Allogeneic Hematopoietic Cell Transplantation with FLAMSA-RIC Can Overcome the Poor Prognosis of Primary Refractory or Relapsed AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1938-1938
Author(s):  
Dominik Schneidawind ◽  
Birgit Federmann ◽  
Christoph Faul ◽  
Wichard Vogel ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Salvage Therapy ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Free Survival ◽  
Secondary Aml ◽  
Off Label ◽  
Dismal Prognosis ◽  
De Novo Aml ◽  
Refractory Aml

Abstract Abstract 1938 Introduction: Patients with relapsed or primary refractory AML have a dismal prognosis. Even salvage therapy with allogeneic hematopoietic cell transplantation (HCT) could not improve outcome due to high incidence of relapse and high non-relapse mortality (NRM). Recently, promising results in patients with unfavorable karyotype or treatment refractory AML have been reported using a sequential treatment with aplasia inducing chemotherapy consisting of Fludarabine, Ara-C and Amsacrine (FLAMSA) followed within 3 days by reduced intensity conditioning (RIC) for allogeneic HCT (Schmid et al., Blood 2006 Aug 1;108(3):1092–9). Methods: We report a retrospective analysis of our single center experience with FLAMSA-RIC in primary refractory or relapsed AML patients. We searched our database for patients receiving FLAMSA-RIC in the past 10 years. Details on characteristics and clinical course of the patients were confirmed by retrospective chart review. Results: We retrospectively identified and analyzed 51 consecutive patients (f=22, m=29) transplanted after FLAMSA-RIC at our institution from 2006–2011. At time of HCT patients were refractory after chemotherapy (n=22) or had an untreated relapse (n=29). Data on molecular and cytogenetic markers were available in 36 and 44 patients, respectively. 34 were initially high-risk because of unfavorable karyotype (n=25) or molecular genetic alterations (n=9). Median age of patients was 56 years (range, 20–72) and diagnosis of all patients was acute myeloid leukemia (de-novo AML, n=27, secondary AML, n=24). FLAMSA (Fludarabine 30 mg/m2 day −12 to −9, AraC 2000 mg/m2 day −12 to −11 and Amsacrine 100 mg/m2 day −12 to −9) was used as salvage therapy followed by RIC (Fludarabine 30 mg/m2 day −5 to −4/Busulfan 0.8 mg/kg day −6 to −4, n=10; TBI 4Gy on day −5/Cyclophosphamide 60 mg/kg on day −4 to −3, n=28; Busulfan 0.8 mg/kg day −6 to −4/Cyclophosphamide 60 mg/kg for matched and mismatched unrelated donors (MUD/MMUD) or 40 mg/kg for matched related donors (MRD) on day −3 to −2, n=13). As GVHD prophylaxis calcineurin inhibitor combined with mycophenolate mofetil and anti-thymocyte globuline (ATG-Fresenius®, 10 mg/kg for MRD and 20 mg/kg for MUD/MMUD) was used. 10 patients were transplanted from MRD, 16 from MUD, 21 from a MMUD and 4 from a MMRD. 14 patients received DLI (2 × 106 - 1 × 108 /kg after a median of 186 days, range 72–922) in absence of GVHD in case of mixed chimerism or relapse after HCT. Current overall survival (OS) was 18/51 patients with a median follow-up of 410 days (range, 179–1557) of patients alive resulting in a Kaplan-Meier estimated 2-year OS and event-free-survival (EFS) of 34% and 29%, respectively. There was no significant difference between the different RIC regimens with 50% Fludarabine / Busulfan vs. 26% TBI 4Gy / Cyclophosphamide and 40% Fludarabine / Busulfan (p=0.37). Causes of death were relapse (n=19), infections (n=5), GVHD (n=2), multi-organ-failure (n=5), cerebral hemorrhage (n=1) and progressive multifocal leukencephalopathy (n=1). Cumulative incidence of relapse at 2 years with death due to NRM as competing risk was 40% and cumulative incidence at 2 years of NRM with death due to relapse as competing risk was 27%. 2-year OS was inferior in patients with secondary AML compared to patients with de-novo AML (28% vs. 38% p=0.79). The outcome in the elderly subgroup defined by age ≥60 years (median age 67, n=22) was similar to the group of younger patients (median age 46, n=29) with 2-year OS of 31% vs. 37% (p=0.87). Patients with a blast count < 10% in the bone marrow at time of HCT had a better outcome with 64% vs. 25% OS (p=0.09). 2-year-OS was inferior in patients being refractory after chemotherapy (25% vs 38%, p=0.78). Incidence of acute GVHD (aGVHD) ≥II and chronic GVHD (cGVHD, limited, n=11, extensive, n=3) was 22% and 27%, respectively. Presence of aGVHD did not influence survival while presence of cGVHD was associated with an improved overall survival after HCT (58% vs 24%, p=0.009). Conclusion: FLAMSA-RIC followed by allogeneic HCT enables long-term disease free survival, even in primary refractory or relapsed AML patients. The sequential approach of this regimen seems to overcome the dismal prognosis of these patients. Its moderate toxicity allows the application of this curative salvage therapy option even in an elderly patient population. Disclosures: Off Label Use: The use of some agents in the conditioning is off-label.

