scholarly journals Prognostic Impact of Chromosomal Variation in Patients with Acute Promyelocytic Leukemia (APL); Analysis of 775 Cases Enrolled in the Japan Adult Leukemia Study Group APL Studies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2329-2329
Author(s):  
Miwa Adachi ◽  
Akihiro Takeshita ◽  
Tomohiko Taki ◽  
Shigeki Ohtake ◽  
Katsuji Shinagawa ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Clinical Outcomes ◽  
Acute Promyelocytic Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Leukocyte Count ◽  
Promyelocytic Leukemia ◽  
Chromosome 9 ◽  
Chromosome 15 ◽  
Free Survival

Abstract Background: A combination of all-trans retinoic acid (ATRA) and chemotherapy (CT) has dramatically improved the prognosis of acute promyelocytic leukemia (APL). Nevertheless, considerable number of patients are either refractory to the treatment or relapse after an initial complete remission (CR). Although prognostic factors for APL have been studied, the influence of chromosomal variations in addition to t(15;17) remains controversial. One of the reasons is due to the numbers of cases studied were relatively small (47 to 513 cases). Here, we analyzed clinical features and outcomes of 775 APL caseswith or without additional chromosome abnormalities (ACAs) who were treated with ATRA and CT in the JALSG-APL studies including a large number of cases analyzed for karyotype. Methods: 1,024 cases aged between 15 and 70 yrs with newly diagnosed APL were enrolled in the JALSG APL92, 95, 97 and 204 studies and 775 patients were assessable for karyopypes. All protocols included induction therapy with ATRA and CT, following several courses of post-remission chemotherapy including anthracyclines. Arsenic trioxide (ATO) was not included. Clinical and biological characteristics such as age, gender, initial leukocyte count, platelet count, number of APL cells, DIC score, lack of Auer-rod and incidence of variant type were analyzed in relation to chromosomal abnormalities in 766 cases. CR rate, relapse rate (RR), overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were assessed and compared between patients with or without ACAs. Each variation of ACAs was also analyzed with clinical and biological features. This work was supported in part by the National Cancer Center Research and Development Fund (26-A-24), Grants-in-Aid from the Cancer Research from the Japanese Ministry of Health, Labor and Welfare (#23-004 and #25100501). These studies were approved by our IRB. Results: ACAswere noted in 235 patients (30%). Sanz score and the initial leukocyte count were significantly lower in patients with ACAs (p=0.027 and p=0.027, respectively). No other clinical or biological differences were found between patients with and without ACAs. The subgroups of ACAs were shown in Figure 1. Trisomy 8 was found in 76 cases (32%). Other ACAs were found involving chromosome 15 in 37 cases (16%), both chromosomes 15 and 17 in 31 cases (13%), chromosome 7 in 19 cases (8%), chromosome 9 in 12 cases (5%), chromosome 6 in 8 cases (3%), chromosome 21 in 7 cases (3%) and alternative ACAs in 43 cases (18%). A low initial leukocyte count (<3,000/µl) was significantly associated with an abnormality of chromosome 15 (p=0.039) and a high initial leukocyte count (≥10,000/µl) was associated with other unspecified chromosomal abnormalities (p=0.010). In all cases, CR rate, OS, EFS and DFS were not different between patients with and without ACA (p=0.341, p=0.694, p=0.414, p=0.852, respectively). However, in elderly patients (≥50 yrs) with ACAs, OS, EFS and DFS were significantly lower compared to younger patients (<50 yrs) (p=0.019, p=0,023 and p=0.030, respectively) (Figure 2). No such age related difference was observed for patients without ACAs (OS, p=0.068; EFS p=0.485; DFS, p=0.672). In each risk group divided by initial leukocyte count, clinical outcomes were not different between patients with and without ACAs. In patients without ACAs, OS, EFS and DFS of patients assigned to no maintenance or retinoid maintenance were significantly better than in those allocated to the maintenance CT (p<0.001, for all). (Figure 3) The significance was not observed in patients with ACAs except DFS (OS, p=0.161; EFS p=0.293; DFS p=0.043). Conclusions: The present study is the largest to date to focus on the influence of ACAs on clinical outcomes of patients with APL treated with ATRA and CT. The analysis revealed exact variation and frequency of ACAs. We found that patients with ACAs were associated with the lower initial leukocyte count and the lower survival outcomes in elderly patents, suggesting a possible link to age and post-remission chemotherapy. Some promising agents, such as ATO, tamibarotene and gemtuzumab ozogamicin might change the prognostic factors, including ACAs. Careful chromosomal analyses, especially ACAs related to chromosome 15 and/or 17, need to be analyzed by molecular methods and performed in future prospective studies with alarge number of cases. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Kiyoi: Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co. LTD: Research Funding; Kyowa Hakko Kirin Co. LTD.: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Zenyaku Kogyo: Research Funding; FUJIFILM Corporation: Research Funding. Kobayashi:Ohtsuka: Research Funding; Behringer: Research Funding; Simic: Research Funding. Asou:Chugai Pharmaceutical Co., Ltd.: Research Funding. Miyazaki:Nippon-Shinyaku: Honoraria.

