Decitabine and Gemtuzumab Ozogamicin in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3619-3619 ◽  
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Zeev Estrov ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Group 4 ◽  
Acute Myelogenous ◽  
Group 3 ◽  
Group 2 ◽  
Refractory Aml ◽  
Group 1

Abstract Abstract 3619 Background: Gemtuzumab ozogamicin (GO) is a humanized monoclonal antibody directed against the CD33 epitope linked to calicheamicin. Concomitant use of hypomethylating agent (HMA) can potentially open up the chromatin structure and make it more accessible to calicheamicin. Alternately HMAs can increase expression of tumor suppressor Syk (inactivated by hypermethylation), which docks to intracellular tail of CD33 upon its ligation by anti-CD33 antibody. We report on a phase 2 study of GO with decitabine (DAC) in patients with acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Methods: Patients were eligible if they belonged to one of 4 groups; Group1: relapsed/refractory AML with remission duration (CRD) < 1 year, Group 2: relapsed/refractory AML with CRD ≥ 1 year, Group 3: untreated AML/MDS not candidates for intensive chemotherapy and Group 4: patients treated for MDS evolving to AML. All patients had adequate performance status (ECOG ≤ 3) and organ function. Treatment regimen included Decitabine 20mg/m2 daily for 5 days and GO 3 mg/m2 on day 5. If day 14 bone marrow aspirate had > 5% blasts patients received additional Decitabine 20 mg/m2 IV on day 15. Patients with response or stable disease could get up to 5 post-induction cycles of therapy with DAC+GO (without day 15 DAC) and responding patients could continue with single agent DAC every 4 – 6 weeks beyond post-induction therapy up to a total of 24 cycles of therapy. Results: A total of 110 were enrolled including 81 patients with AML (74%) and with 29 high-risk MDS (26%); Group 1= 28 (25%), Group 2=5 (5%), Group 3= 57 (52%), Group 4= 20(18%). Median age was 70 years (range, 27–89) and 63 (57%) were males. Median ECOG PS was 1 (range, 0 – 3). Median white cell count, hemoglobin, platelet count and bone marrow (BM) blast percentage at diagnosis were 2.5 × 109/l (range, 0.3 – 121.9), 9.3 g/l (range, 6.9 – 31.9), 37 × 109/l (range, 3 – 816), and 32% (range, 0 – 96), respectively. FLT3 mutations were identified in 12 (13%) of 95 evaluated patients. 45 (41%) patients had high-risk cytogenetic features. Complete remission (CR/CRi) was achieved in 39 (35%) of 110 evaluable patients; Group 1= 5/28 (17%), Group 2 = 3/5 (60%), Group 3 = 24/57 (42%), and Group 4 = 7/20 (35%) (Table 1). Patients received a median of 2 (1 – 23) treatment cycles with the median number of cycles to response among those who responded being 2 (1 – 5). Median duration of CR/CRi was 5.8 (range, 1 – 41) months. The most common study drug-related adverse events were hemorrhage/bleeding, gastrointestinal toxicities including nausea and mucositis and cardiac related issues in 10%, 7%, and 4% of patients; respectively. Grade 3 and 4 toxicities were note in 16 (14.5%) patients. Neutropenic fever requiring hospitalization occurred in 59 of 110 treated patients (49%) with 7 of these being documented as fungal infection. Conclusion: Combination of GO and Decitabine is effective and well tolerated particularly in patients with less heavily pre-treated AML/high-risk MDS and not eligible for intensive induction regimens. Disclosures: Off Label Use: Use of decitabine, 5-azacytidine, SAH, and valproic acid in the treatment of older patients with AML. Kantarjian:Genzyme: Research Funding. Burger:Pharmacyclics: Consultancy, Research Funding. Verstovsek:Incyte Corporation: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; SBIO: Research Funding; Lilly Oncology: Research Funding; Bristol-Myers: Research Funding; Geron Corp.: Research Funding; Gilead: Research Funding; YM Biosciences: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Infinity Pharmaceuticals: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Pfizer: Research Funding. Borthakur:Easia: Research Funding.

