Acute Promyelocytic Leukemia Pts Research Articles

Characterization of Comparative Clinical Outcomes and Molecular Features of Black Patients with Acute Promyelocytic Leukemia (APL) Reveals Similar Survival and Distinct Genomic Profiles

Introduction: Although APL, a subtype of acute myeloid leukemia (AML), is an aggressive disease, its treatment was revolutionized with combination all- trans retinoic acid (ATRA) and arsenic trioxide (ATO), making APL a highly curable malignancy. Molecularly, APL is characterized by t(15;17) resulting in PML:: RARA gene fusion as disease-initiating event and by several recurrent gene mutations (eg, FLT3) identified in previous studies. In AML, prior studies have established inferior overall survival (OS) of Black versus White AML patients (pts) in both population-based analyses and clinical trials, found a negative prognostic impact of higher social deprivation (SDI), and characterized differences in frequencies and impact of disease-associated gene mutations. Herein, we compared OS of Black and White APL pts and evaluated genomic landscape of Black pts, which has not been comprehensively assessed to date. Methods: For nationwide population analysis, 2 sets of cancer registries were included in the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 829 adults diagnosed with de novo APL (confirmed by cytogenetic and/or molecular findings) in 1995-2019. To assess survival in the setting of clinical trials, we analyzed 249 pts treated on historic frontline Cancer and Leukemia Group B (CALGB)/Alliance for Clinical Trials in Oncology (Alliance) trials with or without inclusion of ATRA (CALGB 9191, 1992-1995; CALGB 9710, 1999-2005). For Alliance pts, neighborhood SDI was assigned based on pt-reported residence zip code and classified as low (1-25, n=33) or high deprivation (26-100, n=95). OS was analyzed separately for pts diagnosed before and after 2012 to account for treatment advances with ATRA/ATO. To assess molecular features, we performed integrated genomic profiling (paired tumor/normal whole-exome and transcriptome sequencing) on 31 Black APL Alliance pts (9/31 completed, with complete results to be presented at the Annual Meeting). Results: On a population level using SEER data, 3-year (3y) OS significantly improved from 65% for cases diagnosed in 1995-2012 to 75% in those diagnosed after 2012 (p=<0.001), concordant with ATRA/ATO use. Notably, OS of Black and White pts did not differ significantly before or after 2012. This held true in race-specific findings for median household income, Yost index and urban/rural status; none of which significantly associated with OS. Older age was the only parameter associated with OS (3y rates, 1995-2012: <40y, 79%; 40-59y, 71%; ≥60y, 44%; and 2012-2019: <40y, 92%; 40-59y, 80%; ≥60y, 56%). Again, OS of Black and White pts did not differ within age groups. Likewise, OS of Black and White APL pts treated in a relatively controlled setting of clinical trials was not significantly different. As in population-based findings, OS improved over time and with ATRA addition (3y OS rates, 1992-1995, 66%; 1999-2005, 85%), and older age was a strong negative OS predictor (p<0.001). When comparing OS of pts treated on clinical trials with population-based OS, trial pts had a longer 3y OS (84% vs 64%, p<0.001). Notably, pts with SDI >25 (n=95) had a worse OS than pts with SDI <25 (n=33, p=0.03). On a molecular level, preliminary results of whole-exome sequencing (finalized for 9/31 Black pts) showed frequent mutations in FLT3 (5/9 pts), a known APL-associated event, but also revealed several recurrent gene mutations not reported in prior APL sequencing efforts, which were almost exclusively based on White pts, including mutations in DPP6, GOLA6L, NLGN2 and SP8 (found in ≥2 pts). Intriguingly, CALR mutations were found in 3/9 pts. Mutations in FLT3 and CALR were mutually exclusive and found in 8/9 pts, with the remaining pt harboring a SORBS2 mutation. Conclusions: In contrast to most cancer types, including AML, there was no OS disparity with respect to race in APL pts, both in population-based analyses and in the setting of historic clinical trials. Older age and residence with high SDI (>25) were negative OS predictors. Molecularly, our pilot data reveal existence of ancestry-associated differences in driver mutations, suggesting that FLT3 and CALR mutations represent necessary proliferative signals in addition to PML:: RARA-driven differentiation arrest. Support: U10CA180821, U10CA180882, U24CA196171; Clinicaltrials.gov IDs: NCT00048958, NCT00899223, NCT00900224; https://acknowledgments.alliancefound.org

A Comparison of Outcomes in Patients with Secondary Acute Promyelocytic Leukemia (APL) and De Novo APL - a Case-Match Retrospective Analysis of Polish Adult Leukemia Group (PALG)

Introduction Acute promyelocytic leukemia (APL) is a very rare subtype of acute myeloid leukemia. APL might develop de novo or secondary after previous exposure to genotoxic agents or immunosuppression (sAPL). The data regarding sAPL is limited. The prognosis of sAPL patients (pts) and also the presence of any additional prognostic markers as compared to de novo APL, as well as the therapeutic approach still remain unclear. Here we present a case-matched analysis of sAPL diagnosed and treated according to the Polish Adult Leukemia Group/Programa Español de Tratamientos en Hematología (PALG/PETHEMA) protocols, compared with de novo APL. Methods The PALG's database of APL pts from 2006 to 2022 was screened and the cases of sAPL were selected. sAPL pts were matched based on sex, age, time of diagnosis, and treatment protocol with de novo APL pts from the same database. A variety of baseline variables as well as treatment outcomes were compared using U-Mann-Whitney, Chi2, Fisher tests, and Cox models. Results Out of 404 pts in the database, we found 27 pts with sAPL (6.7%), and 18 pts were female (66.6%). The median (Me) age in sAPL group was 58yo (range: 19-70yo). All reported cases of sAPL have developed after previous exposure to chemo- and/or radiotherapy. In 26 (96%) pts sAPL was proceeded with neoplasm treatment and in one (4%) multiple sclerosis therapy. The most often sAPL was diagnosed after treatment of breast cancer (29.6%), followed by therapy for kidney, colon, testis, lung, laryngeal, endometrial, ovarian cancers, and as well as Hodgkin lymphoma, B-acute lymphoblastic leukemia, liposarcoma, Merkel cell tumor, and GIST. In the analysis after pairs matching, we did not find any differences between sAPL and de novo APL regarding the ECOG performance status (p=0.29), WBC (Me 2.4G/L vs. 1.8G/L; p=0.52), coagulopathy described as a platelet counts (Me 24.5G/L vs. 37G/L, p=0.14), fibrinogen concentration (Me 1.0g/l vs. 1.4g/l, p=0.27) and d-dimers (Me 35.2ng/ml vs. 13.8ng/ml, p=0.23). We also did not observe any differences in additional cytogenetic abnormalities (p=0.13) between the examined groups. The frequency of FLT3-ITD expression in sAPL and de novo APL was 28.6% vs. 26.7%, respectively, (p=1.0), and FLT3-TKD expressions was 50% vs. 0%, respectively (p=0.43), however only a small number of pts had assessed FLT-TKD status (n=7 in both groups). The Me overall survival (OS) for the whole group was not reached. The Me OS for sAPL was 156 months (95%CI 26.9-156) and for de novo APL was not reached (p=0.29) (Figure 1A). In the univariate analysis, shorter OS was influenced by a high-risk group according to Sanz Score (HR 3.0, 95%CI 1.1-8; p<0.03), and ECOG 3 or 4 performance status at diagnosis (HR 11.52, 95%CI 3.8-34.9; p=<0.001). In the multivariate analysis shorter OS was associated with the presence of additional cytogenetic abnormalities other than t(15;17) (HR 16.8, 95%CI 2.7-103; p=0.002), older age (continuous variable) (HR 1.1, 95%CI 1-1.1; p=0.02) and lower platelets count (continuous variable) (HR 0.96, 95%CI 0.93-1.0; p=0.03). The relapse rate was not significantly higher in sAPL 19% (n=5) vs. de novo APL 3.7% (n=1)(p=0.2). The Me relapse-free survival (RFS) was not reached for the whole group. The Me RFS was 97.4 months (95%CI 26.3-97.4) in sAPL pts vs. not reached in de novo APL (p=0.31) (Figure 1B). Shorter RFS in the univariate analysis was affected by ECOG 3 or 4 at diagnosis and a high-risk group of Sanz Score (HR 8.6, 95%CI 3.1-23.8; p<0.001 and HR 4.3, 95%CI 1.6-10.8; p=0.002, respectively). In the multivariate analysis older age (continuous variable) (HR 1.1, 95%CI 1.0-1.1; p=0.03), lower platelets count (continuous variable) (HR 0.97, 95%CI 0.95-0.99; p=0.03) and additional cytogenetic abnormalities other than t(15;17) (HR 19.8, 95%CI 3.5-113.9; p=0.0008) negatively influenced RFS. sAPL diagnosis affected neither OS nor RFS. There are some limitations of our analysis, which include a low number of patients with sAPL and a lack of prospective data. Conclusions The results of this case-matched study are in line with the previous suggestions that outcomes of pts with sAPL may be similar to those with the disease de novo. We also conclude that there is no difference in the clinical and biological presentation of sAPL and de novo APL at the time of diagnosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival Among Acute Myeloid Leukemia Patients Conditional on Years Already Survived and Relative to the General Population in the United States

