scholarly journals Decrease in Transfusion Needs in Patients with Higher-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia Treated with 5-Azacytidine. a Retrospective Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5608-5608
Author(s):  
Panagiotis Theodorou Diamantopoulos ◽  
Konstantinos Zervakis ◽  
Athanasios G. Galanopoulos ◽  
Panagiotis Bakarakos ◽  
Vasiliki Papadopoulou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Safety Data ◽  
Supportive Treatment ◽  
Efficacy And Safety ◽  
Red Blood Cell Transfusions ◽  
Acute Myeloid

Abstract Introduction The hypomethylating agent 5-azacytidine (AZA) has been the standard of care for higher risk Myelodysplastic Syndromes (MDS) for the last few years. Its efficacy has been proven in large clinical trials, and its safety has been shown to be superior to that of conventional treatments. We have conducted a retrospective study about the efficacy and safety of 5-azacytidine, as reported and analyzed in our center. Patients and Methods Forty four consecutive patients with MDS or Acute Myeloid Leukemia (AML) with 20-30% bone marrow blasts that were treated with AZA during the last 63 months were included in the study. The clinical and laboratory characteristics of the patients were recorded, and the efficacy and safety data were analyzed. Results The epidemiologic and hematologic characteristics of the patients are shown in Table 1. The median overall survival was 13 months (1-101) and there was no primary treatment failure (Table 2). Serious adverse events consisted mostly of neutropenic infections (blood stream and pneumonia) (Table 3). Discussion Treatment with AZA offered a favorable (complete and partial) response in 34.1% of the patients, and an overall survival of 13 months, with generally predictable toxicities, although hospitalization was frequently inevitable during the first treatment cycles, when supportive treatment was a significant part of the management. A valuable observation is that there was a considerable decrease in the patients’ transfusion needs following treatment (p<0.0001). Our results are consistent with the results of other clinical trials and point out the need for investigational 5-azacytidine combinations. Table 1. Epidemiologic and hematologic characteristics. Male: Female ratio 30:14 (2.1 : 1) Age, Median (Range) 73 (54-81) WHO classification of MDS/AML, N (%) RAEB-I RAEB-II RCMD-RS RCMD RARS CMML AML 9 (20.5) 18 (40.9) 2 (4.5) 3 (6.7) 1 (2.3) 4 (9.1) 7 (15.9) IPSS classification, N (%) Low Intermediate-1 Intermediate-2 High Not Applicable (AML) 0 (0) 3 (6.8) 29 (65.9) 5 (11.4) 7 (15.9) Complete Blood Count Parameters, Median (Range) Hemoglobin (g/dL) Absolute Neutrophil Count (x109/L) Platelet count (x109/L) 8.55 (4.5 - 12.5) 1.08 (0.0 – 16.3) 80.0 (2 – 820) Transfusion dependence, N (%) 39 (88.6) Transfusions per month, Median (Range) 3 (0 – 7) Table 2. Efficacy data AZA cycles, Median (Range) 5 (1-22) Actual AZA dose (mg/m2/cycle), Median (Range) 75 (59-75) Actual cycle duration (days), Median (Range) 28 (28-40) Dose reductions due to sustained neutropenia, N (%) 6 (13.6) Temporary AZA interruption, N (%) 26 (59.1) Reason Sustained cytopenia 10/26 (38.5) Neutropenic Infection 15/26 (57.7) Hemorrhagic Complication 1/26 (3.8) Permanent AZA discontinuation, N (%) 23/44 (52.3) Reason AML transformation 17/23 (73.9) Recurrent or severe infection 4/23 (17.4) Pyoderma gangrenosum 1/23 (4.3) Allogeneic Bone Marrow Transplantation 1/23 (4.3) AZA cycles till response (according to the IWG criteria), Median (Range) 4 (1 – 7) Response (IWG criteria), N (%) Complete response Partial response Stable disease Failure 7 (15.9) 8 (18.2) 29 (65.9) 0 (0) Overall survival (months), Median (Range) 13 (1 – 101) Post treatment transfusion dependence, N (%) 34 (77.3) Transfusions per month (post-treatment), Median (Range) 1 (0 – 5) Death rate, N (%) 29/44 (65.9) Cause of death, N (%) Infection Hemorrhage Cardiac dysrhythmia 24/29 (82.8) 3/29 (10.3) 2/29 (6.9) Table 3. Safety data Clinical adverse events, N (%) 29/44 (65.9) Neutropenic Infections 26/29 (89.7) Bloodstream Infection 9/26 (34.6) Lower respiratory infection 10/26 (38.5) Neutropenic Fever 8/26 (30.1) Septic shock 2/26 (7.7) Hemorrhagic events 2/29 (6.7) Cerebral hemorrhage (Grade 5) 1/2 (50.0) Epistaxis (Grade 3) 1/2 (50.0) Other (pyoderma gangrenosum) 1/29 (3.4) Laboratory incidents1, N (%) 44/44 (100) All grades Grades 3/4 Neutropenia 36/44 (81.8) 34/44 (77.3) Anemia 44/44 (100) 24/44 (54.5) Thrombocytopenia 31/44 (70.5) 21/44 (47.7) Supportive treatment (during AZA administration), N (%) GCSF administration 16/44 (36.4) Erythropoietin administration 7/44 (15.9) Red blood cell transfusions 39/44 (88.6) Red blood cell transfusions (units/cycle), Median (range) 3 (0-7) Pooled random donor platelet transfusions 17 (38.6) 1According to the CTCAE Version 4.0 Disclosures No relevant conflicts of interest to declare.