Decitabine and Gemtuzumab Ozogamicin in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2985-2985 ◽  
Author(s):  
Gautam Borthakur ◽  
Zeev Estrov ◽  
Guillermo Garcia-Manero ◽  
Betsy Williams ◽  
Jay K. Wathen ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Hypomethylating Agents ◽  
Group 4 ◽  
Acute Myelogenous ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Background: Hypomethylating agents are approved for the treatment of myelodysplastic syndrome (MDS) and have activity in acute myelogenous leukemia (AML) (Issa, JP et al. Blood. 2004;103:1635–40)(Silverman LR et al. Journal of Clinical Oncology2006; 24: 3895–3903). Exposure of AML cells to hypomethylating agents increase their CD33 expression (Balain and Ball. Leukemia. 2006; 20:2093–2101). This establishes a rationale for the combination of hypomethylating agent with CD33 antibody for treatment of high-risk MDS and AML. A preliminary report of the combination of 5-azacitidine (Aza) and gemtuzumab ozogamicin (GO) in elderly patients with previously untreated AML and MDS showed promise (Nand, S. et al. Blood2006;108: Abstract 1981). Patients and Method: We have started enrolling patients in a phase 2 study of Decitabine (DAC) with GO in patients with AML and high-risk myelodysplastic syndrome (MDS). Treatment includes DAC 20 mg/m2/day intravenously (IV) × 5 days and GO 3 mg/m2 IV on day 5. GO is repeated on day 15±2 of first cycle if peripheral blood blast count is &gt; 109/L. Six such cycles are planned every 4–8 weeks. Patients achieving clinically relevant response e.g. complete remission (CR), CR with incomplete platelet recovery (CRp), marrow clearance/reduction of blasts etc. can continue on DAC alone approximately every 4–8 weeks for up to 24 cycles of total therapy duration. Based on historical expectations patients are divided into four groups according to study design: relapsed AML 1st CR duration &lt;= 1 year or beyond first relapse, relapsed AML 1st CR duration &gt; 1 year, untreated AML (not eligible for standard induction)/MDS, previously treated MDS, secondary MDS or AML. Results: Thirty-seven patients have been treated till date; Group 1=19, group 2=1, Group 3=12 and group 4=5. Median age is 63.5 years (range, 26–82), performance status =1 (range, 0–3), prior therapy =1 (range, 0–7). Eighteen (49%) patients has adverse cytogenetics and 14 (38%) has prior malignancies. Two patients received day 15±2 administration of GO. Median number of treatment cycles is 2 (range, 1–5). Eight patients died while on study. Except for cytopenias, infections, infusion related reactions etc. no significant grade 3/4 toxicities have been encountered. Three patients have achieved CR/CRp and 5 patients achieved other clinically relevant responses with an overall response rate of 22%. Responses according to patient groups are; Group 1=2/19 (4 ongoing), group 2=1/1, group 3=2/12 (3 ongoing), group 4=3/5. Seven additional patients are continuing on study with stable disease. Accrual to the study is ongoing. Conclusion: The combination of DAC and GO appears promising particularly in less heavily pre-treated patients with high-risk MDS and AML.

Atypical BCR-ABL Transcripts Chronic Myelogenous Leukemias Show Particular Features, and Their Classical Worse Prognosis Seems Abrogated by Imatinib Mesylate. A Retrospective Analysis of 22 Patients, on the Behalf of the French Intergroup of CML (Fi(ϕ)-LMC Group).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3285-3285
Author(s):  
Franck E. Nicolini ◽  
Nathalie Grardel ◽  
Sandrine Hayette ◽  
Jean-Michel Cayuela ◽  
Agnès Buzyn ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Chromosome 22 ◽  
Group 4 ◽  
Blastic Phase ◽  
Group 3 ◽  
Group 2 ◽  
Worse Prognosis ◽  
Group 1

Abstract Chronic Myelogenous Leukemia (CML) originates in the chromosome (Ph1), a reciprocal translocation, corresponding to the BCR-ABL fusion oncogene. A small proportion (1–2%) of CML patients show breakpoints falling outside of the M-BCR gene on chromosome 22, leading to the synthesis of a variety of atypical BCR-ABL transcripts [either shortened: e1a2 (m-BCR), e6a2, e8a2, b2a3 (e13a3), b3a3 (e14a3), or elongated transcripts: e19a2 (m-BCR)] and to the synthesis of different BCR-ABL proteins. In this study, we retrospectively analysed the clinical characteristics and outcomes of cohorts of CML patients harbouring atypical transcripts in and treated with imatinib (IM). Twenty-two patients were analysed: 9 e1a2 [Group 1 (G1)], 4 e6a2 [Group 2 (G2)], 5 e19a2 [Group 3 (G3)], and 4 e8a2 [Group 4 (G4)] BCR-ABL transcripts. Two patients were in myeloid blastic phase at onset (1 in G1 and 1 in G2) and others in chronic phase. Age at diagnosis was significantly younger for e19a2 patients (39.5 years versus 64 for G1, 58.5 for G2, 72 for G3, p=0.005). Female patients were predominant for G1 (5F/3M), but not for other groups. All patients presented a classical Ph1 at karyotyping analysis at diagnosis, but 1 had a -7 (G1), 1 an additional t(11;16) with the Ph1 (G2), 1 a +8 (G3) and 1 a -Y (G3). The majority of patients presented typical CML features at diagnosis, however number of differences could be found: WBC counts were higher for e1a2 and e8a2 patients (74.2 109/l and 62.7 respectively vs 20.9 for G2, and 37.8 for G3, p&lt;0.03). A significant relative monocytosis was present for e1a2 patients (10% vs 4 (G2), 2.5 (G3), 5.5 (G4), p&lt;0.05), and a marked basophilia was present for e6a2 patients vs others (p&lt;0.0008). There was a trend for higher platelet counts in G3 vs others. Hasford and Sokal scores were somewhat comparable in all groups. Median follow-up since diagnosis was 24 months for G1, 10 for G2, 17 for G3 and 31 for G4. Only one patient received interferon for 7 months before IM (G1), all other patients did not receive any other treatment than hydroxyurea before IM. All patients were treated with IM alone initially at 400–600 mg/day. Median duration of IM was 18 months for G1, 9 for G2, 12 for G3, and 30 for G4. At time of analysis 1 pt in G2 and 1 patient in G3 died of progression (blastic phase), and the overall survival (OS) since IM start was better for e19a2 and e8a2 patients, but patients remain very few. However, these OS do not seem different from what has been observed for M-BCR transcripts (IRIS study). In conclusion, atypical BCR-ABL transcripts CMLs show particular diagnosis features, but their poor prognosis reputation seems abrogated by IM.

