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Marie-Luise Hütter-Kr?nke Axel Benner Konstanze D?hner Jürgen Krauter Daniela Weber Margit Moessner Claus-Henning K?hne Heinz A. Horst Ingo G.H. Schmidt-Wolf Mathias Rummel Katharina G?tze Elisabeth Koller Andreas L. Petzer Hans Salwender Walter Fiedler Heinz Kirchen Detlef Haase Stephan Kremers Matthias Theobald Axel C. Matzdorff Arnold Ganser Hartmut D?hner Richard F. Schlenk 《Haematologica》2016,101(7):839-845
Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m2 intravenously on day 1), all-trans retinoic acid (45 mg/m2 orally on days 4–6 and 15 mg/m2 orally on days 7–28), high-dose cytarabine (3 g/m2/12 h intravenously on days 1–3) and mitoxantrone (12 mg/m2 intravenously on days 2–3) in 93 patients aged 18–60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975) 相似文献
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Pirrotta MT Bocchia M Bucalossi A Defina M Forconi F Gozzetti A Lauria F 《Acta haematologica》2007,118(1):7-9
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Akihiro Takeshita 《International journal of hematology》2013,97(6):703-716
Seventy to 80 % of patients with acute myeloid leukemia (AML) achieve complete remission following intensive chemotherapy, but more than 50 % of patients in remission subsequently relapse, which is often associated with clinical drug resistance. Therapy based on monoclonal antibodies (mAbs) has been developed to increase the selectivity of cytotoxic agents by conjugating them with a mAb. Gemtuzumab ozogamicin (GO) is a conjugate of a cytotoxic agent, a calicheamicin derivative, linked to a recombinant humanized mAb directed against the CD33 antigen, which is expressed on leukemia cells from more than 90 % of patients with AML. This conjugated mAb was introduced following promising results from phase I and II studies. However, the initial phase III study did not confirm the efficacy of GO in combination with conventional chemotherapies. Several subsequent phase III studies have shown the efficacy of GO in favorable and intermediate risk AML. Several resistance mechanisms against GO have been reported. Multidrug resistant (MDR) P-glycoprotein (P-gp), a trans-membrane glycoprotein that pumps out many anti-leukemic agents from cells, also affects GO. For this reasons, GO has been used in combination with MDR modifiers, such as cyclosporine, and in cases without P-gp. Several investigators have reported successful results of the use of GO in acute promyelocytic leukemia (APL). GO has also been described as effective in cases relapsed after treatment with all-trans retinoic acid (ATRA), arsenic acid and conventional chemotherapeutic agents. The efficacy of GO will be studied mainly in a favorable risk of AML, such as core binding factor leukemia and APL. In addition, suitable combinations with other chemotherapies and administration schedules should be discussed. 相似文献
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Brethon B Auvrignon A Cayuela JM Lapillonne H Leverger G Baruchel A 《Haematologica》2006,91(3):419-421
Phase I/II studies of gemtuzumab ozogamicin (GO) in pediatric refractory/relapsed acute myeloid leukemia (AML) have been reported. We present the cases of two children with relapsed AML who were treated with GO plus cytarabine, leading to a decrease of minimal residual disease down to levels not previously obtained. The toxicity profile of this treatment was relatively mild, except for severe but manageable myelosuppression. 相似文献
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Post‐transplant maintenance therapy with azacitidine and gemtuzumab ozogamicin for high‐risk acute myeloid leukaemia 下载免费PDF全文
Gaku Oshikawa Kazuhiko Kakihana Makoto Saito Jun Aoki Yuho Najima Takeshi Kobayashi Noriko Doki Hisashi Sakamaki Kazuteru Ohashi 《British journal of haematology》2015,169(5):756-759
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Gemtuzumab ozogamicin (GO) is a recently developed antibody-targeted chemotherapeutic agent and has been expected to be less toxic than conventional chemotherapy. We retrospectively evaluated the use of GO in 38 patients. Patients with acute myeloid leukemia (AML) at diagnosis and relapsed AML were treated with 6 and 9 mg/m(2) GO. Efficacy and toxicity of GO were analyzed, as well as several prognostic factors. A complete response (CR) was observed in 12 of 38 patients, including five patients with CR plus incomplete regeneration of platelets. In one patient a partial remission was observed. Twenty-five patients showed no change or progressive disease. The overall response (OR) in patients with AML at diagnosis was 47%, with the best response in patients with primary AML (OR 60%, compared with 21% OR in non-primary AML, P = 0.045). The OR in patients with relapsed AML was 22%. Median white blood cell (WBC) before treatment, CD33 expression on leukemic blasts, and kinetics of response were analyzed as prognostic factors. Median WBC was significantly lower in patients who responded to GO, compared with non-responders (2.1 x 10(9)/L vs. 6.8 x 10(9)/L, P = 0.036). CD33 expression and kinetics of response was not correlated to clinical outcome. Median days to reach 500 x 10(6)/L neutrophils and 100 x 10(9)/L platelets were 36 and 39 d, respectively. Infections and bleedings occurred in 45% and 12%, respectively. This report shows that GO has potent clinical activity and that the OR rate was by far the best in untreated primary AML patients. 