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

Targeted Intravenous Busulfan and Fludarabine Allogeneic Transplantation Conditioning in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2290-2290
Author(s):  
Joseph A. Pidala ◽  
Jongphil Kim ◽  
Claudio Anasetti ◽  
Melissa Alsina ◽  
Ernesto Ayala ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Large Series ◽  
Myelogenous Leukemia ◽  
Secondary Aml ◽  
Relapsed Disease ◽  
Acute Myeloid

Abstract Abstract 2290 Poster Board II-267 Reduced and intermediate intensity conditioning with allogeneic hematopoietic cell transplantation (HCT) offers promise to effectively control hematologic malignancies, while limiting treatment related toxicity and mortality (TRM). We aimed to examine the efficacy of IV targeted Busulfan and Fludarabine (IV-Bu/Flu) in a large series of adults with exclusively acute myelogenous leukemia (AML). One hundred adults (median age 48) with AML (CR1 49, CR2 25, REL1 8, REL2 1, PIF 16, untreated 1) were treated with Busulfan 130-145 mg/m2/day for four days with pharmacokinetic targeting on the final two days to achieve an area under the curve (AUC) of 5300 (+/-10%) μmol*min/L/day and Fludarabine 40mg/m2/day for 4 days, followed by transplantation of G-CSF mobilized peripheral blood stem cells (PBSC) (N=98) or unstimulated bone marrow (BM) (N=2) from allogeneic donors (MRD 38, MUD 38, MMUD 24). Acute GVHD prophylaxis consisted of tacrolimus/methotrexate (N = 77), tacrolimus/mycophenolate mofetil (N = 22), or tacrolimus/sirolimus (N = 1). Median time to neutrophil and platelet engraftment was 16 and 12 days, respectively. Non-relapse mortality was 3% at 100 days, and 15% by 1 year. The cumulative incidence of relapse was 41%. Overall survival (OS) was 59% (95% CI: 48.1 – 67.5) at 1 year, and 42% (95% CI: 30.8-53.3) at 4 years. OS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 52.9%, 40.1%, 41.2%, and 57.5% respectively; none with relapsed disease survived to 4 years (log-rank p = 0.0014). Progression-free survival (PFS) was 53% (95% CI: 42.8 – 62.2) at 1 year, and 32.3% (95% CI: 21.8 – 43.2) at 4 years. PFS at 4 years for primary AML in CR1, secondary AML in CR1, CR2, and PIF were 44.1%, 33.4%, 33.9%, and 33.1%, respectively, while none with relapsed disease at transplant reached this endpoint (p = 0.0264). On multivariable modeling, remission status at HCT (relapsed disease HR 14.85 (95% CI: 2.12 - 104.2), p = 0.007), moderate/severe cGVHD (HR 0.281, 95% CI: 0.10 - 0.76; p = 0.013), and day 90 bone marrow (BM) chimerism ≥ 90% (HR 0.245, 95% CI: 0.08 - 0.79; p = 0.018) predicted overall survival, and day 90 BM chimerism ≥ 90% (HR of 0.18 (95% CI: 0.08 - 0.45), p = 0.0002) predicted PFS. The following were not significantly related with OS or PFS: age, cytogenetics, donor relation, number of induction cycles, aGVHD prophylaxis regimen, maximum aGVHD grade, WBC at diagnosis, time in first CR, or % BM blasts prior to transplant. Day 90 BM chimerism and cGVHD were significantly related with relapse. Maximum grade of aGVHD predicted non-relapse mortality. These data support the low TRM and efficacy of IV-Bu/Flu in a large series of exclusively AML patients, and demonstrate the impact of day 90 bone marrow chimerism as an important prognostic factor. Further efforts to mitigate relapse risk after HCT are warranted, particularly in those with advanced disease at time of transplant. Disclosures: Off Label Use: IV busulfan and fludarabine for the treatment of acute myeloid leukemia. Alsina:Ortho Biotech: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau. Field:PDL BioPharma: Research Funding. Fernandez:Otsuka: Honoraria.

