The Addition of Gemtuzumab Ozogamicin to Low Dose Ara-C Improves Remission Rates but Not Survival: Results of the UK LRF AML14 and NCRI AML16 “Pick a Winner” Comparison

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 18-18 ◽  
Author(s):  
Alan Burnett ◽  
Robert Hills ◽  
Ann Elizabeth Hunter ◽  
Donald Milligan ◽  
William J. Kell ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Older Patients ◽  
Low Dose ◽  
Remission Rate ◽  
Significant Proportion ◽  
Gemtuzumab Ozogamicin ◽  
Fixed Dose ◽  
The Uk

Abstract Abstract 18 In a significant proportion of older patients with AML intensive chemotherapy is not considered a viable option[1]. Such patients may receive low-dose Ara-C (LDAC), best supportive care (BSC) with hydroxyurea or an experimental agent but outcomes are poor. We have shown that LDAC is superior to BSC [2], but only in patients who enter CR (fewer than 20%).[2]. There is therefore scope to improve outcomes in these patients, and a number of possible treatments have been evaluated in the randomised UK NCRI AML16 trial, one of which is gemtuzumab ozogamicin (GO), which we have shown to benefit the majority of younger patients when given in conjunction with standard chemotherapy[3]. In AML16 novel agents or combinations are tested in untreated older patients with AML or high risk MDS (marrow blasts >10%) using a “pick a winner” design. The design allows unpromising treatments to be identified early (typically after 50 or 100 patients per arm): only those arms which show promise will continue to a trial with OS and DFS as endpoints. The aim is to at least double the remission rate from 15% to 30%, and thus improve overall survival. We now report the results of LD Ara-C (20mg bd days 1–10 for 4 courses) versus LDAC combined with GO (at a fixed dose of 5mg on day 1 of each course for 4 courses at 6–8 week intervals). Patient Details: The comparison opened as part of the UK LRF AML14 trial and was carried forward to AML16 unchanged. Between June 2004 and June 2010, 495 patients were randomised, 249 to LDAC plus ATO, 246 to LDAC. The median age was 75 years (range 54–90); 83% of patients were aged over 70 years, and 61% were male. To be eligible patients’ LFTs had to be less than twice ULN. Treatment arms were balanced for age, gender, performance status, de novo/secondary AML/high risk MDS, presenting WBC and cytogenetic risk group. Follow-up is complete to 1st January 2010, with median follow up of 21 months. Survival and remission data is available on 412, 404 patients respectively. Treatment Results: The trial passed through both stopping hurdles based on CR/CRi rates and therefore continued to full accrual, with overall survival as primary outcome measure. The table shows the distribution of outcomes: there was no heterogeneity by recruitment period (AML14 vs AML16). The causes of death (316) were:- There were no significant interactions between treatment and any of the baseline variables on either remission or survival outcomes. Likewise there were no major toxicity implications, although resource usage tended to be higher in patients given GO. Discussion: While the addition of GO significantly improves CR rate, achieving the 30% response originally sought, this does not translate into survival. This is predominantly due to an increase in relapse, indicating that if GO is to have a role in this setting, it will require effective treatment to maintain remission. [1] Juliusson G et al. Blood 2009; 113: 4179 – 4187 [2] Burnett et al. Cancer 2007 109: 1114–1124 [3] Burnett et al. JCO 2010 to appear. Disclosures: Off Label Use: Mylotarg (gemtuzumab ozogamicin).

Low Dose Ara-C Versus Low Dose Ara-C and Arsenic Trioxide: the UK NCRI AML16 “Pick a Winner” Comparison.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 486-486
Author(s):  
Nigel H. Russell ◽  
Robert K Hills ◽  
Ann E. Hunter ◽  
Donald Milligan ◽  
William J. Kell ◽  
...  
Keyword(s):  
High Risk ◽  
Arsenic Trioxide ◽  
Older Patients ◽  
Low Dose ◽  
Remission Rate ◽  
Randomised Trial ◽  
Age Distribution ◽  
Significant Proportion ◽  
The Uk

