Incidence Of Acute Promyelocytic Leukemia Research Articles

Characteristics and complications of acute promyelocytic leukemia in children: an analysis of a national database

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) that was previously one of the most fatal forms of acute leukemia. With advances in diagnosis and treatment, APL has become one of the most curable myeloid leukemias. The major reason for treatment failure in APL is early death after initiation of treatment. We performed a retrospective cross-sectional analysis of the Healthcare Cost and Utilization Project 2016 and 2019 Kids’ Inpatient Database, with the diagnosis of APL or AML not in remission as defined by ICD-10-CM codes. We compared complications and outcomes associated with APL and AML (exclusive of APL) in hospitalized children in the U.S. and described yearly national incidence. The national incidence of APL was 2.2 cases per million children per year. Children with APL were more likely to have cardiopulmonary complications (OR 1.79; CI 1.20–2.67; p = 0.004), coagulation abnormalities or DIC (OR 7.75; CI 5.81–10.34; p < 0.001), pulmonary hemorrhage (OR 2.18; CI 1.49–3.17; p < 0.001), and intracranial hemorrhage (OR 10.82; CI 5.90–19.85; p < 0.001) and less likely to have infectious complications (OR 0.48; CI 0.34–0.67; p < 0.001) compared to children with AML. In-hospital mortality rates were similar in children with APL and AML (4.2% vs 2.6%; OR 1.62; CI 0.86–3.06; p = 0.13), while the median length of stay for children who died from APL was shorter compared to AML (2 (IQR: 1–7) versus 25 (IQR: 5–66) days; p < 0.05). Hemorrhagic complications occur more often, and infectious complications occur less often in hospitalized children with APL compared to AML.

AML-179: Seasonal Association of Acute Promyelocytic Leukemia: A 6-Year Single-Center Experience

Context: Oncogenes, pollution, infections, or the dysregulation of the immune system can be triggering factors for leukemias, but there is not a specific factor for acute promyelocytic leukemia (APL). Objectives: Investigating the impacts of seasonality in the incidence of APL in our center and its characteristics were the aims of the study. Design: Six-year records of 21 APL patients who were diagnosed and treated in Gülhane Education and Training Hospital from 2015 to 2021 were evaluated retrospectively. Patients were categorized on the basis of the seasons in which they were diagnosed: winter (December–February), spring (March–May), summer (June–August), and autumn (September–November). Results: The mean age of the patients was 47.7 years (30–79) M/F: 3/1. Seven patients (33.3%) were diagnosed in winter, 7 patients (33.3%) in autumn, 5 patients in spring (23.8%), and 2 patients (9.5%) in summer. There was a significant difference in terms of APL incidence in winter and autumn versus summer. Conclusion: Seasonal variations in hematologic diseases and leukemias have been largely reported by several epidemiological studies. In contrast to our study, Hassan et al. could not find any seasonal variations in APL. A Brazilian study reported a correlation between rainfall and APL. Timonen hypothesized that viral infections, sunlight deficiency, and cold temperatures could be effective for triggering leukemias. Acute myeloblastic leukemia (AML) showed the highest risk during dark seasons, which can be explained by vitamin D insufficiency. Parallel to this study, we can explain that decreased sun exposure in winter and autumn can trigger vitamin D deficiency and APL occurrence. Similarly, elevated viral infections can trigger leukemogenesis in winter. Supplementation with vitamin D and vaccination against influenza may be beneficial to prevent APL occurrence. Oncogenes, pollution, infections, or the dysregulation of the immune system can be triggering factors for leukemias, but there is not a specific factor for acute promyelocytic leukemia (APL). Investigating the impacts of seasonality in the incidence of APL in our center and its characteristics were the aims of the study. Six-year records of 21 APL patients who were diagnosed and treated in Gülhane Education and Training Hospital from 2015 to 2021 were evaluated retrospectively. Patients were categorized on the basis of the seasons in which they were diagnosed: winter (December–February), spring (March–May), summer (June–August), and autumn (September–November). The mean age of the patients was 47.7 years (30–79) M/F: 3/1. Seven patients (33.3%) were diagnosed in winter, 7 patients (33.3%) in autumn, 5 patients in spring (23.8%), and 2 patients (9.5%) in summer. There was a significant difference in terms of APL incidence in winter and autumn versus summer. Seasonal variations in hematologic diseases and leukemias have been largely reported by several epidemiological studies. In contrast to our study, Hassan et al. could not find any seasonal variations in APL. A Brazilian study reported a correlation between rainfall and APL. Timonen hypothesized that viral infections, sunlight deficiency, and cold temperatures could be effective for triggering leukemias. Acute myeloblastic leukemia (AML) showed the highest risk during dark seasons, which can be explained by vitamin D insufficiency. Parallel to this study, we can explain that decreased sun exposure in winter and autumn can trigger vitamin D deficiency and APL occurrence. Similarly, elevated viral infections can trigger leukemogenesis in winter. Supplementation with vitamin D and vaccination against influenza may be beneficial to prevent APL occurrence.