Background: Prognostic models for AML patients (pts) predict outcomes based on clinical and cytogenetic features at diagnosis. However, as a pt lives beyond the initial date of diagnosis following treatment, his/her estimated survival period improves and these models lose accuracy. Conditional survival (CS) probability estimations use the time a pt has survived since diagnosis to improve on prognostic accuracy and provide personalized survival information. Here we report population-level, 5-yr relative cancer survival probabilities of AML pts conditional on having already survived ≥1 yr(s) after diagnosis.Methods: A total of 13,933 adult AML cases diagnosed during 2000-2009, and followed through 2014 were assembled from all 18 registries of the Surveillance, Epidemiology and End Results (SEER). Pts who did not receive chemotherapy in the first 3 months after diagnosis were excluded. Survival probabilities were calculated using the SEER Survival System (SEER*Stat). We calculated relative survival (RS) probability estimates that compare survival in the pt cohort relative to the expected survival of the general population (matched for age, sex, race and calendar period over a standard follow-up time). Trends in 5-year RS estimates conditional on already having survived 0-5 years from diagnosis were modeled using regression modeling. Estimates were adjusted for age group [adolescents and young adults (AYA) (18-39 yrs); middle-aged (40-59 yrs) and elderly (> 60 yrs)], yr of diagnosis, years already survived (YAS), sex and race. We performed subset analyses for AML categories with adequate sample size for analysis in SEER - AML with myelodysplasia (MDS)-related changes or AML-MRC (n = 794), core-binding factor (CBF) AML (n = 462) and acute promyelocytic leukemia (APL) (n = 1499). Tests of significance were based on two-sided hypothesis at the .05 level. Analyses were performed using STATA.Results: Figure 1A shows survival of all AML pts relative to the expected survival of the general population by age groups. At 10 yrs after diagnosis, the RS probabilities of AML (all categories) was 50% for AYA, 35% for middle-aged and 10% for elderly cohort. When conditioned on YAS, the estimated 5-year RS probabilities of AML pts consistently improved with successive yrs as shown in Figure 1B. Figures 2A-2C show RS probability estimates for specific AML categories by age subgroups - 10-yr RS was highest for APL [80% - AYA, 70% - middle-aged, 50% - elderly] as expected but surprisingly lower than expected in CBF-AML [65% in AYA group, 50% in middle-aged and 30% in elderly]. Figures 2D-2F illustrate the influence of AML categories and advancing age on CS estimates. The estimated 5-yr RS probabilities when conditioned on successive YAS increased for all age groups and for each AML category. The 5-yr relative CS was highest in APL pts among all AML categories and almost reached 100% for all three age groups, thereby approximating survival of the general population. Pts with CBF-AML had high 5-yr relative CS probabilities of 90% in all age groups, consistent with their favorable prognosis. The 5-yr conditional RS probability for AML-MRC exceeded 90% and 80% for AYA and middle-aged groups, respectively but reached only 60% in the older cohort. AML-MRC is considered a biologically heterogeneous disease and this finding suggests a biologically aggressive course in older patients. In multivariable analyses, the 5-yr RS estimates were significantly lower in > 60 yrs cohort (vs. 18-39 yrs, 36.09% drop (95% CI, 35.81-36.09)] but better in females (vs. males, 5.07% improvement (95% CI, 4.89-5.25), with YAS [conditioned on 1 to 5 YAS, 5-yr RS improved from 19.92% (95% CI, 15.03-24.81) to 53.77% (95% CI, 49.55-57.98)] and in recent treatment period [2006-2009 vs, 2002-2005, 9.07% improvement (95% CI, 8.93-9.21).Conclusions: Following treatment completion, survival prognosis in AML can be further refined using a population-derived, 5-yr CS estimates based on YAS. While CBF-AML is often considered “favorable-risk” AML, long-term RS probabilities belied this, with unexpectedly lower survival probabilities (~30-65% at 10 yrs). This data suggests the need for a longer period of leukemia surveillance following treatment completion. RS and CS information can be applied clinically at the individual level and can be used in the design of clinical trials to determine appropriate length of follow up. [Display omitted] DisclosuresAdvani:Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Gerds:CTI BioPharma: Consultancy; Incyte: Consultancy. Majhail:Anthem, Inc.: Consultancy; Sanofi: Honoraria. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia

Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia

Characteristics and Outcome of Older Patients with Acute Promyelocytic Leukemia Front-Line Treated with or without Arsenic Trioxide — an International Collaborative Study

Background: Characteristics and outcome of older patients (pts) with acute promyelocytic leukemia (APL) are unclear due to lack of clinical data.Aims: To describe a large series of older APL pts and compare outcome according to treatment strategy.Methods: We retrospectively studied 475 APL pts (median age, 73.8 yrs; range, 70-90.3 yrs), treated between 1990 and 2018 within four study groups/institutions of the US and Europe (Acute Leukemia French Association, n=228; Programa Espanol de Tratamientos en Hematologia, n=211; Study Alliance Leukemia, n=28; Johns Hopkins School of Medicine, Baltimore, n=8). APL was confirmed either by cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction. For analysis, pts were grouped according to treatment: i) chemotherapy/all-trans retinoic acid (CTX/ATRA, n=260; consisting of daunorubicin/idarubicin and ATRA for induction and different CTXs+ATRA for consolidation), ii) ATO/ATRA±CTX, n=177 (according to Lo-Coco F, et al. NEJM, 2013, n=23 or CTX/ATO/ATRA, n=154), iii) less intensive therapy, n=26 (reduced CTX, n=2 or ATRA only, n=24) and iv) no treatment/unknown, n=12.Results: Median white blood cell (WBC) and platelet counts at diagnosis were 1.5/nl (range, 0.1-242/nl) and 37/nl (range, 2-261/nl), respectively. Two-hundred twenty-nine pts (48%) were female. Cytogenetic analysis was available in 408 pts and 85 (21%) had additional abnormalities. BCR3 was positive in 138 (44%) of 316 available pts. Only 15 (22%) of 69 tested pts were FLT3-ITD positive. One hundred (22%) of 464 pts had a WBC count >10/nl. Median WBC was significantly lower (P<0.001) in the ATO/ATRA±CTX group (1.2/nl) as compared to the CTX/ATRA (2.05/nl) or less intensive (2.8/nl) group. Median age was comparable in CTX/ATRA (73.5 yrs) and ATO/ATRA±CTX (73.6 yrs) but significantly higher (P<0.001) in the less intensive group (79.6 yrs). Median platelet counts were comparable (P=0.08) in the three groups (CTX/ATRA, 34.5/nl; ATO/ATRA±CTX, 41/nl; less intensive, 39/nl). Response data were available in 459 (97%) pts.Complete remission (CR) after induction therapy was achieved in 75% (194/259) of the CTX/ATRA group, in 93% (162/174) of the ATO/ATRA±CTX group, and in 50% (13/26) of the less intensive group. Two pts of the CTX/ATRA group and one patient after ATRA only were refractory. Early death rates were 24% (n=63) after CTX/ATRA, 7% (n=12) after ATO/ATRA±CTX and 46% (n=12) in the less intensive group. A logistic regression model revealed age above 75 yrs (odds ratio [OR], 0.53; P=0.02) higher WBC (OR, 0.35; P<0.001), less intensive treatment (OR, 0.46; P=0.08) and therapy with ATO/ATRA±CTX (OR, 4.2; P<0.001) as significant factors for achievement of a CR. Median follow-up was 4.7 yrs (95%-CI, 4.2-5.4 yrs) and 5-yrs overall survival (OS) 62% (95%-CI, 57-67%). Treatment with ATO/ATRA±CTX was associated with significantly higher 5-yrs relapse-free (RFS; 96% [95%-CI, 92-99%] vs. 88% [95%-CI, 83-93%]; P=0.007) and OS rates (78% [95%-CI, 72-85] vs. 58% [95%-CI, 52-65%]; P<0.001) as compared to CTX/ATRA. Of note, higher WBC count (>10/nl) was associated with an inferior RFS in CTX/ATRA (P<0.001), but not in ATO/ATRA±CTX (P=0.47). When restricting the analysis according to treatment period after the year 2000, ATO/ATRA±CTX was still associated with a significant better RFS (P=0.05) and OS (P<0.001) as compared to CTX/ATRA. Overall, only five pts relapsed after ATO/ATRA±CTX as compared to 33 after CTX/ATRA. As expected, higher WBC (>10/nl; hazard ratio [HR], 2.36; P<0.001), age >75 yrs (HR, 2.07; P<0.001) and therapy with ATO/ATRA±CTX (HR, 0.48; P<0.001) were significant factors for OS.Conclusions: The ATO-based regimen for first line treatment of elderly APL pts was associated with excellent and sustained response rates. Our data demonstrate the important potential of ATO/ATRA in the primary management of older APL pts. DisclosuresFenaux:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.

