Copy number variants signature in two patients with relapsed acute promyelocytic leukemia.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23207-e23207
Author(s):  
Jacopo Nanni ◽  
Giovanni Marconi ◽  
Maria Chiara Fontana ◽  
Cristina Papayannidis ◽  
Silvia Lo Monaco ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Receptor Binding ◽  
Copy Number ◽  
Promyelocytic Leukemia ◽  
High Rate ◽  
Molecular Characteristics ◽  
Beta Catenin ◽  
Nucleotide Polymorphisms ◽  
Copy Number Alterations

e23207 Background: Nowadays, Acute Promyelocytic Leukemia (APL) is a disease entity with a very high rate of cure and an estimated 2-year overall survival of 97%. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure, and relapse is a very rare occurrence. Methods : We collected data of all the APL referred to our institution from 2014. Within 23 patients, we encountered 20 new diagnosis and 2 relapse of APL. We analyzed blasts in samples obtained from Bone Marrow with Single Nucleotide Polymorphisms Array Cytoscan HD. Results: We compared copy number alterations in both relapsed patients with alterations detected in the pool of 20 newly diagnosed APL and we found specific signatures of CNVs for each patient. There were several copy number alterations related to each patient: the first patient presented gain of ROBO2, GRIP1, CTNNB1, SOX6, PBX1, GRIK2, CDKAL1 and loss FAF1, CREBBP, SBF1; the second patient presented gain of ROBO1, MAPK10, CADPS2, APBA1 and loss of GRIP1 and MYB. Subsequently we focused our attention on ROBO and GRIP1genes because they were alterated in both relapsed patients: ROBO proteins are associated to K channels while GRIP1 is involved in various critical functions, for example in androgen receptor binding, beta-catenin binding, glucocorticoid receptor binding, and it is also a regulator of glutamate metabolism, a well-known pathway in Leukemic Stem Cells. Conclusions: APL relapse is a very rare entity, and it is announced to become rarer with the advances in first line therapy. Molecular characteristics are hard to analyze without an effort to collect and bank samples together from multiple institutions. Since relapses, especially relapses out of follow-up period, represent a sudden life-treating condition for patients, to predict patients at higher risk of relapse we selected two candidate genes that could be involved in pathways favoring relapse. By the analysis of ROBO 1-2 and GRIP1 at the diagnosis of APL we could establish a different and strict follow-up program for patients with these alterations. Acknowledgement: ELN,AIL,AIRC,prog. Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project,HARMONY.

High Density SNP Array Analysis of Acute Promyelocytic Leukemia (APL) Detects New Common Genomic Copy Number Alterations as Possible Cooperating Lesions

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2721-2721
Author(s):  
Daniel Nowak ◽  
Marion Klaumuenzer ◽  
Benjamin Hanfstein ◽  
Maximilian Mossner ◽  
Florian Nolte ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Promyelocytic Leukemia ◽  
Copy Number ◽  
Genomic Dna ◽  
Snp Array ◽  
Promyelocytic Leukemia ◽  
High Density ◽  
Copy Number Alterations ◽  
Array Analysis ◽  
Snp Array Analysis