Clinical Characteristics and Outcomes In Patients With Acute Promyelocytic Leukemia (APL) and Hyperleukocytosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1343-1343
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Stefan H. Faderl ◽  
Guillermo Garcia-Manero ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Research Funding ◽  
White Cell Count ◽  
Promyelocytic Leukemia ◽  
Chromosome 9 ◽  
Chromosome 21 ◽  
Cancer Center ◽  
Entire Group ◽  
Tyrosine Kinase Domain ◽  
Limited Information

Abstract Background There is limited information on the best management of hyperleucocytosis at presentation in patients with acute promyelocytic leukemia (APL) and few studies have evaluated the clinical features and treatment options in this subset of patients (pts). Methods We reviewed the medical records of 233 pts with a diagnosis of APL at University of Texas - MD Anderson Cancer Center between January 1990 and December 2011. Twenty-nine (12%) had a white cell count (WBC) ≥ 50 x 109/L at presentation. Kaplan-Meier methods and log-rank tests were used to assess survival. Results Among the 29 pts, 13 (45%) were male and median age at presentation was 48 years (29 - 77). Thirteen pts (45%) had the microgranular variant of APL. Karyotype analysis was available in 23 pts (79.3%). All 23 pts harbored the t(15:17)(q22; q21). Additional cytogenetic abnormalities involved chromosome 9 in 3 (10%), chromosome 21 in 2 (7%) and others in 6 (18%) each. Median PML-RARA transcript value was 24.0 (0.13 - 42.7). FLT3 analysis was performed in 11 pts presenting after 2003 with 100% having FLT3-internal tandem duplication and one having both FLT3-ITD and FLT3-tyrosine kinase domain mutations. No RAS or c-KIT mutations identified. Median WBC count, peripheral promyelocyte percentage, hemoglobin and platelet count at presentation were 85.5 x 109/L (53.8 - 194.8), 86.5% (0 - 97), 9.60 g/dL (7.7 - 12.8), and 25 x 109/L (10 - 124), respectively. Median bone marrow (BM) cellularity, BM promyelocyte, and BM blasts at presentation were 95% (75 - 100), 82% (0 - 90), and 5% (0 - 97), respectively. 23 (79%) pts had clinical evidence of leucostasis at presentation including hypoxia in 10 (34%), hemoptysis or diffuse alveolar hemorrhage in 6 (21%), stroke or intracranial bleeding in 4 (14%), intraocular bleeding in 4 (14%), and gastrointestinal bleeding in 4 (14%). Chemical DIC seen in 27 pts (93%) with median fibrinogen of 243 mg/dL (125 - 662), median PT of 16.6 seconds (12.6 - 24.2), median PTT of 25 seconds (21.0 - 33.8) and median INR of 2.21 (1.56 - 2.95). Treatment regimens included all-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combinations in 15 (52%) patients including ATRA+ ATO in 4 (14%) and ATRA+ATO+GO (gemtuzumab ozogamicin) in 11 (38%). Non-ATRA/ATO regimens were used in 14 (48%) patients including ATRA+idarubicin (IDA) in 8 (27%), ATRA+GO in 4 (14%), and ATRA+IDA+GO in 2 (7%), respectively. Leukapheresis was performed in 11 pts (38%) with a median of 3 leukapheresis procedures (1 - 6). Median WBC at initiation and completion of leukapheresis were 106.0 (80.2 - 194.8) and 26.1 (1.7 - 35.9), respectively. 6 pts died within 4-weeks of initiating therapy. All remaining 23 pts achieved morphological complete remission (CR) after induction with median time to CR of 21.5 days (15 - 35). 6 pts relapsed and 5 achieved a second CR with salvage regimens including allogeneic transplant in 2 pts. Median OS for the entire group is 67 months. CR rate and 3-year overall survival (OS) for the pts who underwent leukapheresis were 82% and 73% versus 78% and 67% for those who did not receive leukapheresis (P=0.79 and P=0.64; respectively). CR rate and 3-year OS for the pts treated with ATRA/ATO combinations were 100% and 100% versus 57% and 35% for those treated with non-ATRA/ATO combinations (P=0.004 and P=0.002, respectively). Conclusions ATRA/ATO based combinations are superior to other therapeutic regimens in patients with APL who have hyperleukocytosis and WBC ≥ 50 x 109/L at presentation with an improved CR rate and improved 3-year OS. Disclosures: Kantarjian: Sanofi-Aventis: Research Funding. Faderl:Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Garcia-Manero:Novartis Pharmaceutical: Research Funding. Verstovsek:Incyte Corporation: Research Funding. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria.

Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group.

1998 ◽  
Vol 16 (1) ◽  
pp. 78-85 ◽  
Author(s):  
N Asou ◽  
K Adachi ◽  
J Tamura ◽  
A Kanamaru ◽  
S Kageyama ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Retinoic Acid ◽  
Leukocyte Count ◽  
Promyelocytic Leukemia ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

PURPOSE We conducted a multicenter study of differentiation therapy with all-trans retinoic acid (ATRA) followed by intensive chemotherapy in patients with newly diagnosed acute promyelocytic leukemia (APL) and analyzed the prognostic factors for predicting complete remission (CR), event-free survival (EFS), and disease-free survival (DFS). PATIENTS AND METHODS All patients received ATRA until CR. If patients had an initial leukocyte count greater than 3.0 x 10(9)/L, they received daunorubicin (DNR) and behenoyl cytarabine (BHAC). During therapy, if patients showed blast and promyelocyte counts greater than 1.0 x 10(9)/L, they received additional DNR and BHAC. After achieving CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy. RESULTS Of 198 registered, 196 were assessable (age range, 15 to 86 years; median, 46) and 173 (88%) achieved CR. Multivariate analysis showed that no or minor purpura at diagnosis (P = .0046) and age less than 30 years (P = .0076) were favorable factors for achievement of CR. Predicted 4-year overall survival and EFS rates were 74% and 54%, respectively, and the 4-year predicted DFS rate for 173 CR patients was 62%. Multivariate analysis showed that age less than 30 years (P = .0003) and initial leukocyte count less than 10 x 10(9)/L (P = .0296) were prognostic factors for longer EFS, and initial leukocyte count less than 10.0 x 10(9)/L was a sole significant prognostic factor for longer DFS (P = .0001). CONCLUSION Our results show that age, hemorrhagic diathesis, and initial leukocyte count are prognostic factors for APL treated with ATRA followed by intensive chemotherapy.

