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.

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.

Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8009-8009 ◽  
Author(s):  
B. Coiffier ◽  
P. Feugier ◽  
N. Mounier ◽  
P. Franchi-Rezgui ◽  
E. Van Den Neste ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Good Survival ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Large B Cell

8009 Background: The prospective randomized study LNH-98.5 was first reported in the N Engl J Med and J Clin Oncol with a median follow-up of 2 and 5 years. Here, we present the 7-year follow-up of the 399 patients included in the study. Methods: Patients had untreated diffuse large B-cell lymphoma and were 60 to 80 years old with a median age at diagnosis of 69 years. 60% had a poor risk lymphoma as defined by the aaIPI risk score of 2 or 3. 197 patients were randomized in CHOP arm and 202 in R-CHOP arm. Treatment consisted of 8 cycles of CHOP every 3 weeks with rituximab the same day in R-CHOP. Results: With a median follow-up of 7.1 years, 76% of the patients had an event in CHOP compared to 58% in R-CHOP, p=0.0002 ( Table ). 65% of patients died in CHOP arm compared to 47% in R-CHOP arm: 80% and 71% of them from lymphoma or treatment toxicity, 5% and 5% from another cancer, and 15% and 22% in CR from other causes, respectively. Survival curves show the same difference as reported before with a large difference in favour of R-CHOP ( Table ). Patients not expressing bcl-2 protein treated with R-CHOP have a statistically longer PFS but only a trend for OS because they responded better to salvage treatment. No statistically significant difference was observed for patients <70, 70–74, or ≥75 years old. Patients treated with R-CHOP have good survival even with poor risk parameters: 43% are alive for age ≥75 years, 38% for PS=2, 54% for B symptoms, 47% for stage IV, 45% for high LDH level, 54% for Hb ≤10 g/dl, and 42% for high aaIPI score. Death in CR was associated with high risk aaIPI score and presence of other diseases before lymphoma diagnosis. Conclusions: This analysis confirms the long term benefit associated with the combination of rituximab and CHOP and shows that older patients must be treated as younger patients even in presence of high risk characteristics or concomitant diseases. [Table: see text] [Table: see text]

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 &gt;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.

Modification or Dose or Treatment Duration Has No Impact on Outcome of AML in Older Patients: Preliminary Results of the UK NCRI AML14 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 543-543 ◽  
Author(s):  
Alan K. Burnett ◽  
Donald W. Milligan ◽  
Archie G. Prentice ◽  
Anthony H. Goldstone ◽  
Mary F. McMullin ◽  
...  
Keyword(s):  
High Risk ◽  
Confidence Intervals ◽  
De Novo ◽  
Standard Dose ◽  
Disease Free Survival ◽  
All Trans Retinoic Acid ◽  
Total Treatment ◽  
The Uk ◽  
To Receive