Recent Trends in the Incidence and Outcomes of Acute Promyelocytic Leukemia in United States

Background:Outcomes of acute promyelocytic leukemia (APL) have significantly improved in the current era with clinical trials demonstrating excellent survival using ATRA, arsenic trioxide and chemotherapy based regimens. However, population level data on the disease incidence and survival in the last decade from United States is sparse.Methods:Using Surveillance Epidemiology and End Results database, we identified patients aged ≥ 20 years with pathologically confirmed APL (ICD-0-3 code 9866) as the only primary malignancy, known race, diagnosed between the years 2000-2014 and actively followed. We calculated the incidence and overall survival (OS) in this population. Incidence rate per 100000 population and incidence rate ration (IRR) were calculated to determine the relative difference in disease incidence among subgroups. Period of diagnosis was stratified into 3 groups - 2000-2004, 2005-2009, 2010-2014. Kaplan-Meier method and log rank test were used to analyze the OS among subgroups. For survival analysis, only patients who received treatment were included. Early mortality was defined by death within 30 days of diagnosis. Cox proportional hazard regression method was used to determine the influence of time and demographic factors on OS. Statistical analyses were carried out with significant two sided p< 0.05.Results:A total of 2367 patients with a median age of 46 years (range 20-92 years) were included. Males (51.5%) and White race (79.8%) contributed to the majority. Overall incidence of APL was 0.32 per 100000 population during the period 2000-2014.The disease incidence increased significantly with age (upto 79 years) and from the year 2005 onwards (Table 1). The disease incidence was lower in females (0.30 per 100000, p<0.01) as compared to males (0.34 per 100000) and lower in American-Indians (0.16 per 100000, p <0.01) and Asian/pacific islanders (0.27 per 100000, p< 0.01) as compared to Whites (0.33 per 100000). When stratified by the period of diagnosis, the 5-year OS was significantly higher for patients diagnosed between the year 2010-2014 (81.7%) as compared to those diagnosed from 2005-2009 (73.3%) and 2000-2004 (65.3%, p <0.001) (Figure 1). The 5-year OS was not significantly different by gender (females-75.1%, males 72.6%, p=0.18) or race (Whites-73.9%, Blacks 73.8%, Asians 72.1%, American-Indians 82.5%, p=0.85). The 5-year OS decreased with increasing age (age < 40 - 84.7%, age 40-59 -75.3%, age 60-79- 57.5%, age ≥80 -19.6%, p< 0.001). Early mortality did not significantly differ over time (year 2000-2004 - 13.2%, 2005-2009 - 11.7%, 2010-2014 - 10.1%, p=0.17). On multivariate analysis, increasing age (HR 1.04, 95% CI 1.03-1.04, p< 0.001) was associated with higher mortality. Diagnosis in the period 2005-2008 (HR 0.68, 95%CI 0.56-0.82 p<0.001) and 2010-2014 (HR 0.45, 95%CI 0.36-0.56, p< 0.001) were associated with significantly lower mortality hazard.Conclusions:Survival of patients with APL has continued to improve over time, however early mortality has not changed significantly. Incidence of APL varies by factors such as age, gender, race and has increased in the recent period. Age remains as an important predictor of survival even in the current era. [Display omitted] DisclosuresGuru Murthy:Janssen: Other: Fellows advisory board. Dhakal:Celgene: Honoraria. Hamadani:Celgene, Cellerant, Jansen, MedImmune: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda, Otsuka, MedImmune, Merck, ADC Therapeutics: Research Funding. Michaelis:Celgene: Speakers Bureau; Novartis: Other: Consultation for New Product; Incyte: Other: consultation for product. Atallah:ADC Therapeutics: Research Funding.

Pediatric Acute Promyelocytic Leukemia: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome.

Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among the geographic regions with relatively higher percentages in the Latin American population. We aimed to explore the population burden of pediatric APL, gathering information from the population-based cancer registry (PBCR) and the diagnosis of APL obtained through incident cases from a hospital-based cohort. The homozygous deletion in glutathione S-transferases (GSTs) leads to a loss of enzyme detoxification activity, possibly affecting the treatment response. Mutations in the RAS pathway genes are also considered to be a key component of the disease both in the pathogenesis and in the outcomes. We have assessed mutations in a RAS–MAP kinase pathway (FLT3, PTPN11, and K-/NRAS) and GST variant predisposition risk in the outcome. Out of the 805 children and adolescents with acute myeloid leukemia (AML) who are registered in the PBCR, 35 (4.3%) were APL cases. The age-adjusted incidence rate (AAIR) was 0.03 per 100,000 person-years. One-hundred and sixty-three patients with APL were studied out of 931 AML cases (17.5%) from a hospital-based cohort. Mutations in FLT3, KRAS, and NRAS accounted for 52.1% of the cases. Patients with APL presented a 5-year probability of the overall survival (OS) of 67.3 ± 5.8%. A GST-theta 1 (GSTT1) null genotype conferred adverse prognosis, with an estimated hazard ratio of 2.8, 95% confidence interval (CI) 1.2–6.9. We speculate that the GSTT1 polymorphism is associated with therapeutics and would allow better OS of patients with APL with a GSTT1 null genotype.

Second Primary Malignancy after Acute Promyelocytic Leukemia: A Population-Based Study.