Prognostic Implications of CD14 Positivity in Acute Myeloid Leukemia Arising From Myleodysplastic Syndrome,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3523-3523
Author(s):  
Yunsuk Choi ◽  
Sungdoo Kim ◽  
Young-Hun Park ◽  
Jae Seok Lee ◽  
Dae-Young Kim ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Free Survival ◽  
Secondary Aml ◽  
Hla Dr ◽  
Prognostic Implications ◽  
De Novo Aml

Abstract Abstract 3523 Introduction: Secondary AML that has evolved from MDS shows different clinical features and outcomes compared to de novo AML. Prognostic implications of immunophenotypes have been studied in de novo AML, whereas those have not well been defined in secondary AML from MDS. Methods: This retrospective study involved analysis of data from 65 adult patients, 37 males and 28 females, who were diagnosed with AML arising from MDS at a single institute. Data for baseline clinico-pathological features, treatments, and outcomes were collected from medical records of each patient. Immunophenotyping was performed for the markers including TdT, CD34, CD13, CD33, CD117, CD14, CD56, HLA-DR, CD3, CD7, CD10, and CD19 using flow cytometry. Results: At the time of MDS diagnosis, the WHO subtype was RA/RARS in 5, RCMD in 10, RAEB-1 in 17, RAEB-2 in 29, and unknown in 4. For the treatment of MDS, hypomethylating agents were given to 17 patients and 2 patients underwent allogeneic hematopoietic cell transplantation (HCT). Median duration of MDS prior to diagnosis of AML was 4.9 months (range, 0.3–91.1). At the time of AML evolution, median age was 50.7 years (range, 18–80), and cytogenetic risk group was good-risk in 1, intermediate-risk in 45, and poor-risk in 18. Proportion of positivity of each immunophenotype marker was as follows: TdT (5%), CD34 (65%), CD13 (98%), CD33 (97%), CD117 (90%), CD14 (22%), CD56 (10%), HLA-DR (93%), CD3 (2%), CD7 (35%), CD10 (8%), and CD19 (2%). After the evolution to AML, 52 patients received induction chemotherapy consisted of cytarabine plus idarubicin or daunorubicin and 8 patients underwent allogeneic HCT as initial treatment of AML. Complete remission (CR) was induced in 27 patients after treatment. At a median follow-up time of 29.2 months (range, 2.6–116.2) among surviving patients, 49 patients died, 13 relapsed, and 53 died or relapsed. Median overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 7.6, 26.1, and 5.4 months, respectively. Of immunophenotype markers, CD14 positivity only showed prognostic implications at the univariate analyses: lower CR rate after induction chemotherapy (P=0.034) and shorter survivals (OS, P<0.001; RFS, P=0.078, and EFS, P<0.001). Differences in OS and EFS remained significant after adjustment for other variables (OS, HR, 4.49, 95% CI, 2.16–9.87, P<0.001; EFS, HR, 4.06, 95% CI, 2.03–8.13, P<0.001). Other prognostic variables included age of 60 years or older (shorter OS [P=0.003] and EFS [P=0.020]), WBC over 60,000/mcl (shorter OS [P<0.001] and EFS [P=0.001]), and poor cytogenetic risk group (shorter OS [P=0.005]). Conclusions: Surface expression of CD14 on leukemic blasts was an independent prognostic factor for survivals in the patients with AML arising from MDS. Disclosures: No relevant conflicts of interest to declare.

Different Cytogenetic Patterns in Specified Categories of Secondary AML: Results of a Population-Based Registry Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3586-3586
Author(s):  
Jan M. Norgaard ◽  
Lene S.G. Oestgaard ◽  
Mette K. Andersen ◽  
Maria Kallenbach ◽  
Preben Johansen ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Risk Group ◽  
Prognostic Parameters ◽  
Cytotoxic Therapy ◽  
Cytogenetic Abnormalities ◽  
Secondary Aml ◽  
Hematological Neoplasm ◽  
Previously Treated ◽  
De Novo Aml