Abstract The NCRI AML14 Trial was devised for patients aged over 60 years with de novo or secondary AML or high risk MDS (defined as &gt;10% blasts). There was a non-intensive option which compared Low Dose Ara-C vs Hydroxyurea each with or without All-Trans Retinoic Acid which has been reported previously (Burnett et al Blood2004: 249a), and an intensive approach which we now report. This compared two dose levels of Daunorubicin (50mg/m2 vs 35mg/m2) and Ara-C (200mg/m2 vs 400mg/m2) within a Daunorubicin/Ara-C (3+10) followed by (3+8) schedule. After a 3rd course (MidAC: Mitoxantrone/Ara-C), patients were randomised to receive or not a 4th course (ICE: Idarubicin/Ara-C/Etoposide). In addition some patients (n=200) were randomised to receive PSC-833 in addition to Dauno 35. The results of this randomisation have been reported previously (Burnett et al Blood 2003614a). A total of 1273 patients entered the trial between December 1998 and closure in May 2005, from 136 centres. Follow-up is complete to 1st April 2005, with median follow-up of 33 months. The median age was 67 (range 44-88). Cytogenetics were known for 67% of patients: of these, 3% had favourable, 74% intermediate and 23% adverse cytogenetics. 72% had de novo AML, 17% had secondary disease and 11% had high risk MDS. The overall CR rate was 62% and the Relapse Risk (RR), Disease Free Survival (DFS), and Overall Survival (OS) were 84%, 13%, and 13% at 5 years. 896 patients were randomised to D50 vs D35. No significant differences were found in CR (63% vs 64% OR 1.04 (95% CI 0.78–1.37)), RR (84% vs 85% OR 0.85 (95%CI 0.65–1.06)), DFS 14% vs 13% OR 0.86 (95% CI 0.70–1.06)), or OS (15% vs 13% OR 0.92, 95% CI (0.72–1.08)). Likewise, there were no significant differences in outcome for the 1264 patients randomised to Ara-C 200 vs 400: CR (62% vs 62% OR 1.00 (95% CI 0.80–1.27)), RR (84% vs 85% OR 1.14 (95% CI 0.95–1.37)), DFS (13% vs13% OR 1.14 (95% CI 0.96–1.14)) or OS (13% vs 12% OR 1.00 (95%CI 0.87–1.14)). In the 255 patients randomised to a total of 4 vs 3 courses the RR (83% vs 76% OR 0.90 95%CI 0.66–1.24), DFS (16% vs 18% OR 0.94 95% CI 0.69–1.28) and OS (23% vs 22% OR 1.05, 95% CI 0.75–1.47) were not significantly different. From this preliminary analysis we conclude that there is no difference between a reduced dose of Daunorubicin (35mg/m2) compared with standard dose, or between enhanced Ara-C dose (400mg/m2) or standard dose and the confidence intervals are consistent with at most a moderate difference in treatment effect. We found no benefit for giving more than 3 courses of total treatment to patients in this age group, although the confidence intervals here do not rule out moderate, but potentially meaningful differences.

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.

scholarly journals A Comparison of 1 or 2 Courses of High Dose Cytarabine As Consolidation in Younger Patients with AML: First Results of the UK NCRI AML17 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 221-221
Author(s):  
Nigel H. Russell ◽  
Robert K Hills ◽  
Sylvie Freeman ◽  
Steven Knapper ◽  
Lars Kjeldsen ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Group ◽  
Wild Type ◽  
Younger Patients ◽  
Protocol Amendment ◽  
Poor Risk ◽  
The Uk ◽  
Standard Risk