Abstract Abstract 2721 Introduction: Acute Promyelocytic Leukemia (APL) is characterized by the typical chromosomal translocation t(15;17)(q22;q21) leading to the fusion product PML-RARA, which blocks granulocytic differentiation in the promyelocyte stage. Several experimental in vitro and in vivo studies have demonstrated that PML-RARA is necessary but not sufficient for the generation of APL. This circumstance has motivated the search for additional leukemogenic and cooperating molecular lesions. Patients and Methods: We have analyzed 101 APL patient bone marrow samples with high density Genome-Wide Human SNP 6.0 arrays, which interrogate >900.000 SNPs and >900.000 non-polymorphic copy number markers throughout the genome (Affymetrix, Santa Clara, CA, USA) in search for copy number alterations (CNAs) potentially relevant in the pathogenesis of APL. Genomic DNA from samples at initial diagnosis of 94 patients was analyzed. Furthermore, DNA from 11 samples at relapse was available, whereby 4 of these relapse samples also had paired DNA from initial diagnosis. Data analysis was carried out with the CNAG 3.3 software using anonymous references. For exclusion of copy number polymorphisms, all detected CNAs were compared with the databases of known copy number polymorphisms in the UCSC genome browser. For data validation, putatively acquired CNAs and regions of copy number neutral loss of heterozygosity (CNLOH) were confirmed by hybridization of DNA from paired normal samples when the patients were in remission, by quantitative real time PCR of genomic DNA and by direct sequencing of informative SNPs. Results: The high density SNP array analysis detected a total of 120 heterozygous deletions, 97 duplications or amplifications and 7 regions of telomeric CNLOH leading to an average of 2.3 CNAs per sample (range 0–30). The most common numerical and large structural aberrations were found on chromosome (chr.) 8 with either trisomy 8 (n=11) or duplication of regions on chr. 8q (n=10) followed by heterozygous deletions of chr. 7q (n=5) and chr. 16q (n=5). Furthermore, unbalanced translocations of chr. 15 and 17 involving PML and RARalpha were detected in five cases leading to duplication of the PML-RARA fusion or deletion of genomic regions flanking either PML or RARalpha. Recurrent microlesions (<1Mbp) were found in several regions as heterozygous deletions on chr. 1q31.3 containing the micro RNAs MIR181B1 and MIR181A1 (n=5), on chr. 2q32.3 containing serine/threonine kinase 17b (STK17B) (n=5) or chr. 3p24.3 containing ankyrin repeat domain 28 (ANKRD28) (n=5). One recurrent region of telomeric CNLOH was found on chr. 19q in two samples. Of note, besides the few regions of telomeric CNLOH a large number of intrachromosomal CNLOH regions (n=265) was identified, with recurrent regions on chr. 6p21.1 (n=10) or chr. 5q23.3-5q31.1 (n=6) containing genes relevant in hematopoiesis such as IL3, CSF2 or DNA damage repair such as RAD50. Although these CNLOH regions were not somatically acquired they may possibly harbor genetic predispositions for disease. Conclusions: We describe a detailed high density SNP array genomic profiling of bone marrow DNA from patients with APL, which has led to the identification of several new cryptic recurrent genomic lesions. These genomic alterations point to candidate genes, which could be cooperating factors in addition to PML-RARA. Therefore, our data helps to provide a better understanding of the molecular mechanisms underlying the development of APL. Disclosures: Kohlmann: MLL Munich Leukemia Laboratory: Employment. Lengfelder:Cephalon: Research Funding.

Studies on Treatment of Acute Promyelocytic Leukemia With Arsenic Trioxide: Remission Induction, Follow-Up, and Molecular Monitoring in 11 Newly Diagnosed and 47 Relapsed Acute Promyelocytic Leukemia Patients

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3315-3324 ◽  
Author(s):  
Chao Niu ◽  
Hua Yan ◽  
Ting Yu ◽  
Hui-Ping Sun ◽  
Jian-Xiang Liu ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Pcr Analysis ◽  
Remission Induction ◽  
Newly Diagnosed ◽  
First Choice ◽  
Wbc Count

Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RAR fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RAR expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 × 109/L at relapse had better survival than those with WBC count over 10 × 109/L (P = .038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P = .01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.

DNA copy number alterations, gene expression changes and disease-free survival in patients with colorectal cancer: a 10 year follow-up

2016 ◽  
Vol 39 (6) ◽  
pp. 545-558 ◽  
Author(s):  
Elisabetta Bigagli ◽  
Carlotta De Filippo ◽  
Cinzia Castagnini ◽  
Simona Toti ◽  
Francesco Acquadro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Copy Number ◽  
Disease Free Survival ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Free Survival ◽  
Dna Copy Number Alterations ◽  
Disease Free

scholarly journals Early Detection of t(8;21) Chromosomal Translocations during Treatment of PML-RARA Positive Acute Promyelocytic Leukemia: A Case Study

2010 ◽  
Vol 4 ◽  
pp. CMO.S6446 ◽  
Author(s):  
Walter Kleine Neto ◽  
Mariana Serpa ◽  
Sabri Saeed Sanabani ◽  
Patricia Torres Bueno ◽  
Elvira Deolinda Rodrigues Pereira Velloso ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Genetic Screening ◽  
Treatment Initiation ◽  
Single Case ◽  
Promyelocytic Leukemia ◽  
Chromosomal Translocations ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Here we describe a female patient who developed acute promyelocytic leukemia (APL) characterized by t(l5;17) translocation at diagnosis. The patient began treatment with all-trans retinoic acid (ATRA) + chemotherapy. During follow up, the patient was found to be negative for the t(15;17) transcript after 3 months of therapy which remained undetectable, thereafter. However, the emergence of a small clone with a t(8;21) abnormality was observed in the bone marrow and peripheral blood (PB) cells between 3 and 18 months following treatment initiation. The abnormal translocation observed in PB cells obtained at 3 months was detected after the second cycle of consolidation therapy and reappeared at 15 months during maintenance treatment, a period without ATRA. Although based on a single case, we conclude that genetic screening of multiple translocations in AML patients should be requested to allow early identification of other emerging clones during therapy that may manifest clinically following treatment.