5-Azacitidine In Patients with Myelodysplasia and Acute Myeloid Leukemia: a Single Centre Experience

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4969-4969 ◽  
Author(s):  
Capodanno Isabella ◽  
Paolo Avanzini ◽  
Francesco Merli
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Progression Free Survival ◽  
Median Number ◽  
Study Population ◽  
Blast Count ◽  
Acute Myeloid

Abstract Abstract 4969 Introduction Hypomethylating agents have recently been shown to prolong overall survival and improve quality of life in patients with INT-2 and high IPSS risk myelodysplasia (MDS) and low bone marrow blast count acute myeloid leukemia (AML). Patients and Methods Since September 2008 we have been treating 26 patients affected by acute myeloid leukemia (13 patients), MDS (11 patients) or chronic myelomonocytic leukemia (2 patients) with 5-azacitidine. According to recent guidelines, most of myelodysplastic patients eligible for treatment belonged to the IPSS INT-2 or high risk groups. Patients with acute myeloid leukemia had a medullary blast count of 20–30%, except for four cases. Patients with chronic myelomonocytic leukemia had a medullary blast count > 10% and < 20%. The median age of patients when treatment was started was 69,5 years (range: 51–82). Azacitidine was administered subcutaneously (75 mg/m2/d) for 7 days of every 28-day cycle until loss of response or disease progression. Patients received a median number of 5,5 cycles of therapy (range 1–24). We evaluated overall improvement (CR + PR+ HI), the best response obtained and adverse events in the overall study population, according to International Working Group MDS and LMA criteria. In the subgroup of patients who received at least 6 cycles of therapy (10 patients) we also evaluated overall survival (OS) and progression free survival (PFS). Results The results of 5-azacitidine therapy in our cohort of patients are described in Table 1. In the AML cohort, after a median number of 4 cycles (range 1–10), we observed a hematological improvement (HI) in 15% of the patients, a stable disease (SD) in 31% of patients and a lack of response in 38% of patients. In the MDS cohort, after a median number of 7 cycles (range 2–24), we observed a complete response (CR) (including a cytogenetic response) in 36.5% of patients, a partial response (PR) in 9% of patients, a hematological improvement in 45.5% of patients and a stable disease in 18% of patients. The overall improvement (CR + PR + HI) was 15% in the AML cohort and 91% in the MDS cohort. In the LMMC cohort, after a median number of 2.5 cycles (range 1–4), we observed a hematological improvement in 50% of the patients. In the subgroup of patients who received at least six cycles of therapy, the overall survival was 11.5 months and the progression free survival was 9 months. In the overall study population, two patients (8%) discontinued treatment as a result of adverse events. In four non-responder patients (15%) death was due to a rapid progression of disease. Discussion In this analysis we have reported good response rates in MDS patients, with 36.5% of complete response (including a complete cytogenetic response). No CR or PR were observed in AML patients; however, in this subgroup of patients the median follow-up was short (median number of cycles of therapy: four). Furthermore, in these patients even a stable disease with no need of hospitalization and a good quality of life can be considered an important result. Due to the short period of follow-up, 57.5% of our patients received fewer than 6 cycles of 5-azacitidine and their therapy is still ongoing. Conclusions The limited number of cases and the short period of follow-up did not allow us to evaluate overall survival and progression free survival in the overall study population. We will update these data as time progresses. We reported these data in the subgroup of patients who received at least six cycles of therapy. According to current evidence, we observed that 5-azacitidine plays an important role in the treatment of patients with MDS (both with high- and low-IPSS risk) and low bone marrow blast counts AML. In these subgroups of patients, 5-azacitidine prolongs survival and is well tolerated. In our limited experience, this drug had no efficacy when a higher degree of bone marrow blasts (> 30%) was present. Further trials should assess the number of cycles required for treatment, the role of hypometilating agents in low-risk MDS and in patients with AML and a bone marrow blasts counts > 30%. Disclosures: No relevant conflict of interest to declare. Disclosures: No relevant conflicts of interest to declare.