相似文献
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Feasibility and efficacy of outpatient therapy with intermediate dose cytarabine,fludarabine and idarubicin for patients with acute myeloid leukaemia aged 70 or older 下载免费PDF全文
Susana Vives Albert Oriol Sònia Piernas Salut Brunet Victòria Clapés Ramon Guardia Maricel Subirà Jordi Sierra Josep‐Maria Ribera the CETLAM Group 《European journal of haematology》2015,95(6):576-582
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Sung‐Soo Yoon Seonyang Park Byoung Kook Kim Dae‐Young Kim Jung‐Hee Lee Kyoo‐Hyung Lee June‐Won Cheong Hong‐Kee Lee Sung‐Hyun Kim Hyuk Kim Young Don Joo Sang‐Min Lee Jong‐Ho Won Sung‐Kyu Park Dae‐Sik Hong Se‐Hyung Kim Sang Kyun Sohn Chul‐Soo Kim Eunkyung Park Min Kyoung Kim Moo Rim Park Je‐Hwan Lee Yoo Hong Min for the Korean Society of Hematology AML/MDS working party 《American journal of hematology》2013,88(1):10-15
We performed a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated‐dose idarubicin (m‐FLAI) regimen in elderly acute myeloid leukemia (AML) patients. Elderly (≥60 years) AML patients who had not previously received chemotherapy were enrolled in the study. Patients received two consecutive cycles of m‐FLAI chemotherapy as an induction. The m‐FLAI regimen comprised fludarabine (25 mg/m2, days 1–4), cytarabine (1,000 mg/m2, days 1–4), and attenuated‐dose idarubicin (5 mg/m2, days 1–3). The primary end point was complete remission (CR) rate. Secondary end points were overall survival (OS), event‐free survival (EFS), and treatment‐related mortality (TRM). There were 108 patients (median age 68.4 years, M:F = 64:44) enrolled in the study. CR was achieved in 56.5% of patients, and the TRM rate was 21.3%. Median OS and median EFS were 10.2 and 6.6 months, respectively. The mortality at 30 and 60 days was 15 and 21%, respectively. Performance status and comorbidity did not have prognostic value in this patient cohort. Bone marrow expression of CD117 was associated with increased EFS and OS. m‐FLAI is an effective induction regimen for previously untreated AML in elderly patients. In addition, bone‐marrow CD117 expression is an independent favorable prognostic factor in elderly AML patients. (ClinicalTrials.gov number, NCT01247493). Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc. 相似文献
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目的:探讨标准剂量的去甲氧柔红霉素(IDA)联合阿糖胞苷(Ara-C)治疗急性髓细胞白血病(AML)的疗效和不良反应。方法:14例AML患者,年龄13~70岁(中位年龄36岁),男8例,女6例。初治AML10例,难治、复发AML4例。所有患者均在治疗前进行染色体核型分析,4例染色体异常。诱导方案为IDA 12 mg·m-2·d-1,第1~3天,Ara-C 100 mg·m-2·d-1,持续静脉点滴,第1~7天。结果:1个疗程结束后总有效率92.9%(13/14),完全缓解率85.7%(12/14),其中初治AML的CR率为90.0%(9/10),复发、难治AML的CR率为75.0%(3/4),3例染色体异常患者达细胞遗传学缓解,未发生早期死亡。化疗的不良反应主要为骨髓抑制和粒细胞缺乏所致感染,未见严重的非造血系统不良反应。结论:标准剂量的IDA联合Ara-C 24 h持续静脉点滴,为初治、复发难治AML的高效、安全的方案。 相似文献
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G‐CSF Priming,clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia,advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm 下载免费PDF全文
Pamela S. Becker Bruno C. Medeiros Anthony S. Stein Megan Othus Frederick R. Appelbaum Stephen J. Forman Bart L. Scott Paul C. Hendrie Kelda M. Gardner John M. Pagel Roland B. Walter Cynthia Parks Brent L. Wood Janis L. Abkowitz Elihu H. Estey 《American journal of hematology》2015,90(4):295-300
Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony‐stimulating factor (G‐CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G‐CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse‐free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m?2 day?1 × 5 and cytarabine at 2 g m?2 day?1 × 5 after G‐CSF priming in 50 newly‐diagnosed patients ages 18–64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64–88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71–93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well‐tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. Am. J. Hematol. 90:295–300, 2015. © 2014 Wiley Periodicals, Inc. 相似文献
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Hiroko Tsunemine Hiroshi Akasaka Emiko Ishikawa Sakane Kiminari Ito Taiichi Kodaka Takayuki Takahashi 《International journal of hematology》2014,99(2):193-197
