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It is now 75 years since the publication of Sir Austin Bradford Hill's classic textbook on Medical Statistics, and half a century since the formation of the Medical Research Council Working Party on Leukaemia. In the intervening p...
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It is now 75 years since the publication of Sir Austin Bradford Hill's classic textbook on Medical Statistics, and half a century since the formation of the Medical Research Council Working Party on Leukaemia. In the intervening period, trials in haematological malignancies have been at the forefront of cancer research, both in the proportion of patients recruited, and in the adoption of novel trial designs. In this paper, the principles propounded by Hill for reliable evaluation of new treatments are considered and placed in the context of the development and evaluation of novel treatments in the 21st century. Many of the original principles espoused are still highly relevant today, while the emerging heterogeneity of the conditions, both in aetiology and outcome provide their own newer challenges, which are discussed here.
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Aa total of 105 patients (age ≥18 years) with newly diagnosed low or intermediate risk acute promyelocytic leukaemia (APL) were treated with a standard induction and consolidation regimen including arsenic trioxide (ATO). Sixty-e...
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Aa total of 105 patients (age ≥18 years) with newly diagnosed low or intermediate risk acute promyelocytic leukaemia (APL) were treated with a standard induction and consolidation regimen including arsenic trioxide (ATO). Sixty-eight patients who were polymerase chain reaction (PCR) negative for PML-RARA post-consolidation were randomized to either 1 year of maintenance with tretinoin, mercaptopurine and methotrexate, or observation. Enrollment in this non-inferiority trial was stopped prematurely due to slow accrual. With a median follow up of 36·1 months, the overall survival of the 105 patients was 93%, and there have been no relapses in the patients randomized to maintenance or observation. These results demonstrate that cures can be expected in >90% of patients with low and intermediate risk APL and suggest that maintenance therapy may not be needed if patients are treated with an intensive post-remission regimen including ATO. This trial was registered at clinicaltrials.gov as #NCT00492856.
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Vincristine plus steroid pulses have long been a part of maintenance treatment in many protocols for childhood acute lymphoblastic leukaemia (ALL). A collaborative individual patient data meta-analysis of all randomised trials of ...
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Vincristine plus steroid pulses have long been a part of maintenance treatment in many protocols for childhood acute lymphoblastic leukaemia (ALL). A collaborative individual patient data meta-analysis of all randomised trials of the addition of vincristine plus prednisone/ prednisolone (VP) pulses in childhood ALL was updated and extended to include trials comparing vincristine plus dexamethasone (VD) pulses to maintenance without pulses. VP pulses improved event-free survival (EFS) (70.1% vs. 62.0% at 5 years; odds ratio (OR) = 071; 95% confidence interval (CI) = 0.61-0.84; P = 0.00004); VD pulses did not have a significant effect (80.9% vs. 79.9% 5 year EFS; OR = 0.94; 95% CI = 0.80-1.11; P = 0.5). Heterogeneity between groups (VP or VD) was significant (P = 0.02). Neither treatment clearly affected overall survival. The difference between the VP and VD results is probably due to the greater early intensity of the backbone of the VD trial protocols and improved outcome seen in the VD trials, which were more recent. Pulses may still be useful in cases where less intensive early therapy is used and the balance between these treatments in terms of both effectiveness and toxicity needs to be considered.
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SummaryVincristine plus steroid pulses have long been a part of maintenance treatment in many protocols for childhood acute lymphoblastic leukaemia (ALL). A collaborative individual patient data meta-analysis of all randomised tri...
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SummaryVincristine plus steroid pulses have long been a part of maintenance treatment in many protocols for childhood acute lymphoblastic leukaemia (ALL). A collaborative individual patient data meta-analysis of all randomised trials of the addition of vincristine plus prednisone/prednisolone (VP) pulses in childhood ALL was updated and extended to include trials comparing vincristine plus dexamethasone (VD) pulses to maintenance without pulses. VP pulses improved event-free survival (EFS) (70·1% vs. 62·0% at 5 years; odds ratio (OR) = 0·71; 95% confidence interval (CI) = 0·61–0·84; P = 0·00004); VD pulses did not have a significant effect (80·9% vs. 79·9% 5 year EFS; OR = 0·94; 95% CI = 0·80–1·11; P = 0·5). Heterogeneity between groups (VP or VD) was significant (P = 0·02). Neither treatment clearly affected overall survival. The difference between the VP and VD results is probably due to the greater early intensity of the backbone of the VD trial protocols and improved outcome seen in the VD trials, which were more recent. Pulses may still be useful in cases where less intensive early therapy is used and the balance between these treatments in terms of both effectiveness and toxicity needs to be considered.
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The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (<16?years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten-year event-free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate [32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00] and disease-free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care....
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The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (<16?years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten-year event-free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate [32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00] and disease-free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.
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There is now a plethora of new precision medicines for B-cell malignancy including 'classical' kinase inhibitors, rationally designed inhibitors of anti-apoptotic proteins and antibody or antibody drug/toxin conjugates with functi...