Prophylactic Use of a Combination of an Anticoagulant and Ursodeoxycholic Acid for Sinusoidal Obstruction Syndrome after Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5755-5755
Author(s):  
Hiroshi Okamura ◽  
Mitsutaka Nishimoto ◽  
Takahiko Nakane ◽  
Hideo Koh ◽  
Yasuhiro Nakashima ◽  
...  
Keyword(s):  
Risk Factors ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Adult Patients ◽  
Allogeneic Hsct ◽  
History Of ◽  
Group 3 ◽  
Group 2 ◽  
Prophylactic Use ◽  
Group 1

Abstract Introduction: Sinusoidal obstruction syndrome (SOS) is one of the potentially fatal complications of hematopoietic stem cell transplantation (HSCT). In particular, severe SOS frequently leads to multiple organ failure, and a worse prognosis. Thus, prophylaxis against development of SOS could contribute improved survival after HSCT. Previous reports demonstrated the effectiveness of the prophylactic use of ursodeoxycholic acid (UDCA) or certain anticoagulants, including unfractionated and low-molecular-weight heparin, for SOS. In two randomized controlled trials and two meta-analyses it was reported that UDCA, a hydrophilic bile acid, was an effective and safe drug for prophylaxis against SOS. The usefulness and feasibility of prophylactic use of anticoagulants after allogeneic HSCT are however still controversial. In addition, to our knowledge no study has evaluated the feasibility of usage of UDCA combined with an anticoagulant for SOS prevention after allogeneic HSCT in adult patients. To assess the efficacy and safety of use of UDCA combined with an anticoagulant as SOS prophylaxis, we performed a retrospective cohort study to examine the occurrences of SOS and hemorrhagic events in patients who underwent myeloablative allogeneic HSCT at our institution. We examined use of any anticoagulant together with simultaneous administration of UDCA, in comparison with UDCA alone for the prevention of SOS. Patients and methods: We reviewed the charts of consecutive adult patients in whom myeloablative allogeneic HSCT was performed at our hospital from November 1994 to May 2014, and who received either unfractionated heparin or dalteparin (low-molecular-weight heparin) with UDCA (group 1), danaparoid with UDCA (group 2), or UDCA only (group 3), used for prophylaxis against SOS. Results: A total of 280 patients (group 1: n=52; group 2: n=33; and group 3: n=195) were investigated. The proportions of patients with risk factors for SOS-including non-remission at the time of HSCT, a second or subsequent HSCT, high aspartate aminotransferase (AST) levels before HSCT, high ferritin levels before HSCT, a history of receiving gemtuzumab ozogamicin, and HLA disparity-were similar across the three groups. In group 1, a conditioning regimen containing busulfan was used less frequently (P = 0.002). SOS occurred in seven patients (13.7%) in group 1, five patients (15.2%) in group 2, and 28 patients (14.4%) in group 3, all meeting the Seattle criteria. None of the patients in group 1, two (6.1%) in group 2, and nine (4.6%) in group 3 had SOS diagnosed according to the Baltimore criteria. There was no significant difference in the incidence of SOS among the three groups. In addition, with regard to the cumulative incidence of severe SOS, no statistically significant difference was present among the three groups. The incidence of hemorrhagic events within 30 and 100 days following allogeneic HSCT was not significantly different across the three groups (30 days; 5.8%, 3.0%, 5.1%, P = 0.843, 100 days; 17.6%, 15.2%, 14.4%, P=0.843, respectively). Furthermore, the probabilities of OS and NRM until day 100 after allogeneic HSCT were similar among the three groups (P = 0.733 and P = 0.637, respectively). In a univariate model, a history of gemtuzumab ozogamicin treatment, high serum ferritin levels before HSCT, an HLA mismatched donor, and non-complete remission of disease at the time of allogeneic HSCT were found to be significant risk factors for SOS. Multivariate analysis revealed that a history of gemtuzumab ozogamicin therapy, a mismatched HLA donor, and non-complete remission of disease at the time of allogeneic HSCT were significant and independent risk factors for SOS. In the multivariate as well as univariate analyses, combined administration of UDCA and any anticoagulant for SOS prophylaxis did not have a significant effect on the incidence SOS, when compared to prophylaxis with UDCA alone. Conclusion: Our study results suggest that the combined use of UDCA and an anticoagulant for SOS prophylaxis after myeloablative allogeneic HSCT in adult patients was not beneficial. Establishment of an optimal strategy for prophylaxis against SOS after HSCT is still needed. Disclosures Nakane: Mundipharma KK: Research Funding. Koh:Pfizer: Consultancy, Honoraria. Hino:Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Speakers Bureau; Alexion: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding.