Abstract Abstract 486 A significant proportion of older patients with AML are not treated with conventional intensive chemotherapy [1] because they are unfit or not considered likely to benefit from an intensive treatment approach. Their outcomes are poor. Such patients have typically been treated with low-dose Ara-C (LDAC) or best supportive care (BSC) with hydroxyurea, and unrandomised studies of new agents have been used in this population. A recent randomised trial has shown that LDAC is superior to BSC in these patients [2]. Randomised trials are underway to assess the value of other novel treatments compared to LDAC. In an unrandomised phase 2 trial in 64 patients, Roboz et al found encouraging results using the combination of Arsenic Trioxide and LDAC. [3]. The UK NCRI AML16 trial is a programme of development which aims to test novel agents or combinations in untreated older patients with AML or high risk MDS (marrow blasts >10%) following a “pick a winner” design. The intention is to identify a “winner” which will produce a remission rate in excess of 30%, compared with 15-20% with LDAC. Using LDAC as the standard arm,the design allows unpromising treatments to be identified early (typically after 50 patients per arm), so that only those arms which show promise will continue to a trial with OS and DFS as endpoints. We report our experience of LD Ara-C (20mg bd days 1-10 for 4 courses) versus LDAC combined with Arsenic Trioxide (ATO, 0.25 mg/kg d1-5, d9, d11 for 4 courses at 6-8 week intervals). Patient Details: Between December 2006 and until its conclusion in May 2009, 166 patients were randomised, 84 to LDAC plus ATO, 82 to LDAC. The median age was 74 years; 80% of patients were aged over 70 years, 62% were male. There were no differences between the treatment arms with respect to age distribution, gender, performance status, de novo/secondary AML, high risk MDS, presenting WBC or cytogenetic risk group. Follow-up is complete to 1st January 2009, with median follow up for survivors of 8 months (range 0.1-17), at which point 122 patients had been recruited, and there were a total of 60 deaths (LDAC n=25; LDAC+ ATO, n=35). CR status is known on 113 patients. Overall, 24 patients have entered CR/CRi (LDAC n=13, LDAC+ATO n=11) with 8 relapses (2 vs 6; 1 vs 3 patients have died following relapse). The causes of death (60) were:- The DMEC recommended closure of the LDAC + ATO arm of the trial because follow-up data on the first 50 patients per arm showed that ATO had failed to provide the 2.5% improvement in CR/CRi required for continued recruitment and that the required improvement in remission was unlikely with LDAC + ATO. Conclusions: While ATO has a definite role in treating patients with APL, and may be of benefit in combination with other drugs in AML, the combination of LDAC + ATO in this patient population was not beneficial. [1] Juliusson G et al. Blood 2009; 113: 4179—4187 [2] Burnett et al. Cancer 2007 109: 1114—1124 [3] Roboz Gail J et al. Cancer 2008;113(9):2504—11. Disclosures: Off Label Use: Arsenic Trioxide is not licensed in this indication.

Low Dose Ara-C Versus Low Dose Ara-C and Tipifarnib: Result of the UK NCRI AML16 “Pick a Winner” Comparison

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2962-2962 ◽  
Author(s):  
Alan K. Burnett ◽  
Robert Hills ◽  
Donald Milligan ◽  
William J. Kell ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Low Dose ◽  
De Novo ◽  
Remission Rate ◽  
Performance Status ◽  
Randomised Trial ◽  
Age Distribution ◽  
Best Supportive Care ◽  
The Uk

Abstract Novel treatments are needed for older patients with AML who are not thought likely to benefit from standard chemotherapy. A recent randomised trial demonstrated that Low Dose Ara-C (LD Ara-C) was superior to best supportive care (BSC) (Burnett et al Cancer2007: 109: 1114–1124). The Farnesyl Transferase inhibitor, Tipifarnib, has produced encouraging responses in this patient group (Lancet 109; 1387–1394) although in a subsequent randomised comparison vs BSC it was not superior (Haroussea et al Blood1997:110,135a) The UK NCRI AML16 trial aims to test novel agents or combinations in untreated older patients with AML or high risk MDS (marrow blasts >10%) following a “pick a winner” design. The intention is to randomise up to 50 patients per arm with the expectation that a “winner” will achieve a remission rate in excess of 30%, compared with 15–20% with LD Ara-C. If that is achieved randomisation will continue with OS and DFS as endpoints. We report our experience of LD Ara-C (20mg bd days 1–10 for 4 courses versus LD Ara-C combined with Tipifarnib (300mg bd days 1–21) for 4 courses at 6–8 week intervals. Patient Details: Sixty-five patients were randomised between December 2006 and October 2007. The median age was 74.4 years with 82% of patients over 70 years. There were no differences between the treatment arms with respect to age distribution, gender, performance status, de novo/secondary AML, high risk MDS presenting WBC or cytogenetic risk group. Because of concerns about excess deaths in the Tipifarnib arm and therefore the low probability that LD Ara-C + Tipifarnib would be superior to LD Ara-C alone, the DMEC recommended premature closure of the Tipifarnib arm. Conclusions: While other agents combined with Tipifarnib may continue to show promise, the combination with LD-Ara-C in this patient population was not beneficial.