Simple SummaryAcute promyelocytic leukemia (APL) is a rare and aggressive subtype of acute myeloid leukemia (AML). Since the introduction of all-trans-retinoic acid (ATRA) in APL management, the survival rate has increased substantially. However, there is evidence that retinoids might enhance tumor growth and the risk of secondary malignancies. The relationship between secondary cancer risk and APL treatment that includes ATRA is incompletely characterized. In this study, we investigated the risk factors associated with second primary malignancies after treatment of APL. Age ≥ 40 years at diagnosis of APL was significantly associated with an increased risk of second malignancies. Our findings suggest a potential carcinogenic role for ATRA in the salivary gland, liver, and soft tissue malignancies. Moreover, secondary tumors were significantly more frequent among patients with primary APL than in individuals with non-APL malignancies. Our finding suggests opportunities for surveillance for patients who completed treatment for APL.Acute promyelocytic leukemia (APL), is now highly curable with treatment approaches that include all-trans retinoic acid (ATRA). The high incidence of APL in the Hispanics suggests an association with genetic variants in this population. Information on second primary malignancies (SPMs) in patients with APL is limited. The Surveillance, Epidemiology, and End Results (SEER) database was used to interrogate whether the rate of SPMs in patients with APL was associated with ethnicity and/or ATRA treatment. Between 2000 and 2016, 116 cases of SPM were diagnosed among 4019 patients with APL. The mean age at diagnosis of primary APL was 53.9 years (±15.7 years), and the mean age at diagnosis of SPMs was 59.0 years (±14.5 years). Comparisons with 3774 APL survivors who did not develop SPMs revealed that age ≥40 years at diagnosis of APL (p < 0.001) and non-Hispanic white ethnicity (p = 0.025) were associated with SPMs in APL survivors. Salivary gland, liver, and soft tissue malignancies were significantly more common in patients with primary APL than in individuals with non-APL malignancies. A risk analysis comparing patients who had APL with patients who had non-APL AML suggests that SPMs after APL is associated with ATRA treatment. Therefore, patient follow-up after APL should focus on early diagnosis of SPMs.

Abstract D055: Molecular mechanisms of cisplatin-induced toxicity to acute promyelocytic leukemia cells

Abstract Purpose: Acute promyelocytic leukemia (APL), is a blood cancer that accounts for about 10% of all acute myloid leukemia cases. Each year in the United States, APL affects about 1,500 patients of all age groups and causes approximately 1.2% of cancer deaths. Research has also pointed out the Hispanic populations have a higher incidence of APL compared to other racial groups. Cisplatin) is a widely used anti-tumor drug for the treatment of a broad range of human malignancies with successful therapeutic outcomes for head and neck, ovarian, and testicular cancers. It has been found to inhibit cell cycle progression and to induce oxidative stress and apoptosis in APL cells. However, its molecular mechanisms of cytotoxic action are poorly understood. We hypothesized that cisplatin induces cytotoxicity through DNA adduct formation, oxidative stress, transcriptional factors (p53 and AP-1), cell cycle regulation, stress signaling and apoptosis in APL cells. Methods: We used the APL cell line as a model, and applied a variety of molecular tools (cytotoxicity and oxidative stress assays, western blot analysis, flow cytometry, and confocal microscopy) to elucidate cytototoxic mode of action of cisplatin. Results: We found that cisplatin inhibited cell proliferation by a cytotoxicity characterized by DNA-adduct formation, oxidative stress, cell cycle arrest, stress signaling and apoptosis in APL cells. Cisplatin also activated p53 and phosphorylated activator protein (AP-1) component, c-Jun at serine (63, 73) residue simultaneously leading to cell cycle arrest through stimulation of p21 and down regulation of cyclins and cyclin dependent kinases (cdks) in APL cell lines. It strongly activated the intrinsic pathway of apoptosis through alteration of the mitochondrial membrane potential, release of cytochrome C, and up-regulation of caspase 3 activity by modulating p38MAPK pathway in APL cells. Conclusion: Overall the findings from this study provide novel targets of cisplatin mode of action that may be very useful in designing of new APL drugs. Citation Format: Paul Tchounwou, Sanjay Kumar, Andrea Brown. Molecular mechanisms of cisplatin-induced toxicity to acute promyelocytic leukemia cells [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D055.

Nuclear import of NLS- RARα is mediated by importin α/β

The promyelocytic leukemia-retinoic acid receptor α (PML/RARα) is hypothesized to play a vital role in the pathogenesis of acute promyelocytic leukemia (APL). A previous study has demonstrated that PML/RARα is cleaved by neutrophil elastase (NE) in early myeloid cells, which leads to an increase in the nuclear localization signal (NLS) in RARα and in the incidence of APL. In this study, we explored the effects of NLS-RARα on acute myeloid leukemia (AML) cells and studied the mechanism of its localization. LV-NLS-RARα recombinant lentivirus and negative control LV-NC lentivirus were transfected into HL-60 cells and U937 cells while mutant NLS-RARα were transfected into U937 cells, and all groups were treated with 1α, 25-dihydroxyvitamin D3(1,25D3). The results showed that NLS-RARα was located mainly in the nucleus while mutant NLS-RARα was located in the cytoplasm. Overexpression of NLS-RARα downregulated the expression of CD11b, CD11c, CD14, and three forms of CEBPβ compared to the overexpression of NC and mutant NLS-RARα. It was speculated that the abnormal localization of NLS-RARα was mediated via importin-α/β in the pathogenesis of APL. By producing point mutations in the two NLSs in NLS-RARα, we showed that the nuclear import of NLS-RARα was mainly dependent on the NLS of the RARα portion. Subsequently, we found that importin-α1 (KPNA2)/importin-β1 (KPNB1) participates in the nuclear transport of NLS-RARα. Taken together, abnormal localization of NLS-RARα blocks the differentiation of APL cells, and nuclear localization of NLS-RARα depends on NLS of the RARα portion and is mediated via binding with importin-α/β.

Improving Outcomes of Acute Promyelocytic Leukemia in the Current Era: Analysis of the SEER Database.