scholarly journals Improvement in Survival of Multiple Myeloma Patients: A Long-Term Institutional Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4573-4573
Author(s):  
Jordan Nunnelee ◽  
Qiuhong Zhao ◽  
Don M. Benson ◽  
Ashley E. Rosko ◽  
Maria Chaudhry ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Therapy Group ◽  
Standard Of Care ◽  
Group 4 ◽  
Dexamethasone Group ◽  
Group 3 ◽  
Group 5 ◽  
Group 2 ◽  
Group 1

Introduction-Multiple myeloma (MM) represents 1.8% of all new cancer cases in the U.S., with an estimated 32,110 new cases in 2019. While not curable, advances in treatment, including autologous stem cell transplant (ASCT) and maintenance therapy, have dramatically improved progression free survival (PFS) and overall survival (OS). The Ohio State University bone marrow transplant program began utilizing ASCT for newly diagnosed MM (NDMM) patients in 1992. With the introduction of new and more effective drugs used before and after ASCT, we performed survival analysis in NDMM patients from 1992-2016 receiving ASCT to examine our institutional progress. Method-We performed a retrospective analysis of 1002 consecutive transplant eligible NDMM patients. Patients were split into five groups based on historic changes in novel agents for treatment of MM: 1992-1998 (vincristine/doxorubicin/dexamethasone-group 1), 1999-2002 (thalidomide/dexamethasone-group 2), 2003-2008 (bortezomib/lenalidomide/dexamethasone-group 3), 2009-2013 (carfilzomib/pomalidomide/dexamethasone, and maintenance therapy-group 4), and 2014-2016 (agents used for relapsed MM, including daratumumab/elotuzumab/ixazomib/dexamethasone, and maintenance therapy-group 5). Pre-ASCT conditioning regimen was melphalan 140-200 mg/m2 in 94.4% of patients. Data were consistently obtained since 2003 for both standard and high-risk patients at diagnosis. High-risk patients had del17, t(4:14), t(14:16), hypodiploidy and/or 1q abnormality. Primary endpoints were PFS and OS. PFS was defined as time to progressive disease or death from any cause from the date of transplantation. OS was defined as time from transplantation to death from any cause, censoring those who were still alive at the last follow up. Kaplan Meier curves were used to calculate PFS and OS. Results-The median age of all patients at transplant was 58 years (range: 18-81 years) and 58.5% were male. The median patient age increased significantly, from 54 to 60 years, over 1992-2016 (p<0.001). The majority of patients (53.6%) had IgG myeloma and 19.3% had light chain disease. 30% of patients with known cytogenetic data were high-risk. Melphalan 200 mg/m2 was used in 80.5% of patients. It was noted that across the years (1992-2016), there was a statistically significant improvement in both PFS (p<0.01) and OS (p<0.01). Median PFS and OS of all patients was 1.3 and 2.0 years in group 1 (1992-1998); 1.0 and 3.2 years in group 2 (1999-2002); and 2.0 and 5.8 years in group 3 (2003-2008), respectively. This response was further improved to PFS and OS of 4.1 years and not reached (NR) in group 4 (2009-2013), and 3.8 years and NR in group 5 (2014-2016), respectively (Figure 1). The 3 year PFS of groups 1 through 5 was 26%, 25%, 35%, 57% and 58%, respectively. The 3 year OS of groups 1 through 5 was 45%, 54%, 74%, 82% and 80%, respectively. On subset analysis, across years, significant increases in PFS (p<0.01) and OS (p<0.01) were seen in patients ≤65 years of age. For patients >65 years old, there was a statistically significant improvement in PFS (p<0.01) but not in OS (p=0.054). For both standard and high-risk disease, there was significant improvement in PFS (p<0.01 and p<0.01), and OS (p=0.02 and p=0.02), respectively. The rate of response both pre- and post-transplant showed statistically significant improvement across the years (p<0.01). The pre-transplant rate of very good partial response (VGPR), or better, increased from 5.3% in early 1990's (group 1), 15.3% (group 2), 39.8% (group 3) to 51.2% (group 4) and 54% (group 5). The post-transplant rate of response (VGPR or better) also increased from 31.5% (group 1), 28.8% (group 2), 65.6% (group 3), to 79.6% (group 4) and 76.3 % (group 5). Conclusion-Our data show that NDMM patients' survival and response to standard of care treatment have improved dramatically since 1992, primarily due to inclusion of novel therapies and maintenance. For NDMM patients receiving ASCT, the 3 year overall survival rate has significantly improved from 45% in 1992-1998 to 80% in 2014-2016, which is similar to the post-ASCT OS shown in the 2012 study by McCarthy et al. The significantly increasing age of NDMM patients receiving ASCT over time suggests improving supportive care and expansion of standard of care therapies to more of the population, improving survival and quality of life. Disclosures Rosko: Vyxeos: Other: Travel support. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau.