A Comparison of Daunorubicin/Ara-C (DA) Versus Daunorubicin/Clofarabine (DClo) and Two Versus Three Courses of Total Treatment for Older Patients with AML and High Risk MDS: Results of the UK NCRI AML16 Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 892-892 ◽  
Author(s):  
Alan K. Burnett ◽  
Nigel H Russell ◽  
Jonathan Kell ◽  
Lars Kjeldsen ◽  
Donald Milligan ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
De Novo ◽  
Demographic Variable ◽  
Gemtuzumab Ozogamicin ◽  
Demographic Feature ◽  
Poor Risk ◽  
Best Response ◽  
The Uk

Abstract Abstract 892 Introduction: The UK NCRI AML16 trial randomised older patients to two courses of DA vs DClo with or without gemtuzumab ozogamicin (GO) on day 1 of course 1. Patients who had at least a PR to course 1 and were in CR/CRi after course 2 could be randomised to a third course (DA) or not, after which they were randomised to maintenance, or not, with 9 six weekly courses of Azacitidine. The benefit of the addition of GO has been reported [1]. Based on a feasibility study [2] a schedule of Clofarabine 20mg/m2 days 1–5 was combined with Daunorubicin (Dauno) 50mg/m2 days 1–3, to be compared with Dauno 50mg/m2 days 1–3 + ara-C 100mg/m2 bid days 1–10 (course 1) or days 1–8 (course 2). Those randomised to a 3rd course received Dauno 50mg/m2 days 1, 2 + ara-C 100mg/m2 bid days 1–5. The results of the 530 patients in the Azacitidine randomisation have insufficient follow up. Methods: Between August 2006 and December 2009, 806 patients were randomised between DA and DClo, of whom 683 entered the GO randomisation. The median age was 67 (56-84) years: 72% had de novo, 17% had secondary, and 11% has high risk MDS (marrow blasts >10%): 4%, 73% and 23% had favourable, intermediate or poor risk cytogenetics: 14% were FLT3-ITD and 20% were NPM1 mutant: 30%, 34% and 36% had good, standard or poor Wheatley Scores [3]. Between November 2006 and August 2012, 570 patients were randomised to 2 vs 3 courses. Of these 34% were Wheatley good risk, 40% standard risk and 26% poor risk. The 307 patients in the consolidation randomisation not in the DA vs DClo induction randomisation received DA with or without GO. The demographic, cytogenetic, molecular and allocated treatments were balanced between the arms. Follow-up is complete to 1st January 2012. Results: In the DA vs DClo randomisation, the overall response rate (ORR) was 68% (CR 60%+ CRi 8%) and survival at 3 years was 22%. The ORR was not different between DA: 71% (CR 63%, CRi 8%) and DClo 66% (CR 57%, CRi 9%), OR 1.26 (0.94-1.70) p=0.12, with 60 day all-cause mortality of 15% and 14% respectively. There were no significant differences between DA and DClo at 3 years in RFS (18% vs 21%, HR 1.00 (0.83-1.20) p=1.0) CIR (74% vs 68%, HR 0.93 (0.77-1.14) p=0.5), death in CR (8% vs 12%, HR 1.52 (0.89-2.57) p=0.12): survival from CR (31% vs 32%, HR 1.02 (0.83-1.24) p=0.9): survival from relapse (7% vs 9%, HR 0.96 (0.77-1.19) p=0.7) and overall survival (23% vs 22%, HR 1.08 (0.93-1.26) p=0.3). The schedules were equi-toxic, and although the recovery of neutrophils and platelets was quicker in the DA arm in both courses DClo patients received significantly less transfusion support, days on antibiotics and hospitalisation. There was no evidence of interaction between the two induction randomisations, or between the DA vs DClo randomisation and any demographic feature. In the consolidation randomisation, 3 year survival from entry was 34%, with an RFS of 20%. Overall there were no significant differences between the two arms (3-year survival 34% vs 34%; HR 0.91 (0.72-1.15) p=0.4; RFS 19% vs 21%; HR 0.88 (0.72-1.09) p=0.2). There was no evidence of interaction between the number of courses given and any demographic variable including number of courses to CR and best response (CR/CRi), and, importantly, no interaction between consolidation and induction randomisations. Conclusions: DA and DClo in induction give similar outcomes, with equivalent toxicity, and slightly lower resource usage on the DClo arm. In patients who achieve at least partial remission following course 1 and reach CR or CRi by the end of their second course, there is no significant benefit for a third course of chemotherapy, and no evidence of a particular subgroup who would benefit from a third course. Acknowledgments: This study received research support from Genzyme and Cancer Research UK. Disclosures: Hills: Genzyme: Consultancy.

