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.

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.

A Retrospective Comparison of Matched Elderly Patients Treated with Laromustine (Cloretazine®) or Best Supportive Care or Low Dose Ara-C in the LRF AML14 Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2960-2960 ◽  
Author(s):  
Robert Hills ◽  
Susan O’Brien ◽  
Verena Karsten ◽  
Alan K. Burnett ◽  
Francis Giles
Keyword(s):  
High Risk ◽  
Supportive Care ◽  
Low Dose ◽  
De Novo ◽  
Performance Status ◽  
Single Agent ◽  
Best Supportive Care ◽  
Cell Counts ◽  
Retrospective Comparison ◽  
De Novo Aml

Abstract Background : A substantial proportion of older patients with AML are considered unlikely to benefit from an intensive treatment approach. They often receive either best supportive care (BSC), low dose treatment such as Low Dose Ara-C (LDAC), or clinical trials of novel agents. In one of the few randomised studies where patients were prospectively considered likely to be unfit for intensive therapy, LDAC was superior to BSC with 18% v 1% patients achieving CR. No patients with high risk cytogenetics (Grimwade 1998), achieved CR (Burnett 2007). Laromustine (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Laromustine has previously shown clinical activity in patients with de novo AML and high risk MDS (Giles et al. JCO 2007). A confirmatory phase II study of single agent laromustine was conducted in previously untreated patients ≥ 60 years old with de novo AML, prospectively considered likely to be unfit for intensive chemotherapy. Patients had at least one poor risk factor, defined by age ≥70, performance status 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Eighty-five patients received induction therapy with 600 mg/m2 laromustine. Second induction cycles were administered in 14 patients after partial response or hematologic improvement. Eighteen patients received at least one consolidation cycle of cytarabine 400 mg/m2/day CIV for 5 days. Methods: A retrospective non-randomised comparison was performed between the 85 patients treated with laromustine, and 121 patients satisfying the same entry criteria, treated in the AML 14 trial with either BSC or LDAC. Outcomes were compared using Mantel-Haenszel and logrank methods for unadjusted comparisons, and regression methods for adjusted analyses. Results : Patients in AML14 were slightly older than those treated with laromustine (median age 75 v 73), and tended to have higher white blood cell counts; by contrast, there were significantly fewer cardiac or respiratory comorbidities reported in the AML14 population. Other important risk factors such as performance status and cytogenetics were similar between the groups. Responses overall (CR/CRp) were seen in 33% (28/85) of patients treated with laromustine, compared with 2% (1/60) and 23% (14/61) in patients treated with BSC and LDAC (p<0.0001, p=0.2, respectively). In particular, 1 patient with −5/del(5q), and 3 patients with −7/del(7q) cytogenetics experienced a CR with laromustine; patients in AML 14 with adverse cytogenetics saw no remissions. Survival was significantly improved in the laromustine group compared to BSC (1 year survival 20% v 8%, unadjusted HR 0.58 [0.40–0.84] p=0.004), and roughly comparable to that of LDAC (1 year survival 20% v 25%, HR 1.04 [0.73–1.49] p=0.8). Analyses adjusted for differences in baseline demographics, and using propensity scores gave consistent figures. Conclusions: Retrospective comparison of unrandomised data has significant limitations even though care has been taken to match for factors known to be predictive for survival. Laromustine was able to achieve a higher CR rate than LDAC or BSC, and produced remissions in groups where no remissions have previously been seen with LDAC or BSC. Laromustine gave significantly better survival than BSC, and demonstrated similar survival to LDAC.

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).

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.

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.

A Randomised Comparison of Daunorubicin 90mg/m2 Vs 60mg/m2 in AML Induction: Results from the UK NCRI AML17 Trial in 1206 Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 7-7 ◽  
Author(s):  
Alan K. Burnett ◽  
Nigel Russell ◽  
Robert K. Hills ◽  
Jonathan Kell ◽  
Jamie Cavenagh ◽  
...  
Keyword(s):  
Dose Level ◽  
Survival Benefit ◽  
Group Performance ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Remission Rate ◽  
Standard Dose ◽  
Randomised Trial ◽  
Significant Benefit ◽  
The Uk