Abstract On behalf of the UK NCRI AML Working Party Introduction Outcomes in younger patients with AML have steadily improved over the last 4 decades. However, the question of the optimal chemotherapy schedule remains open. As outcomes improve attention turns from survival to survivorship: can similar - or better - outcomes be obtained with less cost to the patient. We have previously shown in our MRC AML12,15 trials that a fifth course of chemotherapy did not improve outcomes in these younger patients. A retrospective analysis of patients who received 3 or 4 courses of treatment showed that, while patients with poor risk disease had better outcomes with four courses, any effect of a fourth course was much less clear for patients with good or standard risk disease. Methods The UK NCRI AML17 trial (ISRCTN: 55675535) was designed for patients with AML or high risk MDS up to the age of 60. Following their first course of treatment, patients were allocated a risk group based upon a validated score (comprising cytogenetics, WBC, age, secondary disease and blast response to course 1)[1]; additionally, patients who failed to achieve at least a 50% reduction in blasts were considered poor risk. A protocol amendment included patients who were otherwise standard risk, but were FLT-3 ITD mutant/NPM1c wild type in the poor risk group. Remaining adults who were either good or standard risk could be randomised after 2 courses of treatment (DA or ADE, with or without GO at 3/6 mg/m2) to receive 1 or 2 courses of consolidation (3 or 4 courses in total). Before mid-2010 patients were randomised between MACE/MidAC vs MACE; based on the results of AML15 [2], a protocol amendment changed consolidation to 1 or 2 courses of Ara-C 3g/m2/d for 5 days. Follow-up is complete to 1st March 2015, with median follow-up of 28.8 months (range 0.1-68.2). Results From July 2009 to June 2015, 1017 patients were randomised. Median age was 48 (range 16-72); 45% were male; 24% had core binding factor leukaemia; 76% intermediate risk disease; 1% had secondary disease, and 3% high risk MDS; WHO PS was 2+ in 4% of patients. Overall survival at 5 years was 57%. An additional course of consolidation reduced relapse (CIR 53% vs 57%; HR 0.81 (0.67-0.99) p=0.04), with no difference in death in remission (7% vs 6%; HR1.10 (0.61-2.00) p=0.8), leading to some evidence of improved relapse free survival (41% vs 37%, HR 0.84 (0.70-1.01) p=0.06). Survival however, did not differ significantly between the arms (58% vs 55%, HR 0.90 (0.71=1.14) p=0.4), reflecting the effect of salvage: 3 year survival from relapse was 32% vs 31% (HR 0.97 (0.75-1.26) p=0.8). In stratified analyses, there was no difference in the effect of the extra course by cytogenetics (p-values for interaction between cytogenetics and treatment p=1.0 for survival); while relapse was reduced more in CBF leukaemias (HR 0.63 (0.40-1.00), p=0.05) than in others (HR 0.91 (0.73-1.13) p=0.4), the test for interaction was not significant (p=0.16). Information on minimal residual disease (by immunophenotype to a sensitivity of up to 1 in 104) was available for 353 patients post course 1 and 265 patients post course 2. There was no evidence of a differential effect of an extra course of consolidation by MRD status after either course (p=1.0 for survival post course 1; p=0.3 for survival post course 2). In stratified analyses, there was no interaction between treatment and age, sex, performance status or diagnosis. However, there was a significant benefit for FLT3-ITD WT patients (OS: 63% vs 54%, HR 0.75 (0.57-0.99) p=0.04), which was not present for ITD mutant patients (41% vs 58%; HR 1.38 (0.84-2.26) p=0.2; p=0.04 for interaction), and evidence of greater benefit for 4 courses in patients with lower WBC at diagnosis (p=0.04 for trend). There was no heterogeneity by induction therapy (p=0.7), in particular the use of gemtuzumab ozogamicin or not (p=0.2). Conclusions These data in good and standard risk patients (as defined comprising 63% of patients diagnosed) suggests no overall survival benefit of a 4th course of chemotherapy in younger patients with AML, although relapse was significantly reduced. With respect to subgroups, there was a suggestion that 4 courses of treatment was beneficial for FLT3 wild type patients. Attention now turns to whether the use of more intensive induction regimens such as FLAG-Ida can improve outcomes while delivering fewer courses. [1] Burnett et al. Blood 2006:108 (11): Abstract 18 [2] Burnett et al. JCO 2013: 31(27);3360-8 Disclosures Russell: Therakos: Other: shares. Cavenagh:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

scholarly journals Low-Dose Weekly Decitabine and Venetoclax in TP53-Mutated Myeloid Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4428-4428
Author(s):  
Lauren C Shapiro ◽  
Ioannis Mantzaris ◽  
Aditi Shastri ◽  
R. Alejandro Sica ◽  
Lizamarie Bachier-Rodriguez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Median Time ◽  
Research Funding ◽  
Low Dose ◽  
De Novo ◽  
Publicly Traded ◽  
Best Response ◽  
Previous Clinical Trial

