scholarly journals Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Sonia Jaramillo ◽  
Johannes Krisam ◽  
Lucian Le Cornet ◽  
Markus Kratzmann ◽  
Lukas Baumann ◽  
...  
Keyword(s):  
Overall Survival ◽  
Induction Therapy ◽  
Low Dose ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Event Free Survival ◽  
Free Survival ◽  
Primary Endpoints ◽  
Double Blinded ◽  
Low Dose Cytarabine

Abstract Background Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial. Methods/Design This is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. Ethics and dissemination Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. Trial status Protocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st. Trial registration ClinicalTrials.govNCT04093505; EudraCT 2019-003913-32. Registered on October 30, 2018.

scholarly journals Rationale and Design of GnG-Trial: A Randomized Phase-III Study to Compare Two Schedules of Gemtuzumab Ozogamicin as Adjunct to Intensive Induction Therapy and to Compare Double-Blinded Intensive Postremission Therapy with or Without Glasdegib in Older Patients with Newly Diagnosed AML

2021 ◽  
Author(s):  
Sonia Jaramillo ◽  
Johannes Krisam ◽  
Lucian Le Cornet ◽  
Markus Kratzmann ◽  
Lukas Baumann ◽  
...  
Keyword(s):  
Overall Survival ◽  
Induction Therapy ◽  
Low Dose ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Event Free Survival ◽  
Free Survival ◽  
Primary Endpoints ◽  
Double Blinded ◽  
Low Dose Cytarabine

Abstract BackgroundOverall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after five years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial.Methods/DesignThis is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4 and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7+3 schedule with cytarabine 200mg/m² continuously days 1 to 7, daunorubicin 60mg/m² days 1, 2 and 3 and high-dose cytarabine (1g/m², bi-daily, days 1,2,3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%. ETHICS AND DISSEMINATION: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04093505; EudraCT Number: 2019-003913-32.TRIAL REGISTRATION DATE: October 30, 2018

Treatment of 11q23/MLL + AML with Gemtuzumab Ozogamicin: Results from the Randomized Phase III Children's Oncology Group Trial AAML0531

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 799-799
Author(s):  
Jessica Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Susana C. Raimondi ◽  
Betsy A. Hirsch ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Study Entry ◽  
Cell Transplant ◽  
Event Free Survival ◽  
Conventional Chemotherapy ◽  
Free Survival ◽  
Pediatric Aml ◽  
To Receive