Abstract Recent randomised trials have suggested that intensification of daunorubicin in induction with a higher dose (90mg/m2) vs standard dose (45mg/m2) resulted in improved remission rate and overall survival. Apart from concerns about the outcome of the comparator arm in younger patients, exploratory subgroup analysis suggested that the benefit was seen in patients <50yrs, platelet counts >50, WBC <10 and intermediate cytogenetics while in older patients there was a survival benefit only in patients aged 60-65yrs, and a beneficial trend in core binding factor leukaemia. However, 60mg/m2 is widely used. In a retrospective comparison of non-contemporaneous patients no difference was found between a 90mg and a 60mg dose level. It has also been suggested that the beneficial effect of gemtuzumab ozogamicin in CBF leukaemia could be mimicked by a higher Daunorubicin dose. To clarify these issues we undertook the first randomised trial of 90mg/m2 vs 60mg/m2. As part of the UK NCRI AML17 trial patients were randomised in a 1:1 fashion to either 90mg/m2 or 60mg/m2 on days 1,3 and 5 of their first induction course, followed by 50mg/m2 on days 1,3 and 5 in course 2. Ara-C was given 100mg/m2 12 hourly days 1-10 (course 1) and days 1-8 (course 2). Between 09/2011 and 10/2013, 1206 patients were randomised. The median age was 53yrs (16-72); 54% were male; 84% had de novo AML, 10% secondary, and 6% high risk MDS; median presenting WBC was 8.5 (0.3-430); 10% had favourable cytogenetics; 72% intermediate and 18% adverse. The distribution of genotype was: FLT3+/NPM1cwt 7%/ FLT3+/NPM1c+ 11%/ FLT3-/NPM1cwt 64%/ FLT3-/NPM1c+ 18%. There was no difference in characteristics between the arms. Results: There was no difference in remission rate between the arms (90mg/m2 81% vs 60mg/m2 84%. OR 1.21(0.90-1.64) p=0.1). The 30 and 60 day mortality was 6% vs 4% and 10% vs 5% (30-day HR 1.57 (0.94-2.61) p=0.09; 60-day HR 1.98 (1.30-3.02) p=0.001). Causes of 60-day mortality by treatment arm were: infection 25 vs 11; infection+haemorrhage 1 vs 3; haemorrhage 5 vs 3; resistant disease 14 vs 2; pulmonary 2 vs 4; cardiac 1 vs 2, multiple 5 vs 3; and unknown 5 vs 1.The 2-year RFS was 52% vs 50%, HR 1.06 (0.85-1.32) p=0.6; cumulative incidence of relapse was 37% vs 41%, HR 1.01 (0.79-1.30) p=0.9. With excess early mortality, and no corresponding improvement in RFS, survival in the 90mg arm was non-significantly worse (2-year OS 59% vs 60%; HR 1.17 (0.95-1.44) p=0.14). Beyond day 60, there was no difference in survival (HR 0.99 (0.78-1.25) p=0.9) 30% of patients were transplanted (169/604 in 90mg/m2; 197/602 in 60mg/m2, p=0.07; with 271 transplants in CR1 (123 vs 148), and 56 in CR2 (28 vs 28); 314 allografts were performed, 234 in CR1). When the data is censored at SCT results remain consistent (60% vs 61%; HR 1.21 (0.96-1.52) p=0.10). Figure 1 Figure 1. Stratified analyses involving Age, Sex, Diagnosis (de Novo/Secondary/MDS), Cytogenetic group, Performance Status, ITD/NPM1 genotype was undertaken to identify whether any subgroups might show benefit for the 90mg dose. There was evidence of interaction between treatment and cytogenetics (p=0.01 for heterogeneity) and also with FLT-3 ITD status (p=0.03 for heterogeneity). However, in no subgroup was there a significant benefit for 90mg/m2. There was no benefit (90 vs 60) within the favourable (87% vs 100%) or intermediate risk (65% vs 64%) and adverse (24% vs 28%) risk groups, thus the suggestion that the favourable risk group might benefit based on the GO experience was not substantiated. Similarly, while there was a non-significant benefit for patients who were FLT-3 mutant (HR 0.74 (0.47-1.17) p=0.2) the survival was significantly worse in patient who were FLT3-ITD wild type (HR 1.31 (1.03-1.67) p=0.03). In particular, looking at patients with either age <50, WBC<10 or platelets >50, there was no evidence of either benefit for 90mg/m2 or heterogeneity of treatment effect. In the 304 patients >60 yrs. the OS was identical (HR 1.00 (0.69-1.45)) including for those aged 60-65yrs (HR 1.05 (0.69-1.61)). Supportive care in courses 1 or 2 were not significantly different between the two arms, and haematological recovery times were similar between the two arms. Conclusion: In this first randomised comparison of Daunorubicin 90mg/m2 vs 60mg/m2 there was no survival benefit overall or in any of the subgroups examined for the 90mg/m2 dose level. (We are grateful to Cancer Research UK for research support for this trial) Disclosures No relevant conflicts of interest to declare.