Abstract Decitabine (Dec) and Azacitidine (Aza) that target DNA methyltransferase 1 (DNMT1) are hypomethylating agents (HMAs) approved to treat acute myeloid leukemia (AML) in combination with Venetoclax (Ven). The combination is also used to treat high-risk myelodysplastic syndromes, especially TP53-mutated (TP53mut) cases in which responses to HMA alone are short-lived. In most patients (pts), however, myelosuppression from treatment leads to frequent Ven duration and/or dose-reductions, and/or cycle delays. An approach to decrease HMA-mediated myelosuppression but maintain S-phase dependent DNMT1-targeting, evaluated in a previous clinical trial (https://doi.org/10.1111/bjh.16281), is to administer noncytotoxic doses/concentrations of Dec (0.2 mg/kg; ~5 mg/m 2) by a frequent-distributed schedule of 1X/week. An approach to decrease Ven mediated myelosuppression but maintain cooperation with HMA, shown in pre-clinical studies, is to administer a single-dose prior to HMA. Ven can depolarize mitochondrial membranes; mitochondrial membrane-potential is essential to function of the mitochondrial enzyme DHODH that produces cytidine/deoxycytidine that competes with HMA in cells. Thus, Ven prior to HMA dosing temporarily inhibits de novo pyrimidine synthesis, to counter a major mechanism of resistance to HMA in MDS/AML, without suppressing normal myelopoiesis (https://doi.org/10.1182/blood-2020-143200). We conducted a retrospective analysis of all pts with TP53mut MDS or AML treated with weekly Ven and low-dose subcutaneous Dec at our institution. We analyzed the characteristics of these pts, response to therapy, and outcomes using standard descriptive statistics. Mutational testing was performed using a commercial next-generation sequencing (NGS) panel. Five pts, 3 male and 2 female, with TP53mut MDS or AML were treated with weekly Ven 400 mg on D1 and subcutaneous Dec 0.2 mg/kg on D2, administered weekly in 28 day cycles. Two pts had MDS (1 de novo, 1 treatment related) and 3 pts had AML (1 de novo, 2 secondary from prior MDS). Four pts (80%) received the treatment in frontline, all with poor performance status (PS), and 1 pt (20%) had R/R disease. Median age at diagnosis was 79 years [41-82]. The only young pt had prolonged severe cytopenias after 1 cycle Dec standard dosing during the peak of COVID-19 pandemic so was switched to this regimen. Of the 4 frontline treated pts, 2 pts had high-risk MDS, and 2 pts had adverse risk AML. The R/R pt had high-risk MDS transformed to AML that was refractory to 2 prior lines of therapy: standard Aza/Ven x5 cycles, then standard Vyxeos. Disease cytogenetics were complex in all pts. 60% (3/5) pts had sole TP53mut on NGS, with median variant allelic frequency (VAF) 48% [28-79]. 80% (4/5) pts were transfusion dependent prior to treatment. Median time to initiating therapy was 7 days from initial or refractory diagnosis [3-59] and median follow-up was 7.8 months (mo) [2.9-11.4]. The overall response rate (ORR) was 100%: 4/4 frontline pts had complete remissions (CR), and the 1 R/R pt achieved morphologic leukemia-free state (MLFS). Median time to best response was 2.9 mo. 50% (2/4) pts became transfusion independent. 40% (2/5) pts lost their TP53mut at best response, and another 40% (2/5) pts had significant reductions (83% and 38%) in TP53 mut VAF. The regimen was well tolerated with no pts stopping therapy due to adverse effects (AE) . AE included G3/G4 neutropenia (80%), G1 thrombocytopenia (40%), nausea (20%), fatigue (20%), lower extremity edema (20%), pneumonia (60%), and neutropenic fever (20%) with a median of 1 unplanned hospitalization per pt during follow-up. 60% (3/5) pts remain in CR on continued therapy for a median of 7.8 mo [7.2-9.4] thus far. One pt underwent allogeneic stem cell transplantation, however, died 11.4 mo after conditioning due to transplant related mortality. The R/R pt died after being lost to follow-up 2.9 mo after therapy initiation. No pt had measurable relapse during follow-up. Combination weekly Ven with subcutaneous low-dose Dec is well tolerated yielding high rates of clinical and molecular response in pts with TP53mut MDS/AML. Although small, this case-series extends previous clinical trial proof-of-activity of non-cytotoxic DNMT1-targeting to a high-risk, poor PS, historically chemorefractory patient population. The regimen allowed frequent, sustained exposure to therapy often not possible with standard HMA/Ven regimens. Figure 1 Figure 1. Disclosures Shastri: Kymera Therapeutics: Research Funding; Guidepoint: Consultancy; GLC: Consultancy; Onclive: Honoraria. Gritsman: iOnctura: Research Funding. Feldman: Glycomimetics: Current Employment, Current holder of stock options in a privately-held company. Verma: Celgene: Consultancy; Acceleron: Consultancy; Novartis: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company. Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals Implementation of the acutely presenting older patient (APOP) screening program in routine emergency department care