Patients with FLT3 Negative Acute Myeloid Leukemia and Normal Cytogenetic who Have the Combination Mutations (NPM1-/CEBPA-) Have Better Survival Than Patients Who Have the Combination Mutations (NPM1+/CEBPA+)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4874-4874
Author(s):  
Shamail Butt ◽  
Pascal Akl ◽  
Himanshu Bhardwaj ◽  
Samer A Srour ◽  
Terry Dunn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Intermediate Risk ◽  
Cebpa Mutations ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Abstract 4874 Introduction: Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. About 50% of patients with AML have normal karyotype, and are categorized as intermediate risk group. However, the clinical behavior and response to treatment in this group is heterogeneous. As a result, there is strong interest in characterizing molecular genetic features in the intermediate-risk AML patients that might rectify their stratification risk. In this group, FLT3-ITD (Internal Tandem Duplication) and FLT3-TKD (Tyrosine Kinase Domain) mutations are known to confer unfavorable risk whereas NPM1 and CEBPA mutations are known to be favorable risk markers. The purpose of this study is to analyze the combination of NPM1 and CEBPA mutations in presence or absence of FLT3 mutations on prognosis of AML patients referred to the State's largest tertiary care center over a period of 10 years for the treatment of leukemia. Patients and Method: We performed a retrospective chart review of all patients with AML evaluated at University of Oklahoma Health Sciences Center between January 2000 and December 2010. Patient's age, gender, race, laboratory and clinical data as well as bone marrow biopsy and aspirate findings were reported. PCR and Fragment Analysis were conducted on all available DNA preserved bone marrow materials to test the FLT3, NPM1 and CEBPA mutations. For statistical analysis, Kaplan-Meyer curve was used. Results: A total of 239 patients were evaluated. Male to female ratio was 2/1. Median age at diagnosis was 46y. 21 out of the 239 patients were less than 18 year old. DNA samples were present on 132 patients and mutation analysis for FLT3, CEBPA and NPM1 was performed. Correlation between mutations and AML prognosis was determined. 67/132 (50.8 %) patients were categorized into intermediate risk group (majority of patients had normal cytogenetics). 14/67 (20.9%) pts were FLT3+ (FLT3-ITD or FLT3-TKD mutation). 17/67 (23.9%) were NPM1+. 7/67 (10.4%) were CEBPA +. Kaplan-Meier curve was used to identify cumulative proportion surviving over time. FLT3 presence or absence itself was not identified to be statistically significant (p 0.416) in terms of overall survival. Interestingly, presence or absence of combined NPM1/CEBPA mutation in FLT3 negative patients, among intermediate risk group, was found to be statistically significant (p<0.05) in determining overall survival. In this subgroup, presence of NPM1/CEBPA combination (NPM1+/CEBPA+) was associated with poor prognosis (figure 2, lower curve), while absence of NPM1/CEBPA combination (NPM1-/CEBPA-) carries a better prognosis (figure 2, upper curve). Conclusion: Results of our study highlight the importance of performing combinations of mutation analysis in evaluation of overall prognosis in AML patients. FLT3-/NPM1+ profile in patients with normal cytogenetics is thought to confer a favorable prognosis. We demonstrated in this study that using combination mutation analysis in patients with FLT3- can change the risk stratification in patients with intermediate risk group and might affect therapeutic interventions in this patient population. Larger prospective studies are needed in the future for further validation of our findings. Disclosures: No relevant conflicts of interest to declare.