Survival until First Progression and Post First Progression Survival Equally Contribute to the Overall Survival of Myeloma Patients: Differences in Patients ≤65 Years of Age Compared to Patients >65 Years

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4030-4030
Author(s):  
Efstathios Kastritis ◽  
Evangelos Terpos ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
Dimitra Gika ◽  
...  
Keyword(s):  
High Risk ◽  
Renal Impairment ◽  
Initial Phase ◽  
Older Patients ◽  
Performance Status ◽  
Age Groups ◽  
First Line ◽  
Younger Patients ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 4030 Age is a major prognostic factor for the outcome of patients with multiple myeloma (MM), due to more intensive treatment in younger vs. older patients, comorbidities and toxicity, resulting in early discontinuation of treatment in older patients or even differences in disease characteristics. It is believed that the longer survival of patients ≤65 years is, to a large extent, due to the receipt of more lines of therapy and thus they can have an extended survival even after relapse to first line therapy. In order to decipher these differences in the outcome of MM patients of different ages, we analyzed 438 consecutive, unselected patients who were treated in a single center (Department of Clinical Therapeutics, University of Athens School of Medicine) from April 1994 to April 2012, and compared the characteristics and outcome of patients ≤65 years (166 patients), which are usually treated with more intensive therapies (including HDT), to that of patients 66–75 years (154 patients) and >75 years of age (118 patients). Some of these patients were included in clinical trials; however, even patients who were ineligible because of poor performance status, renal impairment or comorbidities were also included, thus, being more representative of the general myeloma population. Differences in the characteristics of patients of different age groups are depicted in the table. Younger patients presented less often with ISS-3, severe anemia, renal impairment or impaired PS than older patients. However, there was no difference in the detection of high risk cytogenetics. Response was higher and deeper in younger patients. Early deaths, within 2 months from initiation of therapy, occurred more often in older patients. Median PFS was longer in younger patients. Similar proportion of patients who relapsed have received 2nd line therapy (p=0.365). Post relapse survival (PRS) was 31 months for patients ≤65 years, 20 months for patients 66–75 years and 15 months for patients >75 years (p<0.001). The difference of PRS between patients 66–75 years and patients >75 years was also significant (p=0.004). Median OS was 71 months for patients <65 years, 46 months for patients 66–75 years and 31.5 months for patients >75 years (p<0.001). Thus, it seems that the OS of patients in each age group is distributed almost equally between the initial phase of the disease and post first relapse/progression (see Table). PFS <12 months was observed in 10% of patients ≤65 years vs. 22.5% and 29% of patients 66–75 and >75 years (p=0.003). PRS for patients with a PFS<12 months was 8 months for those ≤65 years, 10 months and 6 months for patients 66–75 and >75 years. Median OS was significantly better for patients who achieved CR or VGPR (58 months) vs. patients who achieved a PR (39 months) (p<0.001). For patients <65 years who achieved a CR/VGPR median OS has not been reached (4-year OS was 79%), for patients 66–75 years was 52 months and 40 months for those >75 years (p<0.001). Among patients with a minimum follow up ≥10 years (76 patients), 5 (6.5%) remained without progression for ≥10 years (4 of them had received HDT). In order to adjust for imbalances in baseline characteristics and depth of response (CR/VGPR vs. PR), we performed a multivariate analysis in which ISS stage (p<0.001), novel agent-based first line therapy (p=0.01), CR/VGPR (p=0.005) and age ≤65 (p<0.001), but not 66–75 vs. >75 years (p=0.092) were independently associated with improved survival. In conclusion, our data indicate that the survival of MM patients is distributed almost equally between the initial phase i.e. before relapse to first line therapy, and to subsequent phases of their disease i.e. post relapse survival. This is observed across all age groups, but in patients ≤65 years the duration of first response is significantly longer, perhaps due to more intensive therapies and to less frequent early deaths. In this unselected series of patients, the 10-year free of progression rate was 6.5%. Table ≤65 years 66–75 years >75 years p-value Males 60% 43.5% 51% 0.015 ISS-1 21% 18% 9% 0.02 ISS-2 50% 46% 47% ISS-3 29% 37% 45% Hb <10 g/dl 40% 45% 53% 0.075 eGFR <60 ml/min 29% 45% 55% <0.001 Performance status ≥2 39% 55% 59% 0.001 High risk cytogenetics (n=194) 50% 48% 41% 0.5 Upfront novel agents 73.5% 63% 81% 0.023 CR 34% 27% 17% 0.005 >VGPR 56% 49% 34% 0.001 ≥PR 81% 79% 64% 0.003 Early deaths 2% 6% 12% 0.005 Median PFS (months) 34 19.5 15 0.001 Median PRS (months) 31 20 15 <0.001 Median OS (months) 71 46 31.5 <0.001 Disclosures: No relevant conflicts of interest to declare.