Competing Risk Survival Analysis In Patients With Symptomatic Waldenström’s Macroglobulinemia (WM): Disease Unrelated Mortality Accounts For Differences In Survival In Patients >75 Years

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3197-3197
Author(s):  
Efstathios Kastritis ◽  
Marie-Christine Kyrtsonis ◽  
Evdoxia Hatjiharissi ◽  
Argiris S. Symeonidis ◽  
Amalia Vassou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Analysis ◽  
High Risk ◽  
Death Rate ◽  
Older Patients ◽  
Risk Groups ◽  
Competing Risk ◽  
Advanced Age ◽  
Primary Therapy

Abstract WM is a disease of the elderly with a protracted course in many patients. There are limited data which indicate that several WM patients die due to causes which are not directly related to their underlying malignancy. However, the realization and the estimation of the contribution of unrelated mortality in WM are important for the design of treatment strategy in patients of advanced age. To our knowledge there are no such data published for WM patients. Thus, we analyzed the outcomes of 408 patients with symptomatic WM who received therapy within the centers of the Greek Myeloma Study Group in order to assess disease related survival. In this analysis unrelated death was considered to be a competing risk event. Causes of death other than WM, treatment toxicity or myelodysplasia/transformation were considered as unrelated deaths. Median age of patients was 68 (28-92) years; 21% were >75 years and 9% were ≤50 years of age. Patients who started therapy after 2000 were older (median age 70 vs. 65 years before 2000, p<0.001) while 25% were >75 years (vs. 13% before 2000). In terms of ISSWM stage, more patients had high and intermediate risk disease after 2000 (41% & 42% vs. 25.5% & 38% before 2000, p<0.001), probably due to increased proportions of older patients in the recent era. Only 4% of patients before 2000 vs. 79% after 2000 received primary therapy with rituximab; however, similar rates of at least 50% IgM reduction were recorded (63% vs. 58%, p=0.361). Median follow up for all patients was 5.5 years (9 years in the pre-2000 and 4.5 years in the post-2000 group) and 52% of patients have died (77% in the group before 2000 and 40% in the group after 2000). However, 23% of deaths were considered unrelated to WM. Thus, 5-year and 8-year overall survival (OS) was 70% and 54% respectively, with a median OS of all patients of 8.8 years. When we performed survival analysis with unrelated deaths as competing risk, then 5-year risk of WM-related death was 21.4% (95% CI 17-26%) and of unrelated death was 7.6% (95% CI 5-10.5%), while 8-year WM-related death rate was 32% (95% CI 27-37%) and unrelated death 11.5% (95% CI 8-15%). Because older patients are at higher risk of unrelated deaths we performed an age-specific analysis. The median survival of patients >75 years was 5.3 vs. 9.7 years for patients ≤75 years (p<0.001). However, for patients >75 years, the 5-year death rate due to WM was 22% (95% CI 13-32%) vs. 21% (95% CI 16-26%) for patients ≤75 years (p=0.193), while the 5-year unrelated death rate was 17% (95% CI 10-27%) and 5.1% (3-8%), respectively (p<0.001). Thus, in patients with advanced age (>75 years) >40% of deaths are unrelated to WM, while WM-specific death rates were similar for patients >75 or ≤75 years. In patients ≤50 years there were no WM-unrelated deaths. We then evaluated the prognostic significance of IPSSWM, which discriminated 3 groups with 5-year overall survival of 86%, 68% and 51% for low, intermediate and high risk groups, respectively (p<0.001). However, because intermediate and high risk IPSS groups are enriched for older patients we performed the analysis with unrelated deaths as competing event. The 5-year WM-specific death rate was 10%, 19% and 27% for the three risk groups (p=0.035), while the 5-year unrelated death rate was 1.5%, 5% and 14%, respectively (p=0.003). The median OS for patients who started therapy before and after 2000 was similar (9 vs. 8.1 years, respectively, p=0.474). However, when we performed competing event survival analysis, then the 5-year WM-related death rate was 21% for both groups, but the 5-year unrelated death rate was 4.6% for patients before 2000 vs. 9.1% for patients after 2000 (p=0.026). Thus, the lack of a significant improvement of survival after the era of monoclonal antibodies is partly due to the doubling of WM-unrelated deaths as a result of the increasing numbers of patients of advanced age who are diagnosed and treated for WM. Additional follow up is needed for patients after 2000 in order to evaluate the WM-related risk of death at later time points (at 10 or 15 years). In conclusion, this is the first analysis in a large cohort of patients with symptomatic WM in which WM-unrelated death is treated as a competing risk. Many patients of advanced age die of causes unrelated to WM and this fact should be taken into account in the evaluation of long term outcomes and the design of clinical trials in patients with WM, especially since more patients of advanced age are diagnosed and treated for WM. Disclosures: No relevant conflicts of interest to declare.