scholarly journals Mean arterial pressure within 24 hours of admission predicts short-term prognosis in patients with intermediate-risk and high-risk pulmonary embolism

2020 ◽  
Author(s):  
Jialong Chen ◽  
Jing Lin ◽  
Dansen Wu ◽  
XiaoLan Guo ◽  
XiuHua Li ◽  
...  
Keyword(s):  
High Risk ◽  
Cox Regression ◽  
Hospital Death ◽  
Intermediate Risk ◽  
Short Term ◽  
Group 4 ◽  
Group 3 ◽  
Group 5 ◽  
Group 2 ◽  
Group 1

Abstract Objective: Pulmonary embolism is a terrible cardiovascular condition with considerable morbidity and mortality. Previous studies have investigated systolic blood pressure (systolic BP) and diastolic blood pressure (diastolic BP) as being related to 30-day and in-hospital mortality. We aimed to determine whether the average mean arterial pressure (aMAP) in the first 24 hours of hospital admission is useful in predicting short-term outcomes of intermediate-risk and high-risk PE patients. Method: We conducted a single-center retrospective study. From May 2012 to April 2019, 122 intermediate-risk and high-risk PE patients were included. The primary outcome was in-hospital mortality. The secondary outcome was adverse events. ROC curves and cut-off values for aMAP predicting in-hospital death were computed. According to cut-off values, we categorized five groups defined as follows: group 1: aMAP<70 mmHg; group 2: 70 mmHg≤aMAP<80 mmHg; group 3: 80 mmHg≤aMAP<90 mmHg; group 4: 90 mmHg≤aMAP<100 mmHg; and group 5: aMAP≥100 mmHg. Cox regression models were calculated to investigate associations between aMAP and in-hospital death. Results: In the study group of 122 patients, 15 patients (12.30%) died in the hospital due to PE. ROC analysis for MAP predicting in-hospital death revealed an AUC of 0.729 with a cut-off value of 79.4 mmHg. Cox regression models showed a significant association between in-hospital death and aMAP group 1 (ref), aMAP group 2 (OR 1.680, 95% CI 0.020-140.335), aMAP group 3 (OR 0.003, 95% CI 0.0001-0.343), aMAP group 4 (OR 0.006, 95% CI 0.0001-1.671), and aMAP group 5 (OR 0.003, 95% CI 0.0001-9.744). In particular, those with an aMAP of 80-90 mmHg suffer from minimum adverse events. Conclusion: The prognostic role of MAP during the first 24 hours of hospital admission should be emphasized in patients with PE. The optimal range of MAP for intermediate-risk and high-risk PE patients may be 80 to 90 mmHg.

Clinical Phenotype and Response to Imatinib of Chronic Myelogenous Leukemia Patients Harbouring Atypical BCR-ABL Transcripts. A Retrospective Analysis From the French Group of CML (Fi-LMC) and the French Group of Molecular Biologists for Hematological Malignancies (GBMHM).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3378-3378
Author(s):  
Benedicte Deau ◽  
Mathias Montveneur ◽  
Valérie Coiteux ◽  
Aline Renneville ◽  
Francoise Rigal-Huguet ◽  
...  
Keyword(s):  
Myelogenous Leukemia ◽  
Group 4 ◽  
Best Response ◽  
Group 6 ◽  
French Group ◽  
Group 3 ◽  
Group 5 ◽  
Group 2 ◽  
Group 1