Outcomes of acute promyelocytic leukemia (APL) have significantly improved with the availability of targeted agents. It remains unclear whether the population-level outcomes of APL have improved over time. Using the SEER database, we identified patients aged ≥20 years with pathologically confirmed APL diagnosed in 2000 through 2014 and who were actively followed. Patients were stratified by diagnosis period into 3 groups (2000-2004, 2005-2009, and 2010-2014) to assess the temporal trends in overall survival (OS), cause-specific survival (CSS), and other outcomes. A total of 2,962 patients with a median age of 48 years (range, 20-96 years) were included. Hispanic patients constituted 21.5% of the cohort and the largest proportion (47.9%) of uninsured patients. The incidence of APL was 0.33 cases per 100,000 population per year. Incidence varied significantly by age, sex, race/ethnicity, and diagnosis period. Survival was significantly higher for patients diagnosed in 2010 through 2014 compared with those diagnosed in 2005 through 2009 and in 2000 through 2004 (4-year OS, 73.4% vs 65.6% vs 57.3%, respectively; 4-year CSS, 78.3% vs 70.8% vs 60.8%, respectively). Early mortality improved significantly over time (2000-2004, 25.3%; 2005-2009, 20.6%; 2010-2014, 17.1%) and was higher in men and Hispanic patients. According to multivariate analysis, diagnosis before 2010 and unmarried status were associated with a higher mortality risk. Uninsured patients had a significantly higher early mortality without a significant difference in post-30-day CSS. No significant changes were noted in risk of secondary malignancies. Population-level outcomes of APL have continued to improve over time. However, significant discrepancies in disease outcomes continue to exist, highlighting the need for more research.

Seasonality in acute promyelocytic leukemia: Fact or myth?

BACKGROUND: Acute promyelocytic leukemia (APL) is a biologically and clinically distinct subtype of acute myeloid leukemia (AML) Etiological and seasonal factors that play a role in APL still unclear.OBJECTIVES: The aim of the study was to retrospectively evaluate the available data to assess the impact of seasonal variations on incidence of APL over a period of 6 years.PATIENTS AND METHODS: A retrospective, observational study based on APL record of a Hematology Nasiriyah Center from January 2014 to January 2020 was processed. The collected data of diagnosed (APL) patients at this center for 6 years was analyzed, and APL presenting in each month of the year was also assessed for any evidence of seasonality.RESULTS: Fifty-eight cases of APL were included in this study: there were 22 males (37.93%) and 36 females (62.07%). The mean age was 31.1 ± 14.4 years (minimum 15 and maximum 67). We found a pronounced peak of APL occurrence in March (within winter and early spring months) and decline in summer to zero point in August, which was repeated periodical all studied 6 years.CONCLUSIONS: Seasonal pattern of APL was observed. Investigation of specific seasonal risk factors would be informative in explaining the etiology behind the observed variation.

Pediatric Acute Promyelocytic Leukemia in Brazil: Epidemiology, Molecular Features, and Importance of GST-Theta 1 in Chemotherapy Response and Outcome

Background. Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among geographic regions with relatively higher percentages within the Latin American population. We aimed to describe the population burden of pediatric APL (p-APL) in Brazil assessing the incidence rates according to a hospital-based and population-based cancer (PBCR) registries. We also explored mutations in genes of the RAS pathway and the association of polymorphisms in genes of glutathione S-transferases (GSTs) with outcome. Our goal was to provide insights into the distribution of clinical-demographic data and the molecular epidemiology characteristics associated with APL outcome. Methods. One hundred and sixty-four p-APL cases (&lt;19 years old) were identified from a dataset of a hospital-based registry based at a leukemia diagnostic central reference laboratory (2002-2018) and from 15 PBCR (2002-2009). Diagnostic criteria included morphological, immunophenotypic, and cytogenetic-molecular features. The PML-RARafusion gene was detected by FISH and/or RT-PCR. Additionally, mutations in FLT3 [D835 and internal tandem duplications (ITD)], KRAS, NRAS, and PTPN11 mutations were analyzed. We also evaluated the risk association of pharmacogenetically important GST deletion polymorphisms (GSTT1 and GSTM1) by multiplex-PCR, in a case-case analysis to test the effect of genetic susceptibility on overall survival (OS). Patients were treated with the inclusion of all-trans retinoic acid in chemotherapy with anthracyclines and cytarabine. Kaplan-Meier survival analysis was used to calculate the 5-year probabilities of OS (pOS), and estimated survival values were compared using the log-rank test. Cox proportional-hazard regression model estimated the hazard ratio (HR) and 95% confidence intervals (CI). All p-values were two-sided using significance level of 0.05. Results. From the hospital-based registry, APL patients represented 17.6% of the cohort (164 out of 933 acute myeloid leukemia cases), while in the PBCR, they represented 4.4% (35 out of 805 acute myeloid leukemia cases registered). The age-adjusted incidence rate was 0.32 per million persons during 2000-2009 based on PBCR. According to the hospital-based registry, we found similar distribution of patients among age ranges &gt;2-10 and &gt;10-21 years old (43.3% and 51.8%, respectively) and sex. RAS mutations were observed in 51.7% of APLs, including FLT3 (43.0%), NRAS (6.5%), and KRAS (2.2%). Variants in PTPN11 were silent amino acid substitutions (rs61736914; 4.9%). We observed a statistically significant association between FLT3 mutations and high white blood cell count at diagnosis (&gt;10x109/L; 72.6%), low platelet count (&lt;40×109/L; 83.0%), and the PML-RARa breakpoint cluster region 3 (90.5%). Death in the first ten days after diagnosis (early death) affected 17.5% (24/137) patients and these cases were excluded from the survival analysis. The mean of overall survival was 45.1 months (95% CI 40.1-50.1 months; pOS 66.9±5.8%). Univariate analysis did not show an association between variables and OS rates, except for APL patients carrying the GSTT1 polymorphism. GSTT1 null genotype conferred adverse prognosis compared to wild-type genotype (pOS 48.2±13.4% and 79.0±6.3%, p=0.024; hazard ratio 2.6, 95% CI 1.1-6.2, p=0.030; Figure 1). Conclusions. APL represented 17.6% of acute myeloid leukemia in our cohort of Latino patients, which is a higher proportion compared to Northern European countries and the United States (5-10%). GSTT1 polymorphism modulated outcome, suggesting that lower enzyme activity may impact response to therapy. Decreasing early death and inclusion of GSTT1 polymorphism in therapeutic protocols for chemotherapy dose modulation may allow patients to reach the same overall survival observed in the United States (&gt;70%). Disclosures No relevant conflicts of interest to declare.

