Maintenance Hypomethylating Therapy Post Allogeneic Stem Cell Transplantation Provides Favorable Progression Free Survival in High Risk Acute Myelogenous Leukemia or Non Responsive Myelodysplastic Syndrome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4468-4468
Author(s):  
Connie A. Sizemore ◽  
Xu Zhang ◽  
Melissa Sanacore ◽  
Asad Bashey ◽  
Scott R. Solomon ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Complete Remission ◽  
Myelodysplastic Syndrome ◽  
Progression Free Survival ◽  
Myelogenous Leukemia ◽  
Hypomethylating Agents ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Acute Myelogenous

Abstract Abstract 4468 Introduction Patients with acute myelogenous leukemia (AML) or non responsive myelodysplastic syndrome (MDS) who fail to achieve a complete remission, have unfavorable cytogenetics or are refractory to therapy have a poor prognosis. Allogeneic HSCT is frequently considered a salvage option for these patients although remissions are short-lived. New strategies are needed for maintaining remission in this extremely high risk patient group. We hypothesized hypomethylating agents post allogeneic HSCT would enable patients to remain in complete remission. Methods Eleven patients were treated. Patient characteristics: median age, 48 years (range, 18–70 years), PBSC (n=9) or bone marrow (n=2); Diagnoses AML= 10, Non- responsive MDS=1, CIBMTR disease risk category: High [n=8], Intermediate [n=1], Low [n=2]; 36% of the patients had primary induction failure, 54% had complex molecular abnormalities with 18% of the patients having deletion 11q 23 molecular abnormality. Donors were unrelated (36%) and related (64%). All but 1 donor-recipient pairs were fully matched. Preparative regimen- busulfan based (16mg/kg or equivalent) (82%), TBI ≥ 12 Gy (9%) based or reduced-intensity haplo-identical regimen (9%). The median number of prior chemotherapy regimens was 2.5 (range, 2–6). Azacitidine (n=10) or decitabine (n=1) was selected at physician discretion as a planned prophylactic regimen post allogeneic HSCT engraftment. Initial starting doses were based on hematological conditions at the time of therapy initiation. Results Ten patients received azacitidine subcutaneously daily for seven days for a median of 5 cycles (range, 1–10 cycles) and one patient received decitabine 20mg/m2 intravenously for 5 days for 3 cycles. Median initial Azacitidine dose of 50 mg/m2 (range, 25–75mg/m2) daily were given at a median of 40 days (range, 38–101 days) post HSCT engraftment. Azacitidine doses were increased based on counts to a maximum dose of 75mg/m2. With a median follow-up of 24 months (range, 1.7–49 months) 6 patients are alive in complete remission. Twenty-four month progression free survival is 51% with overall survival of 76%. Conclusion Given the dismal results of progression free survival and overall survival following allogeneic HSCT in high risk AML or non responsive MDS, hypomethylating agents given post transplantation provide a valuable approach to prolonging remission. Disclosures: No relevant conflicts of interest to declare.

Extended Study for Topotecan, Idarubicin, and Intermediate-Dose Cytarabine Combination Chemotherapy in Patients with Refractory or Relapsed Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4609-4609
Author(s):  
Yuri Kim ◽  
June-Won Cheong ◽  
Jin Seok Kim ◽  
In Hae Park ◽  
Sun Young Park ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Myelodysplastic Syndrome ◽  
Combination Chemotherapy ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Group 4 ◽  
Remission Duration ◽  
Acute Myelogenous ◽  
Intermediate Dose

Abstract The development of more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS) is a major concern in hematology. We previously reported a preliminary data that combination chemotherapy with topotecan, idarubicin, and intermediate dose cytarabine had a significant anti-leukemia activity and acceptable range of toxicity for the high-risk AML/MDS patients. In this study, we demonstrate an extended data for investigating larger number of patients with long-term follow-up of five years. The forty-seven patients were enrolled: 10 with primary refractory AML, 16 with AML in first relapse, 9 with AML in second relapse, and 12 with MDS-RAEB/RAEBT. Patients received as salvage therapy a single course of idarubicin 12 mg/m(2) IV bolus on days 1–3, cytarabine 1 g/m(2) over two hours q 12 hr on days 1–5, and topotecan 1.25 mg/m(2) over 24 hr on days 1–5. Median age of patients was 47 years (range 17–69 years). Patients with AML were categorized to high-risk (n=21), intermediate-risk (n=11), and low-risk (n=3) cyrogenetic group. All patients were evaluable for response: 23 (48.9%) achieved complete remission, 18 with AML (51.4%) and 5 with MDS (41.7%), respectively. The median remission duration and survival of patients with AML were 7 and 13 months, respectively. Median remission duration and survival of MDS patients was 10 and 15 months, respectively. Severe myelosuppression was observed in all patients, resulting in the fever or documented infections in 85.1% of patients. Median time to recovery of neutrophils > or =0.5 x 10(9)/l was 23 days (11–37 days) and for platelets > 20 x 10(9)/l 37 days (11–63 days). Reversible grade 3–4 toxicities included diarrhea (3 patients) and mucositis (13 patients). The relapsed AML patients (n=16) were grouped into four categories to stratify the probability of achieving complete remission (CR): group 1, first CR duration > or = 2 years and receiving first salvage treatment (S1); group 2, first CR duration 1–2 years and receiving S1; group 3, first CR duration 0–1 years and receiving S1; and group 4, first CR duration 0–1 years and receiving S2, S3, or S4 after failing S1. The response rate of group 4 (33.3%) was significantly lower than that of other groups (P < 0.05). We conclude that combination chemotherapy with topotecan, idarubicin, and intermediate dose cytarabine is an effective salvage chemotherapy for high risk AML/MDS patients, and the first CR duration is a significant predictor for response.