Targeting Antagonists of Retinoic Acid Signaling in Acute Myeloid Leukemia

Introduction: Retinoic acid (RA), the active metabolite of vitamin A, influences biological processes by activating the retinoic acid receptor (RAR). RARs are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate homeostasis of cellular growth. The success of RAR modulation in the treatment of acute promyelocytic leukemia (APL) particularly by the use of all-trans retinoic acid (ATRA) has stimulated considerable interest in the development of small molecules that can modulate RAR and RXR. Recent studies have demonstrated that RA can also activate the peroxisome proliferator-activated receptor β/δ (PPARβ/δ). In the aqueous intracellular milieu, RA is transported by the cellular retinoid-binding protein CRABP-II, or by the fatty-acid-binding protein FABP5, depending on the ratio of FABP5 to CRABP-II. In cells expressing high CRABP-II and low FABP5, RA activates the RAR, whereas in the presence of the reverse ratio, RA activates PPARβ/δ (Fig 1). These two different modes of RA delivery due to the different ratio of these two cargos leads to opposite cellular outcomes. Cells harboring high level of CRABP-II, RA is delivered to RAR leading to apoptosis, growth arrest, and anticancer activity. However, when FABP5 expression is high, RA is delivered to PPARβ/δ resulting in survival, proliferation, and tumor growth. In both cases, retinoid X receptor (RXR) is the indispensable partner of the nuclear receptor involved. Therefore, preventing FABP5 from such antagonism may be a novel therapeutic strategy for AML. Here we report the development of a therapeutic strategy based on a highly specific FABP5 inhibitor (iFABP5) (Fig 2) that will allow the delivery of RA by CRABP-II to activate tumor suppressor function of RAR and RXR. Methods: An iterative approach of design synthesis and activity were employed to select the most potent hit, iFABP5, for further experiments. Expression levels were analyzed by western blot analysis and qRT-PCR. Colony forming assays were used to analyze iFABP5 activity against AML cell lines. Flow cytometry based cell differentiation assay were performed to assess the efficacy of iFABP5 and ATRA combination treatment. Results: The analysis of TCGA data set revealed that a certain class of AML patients (pts) (Trisomy 8 AML) have low levels of CRABP-II and high levels of FABP5, presumably due to gene duplication, that in part explains the inability of ATRA to induce terminal differentiation in AML cells. To test our hypothesis, we screened AML and APL patient (pt) bone marrow cells and found that a number of AML pts bone marrow have high FABP5 and low CRABP-II protein levels while the ATRA responding APL pts has opposite ratio determined by western blotting. Therefore, low CRABP-II and high FABP5 levels in a subset of AML pts lead to the activation of pro-survival PPARβ/δ pathway that promotes proliferation and opposes the differentiation. We also analyzed AML and APL pt samples along with different AML cell lines for mRNA expression using qRT-PCR. High FABP5 levels were observed in the majority of the AML cell lines. Efficacy of novel small molecule FABP5 inhibitor as a single agent and in combination with ATRA was evaluated in HL-60 cells. The FABP5 inhibitor iFABP5 was found to increase differentiation at 72 hours as assessed by both CD11b and CD14 levels in HL-60 cells. To confirm that iFABP5 is targeting FABP5 and indirectly targeting the PPARβ/δ pathway, levels of RAR and PPARβ/δ target genes were evaluated in the absence and presence of iFABP5. Changes in the gene expression of RAR and PPARβ/δ target genes in the presence and absence of iFABP5 were also examined in shFABP5, shPPARβ/δ, and shCRABP2 versus wild type cells. Conclusion: We demonstrated that a small molecule inhibitor of FABP5 synergizes with ATRA and induces the differentiation in AML cells. High FABP5 levels (mRNA and protein) were observed in the majority of the AML cell lines. Hence, FABP5 can be a therapeutic target in AML. Utilizing virtual screening and structurally guided design, we developed a small molecule FABP5 inhibitor that induces monocytic differentiation as observed by increased CD14 surface expression as a single agent and in combination with ATRA. FABP5 is not only a strong target to treat AML pts but also an excellent approach for developing a novel therapeutic for pts where FABP5 expression and activity is high. [Display omitted] DisclosuresMaciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy. Carraway:Agios: Consultancy, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; FibroGen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau.

Telomere Length Recovery Strongly Predicts Overall Survival in Acute Promyelocytic Leukemia

Telomeres are the ends of linear chromosomes composed of tandem hexameric nucleotide repeats, maintained by a telomerase enzyme complex, made of reverse transcriptase catalytic subunit (TERT) and an RNA template (TERC). Present in very specific cells, such as embryonic and adult stem cells, the telomerase complex functions to elongate and slow the attrition of telomeric repeats associated with cellular division during replicative cellular age, as well as conferring stability to the ends of the chromosomes. In humans, both telomere length (TL) and loss-of-function mutations in the telomerase complex genes have been linked to malignant transformation and alteration of normal hematopoiesis. Though very short telomeres and germline mutations in TERT and TERC are associated with acute myeloid leukemia (Calado et al. PNAS 2009), the association between TL or telomerase complex integrity and outcome in patients (pts) with acute promyelocytic leukemia (APL) has not been thoroughly analyzed.We present the largest analysis to date of mean telomere content, as a function of TL, and germline mutations in TERT and TERC in peripheral blood leukemic promyelocytes or total mononuclear cells (remission) from 164 APL pts at diagnosis, complete remission (CR) and relapse, enrolled in the intergroup trials, E2491 and C9710. The goal was to evaluate the correlation of TL in APL blasts at diagnosis and at relapse, in CR in normal total mononuclear cells, as well as delta TL (the difference between TL at diagnosis and CR) with clinical and laboratory parameters, including disease risk status by presenting white blood cell count (WBC ≤ or > 10,000/μl), early mortality, achievement of CR and overall survival (OS). Peripheral blood leukocytes from healthy subjects (ages 0-90 yrs) were collected and analyzed as controls. TL was measured by real-time quantitative PCR, and was dichotomized into short or long by the third quartile. Patient demographics and outcomes were compared using Fisher’s exact test, the Kruskal-Wallis test, and the Wilcoxon signed rank test. To evaluate the effect of TL on clinical outcomes, the Cochran-Mantel-Haenszel statistic was used in the association test on early mortality and CR. OS were compared using stratified log-rank tests. Hazard ratios were computed using stratified univariate and multivariate Cox models.Median TL at presentation was significantly shorter in the APL than in the control healthy volunteer group (5.1 vs. 7.8 kb, p<0.0001). At CR, the median increase in TL was 2.0 kb (p<0.0001 against 0). There was a statistically significant association between TL at diagnosis and the WBC risk group status (p=0.001). There was no statistically significant difference in pretreatment characteristics (age, sex, ECOG performance status (PS), and risk status) and early mortality (p=0.40) across studies/regimens. However, TL at presentation (p=0.004) and CR (p=0.0003) was shorter in study C9710 than study E2491, though there was no difference in delta TL (p=0.21). TL at diagnosis was not prognostic of achievement of CR (p=0.78) or early mortality (p=0.19). However, delta TL was identified as a powerful predictor for OS (p=0.006), which remained true after adjusting for WBC risk status (p=0.009). In patients who achieved a CR, results from Cox regression with the forward selection criterion demonstrated that delta TL was more potent in predicting OS than the WBC risk status, TL at presentation, age, sex, or ECOG PS. TL at CR (p=0.96) and delta TL (p=0.31) did not predict for likelihood of relapse. Relapsed pts had significantly shorter median OS (p<0.0001) compared to those who did not relapse (2.2 yrs vs. OS not reached). We did not find mutations in the TERT or TERC genes apart from codon 279 and 1062 polymorphisms, which were identified at a frequency similar to that found in normal healthy volunteers.In the largest study of APL pts analyzed to date, we demonstrate that APL blasts consistently harbor shorter TL at presentation compared to healthy people, and that TL at presentation correlates with higher risk disease. TL significantly recovers by the time of disease remission, and among those pts who achieve CR, delta TL is the most powerful predictor of OS. These findings warrant confirmation in a prospective fashion, and if corroborated, may offer TL measurement as a simple and inexpensive parameter in disease risk stratification and as meaningful predictor of OS in pts with APL. DisclosuresDumitriu:GSK: Research Funding. Stein:Seattle Genetics, Inc.: Research Funding; Janssen Pharmaceuticals: Consultancy. Larson:Novartis: Consultancy, Research Funding.

Survivorship in APL- Outcomes of Acute Promyelocytic Leukemia (APL) Patients (pts) after Maintaining Complete Remission (CR) for at Least 3 Years