The Impact of Bone Marrow Hematogones on Umbilical Cord Blood Transplant Outcomes in Acute Myeloid Leukemia Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4148-4148
Author(s):  
Theodore Honebrink ◽  
Vanessa J. Dayton ◽  
Karen Larsen ◽  
Qing Cao ◽  
Claudio Brunstein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Donor Number ◽  
Free Survival ◽  
Cord Blood Transplant ◽  
Differential Counts ◽  
Related Mortality ◽  
Acute Myeloid

Abstract Abstract 4148 Hematogones are B-lymphocyte precursors which reside in the marrow and undergo an orderly maturation sequence to give rise to mature B cells. (McKenna, Blood 2001) Recently, the percentage of hematogones detected in the bone marrow (BM) after induction therapy for acute myeloid leukemia (AML) has been associated with improved leukemia-free survival and overall survival. (Chantepie, Blood 2011) Early after umbilical cord blood transplant (UCBT), patients show marked differences in BM hematogone percentages. Little is known about whether such differences are clinically relevant, which may explain why hematogones are not routinely reported in BM differential counts and are, instead, combined with other lymphocytes. We hypothesized that increased hematogones would be associated with superior transplant outcomes. Two independent reviewers assessed hematogone percentages in BM aspirates performed on day 21 and 100 post-UCBT (i.e. D21 & D100) from 88 patients with AML undergoing myeloablative UCBT at the University of Minnesota between 02/1999 and 07/2008. Patients with evidence of relapse at the time of the marrow analysis were excluded. Because of the morphological similarity between hematogones and leukemic lymphoblasts, only patients with AML were included in this analysis. The reviewers were blinded to clinical outcomes. Correlation coefficients for the morphologic assessment of hematogones at D21 and D100 were each >0.8, confirming good interobserver reproducibility (p<0.01). Prospective outcome data for patients in the lowest marrow hematogone quartile (0% at D21 after UCBT and ≤0.9% at D100 after UCBT) were compared with those of patients in the upper three quartiles using a multivariate analysis (MVA) model. This model incorporated donor number (single vs. double), recipient age (<21 vs. ≥ 21), recipient CMV status (negative vs. positive), total, post-thaw CD34 (<0.50 vs. ≥0.50), total, post-thaw CFU (<0.042 vs. ≥ 0.042), and total nucleated cell (TNC) (<0.38 vs. ≥0.38). Endpoints studied included time to neutrophil and platelet recovery, overall survival, disease free survival (DFS), transplant related mortality (TRM), risk of relapse, acute GVHD (aGVHD), and chronic GVHD (cGVHD). At D21 after UCBT, the percentage of marrow hematogones varied from 0 to 10.8% (N = 85). In MVA, a high percentage of hematogones at D21 was associated less aGVHD grade 3–4 (RR=0.3 [0.15–0.59], p=0.01). At D100 after UCBT the percentage of marrow hematogones varied from 0 to 29.8% (N = 69). In MVA, a high percentage of BM hematogones at D100 was associated with improved overall survival (p=0.02) and this was due to a lower treatment related mortality (p=<0.01). (See Table 1) Table 1: MVA examining the percentage hematogones detected in the BM at D100 after UCBT. Outcome Variable RR (95% CI) p value Overall Survival Hem @ Day 100 <0.9 1.00 >=0.9 0.20 (0.05–0.76) 0.02 Donor number 1 1.00 2 0.19 (0.04–0.84) 0.03 Transplant Age <20.5 1.00 >=20.5 4.89 (1.11–21.51) 0.04 Relapse Hem @ Day 100 <0.9 1.00 >=0.9 2.84 (0.32–24.91) 0.35 TRM Hem @ Day 100 <0.9 1.00 >=0.9 0.03 (0–0.34) <0.01 HLA (engrafting unit) 4/6 1.00 5/6 0.61 (0.05–7.13) 0.69 6/6 0 <0.01 CGVHD Hem @ Day 100 <0.9 1.00 >=0.9 0.44 (0.11–1.69) 0.23 Transplant Age <20.5 1.00 >=20.5 3.61 (1.18–11.06) 0.02 RR = relative risk. Hem = percentage hematogones. TRM = transplant-related mortality. HLA = human leukocyte antigen; values correspond to number of matched allelic loci for HLA-A, HLA-B and HLA-DR between recipient and engrafting donor. CGVHD = chronic graft vs. host disease. This study shows that BM hematogone percentage may be a useful prognostic indicator in AML patients following UCBT. We propose that hematogones be routinely reported in BM differential counts. Disclosures: No relevant conflicts of interest to declare.