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.

Myeloablative Timed Sequential Busulfan Is Safe in Older Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3859-3859 ◽  
Author(s):  
Uday R. Popat ◽  
Patricia S Fox ◽  
Roland Bassett ◽  
Julianne Chen ◽  
Benigno C. Valdez ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Older Patients ◽  
Disease Risk ◽  
Risk Index ◽  
Fixed Dose ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
Antileukemic Effect ◽  
Very High

Abstract Background: Reduced intensity conditioning regimen (RIC) extends allogeneic hematopoietic cell transplantation (HCT) to older patients and patients with comorbidities. Compared to myeloablative (MA) conditioning, RIC has higher rate of relapse but lower rate of non-relapse mortality (NRM), resulting in similar survival. BMT CTN is conducting a prospective study to compare these two approaches. To further improve survival for older patients, a MA regimen with low NRM is needed. Timed sequential therapy (TST), giving two courses of chemotherapy 1 week apart, has higher antileukemic effect in in-vitro and in-vivo in studies of patients with AML, including phase 3 studies. We hypothesized that MA dose of busulfan delivered per principles of TST enhances antileukemic effect without increasing toxicity. We therefore designed a study to test safety of two MA schedules of busulfan targeting busulfan exposure (AUC) of 16000 μmol.min and 20000 μmol.min. AUC of 20000 μmol.minis close to total average drug exposure achieved with IV busulfan fixed dose of 12.8mg/kg. Methods: Patients were randomized to receive total busulfan exposure of 16,000 μmol.min(16K) or 20,000 μmol.min( 20K). Patients received IV busulfan 80 mg/m2 per day on day -13 and -12 in outpatient clinic, fludarabine 40 mg/m2 day x 4 (day -6 to -3) and IV busulfanx 4 (day -6 to -3). Busulfan was dosed to achieve target AUC of 16K or 20K based on pharmacokinetic studies done on day -13 and day -6. GVHD prophylaxis was Tacrolimus (day -2 onwards) and mini dose methotrexate-5mg/m2 on day 1, 3, 6, and 11. Stem cells were infused on day 0. Primary endpoint of the study was to compare 100 day non-relapse mortality in two arms with stopping rules built in for safety. Patients with hematological malignancies were eligible for the study if they had adequate organ function and 8/8 matched related or unrelated donor. We enrolled patients on this study who were suitable for RIC. When the study began, upper age limit for eligibility was 70 years, but this was increased to 75 years during the course of the study as safety was established. Fisher’s exact test was used to compare toxicity and NRM rates between arms. Cox proportional hazards regression was used to estimate the effects of clinical variables on overall survival. Results: 97 patients were enrolled on the study until the DSMB stopped the randomization and permitted continued accrual onto the higher dose arm with busulfan AUC of 20,000 μmol.min. 49 were randomized to busulfan AUC of 16K and 48 to 20K. For all patients, median age was 60 (18-75) years. 3 (2%) patients were less than 40 years of age, 12 (12%) 40-49, 33 (34%) 50-59, 39 (40%) 60-69, and 10 (10%) 70-79 years. 53 patients had AML/MDS, 24 CML/MPD, 16 myeloma, and 4 lymphoid malignancies. Based on revised disease risk index, 3 had low risk, 53 intermediate risk, 35 high risk, and 6 very high risk disease. Donor was related for 43 and unrelated for 54. Comorbidity scores were 0 in 23, 1-2 in 24, and ≥ 3 in 50. With a median follow up of 9.2 months (range 1.8-24) in surviving patients, 100 day NRM was similar in two groups, 4% in 16K and 6% in 20K (p=0.68). Maximum toxicity per patient was not significantly different between arms (Table 1, p=0.37). The 1-year unadjusted survival rates (95% CI) in combined disease risk indexes low and intermediate vs high and very high were 67 (50-79)% and 38 (19-57)%, respectively for all 97 patients. Multivariable Cox regression analysis for overall survival showed increased risk of death for older age (HR 1.05; p=0.03), comorbidity 3 and higher (HR 1.89 p=0.08), and high or very high risk index (HR 2.04; p= 0.05). After also accounting for donor relation and cell type, Bu AUC of 20k showed improved overall survival and a 50% reduction in the risk of death (HR 0.50, P= 0.058). Table 1. Maximum grade of toxicity per patient, N (Row %) MaximumGrade per Patient AUC=16k AUC=20k Total p-value 5 7 (54%) 6 (46%) 13 0.37 4 6 (50%) 6 (50%) 12 3 23 (44%) 29 (56%) 52 2 11 (73%) 4 (27%) 15 1 2 (40%) 3 (60%) 5 Total Patients 49 48 97 Conclusion: Myeloablative timed sequential busulfan regimen is safe in older patients and patients with comorbidities. The regimen with busulfan AUC of 20,000 μmol.min appears promising and needs to be studied further. Disclosures Popat: Otsuka: Research Funding. Off Label Use: Busulfan.