Abstract Abstract 3378 Chronic Myelogenous Leukemia (CML) originates in the Philadelphia chromosome, a reciprocal translocation creating the fusion oncogene BCR-ABL. In 1–2% of CML cases, breakpoints fall outside the M-BCR gene on chromosome 22, leading to the synthesis of a variety of atypical BCR-ABL transcripts [shortened: e1a2 (m-BCR), e6a2, e8a2, b2a3 (e13a3), b3a3 (e14a3), or elongated transcripts: e19a2 (m-BCR)] and to the synthesis of different molecular weight BCR-ABL proteins that might have different tyrosine kinase activities. Thus, clinical phenotypes and BCR-ABL inhibition by tyrosine kinase inhibitors might be different and lead to different prognostic features. We retrospectively analysed at the national level, the clinical characteristics and the responses to imatinib (IM) of 63 patients with CML harbouring atypical BCR-ABL transcripts: 22 e1a2 [Group 1 (G1)], 20 e19a2 [Group 2 (G2)], 5 e8a2 [Group 3 (G3)], 4 e6a2 [Group 4 (G4)], 5 b2a3 [Group 5 (G5)], and 3 b3a3 [Group 6 (G6)] BCR-ABL transcripts. The general characteristics of the patients and their best response to IM are depicted in Table 1: Table 1 Group 1(e1a2) Group 2 (e19a2) Group 3 (e8a2) Group 4 (e6a2) Group 5 (b2a3) Group 6 (b3a3) n 22 20 5 8 5 3 M/F 7/15 6/14 4/1 4/4 5/0 0/3 Median age (years) 70 69 43 57 62 47 CP/AccP/MBC 20/0/2 17/1/2 5/0/0 4/1/3 4/1/0 2/1/0 Sokal (L/H/I/Ukn)* 6/8/2/4 1/3/9/4 3/1/0/1 1/2/1/0 1/2/0/1 0/2/0/0 Leukocytes (G/l, median) 60.85 28.3 55 28.4 93 82.4 Hemoglobin (g/dl, median) 12 10.2 11.7 10.95 11.1 10.2 Platelets (G/l, median) 303 848 253 259 167 363 Monocytes (G/l median) 4.8 0.8 2.34 0.05 1.08 0.825 Additional Clonal Abnormalities at diag (% of patients) 20 28 0 29 25 0 IM duration (median, years) 1.55 1.38 1.58 0.8 1.13 1.42 Interval Diagnosis-IM (median, years) 1.31 1.48 1 1.17 0.87 1.66 Best response to IM* No response 20 0 0 0 0 0 CHR (%) 13 32 0 0 0 0 Minor CyR (%) 47 0 0 0 0 0 PCyR (%) 0 10 20 10 25 67 CCyR (%) 13 32 60 50 0 0 MMR (%) 7 26 20 40 75 33 Follow-up since diag (median, years) 3.24 1.57 1.6 3.82 1.5 1.68 (CP states for Chronic phase, AccP for accelerated phase, MBC for myeloid blast crisis, L for Low, I for intermediate, H for High, Ukn for Unknown, * For CP patients only) Surprisingly, e1a2 and e19a2 transcripts seem significantly more frequent in females than in males conversely to typical BCR-ABL transcripts (p=0.01) and occurring more often in the elderly (p=0.05). The majority of the patients presented with typical cytological CML features, however, a significant monocytosis was observed in e1a2 and e8a2 atypical transcripts (p=0.0002). The median time on IM and the interval between diagnosis and IM were not statistically different between the 6 groups. Overall, there was no significant difference in the (hematologic, cytogenetic, molecular) responses to IM, but e1a2 transcripts seem less sensitive to this agent. The overall survival since diagnosis or since IM initiation was not different between atypical transcripts (p=0.55 and p=0.73 respectively), however, the progression-free survival (PFS) since diagnosis with e1a2 transcripts was significantly worse than for all other atypical transcripts (p=0.02) as shown in Figure 1: The PFS since IM initiation was somewhat worse for e1a2 transcripts, but close to significance (p=0.09), but the follow-up is not very long yet. Fifteen patients among 63 had second generation TKIs (TKI2), 7 in group 1, 3 in group 2, 1 in groups 3, 4, 5, and 2 in group 6. Only one patient (b3a3 transcript) developed a MBC being on IM. Two patients developed a T315I BCR-ABL mutation (1 e1a2, and 1 e6a2). Two patients got allo-transplanted (1 e1a2 alive and well at last follow-up, 1 e19 a2 died from GVHD). In conclusion, atypical BCR-ABL transcripts induce a particular molecular and subsequent clinical phenotypes, particularly e1a2 transcripts showing in this study poor prognosis features. The response of atypical BCR-ABL transcripts to IM might vary from that what it is for classical M-BCR transcripts, but a longer follow-up is needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Optimal Mean Arterial Pressure Within 24 Hours of Admission for Patients With Intermediate-Risk and High-Risk Pulmonary Embolism