A 68-year-old female was diagnosed with acute myeloid leukemia (AML-M2 without 8/21 translocation) in December 2006. Although a complete remission (CR) was obtained after induction chemotherapy, the first post-remission therapy was discontinued because of severe cardiovascular complications. She had a relapse of AML with CD33-positive myeloblasts which comprised 38.4 % of the bone marrow cells in November 2007. She received two courses of low-dose chemotherapy because of the previous complications. The amount of Wilm’s tumor 1 (WT1) mRNA in the peripheral blood was 13,000 copies/μg RNA after the first course of the chemotherapy, and 4.8 % myeloblasts remained in the bone marrow after the second course. She was treated with a single course of gemtuzumab ozogamicin (GO), with a subsequent CR with 0.9 % marrow myeloblasts and fewer than 50 copies of WT-1 mRNA (normal level). Thereafter, she received five courses of GO monotherapy at each occasion of early AML relapse. Hematological remission has been sustained over a period of about 24 months with the GO monotherapy alone. This case suggests that GO monotherapy is a useful salvage therapy for early relapse of CD33-positive AML in situations in which standard chemotherapy is not indicated. 相似文献
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Hawk Kim Jae‐Hoo Park Je‐Hwan Lee Jung‐Hee Lee Young‐Don Joo Won‐Sik Lee Sung‐Hwa Bae Hun Mo Ryoo Kyoo‐Hyung Lee 《American journal of hematology》2009,84(3):161-166
We assessed continuous infusion (CI) of fludarabine and cytarabine (FLAG) plus idarubicin for patients under 60‐years old with resistant acute myeloid leukemia (AML). Induction chemotherapy consisted of idarubicin (12 mg/m2 iv infusion over 30 min on Days 1–3), plus fludarabine (30 mg/m2/day) and cytarabine (1,000 mg/m2/day) on Days 1–5 as a 24‐hr CI. G‐CSF was added on Days 1–5. The 29 patients enrolled were of median age 40 years (range, 18–57 years); of these, 8 (27.6%) had primary refractory disease, 19 (65.5%) were in early relapse, and 1 each (3.4%) was in multiple relapse and relapse after SCT. In response to induction, 8 patients (27.6%) achieved CR, 2 (6.9%) achieved CRp, and 19 (65.5%) failed treatment; of the latter, 14 had aplasia, three had an indeterminate course, and two showed resistance. Seven patients remain alive, while two were lost to follow‐up. Nineteen patients died, 14 of infection, one of toxicity during consolidation, three of relapse after SCT, and two of persistent disease. These findings indicate that although CI of FLAG plus idarubicin was effective for eradicating blasts, it carried a high risk of toxicity. Reduced doses are recommended for CI of FLAG plus idarubicin. Am. J. Hematol., 2009. © 2008 Wiley‐Liss, Inc. 相似文献
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Christian M. Zwaan Dirk Reinhardt Martin Zimmerman Henrik Hasle Jan Stary Batia Stark Michael Dworzak Ursula Creutzig Gertjan J.L. Kaspers 《British journal of haematology》2010,148(5):768-776
The prognosis of children with relapsed/refractory acute myeloid leukaemia (AML) is poor, and new therapies are needed. Gemtuzumab ozogamicin (GO) is an anti‐CD33 antibody linked to the antitumor antibiotic calicheamicin. We conducted an investigator‐initiated phase II study with GO to assess its efficacy and safety, administering two dosages of 7·5 mg/m2 with a 14 d‐interval. Thirty children who were refractory to re‐induction at first relapse or suffered from second relapse of AML received a total of 64 infusions of GO. The response rate [complete remission (CR) and CR with insufficient platelet recovery] was 37%. Nine patients were subsequently transplanted (median time to transplant, 4 weeks, range 3–21 weeks), and three of these patients are currently in continuous CR with a median follow‐up of >3 years, and can considered to be cured. This resulted in a statistically significant survival advantage for children who responded to GO versus those who did not [27% (standard error 13%) vs. 0%, respectively, P = 0·001]. All other children died, mainly from progressive disease. The treatment was generally well tolerated by most patients. The frequency of transient transaminatis was low. All but one patient received defibrotide prophylaxis during the transplant procedure, and no cases of veno‐occlusive disease were noted. This study showed a favourable safety/efficacy profile of single‐agent GO in children with refractory first or second relapse of AML. 相似文献
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Aziz Nazha Hagop Kantarjian Farhad Ravandi Xuelin Huang Sangbum Choi Guillermo Garcia‐Manero Elias Jabbour Gautam Borthakur Tapan Kadia Marina Konopleva Jorge Cortes Alessandra Ferrajoli Steve Kornblau Naval Daver Naveen Pemmaraju Michael Andreeff Zeev Estrov Min Du Mark Brandt Stefan Faderl 《American journal of hematology》2013,88(11):961-966