Abstract CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is the target of gemtuzumab ozogamicin (GO). We previously demonstrated the clinical benefit of GO treatment in children with AML treated on COG AAML0531 in which patients were randomized to receive standard Medical Research Council-based chemotherapy with or without GO. We also demonstrated that CD33 expression is highly variable in pediatric AML and that children with 11q23 translocations involving the KMT2A gene, previously known as the mixed lineage leukemia gene and referred to here as MLL+, have significantly higher CD33 expression, as defined by mean fluorescent intensity (MFI) values, than patients without 11q23/MLL + leukemia (MLL-) [median CD33 MFI: MLL + 229.13 (range 6-1351) vs. MLL-129 (range 2.68-1225.87) P <0.001.] Given significantly elevated levels of CD33 expression in MLL + AML and our previous findings showing an association between high CD33 expression and improved response to GO, we evaluated MLL + AML patients treated on COG AAML0531 to determine whether GO treatment improved their clinical outcomes. COG AAML0531 included 1022 eligible patients ages 1 month-29.99 years of which 215 harbored a 11q23/MLL rearrangement that was confirmed by central cytogenetic review (including G-banding and FISH). Analysis of overall outcomes revealed similar complete remission (CR) rates after Induction I for MLL + and MLL-patients (71% vs. 73%, P = 0.494). However, MLL + patients had lower 5-year overall survival (OS) and event-free survival (EFS) than MLL-patients (OS 58% vs. 66%, P =0.012, EFS 38% vs. 51%, P =<0.001) as well as higher rates of relapse (RR) (52% vs. 36%, P =<0.001) and lower disease-free survival (DFS) (46% vs. 58%, P =0.002). Of the 215 MLL + patients, 107 were treated with conventional chemotherapy only (No-GO) and 108 with chemotherapy and GO (GO). CD33 expression data from flow cytometry analysis were available for 170 MLL + patients. The median CD33 MFI was similar for MLL + patients on both treatment arms [No-GO: 226.5 (range 6-911), GO 237.345 (range 7.6-1351), P = 0.648]. CR rate was higher for MLL + patients treated with GO vs. No-GO (77% vs. 64%; P =0.035). Evaluation of clinical outcomes for patients in the MLL + cohort by treatment arm revealed a superior outcome for GO recipients. EFS at 5 years from study entry was 48% for patients in the GO group vs. 28% for those in the No-GO group (P =0.002) with a corresponding OS of 64% vs. 53% (P =0.053). MLL-patients had similar EFS and OS regardless of GO exposure (P =0.435 and P =0.861, respectively, Figure 1). In MLL + patients who achieved CR, GO exposure translated to lower RR (40% vs. 66% No-GO, P =0.001) and improved DFS (57% vs. 33% No-GO, P =0.002) demonstrating that MLL + patients receiving GO treatment have improved outcomes. In COG AAML0531 a subset of patients was allocated to receive allogeneic hematopoietic stem cell transplant (HSCT) in 1st CR based on donor availability and risk status. This allowed us to evaluate the effect of HSCT in MLL+ patients in the context of GO exposure as any MLL+ patient with a matched family donor or poor induction response (>15% blasts) underwent HSCT. HSCT was conducted in 19 of 83 MLL+ patients (23%) in the GO group after one course of intensification therapy and in 11 of 73 (15%) patients in the No-GO group. Patients in the GO group who received HSCT consolidation had better outcomes than those not receiving HSCT. Specifically, MLL+ patients who received HSCT after prior treatment with GO had a RR of 28% at 5 years from HSCT compared with a RR of 73% for MLL + patients who received HSCT without GO prior (P =0.006). The corresponding DFS at 5 years from HSCT for patients in the GO and No-GO groups was 72% vs. 27% (P =0.004) respectively. These results highlight that the clinical impact of induction GO maintains clinical significance in the post-HSCT setting. Our analysis of data from AAML0531 suggests that pediatric MLL + AML might benefit from the addition of GO to conventional chemotherapy. HSCT might further enhance GO benefit in this subset of patients. Future studies, utilizing GO or other novel CD33 targeted agents, should be considered for MLL + pediatric AML given the superior outcomes observed. Figure 1. Event-free survival from study entry for 11q23/MLL + vs. MLL - patients by treatment arm (GO vs. No-GO). Figure 1. Event-free survival from study entry for 11q23/MLL + vs. MLL - patients by treatment arm (GO vs. No-GO). Disclosures Aplenc: Sigma Tau: Honoraria. Loken:Hematologics Inc.: Equity Ownership.

scholarly journals Single Centre Experience in Treating Elderly Patients with Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndrome with a Combination of Low Dose Cytarabine, Venetoclax and Fluconazole (VeLDAC-F)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5220-5220 ◽  
Author(s):  
Lauren Child ◽  
Henry Chan ◽  
Ross Alistair Henderson ◽  
Anna Elinder ◽  
Eileen Merriman ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Low Dose ◽  
Complete Response ◽  
Event Free Survival ◽  
Free Survival ◽  
Haematological Response ◽  
Tumour Lysis ◽  
Low Dose Cytarabine