Treatment with FLAG followed by second allogeneic stem cell transplant for relapsed acute myeloid leukemia and myelodysplastic syndrome.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18503-e18503
Author(s):  
Brian Pham ◽  
Rasmus Hoeg ◽  
Nisha Hariharan ◽  
Kathyryn Alvarez ◽  
Aaron Seth Rosenberg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Time To Relapse ◽  
Acute Myeloid

e18503 Background: There is no standard treatment for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) relapsing after allogeneic stem cell transplant (SCT). Options include combination chemotherapy, withdrawal of immunosuppression, donor lymphocyte infusion (DLI), and second SCT. Previous studies have used fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG) or second SCT separately for salvage therapy. Our institution uses FLAG followed by SCT from the same donor (FLAG/SCT) in this setting. We report a retrospective study of FLAG/SCT in MDS and AML patients relapsed after SCT. Methods: Patients who received FLAG/SCT for treatment of relapsed AML or MDS between 2009 and 2018 were identified using the bone marrow transplant database at University of California Davis. Their baseline characteristics and outcomes were determined using the electronic medical record. Descriptive statistics and Kaplan-Meier survival analysis were used to describe patients, rates of graft-versus-host disease (GvHD) and estimate survival times. Results: Nineteen patients received FLAG/SCT for AML (n=18) and MDS (n=1). Median time to relapse from first SCT was 145 days (range 41 to 960 days). Prior to FLAG/SCT, 17 patients had medullary relapse (median bone marrow blasts 27%; range 7-85%). Two patients had extramedullary relapse. Eighteen (94.7%) patients achieved complete remission (CR) after FLAG/SCT. Median follow-up time was 354 days from the first day of FLAG/SCT (range 7 to 2144 days). Six patients (31.6%) relapsed with median time to relapse of 334 days (range 78 to 679 days) after treatment. Overall survival at 2 years was 52.5%. Causes of death were relapsed AML (n=4; 21.1%), infection (n=4; 21.1%) complications of GvHD (n=3,15.8 %), and brain herniation (n=1, 5.3%). Acute GvHD grade I-IV and new onset chronic GvHD occurred in thirteen (68.4%) and eight patients (42.1%), respectively. Conclusions: FLAG/SCT for AML and MDS relapsing after SCT resulted in a high remission rate. The overall survival of over two years suggests that the second SCT augmented the graft versus leukemia effect. The GvHD rate increased after second SCT, but the rate and severity were manageable. FLAG/ SCT is a reasonable option for relapsed AML and MDS after SCT.

scholarly journals Extramedullary Disease in Adult Acute Myeloid Leukemia Is Common but Lacks Independent Significance: Analysis of Patients in ECOG-ACRIN Cancer Research Group Trials, 1980-2008

2016 ◽  
Vol 34 (29) ◽  
pp. 3544-3553 ◽  
Author(s):  
Chezi Ganzel ◽  
Judith Manola ◽  
Dan Douer ◽  
Jacob M. Rowe ◽  
Hugo F. Fernandez ◽  
...  
Keyword(s):  
Cancer Research ◽  
Overall Survival ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Research Group ◽  
Large Study ◽  
Myeloid Leukemia ◽  
Extramedullary Disease ◽  
Acute Myeloid