2021 ◽  
Author(s):  
Laura C. Blomaard ◽  
Bas de Groot ◽  
Jacinta A. Lucke ◽  
Jelle de Gelder ◽  
Anja M. Booijen ◽  
...  
Keyword(s):  
Emergency Department ◽  
High Risk ◽  
Older Patients ◽  
Screening Program ◽  
Admission Rate ◽  
Older Patient ◽  
Hospital Admission Rate ◽  
High Risk Patients ◽  
Risk Patients

Abstract Objective The aim of this study was to evaluate the effects of implementation of the acutely presenting older patient (APOP) screening program for older patients in routine emergency department (ED) care shortly after implementation. Methods We conducted an implementation study with before-after design, using the plan-do-study-act (PDSA) model for quality improvement, in the ED of a Dutch academic hospital. All consecutive patients ≥ 70 years during 2 months before and after implementation were included. The APOP program comprises screening for risk of functional decline, mortality and cognitive impairment, targeted interventions for high-risk patients and education of professionals. Outcome measures were compliance with interventions and impact on ED process, length of stay (LOS) and hospital admission rate. Results Two comparable groups of patients (median age 77 years) were included before (n = 920) and after (n = 953) implementation. After implementation 560 (59%) patients were screened of which 190 (34%) were high-risk patients. Some of the program interventions for high-risk patients in the ED were adhered to, some were not. More hospitalized patients received comprehensive geriatric assessment (CGA) after implementation (21% before vs. 31% after; p = 0.002). In 89% of high-risk patients who were discharged to home, telephone follow-up was initiated. Implementation did not influence median ED LOS (202 min before vs. 196 min after; p = 0.152) or hospital admission rate (40% before vs. 39% after; p = 0.410). Conclusion Implementation of the APOP screening program in routine ED care did not negatively impact the ED process and resulted in an increase of CGA and telephone follow-up in older patients. Future studies should investigate whether sustainable changes in management and patient outcomes occur after more PDSA cycles.

Results after Laparoscopic Fundoplication: Does Age Matter?

2006 ◽  
Vol 72 (9) ◽  
pp. 778-784 ◽  
Author(s):  
Sarah M. Cowgill ◽  
Dean Arnaoutakis ◽  
Desiree Villadolid ◽  
Sam Al-Saadi ◽  
Demetri Arnaoutakis ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
High Risk ◽  
Older Patients ◽  
Laparoscopic Fundoplication ◽  
Nissen Fundoplication ◽  
Younger Patients ◽  
Before And After ◽  
Laparoscopic Nissen ◽  
Age Range

Antireflux fundoplications are undertaken with hesitation in older patients because of presumed higher morbidity and poorer outcomes. This study was undertaken to determine if symptoms of gastroesophageal reflux disease (GERD) could be safely abrogated in a high-risk/reward population of older patients. One hundred eight patients more than 70 years of age (range, 70–90 years) underwent laparoscopic Nissen fundoplications undertaken between 1992 and 2005 and were compared with 108 concurrent patients less than 60 years of age (range, 18–59 years) to determine relative outcomes. Before and after fundoplication, patients scored the severity of reflux and dysphagia on a Likert Scale (0 = minor, 10 = severe). Before fundoplication, older patients had lower reflux scores ( P < 0.01), but not lower dysphagia scores or DeMeester scores. One patient (86 years old) died from myocardial infarction; otherwise, complications occurred infrequently, inconsequentially, and regardless of age. At similar durations of follow-up, reflux and dysphagia scores significantly improved ( P < 0.01) for older and younger patients. After fundoplication, older patients had lower dysphagia scores ( P < 0.01) and lower reflux scores ( P < 0.01). At the most recent follow-up, 82 per cent of older patients rated their relief of symptoms as good or excellent. Similarly, 81 per cent of the younger patients reported good or excellent results. Ninety-one per cent of patients 70 years of age or more versus 85 per cent of patients less than 60 years would undergo laparoscopic Nissen fundoplication again, if necessary. With fundoplication, symptoms of GERD improve for older and younger patients, with less symptomatic dysphagia and reflux in older patients after fundoplication. Laparoscopic fundoplication safely ameliorates symptoms of GERD in elderly patients with symptomatic outcomes superior to those seen in younger patients.

Sign in / Sign up

Export Citation Format

Share Document