Low Dose Ara-C Versus Hydroxyurea with or without Retinoid in Older Patients Not Considered Fit for Intensive Chemotherapy: The UK NCRI AML14 Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 872-872 ◽  
Author(s):  
Alan K. Burnett ◽  
Donald Milligan ◽  
Archie G. Prentice ◽  
Anthony H. Goldstone ◽  
Mary F. McMullin ◽  
...  
Keyword(s):  
Older Patients ◽  
Low Dose ◽  
Significant Proportion ◽  
Standard Of Care ◽  
Hazard Ratio ◽  
Intensive Chemotherapy ◽  
Adequate Treatment ◽  
And Performance ◽  
The Uk ◽  
Care Requirements

Abstract There is no adequate treatment for older patients with AML who are not considered fit for intensive chemotherapy who comprise a significant proportion of the AML population. As part of the ongoing NCRI (formerly MRC) AML14 Trial in patients over 60 years patients were randomised to Low Dose Ara-C (20mg bd for 10 days every 4–6 weeks) versus Hydroxycarbamide (Hydroxyurea). Because of preclinical studies showing sensitization to Ara-C, patients were in addition randomised to receive All-transretinoic acid or not (45mgs/m2 for 60 days). Two hundred and four patients entered; 129 had a WHO score of <2; 155 patients were >65 yrs; 108 had do novo, 53 secondary disease and 28 had high risk MDS (blasts >10%). One hundred and ninety-nine patients entered the HU vs LD-Ara-C randomisation and 204 entered the ATRA randomisation. The arms were balanced with respect to age; sex; disease type; WBC and performance score. Complete remission was seen in 1 of 92 (1%) patients in the HU arm and 15 of 94 (17%) in the LD Ara-C arm (P=0003). Overall survival was considerably improved (hazard ratio 0.61, 95% Cl 0.45 to 0.82, p=0.001). This improvement in outcome was not obtained at the expense of less well tolerated treatment: toxicity and supportive care requirements were similar between the two groups. However, there were no significant differences in outcome between patients given ATRA or not overall or within the treatment arms, although numbers were too small to rule out moderate benefits or disbenefits of treatment (hazard ratio for OS 0.97, 95% Cl 0.73 to 1.28, p=0.8). We conclude that LD-Ara-C in the schedule chosen could be adopted as a standard of care for older patients not fit for intensive chemotherapy but the outcome remains poor. Future strategies could combine Low Dose Ara-C with novel agents. This trial received a research grant from the UK Leukaemia Research Fund.