Clofarabine is a second generation nucleoside analogue with activity in adults with acute myeloid leukemia (AML). A phase I trial of clofarabine, idarubicin, and cytarabine (CIA) in relapsed and refractory AML had shown an overall response rate (ORR) of 48%. To explore this combination further, we conducted a phase II study of (CIA) in patients with newly diagnosed AML ≤60 years. Patients ≥18–60 years with AML and adequate organ function were enrolled. Induction therapy consisted of clofarabine (C) 20 mg m?2 IV daily (days 1–5), idarubicin (I) 10 mg m?2 IV daily (days 1–3), and cytarabine (A) 1 g m?2 IV daily (days 1–5). Patients in remission received up to six consolidation cycles (C 15 mg m?2 × 3, I 8 mg m?2 × 2, and A 0.75 g m?2 × 3). Fifty‐seven patients were evaluable. ORR was 79%. With a median follow up of 10.9 months, the median overall survival (OS) was not reached, the median event‐free survival (EFS) was 13.5 months. Most toxicities were ≤grade 2. Four week mortality was 2%. In subgroup analysis, patients ≤40 years had better OS (P = 0.04) and EFS (P = 0.04) compared to patients >40 years. Compared to historical patients treated with idarubicin and cyarabine (IA), the OS and EFS were significantly longer for CIA treated patients. In multivariate analysis, CIA retained its favorable impact on OS compared to IA. Thus, CIA is an effective and safe therapy for patients ≤60 years with newly diagnosed AML. Am. J. Heamtol. 88:961–966, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
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Pamela S. Becker Hagop M. Kantarjian Frederick R. Appelbaum Barry Storer Sherry Pierce Jianqin Shan Stephan Faderl Elihu H. Estey 《Haematologica》2013,98(1):114-118
We recently reported that clofarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (GCLAC) produced a 46% complete remission rate in relapsed/refractory acute myeloid leukemia. GCLAC differs from FLAG by substitution of clofarabine for fludarabine, raising the question of the relative efficacy of these two regimens. We compared GCLAC given at the University of Washington Medical Center/Fred Hutchinson Cancer Research Center to fludarabine and cytarabine (FA) and FLAG given at MD Anderson Cancer Center. Independent multivariate analyses conducted at both institutions showed that after accounting for duration of first complete remission, salvage number, age, and cytogenetics, GCLAC was associated with a higher complete remission rate (odds ratio 9.57, P<0.0001) and longer survival (mortality hazard ratio 0.43, P=0.0002). Despite the retrospective nature of the analyses, GCLAC may be superior to FA/FLAG, particularly in patients with short duration of first complete remission or unfavorable cytogenetics. 相似文献
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Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia 总被引:4,自引:0,他引:4 下载免费PDF全文
Arceci RJ Sande J Lange B Shannon K Franklin J Hutchinson R Vik TA Flowers D Aplenc R Berger MS Sherman ML Smith FO Bernstein I Sievers EL 《Blood》2005,106(4):1183-1188
This open-label, dose-escalation study evaluated the safety and efficacy of single-agent gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted chemotherapeutic agent, for pediatric patients with multiple relapsed or primary refractory acute myeloid leukemia (AML). Twenty-nine children 1 to 16 years of age (relapsed disease, 19; refractory disease, 10) received gemtuzumab ozogamicin ranging from 6 to 9 mg/m2 per dose for 2 doses (separated by 2 weeks) infused over 2 hours. All patients had anticipated myelosuppression. Other toxicities included grade 3/4 hyperbilirubinemia (7%) and elevated hepatic transaminase levels (21%); the incidence of grade 3/4 mucositis (3%) or sepsis (24%) was relatively low. One patient treated at 9 mg/m2 developed veno-occlusive disease (VOD) of the liver and defined the dose-limiting toxicity. Thirteen patients underwent hematopoietic stem-cell transplantation less than 3.5 months after the last dose of gemtuzumab ozogamicin; 6 (40%) developed VOD. Eight of 29 (28%) patients achieved overall remission. Remissions were comparable in patients with refractory (30%) and relapsed (26%) disease. Mean multidrug resistance-protein-mediated drug efflux was significantly lower in the leukemic blasts of patients achieving remission (P < .005). Gemtuzumab ozogamicin was relatively well tolerated at 6 mg/m2 for 2 doses and was equally effective in patients with refractory and relapsed disease. Further studies in combination with standard induction therapy for childhood AML are warranted. 相似文献