Incidence of acute promyelocytic leukemia across Europe: results of RARECAREnet—a population-based study

The scarcity of studies performed over the past decades in Central and South America provided clues that the prevalence of acute promyelocytic leukemia (APL)-a rare and distinct subtype of acute myeloid leukemia-might be higher among descendants of Spaniards, as compared to other ethnic groups. Currently, a comprehensive apprehension on APL incidence across Europe has yet been established. Therefore, we conducted a population-based study to assess the incidence of APL across Europe. We selected all patients diagnosed with APL in Europe from the RARECAREnet database that holds data from 94 cancer registries across 27 European countries on rare malignancies diagnosed during 2000-2007. Age-standardized incidence rates (ASRs) with 95% confidence intervals (CIs) were calculated for the European pool per 100,000 person-years. Also, crude incidence rates with 95% CIs were calculated per 100,000 person-years by country. Overall, 1,876 patients with APL (48% male and 24% aged ≥65 years) were included in our analytic cohort. The overall ASR of APL was 0.112 (95% CI, 0.107-0.117) in Europe. The incidence of APL varied considerably across Europe, with the highest incidence in Spain (0.257; 95% CI, 0.205-0.317), as compared to the European average. Altogether, these finding adds additional support to the hypothesis that APL might be more prevalent among individuals with Spanish ancestry. Future research is warranted to specifically explore etiologic factors of APL across different genetic and environmental backgrounds.

The epidemiological trend of acute promyelocytic leukemia over past four decades: a population-based analysis

The treatment regimens for acute promyelocytic leukemia (APL) dramatically changed over time. However, its survival trend, based on a large sample size has not been reported. Patients diagnosed with APL were accessed from the Surveillance, Epidemiology, and End Results database. Their incidence and survival trend were evaluated in overall and subgroup levels. The overall incidence of APL increased with an annual percentage change of 5.5% from 1992 to 2006 and remained stable thereafter. In addition, the 5-year relative survival rates of APL improved significantly, from 12.3 to 32.2% to 59.5 to 72.1% over past four decades (p < .0001), sharing similar trend with different subgroups. Importantly, survival disparities exist among races and different socioeconomic status groups, with superior survival in whites and patients in low-poverty regions. Increasing incidence urges for increased awareness of clinicians over diagnosis of APL. In addition, a wider insurance coverage may help balance survival gap.

PML(NLS¯) protein: A novel marker for the early diagnosis of acute promyelocytic leukemia.

Promyelocyte leukemia-retinoic acid receptor α (PML-RARα) is known as a fusion gene of acute promyelocytic leukemia (APL). Previous studies have reported that neutrophil elastase (NE) cleaves PML-RARα in early myeloid cells, which leads to the removal of the nuclear localization signal (NLS) in PML and increases the incidence of APL. The resultant PML without the NLS is termed PML(NLS−). The aim of the present study was to verify the existence and location of the PML(NLS−) protein in NB4 cells. NB4 cells underwent electroporation with the pCMV-HA-NE plasmid to form NB4-HA-NE cells, which were then transplanted to produce tumors in nude mice and samples were collected from patients with APL. Western blot analysis, an immunofluorescence assay, confocal laser microscopy and immunohistochemistry were performed to detect the expression and localization of the PML(NLS−) protein. The findings demonstrated that PML(NLS−) was detectable in the cytoplasm of NB4-HA-NE cells, the tumors in nude mice and in neutrophils from patients with APL. This indicated that PML(NLS−) may be an effective and novel target for the diagnosis of APL.

Acute Leukemia in Adult Hispanic Americans: Differences in Incidence Rates by Nativity

The incidence pattern of adult acute leukemia (AL) in Hispanics is distinct, with increased B-cell acute lymphoblastic leukemia (ALL) and acute promyelocytic leukemia (APL) and decreased non-APL acute myeloid leukemia (AML). To better understand genetic versus environmental contributors, we assessed AL incidence rates in a population of adult California Hispanics according to birthplace. Using data from California AL patients ≥20 diagnosed between 2000-2009, incidence rate ratios (IRR) were employed to compare incidence rates of AL in foreign- versus United States (US)-born Hispanics. Compared to whites, Hispanics had increased incidence rates of B-cell ALL and APL, IRR2.13 (1.93-2.35) and 1.33 (1.12-1.57), respectively. No nativity differences in B-cell ALL were noted. Foreign-born Hispanics had a higher incidence rate of APL versus US-born Hispanics (IRR 1.79, 1.11-2.94). For adult Hispanics, increased B-cell ALL incidence rates may be due to heritable genetic factors; increased APL incidence rates may be due to as yet unknown environmental exposures.