scholarly journals Second-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia with Additional Chromosomal Abnormalities

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1640-1640
Author(s):  
Naoto Takahashi ◽  
Tomoko Yoshioka ◽  
Masahiro Kizaki ◽  
Tatsuya Kawaguchi ◽  
Ritsuro Suzuki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
Observational Study ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Rank Test ◽  
Log Rank Test ◽  
Cytogenetic Analyses ◽  
Tki Treatment

Background: In the New TARGET observational study, 452 newly diagnosed chronic myeloid leukemia chronic phase (CML-CP) patients were analyzed and the results reported recently in International Journal of Hematology (IJH). The median follow-up period was 5.4 years, and eight patients progressed to AP/BC and six had a CML-related death. Herein, we evaluated the impact of additional chromosomal abnormalities (ACAs) on the clinical outcomes of participants in this study. Methods: Cytogenetic analyses of bone marrow aspiration were performed at enrollment and every 6 months until complete cytogenetic response (CCyR) was achieved. If physicians switched to TKI because of resistance or intolerance to the first TKI, cytogenetic analyses of bone marrow aspiration were performed at baseline of the second-line treatment. Chromosome banding analysis was performed on bone marrow cells after short-term culture (24 hours). At least 20 metaphases were analyzed by the G-banding method according to the International System for Human Cytogenetic Nomenclature. This sub-analysis in the New TARGET observational study 1 was approved by the ethics committee of Akita university school of medicine (No. 2178). Results: For cytogenetic analyses, 1,732 samples were collected over the entire observation period from 452 patients. Chromosomal abnormalities, besides standard Ph translocation, were identified in 164 samples from 61 patients. Constitutional alterations (n=7) and single abnormality with -Y at the onset of CML (n=11), clonal chromosomal abnormalities in Ph negative metaphases during TKI treatment (n=10) and t(v;22) including three-way Ph translocation at the onset of CML (n=9) were excluded from patients with ACAs. ACAs were detected in 24 patients either at the onset of CML (n=19) or over the duration of TKI treatment (n=5). Among them, i(17q), monosomy7/7q-, chromosome3q26, and complex karyotype composed of these 3 abnormalities, which were proposed as a high-risk ACAs in a previous study were identified in three patients. Among 24 patients with ACAs, 8 patients received imatinib(IM) and 16 patients 2G-TKI. There were no statistically significant differences in the clinical background between the group with and without ACAs.Six patients with TKI resistance could hardly achieve MMR, and 4 patients died after progression to AP/BC. In a multivariate analysis of prognostic factors for predicting the clinical outcomes, including age, 2G-TKI, Charlson Comorbidity Index (CCI) score, performance status (PS), EUTOS long-term survival score (ELTS), and the presence of ACAs (Table), ACAs was one of the independent adverse prognostic factors for OS (HR 3.701 [95%CI: 1.175−11.660] P= 0.025), EFS (HR 3.920 [95%CI: 1.563−9.833] P= 0.036), PD (HR 39.02 [95%CI: 7.103−214.30] P< 0.0001), and loss of response (HR 8.346 [95%CI: 3.221−21.630] P<0.0001). The 2G-TKI was also a prognostic factor for OS (HR 0.36 [95%CI: 0.156−0.831] P= 0.017), PFS (HR 0.35 [95%CI: 0.158−0.775] P= 0.0095), and PD (HR 0.108 [95%CI: 0.021−0.558] P= 0.0079). CCI and PS were independent prognostic factors for each survival, but not for MMR, loss of response or PD, which is associated with TKI response or resistance. The Kaplan-Meier curve for PFS, and OS were significantly lower for the group with ACAs than without (Figure A, D: Log-rank test P= 0.00842, 0.00408, respectively); the 5-year PFS and OS rates of the group with ACAs were 81.3% (95%CI: 56.6−92.7), and 77.6% (95%CI: 49.8−91.2), respectively. Although there were statistically significant differences in PFS, and OS between the group with and without ACAs in imatinib arm (Figure B, E: Log-rank test P= 0.00007, 0.00007, respectively), there were no differences in 2G-TKI arm (Figure C, F: Log-rank test P= 0.478, 0.515, respectively). Conclusions: In the present cytogenetic analysis of the New TARGET observational study 1, ACAs had a negative impact on clinical outcomes. However, we discovered that 2G-TKI might be able to overcome the poor prognosis of CML patients with ACAs in 2G-TKI era. Therefore, cytogenetic analysis at CML diagnosis and during TKI treatment is very important for the prediction of outcome and the selection of TKI. Acknowledgments: This study was supported by research fundingfrom Novartis Pharmaceuticals and Bristol-Myers Squibb to Japanese Society of Hematology. Disclosures Takahashi: Pfizer: Research Funding, Speakers Bureau; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Chug Pharmaceuticals: Research Funding; Asahi Kasei Pharma: Research Funding; Novartis Pharmaceuticals: Research Funding, Speakers Bureau; Eisai Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Otsuka Pharmaceutical: Research Funding, Speakers Bureau. Kizaki:Daiichi Sankyo: Research Funding; Janssen Pharm: Speakers Bureau; Takeda Pharm: Research Funding, Speakers Bureau; Ono Pharm: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Kyowa Kirin: Research Funding; Chugai Pharm: Research Funding; Celgene: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Sumitomo Dainippon Pharm: Consultancy. Kawaguchi:Pfizer: Honoraria; Novartis: Honoraria; Alexion: Honoraria. Suzuki:AbbVie: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical Co.,Ltd.: Honoraria; Janssen: Honoraria; Meiji Seika: Honoraria; Bristol-Myers Squibb: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Celgene: Honoraria; Eisai: Honoraria. Yamamoto:Meiji Seika Pharma: Consultancy, Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Bayer: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ARIAD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; SymBio: Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Eisai: Consultancy, Honoraria, Research Funding; Gilead Sciences: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; MSD: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