A Comparison of Single Dose Gemtuzumab Ozogamicin 3mg/m2 and 6mg/m2 Combined with Induction Chemotherapy in Younger Patients with AML: Data from the UK NCRI AML17 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2308-2308 ◽  
Author(s):  
Alan K Burnett ◽  
Nigel Russell ◽  
Robert K. Hills ◽  
Jamie Cavenagh ◽  
Jonathan Kell ◽  
...  
Keyword(s):  
Overall Survival ◽  
Single Dose ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Meta Analysis ◽  
Randomised Trial ◽  
Gemtuzumab Ozogamicin ◽  
Platelet Recovery ◽  
Grade 3 ◽  
The Uk

Abstract On behalf of the UK NCRI AML Study Group. Gemtuzumab Ozogamicin (GO) was the first antibody directed chemotherapy in cancer, but has had a chequered development in AML. We recently completed an individual patient data meta-analysis (Hills et al Lancet Oncology 15 (9): 986-96, 2014) which confirmed, in an analysis of the 5 randomised trials in adults, that simultaneous administration with induction chemotherapy significantly improved survival by reducing relapse risk in favourable and intermediate risk groups, but not in patients with adverse risk. The analysis further suggested that a single dose of 3mg/m2 was as effective at preventing relapse as a 6mg/m2 dose, while having less toxicity, and therefore may be the optimal dose level. A question posed in the UK NCRI AML17 Trial was to directly compare 3mg/m2 with 6mg/m2 to ascertain whether efficacy or toxicity differences overall or within subgroups could be found. Between 06/2009 and 10/2011 788 patients were randomised: the median age was 50yrs (0-81, 29 <16yrs). 86% had de novo, 9% secondary disease and 5% MDS; 53% were male. 13% were favourable/ 69% intermediate, and 18% adverse cytogenetic risk; median presenting WBC was 9.2 (0.4-386); 18% had a FLT3 ITD and 28% had an NPM1c mutation. The associated chemotherapy was DA (3+10) (n=380) or ADE (10+3+5)(n=403); all children received ADE. GO was administered on day one of the induction chemotherapy. WBCs >30 could be cytoreduced with hydroxyurea or the GO delayed till day 4 of chemotherapy. Liver function biochemistry required to be <2XULN. Toxicity was defined as in NCICTC v.3. Results: Eighty-seven percent of patients entered CR/CRi with no difference between the arms overall or with in any demographic subgroup (3mg 89% vs 6mg 85%; OR 1.34 (0.88-2.04), p=0.17). The 30-day (3% vs 7%; OR 2.04 (1.10-3.80), p=0.02) and 60-day mortality (5% vs 9%; OR 1.99 (1.17-3.39), p=0.01) were both increased in the 6mg arm. There were 18 vs 36 deaths within 60 days: causes were infection (10 vs 11); infection+haemorrhage (0 vs 1); haemorrhage 3 vs 4; resistant disease 2 vs 6; veno-occlusive disease 0 vs 5; cardiac 1 vs 3; pulmonary 2 vs 1; renal 0 vs 3; multiple 0 vs 2.Relapse free survival at 3 years was 44% overall and 45% for 3mg and 42% for 6mg (OR 1.11 (0.91-1.35), p=0.3). Overall survival at 3 years was 52% and 53% for 3mg and 50% for 6mg (OR 1.12 (0.91-1.36), p=0.3). There was no difference in mortality after day 60. Allografts were given to 324 patients, 183 in CR1, but the distribution on numbers and transplant type was not different between the arms. Neither the 3mg or 6mg dose caused excess post- transplant toxicity. No subgroup showed any suggestion of response or survival benefit from the 6mg dose with the exception of a non-significant benefit for both response rate (test for heterogeneity p=0.02) and overall survival (test for heterogeneity p=0.04) in the adverse cytogenetics patients (n=133). When grade 3 or 4 toxicities are compared, ALT, creatinine and haematuria in course 1 (7% vs 17%; 1% vs 2%; 1% vs 2% respectively), were the only significant differences in courses 1 & 2. The requirement for red cell and platelet transfusions and days on antibiotics was increased in the 6mg patients in course 1, with slower platelet recovery in course 1. There were no significant grade 3 or 4 toxicity differences or supportive care required in course 2. Central assessment of VOD was confirmed as definite (n=17) or possible (n=5) in 22 of 395 (5.6%) patients on 6mg compared with 2 definite and 0 possible in 2 of 393 on the 3 mg arm (0.5%) (p<0.0001). Conclusion: Although both the 3mg and 6mg dose have provided benefit when combined with induction chemotherapy, in this large randomised trial we found no benefit in giving a single 6mg/m2 dose of GO when compared with 3mg/m2, with the possible exception of in the adverse risk patients who showed no evidence of benefit in the recent meta-analysis. Although the difference in toxicity was modest and VOD, although increased, uncommon, this experience suggests that future studies should focussing on optimising the schedule for GO at the 3mg/m2 dose, such as the fractionated approach developed by the French ALFA Group. Such studies are underway. (We are grateful to CRUK for research funding for this trials and to Pfizer for the provision of gemtuzumab ozogamicin) Disclosures Off Label Use: Gemtuzumab Ozogamicin for AML.