Introduction: The outcome for pts with APL has improved over time most recently with the use of ATRA and arsenic trioxide (ATO). The purpose of this study was to investigate the survivorship outcomes of APL pts who maintained CR for at least 3 years treated with both chemotherapy and non-chemotherapy based regimens (i.e. potentially cured).Methods: We performed a chart review of pts with APL treated at our institution who achieved CR for at least 3 years after their initial treatment to analyze their long-term outcomes.Results: 185 pts with APL were treated between 1991 and 2010 at our institution. 165 (89%) pts achieved CR. Among them, 124 (75%) maintained 1st CR for at least 3 years. Of these 124 pts, 91 pts were treated without chemotherapy (ATRA and ATO ± gemtuzumab ozogamicin), while 33 pts pts were treated with chemotherapy (anthracyclines) as part of their treatment. The median age for each group was 46 years (range, 25-80) for those treated without chemotherapy and 40 year (range, 26-63) with chemotherapy. Characteristics of APL survivor pts at the time of diagnosis were as follows: hypertension (HTN) was present in 24% of the pts; cardiac disease in 13%; diabetes (DM) in 21%; pulmonary disease in 8%. Median number of medications per pt at baseline was 1 (0-20). Relapses after maintaining CR for ≥3 years were noted in 4% of the pts: 3% of the pts treated without chemotherapy and 6% of pts with chemotherapy (p=0.55). The median CR duration for those who relapsed was 7.5 years (4.1-9.7) and 3.75 years (3.5-4), respectively. A 2nd complete remission (CR2) was achieved in 100% of pts. 60% of all pts were treated without chemotherapy, while 40% were treated with chemotherapy. New medical problems that were present at the 3 year mark in pts treated without chemotherapy included: HTN in 39% of pts; cardiac disease, including coronary artery disease (CAD), myocardial infarctions (MI) and arrhythmias in 11%; renal insufficiency in 3%; DM in 25%; hematological disorders in 8%; pulmonary disorders occurred in 5%; neurological disorders in 9%. The median number of medications per pt 3 yrs from initial CR treated without chemotherapy was 3 (range, 0-15). New medical problems that were present at the 3 year mark in pts treated with chemotherapy included: HTN in 19% of pts; cardiac disease in 7%; DM in 7%; neurological disorders were noted in 7%. No pulmonary, renal or hematological disorders in pts treated with chemotherapy were noted at the 3 year mark. The median number of medications per pt 3 yrs from initial CR treated with chemotherapy was 0 (range, 0-5). New medical problems that developed at time of last follow up in pts treated without chemotherapy included: HTN in 43% of pts; cardiac disease in 14%; renal insufficiency in 7%; DM in 26%; hematological disorders in 11%; pulmonary disorders occurred in 8%; neurological disorders in 11%. The median number of medications per pt at the time of last follow up from initial CR treated without chemotherapy was 4 (range, 0-23). New medical problems that were present at the time of last follow up in pts treated with chemotherapy included: HTN in 26% of pts; cardiac disease in 15%; DM in 15%; neurological disorders were noted in 15%. No pulmonary, renal or hematological disorders in pts treated with chemotherapy were noted at the time of last follow up. The median number of medications per pt at the time of last follow up from initial CR treated with chemotherapy was 0 (range, 0-14). Second malignancies occurred in 8% of pts. The most common 2nd malignancy was breast cancer, occurring in 2% of pts. At a median follow up of 6.3 years (3.2-10.2) and 7.9 years (3.9-14) respectively, 88% and 82% of pts are alive. The most common causes of death included second malignancies, accounting for 41% of all deaths and cardiac diseases, accounting for 29% of all deaths.Conclusion: APL pts who achieved CR for at least 3 years have a very low incidence of late relapses. While most are alive today, ongoing medical care and surveillance is required to manage chronic and emerging comorbidities. The extent to which prior therapy contributes to these co-morbidities requires further study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Invasive Fungal Infections in Acute Promyelocytic Leukemia Patients. Results of a Prospective Multicenter Study in Italy

OBJECTIVESAim of this prospective study was to evaluate the risk of invasive fungal infection (IFI) in patients (pts) with acute promyelocytic leukemia (APL) and to compare APL pts with patients affected by non promyelocytic acute myeloid leukemia (npAML) in order to evaluate factors potentially linked to IFI in these two subsets of acute myeloid leukemia.PATIENTS AND METHODSFrom January 2010 to April 2012 all pts with newly diagnosed AML were registered in 33 Italian participating centers. A minimum follow up of 90 days after 1st induction chemotherapy was requested for all pts. A prolonged follow up until June 2014 was made only for APL. Data were collected about age, gender, AML subtype, treatment and also about post chemotherapy risk factors for IFI (duration of neutropenia, mucosal damages, vomiting, diarrhea, presence of medical devices), antifungal prophylaxis, onset of IFI, level of certainty (possible/probable/proven), and antifungal treatment. Only for APL the survey was prolonged for at least 3 months in order to analyze if these pts have an IFI risk during other than first induction phases.RESULTS1,192 consecutive newly diagnosed adult AML pts (npAML:1,086/APL:106) were enrolled in the study.Among npAML pts, those receiving low dose chemotherapy and/or palliative treatment were excluded from the analysis; in the remaining 881 pts 214 cases (24%) of IFI were recorded.Considering APL, 3 pts were excluded from the analysis due to early death (1 pt) or bad performance status (2 pts). The remaining 103 pts received APL treatment according to local protocols: all trans retinoic acid (ATRA) plus chemotherapy (90 pts) or ATRA plus arsenic trioxide (ATO)(13 pts). Only 8 (8%) APL pts developed an IFI after the induction phase: 1 proven, 3 probable and 4 possible IFI. All cases were caused by molds. All APL were followed for a median follow up of 36 months (range 3-54). During this time only 2 other cases of IFI were observed: 1 possible IFI during consolidation at 16 weeks from APL diagnosis and 1 probable aspergillosis in a rare case of APL relapse at 132 weeks from APL diagnosis. All the IFI occurred in pts treated with ATRA plus chemotherapy.IFI was fatal in only 1 case (cerebral aspergillosis), all the other pts recovered after antifungal treatment.A comparison between npAML and APL was made in order to analyze the risk of IFI within 90 days after induction treatment among these 2 groups of patients (see table). A significantly lower number of overall IFI and systemic antifungal treatment was observed in the APL group, in spite of the fact that systemic anti mold prophylaxis was significantly less frequently utilized. Table 1Comparison between APL and npAML in induction phaseAPLnpAMLpNumber of pts103881Mean age51550.01m/f50/53448/433N.S.Performance status (WHO)0-1>1. 76 27. 284 597. <0.0001Central venous catheter52 (50%)687 (78%)<0.0001Neutropenia (<1000/mm3)103 (100%)874 (99%)N.S.Mean duration of neutropenia (<1000/mm3)23 days25 days0.1Mean duration of deep neutropenia (<500/mm3)17.5 days24 days0.04Antifungal prophylaxis94 (91%)837 (95%)N.S.Topical antifungal prophylaxis17 (17%)60 (7%)0.0005Drug in prophylaxisfluconazoleitraconazoleposaconazoleother.33 (32%)13 (12%)38 (37%)1 (1%).168 (19%)117 (13%)513 (58%)23 (3%).0.002N.S. <0.0001IFIsall casesproven/probable.8 (8%)4 (4%).214 (24%)77 (9%).0.00010.08moldsall casesproven/probable.8 (8%)4 (4%).191 (22%)55 (6%).0.0006N.S.yeastsall cases.0.23 (3%). <0.0001Antifungal treatmentMean duration11 (11%)17 days275 (31%)14 days<0.0001 N.S.Overall mortality at 30 days8 (8%)110 (12%)N.S.Mortality due to IFI at 30 days1 (1%)25 (3%)N.S.Comparing APL among them in order to identify parameters that could be correlated to IFI presentation, no significant factors were identified.DISCUSSIONIn our prospective study we specifically analyzed the incidence and the type of IFI in APL during a prolonged follow-up. Only 10 cases of IFI were documented and in most cases (6 pts) the infection was only possible. Comparing APL to npAML a lower incidence of overall IFI was observed despite less use of mold active drugs as prophylaxis. It could be attributed to the different chemotherapy (less aggressive in APL) and to lower duration of deep neutropenia. No yeast infection was observed in APL. On the basis of this study, APLs may be considered at low risk of IFI so probably the use of a mold active antifungal prophylaxis could be omitted. DisclosuresNo relevant conflicts of interest to declare.

Association Of FLT3 Mutations With Unfavorable Factors In AML and APL Patients

BackgroundMutations in the fms-like tyrosine kinase 3 (FLT3) gene have been considered to predict a poor prognosis in acute myeloid leukemia (AML). Internal tandem duplication (ITD) of the FLT3 is one of the most frequent mutations activating aberrant signal-transduction in AML. The impact of D835 point mutations in tyrosine kinase domain (TKD) on prognosis is less clear. AimsCharacterization of AML and APL (acute promyelocytic leukemia) patients with FLT3 mutations. MethodsFLT3 status in bone marrow samples of adult patients (pts) with AML (63 pts) (m\\28; f\\35; median 53 yrs, 19-73 yrs) and APL (14 pts) (m\\3; f\\11; median 43 yrs, 25-62 yrs) at diagnosis was examined. Genomic PCR amplification of ITD and TKD containing regions of the FLT3 gene was performed. The TKD amplicon product was restricted with the EcoRV enzyme. Results were detected by gel electrophoresis. ResultsFLT3\\ITD was found in 8 AML pts (12.7%) and in 5 APL pts (35.7%), p=0.053 (Fisher Exact test). FLT3\\TKD was found in 4 AML pts (6.4%) and in 1 APL pt (7.1%).In AML group there were 1 pt with t(6;9) in FLT3\\ITD+ subgroup and 1 pt with inv16 in FLT3\\TKD+. There were 1 pt with t(6;11), 1 with dupMLL, 3 with t(8;21), 7 with inv16 in AML pts without FLT3 mutations (FLT3-). There were no significant differences in sex, age, WT1 expression at diagnosis between AML pts with FLT3\\ITD, FLT3\\TKD and without FLT3 mutations. But the presence of FLT3 mutations was related to high peripheral white blood cell (WBC) count in AML pts at diagnosis. The median value (m) of WBC was 49.2 x109\\L (range 2.75-191) in FLT3\\ITD+; m= 81 x109\\L (range 7.2-153) in FLT3\\TKD+; m= 5.4 x109\\L (range 0.2-230) in FLT3-. The differences are statistically significant between subgroups with FLT3\\ITD+ and FLT3- (p<0.05, Mann–Whitney U test); FLT3\\ITD+TKD and FLT3- (p<0.01, Mann–Whitney U test). In FLT3\\ITD+TKD subgroup 66.7% of pts had WBC over 30 x109\\L, whereas in subgroup without FLT3 mutations only 23.4% of pts had the same unfavorable factor, p=0.012 (Fisher Exact test).In APL group the t(15;17) translocation was detected in 11 pts. 3 pts were without PML\\RARa, NPM1\\RARa, PLZF\\RARa fusions. One FLT3\\TKD+ pt had bcr1 PML breakpoint. In FLT3\\ITD+ subgroup 4 pts (80%) had bcr3 PML breakpoint, whereas in FLT3- subgroup only 1 pt (12.5%) had bcr3, p=0.032 (Fisher Exact test). In FLT3\\ITD+ subgroup all pts had WBC >10 x109\\L; moreover, 3 pts (60%) had two unfavorable factors in combination (WBC >10 x109\\L plus platelet count < 40 x109\\L) at diagnosis, and in FLT3- subgroup nobody had the same combination, p=0.035, (Fisher Exact test). Out of 5 pts with FLT3\\ITD 2 ones had death in induction, 1 pt had late molecular remission, 1 had molecular persistence and 1 pt without RARa fusion had failure in WT1 reduction after induction (under 2 log). One FLT3\\TKD+ pt had the early relapse. SummaryThe results confirm previous reports. FLT3\\ITD mutations are seen more frequently in APL than in other subtypes of AML. FLT3 mutations in AML have association with such unfavorable prognostic factor as high WBC count at diagnosis. FLT3\\ITD in APL associates with bcr3 and with combination of high WBC count plus low platelet count. The presence of FLT3 mutations is related to unfavorable events in APL pts. Disclosures:No relevant conflicts of interest to declare.

Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR) on Peripheral Blood (PB) and Bone Marrow (BM) Samples for Monitoring Minimal Residual Disease (MRD) in Patients (pts) With Acute Promyelocytic Leukemia (APL) Treated With All-Trans-Retinoic Acid (ATRA) and Arsenic Trioxide (ATO)

Abstract 2623 Background: Monitoring minimal residual disease (MRD) using reverse transcriptase polymerase chain reaction (RT-PCR) for the PML-RARA fusion transcript in bone marrow (BM) samples has been used to predict relapse in patients (pts) with acute promyelocytic leukemia (APL). Rigorous, serial real-time quantitative PCR (RQ-PCR) has been shown to be the strongest predictor of relapse-free survival in APL (Grimwade D, JCO, 2009), and BM was more sensitive than peripheral blood (PB) for detecting pending relapse. However, the clinical utility of MRD monitoring and use of PB as a sample source for MRD detection remains to be established for APL pts treated with ATRA and ATO without chemotherapy. Purpose: To evaluate the reliability of using PB real-time quantitative PCR (RQ-PCR) in monitoring MRD in patients with APL treated with ATRA and ATO ± gemtuzumab ozogamicin (GO). Methods: From June 2007 to August 2011, 78 pts with newly diagnosed APL were treated on a clinical trial (NCT00413166) combining ATRA and ATO at our institution. High risk pts (WBC > 10 × 109/L) and pts with rising WBC also received GO on the first day or when WBC rose above 10, respectively. RQ-PCR for PML-RARα fusion transcript was performed on BM and PB after induction, every 3 months throughout consolidation (8 months of ATRA and ATO) for the first 2 years and then PB and/or BM analysis was performed every 6 months with follow up. The Spearman correlation and Paired Wilcoxon test were used to analyze the relation, generate the correlation coefficient and analyze the differences between BM and PB RQ-PCR values. Results: A total of 432 PB and 618 BM samples were obtained for RQ-PCR analysis. The median number of PB RQ-PCR and BM RQ-PCR obtained per patient were 6 (range, 0–16) and 8 (range, 0–14), respectively. Two hundred thirty six samples were obtained concomitantly from PB and BM (defined as obtained within a day of each other) from 63 patients. The median time to CR was 30 days (range, 9–63). The median time to complete molecular response (CMR) was 130 days (range, 20–271). Two patients died, 1 during induction (before assessing his response to treatment), the other one during 4th consolidation while in CR of unknown cause. Two pts have relapsed, one of them with CNS disease only, the other one with systemic then CNS relapse. Both patients had previously achieved CMR. The patient with CNS relapse remained RQ-PCR-negative on BM at the time of relapse (PB not available at time of relapse). The other relapsed patient had a positive PB RQ-PCR at time of relapse. There was a strong correlation (Spearman correlation, r=0.8, p Conclusions: Among the available paired samples, there is a strong correlation between BM and PB RQ-PCR for PML-RARα fusion transcripts for patients treated with ATRA+ATO. PB RT-PCR is a reliable and practical method to monitor pts in CMR and for possible impending relapse. Disclosures: Off Label Use: Arsenic trioxide is used off label for the treatment of acute promyelocytic leukemia.

Early Deaths (ED) in Acute Promyelocytic Leukemia (APL) in France: A Retrospective Multicenter Study in 355 Patients (pts)

AbstractAbstract 890 Background:While, with the combination of ATRA and anthracycline-based chemotherapy, 90–95% of APL pts included in APL clinical trials achieve complete remission (CR), it has been suggested that the actual early death (ED) rate may be as high as 15–17%, many pts being unable to enter clinical trials (Park JH, Blood 2011, Lehmann S, Leukemia. 2011 ). In some cases, an important delay in starting ATRA was also incriminated in ED (Altman, Blood 2011). We assessed the early outcome of newly diagnosed APL pts diagnosed in 16 large French centers during a period of 5 years, included or not in a clinical trial. Methods:16 French University hospitals retrospectively provided data on all their APL pts diagnosed between Dec 2006 and Dec 2011, included or not in APL 2006 trial, the only active French APL trial during that period, which randomly assessed the role of ATO and ATRA during consolidation treatment, after ATRA – anthracycline based chemotherapy induction, and which had no upper age limit for inclusions. Every effort was made to collect all cases, by checking all APL diagnoses made in the lab and including pts admitted directly to ICU or to departments other than that of hematology, to avoid any bias. Intervals between first blood count, hospital admission and ATRA onset were particularly analyzed. ED was defined as death within 30 days of admission, irrespective of its cause. Results:355 cases of newly diagnosed APL were seen during that period: 52% men, median age 52 years (range 16 –87). 26% of the pts had WBC >10 G/L. 65.6% pts were included in APL 2006 trial and 34.4% not included. Reasons for non-inclusion in APL 2006 trial were: 32 patients refusing or unable to give consent (9%), 20 initial admissions in ICU (5.6%), 20 older age and/or comorbidities (5.6%), 8 previous cancer (2.3%), 11 contraindications to anthracyclines (3.1%), 5 other exclusion criteria (pregnancy, HIV, poor socioeconomic conditions) (1.4%), 2 deaths before ATRA onset (0.6%), 2 CNS bleeding at admission (0.6%) and 22 unknown reasons (6.2%). Pts not included were characterized by older age (median 62 vs 48 y, p < 0.0001) but a similar proportion of pts with high WBC (31% vs 24%,p=0.16). 20/33 (61%) pts aged ≥ 75 and 19/26 (73%) pts initially admitted in ICU were not included in APL 2006 trial. Median interval from first abnormal blood count to hospitalization was < 1 day (1 d and > 1 d in 20% and 22% pts, respectively), from hospitalization to ATRA onset < 1 day (1 d and > 1 d in 24.5% and 25% pts respectively) and from bone marrow aspirate to ATRA onset < 1 day (<1 d, 1 d, and > 1d in 66%, 19%, 15% pts respectively), without significant difference between pts included and not included in APL 2006.316 (89.8%) pts reached CR, 1 had resistant leukemia and 35 pts (9.9%) had ED. 8 of the 35 ED (2.2% of the whole population) occurred before ATRA onset. Causes of ED in pts who received ATRA were: differentiation syndrome (DS) (n=5), CNS bleeding (n=4), sepsis (n=7), myocardial infarction (n=2), multiple organ failure (n=4), uncertain (n=5). No significant differences in the incidence of ED were seen based on the various intervals analyzed (from first blood count to hospital admission, admission to ATRA onset, BM aspirate to ATRA onset). In particular, ATRA onset within <1, 1 and >1 day of hospitalization was associated with ED rates of 9.4%, 7% and 8%, respectively (p=0.961). ED was seen in 3% (7/233) of pts included in APL 2006 trial and 23% (28/122) of non protocol pts (p < 0.0001), and the CR rate was 97% and 77% in APL trial and non protocol pts (p < 0.0001). In particular, in pts aged ≥ 75, the ED rate was 0% and 30% in protocol and non protocol pts, respectively (p=0.06). Still, overall, 16/26 (61.5%) of the pts admitted directly in ICU, 27/33 (82%) of the pts aged ≥ 75, and 77/92 (83.7%) of the pts with WBC > 10G/L achieved CR. Conclusions:(1) A large majority of APL pts are rapidly admitted to hospital and rapidly treated with ATRA in France, with an overall CR rate of 89.8%. (2) One third of the pts are not included in clinical trials, especially due to their age or critical condition, and their outcome is less favorable than that of protocol patients (77% versus 97% CR). On the other hand, 61.5% of the pts directly admitted to ICU and 82% of those aged ≥ 75 y achieved CR. (3) Our overall early death rate (9.9%) appears inferior to those published in several recent studies. Disclosures:No relevant conflicts of interest to declare.

Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR) On Peripheral Blood (PB) and Bone Marrow (BM) Samples for Monitoring Minimal Residual Disease (MRD) in Patients (pts) with Acute Promyelocytic Leukemia (APL) Treated with All-Trans-Retinoic Acid (ATRA) and Arsenic Trioxide (ATO).

Abstract 2623▪▪This icon denotes a clinically relevant abstract Background:Monitoring minimal residual disease (MRD) using reverse transcriptase polymerase chain reaction (RT-PCR) for the PML-RARA fusion transcript in bone marrow (BM) samples has been used to predict relapse in patients (pts) with acute promyelocytic leukemia (APL). Rigorous, serial real-time quantitative PCR (RQ-PCR) has been shown to be the strongest predictor of relapse-free survival in APL (Grimwade D, JCO, 2009), and BM was more sensitive than peripheral blood (PB) for detecting pending relapse. However, the clinical utility of MRD monitoring and use of PB as a sample source for MRD detection remains to be established for APL pts treated with ATRA and ATO without chemotherapy. Purpose:To evaluate the reliability of using PB real-time quantitative PCR (RQ-PCR) in monitoring MRD in patients with APL treated with ATRA and ATO ± gemtuzumab ozogamicin (GO). Methods:From June 2007 to August 2011, 78 pts with newly diagnosed APL were treated on a clinical trial (NCT00413166) combining ATRA and ATO at our institution. High risk pts (WBC > 10 × 109/L) and pts with rising WBC also received GO on the first day or when WBC rose above 10, respectively. RQ-PCR for PML-RARα fusion transcript was performed on BM and PB after induction, every 3 months throughout consolidation (8 months of ATRA and ATO) for the first 2 years and then PB and/or BM analysis was performed every 6 months with follow up. The Spearman correlation and Paired Wilcoxon test were used to analyze the relation, generate the correlation coefficient and analyze the differences between BM and PB RQ-PCR values. Results:A total of 432 PB and 618 BM samples were obtained for RQ-PCR analysis. The median number of PB RQ-PCR and BM RQ-PCR obtained per patient were 6 (range, 0–16) and 8 (range, 0–14), respectively. Two hundred thirty six samples were obtained concomitantly from PB and BM (defined as obtained within a day of each other) from 63 patients. The median time to CR was 30 days (range, 9–63). The median time to complete molecular response (CMR) was 130 days (range, 20–271). Two patients died, 1 during induction (before assessing his response to treatment), the other one during 4th consolidation while in CR of unknown cause. Two pts have relapsed, one of them with CNS disease only, the other one with systemic then CNS relapse. Both patients had previously achieved CMR. The patient with CNS relapse remained RQ-PCR-negative on BM at the time of relapse (PB not available at time of relapse). The other relapsed patient had a positive PB RQ-PCR at time of relapse. There was a strong correlation (Spearman correlation, r=0.8, p <0.05) between PB and BM RQ-PCR on the 236 concomitant samples (fig 1); no significant difference were found between quantitative PCR values for BM and PB by paired Wilcoxon test analysis (p = 0.30, paired Wilcoxon test). The patient with systemic relapse (who had secondary APL) was successfully retreated with ATRA+ATO, then with systemic and intrathecal (IT) chemotherapy prior to allogeneic stem cell transplant at second relapse. The patient with CNS relapse was successfully treated with IT chemotherapy. Conclusions:Among the available paired samples, there is a strong correlation between BM and PB RQ-PCR for PML-RARα fusion transcripts for patients treated with ATRA+ATO. PB RT-PCR is a reliable and practical method to monitor pts in CMR and for possible impending relapse. [Display omitted] Disclosures:Off Label Use: Arsenic trioxide is used off label for the treatment of acute promyelocytic leukemia.

Administration of All-Trans Retinoic Acid (ATRA) to Newly Diagnosed Patients (pts) with Acute Promyelocytic Leukemia (APL) Is Delayed Even At Experienced Centers and Associated with An Increased Early Death Rate (EDR): A Retrospective Analysis of 205 Pts

Abstract 942 Background:Early death in APL, most often due to bleeding, has emerged as the major cause of treatment failure now that curative strategies exist. Despite the routine use of ATRA, EDR remains high (Lehmann et al Leukemia 2011, Park et al Blood 2011). Although the optimal strategy to prevent early death is not clear, the recommendation is to initiate ATRA immediately at first suspicion of the disease without waiting for genetic confirmation. Therefore, we examined the timing of ATRA administration. Methods:To determine time interval from initial presentation to ATRA administration, we retrospectively collected data on all newly diagnosed APL pts presenting between 1992–2009 to 4 institutions: Northwestern University, Chicago, IL (university medical center); Memorial Sloan-Kettering Cancer Center, New York, NY (free standing cancer center); John J. Stroger Hospital of Cook County, Chicago, IL (public hospital); and Rambam Medical Center, Haifa, Israel, (Northern Israel’s largest hospital; a tertiary referral center). We also examined 3 other time intervals: presentation to suspicion of APL, suspicion of APL to ordering ATRA, and ordering ATRA to its administration. Results:We identified 205 newly diagnosed APL pts: 46% men, median 48 years (range 1.5–85). Median white blood cell (WBC) count at presentation was 2,100/uL (range 300/uL-222,500/uL); 25% had high risk (HR) disease (WBC >10,000/uL). Median time interval from initial presentation to suspicion of APL was 1 day and median time from suspicion of APL to ordering ATRA was an additional day (table 1). ATRA was ordered on the day APL was suspected in 32% pts, the next day in 31%; 2 days after suspicion in 17%; and after 3 or more days in 16%. 89% received ATRA on the day ordered. At least 1 bleeding episode was identified in 34% of 185 pts with bleeding data available. Bleeding was associated with higher WBC count (p=0.0003) and lower hemoglobin (p=0.027) at presentation. 46 of 186 pts with complete information on time from presentation to administration of ATRA died. 23 (12%) died within 30 days of presentation; comprising half of all fatalities. Causes of death were: hemorrhage −15, sepsis −4, suspected MI −2, pneumonia −1, and sepsis plus differentiation syndrome -1. Among deaths within 30 days, 48%, 22%, 26% and 7% were in 1st through 4th weeks, respectively. 4 (18%) of these 23 pts died before ATRA was administered, all day 1 or 2 after presentation and all from bleeding. Only 15/182 pts received ATRA on day of presentation. Two of these 15 (13%) died within 30 days (none from bleeding). In comparison, 7/40 (18%) who received ATRA on day after presentation died within 30 days (71% from bleeding). 10/127 (8%) who received ATRA on day 2 or after died within 30 days (6 from bleeding). 20% in each group who received ATRA on either day of presentation or day 1 after presentation had HR disease. For this subgroup, if ATRA was administered on the day APL was suspected or one of the following 2 days, EDR was 19% (7/37). However, if ATRA was initiated on day 3 or 4, EDR was 80% (4/5); (p=0.013). 59% received ATRA prior to confirmation and 41% received ATRA on the day APL was confirmed or later.Table 1Median (days)Range (days)Time from presentation to suspicion of APL1.00–34Time from suspicion of APL to ordering ATRA1.00–24Time from ordering to administration of ATRA0.00–3Time from presentation to ordering ATRA2.00–39Time from presentation to administration of ATRA2.00–39 Conclusions:(1) APL was suspected rapidly upon presentation, usually within 1 day and ATRA was almost always administered on the day ordered. (2) However, ATRA was not given to most pts the day APL was suspected and for some 2 or more days elapsed. This time interval contributed to the delay in ATRA administration, suggesting physicians waited for marrow morphology or genetic confirmation before ordering ATRA. (3) Although at these centers a lower EDR (12%) than reported from the SEER database (17.3%) was observed, the current recommendation to give ATRA at first suspicion of APL was often not practiced. (4) There appears to be an association between EDR and timing of ATRA administration; other factors contribute to the EDR including variability in blood product support. (5) Our study argues that educating health care professionals who are the first to encounter APL pts as to the urgency of ATRA administration will reduce early deaths that occur even in the ATRA era. Disclosures:No relevant conflicts of interest to declare.