Evaluation Of Seasonality In The Incidence Of Promyelocytic Leukemia In Brazil

Besides the known factors such as the presence of oncogenes, the macro-environment (pollution, infections) or organic microenvironment (dysregulation of the immune system) can be the triggering factor of the process of leukemogenesis. It is known that the amount of rainfall can affect the distribution (dilution) of pollutants in the air and water reserves. There is no description of the climate influence in the incidence of Acute Promyelocytic Leukemia (APL), which has its own clinical laboratory characteristics, and is defined by the presence of the PML-RARA rearrangement.The aim of this study was to investigate the impact of seasonality in the incidence of Promyelocytic Leukemia in Brazil, and its characteristics. Patients and methodswe analyzed the clinical laboratory data and origin of participant cases of the International Consortium on Acute Promyelocytic Leukemia (IC-APL), a group multicenter treatment of APL with standardized diagnosis and treatment. We included all patients diagnosed with APL of Brazilian centers between 2006 and 2011. We excluded patients without demographics. Patients were divided into macro-climate (Northeast, South and Southeast). Northeast: 49 cases of Pernambuco, Southeast: 16 cases of Minas Gerais, São Paulo 88 cases; South: 27 cases of Rio Grande do Sul and 19 cases of Paraná. Meteorological data were extracted from the database Meteorological Research and Education (BDMEP) of the National Institute of Meteorology (INMET), and grouped by quarter. We studied the mean maximum temperature, mean minimum temperature and rainfall. The relationship between the number of cases and meteorological data were analyzed by the Spearman test. ResultsWe included 149 patients with APL. In the South, there were 46 patients, 50% female and 50% male, mean age: 37 years, 16 cases occurred on the first quarter (January-March), 12 on the second quarter (April-June), 8 cases on third quarter (July-September) and 10 on the fourth quarter (October to December). In the Northeast, there were 49 cases, 25 female and 24 male, mean age 34 years with 11 cases on the first and second quarters, 12 cases on the third quarter and 15 cases on the fourth quarter. Southeast: 54 cases with 29 female cases and 25 male cases, mean age 25 years, with 12 cases on the first and second quarter, 11 cases on the third quarter and 19 cases on the fourth quarter. In the South, there was no statistically significant correlation between the weather and the number of registered cases of APL. In the Northeast, there was a negative correlation between the number of cases of APL and rainfall (r = -0.57, p = 0.004) and a trend with the maximum temperature (r = 0.34, p = .07). In the southeast, there was positive correlation between rainfall (r = 0.42, p = 0.02) but not with temperature. In the northeast, the smallest amount of rainfall is associated with higher temperatures (r = -0.49, p <0.0002), whereas in the Southeast, the greater amount of rainfall is associated with warmer temperatures. ConclusionThere is no known etiology of APL, but the correlations found between rainfall and number of cases could be related to the dispersion of pollutants into the environment. Disclosures:No relevant conflicts of interest to declare.

Acute Promyelocytic Leukemia In Canada: Poor Outcomes In Older Patients Remain

IntroductionDespite widespread use of all-trans retinoic acid (ATRA) in treatment of Acute Promyelocytic Leukemia (APL), recent studies in the US1 and Sweden2 have reported continuing high rates of early death. Patient age has appeared to be an important factor affecting outcomes. We studied the incidence and outcomes in the Canadian APL patients to determine which patients may be at higher risk, and to analyze the success of current management. MethodsWe used data from the Canadian Cancer Registry, which included all patients diagnosed between 1993-2007. We obtained incidence, Early Death (ED) (death within 30 days of diagnosis), and 1 and 5-year overall survival (OS). This was stratified by age, sex, and time period of diagnosis. Detailed information was obtained on a subset of patients managed at five Canadian leukemia referral centres from 1999 to 2010. ResultsThere were 399 cases of APL diagnosed in Canada between 1993-2007.This accounted for 3.01% of Acute Myeloid Leukemia cases. Incidence (age-standardized to the 1991 Canadian census population) was 0.083/100000. The incidence was greater in the population aged 50 and over, with an incidence rate ratio (IRR) of 2.192 (95% C.I.1.80 - 2.67, p<0.001). ED was 21.8% overall, with a rate over three times higher in older patients as compared to younger patients. The ED rate was 10.6% in younger (<50 years) patients and 35.5% in older (≥50 years) patients. One-year overall survival was 84.1% in younger patients as compared to 52.3% in older adults. The rate of death at one year is nearly three times higher in the older patients. Five-year survival was 54.6%; this was 73.3% in the younger patients (<50), and 29.1% in the older group (≥50 years). There were 131 patients in the leukemia referral centre cohort, who predominantly received tretinoin (ATRA) based therapy. In this population, ED was 14.6%. Two-year OS was 76.5% (95% C.I. 68%-83%). Age over 60 predicted an inferior outcome at 2-years with a hazard ratio of 4.051 (95% CI 1.17-7.57). ConclusionsTo our knowledge, this is the largest nationwide epidemiologic study of APL. Despite widespread use of ATRA in Canada and low rates of ED reported in clinical trials (often 3-8%), we found that the real survival outcomes of APL were worse than anticipated. However they were similar to those reported recently from other developed counties1,2. The outcomes were much poorer for the older patients with APL. This included a higher rate of early death as well as poorer rates of survival at one, two and five year follow-up times. The ED rates of patients <50 more closely matched rates reported in clinical trials. We compared the survival outcomes of the entire population with APL to a sample of only patients treated at specialized referral centres. Despite receiving care in a specialized tertiary centre, the survival of older patients remained significantly poorer than the younger patients. The incidence of APL was also double in the older population as compared to the younger population. Overall the age-standardized incidence was lower in Canada than has been reported in other countries1,2. This emphasizes that, although APL is a type of AML that does affect younger patients, there is a large and important impact of this disease on older patients. Recent studies in the US and Sweden have also reported higher rates of APL in older populations and poorer rates of survival at various follow up times. Overall the patients with high-risk Sanz scores had the worst survival outcomes. The survival at most time points was slightly higher for patients scored as intermediate-risk compared to those who were in the low-risk category. When arsenic becomes widely available as a first line therapy it will be important to continue population-based analysis to see how this affects outcomes and whether the outcomes are difference in difference age groups or populations. Disclosures:No relevant conflicts of interest to declare.