Abstract Abstract 3586 The prognosis of leukemia patients suffering from secondary AML (sAML) compared to that of patients with de novo AML is dismal. The group of sAMLs is heterogeneous and includes AML arising from an antecedent myelodysplastic (MDS) or myeloproliferative neoplasm (MPN), and AML caused by cytotoxic therapy (tAML). In the present retrospective population- and national registry-based analysis we identified 612 (27%) patients as having some form of sAML. Cytogenetic risk group patterns and clinical outcomes among the different categories of sAML were compared to those of 1635 de novo AML cases identified in a total population of 2261 patients (data missing in 14 cases). The cohort represents >90% of all AML patients diagnosed and treated in Denmark during the eleven-year period January 2000 through December 2010. The following groups of sAMLs were identified: A. Patients with an antecedent MDS or chronic myelomonocytic leukemia (324 cases), B. Patients with antecedent MPN (excluding chronic myeloid leukemia, 108 cases), C. Patients previously treated with chemo- and/or radiotherapy for another hematological neoplasm (113 cases), and D. Patients previously treated with chemo- and/or radiotherapy for another non-hematological neoplasm or disease (67 cases). For all 1168 curatively treated patients in the total cohort, presenting cytogenetic abnormalities (categorized according to revised MRC-criteria, D. Grimwade et al. Blood, 2010), age, leukocyte count, and type of leukemia (secondary vs. de novo) were all prognostic parameters found to be highly statistically significant to probability of attainment of complete remission (CR) and to overall survival (OS) in univariate as well as multivariate analyses, data not shown. There were strikingly fewer patients showing favorable cytogenetic abnormalities among sAMLs. Focusing on the above defined 4 categories of sAML, patterns of cytogenetic risk group distribution were strikingly and statistically significantly different (nevaluable= 418, p-value, Chi-square <10−4), Table 1, with favorable cytogenetic abnormalities being relatively more frequent in sAML-category D.Table 1.Category of sAML and cytogenetic abnormalitiesCategory of sAMLCytogenetics, (revised MRC-categories)A (MDS and CMML) (%)B (MPN) (%)C (Cytotoxic therapy, hematological neoplasm) (%)D (Cytotoxic therapy, non-hematological neoplasm a.o.) (%)TotalFavorable1 (0.5)1 (1.3)2 (2.9)10 (18.5)14Intermediate157 (72)52 (68.4)49 (70)29 (53.7)287Unfavorable60 (27.5)23 (30.3)19 (27.1)15 (27.8)117Total218767054418 Additionally, in the sAMLs we found age, cytogenetic abnormalities, and white blood cell count (WBC) to be highly statistically significant to probability of attainment of CR and to duration of OS. By contrast, we did not find the specific sAML category to be of significance to probability of attainment of CR or to duration of OS, Table 2, Fig. 1.Table 2.Factors of significance to probability of attainment of CR and to OS in 246 cases of secondary AMLProbability of CR (Logistic regression, nevaluable= 246)Probability of overall survival (Cox regression, nevaluable= 246)VariableOdds ratio (OR)95% CI of ORP valueHazard ratio95% CI of HRP valueAge1.071.03–1.11<10-41.021.01–1.040.006Cytogenetics3.291.71–6.34<10-42.021.46–2.78<10-4Male gender--NS--NSWBC1.011.003–1.0170.0061.0041.002–1.0070.001sAML-category--NS--NS In conclusion, from these analyses we confirm the prognostic significance of presence of sAML as well as other well established prognostic parameters in AML. We find cases of sAML-category D, i.e., patients previously treated with chemo- and/or radiotherapy for another non-hematological neoplasm or disease, to exhibit favorable cytogenetic abnormalities relatively frequently. Probability of attainment of CR and OS duration were similar in the four different specific categories of sAML. Well established prognostic parameters including age, cytogenetic abnormalities, and WBC are of significant prognostic value in sAML. Disclosures: No relevant conflicts of interest to declare.

Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with High-Risk AML in Complete Remission: A Survey from the ALWP of the EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3105-3105
Author(s):  
Florent Malard ◽  
Myriam Labopin ◽  
Gernot Stuhler ◽  
Johanna Tischer ◽  
Joerg Thomas Bittenbring ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Research Funding ◽  
Antithymocyte Globulin ◽  
De Novo ◽  
Conditioning Regimen ◽  
Secondary Aml ◽  
Off Label ◽  
Advisory Boards ◽  
De Novo Aml