Purpose Extramedullary disease (EMD) at diagnosis in patients with acute myeloid leukemia (AML) has been recognized for decades. Reported herein are results from a large study of patients with AML who were treated in consecutive ECOG-ACRIN Cancer Research Group frontline clinical trials in an attempt to define the incidence and clinical implications of EMD. Methods Patients with newly diagnosed AML, age 15 years and older, who were treated in 11 clinical trials, were studied to identify EMD, as defined by physical examination, laboratory findings, and imaging results. Results Of the 3,522 patients enrolled, 282 were excluded, including patients with acute promyelocytic leukemia, incorrect diagnosis, or no adequate assessment of EMD at baseline. The overall incidence of EMD was 23.7%. The sites involved were: lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingiva (4.4%), and CNS (1.1%). Most patients (65.3%) had only one site of EMD, 20.9% had two sites, 9.5% had three sites, and 3.4% had four sites. The median overall survival was 1.035 years. In univariable analysis, the presence of any EMD ( P = .005), skin involvement ( P = .002), spleen ( P < .001), and liver ( P < .001), but not CNS ( P = .34), nodal involvement ( P = .94), and gingival hypertrophy ( P = .24), was associated with a shorter overall survival. In contrast, in multivariable analysis, adjusted for known prognostic factors such as cytogenetic risk and WBC count, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic. Conclusion This large study demonstrates that EMD at any site is common but is not an independent prognostic factor. Treatment decisions for patients with EMD should be made on the basis of recognized AML prognostic factors, irrespective of the presence of EMD.

scholarly journals High Expression of Myocyte Enhancer Factor 2C (MEF2C) Is Associated with Adverse Risk Features and Poor Outcome in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2570-2570
Author(s):  
George S. Laszlo ◽  
Todd A. Alonzo ◽  
Chelsea J. Gudgeon ◽  
Kimberly H. Harrington ◽  
Alex Kentsis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Event Free Survival ◽  
Free Survival ◽  
Expression Levels ◽  
Acute Myeloid ◽  
Enhancer Factor

Abstract Background: Myocyte enhancer factor 2C (MEF2C) was initially identified as essential transcription factor for cardiac muscle development. However, subsequent studies have indicated that MEF2C plays a much broader biological role, including in the normal hematopoietic system. Recent studies have now identified MEF2C as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML. These findings raised the possibility that MEF2C could serve as marker of poor-risk disease and, therefore, have prognostic significance in AML. To test this hypothesis, we retrospectively quantified MEF2C expression in participants of the AAML0531 trial and correlated expression levels with disease characteristics and clinical outcome. Patients and Methods: AAML0531 (NCT00372593) was a multicenter phase 3 study that determined the addition of gemtuzumab ozogamicin to intensive chemotherapy among 1,022 eligible patients aged <30 yearswith newly diagnosed de novo non-APL AML, excluding those with bone marrow failure syndromes, juvenile myelomonocytic leukemia, or Down syndrome (if ≤3 years of age) between 2006 and 2010. Cryopreserved pretreatment ("diagnostic") specimens from patients enrolled on AAML0531 who consented to the biology studies and had bone marrow samples were available were included in this study. Total RNA from unsorted specimens was extracted, quantified, and subjected to quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) using TaqMan primers to determine expression of MEF2C and, for normalization, the housekeeping gene, β-glucuronidase (GUSB). Patient samples were run in duplicate, and the ΔΔCT method quantified as 2(-ΔΔCT) was used to determine the expression levels of MEF2C relative to GUSB. Results: In all 751 available patient specimens, MEF2C mRNA was detectable and varied >3,000-fold relative to GUSB (0.0091-29.1272 [median: 0.7978]). Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67% vs. 78%, P=0.005). They also had an inferior overall survival (P=0.014; at 5 years: 55±8% vs. 67±4%), inferior event-free survival (P<0.001; at 5 years: 38±7% vs. 54±4%), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P<0.001; at 5 years: 53±9% vs. 35±5%). Of note, exploratory multiple cutpoint analyses for overall and event-free survival indicated that the most statistically significant results were centered around the Q4 cutpoint region, supporting our approach of comparing patients with the highest quartile of relative MEF2C expression with those having lower relative MEF2C expression. Importantly, MEF2C expression was strongly associated with cytogenetic and molecular abnormalities. Specifically, patients with high MEF2C expression less likely had CBF translocations (inv(16): P=0.007, and t(8;21): P<0.001) or normal karyotype AML (P<0.001); conversely, they were more likely to have leukemia with monosomy 7 (P<0.001) and abnormalities involving 11q23 (P<0.001). Furthermore, patients with high MEF2C less likely had a FLT3/ITD (P =0.018) or a mutation in either NPM1 (P=0.010) or CEBPA (P =0.002). Consistently, patients with high MEF2C expression less likely had low-risk disease (16% vs. 46%, P<0.001) and more likely had standard-risk disease (68% vs. 42%, P <0.001) than those with lower MEF2C expression. Indeed, after adjustment for disease risk, age, FAB category, and treatment arm, high MEF2C expression was no longer statistically significantly associated with inferior overall survival (hazard ratio [HR]=0.99 [95% confidence interval: 0.72-1.36], P=0.929), inferior event-free survival (HR: 1.14 [0.86-1.49], P=0.365), or higher relapse risk (HR: 1.32 [0.91-1.92], P=0.137), suggesting that MEF2C cooperates with additional pathogenic abnormalities. Conclusion: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. These findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML. Disclosures Walter: AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Pfizer, Inc.: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