Abstract Introduction Acute myeloid leukaemia (AML), high risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukaemia (CMML) are bone marrow disorders that predominately affect the elderly population. The treatment options for this patient group have been limited and those unable to undergo intensive chemotherapy have historically had a poor prognosis. Low dose cytarabine (LDAC) is an accepted treatment option in patients who are ineligible for intensive therapy. LDAC has been shown to achieve a complete response (CR) and complete response with incomplete count recovery (CRi) in 11-18% of patients with a median overall survival of 5- 12 months. Recent evidence suggests that venetoclax (VEN) has a synergistic effect with LDAC with a phase I/II trial reporting a CR +CRi of 33/61 (54%) with this combination. Antifungal agents are commonly used in AML treatment protocols due to the increased risk of invasive fungal infections in this population. Fluconazole, a moderate CYP3A4 inhibitor, increases the maximum concentration (Cmax) of VEN resulting in a 2-5-fold increase in the area under the curve (AUC), thereby significantly increasing drug exposure. When using an azole antifungal, a dose reduction of VEN is recommended to maintain safe therapeutic levels. Here, we present our experience with using a lower dose of VEN in combination with fluconazole and LDAC (VeLDAC-F) in patients with AML, high risk MDS and CMML. Methods Patients with a diagnosis of AML, high risk MDS or CMML that required treatment but were not candidates for high intensity chemotherapy were offered the combination of VeLDAC-F. In cycle 1, VEN was started at 100mg daily and ramped up over the first 4 days to 200mg. This dose was continued from days 4-10. Fluconazole was started on day 3 and continued at 200mg until day 10. On subsequent cycles, VEN was administered at 200mg daily on days 1-10 with 200mg of fluconazole. Subcutaneous LDAC 20 mg/m2/day was given on days 1-10 of each cycle. Treatment cycles were repeated every 4-6 weeks. Patients were not routinely admitted for initiation of chemotherapy, unless the circulating blast count was high. Patients who received at least one dose of VeLDAC-F were included. Event-free survival was the time to either treatment termination, disease progression or death; overall survival was the time to death from all cause. Patients who achieved a haemoglobin > 100g/L, platelets >100 x 109/L and neutrophils > 1 x 109/L were said to have reached a modified haematological response (HR), and time to modified haematological response was analysed using competing risk model with death as the competing factor. All statistical analysis was done using IBM SPSS version 20 and R Statistics. Results Nineteen patients received at least one dose of VeLDAC-F between the 1st of June 2017 and the 1st of June 2018. The majority of patients were male (89.5%). 14/19 (73.7%) had an ECOG performance status of 0 or 1 and the median Charleston co-morbidity index was 6. The median age at diagnosis was 77 years (range 64.4- 87.7 years). The cohort included 9 patients with AML (47.4%), 7 with high risk MDS (36.8%) and 2 with CMML (15.8%). Twelve patients were still alive at the time of analysis (63.2%). The median follow-up was 182 days. Ten patients achieved a modified HR (52.6%). The median duration of response in these patients was 210 days and the 100 day probability of achieving a modified HR was 50.1%. The majority of patients who achieved a modified HR did so within 2 cycles of treatment with only one patient achieving a modified HR after 100 days. Seven patients died over the follow-up period (36.8%) with one patient dying within 30 days of commencing treatment (5.3%). Four patients died of progressive disease, 2 from sepsis and 1 from catastrophic bleeding. The median OS had not been reached at the time of analysis. The 180-day OS was 61%. The median event free survival was 217 days. There were no cases of clinical tumour lysis and three cases of biochemical tumour lysis (15.8%). Only 10 patients were admitted to hospital with neutropenic fever over the course of the follow up period (52.6%). Discussion The combination of VeLDAC-F appears to be an effective regimen for elderly patients with AML, high grade MDS and CMML who are otherwise ineligible for intense chemotherapy. The risk of tumour-lysis is low in this real-world cohort, but ongoing follow-up and further clinical trials are needed to establish the longer-term outcomes of this regime. Figure. Figure. Disclosures Chan: Amgen: Honoraria; Karyopharm: Research Funding. Simpson:Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; MSD: Honoraria; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding.

A Phase IIIb Study of Rituximab Maintenance Therapy in Patients with Follicular Non-Hodgkin’s Lymphoma Who Have Responded to Induction Therapy - MAXIMA-Protocol.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4706-4706 ◽  
Author(s):  
Manfred Hensel ◽  
Mathias Witzens-Harig ◽  
Peter Dreger ◽  
Anthony D. Ho ◽  
Daniel Thurley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Induction Therapy ◽  
Randomized Trials ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
Rituximab Maintenance