Cloretazine is an effective induction therapy in elderly patients (pts) with poor-risk de novo AML

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6512-6512 ◽  
Author(s):  
J. E. Karp ◽  
D. Rizzieri ◽  
N. Vey ◽  
G. Mufti ◽  
R. Geller ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Performance Status ◽  
Single Agent ◽  
Early Death ◽  
Hematologic Malignancies ◽  
Hematologic Toxicity ◽  
Nccn Guidelines ◽  
Poor Risk ◽  
De Novo Aml

6512 Background: The incidence of AML increases with age with a median of 68 years in the US. The treatment of elderly pts (≥60 years) with AML poses challenges related to pt characteristics (age, performance status (PS), comorbidities) and adverse biological features. The majority of elderly pts are not considered for standard induction therapies that incorporate araC + anthracycline, and complete remission rates (CR+CRp), leukemia-free (LFS) and overall survival (OS) are significantly lower than in younger pts. As a result, NCCN guidelines recommend investigational therapy for this population. Cloretazine (C) is a novel DNA alkylating agent that selectively targets the O-6 position in guanine and has been developed in AML, based on phase I data demonstrating activity in refractory hematologic malignancies with acceptable toxicity. Methods: A multi-center trial in elderly pts with untreated poor-risk AML and high risk MDS was performed. Pts received C (600 mg/m2) as a single 30–60 minute infusion. Retreatment for induction was permitted for pts who showed improvement. A consolidation course of C at 400 mg/m2 was an option for pts who achieved a CR. Results: 105 pts were treated, of whom 45 pts (median age 72, range 60–84) had de novo AML, 44 had secondary AML, and 16 had high-risk MDS. Considering only de novo AML pts, pt characteristics are the following: M/F=25/20; favorable/intermediate/poor/NA cytogenetics =0/28(62%)/15(33%)/2; and PS 0/1/2=8(18%)/21(47%)/16(36%). The CR rate was 49% (N=22). CR was 50% for pts with intermediate cytogenetics and 53% for pts with poor risk cytogenetics. CR remained consistent despite increasing PS (PS0=50%, PS1=48%, PS2=50%). For responders, the median time for ANC≥1000 cells/dl was 31 days (range 27–44) and for plt≥20,000/dl was 22 days (range 14–29). There was no significant non-hematologic toxicity; the early death rate was 20%. Of the 22 pts who achieved CR, 8 remain alive and disease-free at a median of 337 days (range 137–546). At one year, the LFS is 27% and the OS is 22%. Conclusion: C is very well tolerated and has demonstrated impressive response results as a single agent in an elderly pt population with poor risk AML. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document