Impact of Additional Cytogenetic Abnormalities and Complex Karyotype on Event-Free Survival in Acute Promyelocytic Leukemia: Analysis from a Single Academic Center Plus the APML4 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Zachary D. Epstein-Peterson ◽  
Sridevi Rajeeve ◽  
Andriy Derkach ◽  
Jae H. Park ◽  
Eytan M. Stein ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Acute Promyelocytic Leukemia ◽  
Research Funding ◽  
Promyelocytic Leukemia ◽  
Complex Karyotype ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Cytogenetic Abnormalities

Background: Current risk stratification for patients with acute promyelocytic leukemia (APL) is based solely on the presenting white blood cell count. There are conflicting data concerning the prognostic relevance of additional cytogenetic abnormalities (ACA) beyond t(15;17) and whether the presence of such abnormalities might influence treatment decisions for patients with APL. This is especially unclear among patients receiving ATO given that many existing data are from patients treated prior to incorporation of ATO into treatment paradigms. We sought to determine the prognostic importance of ACA and complex karyotype (CK) in influencing event-free survival in patients with APL. Methods: We analyzed patients with APL evaluated at our center since 2005 and patients treated in the Australasian Leukaemia and Lymphoma Group APML4 study (frontline ATRA + ATO + idarubicin,Lancet Haematology2015). We included all patients with baseline karyotype and those without karyotype but with FISH at diagnosis revealing ACA. Chart review extracted patient, disease, and clinical data. Only patients who commenced induction therapy with an ATO-based regimen were included in this analysis to ensure uniformity of the study population and applicability of results to contemporary clinical practice in APL. We also included patients deceased early in the disease course (&lt;1 month). We excluded patients with absent follow-up information given our interest in relapse and patients who relapsed prior to transferring care to our center. We defined CK as the presence of &gt;1 ACA beyond t(15;17). Coagulopathy was defined as either APTT/mean laboratory normal APTT &gt;1.5, INR &gt;1.5 (PT/mean laboratory normal PT &gt;1.5 when INR and ISI unavailable), or fibrinogen &lt;100 mg/dL. We defined events as either relapse or death. Associations between time-to event outcomes and patient and disease characteristics were assessed were calculated using univariate Cox proportional hazards models in each study separately. Fixed-effect meta analyses was used to combine estimates from both studies. Results: A total of 168 patients were included (N = 49 MSKCC, 109 APML4); 6 patients were removed from the MSKCC cohort due to relapse prior to initial visit and one from APML4 due to lack of follow-up information (Table 1). The mean age at diagnosis was 47 years in the MSKCC cohort and 43 years in the APML4. Median follow-up among survivors was 36 months (MSKCC, range 2-144) and 54 months (APML4, range 28-96); overall survival is displayed in Figure 1. Forty-nine (31%) patients' disease harbored ACA (most commonly trisomy 8 in 25 patients), and 17 CK (12% MSKCC, 10% APML4, denominator excludes one patient with single ACA by FISH). The event-free survival did not differ between ACA+ and ACA- (Table 2), but patients with +CK harbored inferior EFS (9/139 events non-CK vs. 4/17 events CK). No other clinical parameters that we queried correlated with EFS. Conclusions: In a large cohort pooled from a single-center experience and a cooperative prospective trial, the presence of an ACA beyond t(15;17) did not influence EFS in patients with APL. However, our data suggested that CK influences EFS. Further studies could collect data from other cooperative trials and/or single institutions to garner adequate power to better address the question of CK influencing EFS and confirm these preliminary findings. If a convincing signal emerges, treatment paradigms could be altered in the context of a prospective study (for example, intensifying or prolonging treatment) towards overcoming this adverse effect. Disclosures Park: Minverva:Consultancy;Kite:Consultancy, Research Funding;Amgen:Consultancy, Research Funding;Intellia:Consultancy;Artiva:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Consultancy;Incyte:Consultancy, Research Funding;GSK:Consultancy;Juno Therapeutics:Research Funding;Autolus:Consultancy, Research Funding;Genentech/Roche:Research Funding;Fate Therapeutics:Research Funding;Servier:Consultancy, Research Funding;Takeda:Consultancy, Research Funding;Novartis:Consultancy;Allogene:Consultancy.Stein:Biotheryx:Consultancy;Bayer:Research Funding;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees;Syndax:Consultancy, Research Funding;Seattle Genetics:Consultancy;Abbvie:Consultancy;Amgen:Consultancy;Celgene Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Agios Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astellas Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;PTC Therapeutics:Membership on an entity's Board of Directors or advisory committees;Syros:Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.Tallman:Bioline rx:Membership on an entity's Board of Directors or advisory committees;Amgen:Research Funding;Rafael:Research Funding;Orsenix:Research Funding;ADC Therapeutics:Research Funding;BioSight:Membership on an entity's Board of Directors or advisory committees, Research Funding;Glycomimetics:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;UpToDate:Patents & Royalties;KAHR:Membership on an entity's Board of Directors or advisory committees;Rigel:Membership on an entity's Board of Directors or advisory committees;Delta Fly Pharma:Membership on an entity's Board of Directors or advisory committees;Oncolyze:Membership on an entity's Board of Directors or advisory committees;Jazz Pharma:Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Membership on an entity's Board of Directors or advisory committees;Cellerant:Research Funding;Abbvie:Research Funding.

