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Key Points First report of an FLT3-targeted therapy added to nonintensive chemotherapy that has improved survival in older FLT3-ITD patients with AML.Quizartinib is well tolerated, improves response and survival in older FLT3-ITD AML patients and merits consideration in future therapies. Now amended as text above., Visual Abstract, Survival for older patients with acute myeloid leukemia (AML) unsuitable for intensive chemotherapy is unsatisfactory. Standard nonintensive therapies have low response rates and only extend life by a few months. Quizartinib is an oral Fms-like tyrosine kinase 3 (FLT3) inhibitor with reported activity in wild-type patients. As part of the AML LI trial, we undertook a randomized evaluation of low-dose ara-C (LDAC) with or without quizartinib in patients not fit for intensive chemotherapy. Overall, survival was not improved (202 patients), but in the 27 FLT3-ITD patients, the addition of quizartinib to LDAC improved response (P = .05) with complete remission/complete remission with incomplete haematological recovery for quizartinib + LDAC in 5/13 (38%) vs 0/14 (0%) in patients receiving LDAC alone. Overall survival (OS) in these FLT3-ITD+ patients was also significantly improved at 2 years for quizartinib + LDAC (hazard ratio 0.36; 95% confidence intervals: 0.16, 0.85, P = .04). Median OS was 13.7 months compared with 4.2 months with LDAC alone. This is the first report of an FLT3-targeted therapy added to standard nonintensive chemotherapy that has improved survival in this population. Quizartinib merits consideration for future triplet-based treatment approaches. This trial was registered at www.clinicaltrials.gov as ISRCTN #ISRCTN40571019 and EUDRACT @2011-000749-19.

The survival of acute myeloid leukaemia (AML) patients aged over 60 has been suboptimal historically, whether they are treated using hypomethylating agents, low-dose cytarabine (LDAC) or venetoclax-based regimens. Progress is being made, however, for subgroups with favourable molecular or cytogenetic findings. Arginine metabolism plays a key role in AML pathophysiology. We report the only randomised study of LDAC with recombinant arginase BCT-100 versus LDAC alone in older AML patients unsuitable for intensive therapy. Eighty-three patients were randomised to the study. An overall response rate was seen in 19.5% (all complete remission [CR]) and 15% (7.5% each in CR and CR without evidence of adequate count recovery [CRi]) of patients in the LDAC+BCT-100 and LDAC arms respectively (odds ratio 0.73, confidence interval 0.23-2.33; p = 0.592). No significant difference in overall or median survival between treatment arms was seen. The addition of BCT-100 to LDAC was well tolerated.

ObjectiveThe aim was to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on the clinical experiences, research opportunities and well-being of rheumatology trainees.MethodsA voluntary, anonymous, Web-based survey was administered in English, Spanish or French from 19 August 2020 to 5 October 2020. Adult and paediatric rheumatology trainees were invited to participate via social media and email. Using multiple-choice questions and Likert scales, the perceptions of trainees regarding the impact of the COVID-19 pandemic on patient care and redeployment, learning and supervision, research and well-being were assessed.ResultsThere were 302 respondents from 33 countries, with 83% in adult rheumatology training. An increase in non-rheumatology clinical work was reported by 45%, with 68% of these having been redeployed to COVID-19. Overall, trainees reported a negative impact on their learning opportunities during rheumatology training, including outpatient clinics (79%), inpatient consultations (59%), didactic teaching (55%), procedures (53%), teaching opportunities (52%) and ultrasonography (36%). Impacts on research experiences were reported by 46% of respondents, with 39% of these reporting that COVID-19 negatively affected their ability to continue their pre-pandemic research. Burnout and increases in stress were reported by 50% and 68%, respectively. Physical health was negatively impacted by training programme changes in 25% of respondents.ConclusionThe COVID-19 pandemic has had a substantial impact on rheumatology training and trainee well-being. Our study highlights the extent of this impact on research opportunities and clinical care, which are highly relevant to future curriculum planning and the clinical learning environment.