Abstract Introduction. Allogeneic hematopoietic cell transplant (HCT) is an established treatment modality that is potentially curative for many patients with acute myeloid leukemia (AML). The development of reduced intensity conditioning (RIC) allows performing HCT in elderly and/or in heavily pretreated patients and in those with comorbidities precluding the use of standard myeloablative conditioning. Post-transplant relapse remains a challenge after RIC, particularly in patients with adverse prognosis factors.The so-called "sequential" transplant approach (e.g. FLAMSA regimen combining both intensive chemotherapy and RIC HCT within the same procedure) initially developed in patients with refractory AML, could be a promising strategy to improve disease control and decrease the risk of relapse in high-risk AML patients in complete remission (CR). Patients and methods. In the current study we analyzed transplantation outcomes in a cohort of 411 adults AML patients in CR at time of transplant, treated between 2002 and 2013. Patients received a "sequential" conditioning regimen based on Fludarabine 30 mg/m2/d, high-dose aracytine 1-2 g/m2/d, amsacrine 100 mg/m2/d for 5 days and after a 3 days rest, total body irradiation (TBI) 4Gy, cyclophosphamide 50-120 mg/kg, and antithymocyte globulin (ATG) for 2 to 3 days (TBI group, n=269 [65%]). In 142 (35%) patients, TBI was substituted by IV Busulfan 3.2 mg/kg/d for 2 days, or orally equivalent dose (Bu group). 323 patients (79%) had de-novo AML and 88 (21%) had a secondary AML (with prior myelodysplastic syndrome). At time of transplant, 300 (73%) patients were in CR1 and 111 (27%) in CR2. Cytogenetic study in de novo AML was favorable in 19 patients (6%), intermediate in 102 (32%) and poor in 41 (13%). Cytogenetic data were missing in 161 (50%). 104 (25%) patients received matched related donors (MRD) and 307 (75%) unrelated donor (URD) HCT. Majority of patients (94%) received mobilized peripheral blood stem cells graft. Results. Median follow-up of surviving patients was 28 months and median age at transplant was 54 years (18-76). ANC>500/μL was achieved at a median of 17 (range, 9-74) days after HCT. Sixteen patients (4%) failed to engraft. Two year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 22% (95%CI, 18-26%) and 22% (95%CI, 18-27%), respectively. The Kaplan-Meier estimate of overall (OS) and leukemia-free survival (LFS) at 2 years were 59% (95%CI, 54-65%) and 56% (95%CI, 50-61%), respectively. Acute GVHD (grade II-IV) occurred in 109 (28%) patients. The 2-year cumulative incidence of chronic GVHD was 31% (95%CI, 26-36), extensive in 17% (95%CI, 12-21). Two years RI, NRM, LFS and OS in TBI vs. Bu patients were 21.8% vs 21.7% (p=0.69), 29.4% vs 18.3% (p=0.008), 48.8% vs 59.6% (p=0.045) and 51.2% vs 64.0% (p=0.013), respectively. In multivariate analysis adjusted for variable with different distribution between Bu and TBI groups, the type of conditioning (TBI vs Bu) has no impact on RI, NRM, LFS and OS. Age over 55 at transplant was an independent adverse prognostic factor in multivariate analysis for NRM (hazard ratio (HR: 1.61, 95% CI: 1.00-2.61, p=0.05)), LFS (HR: 1.39, 95% CI: 1.00-1.92, p=0.05) and OS (HR: 1.55, 95% CI: 1.11-2.18, p=0.01). Being treated in an experienced center (defined as having including 10 or more transplants in the study) was associated with a significant lower RI (HR: 0.84, 95% CI: 0.75-0.93, p=0.001) and better LFS (HR: 0.91, 95% CI: 0.84-0.98, p=0.01) and OS (HR: 0.91, 95% CI: 0.84-0.98, p=0.02). Finally, transplantation from an URD was associated with a significant increase in NRM (HR: 2.11, 95% CI: 1.14-3.91, p=0.02). Of note, CR1 vs. CR2 and de novo vs. secondary AML had no impact on patients' outcome. Conclusions. These results in a rather large cohort of patients with AML suggest that a FLAMSA "sequential" regimen provided an efficient disease control in high-risk AML patients including in CR2 and secondary AML. Furthermore Busulfan and TBI based FLAMSA "sequential" regimens provide a similar outcome. These results should be confirmed in a multicenter well design randomized study. Disclosures Off Label Use: off-label drug use: antithymocyte globulin (ATG) for allo-SCT conditioning. Tischer:Sanofi-Aventis: Other: advisory board. Schmid:Neovii: Consultancy; Janssen Cilag: Other: Travel grand. Mayer:Janssen: Research Funding. Hallek:Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding.

scholarly journals CPX-351 Induces Remission in Newly Diagnosed Pediatric Secondary Myeloid Malignancies

2021 ◽  
Author(s):  
Yixin Hu ◽  
Kenneth J Caldwell ◽  
Mihaela Onciu ◽  
Sara M Federico ◽  
Marta Salek ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Young Patients ◽  
Molar Ratio ◽  
Newly Diagnosed ◽  
Dismal Prognosis ◽  
De Novo Aml ◽  
Cornelia De Lange ◽  
No Innovation ◽  
Favorable Safety

Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children/adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT) but there has been no innovation in cytoreductive regimens. CPX-351, a fixed 5:1 molar ratio of liposomal cytarabine/daunorubicin, has shown favorable safety and efficacy in elderly individuals with sAML and children with relapsed de novo AML. We report the outcomes of seven young patients (six with newly diagnosed sMDS/AML and one with primary MDS/AML) uniformly treated with CPX-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-ALL; one had predisposing genomic instability disorder (Cornelia de Lange); and one MDS-related AML and multi-organ failure. The median age at diagnosis of myeloid malignancy was 17 (13-23) years. Patients received 1-3 cycles of CPX-351 (cytarabine 100mg/m2 plus daunorubicin 44mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding FLT3 inhibitor as individualized therapy in one patient. Six patients were alive and leukemia-free at 0.5-3.3 years after HCT. One patient died from disease progression before HCT. Concluding, CPX-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML warranting prospective studies.

scholarly journals De Novo and Secondary Acute Myeloid Leukemia, Real World Data on Outcomes from the French Nord-Pas-De-Calais Picardie Acute Myeloid Leukemia Observatory