Front Line Treatment of Elderly Patients with Acute Promyelocytic Leukemia: Long-Term Results of the German AML Cooperative Group

Abstract 425The introduction of all-trans-retinoic acid (ATRA) in front line therapy of acute promyelocytic leukemia (APL) has improved the outcome of all age groups. In the elderly patients (pts), multi-morbidity and higher vulnerability to chemotherapy-related toxicity are the main problems reducing the chance of cure. This has led to recommendations to reduce the intensity of therapy in elderly APL pts. We report on the long-term outcome of pts with newly diagnosed APL registered in two prospective studies of the German AML Cooperative Group (AMLCG) from December 1994 until June 2011. The therapy consisted of ATRA and anthracycline/ara-C-based induction and consolidation therapy (TAD/HAM–TAD) followed by maintenance therapy as reported previously in younger APL pts (Lengfelder et al. Leukemia 2009;23:2248–2258). In pts ≥60 years (y), the administration of the second induction cycle (HAM with an age adapted cumulative ara-C dose of 6g/sqm) was at the discretion of the treating physician. After December 2005, the pts were included in the ongoing APL protocol and randomized between the AMLCG strategy and the protocols of the Spanish PETHEMA. Among 295 adult pts with newly diagnosed APL, 83 pts (28%) were ≥60y of age. Seventeen elderly pts (20%) were not enrolled in the study, due to death before start of therapy, contraindications against chemotherapy or concomitant other malignancy. Eleven pts randomized in the PETHEMA arm were excluded from the present analysis to cover homogeneity of therapy. In 53 of 55 pts treated according to the AMLCG protocol, results are available. Median age was 67 y (range 60 to 83); 58% were male, 42% female; 68% had low/intermediate and 32% high risk according to Sanz score. Morphology was FAB M3 in 62%, M3v in 38%. Cytogenetics showed t(15;17) alone in 52%, and combination with other abnormalities in 48% of pts. The bcr1/bcr2 transcript of PML/RARA was found in 41% and the bcr3 transcript in 59% of pts. Forty-four pts (83%) achieved complete remission (CR). Early death (ED) occurred in 9 pts (17%). Median time to ED was 12 days (range 2 to 19) after start of therapy. Causes of ED were bleeding, multi-organ failure and sepsis. Manifest APL differentiation syndrome occurred in 25% of pts and WHO grade ’3 bleeding, fever/infection or cardiac failure in 8%, 43% and 17% of pts, respectively. After consolidation therapy, 96% of pts were in molecular remission. After a median follow up of 5.3 y (1 day to 12.8 y), the 6-year overall (OS), event free (EFS) and relapse free survival (RFS) and the cumulative incidence of relapse (CIR) were 45%, 41%, 50% and 26%, respectively. The outcome was further analyzed according to risk group, number of induction cycles, and age ≥60y to 69y and ≥70y. Pts with pretreatment white blood cell (WBC) count <10 × 109/L (low/intermediate risk; n=36) had a significantly superior outcome compared to pts with high WBC counts (high risk; n=17) resulting in a CR rate of 92% vs. 65% and ED rate of 8% vs. 35%, respectively (p=0.02). The 6-year OS, EFS, RFS and CIR of the low/intermediate risk pts was 56%, 53%, 60% and 14%, respectively, compared to 25%, 15%, 23% and 58% in high risk pts (p=0.006, p=0.0004; p=0.008; p<0.01). All 12 pts, who had received two induction cycles achieved CR, and no relapse occurred so far resulting in a significantly superior outcome compared to patients, who had received only one induction cycle (OS: p=0.007; EFS: p=0.0002; RFS: p=0.01). In the pts ’70y (n=17), 71% entered CR and 29% died from ED. Separated according to low and high WBC counts, the CR rate of this group was 83% vs. 40% and the ED rate 17% vs. 60% (p=0.07), respectively, resulting in an inferior OS (p=0.08) of the pts with high WBC count. Conclusions: Among our elderly pts, we found a high proportion of pts with high risk profile and a high rate of exclusion from the study due to death before the start of therapy or poor condition. In patients included in our study, high WBC count and advanced age are associated with a high risk of ED. The inferior outcome in pts, who received only one induction cycle, suggests that intensification of chemotherapy should be considered in elderly APL pts, if possible. The incorporation of arsenic trioxide might be an alternative, which could be investigated in future trials. Disclosures:No relevant conflicts of interest to declare.

Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL) in the Elderly: A Joint Analysis of the French -Belgian-Swiss and PETHEMA Groups.

Abstract 845 Background:ATRA combined to anthracycline-based chemotherapy (CT) for induction and consolidation followed by prolonged maintenance is a standard treatment of newly diagnosed APL, but the outcome and prognostic factors in the elderly are less well established than in younger patients (pts). Methods:We performed a joint analysis of elderly pts included in two subsequent trials of the PETHEMA group (LPA96 and LPA99) and and on the French -Belgian-Swiss APL group (APL93 and APL2000). In the PETHEMA trials, pts received induction therapy with ATRA and idarubicin (Ida 12 mg/m2/d, d2,4,6,8), consolidation with 3 anthracycline monochemotherapy courses (2 with Ida and 1 with mitoxantrone, with ATRA and higher idarubicin dose for Sanz's int and high risk pts in LPA99 trial), and 2-year maintenance with intermittent ATRA and continuous low-dose CT (6MP + MTX). In APL 93 and 2000 trials: pts received induction therapy with ATRA and DNR (60mg/m2/d ×3d)+AraC, (200 mg/m2/d×7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d × 3) + AraC (1-2 g/m2/12h × 8) course (omitted in pts >65y) and the same maintenance as in PETHEMA trials. Median follow up was 75 and 42 months in PETHEMA and APL trials, respectively. Results:1575 consecutive newly diagnosed APL pts were enrolled in the 4 trials, including 1288 (81%), 105 (6.6%), 91 (5.7%) and 91 (5.7%) aged <60, 60-65, 65-70, and >70, respectively (ie 287 pts (18%) older than 60). CR rates in these age groups were 94.6%, 84.8%, 81.8% and 78.4% (p=0.0002). All failures were due to early death, except one due to resistant leukemia, in a younger adult. The 5-year cumulative incidence of relapse was 16.5%, 19.1% ,11.9% and 13.5% in pts <60, 60-65, 65-70 and >70, respectively (p= 0.63). The 5-year OS in these age groups was 85.8%, 68.7%, 63.8% and 56.4% (p<0.0001). The 5-year rate of death in CR , mainly resulting from myelosuppression during post induction treatment, increased with age, from 3.1%, 11.8%, 14.6% up to 17.9% in patients <60, 60-65, 65-70 and >70 years, respectively (p<0.0001). By multivariate analysis stratified on the trial (APL and LPA), better OS was associated with age <60 (HR 2.645, p<0.0001), female gender (HR 0.77, p=0.05), lower WBC (HR 1.007, p<0.0001) and higher platelets (HR 0.996, p=0.03).In pts >60 yrs, by multivariate analysis, early death was associated with increased WBC (p=0.046), and increased creatinine level (p=0.002). Higher CIR was associated with increased WBC (p=0.002) . In patients older than 60 years, age had no significant impact on CR rate and survival. Finally, no significant differences in outcome were seen between French Belgian Swiss and PETHEMA trials. Conclusion:In pts older than 60, classical APL treatment with ATRA combined to anthracycline based CT followed by prolonged maintenance gives no initial leukemic resistance and similar relapse rate as in younger pts, but significantly lower OS due to a higher incidence of early deaths and of deaths in CR compared with younger pts. Higher WBC counts are associated with an increased incidence of both early deaths and deaths in CR. Improvement in prognosis, therefore, requires better supportive care during induction treatment, while reduction of the amount of myelosuppressive drugs during post induction treatment may be required to reduce deaths in CR. Disclosures:Fenaux:CELGENE: Research Funding; AMGEN: Research Funding.

Outcome of Acute Promyelocytic Leukemia (APL) with Very High WBC Counts Treated with ATRA and Chemotherapy (CT): The European Group Experience.

Background: APL is predominantly associated with low WBC counts. APL with very high WBC counts, i.e. >50 × 109/l, is rare, generally associated with severe coagulopathy and, before the ATRA era, was generally fatal due to early death or subsequent relapse.Methods: we report characteristics and outcome of APL with WBC >50 × 109/l enrolled in two consecutive multicenter trials (APL93 and APL2000) treated with ATRA-CT combinations. In both trials (Blood 1999; 94:1192, JCO 2006; 24:5703) pts with WBC >10×109/L received ATRA combined upfront to DNR+AraC followed by 2 consolidation DNR+AraC courses and, in APL93 trial, randomisation for maintenance to intermittent ATRA, continuous low dose CT (6MP+MTX), both treatments (ATRA+CT) or no treatment. In APL2000, they all received maintenance with ATRA +CT, high dose DXM during induction (to further prevent ATRA Sd), and CNS prophylaxis.Results: Of the 1031 pts included in both trials, 261 (25%), 65 (6.4%) and 14 (1.3%) pts had WBC >10×109/l, 50×109/l and 100×109/l, respectively (resp). As compared to pts with<10×109/l and 10–50×109/l, pts with WBC >50×109/l were younger (48 vs. 44 vs. 40.5 years, p=0.002), had lower baseline plt counts (36 vs. 24.5 vs. 27×109/L, p=0.0002) fibrinogen level (1.8 vs. 1.3 vs. 1.2 g/L, p<0.0001) more often M3 variant (6.7 vs. 27.7 vs. 58.8%, p<0.0001) and BCR3 breakpoint (27.8 vs. 39 vs. 56.4%, p<0.0001) whereas CR rates were 94%, 91% and 87%, resp (p=0.054). All failures were due to early death (ED). 8 (13%) ED occurred in pts with WBC>50×109/L, 6 of them due to ATRA Sd and 1 to bleeding. In pts with WBC > 50×109/l, ED was 6/33 (18%) in APL93 and only 2/32 (6%) in APL 2000 trial (p= 0.25). Thus in APL 2000 trial, the CR rate increased to 94% in pts with WBC>50×109/l (vs. 95% in other pts). 2 year incidence of relapse (CIR), EFS and overall survival (OS) were 31.3%, 17.3%, 8.7% (p<0001), 55.4%, 73%, 82% (p<0.0001) and 62%, 83%, 82% (p=0.0002) in pts with WBC >50, 10–50, <10×109/l, resp. However, in pts with WBC> 50×109/l, only 6/38 (15.7%) of those who received combined maintenance (ATRA + CT) relapsed, vs. 12/16 (75%) of those with no or single maintenance (p<0.001). Therefore in pts who received combined maintenance, there was only a trend for higher 2 year CIR in pts with WBC> 50×109/l: 15.7% (vs. 6.4% and 11% in pts with WBC>10–50 and <10×109/l resp, p=0.067) while 2 year OS did not differ between the 3 groups (87% vs. 91% vs. 89.6%, p=0.86). Post-consolidation PML-RARA RT-PCR, available in 33 WBC>50×109/l pts, was positive in 5 (all relapsed), and negative in 28 (6 relapsed). The 19 relapses in pts with WBC> 50×109/l occurred after a median of 11 months, and included 2 CNS relapses (both in APL93 trial). 16 of those pts achieved CR2, most before the arsenic era. 2 y-OS after relapse was 62%.Conclusion: APL pts with WBC >50×109/l are rare, may achieve CR rates similar to pts with lower WBC with improved supportive care (including systematic DXM?). They have only a trend for higher risk of relapse with combined ATRA+CT maintenance, and possibly CNS prophylaxis.