Risk-Adapted Treatment of Acute Promyelocytic Leukemia: Updated Results of the Spanish PETHEMA LPA99 Trial Using ATRA and Anthracycline Monochemotherapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 590-590 ◽  
Author(s):  
Miguel A. Sanz ◽  
Pau Montesinos ◽  
Edo Vellenga ◽  
Chelo Rayon ◽  
Ricardo Parody ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Consolidation Therapy ◽  
Number Of Patients ◽  
Risk Patients ◽  
Low Toxicity ◽  
High Degree

Abstract Background: A first report of the PETHEMA LPA99 trial in acute promyelocytic leukemia (APL) showed that a risk-adapted treatment strategy combining ATRA and anthracycline alone for induction and consolidation results in high antileukemic efficacy and low toxicity. We report here an updated analysis of this trial including a significantly higher number of patients and longer follow-up. Methods: From November 1999 to July 2005, 564 patients (median age 40 years, range 2–83) with APL received induction with ATRA (45 mg/m2/d) until CR and idarubicin (12 mg/m2/d) on days 2, 4, 6 and 8. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: “low-risk” patients (WBC <10×109/l and platelets >40×109/l), idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); “intermediate-risk “ (WBC <10×109/l and platelet <40×109/l) and “high-risk” (WBC >10×109/l) patients received ATRA (45 mg/m2/d × 15) in combination with reinforced chemotherapy (Idarubicin 7 mg/m2/d in the course #1 and two days instead of one in the course #3). Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 45 mg/m2/d ATRA for 15 days every 3 months. Results: CR was achieved in 511 patients (91%). Except for three cases labelled as resistant, of the remaining 50 patients 56%, 24%, 16% and 4% died due to hemorrhage, infection, retinoic acid syndrome, and acute myocardial infarction, respectively. Multivariate analysis showed that WBC >10×109/l, age >60 years, male gender, and serum creatinine >1.4 mg/dl at presentation had independent predictive value of death during induction. The median follow-up of the cohort was 57 months (range 20–94 months). Thirteen patients (median age 72 years, range 4–81) died in remission and 99% of patients completed the entire assigned therapy. Thirty-six patients presented haematological relapse, 16 molecular relapse, and 8 secondary myelodysplastic syndrome or acute myeloid leukemia. Overall, the 5-year cumulative incidence of relapse (CIR), disease-free survival, and overall survival were 11%, 85%, and 84%, respectively. The 5-year CIR for low-, intermediate- and high-risk patients were 4%, 7% and 28%, respectively. Conclusions: A risk-adapted strategy combining ATRA and anthracycline monochemotherapy for induction and consolidation therapy results in high antileukemic efficacy, low toxicity and a high degree of compliance in newly diagnosed APL.

Treatment of Relapsed Acute Promyelocytic Leukemia with Oral Arsenic Trioxide: An Eleven-Year Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2958-2958
Author(s):  
Wing-Yan Au ◽  
Sidney Tam ◽  
Anskar Y.H. Leung ◽  
Eric Tse ◽  
Cyrus Kumana ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Maintenance Treatment ◽  
Histone Deacetylase Inhibitors ◽  
Significant Proportion ◽  
Gemtuzumab Ozogamicin ◽  
Promyelocytic Leukemia ◽  
Hematopoietic Stem