A Randomised Comparison of Clofarabine Versus Low Dose Ara-C As First Line Treatment for Older Patients with AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 889-889 ◽  
Author(s):  
Alan K Burnett ◽  
Nigel H. Russell ◽  
Mary Frances McMullin ◽  
Jonathan Kell ◽  
Sahra Ali ◽  
...  
Keyword(s):  
Overall Survival ◽  
Patient Group ◽  
Older Patients ◽  
Low Dose ◽  
Response Rate ◽  
De Novo ◽  
Remission Rate ◽  
Final Analysis ◽  
Median Number ◽  
Grade 3

Abstract Abstract 889 Introduction There is no adequate standard of care for older patients with AML who are not considered fit for intensive treatment. In recent years a number of potential novel agents have been tested in single arm studies, but have not been validated in a randomised assessment. Clofarabine is a novel nucleoside analogue which has shown encouraging activity in this patient group in single arm studies [1,2]. As part of our “Pick a Winner” (PaW) trial programme, Clofarabine (CLO) 20mg/m2 IV days 1 to 5 was compared to Low Dose Ara-C (LDAC) 20mg bid SC days 1 to 10, each for up to 4 courses, with patients deriving benefit allowed to continue on treatment. The rules of PaW [3] required a confidential interim analysis after 50 & 100 randomised patients per arm to confirm that the aim of doubling the CR rate to >30% was likely to be achieved, in order to proceed to phase 3 with overall survival as the primary endpoint. Methods Between August 2006 and April 2011, 406 patients entered the randomised comparison from 109 centres in the UK, Denmark and Australia with a median age of 74 yrs (range 51–90). Sixty-two per cent had de novo disease, 24% secondary AML and 14% high risk MDS (>10% blasts): 2% had favourable cytogenetics, 72% intermediate and 26% adverse. By Wheatley Score [4], 3% were good; 46% standard and 51% poor risk; 13% had WHO performance score >2. Results Overall 28% entered CR/CRi and 28% and 13% were alive at 12 and 24 months respectively. The median number of courses given was 2.0 (range 0–8) in both arms. Of the remitters 34% are alive at 2 years compared with 4% of non-remitters. At the two interim analyses 34% and 41% were in CR in the CLO arm compared with 15% and 21% in LDAC. The trial therefore recruited to full accrual. In the final analysis the CLO arm had a superior response rate (CR + CRi) of 38% vs 20% (CR 22% vs 12%, CRi 16% vs 8%; OR 0.41 (0.26-0.62); p<0.0001). The 30 and 60 day all-cause mortality was higher in the CLO arm (18 vs 13% and 32% vs 26%). RFS (2 yrs) was non-significantly better in the CLO arm (20% vs 8%, HR 0.76 (0.49-1.19), p=0.2) but for those achieving CR the survival was non-significantly better in the LDAC arm (44%vs 26% HR 1.19 (0.74-1.91), p=0.5), which is partly explained by a significantly superior survival from relapse in the LDAC arm (8% vs 0%, HR 1.91 (1.10-3.31), p=0.02). The lack of OS benefit in the CLO arm is also partially explained by a better survival for those in the LDAC arm who did not achieve initial CR (HR 1.37 (1.06-1.76), p=0.02). The CLO arm had more reported grade 3/4 toxicities of nausea, diarrhoea and liver biochemistry in course 1 & 2, while LDAC had more reports of grade 3/4 cardiac toxicities. The increased myelosuppression in the CLO arm was reflected in an increased use of RBC and platelet transfusions, and more days on antibiotics and in hospital. In an analysis stratified by demographic, cytogenetic and molecular (FLT3/NPM1) subgroups, clofarabine consistently resulted in a superior remission rate. However, with respect to overall survival, there was no evidence of any subgroup benefit. Conclusion Clofarabine was shown to double the response rate in older patients compared with LDAC, but did not result in an improvement in survival overall, or in any demographic or risk subgroup. CR may not serve as a reliable surrogate for overall survival in this patient group Acknowledgments: This study received research support from Genzyme and Cancer Research UK. Disclosures: Burnett: Genzyme: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Clofarabine in treatment of AML. Hills:Genzyme: Consultancy.