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4013-4013 ◽  
Author(s):  
Loïc Renaud ◽  
Olivier Nibourel ◽  
Celine Berthon ◽  
Christophe Roumier ◽  
Céline Rodriguez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Supportive Care ◽  
Real World ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Secondary Aml ◽  
Secondary Acute Myeloid Leukemia ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background. Population-based registries may provide data complementary to that from clinical intervention studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations like secondary Acute Myeloid Leukemia (AML). Actually, secondary AML are frequently excluded from clinical trials so the registries constitute the only way to fine data for establishing recommendations for the management of these patients in the real world. Method. The French Nord-pas-de-calais Picardie AML observatory containing 1 582 AML patients diagnosed between 2000 and 2015. We compared 974 primary AML to 514 Secondary AML include AML arising from a pre-existing myelodysplastic (n=211), myeloproliferative (n=88) or myelodysplastic/myeloproliferative (n=57) disease and therapy related AML (t-AML) (n=158). Results. Median survival and 5 years overall survival were respectively 420 days [95%IC: 349-491] and 32% for patients with de novo AML; 157 days [95%IC: 118-196] and 7% for patients with secondary AML. 1101 patients were classified according to the MRC as favorable, intermediate and unfavorable, respectively 18(5.2%), 178(51.9%) and 147(42.9%) patients with secondary AML including 100(29.2%) complexes karyotypes and 117(15.4%), 468(61.7%) and 173(22.8%) patients with de novo AML including 121 (15.9%) complexes karyotypes. 987 patients were classified according to the ELN as favorable, intermediate-1, intermediate-2 and unfavorable for respectively 35(11.7%), 53(17.7%), 67(22.%) and 144(48.2%) patients with secondary AML and 219(31.8%), 167(24.%), 136(19.8%) and 166(24.1%) patients with de novo AML. The age at diagnosis was significantly different (p < 10-3) with a median of 72.6 years for secondary AML and 63.2 for de novo AML. 206 (40.4%) patients with secondary AML received demethylating agents versus 184 (19%) for de novo AML and 152(29%) received high dose chemotherapy (HDC) versus 619 (63.9%) patients with de novo AML. Best supportive care was the only treatment for 170 (17.5%) de novo AML and 164 (31.9%) secondary AML patients. For patients over than 60 years old, median survival and 5 years overall survival were respectively 182 days [95%IC: 136.5-127.4] and 12.9% for 559 patients with de novo AML; 128 days [95%IC: 95.0-161.0] and <4% for 413 patients with secondary AML. Conclusion. The poor prognosis of secondary and t- AML is confirmed by this registry study. Possible explanations for this worse outcome could be older age at diagnosis and increased frequency of complex karyotypes which lead to less intensive therapy or supportive care only. In this specific population, the choice of demethylating agent therapy was frequently made because of the weak efficacy of HDC and increased frequency of side effects in this vulnerable group. Disclosures No relevant conflicts of interest to declare.

scholarly journals Smoking Adversely Affects Survival in Acute Myeloid Leukemia Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 979-979 ◽  
Author(s):  
Ramya Varadarajan ◽  
Andrea Licht ◽  
Andrew J. Hyland ◽  
Laurie Ann Ford ◽  
Maurice Barcos ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Smoking Status ◽  
Progression Free Survival ◽  
Free Survival ◽  
Secondary Aml ◽  
Never Smokers ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Abstract 979 Poster Board I-1 Smoking is the leading preventable cause of death. Smokers are approximately 1.5 times more likely to develop acute myeloid leukemia (AML) than non-smokers, but little is known about the relationship between cigarette smoking and AML outcome. We studied the effect of smoking on outcome in 282 newly diagnosed AML patients treated with high-dose cytarabine and idarubicin-containing regimens at Roswell Park Cancer Institute between 9/92 and 12/08. There were 161 males and 121 females (median age 56 years, range 18-85 years). The median follow up was 12.9 (range, <1-195) months. A total of 161 patients were <60 years and 121 patients were ≥60 years old. AML was de novo in 201 patients and secondary (50 with antecedent hematologic disorder; 31 with therapy-related AML) in 81. Karyotypes were favorable in 24 patients, intermediate in 122, unfavorable in 101, unknown-risk in 23 and unavailable in 12. White blood cell (WBC) count was <100×109/L in 251 patients and WBC ≥100×109/L in 31 at the time of diagnosis. Age ≥60 and secondary AML were associated with worse outcome [37.7 vs. 21.8 months; 95% confidence interval (CI) 30.6 to 44.7 vs. 15.5 to 28.1 for age (p=0.002) and 35.7 vs. 18.7 months; 95% CI 29.6 to 41.9 vs. 11.7 to 25.7 for AML presentation (p=0.002)]. Similarly, patients with unfavorable karyotype had worse outcome compared with intermediate and favorable karyotypes [20.4 vs. 34.8 vs. 70.2 months; 95% CI 13.2 to 27.5 vs. 27.3 to 42.2 vs. 45.4 to 95 respectively for karyotype (p<0.001)]. Sixteen patients underwent allogeneic transplantation in first remission. One hundred and eighty patients (64%) were smokers (current smokers 22% and previous smokers 42%), while 102 patients (36%) were non-smokers. There were no significant differences in age, AML presentation, karyotype or WBC count at diagnosis based on smoking status. Never-smokers had a significantly longer overall survival (OS) [39.5 months (95% CI 29.9-49.1)] than smokers [24 months (95% CI 18-30.2) for former smokers and 29.6 months (95% CI 19-40.3) for current smokers] (p=0.02). Similarly, there was a significant difference in progression-free survival between smokers and non-smokers (25.4 vs. 38.4 months; 95% CI 18.4 to 32.3 vs. 27.1 to 49.8; p=.040). Subgroup analysis revealed no difference in OS for the different smoking categories among patients <60 years old. For older patients, previous and current smokers survived only about half as long as never smokers (31.5 vs. 16.7 months; 95% CI 16.1 to 46.9 vs. 11.4 to 21.9; p=0.026). Similarly, smoking among secondary AML patients affected OS [previous and current smokers 13.1 months (95% CI 7.6-18.6) vs. never-smokers 30.6 months (95% CI 12.1-49); p=0.01], while no effect was seen among de novo AML patients (previous and current smokers 31.7 months vs. never smokers 42.5 months; p=0.09). Furthermore, previous and current smokers with intermediate karyotype had a shorter OS when compared to never-smokers [12.2 vs. 34.9 months; 95% CI 8.4 to 13.2 vs. 16.7 to 53.0; p=0.002] but smoking status had no effect among favorable (65.5 vs. 78.2 months; p=0.62) or unfavorable (32.1 vs. 39.2 months; p=0.36) karyotype groups. Finally, previous and current smokers with WBC count <100×109/L had shorter OS when compared to never-smokers (27 vs. 41 months; 95% CI 21.1 to 32.8 vs. 30.6 to 51.0 months; p=0.012), while smoking had no effect among patients with WBC count ≥100×109/L (16.8 vs. 30.4 months; p=0.34). In multivariate analysis using age, AML presentation, karyotype, WBC count and smoking status as covariates, age, smoking status and karyotype remained of prognostic value for overall survival. In conclusion, cigarette smoking has a deleterious effect on OS and progression free survival in similarly treated AML patients. Disclosures: No relevant conflicts of interest to declare.