Prognostic significance of initial clinical and molecular genetic features of acute promyelocytic leukemia (APL): Results from the North American Intergroup Trial, C9710

7016 Background: The impact of previously defined prognostic variables can change with advances in treatment. Thus, the significance of initial clinical and molecular genetic features of APL were explored in the context of the first randomized trial designed to evaluate the potential benefit of adding As2O3 consolidation into front-line all-trans retinoic acid (ATRA)-based therapy of APL (Powell et al, ASCO 2007). Methods: We evaluated pre-treatment white blood cell (WBC) and platelet count, age, PML-RARA transcript level and isoform type in the first 180 untreated APL patients (pts) who underwent molecular analysis on C9710 and explored their relationship to disease- free (DFS) and overall survival (S). PML-RARA transcripts were measured using real-time quantitative RT-PCR and expressed as a normalized quotient (NQ) of PML-RARA/GAPDH. Results: Using a multivariate proportional hazard model, pre-treatment PML-RARA level and WBC count were independently associated with DFS; p = 0.0073 and p = 0.05, respectively. Pre-treatment WBC count was the only feature significantly associated with S; p&lt;0.0001. With a median follow-up of 29 months, neither median DFS nor S have been reached and only 30 DFS events have been reported among these 180 pts. Pts with higher presenting WBC &gt; 10K/μl had both shorter DFS and S with hazard ratios (HR) of 2.3 and 5.5, respectively. The relationships between treatment arm and pre-treatment WBC and PML-RARA transcript level were explored by categorical analyses. For non-As2O3-treated pts, a striking difference was observed in DFS at 2.5 years between those above or below cut-off values: WBC &lt;10K, 78%; WBC &gt;10K, 50%; NQ &lt;median, 87%; NQ &gt;median, 60%. For As2O3-treated pts smaller and the reverse differences were observed: WBC &lt;10K, 94%; WBC &gt;10K, no DFS events reported; NQ &lt; median, 93%; NQ &gt;median, no DFS events reported. Conclusion: These preliminary results (based on analysis of 31% of total C9710 pts) indicate that pre-treatment PML-RARA transcript level and WBC are prognostic variables for newly diagnosed APL pts in first remission treated with standard ATRA-based chemotherapy but suggest that they may not apply in pts receiving two 25-day courses of As2O3 as first consolidation. No significant financial relationships to disclose.

Minimal Residual Disease (MRD) and Risk of Relapse in Acute Promyelocytic Leukemia (APL): Insights from the North American Intergroup Phase III Trial C9710.

MRD results during and following treatment (Rx) of APL have become an important predictor of clinical outcome and are beginning to be used to guide Rx for this highly curable leukemia, but important questions remain. Some studies suggest that low/intermediate (LI)-risk patients (pts), as defined by the Sanz criteria, who achieve a negative PCR result after intensive consolidation Rx have a very low risk of relapse and may not require maintenance Rx, while those with MRD might benefit from hematopoietic stem cell transplantation. However, these data are controversial. We studied whether a single quantitative MRD test obtained immediately after completion of C9710 consolidation Rx (with all-trans retinoic acid, daunorubicin, with or without arsenic trioxide) predicted relapse and could be used to guide further Rx. Real-time quantitative RT-PCR( RQ-PCR) was used to measure PML-RARα in bone marrow (BM) and blood (B) of 43 pts treated on C9710. All 43 pts were in first complete remission after completion of consolidation Rx when MRD was measured, but all of them later relapsed during, or after completion of maintenance Rx. By Sanz criteria, 14/43 were high risk and 29/43 LI-risk at diagnosis. 29 had S-isoform, 12 had L-isoform, and 2 had V-isoform. Median time from MRD assessment to relapse was 253 days (range: 44–1231). RQ-PCR results were expressed as a normalized quotient (NQ) of PML-RARα/GAPDH or ABL control. The sensitivity of the assay was 1 in 104–5. A NQ of >10−5 was found in the prior intergroup study, INT0129, to be strongly associated with risk of relapse and was set as the threshold for considering a result “positive”. MRD with NQ >10−5 was detected in only 4 of 43 (9%) pts after completion of consolidation Rx. 8 others had detectable PML-RARα transcript but had NQs < 10−5. The remaining 31 pts had no evidence of MRD. There was excellent concordance between MRD measurements in 26 paired B and BM NQ values and a strong correlation between NQ values in B and BM using either GAPDH or ABL controls (p = 0.0001 and p <0.0001, respectively). To determine whether a more sensitive assay might identify a higher percentage of pts with MRD, we also evaluated the post-consolidation samples in 19 of these pts using a qualitative nested RT-PCR assay with a sensitivity of detection of 1 in 106. We found 13 of 19 (68%) pts had detectable MRD. In conclusion, RQ-PCR analysis of MRD using a threshold NQ of >10−5 at a single post-consolidation Rx timepoint did not predict relapse of APL in pts on C9710. Setting a lower NQ threshold for the RQ-PCR assay or using a more sensitive, but qualitative PCR assay improved the detection rate; however, neither approach identified all pts destined to relapse, nor has the prognostic value of a positive result using the more sensitive assay been determined. Based on these results, we caution against the use of a single MRD test at the end of consolidation Rx to determine further Rx. Ongoing analysis of serial samples obtained during and following completion of Rx might provide further insights into optimal timing and frequency of MRD measurements needed to identify APL pts at high risk of relapse.

The Results of Molecular Relapses Treatment in Acute Promyelocytic Leukemia (APL) Patients.

Nearly all de novo APL patients (pts) undergo complete remission (CR) when treated with all- trans-retinoid acid (ATRA) plus chemotherapy. Nevertheless a significant portion (20%) of these pts ultimately relapse during the first 2 years of therapy. Minimal residual disease (MRD) monitoring using RT-PCR is widely recognized method for detection of molecular relapses (MR) in APL pts during hematological remission. However, the precise MR definition and significance of therapy changing when MR is detected are still controversial. We report the results of molecular monitoring and MR treatment in 40 pts (17 male, 23 female, median age = 33) who were included in the APL studies from 1997 to 2005. The induction and consolidation consisted of four 7+3+ATRA courses or four courses of 5 days Daunozome + ATRA or AIDA-protocol. Maintenance (MT) was performed for 2 years of CR with chemotherapy (5+2 courses) or chemotherapy combined with ATRA or monotherapy with ATRA+INF-alfa after Daunozome. RT-PCR for PML/RARα was performed on fresh marrow aspirates in all pts before treatment and periodically (2–3month) during 2 years after CR induction (2–18 investigations, median 6, for each pt). RT-PCR was performed using recommendations of BIOMED-1 Concerted Action (1999). MR was defined as probable if chimeric transcript was detected once and was not find out by second investigation and as proved when PML/RARA was detected at least twice by consecutive investigations (in 2–4 weeks). In case of proved MR we changed the type of MT. In pts with early MR (<12 mo of CR) MT was changed to Methotrexate+6-Mercaptopurine +ATRA. Pts with late MR (> 12 mo of CR) were treated with ATRA+IFN-α. After two hematological relapses (HR) in the group of probable MR we started to change the type of MT even if MRD was detected once. The Table 1 reflects the effect of MT changes on the frequency of HR in pts with MRs.Table 1MaintenanceProbable MRProved MRNo MR/relapsedMT changed /pts relapsedMT unchanged/pts relapsedMT changed/pts relapsedMT unchanged /pts relapsedChemotherapy (n=19)3/02/13/01/110/1Chemo+ATRA (n=15)-6/11/0-8/1ATRA+IFN- α (n =6)1/01/11/0-3/2Total (n=40)13/36/121/4Our data shows the equal frequency of HR in pts with and without MR: 4/19 and 4/21. The absence of difference is probably due to the treatment changes in case of MR. We also can admit that ATRA monotherapy as maintenance is ineffective approach (3 MR and 3 HR). We revealed the statistically significant difference in the probability of hetmatological relapse in pts with MR in whom MT was changed (0 from 9 relapsed) and not changed (4 from 10 relapsed) (p= 0,04). So it seems reasonable that in proved and probable MRs MT should be changed. However, more investigations should be done for definition of the best postremission treatment strategy in APL pts with MRD.