The Addition of Gemtuzumab Ozogamicin to Intensive Chemotherapy in Older Patients with AML Produces a Significant Improvement in Overall Survival: Results of the UK NCRI AML16 Randomized Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 582-582 ◽  
Author(s):  
Alan K Burnett ◽  
Robert K Hills ◽  
Ann E. Hunter ◽  
Donald Milligan ◽  
William J. Kell ◽  
...  
Keyword(s):  
Overall Survival ◽  
Induction Chemotherapy ◽  
Older Patients ◽  
De Novo ◽  
Gemtuzumab Ozogamicin ◽  
Oral Toxicity ◽  
Secondary Disease ◽  
Significant Difference ◽  
Chemotherapy Patients ◽  
The Uk

Abstract Abstract 582 We previously showed in the MRC AML15 Trial (Burnett et al JCO 2011:29(4):369-77 that 70% of younger patients with AML derived a 10% survival benefit by the addition of the immuno-conjugate, Gemtuzumab Ozogamicin (GO) (Mylotarg™), to induction chemotherapy. In a second trial (AML16 non-intensive) its addition to Low dose Ara-C doubled the CR rate but did not improve OS (Burnett et al. Blood 2010:116 (21): Abstract 18). We now report the result of the NCRI AML16 (Intensive) Trial in which older patients were randomised to receive, or not, GO 3mg/m2 on day 1 of course 1 of induction chemotherapy. Patients were randomised to two courses of DA (daunorubicin/ara-C) or DClo (daunorubicin/clofarabine), followed, or not, by a 3rd course (DA) with or without Azacytidine maintenance. Between December 2006 and July 2010, 1115 patients were randomised to the GO vs no GO comparison from 149 centres in the UK & Denmark. The median age was 67 years (range 51–84). 806 had de novo AML, 194 secondary disease and 115 high risk MDS (>10% marrow blasts). Of the 806 patients with cytogenetic data, 33 were favourable/629 intermediate/204 adverse risk (Grimwade et al, Blood 1998: 92:2322-33). 96% of those allocated GO received it. The overall response rate was 69% (CR 60%; CRi 9%) with 52% of patients achieving response after course 1. Overall survival at 4 years was 17% with a median follow up of 29.5 months (range 0.5–54.6 months).CR%CRi%ORR%Res Dis %Ind Death %30d mortality %60d mortality %GO629711712915No GO5810682111814p-value0.180.30.070.40.80.8 Induction Results: There was no significant difference in blood count recovery kinetics; other toxicities and resource usage were not significantly increased with the exception that for course 1 nausea and oral toxicity were marginally higher with GO, more platelet transfusions were given (13.7 vs 9.6 mean units; p<0.001), and marginally more days of IV antibiotics (mean 19.2 days v 18.1 days p=0.03). There were no significant differences for course 2 of treatment. Relapse/RFS/OS: The rate of relapse was significantly reduced (GO vs no GO: CIR at 2 years 61% vs 70%; p=0.004), leading to significantly better RFS (28% vs 23% at 2 years; p=0.03), and survival from CR and OS were significantly better on the GO arm (2 year survival from CR 47% vs 39%; p=0.02; 2 year OS 35% vs 29%; p=0.04). While the benefit appeared lower in patients with secondary disease or with adverse cytogenetics (GO vs no GO 2 year OS 19% vs 21% and 13% vs 6%) compared to those with de Novo disease or intermediate cytogenetics (2 year OS 38% vs 32% and 41% vs 36%), as was seen in our previous AML15 trial, in this trial there was no significant evidence of interaction between treatment and any demographics or underlying chemotherapy. Conclusion: The addition of GO to induction chemotherapy did not lead to unacceptable increases in toxicity. It improved disease control and delivered a significant OS benefit for older patients overall. While there is no significant interaction, the greater benefit in patients with de novo disease or intermediate risk cytogenetics is consistent over the 2228 patients randomised in the AML15 and AML16 trials. Disclosures: Burnett: Pfizer: Consultancy. Off Label Use: Gemtuzumab Ozogamicin in AML.

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