Fractionated Doses of Gemtuzumab Ozogamicin (GO) Combined to Standard Chemotherapy (CT) Improve Event-Free and Overall Survival in Newly-Diagnosed De Novo AML Patients Aged 50–70 Years Old: A Prospective Randomized Phase 3 Trial From the Acute Leukemia French Association (ALFA)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 6-6 ◽  
Author(s):  
Sylvie Castaigne ◽  
Cécile Pautas ◽  
Christine Terre ◽  
Emmanuel Raffoux ◽  
Dominique Bordessoule ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Gemtuzumab Ozogamicin ◽  
Primary Study ◽  
Type I ◽  
Front Line ◽  
Phase 3 ◽  
Study Objective ◽  
Free Survival ◽  
De Novo Aml

Abstract Abstract 6 Aim. GO is a potent antibody-directed chemotherapy against CD33 antigen. Two MRC and SWOG Phase 3 studies have compared standard CT alone or combined with one single GO infusion (at 3 and 6 mg/m2, respectively) in younger adults with AML with contradictory results (Burnett, JCO 2011; Petersdof, Blood 2009). We have shown in relapsed AML Phase 2 studies that fractionated infusion of GO 3 mg/m2 on day 1, 4 and 7 was effective and might be safely combined to standard 3+7 DNR/AraC induction (Taksin, Leukemia 2007; Farhat, AJH, accepted). Here, we report the results of the prospective open label randomized multicentric Phase 3 ALFA 0701 trial (ClinicalTrial.gov ID, NCT00927498) designed to evaluate the efficacy and safety of adding this fractionated GO schedule to standard front-line chemotherapy in older AML pts. Methods. Eligible patients (pts) were adults aged 50–70 years old with previously untreated de novo AML. Pts were randomized to receive induction with DNR 60 mg/m2/d on day 1–3 and AraC 200 mg/m2/d CI on day 1–7, without (DA arm) or with GO at 3 mg/m2/d on day 1, 4 and 7(DAGO arm). Pts with persistent marrow blasts at day 15 received additional DNR 35 mg/m2/d on day 1–2 and AraC 1g/m2/12h on day 1–3. Pts achieving CR/CRp received two consolidation courses with DNR 60 mg/m2/d on day 1 and AraC 1 g/m2/12h on day 1–4, ± GO at 3 mg/m2/d on day 1 according to the randomization arm. The primary study objective was event-free survival (EFS). The study was designed to detect a 25% to 40% EFS gain at 3 years, (two-sided test, power 80%, type I error 5%). Secondary objectives were response rate, disease-free survival (DFS), overall survival (OS), and safety. Results. From March 2008 to November 2010, the required sample of 280 pts (median age, 62 years) was enrolled. Nine pts did not satisfy for inclusion criteria and were excluded from analysis. Cytogenetics was favorable (N=9), intermediate (N=177), adverse (N= 57), not done/failure (N=28). Overall, 52 pts had a favorable NPM1+ w/o FLT3-ITD genotype. The two treatment arms were well matched for all pre-treatment characteristics including age, sex, ECOG-PS, WBC, cytogenetics and molecular characteristics. CR+CRp was achieved in 220/271 pts (77%): 100/134 (75%) in the control DA arm versus 110/137 (80%) in the DAGO arm (P=0.31). There were 5/134 (4%) induction deaths in DA arm and 9/137 (6%) in DAGO arm (P=0.41). Primary resistant AML rate was 29/134 (22%) after DA versus 18/137 (13%) after DAGO (P=0.08). At 2 years, EFS was estimated at 15.6% in DA arm versus 41.4% in the DAGO arm (P=0.0018), while DFS was 18.1% in DA arm and 48.5% in the DAGO arm (P=0.0009). This significant benefit in EFS (primary objective) was observed in pts aged <65 years (P=0.035) as well as in older pts (P=0.019), and persisted after censoring the 39 pts who received allogeneic stem cell transplantation in first CR/CRp at transplant time (P=0.015). Subgroup analysis showed that EFS benefit persisted in pts with favorable/intermediate karyotype (P=0.0008) while not in those with adverse karyotype (P=0.25). Interestingly, EFS benefit was still observed when excluding favorable pts (favorable karyotype or genotype) from the comparison (P=0.0017). Finally, in the whole patient population, this gain in EFS translated into a longer OS (median, 25.4 versus 15.3 months in DAGO versus DA pts; P=0.037). Besides treatment arm, cytogenetics and favorable genotype were the only factors predictive of outcome. After adjustment on these factors, DAGO treatment remained significantly associated with longer EFS (P=0.009), DFS (P=0.003), but not OS (P=0.14). The rate of fatal adverse events at least possibly attributable to treatment was 9/134 (6.7%) in the DA and 12/137 (8.7%) in the DAGO arm (P=0.65). Prolonged grade ≥ 3 thrombocytopenia was observed in 19 DAGO pts, either after induction (N= 4) or first consolidation (N=15). Three liver VOD were observed in the DAGO arm (2 during induction, 1 during first consolidation), 