Acute promyelocytic leukemia: Clinical and morphologic features and prognostic factors

2001 ◽  
Vol 38 (1) ◽  
pp. 4-12 ◽  
Author(s):  
Giuseppe Avvisati ◽  
Francesco Lo Coco ◽  
Franco Mandelli
Keyword(s):  
Prognostic Factors ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia

In vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2862-2864 ◽  
Author(s):  
Bruno Cassinat ◽  
Sylvie Chevret ◽  
Fabien Zassadowski ◽  
Nicole Balitrand ◽  
Isabelle Guillemot ◽  
...  
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Event Free Survival ◽  
Free Survival ◽  
Acid Sensitivity ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Acute promyelocytic leukemia (APL) blasts possess a unique sensitivity to the differentiating effects of all-transretinoic acid (ATRA). Multicenter trials confirm that the combination of differentiation and cytotoxic therapy prolongs survival in APL patients. However relapses still occur, and exquisite adaptation of therapy to prognostic factors is essential to aim at a possible cure of the disease. A heterogeneity was previously reported in the differentiation rate of patients' APL blasts, and it was postulated that this may reflect the in vivo heterogeneous outcome. In this study, it is demonstrated that patients of the APL93 trial whose leukemic cells achieved optimal differentiation with ATRA in vitro at diagnosis had a significantly improved event-free survival (P = .01) and lower relapse rate (P = .04). This analysis highlights the importance of the differentiation step in APL therapy and justifies ongoing studies aimed at identifying novel RA-differentiation enhancers.

Characterization of a fusion cDNA (RARA/myl) transcribed from the t(15;17) translocation breakpoint in acute promyelocytic leukemia

1992 ◽  
Vol 12 (2) ◽  
pp. 800-810
Author(s):  
K S Chang ◽  
S A Stass ◽  
D T Chu ◽  
L L Deaven ◽  
J M Trujillo ◽  
...  
Keyword(s):  
Cdna Library ◽  
Acute Promyelocytic Leukemia ◽  
Blot Analysis ◽  
Blot Hybridization ◽  
Promyelocytic Leukemia ◽  
Dna Probe ◽  
Translocation Breakpoint ◽  
Chromosome 15 ◽  
Dot Blot ◽  
Mrna Species

A nonrandom chromosomal translocation breakpoint, t(15;17)(q22;q21), is found in almost all patients with acute promyelocytic leukemia (APL). Most of these breakpoints occur within the second intron of the retinoic acid receptor-alpha (RARA) gene. We screened a cDNA library of APL and have identified and sequenced a cDNA transcribed from the t(15;17) translocation breakpoint. The 5' end of cDNA p1715 consists of 503 bp of the RARA exon II sequence. A 1.76-kb cDNA without homology to any known gene available in GenBank was found truncated downstream. This cDNA sequence was assigned to chromosome 15 by dot blot hybridization of the flow cytometry-sorted chromosomes. We designate this fusion cDNA RARA/myl, which is different from myl/RARA reported by de The et al. (H. de The, C. Chomienne, M. Lanotte, L. Degos, and A. Dejean, Nature (London) 347:558-561, 1990). This result demonstrates that the two different types of hybrid mRNA can be transcribed from this breakpoint. We screened a non-APL cDNA library and identified a 2.8-kb myl cDNA. This cDNA is able to encode a polypeptide with a molecular weight of 78,450. Alternative splicing of the myl gene which resulted in myl proteins with different C terminals was found. Southern blot analysis of the genomic DNA isolated from 17 APL patients by using the myl DNA probe demonstrated that the myl gene in 12 samples was rearranged. Northern (RNA) blot analysis of RARA gene expression in two APL RNA samples showed abnormal mRNA species of 4.2 and 3.2 kb in one patient and of 4.8 and 3.8 kb in another patient; these were in addition to the normal mRNA species of 3.7 and 2.7-kb. The myl DNA probe detected a 2.6-kb abnormal mRNA in addition to the normal mRNA species of 3.2, 4.2, and 5.5 kb. Using the polymerase chain reaction, we demonstrated that both RARA/myl and myl/RARA were coexpressed in samples from three different APL patients. From this study, we conclude that the t(15;17) translocation breakpoint results in the transcription of two different fusion transcripts which are expected to be translated into fusion proteins.

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