Abstract Background. For patients with relapsed acute promyelocytic leukemia (APL), the optimal therapy after arsenic trioxide (As2O3)-induced complete remission (CR) is unclear. Autologous or allogeneic hematopoietic stem cell transplantation (HSCT) has been advocated. These strategies are associated with morbidity and considerable mortality, and not all patients are eligible. The role of maintenance therapy with As2O3 remains undefined. Materials and methods. From 1997–2008, 50 consecutive APL patients (25 men, 25 women, median age: 35 (12–72) years) in relapse (R1, n=47; R2, n=3) were treated with As2O3 until CR. This was followed by idarubicin consolidation (6 mg/m2/day × 9) in 43 patients. Seventeen patients did not receive maintenance treatment. Thirty-two patients received oral-As2O3 maintenance (10 mg/day × 14 every 2 months). All-trans retinoic acid (ATRA, 45 mg/m2/day) maintenance was used together with oral-As2O3 in 27 patients. As2O3 protocol was approved by the institutional review board at Queen Mary Hospital. All maintenance treatment was given in the outpatient clinic as oral medication. Results. Of 50 relapsed cases, As2O3-induced CR was achieved in 49 patients, 1 patient dying of pneumonia. At a median follow-up of 61 (6–122) months, 27 patients (19 with and 8 without As2O3 maintenance) had remained in remission. Further relapses (R2, n=20; R3, n=2.) occurred in 22 patients (13 with and 9 without As2O3 maintenance), at a median of 16 (6–28) months. Concomitant central nervous system (CNS) relapse occurred in 8 cases. Treatment of post-As2O3 relapses included oral-As2O3 (10 mg/day) + ATRA (45 mg/m2/day) with (n=10) or without (n=10) ascorbic acid (1 gm/day) until CR, and then maintenance with As2O3 + ATRA +/− ascorbic acid. Leucocytosis during treatment was controlled with mitoxantrone. In these 22 cases of post-As2O3 relapses, further remission was still achieved in 19 patients (CR3, n=18; CR4, n=1), with 3 patients dying from cerebral bleeding. At a median follow-up of 88 (8–98) months, 8 patients had remained in remission. Further relapses occurred in 11 patients. Salvage therapy consisted of As2O3+ATRA+ascorbic acid, together with chemotherapy (mitoxantrone, n=8; amascrine, n=3), gemtuzumab ozogamicin (n=4), and autologous HSCT (n=1). Eight patients finally died of refractory leukemia after a median of 6 (2–33) months. Three patients had remained in remission (CR4, n=2, CR5 n=1) at a median of 41 (26–102) months. On an intention-totreat basis, our oral-As2O3 treatment/maintenance regimen for patients with relapsed APL resulted in a 4-year overall survival of 71%, and event-free-survival of 53%. Conclusion. Our findings showed that an oral-As2O3-based treatment/maintenance strategy resulted in durable remission in a significant proportion of patients with relapsed APL. As most of the treatment is administered at home, this regimen involves much less financial, personnel and emotional costs as compared with HSCT strategies. Further improvement should be directed towards prevention of CNS relapses with appropriate prophylaxis in high-risk patients. For remissions at or beyond CR3, consideration of HSC harvest and storage at molecular remission should be considered. The use of demethylation agents and histone deacetylase inhibitors in combination with As2O3 remains to be investigated.

Single Agent Arsenic Trioxide Regimen for the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia: Initial Results of a Multicenter Randomized Controlled Study From India to Study the Optimal Duration of Arsenic Trioxide Maintenance Therapy (IAPLSG04).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2082-2082 ◽  
Author(s):  
Vikram Mathews ◽  
Biju George ◽  
Farah Jijina ◽  
Cecil Ross ◽  
Reena Nair ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Single Agent ◽  
Promyelocytic Leukemia ◽  
Controlled Study ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Short Period