scholarly journals Elderly AML: A Five-Year Retrospective Review on Prognostic Features

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5187-5187
Author(s):  
Akshay Amaraneni ◽  
Jennifer Segar ◽  
Trace Bartels ◽  
Onyemaechi Okolo ◽  
Andrew C Rettew ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Retrospective Review ◽  
Myeloid Leukemia ◽  
Small Sample Size ◽  
Small Sample ◽  
Risk Category ◽  
Elderly Aml ◽  
Acute Myeloid

Abstract Background: Acute Myeloid Leukemia (AML) is a disease of the elderly with a median age of diagnosis of 70 years. Prognosis in this age group is poor, with median overall survival of those undergoing treatment ranging from seven to twelve months. Treatment is difficult for a variety of reasons, including - higher incidence of co-morbid conditions (including frailty and decline in functional status), decreased ability to tolerate infections, socioeconomic considerations, and more aggressive disease phenotype. We present a single-institution retrospective review of acute myeloid leukemia outcomes with respect to these and other variables. Methods: A retrospective chart review was performed on all patients with a new diagnosis of AML from November 2013 through October 2017. Descriptive statistics were performed using excel, inferential statistics including Kaplan-Meier with comparison of survival curves by Logrank test and Cox-proportional hazard regression analysis, and correlation coefficients were performed using MEDCALC statistical software package. Results: Eighty-four AML patients in total were diagnosed with acute myeloid leukemia within the specified time frame, of these, 45 patients were age 65 or older (elderly) and were included in further analysis. Median age of elderly AML patients in this study was 70 years. Six of these patients were diagnosed with secondary AML (having arisen from MDS (N = 4), or other hematologic malignancy (N=2), and two had therapy-related AML. Eight patients had favorable risk disease, 13 intermediate risk, and 24 adverse risk according to ELN 2017 criteria. The median survival of all elderly patients was 322 days. Median survival of elderly AML according to ELN 2017 risk category criteria (Favorable, Intermediate, or Poor) was not reached (mean 880 days), 390 days, and 117 days, respectively (p = 0.0368 by cox hazard regression). Survival was not affected by type of treatment (induction vs hypomethylating agent (HMA); median 579 and 166 days (p = 0.1378) and mean 1552 and 364 days, respectively. This is likely due to small sample size, although survival does appear to favor intensive induction. Survival was not affected by number of medical co-morbidities (p = 0.66), presence of infectious complications (p=0.152), or unplanned hospitalization (p = 0.144). Overall use of clinical trials (N=3) and transplant (N=2) were low, precluding meaningful statistical analysis. However, both patients undergoing transplant exceeded the median OS (579 and 4745 days). Median OS of patients identified as White/Caucasian was greater than those identified as Hispanic/Latino (166 days vs 66 days, respectively), this did not reach statistical significance. Conclusion: Given the limitations of a retrospective review and relatively small sample size, our data shows that the 2017 ELN risk category is the strongest predictor of overall survival. Statistically, those undergoing intensive induction did not have a longer overall survival than those treated with HMAs, highlighting the need for careful selection of induction therapy candidates, and the need for clinical trials investigating other less intense treatment options for patients in this category. Interestingly, number of medical co-morbidities did not influence overall survival, nor did unplanned hospitalizations, presence/absence of significant infections during therapy, or race/ethnicity. Our data suggest an under-utilization of clinical trials and allogeneic hematopoietic stem cell transplant, both of which may serve to improve prognosis. Disclosures No relevant conflicts of interest to declare.

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