Expression Profiling Of Selected Polycomb Complex Genes In Childhood Acute Myeloid Leukemia Revealed An Overexpression Of EZH2 In Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) in children and adolescents accounts for about 20% of cases of acute myeloid leukemia (AML) in Brazil. The reasons for the relatively high incidence of APL among children and adolescents in Brazil and other Latin countries remain elusive. Epigenetic constitutional and/or environmental factors might be implicated in the mechanism of APL. The Polycomb group (PcG) genes are critical for differentiation and cell-cycle regulation and maintenance of epigenetic memory of living organisms. Aberrant expression of PcG genes has been observed in human tumors, including AML. In this study, we sought to determine the expression levels of 4 genes from the PcG repressive complexes EZH2, YY1, BMI1 and SUZ12 in acohort of 52 children with AML or APL (male, 32; female, 20; median age 7.8 years, range 4 months-18 years).Cells from healthy children (male, 2; female, 2; median age, 10.7 years, range 6-15 years) were used as the control group. Quantitative determination of mRNA levels was performed using Power SYBR Green PCR Master Mix® (Applied Biosystems, Foster City, CA, USA) in a Rotor Gene® thermocycler (QIAGEN). Expression levels were estimated in triplicate, and ß-actin was used as an internal control. All statistical analyses were performed using the GraphPad Prim 5.0 System. Multiple pairwise comparisons were made using a one-way analysis of variance (ANOVA) test; P<0.05 was considered statistically significant.Despite showing broad variation among patients and controls, the expression levels of YY1 (controls, 1.16 ±SE 0.73; M1/M2, 0.63±1.07; M4/M5 0.217±0.71; APL, 0.62±3.24; p=0.19); SUZ12 (control, 1.11 ±0.93; M1/M2, 0.12±1.65; APL 2.4±3.42; M4/M5, 0.34 ± 10.30; p=0.18), and BMI1 (control, 0.041 ± 0.77; M1/M2: 0.043 ±0.10; M4/M5, 0.016± 0.23; APL, 0.12 ± 0.59; p=0.37)did not differsignificantly between controls and patients grouped according to the major AML subtypes (M1/M2, 15 cases, median age 10.8 years, range 4-18 years; M4/M5, 21 cases,median 4.5 years, range 5 months-18 years; APL 16 cases, median 9.8 years, range, 1-17 years). However, the EZH2 expression levels (control, 0.0008818±0.03675; M1/M2, 0.001495±0.03296; M4/M5 0.008215±0.09313; APL, 0.07180± 0.3402; p=0.0092) were significantly higher in APL. Among patients with APL, the expression levels of EZH2 did not differ significantly according to age (EZH2 expression, 0.23±0.44, age 0-8 years; 0.05±0.46, age 9-18 years; p=0.112), white blood cell count (EZH2 expression 0.07±0.65, WBC < 10 x 109/L; 0.10±0.38, WBC ≥ 10 x 109/L; p=0.148) or platelet count (EZH2 expression 0.20±0.49, platelet count < 40 x109/L; 0.06 ±0.04, platelet count ≥ 40 x 109/L; p=0.13).Several studies have shown that EZH2 is deregulated in several human cancers. Here we extend this data by informing that EZH2 is highly overexpressed in pediatric APL. APL in children less than 8 years of age tends to be associated with higher EZH2 gene expression levels, suggesting that constitutional epigenetic factors may play a driver role in pediatric APL leukemogenesis. Disclosures:No relevant conflicts of interest to declare.

Acute promyelocytic leukemia with an unusual presentation of secondary postpartum hemorrhage

TO THE EDITOR: Acute leukemia during pregnancy is rare [1-8]. The exact incidence of acute promyelocytic leukemia (APL) in pregnant women is unknown; however, approximately 50 such cases have been reported in the literature [1-4, 7, 8]. APL is a unique type of acute myeloid leukemia (AML) characterized by proliferation of neoplastic promyelocytes bearing a specific chromosomal translocation t(15;17). We report a case of APL with an unusual presentation of secondary postpartum hemorrhage (PPH).

Acute Leukemia in Hispanic Americans: Incidence and Incidence Rate Differences by Nativity.