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There is now a plethora of new precision medicines for B-cell malignancy including 'classical' kinase inhibitors, rationally designed inhibitors of anti-apoptotic proteins and antibody or antibody drug/toxin conjugates with functional properties. Some are showing spectacular single agent activity in early phase clinical studies and may reduce or, in combination, even obviate the need for chemotherapy. Nevertheless, significant problems remain if these medicines are to be introduced into routine clinical practice in a rational and affordable manner. Firstly, precision medicines must be carefully matched in a mechanistic fashion with specific subtypes of disease. Whilst sensitivity may be predicted by the detection of key mutations or by expression of target molecules, for therapies that depend on intact intracellular signalling pathways, functional assessment on viable primary malignant cells will be necessary using assays that faithfully mimic in vivo conditions. A second, but no less important challenge is to define mechanism-based synergistic combinations associated with minimal toxicities rather than simply adding new precision medicines to existing chemotherapeutic regimens. Finally, a closer, open, two-way interaction between academic medicine and the pharmaceutical industry will be necessary to achieve these aims. Implementing such changes would change radically how and where patients with B-cell malignancies are managed. ? 2013 Blackwell Publishing Ltd.
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Abstract Objectives Survival outcomes from a single‐arm phase 2 blinatumomab study in patients with minimal residual disease (MRD)‐positive B‐cell precursor (BCP)‐acute lymphoblastic leukaemia (ALL) were compared with those re...
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Abstract Objectives Survival outcomes from a single‐arm phase 2 blinatumomab study in patients with minimal residual disease (MRD)‐positive B‐cell precursor (BCP)‐acute lymphoblastic leukaemia (ALL) were compared with those receiving standard of care (SOC) in a historic data set. Methods The primary analysis comprised adult Philadelphia chromosome (Ph)‐negative patients in first complete haematologic remission (MRD?≥?10 ?3 ). Relapse‐free survival (RFS) and overall survival (OS) were compared between blinatumomab‐ and SOC‐treatment groups. Baseline differences between groups were adjusted by propensity scores. Results The primary analysis included 73 and 182 patients from the blinatumomab and historic data sets, respectively. When weighted by age to the blinatumomab‐treatment group, median RFS was 7.8?months and median OS was 25.9?months in the SOC‐treated group. In the blinatumomab study, median RFS was 35.2?months; median OS was not evaluable. Propensity score weighting achieved balance with seven baseline prognostic factors. With adjustment for haematopoietic stem cell transplantation (HSCT) status, a 50% reduction in risk of relapse or death was observed with blinatumomab vs SOC. Median RFS, unadjusted for HSCT status, was 35.2?months with blinatumomab and 8.3?months with SOC. Conclusions These analyses suggest that blinatumomab improves RFS, and possibly OS, in adults with MRD‐positive Ph‐negative BCP‐ALL vs SOC.
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The UK has made a well-recognised contribution to the international effort to understand and treat acute lymphoblastic leukaemia (ALL) in adults. Work done in the UK by numerous personnel over many years has been instrumental in d...
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The UK has made a well-recognised contribution to the international effort to understand and treat acute lymphoblastic leukaemia (ALL) in adults. Work done in the UK by numerous personnel over many years has been instrumental in developing novel risk stratifications, evaluating treatment strategies for adult patients with de novo and relapsed disease and in making novel scientific contributions. The UK has championed and achieved very high levels of recruitment to clinical trials and, in particular, is known for success in large, investigator-initiated randomised controlled trials. This historical review charts the progress of clinical research in adult ALL from its inception to the present day.
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Summary Since the launch of their first trial in Acute myeloid leukaemia (AML) in 1959, the Medical Research Council (and latterly National Cancer Research Institute) has conducted randomised trials in AML uninterrupted for six de...
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Summary Since the launch of their first trial in Acute myeloid leukaemia (AML) in 1959, the Medical Research Council (and latterly National Cancer Research Institute) has conducted randomised trials in AML uninterrupted for six decades. These sixty years have seen a transformation in the way we diagnose, characterise and treat the disease, (and indeed a sea change in clinical trial regulations) and a continuing improvement in outcomes. The increasing refinement of diagnosis, leading to the advent of tailored therapies, and the use of disease monitoring both have the potential to improve outcomes further, but the associated complexities will require an evolution in our approach to trial design. This article looks at the extent to which the guiding principles of the first AML trials remain relevant today, and the challenges facing the next generation of trials methodologists.
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Chronic lymphocytic leukaemia (CLL) is the commonest haematological malignancy in the western world and is incurable by cytotoxic therapy. Considerable research effort has identified the signal transduction pathways in CLL cells t...
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Chronic lymphocytic leukaemia (CLL) is the commonest haematological malignancy in the western world and is incurable by cytotoxic therapy. Considerable research effort has identified the signal transduction pathways in CLL cells that contribute to anti-apoptotic signalling. Some pathways are constitutively activated in CLL cells but upregulated in normal cells only when protein tyrosine kinases (PTKs) are activated by ligands. This review describes which PTKs are aberrantly activated in CLL cells and are potential targets for inhibition. Additional potential targets within pathways downstream of these PTKs include Mek/Erk, mTorc1, protein kinase C, PI-3 kinase/Akt, nuclear factor-κB and cyclin-dependent protein kinase. Numerous studies have identified chemical agents and antibodies that selectively kill CLL cells, irrespective of their genetic resistance to conventional chemotherapeutic agents, and which can overcome cytoprotective microenvironmental signalling. These studies have resulted in identification of novel therapies, some of which are currently undergoing clinical trials. In vitro and animal model studies and clinical trials could determine which inhibitors of which targets are the likely to be most effective and least toxic either singly or in combination.
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