Abstract Abstract 2082 Poster Board II-59 Single agent arsenic trioxide (ATO) has proven efficacy in the management of newly diagnosed cases of acute promyelocytic leukemia (APL). To validate findings of an initial single center experience (Blood 2006:107; 2627) with this low cost, well tolerated, effective regimen, a multicenter study was undertaken in a resource constrained environment. Additionally, in an effort to improve on the earlier experience and study the role of duration of maintenance on reducing late relapses, patients were randomized to 6 vs. 12 months of ATO maintenance (ClinicalTrials.gov Identifier:NCT00517712). From July, 2004 to December, 2008, 182 patients were initially screened and enrolled based on morphological diagnosis of APL from 7 centers in India. Diagnosis was subsequently confirmed by molecular methods. Twenty seven cases were excluded from analysis (6 RT-PCR negative, 4 IC bleed at diagnosis, 5 septic/pneumonia at diagnosis, 9 withdrew consent prior to randomization and some were treated with other protocols, 1 withdrawn by investigator prior to randomization). Patients were treated with single agent ATO at standard doses (10mg/day for adults and 0.15mg/kg/day for pediatric patients) for up to 60 days in induction; this was followed by a 28 day consolidation after a 4 week break. Four weeks after completion of consolidation patients who were in molecular remission were randomized to 6 vs. 12 months of maintenance therapy with ATO administered for 10 days/month. Hydroxyurea was permitted for control of leucocytosis. Anthracyclines were permitted in induction for patients presenting with or WBC count rising >20×109/L in the first week, >50×109/L in the second week and for those who developed a differentiation syndrome. Of the 155 patients who could be evaluated 136 (87.7%) achieved hematological remission (CHR). One patient had primary induction failure and was removed from the study while the other 18 were induction deaths at a median of 17 days (range: 4 – 69). During induction, 52 (33.5%) patients received an anthracycline and 116 (75%) received hydroxyurea. A differentiation syndrome was documented in 25 (16%) cases and was fatal in one. Grade III/IV non hematological toxicity was seen in 26 (16.7%), which resolved in the majority after discontinuing ATO for a short period. One hundred and thirty six patients were randomized, 64 (47%) and 72 (53%) into a 6 and 12 month maintenance regimen respectively. A protocol change after randomization was done in 3 cases for persistent toxicity. Five (3.6%) patients did not complete the scheduled maintenance regimen due to poor compliance or was discontinued by the investigator. At a median follow up of 24 months, the 3-year Kaplan-Meir estimate of overall survival (OS), event free survival (EFS) and disease free survival (DFS) of the entire cohort was 76.87±4.33%, 71.57±4.64% and 80.69±4.77% respectively. Fourteen patients relapsed, the median time to relapse was 19.3 months (range: 9-51). The baseline characteristics of the two groups (6vs12 months) were not significantly different. Post randomization, the two groups were analyzed on an intention to treat basis. The OS, EFS and DFS of the two groups were not statistically significantly different. There was also no evidence that the group that received 12 months of maintenance had any increased incidence of toxicity. Single agent ATO based regimen as reported previously is well tolerated and results in durable remissions. Longer follow up is required to see if 12 months of maintenance therapy reduces risk of late relapses. Disclosures: No relevant conflicts of interest to declare.

Incidence and Clinical Features of Acute Promyelocytic Leukemia In a Population-Based Canadian Cohort

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4374-4374 ◽  
Author(s):  
Kristjan Paulson ◽  
David Szwajcer ◽  
Arshad Ahsanuddin ◽  
Pascal Lambert ◽  
Donna Turner ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Fusion Gene ◽  
Clinical Care ◽  
Epidemiological Data ◽  
The United States ◽  
Population Based ◽  
Promyelocytic Leukemia ◽  
High Rate ◽  
Cns Disease ◽  
Rare Malignancy

Abstract Abstract 4374 Introduction: Acute promyelocytic leukemia (APL) is a rare malignancy whose causes and epidemiology are not well known. The incidence of APL in the United States was estimated to be 0.22 cases per 100,000 population, and a higher incidence has been suggested in specific geographic or ethnic sub-groups. However, clinical and epidemiological data on APL arise primarily from clinical trials and single centre experiences rather than population-based data, which may lead to selection bias. We studied a cohort of APL cases in a well defined population using the diagnostic gold standard of polymerase chain reaction (PCR) testing. Methods: The Canadian province of Manitoba, with a population of 1.2 million, has a single referral centre for the definitive diagnosis and clinical care of all acute leukemia patients. Only one laboratory is capable of performing PCR based testing for the PML-RARA fusion gene product. We examined consecutively diagnosed patients with APL based on PCR testing from January 1999 until July 31 2010 in order to determine the incidence, clinical characteristics, and outcomes of patients with APL. Results: Over the 11.5 year period of observation, 24 patients were diagnosed with APL. Based on the 2006 Canadian census, the annual incidence of APL in Manitoba is thus 0.18/100,000 population. These cases did not appear to be distributed evenly, with an average of 1.1 cases diagnosed annually between 2002 and 2008 compared to six cases diagnosed in the most recent period between 2009 and 2010 (relative to 2002–2008, incident rate ratio (IRR) 2.61, p = 0.075) and ten cases diagnosed between 1999 and 2001 (IRR 2.94, p = 0.023). Symptomatic CNS disease at diagnosis was present in 3 (12.5%) patients. Thirteen patients developed differentiation syndrome during the course of their therapy (54.1%). In all but one patient, ATRA was able to be successfully resumed. Ten patients presented with DIC (41.7%). Conclusions: In this population-based study, we noted episodic clustering of new cases and a relatively high proportion of CNS disease at diagnosis. While these observations may be due to normal fluctuations in the patterns a rare disease, this could also suggest an underlying environmental trigger. Additional investigation is required to confirm or refute this hypothesis, due to the relatively small numbers in this cohort. The high rate of CNS disease suggests that this finding maybe more common than previously thought. As the pathogenesis of APL remains unclear, these observations deserve additional epidemiological investigation in larger cohorts. Disclosures: Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees.

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