AbstractAbstract 3160 Introduction:Acute leukemias (AL) have a distinct incidence pattern in Hispanics versus Caucasians, with higher rates of B-cell acute lymphoblastic leukemia (ALL) and acute promyelocytic leukemia (APL), and lower rates of non-APL acute myeloid leukemia (AML). Despite the fact that incidence differentials between foreign- and native-born populations can inform the relative contributions of environmental and genetic factors in cancer etiology, no such investigation has been undertaken in Hispanics with AL. Methods:To better understand heritable genetic versus environmental contributors to occurrence patterns, we assessed AL incidence in a large population of California Hispanics according to birthplace. Cancer incidence data were obtained from the California Cancer Registry, part of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. Patients were included if they were living in California and diagnosed between 2000–2009 with AL. Population estimates were obtained from the 2000 Census Summary Files 3, and estimates by nativity were derived from the 20% Integrated Public-Use Microdata Sample of the censuses. Results:Compared to Caucasians, Hispanics had an increased incidence of B-cell ALL and APL, with incidence rate ratios (IRR) of 2.13 (95% confidence interval [CI] 1.93–2.35) and 1.33 (95% CI 1.12–1.57), respectively. There was no difference in B-cell ALL incidence by nativity, with an IRR for foreign- to native-born Hispanics of 1.07 (95% CI 0.85–1.34). However, foreign-born Hispanics had a greater incidence of APL than native-born Hispanics (IRR 1.79, 95% CI 1.11–2.94). Conclusions:Our findings suggest the increased B-cell ALL incidence for foreign-born Hispanics is influenced by heritable genetic factors. Furthermore, the increased incidence of APL for foreign-born Hispanics may result from environmental exposures currently not described and which require further epidemiologic investigation.Table 1:Age-adjusted incidence rates (per 100,000 person-years) of acute leukemias and incidence rate ratios (IRR) by race/ethnicity among non-Hispanic Whites and Hispanics, and nativity among Hispanics*, 2000–2004 and 2000–2009Hematological MalignancyRace/Ethnicity† or NativityMaleFemaleMale and FemaleCasesIncidence Rate* (95% CI)IRR (95% CI)CasesIncidence Rate* (95% CI)IRR (95% CI)CasesIncidence Rate* (95% CI)IRR (95% CI)B-Cell ALL†White4780.78 (0.71–0.85)1.00 (reference)3650.54 (0.48–0.60)1.00 (reference)8430.65 (0.61–0.70)1.00 (reference)Hispanic5421.39 (1.26–1.54)1.80 (1.57–2.06)4511.36 (1.23–1.50)2.53 (2.19–2.94)9931.39 (1.30–1.49)2.13 (1.93–2.35)Non–APL AML†White31184.87 (4.70–5.04)1.00 (reference)24803.17 (3.04–3.30)1.00 (reference)55983.91 (3.81–4.02)1.00 (reference)Hispanic8463.83 (3.54–4.14)0.79 (0.72–0.86)6942.63 (2.42–2.84)0.83 (0.76–0.91)15403.13 (2.96–3.31)0.80 (0.75–0.85)APL†White2070.33 (0.28–0.38)1.00 (reference)1620.24 (0.21–0.29)1.00 (reference)3690.29 (0.26–0.32)1.00 (reference)Hispanic1340.36 (0.30–.044)1.11 (0.87–1.42)1410.40 (0.33–0.47)1.61 (1.26–2.06)2750.38 (0.33–0.43)1.33 (1.12–1.57)B–Cell ALL**US-Born911.28 (1.00–1.63)1.00 (reference)691.10 (0.83–1.42)1.00 (reference)1601.24 (1.04–1.48)1.00 (reference)Foreign-Born1421.33 (1.07–1.65)1.04 (0.75–1.45)1141.23 (0.99–1.50)1.11 (0.80–1.57)2561.32 (1.15–1.52)1.07 (0.85–1.34)Non–APL AML**US–Born1694.37 (3.66–5.18)1.00 (reference)1473.16 (2.65–3.73)1.00 (reference)3163.64 (3.22–4.10)1.00 (reference)Foreign-Born2243.95 (3.34–4.63)0.90 (0.71–1.15)1892.72 (2.31–3.17)0.86 (0.68–1.09)4133.21 (2.86–3.58)0.88 (0.75–1.04)APL**US–Born12******210.29 (0.17–0.47)1.00 (reference)330.23 (0.15–400.34)1.00 (reference)Foreign-Born400.41 (0.27–0.59)***420.42 (0.30–0.59)1.44 (0.78–2.72)820.41 (0.32–0.53)1.79 (1.11–2.94)□Age-adjusted incidence rates (per 100,000 person-years) of acute leukemias and incidence rate ratios (IRR) by race/ethnicity among non-Hispanic Whites and Hispanics age 3 20 in California, 2000–2009*Standardized to the 2000 US population age standard**Age-adjusted incidence rates (per 100,000 person-years) of hematological malignancies and incidence rate ratios by nativity among Hispanics >/= 20 in California, 2000–2004***Insufficient case counts to calculate rate Disclosures:No relevant conflicts of interest to declare.

Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008.

With the introduction of all-trans retinoic acid and arsenic trioxide, the management of acute promyelocytic leukemia (APL) has changed dramatically. We performed a population-based study of APL in the United States to determine its incidence and relative survival (RS) during a 34-year period. We identified 1397 patients diagnosed with APL between 1975 and 2008 in the Surveillance, Epidemiology, and End Results database. Patients were categorized into 4 age groups and 3 calendar periods. As a comparison, we also reviewed the outcome of APL patients treated at our institution during approximately the same time interval. The incidences of APL increased with time period and patient age. Short- and long-term RS improved with each calendar period, with the greatest improvement occurring between 1991 and 1999; 5-year RS rates were 0.18 for patients diagnosed in 1975-1990, 0.52 in 1991-1999, and 0.64 in 2000-2008. Age was an important predictor of survival. For example, the 5-year RS rate in patients diagnosed in 2000-2008 was 0.38 for patients aged ≥ 60 years and 0.73 and 0.75 for patients aged <20 years and 20-39 years, respectively. Similar treads of improvements in the survival were observed in APL patients treated at our institution. The incidence of APL has increased, especially in the last decade. Clinical outcome improved remarkably in patients with APL diagnosed from 1991 to 1999, mainly because of the increased use of all-trans retinoic acid.