2 being associated with a fatal issue. No difference was observed between both arms in the incidence of severe sepsis (DAGO 18.9%, DA 14%), as well as in the rate of intensive care unit admission during the course of therapy (DAGO 14.5%, DA 12.6%). Conclusion. The addition of fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) to standard CT significantly improves EFS and to a less degree OS in AML pts aged 50–70 years old. The main toxicity observed with GO was prolonged thrombocytopenia in 19 patients and 3 episodes of VOD. Disclosures: Castaigne: Pfizer/Wyeth: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Gemtuzumab Ozogamicin is available in Europe as a compassionate treatment for relapsed AML. In this study patients GO was used in front-line treatment.

Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients with De Novo and Secondary Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 149-149 ◽  
Author(s):  
Boglarka Gyurkocza ◽  
Rainer F. Storb ◽  
Barry Storer ◽  
Thomas Chauncey ◽  
Dietger Niederwieser ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Progression Free Survival ◽  
Disease Status ◽  
Progression Rate ◽  
Free Survival ◽  
Secondary Aml ◽  
Allogeneic Hct ◽  
Donor Type ◽  
Unrelated Donors

Abstract We report the results of 256 patients (median age = 59; range, 5–74 years) with de novo AML in first complete remission (CR1; n=100), beyond CR1 (n=79) and with treatment-related or secondary AML (n=77) who underwent allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related (n=109) or from unrelated donors (n=147). Indications of allogeneic HCT in CR1 were persistent cytogenetic or molecular evidence of disease, poor-risk cytogenetics at diagnosis, treatment-related or secondary AML and age more than 60 years. Younger patients were included if they had comorbid conditions that excluded them from conventional allogeneic HCT. Sixteen patients were mismatched with their donors for ≥ one HLA antigen, while the remainder were matched 10/10 at the antigen level. Conditioning consisted of low-dose total body irradiation (TBI; 2 Gy) on day 0 either alone (n=28) or combined with fludarabine, 30 mg/m2/day on days −4 to −2 (n=228). Calcineurin inhibitors (cyclosporine or tacrolimus) and mycophenolate mofetil were used for postgrafting immunosuppression. Durable engraftment was observed in 94% of patients. With a median follow-up of 35 (range, 3 – 111) months in surviving patients, the estimated progression-free and overall survivals at 5 years were 32% (95% CI: 25–38%) and 32% (95% CI: 25–38%), respectively. The cumulative incidences of relapse/progression and non-relapse mortality at 5 years were 40% (95% CI: 33–46%) and 29% (95% CI: 22–35%), respectively. Estimated 5-year survival rates, progression-free survival, relapse/progression rate, and non-relapse mortality according to disease status are shown in Table 1; Table 2 shows the same indices according to donor type. The cumulative incidences of grades II–IV and III–IV acute graft-versus-host disease (GVHD) in patients with related donors were 40% and 13%, and in those with unrelated donors were 58% and 14%, respectively. The cumulative incidence of chronic extensive GVHD at 5 years was 44% in patients with related donors, and 42% in patients with unrelated donors. Age &gt; 60 years at the time of HCT did not have an impact on the outcome (univariate analysis). Additional analyses regarding the impact of HCT comorbidity scores and minimal residual disease at the time of HCT are in progress. Based on this multicenter analysis, we conclude that allogeneic HCT from related or unrelated donors, utilizing a conditioning regimen of low dose TBI (2 Gy) with fludarabine provides long term remission in elderly and/or medically infirm patients with AML, who were not considered candidates for conventional HCT. Table 1. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to disease status. CR1: 1st remission; &gt;CR1: subsequent remission, induction failure/persistent disease; sAML: treatment-related and secondary AML. Disease Status n %OS (95% CI) %PFS (95% CI) RR (95% CI) NRM (95% CI) CR1 100 33 (20–46) 34 (23–46) 36 (26–47) 30 (19–40) &gt;CR1 79 38 (26–49) 35 (23–46) 40 (29–52) 25 (15–35) sAML 77 20 (8–32) 23 (11–35) 45 (32–57) 32 (20–45) Table 2. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to donor type. Donor Type n %OS (95% CI) %PFS (95% CI) RR (95% CI) NRM (95% CI) HLA-identical related 109 34 (23–44) 34 (24–45) 47 (37–58) 18 (10–26) HLA-matched unrelated 131 31 (22–40) 30 (21–39) 37 (29–46) 33 (24–72) HLA mismatched unrelated 16 24 (0–50) 24 (0–50) 6 (0–18) 70 (43–97)