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

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

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

scholarly journals HLA-Mismatched Stem Cell Microtransplantation Compared to Matched-Sibling Donor Transplantation for Acute Myeloid Leukemia in First Complete Remission

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5842-5842
Author(s):  
Limin Liu ◽  
Huiying Qiu ◽  
XiaoWen Tang ◽  
Yue Han ◽  
Miao Miao ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Free Survival ◽  
Sibling Donor ◽  
Acute Myelogenous ◽  
Matched Sibling ◽  
First Complete Remission

Abstract HLA-mismatched stem cell microtransplantation is a new transplantation which has been reported in recent years. We treated 41 patients with intermediate- or high-risk acute myelogenous leukemia (AML) in first complete remission (CR1) undergoing HLA-mismatched stem cell microtransplantation and compared with 56 patients undergoing HLA-matched sibling donor (MSD) transplantation at the same period in our center from July 2012 to August 2015. The estimated leukemia-free survival (LFS) at 2-year was 65.6% ± 9.5% in the MSD group and 27.6% ± 14.0% in the microtransplantation group (P = 0.011). The estimated overall survival (OS) at 2-year was 73.6% ± 8.6% in the MSD group and 46.2% ± 15.6% in the microtransplantation group (P = 0.056). The cumulative incidences of relapse were 22.5% and 58.7% among MSD and microtransplantation groups (P = 0.011). The cumulative incidence of nonrelapse mortality was 7.8% in MSD group, and no nonrelapse mortality in microtransplantation group (P = 0.265). Hematopoietic recovery time was shorter in the microtransplantation group than MSD group (P < 0.05). The infection rate of MSD group was higher than in the microtransplantation group (91.1% vs 75.6%, P = 0.037). The preliminary results suggest that LFS of microtransplantation is inferior to MSD transplantation and a trend toward the OS of microtransplantation was lower than MSD transplantation for intermediate- or high-risk AML in CR1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

2012 ◽  
Vol 30 (18) ◽  
pp. 2204-2210 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Francesco Paolo Tambaro ◽  
Nebiyou B. Bekele ◽  
Hui Yang ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Acute Myelogenous Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Myelogenous Leukemia ◽  
Platelet Recovery ◽  
Free Survival ◽  
Binding Factor ◽  
Deacetylase Inhibitor ◽  
Acute Myelogenous

Purpose To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Patients and Methods Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m2 intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely. Results After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival. Conclusion The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

Improved survival for patients with acute myelogenous leukemia.

1995 ◽  
Vol 13 (3) ◽  
pp. 560-569 ◽  
Author(s):  
A J Mitus ◽  
K B Miller ◽  
D P Schenkein ◽  
H F Ryan ◽  
S K Parsons ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Remission Induction ◽  
Term Survival ◽  
Free Survival ◽  
Significant Difference ◽  
Acute Myelogenous ◽  
To Receive

PURPOSE Despite improvement in chemotherapy and supportive care over the past two decades, overall survival for patients with acute myelogenous leukemia (AML) remains poor; only 25% to 30% of individuals with this disorder will be cured. In 1987, we initiated a prospective multiinstitution study designed to improve long-term survival in adults with AML. METHODS We modified the usual 7-day treatment scheme of daunorubicin and cytarabine with high-dose cytarabine (HiDAC) on days 8 through 10 (3 + 7 + 3). Allogeneic or autologous bone marrow transplantation (BMT) was offered to all patients who entered complete remission (CR) to decrease the rate of leukemic relapse. Data were analyzed by intention to treat. RESULTS CRs were achieved in 84 of 94 patients (89%; 95% confidence interval [CI], 83 to 95). Because of the high remission rate, factors previously thought to predict outcome, such as cytogenetics, WBC count, French-American-British (FAB) classification, sex, and age, were not useful prognostic variables. The overall survival rate for the entire cohort of patients from data of diagnosis is 55% at 5 years. Sixty percent of all patients who achieved a CR underwent marrow grafting. There was no significant difference in event-free survival (EFS) at 5 years comparing patients assigned to receive allogeneic BMT with patients assigned to receive autologous BMT (56% v 45%, P = .54). CONCLUSION The long-term disease-free survival observed in this study is excellent compared with historical data. This improvement in survival is probably due to the high rate of remission induction, as well as to the effective nature of the consolidation therapy.

Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia

2012 ◽  
Vol 153 (41) ◽  
pp. 1622-1628
Author(s):  
Márk Plander ◽  
Judit Skrapits ◽  
Tünde Bozsó ◽  
Tamás Szendrei ◽  
János László Iványi
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Minimal Residual

Introduction: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. Aim: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. Methods: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. Results: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). Conclusion: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients. Orv. Hetil., 2012, 153, 1622–1628.

scholarly journals FCR achieves long-term durable remissions in patients with IGHV-mutated CLL

Blood ◽  
2017 ◽  
Vol 130 (21) ◽  
pp. 2278-2282 ◽  
Author(s):  
Chatree Chai-Adisaksopha ◽  
Jennifer R. Brown
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Randomized Trials ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Inclusion Criteria ◽  
Free Survival

Abstract In chronic lymphocytic leukemia (CLL) patients with mutated IGHV, 3 recent studies have demonstrated prolonged progression-free survival (PFS) after treatment with fludarabine-cyclophosphamide-rituximab (FCR) chemoimmunotherapy. We performed a systematic review to assess the benefit of FCR for patients with CLL and identified 5 randomized trials that met our inclusion criteria. FCR improved complete remission, PFS and overall survival vs the comparator; median PFS was not reached in the subgroup of CLL patients with mutated IGHV.

Chromosome 17 Abnormalities Are Associated with Worse Overall and Relapse Free Survival in Patients with Acute Myelogenous Leukemia and Poor-Risk Cytogenetics.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1501-1501
Author(s):  
Gautam Borthakur ◽  
Constantine Tam ◽  
Hagop Kantarjian ◽  
E. Lin ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Chromosome 17 ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Kaplan Meier ◽  
Variate Analysis ◽  
Acute Myelogenous

Abstract Purpose: Chromosome 17 abnormalities define a group of patients with acute myelogenous leukemia (AML) (Nahi, H. et al. Leukemia and Lymphoma2008;49:508) with poor outcomes. We analyzed the additional impact of chromosome 17 abnormalities (−17, −17p, −17q, der17) among patients with AML and cytogenetic abnormalities traditionally considered to be of adverse prognosis. Patients and Methods: 1086 patients with AML [excluding inv 16, t (8;21), t (15;17), Diploid/-y abnormality] were included in this analysis. Based on cytogenetic abnormalities patients were grouped into: −5,−7,−5and −7, complex. The following parameters were included in uni and multi-variate analysis: age, performance status, WBC, hemoglobin, platelets, marrow blast percentage, bilirubin, creatinine, albumin, LDH, chromosome 17 abnormality (yes/no). Results: Four hundred and fourteen (45%) patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 267 (64.5%) patients relapsed. Two hundred seventy (24.9%) patients had abnormalities of chromosome 17. Abnormalities of chromosome 17 were associated with lower CR or CRp rate (p=0.02) and higher possibility of having cytogenetic abnormality of −5 or −7 (p&lt;0.0001). Multivariate analysis showed that patients with abnormalities of chromosome 17 had worse overall survival (OS) compared to patients without (p= 0.003)(Fig.1). Multi-variate analysis within cytogenetic subgroups showed that chromosome 17 abnormalities were associated with worse OS in patients with chromosome 5 abnormality(p=.02) (data not shown) and in those with complex cytogenetics (p=.04)(Fig.2) and not in patients with chromosome 7 (p=.17)or combined 5 and 7 abnormalities (p=.33). Similar analysis restricted to patients achieving CR/CRp after induction therapy showed that impact of chromosome 17 abnormalities on relapse free survival (RFS) mirrored their impact on OS. Conclusion: chromosome 17 abnormalities are associated with worse OS and RFS in patients with AML and adverse cytogenetics and have additional negative impact on the outcomes in certain well-known adverse cytogenetic subgroups. Figure 1: Kaplan-Meier estimates of overall survival by status of chromosome 17 Figure 1:. Kaplan-Meier estimates of overall survival by status of chromosome 17 Figure 2: Kaplan-Meier estimates of overall survival by status of chromosome 17 in subgroup of patient, complex Figure 2:. Kaplan-Meier estimates of overall survival by status of chromosome 17 in subgroup of patient, complex

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