Abstract Five randomized trials (four Phase III and one phase II) have confirmed that rituximab maintenance therapy provides clinical meaningful improvements in terms of Progression Free Survival, Event Free Survival and response duration for patients. Two studies have also found an overall survival advantage for rituximab maintenance therapy (Hoechster et al. 2005, van Oers et al. 2005) and a third study could demonstrate a strong trend towards overall survival advantage (Dreyling et al. 2006). A Cochrane meta-analysis of several randomised Phase III trials (Schulz et al. 2005) demonstrated that rituximab plus-chemotherapy for first-line treatment of Follicular Lymphoma is superior to chemotherapy alone and significantly prolongs overall survival. To further broaden the available basis for maintenance treatment in the first-line and relapsed setting, the MAXIMA (MAintenance rituXImab in Follicular LymphoMA) trial has been started in August 2006 and will last 5 years. Patients with first line or relapsed/refractory advanced Follicular Lymphoma are included in this trial. In total 500 patients are planned for this international trial running in 23 countries. Patients who achieve a Complete Remission, Complete Remission unconfirmed or Partial Remission after rituximab containing induction therapy (rituximab with or without chemotherapy) are eligible to enter the study to receive rituximab maintenance therapy administered at the standard dose of 375 mg/m2 every 2 months for 2 years. This regimen is also investigated in the ongoing PRIMA study, and also in an ongoing SAKK study which investigates the benefit of rituximab maintenance therapy for up to five years. The previous five randomized trials did not detect significant safety issues for rituximab maintenance therapy. The main objective of the MAXIMA trial is to confirm this safety data in a wider patient population. Secondary objectives of the study include standard time dependent parameters (PFS, EF, OS). In addition, the effect of rituximab maintenance therapy on improving response quality (PR =&gt;CR) after induction therapy will be evaluated.

Ten Year Follow up Analysis of the OSHO Phase III Trial (AML 96) Comparing Different Application Modes of AraC in Patients below 60 Years with Acute Myeloid Leukemia (AML): No Impact of AraCApplication Mode on Remission Rate, Toxicity, Disease-Free Survival or Overall Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2966-2966
Author(s):  
Cornelia Becker ◽  
Rainer Krahl ◽  
Antje Schulze ◽  
Georg Maschmeyer ◽  
Christian Junghanß ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Significant Difference

Abstract Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) &gt; 109/l and median platelets (plt) &gt; 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p&lt;10−6) and for EFS (p&lt;10−6). Other significant prognostic factors for EFS evaluated in the multivariate analysis were de novo vs secondary AML (p=0,0001), WBC (continuous) (p=0,001), LDH (&gt;1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p&lt;10−6) with 0,71±0,1, 0,27±0,05, 0,20±0,06 and 0,03±0,03 for favorable, normal, other and unfavorable cytogenetic karyotype, respectively. Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.

Replacing Gemtuzumab Ozogamicin With Idarubicin In Frontline Fludarabine, Cytarabine and G-CSF Based Regimen Does Not Compromise Outcome In Core Binding Factor Acute Myelogenous Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3971-3971 ◽  
Author(s):  
Gautam Borthakur ◽  
Jorge E. Cortes ◽  
Farhad Ravandi ◽  
Graciela Nogueras Gonzalez ◽  
Rajyalakshmi Luthra ◽  
...  
Keyword(s):  
Overall Survival ◽  
Low Dose ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Core Binding Factor ◽  
Free Survival ◽  
Log Reduction ◽  
Binding Factor ◽  
Acute Myelogenous

Abstract A regimen comprising of fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin (FLAG-GO) has been our frontline treatment regimen for patients with core binding factor acute myelogenous leukemia (CBF-AML) and among 50 patients with median follow up of over 3 years, this regimen resulted in overall survival (OS) and relapse free survival (RFS) of 78% and 85% respectively. This is clearly better than our historical data with idarubicin and cytarabine based regimens (Borthakur et al. JCO. Vol 28, No 15 suppl; 2010:6552). After withdrawal of GO from the market, it has been substituted by low dose idarubicin at 6 mg/m2 on days 3 and 4 in induction and in one post remission cycle during cycles 3-6 (FLAG-Ida). So far 38 patients have been treated with FLAG-Ida (median follow up 1 year) with all patients achieving complete remission. The current report is part of the planned analysis to ensure that patient outcomes have not been compromised by the change in regimen. Univariate and multivariate (MVA) Cox proportional hazards regression was used to identify association of the clinical variables with overall survival (OS), event free survival (EFS) and time to relapse (TTR). Event is defined as death from any cause or relapse. Treatment regimen (FLAG-GO or FLAG-Ida) were included as variables in the analysis. Apart from relevant clinical variables, reduction in fusion transcript ratio (in reference to ABL gene transcript compared to that at diagnosis) at time points 1 month (≥3 log reduction yes/no) and 3 month (≥3 log reduction yes/no) and presence of any mutation (RAS, KIT, FLT3 yes/no) were also added as variables. Stepwise backwards selection method was used to remove variables that did not remain significant in the multivariate model (p ≥ 0.15). T(8;21) is the cytogenetic abnormality in 52% of all 88 patients. Median age of all patients is 51 (range, 19-78 years) and 48% are female. Median time to 3 log reduction in transcript ratio was 1 month (range, 1-22 months). Complete remission rate with or without platelet recovery has been 98% with 2 induction deaths. Kaplan-Meier analysis showed OS (Fig.1), EFS and TTR were not significantly different FLAG-GO and FLAG-Ida regimens. By MVA, OS, EFS and TTR are not different among these regimens (p > 0.5). Three log or more reduction in transcript ration at 1 month was associated with better OS (p=.03) and EFS (p=.008) (not TTR) in MVA. Presence of KIT, RAS or FLT3 gene mutation did not impact outcomes studied. In conclusion, replacing GO with low dose idarubicin in a front-line FLAG regimen does not seem to compromise the excellent outcomes with such a regimen in CBF AML. Disclosures: No relevant conflicts of interest to declare.