scholarly journals Hypomethylating Agents (HMAs) as Salvage Therapy in Relapsed or Refractory AML: An Italian Multicentric Retrospective Study

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 972
Author(s):  
Federica Lessi ◽  
Marica Laurino ◽  
Cristina Papayannidis ◽  
Orsola Vitagliano ◽  
Francesco Grimaldi ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Progressive Disease ◽  
De Novo ◽  
Hypomethylating Agents ◽  
Best Response ◽  
Response Versus ◽  
De Novo Aml ◽  
Clinical Records ◽  
Refractory Aml ◽  
Better Than

Data on the use of azacytidine and decitabine as salvage therapy for acute myeloid leukemia are limited. We retrospectively reviewed clinical records of 100 patients treated with hypomethylating agents (HMA) as salvage therapy in nine Italian institutions. A total of 24% of patients obtained a response to HMA (CR, PR, or CRi), while 26% showed a stable disease (SD); 50% of patients experienced progressive disease. Median OS was 6.5 months. OS in patients with de novo AML was 6.1 months, while OS in patients with secondary AML (sAML) was 12.3 months (p = 0.037). Median OS after HMA in patients with SD as best response to HMA was similar to median OS in patients with response to HMA (10.6 months vs. 13 months). On multivariate analysis, OS difference between patients who obtained a response versus patients who did not was significant (p = 0.0037). OS difference in sAML was significantly better than in de novo AML (p < 0.00001). HMA showed a remarkable efficacy in terms of response rate and OS in a subgroup of patients (sAMLs), historically characterized by a poor outcome. Therefore, 5Azacitidine and decitabine may represent a good clinical option in a selected patient population with relapsed or refractory AML, unsuitable for allo-HSCT.

scholarly journals Advanced melanoma, a pharmacological evaluation

2021 ◽  
Vol 31 (Supplement_2) ◽  
Author(s):  
Anabela Andrade ◽  
Jorge Balteiro
Keyword(s):  
Overall Survival ◽  
Targeted Therapy ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Advanced Melanoma ◽  
New Drugs ◽  
High Rate ◽  
Free Survival ◽  
Dismal Prognosis

Abstract Background Cutaneous melanoma is an aggressive cancer that occurs in melanocytes, located in the epidermis. Historically it has a high rate of morbidity and mortality, due to the resistance and toxicity of traditional therapies. Its incidence has increased annually by 4% to 8%. Until 2011 it was still considered a devastating and almost always fatal disease in a few months. Advances in therapies have significantly improved the results of most patients with advanced melanoma, especially those with a BRAFV600 mutation, which account for almost 50% of tumors. Before the recent evolution in treatment, the prognosis and overall survival were considered very bad. The introduction of new drugs has improved progression-free survival and overall survival, as well as producing faster clinical responses. Methods Comparison of endpoints such as progression-free survival and overall melanoma survival from the Summary of Product Characteristics (SPC) studies of each drug in the therapeutic groups under assessment used in the disease. The variables used were the Endpoints Global Survival at various times (12 months, 24 months, 36 months and the median) and Progression-Free Survival. Results Combined immunotherapy (Nivolumab and Ipilimumab) improves overall survival and progression-free survival, achieving better results than targeted therapy. In this, the combination of a BRAF inhibitor and a MEK inhibitor, presents better results with the combination of Encorafenib and Binimetinib. Conclusions Both targeted therapy and immunotherapy transform melanoma with a dismal prognosis into a life-threatening illness.

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