-supported institutions as well as a private institution. Quality assurance audits were conducted every 6months. The authors should be commended for this indigenously developed study on several levels. First, by using a common strategy in private and public institutions, a certain uniformity of access to clinical expertise, application of diagnostic testing, drug availability, supportive care, and response assessment was provided to all patients regardless of income, no small achievement in a setting with highly disparate family resources characteristic of low/middle-income countries. Second, by combining experience at three large institutions, the results represent near population-based experience (eliminating secular trends associated with referral biases) with regard to the biology of childhood ALL in Pakistan and for that matter from Afghanistan and the countries of Indian subcontinent—Bangladesh, Bhutan, India, Maldives, Pakistan, and Sri Lanka. Nonetheless, the results show continuing caveats related to biology of childhood ALL from South Asia (SA). With regard to categories of risk for relapse of B Precursor ALL (BpALL) (this author prefers over the WHO-suggested B-ALL to prevent confusion), the most widely used algorithms are derived from the Rome/NCI criteria defined in 1996, which takes into account both the age and white count (WBC) at diagnosis and with modifications based on the chromosomal makeup of the leukemias. [2] An inherent problem in using the WBC at diagnosis in low-income countries is the relatively high frequency of prior steroid use, rendering initial WBC unreliable. The expertise for cytogenetic evaluation by G-Banding, FISH, and molecular technologies is evolving in the low-income countries and standardization across the various laboratories is uncertain. Although the public (governmental) funding for the treatment of childhood cancer is improving across the countries of SA, the funds are often not available in a timely manner for the combined diagnostic tests of immunophenotyping and chromosomal/molecular evaluations necessary for European/American style of risk definitions, and such tests may not be done in a substantial number of cases. The technical and fiscal disparities are a primary cause of the continued reporting of low frequencies of ETV6/RUNX1 and high hyperdiploid ALL from SA and the region. In the article by Fadoo et al.,[1] conventional cytogenetic data were reported in less than half of the cases (Table 2; 316/646 or 49%; 63% in AKUH private hospital and only 30% in the NICH) and FISH/PCR studies in a much lower fraction of cases. This is a theme that is common in reports from SA and the Middle East. This contrasts with a <10% rate of unsuccessful cytogenetic studies in large cooperative group studies. [3] In the absence of reliable pretreatment, WBC, and chromosomal data on the vast majority of cases, the investigators may well use age alone as a surrogate for biology in childhood BpALL. Fortunately, in childhood BpALL, age is a very good surrogate for biology. [3] The US SEER data show a distinct age peak at 2–7 years of age, and population-based studies from Nordic countries show that 80% of ETV6/RUNX1 and high hyperdiploid cases occur in this age group. [3] Thus far, African–Americans (AA) are the only racial group with a blunted age peak at 1–6 years and AAs have low frequency of high hyperdiploid and ETV6/Runx1-associated ALL. [4,5] South Asians are by ancestry Caucasians and there is no a priori reason to anticipate that ALL biology is different in this population. Studies from the Middle East show an age peak similar to that seen in European Caucasians, and studies from Malaysia–Singapore indicate that the incidence of ETV6/RUNX1 in South Asian children is 20%. [6,7] Experienced cytogeneticists point out that identification of high hyperdiploid cases is often difficult and some are loathe to exclude hyperdiploidy without looking at 100 metaphases to find the required minimum three spreads with >50 chromosomes. The very high frequency of euploid cases in the present study (84% compared to <13.6% in the NOPHO study) suggests continuing technical issues with the leukemia cytogenetic evaluations. Interestingly in this Nordic study, only 2.8% of children in the 2–7 age group had Ph positive and MLL-rearranged leukemia (the invariant poor prognostic cases). Thus, aside from an apparent increase in BCR/ABL-positive cases, the data presented by Fadoo et al.,[1] in Tables 2 and 3 support the hypothesis advanced in this commentary that the biology of BpALL in Pakistan (or for that matter in South Asia) is likely similar to the Caucasian populations in Europe/Americas—age group>1 and<10 accounts