2020 ◽  
Vol 26 ◽  
pp. 107602962093394
Author(s):  
Jialong Chen ◽  
Jing Lin ◽  
Danshen Wu ◽  
Xiaolan Guo ◽  
XiuHua Li ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
High Risk ◽  
Regression Models ◽  
Cox Regression ◽  
Hospital Death ◽  
Group 4 ◽  
Group 3 ◽  
Group 5 ◽  
Group 2 ◽  
Group 1

We aimed to determine whether the average mean arterial pressure (aMAP) in the first 24 hours of hospital admission is useful in predicting short-term outcomes of patients with intermediate- and high-risk pulmonary embolism (PE). We conducted a single-center retrospective study. From May 2012 to April 2019, 122 patients with intermediate- and high-risk PE were included. The primary outcome was in-hospital mortality. The secondary outcome was adverse events. Receiver operating characteristic (ROC) curves and cutoff values for aMAP predicting in-hospital death were computed. According to cutoff values, we categorized 5 groups defined as follows: group 1: aMAP < 70 mm Hg; group 2: 70 mm Hg ≤ aMAP < 80 mm Hg; group 3: 80 mm Hg ≤ aMAP < 90 mm Hg; group 4: 90 mm Hg ≤ aMAP <100 mm Hg; and group 5: aMAP ≥ 100 mm Hg. Cox regression models were calculated to investigate associations between aMAP and in-hospital death. In the study group of 122 patients, 15 (12.30%) patients died in the hospital due to PE. The ROC analysis for MAP predicting in-hospital death revealed an area under the curve of 0.729 with a cutoff value of 79.4 mm Hg. Cox regression models showed a significant association between in-hospital death and aMAP group 1 (ref), aMAP group 2 (odds ratio [OR] = 1.680, 95% CI: 0.020-140.335), aMAP group 3 (OR = 0.003, 95% CI: 0.0001-0.343), aMAP group 4 (OR = 0.006, 95% CI: 0.0001-1.671), and aMAP group 5 (OR = 0.003, 95% CI: 0.0001-9.744). In particular, those with an aMAP of 80 to 90 mm Hg had minimum adverse events. The optimal range of MAP for patients with intermediate- and high-risk PE may be 80 to 90 mm Hg.

Comparison of Different Treatment Schedules of Mitomycin C Intravesical Instillation in High-Risk Superficial Bladder Cancer Patients

2018 ◽  
Vol 50 (03) ◽  
pp. 292-297 ◽  
Author(s):  
Hong-Ray Chen ◽  
Chien-Chang Kao ◽  
Chih-Wei Tsao ◽  
Shou-Hung Tang ◽  
Meng En ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Mitomycin C ◽  
Recurrence Rate ◽  
Low Grade ◽  
Recurrence Rates ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Objective This study was performed to compare the efficacy of intravesical mitomycin C (MMC) instillation for the prophylaxis of Ta or T1 high-risk nonmuscle invasive bladder cancer (NMIBC) using different schedules. Materials and methods This retrospective cohort study was conducted on 152 patients treated with intravesical MMC from April 2009 to September 2016. The mean follow-up time was 32.67 months. All patients underwent a complete transurethral resection of bladder tumor (TURBT) and postoperative instillation of MMC within 24 h. The patients were divided into 4 treatment groups: Group 1 was followed-up without any maintenance MMC dose treatment; Group 2 received an MMC instillation once per week for the first 8 weeks; Group 3 received an MMC instillation once per week for the first 8 weeks, and once per month for the following 6 months; and Group 4 received an MMC instillation once per week for the first 8 weeks, and once per month for the following 12 months. Results The overall recurrence rate was 27.6 %. Group 1 had a significantly high (p < 0.05) recurrence rate of 50 %, while there was no difference in the recurrence rate between the last 3 schedules (Group 2:15 %; Group 3: 24.1 %; group 4: 27.2 %). Moreover, the recurrence rates of Ta or T1 tumors, and low-grade or high-grade tumors were not statistically different among these patient groups. Conclusion Our comparison of the different schedules of intravesical MMC instillation revealed a significantly higher recurrence rate with one MMC instillation post-TURBT than in patients with a maintenance dose of 8 weeks, 6 months, and 12 months. The time of the MMC maintenance schedule exhibited no significant differences between 8 weeks and 12 months. Thus, we conclude that for T1 or Ta high-risk NMIBC, MMC instillation can be performed once after TURBT, followed by a maintenance treatment once per week for 8 weeks.