Homoharringtonine and Low-Dose Cytosine Arabinoside Combined with G-CSF or GM-CSF Administered in Patients with Advanced Myelodysplastic Syndromes and Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1465-1465
Author(s):  
Caigang Xu ◽  
Juan Xu ◽  
Ting Liu ◽  
Bing Xiang ◽  
Hong Chang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Refractory Anemia ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Gm Csf ◽  
Acute Myeloid

Abstract According to the FAB classification of myelodysplastic syndromes (MDS), subgroups of refractory anemia with excess blasts(RAEB) and refractory anemia with excess blasts in transformation(RAEB-t) are considered as high-risk MDS or advanced MDS which tend to involve into acute myeloid leukemia(AML). Even though various strategies have been in use, chemotherapy remains the main treatment option. With low remission rates, short duration of remission and high relapse rates, conventional chemotherapy for high-risk MDS and AML transforming from MDS is generally unsatisfactory. Relapsed or refractory AML, geriatric AML and secondary AML have a poor response to the classical induction chemotherapy. Studies indicate that CRs have occurred(8∼56%) at the cost of a high incidence of deaths from toxicity(24%∼64%). Although allogeneic stem cell transplantation could potentially be curative, it is appropriate for only a small subset of patients. This challenges us to work towards new reasonable therapeutic strategies. In vitro, studies have confirmed that granulocyte colony stimulating factor(G-CSF) can enhance the cytotoxic effects of S-phase-specific drugs such as Ara-C by the mechanism of driving myeloid leukemic cells of resting G0-phase into the cell cycle as well as intensifying the metabolism of Ara-C and anthracyclines in the leukemic cell. Recently the regimen of low-dose Ara-C and aclarubicin in combination with G-CSF(CAG regimen) has presented both well-tolerated and highly effective in treating the above categories of AML and MDS. The reported overall CR rate is 35∼75%. We designed a combination chemotherapy of homoharringtonine, low-dose cytarabine and G-CSF or GM-CSF(HAG priming regimen) for remission induction in this study which enrolled 42 patients with advanced MDS or AML between January 2002 and July 2005. 42 patients who received HAG chemotherapy were followed up till April 2006. Clinical and laboratory data of all these patients, which concerned with a)medical interventions including induction chemotherapy, post-remission treatment, and management of complications, etc; b)follow up for conditions of remission, relapse-free survival and overall survival after HAG induction therapy; c)adverse events following HAG induction therapy, were recorded in detail. Among Forty appraisable patients, 20 of them (50%) achieved complete remission (CR), including 66.7% patients with MDS-RAEB and 46.2% patients with refractory or relapsed AML. The fact of 80% patients with AML-M1 achieved CR, demonstrates a better response than those with other subtypes of AML. The overall response rate was 52.5%. After a follow-up of 6—47 months(median 23) from the date of remission, the median times of relapse-free survival and overall survival were 7.0±1.1 and 28±12.3 months, respectively. Meanwhile, these patients aged under 60-year-old who have achieved complete remission and received regular post-remission treatment showed a better survival rate. Myelosuppression was the most significant toxicity. More than 80% of patients experienced neutropenia or thrombocytopenia of grade III to IV after the first induction therapy. The incidences of infection and hemorrhage in the total of 64 induction courses were 43.8%(28/64) and 37.5%(24/64), respectively. Nonhematologic adverse-effects were minimal.

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