EXCLI J EXCLI Journal 1611-2156 Leibniz Research Centre for Working Environment and Human Factors 2022-5676 10.17179/excli2022-5676 Doc67 Letter to the editor A temporal cluster of acute promyelocytic leukemia Langabeer Stephen E. * 1 Cancer Molecular Diagnostics, St. James's Hospital, Dublin, Ireland *To whom correspondence should be addressed: Stephen E. Langabeer, Cancer Molecular Diagnostics, St. James’s Hospital, Dublin, Ireland; Phone: +353-1-4162413, Fax: +353-1-4103513, E-mail: slangabeer@stjames.ie 05 01 2023 2023 22 67 69 08 12 2022 19 12 2022 Copyright © 2023 Langabeer 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/) You are free to copy, distribute and transmit the work, provided the original author and source are credited.

This article is available from https://www.excli.de/vol22/excli2022-5676.pdf


Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) that possesses a typical morphology, and in greater than 98 % of cases, the t(15;17) translocation that results in the PML-RARA fusion oncogene. Current therapeutic options include regimens that include all-trans retinoic acid and arsenic trioxide that directly target the underlying molecular abnormalities of APL (Sanz and Barragán, 2021[9]). The incidence of APL in adults has been previously estimated at between two and six cases per 10 million people per year (Mele et al., 1995[8]; Chen et al., 2012[3]). Early in 2022, an increase in newly presenting cases of APL was noted at a central laboratory for leukemia molecular diagnostics that possibly represented a temporal cluster. In order to ascertain the nature of this increase in new patient numbers and additionally to estimate the incidence of this type of leukemia in the Republic of Ireland, an historical audit was performed for molecularly characterized APL.

A database search was performed for all new cases of PML-RARA-positive APL at a central laboratory for leukemia molecular diagnostics from January 2014 to end quarter three (Q3) September 2022 inclusive. PML-RARA transcripts were detected by a standardized real-time quantitative polymerase chain reaction approach (Gabert et al., 2003[5]). Eighty-one cases of newly diagnosed PML-RARA-positive APL were identified within the audit period of whom 40 were male and 41 were female (median age 51 years; range 1-91 years). The distribution of PML-RARA breakpoint cluster (bcr) types was bcr1 n=34, bcr2 n=8 and bcr3 n=39. Cases were grouped into three-monthly quarters with a mean of 8.5 cases per year (equivalent to 2.125 cases per quarter) from Q1 2014 to Q4 2021. The Poisson distribution probability, assuming 2.125 cases per quarter, would suggest that quarters in which there are six (p = 0.006), seven (p = 0.002), or more cases are statistically improbable to happen by chance alone: a conspicuous peak of nine new cases was observed in Q1 of 2022 (Figure 1(Fig. 1)). These nine cases comprised five males and four females with a median presentation age of 52 years (range 24-74 years) with bcr1 (n=2), bcr2 (n=1) and bcr3 (n=6).

During the eight years prior to 2022, the mean incidence of molecularly detected APL in the Republic of Ireland was eight or nine cases per year, higher than that previously reported in alternative, historical, adult cohorts and geographical locations. Reasons may include the inclusion of pediatric APL cases in this study and the heightened awareness of relevant testing given high response rates with modern therapy. Estimating the annual incidence of APL has not only diagnostic implications but will aid in planning treatment services.

An explanation for the temporal clustering within Q1 2022 is not immediately apparent: the demographics of the nine patients were representative of the whole cohort and were from disparate locations. It is acknowledged that this brief report has shortcomings associated with reporting cancer clusters (Coory and Jordan, 2013[4]). Geographical clustering of APL has been previously reported but little or no association demonstrated with respect to race, gender, additional cytogenetic abnormalities, additional mutations or upper respiratory viral illness (Brunner et al., 2018[1]; Li et al., 2020[7]). Evidence for seasonal variation in both APL and AML in general has also been documented (Calip et al., 2013[2]; Hassan et al., 2021[6]), prompting speculation of an environmental factor: identification of which might enlighten understanding of APL etiology and strategies for possible prevention.

DeclarationConflict of interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The author acknowledges the contribution of those members of the Cancer Molecular Diagnostics department involved in molecular testing over the audit period.

Brunner AM Geon Kim P Sadrzadeh H Drapkin BJ Sprague KE Sloan JM Clustered incidence of adult acute promyelocytic leukemia Leuk Res 2018 74 47 50 Calip GS McDougall JA Wheldon MC Li CI De Roos AJ Evaluation of seasonality in the diagnosis of acute myeloid leukaemia among adults in the United States, 1992-2008 Br J Haematol 2013 160 343 350 Chen Y Kantarjian H Wang H Cortes J Ravandi F Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008 Cancer 2012 118 5811 5818 Coory MD Jordan S Assessment of chance should be removed from protocols for investigating cancer clusters Int J Epidemiol 2013 42 440 447 Gabert J Beillard E van der Velden VHJ Bi W Grimwade D Pallisgaard N Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – a Europe Against Cancer program Leukemia 2003 17 2318 2357 Hassan J Adil SO Haider Z Zaheer S Anwar N Nadeem M Seasonal variations in hematological disorders: a 10-year single-center experience Int J Lab Hematol 2021 43 93 98 Li AY Kashanian SM Hambley BC Zacholski K Baer MR Duong VH Clustered incidence of adult acute promyelocytic leukemia in the vicinity of Baltimore Leuk Lymphoma 2020 61 2743 2747 Mele A Stazi MA Pulsoni A Visani G Monarca B Castelli G Epidemiology of acute promyelocytic leukemia Haematologica 1995 80 405 408 Sanz MA Barragán E History of acute promyelocytic leukemia Clin Hematol Int 2021 3 142 152 Quarterly incidence of newly diagnosed acute promyelocytic leukemia (APL) from Q1 2014 to Q3 2022