Outcome of Treatment in Adults With Acute Lymphoblastic Leukemia: Analysis of the LALA-94 Trial

2004 ◽  
Vol 22 (20) ◽  
pp. 4075-4086 ◽  
Author(s):  
Xavier Thomas ◽  
Jean-Michel Boiron ◽  
Françoise Huguet ◽  
Hervé Dombret ◽  
Ken Bradstock ◽  
...  
Keyword(s):  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
Risk Groups ◽  
Group 4 ◽  
Matched Sibling ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Purpose We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-evaluated stem-cell transplantation (SCT) for high-risk ALL. Patients and Methods A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after one course of induction therapy were randomly assigned between intensive and less intensive postremission chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and autologous SCT. Results Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at 37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had improved DFS. Three-year DFS was 24% in group 3. Conclusion Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant benefit over chemotherapy for high-risk ALL.

Phase 2 Study of Decitabine and Gemtuzumab Ozogamicin in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome- Outcome in Previously Untreated Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1053-1053 ◽  
Author(s):  
Gautam Borthakur ◽  
Guillermo Garcia-Manero ◽  
Zeev Estrov ◽  
Marina Konopleva ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Research Funding ◽  
Performance Status ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Induction Regimen ◽  
Acute Myelogenous

Abstract Abstract 1053 Poster Board I-75 Background: Ligation of CD33 antigen on acute myelogenous leukemia (AML) cells by CD33 antibodies results in recruitment of docking protein Syk to the intracellular tail of CD33. Syk is a ‘tumor suppressor’ and anti-leukemic activity of gemtuzumab ozogamicin (GO), a CD33 antibody linked to calicheamicin, correlates with expression of Syk in AML cells (Balaian, L and Ball, ED. Leukemia 2006; 20, 2093). Treatment of AML cells with 5-azacitidine, a hypomethylating agent, increases expression of Syk and enhances antileukemia activity of GO. A report from a phase 2 study of 5-azacitidine with GO and hydroxyurea in older patients with untreated AML showed high remission rates (70%) (Nand S et al. Leuk Lymphoma. 2008;49:2141). We are investigating the efficacy and safety of the combination of GO with decitabine, another hypomethylating agent in AML and myelodysplastic sydromes (MDS). Patients and Methods: Induction regimen comprises of decitabine 20 mg/m2 intravenously (IV) daily for 5 days and GO 3 mg/m2 IV X 1 on day 5. Initially an additional GO dose during induction was allowed if patient had circulating blasts on day 14, but the induction regimen was revised to omit mid-cycle GO and add 5 more days of decitabine, starting day 15±2, if day 14 bone marrow shows >5% blasts. Subsequent therapy allows for 5 additional cycles of decitabine administered at 20 mg/m2 intravenously (IV) daily for 5 days and GO at 3 mg/m2 IV X 1 on day 5 (administered every 4-6 weeks) as in induction without the day 15 ±2 dose of decitabine. Patients showing any response can continue beyond the first 6 cycles with decitabine x 5 days every 4-6 weeks for a total duration of 2 years. Patients with untreated/relapsed/refractory AML and high-risk myelodysplastic syndrome (MDS) (IPSS intermediate 2 or high) are eligible. Eligibility criteria include Serum creatinine </= 2 mg/dL, total bilirubin </= 2 mg/dL, AST (SGOT) and/or ALT (SGPT) </= 2.5 x upper limit of normal IULN) or </= 5 x ULN if related to disease, performance status </= 3. Results: We report on the 33 patients (AML=23, MDS=10) with previously untreated AML or MDS enrolled in the trial. The median age was 67 years (range, 56-84 years), median ECOG performance status= 1 (range, 0-2), 19 (58%) patients were male and 20 (61%) patients have poor risk cytogenetics. Twenty-one (64%) patients were treated according to the original schedule and 12 (36%) according to the revised schedule. Responses were seen in 14 (42%) patients (8/12=67% in revised schedule, 6/21=29% in original schedule). Eight patients (24%) (3/21=14% in original schedule, 5/12=42% in revised schedule) achieved complete remission (CR) or CR without platelet recovery (CRp). Five (15%) patients (3/21 in original schedule and 2/12 in revised schedule) had clearance of marrow blasts and 1 patient had hematological improvement-hemoglobin. Toxicities were mostly related to infusion reactions with GO administration. Twelve patients had infectious episodes requiring hospitalization. Grade 3/4 non-hematological toxicities include atrial flutter (1 patient), transient ischemic attack (1 patient). There was 1 death during induction from sepsis and multi-organ failure. Another death occurred from diffuse pulmonary hemorrhage beyond induction cycle. Responding patients have continued therapy for a median duration of 196 days (range, 70-411 days). Conclusion: The combination of decitabine and GO is an active regimen in patients with untreated AML or high-risk MDS, toxicities are minimal and the regimen can be safely delivered among older patients. The accrual in this study and an analysis of response/survival compared to a similar group of patients treated with decitabine alone or in combination with valproic acid is ongoing and will be updated. Disclosures: Borthakur: Eisai, Inc.: Research Funding. Kantarjian:Eisai: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document