BackgroundAcute myeloid leukaemia (AML) is a heterogeneous disease where outcome is substantially influenced by age. Over the last 30-40 years, significant improvements have been made in survival for younger patients (those under 60). However, with the median age of the disease at diagnosis at 65 years, outcome in older patients has improved much less. Additionally, many elderly patients are not considered suitable for intensive chemotherapy and the current standard treatment is considered unsatisfactory. MethodsLI1 will evaluate several relevant therapeutic questions in AML patients over 60 years of age for whom intensive chemotherapy is not considered suitable. Patients are invited to enter a randomized comparison of standard therapy (LD Ara-C) versus a novel treatment. A number of different treatment options are available at any one time, but there is no comparison between novel agents. If, at initial review, a novel agent is deemed unlikely to demonstrate the required improvement, it may be removed from the protocol and replaced with another novel agent, via protocol amendment. Agents are initially entered into a phase II comparison against standard of care - where an agent is considered promising at interim review (based on remission rates), the randomisation may be extended to a fully powered phase III comparison based on survival. Agents which may prolong survival or improve remission rates will also be required to demonstrate equivalence or better of quality of life in patients – therefore, quality of life assessments are undertaken throughout, in each arm. DiscussionEven when less intensive treatment options are delivered, the outcomes are not satisfactory. The NCRI AML working group has a strong network, required for delivery of this trial program. The UK network is augmented by international collaborative groups, most notably from New Zealand and Denmark. The use of the Pick-a-Winner design improves efficiency and speed of review of the available novel agents with the aim of benefitting the increasing number of patients in this age group.Trial registration: ISCRTN40571019, EUDRACT2011-000479-19 (12th May 2011)

Background: Many patients with Acute Myeloid Leukemia (AML) diagnosed after 60 years of age are not considered suitable for intensive remission induction chemotherapy, either due to co-morbidities or frailty associated with advanced age. Despite treatment with either a hypomethylating agent or low-dose cytarabine arabinoside (LDAC), survival is usually poor, with 1-year survival after LDAC of 24-37% in NCRI AML16 and historical arms of LI-1. Combination therapy with additional agents represents an attractive option, and has the potential to improve patient outcomes without substantially increasing toxicity. Lenalidomide (Revlimid TM) is an immunomodulatory drug, used to treat myeloma, and some cases of myelodysplastic syndrome, and has potent antineoplastic, anti-angiogenic, anti-inflammatory and pro-erythropoietic properties. Early-phase trials of lenalidomide in AML have demonstrated clinical activity with acceptable toxicity. Aim: To assess the efficacy and tolerability of LDAC+lenalidomide versus LDAC alone in patients aged 60+ unsuitable for intensive therapy. The aim was to double 2-year survival from 11% to 22% (HR 0.69). Methods: LI-1 was an international multicentre, multi-arm, randomised phase II trial developed to study the efficacy and tolerability of novel non-intensive therapies in AML using a "pick a winner" design. LDAC was given at 20mg BD SC on days 1-10 of each course. Lenalidomide was administered orally once daily in a flat 10mg dose for 21 days, where day 1 is day 1 of LDAC with courses occurring at 5-week intervals for courses 1-4. Patients considered to be benefitting after 4 courses, i.e. in remission or stable disease, could continue to receive treatment until disease progression, either with LDAC+lenalidomide at 6-week intervals, or lenalidomide only at 4-week intervals if patient had experienced significant toxicity. Toxicities were recorded using CTCAEv3. Primary objectives included overall survival (OS), complete remission (CR + CRi) achievement, reasons for failure, duration of response (CR/CRi), relapse rates and deaths in first CR. Secondary objectives included toxicity, supportive care requirements, and Quality of Life assessments (measured using EORTC QLQ-30, EQ5D and HADS tools). Results: Between Jan-17 and Jun-19, 202 patients from Denmark (8%), New Zealand (16%) and the UK (76%) were randomised. Median age was 78 years (range 62-89). Overall, 58% were male; 76% de novo AML, 20% secondary AML, and 4% high risk MDS; 1% favourable, 66% intermediate, 19% adverse and 14% unknown cytogenetics; WHO performance status 0 for 15%, 1 for 58%, 2 for 22% and 3 for 5%. Median of 2 courses (range 0-24; mean 3.28) was delivered in LDAC arm and 1 course in LDAC+lenalidomide arm (range 0-25; mean 3.48). Overall response (CR/CRi) was achieved in 40/202 patients (20%), (LDAC+lenalidomide 25%, LDAC 14%, OR 0.45 (0.22, 0.93), P=0.031). 30-day mortality was not significantly increased (19% in both arms); and 2-year OS showed no significant difference (14% vs 11.5%, HR 0.94 (0.69, 1.29, P=0.719). Median OS was 3.5 vs 4.6 months; HR 0.96 (0.71, 1.30), P=0.80. 1-year OS for patients that didn't enter CR/CRi was 6.8% for LDAC+lenalidomide vs 16.9% for LDAC (P=0.028). Cause of death for the majority of patients was resistant/recurrent disease: 45(53%) vs 47(58%). Most adverse events (AEs) were grade 1/2 in both arms. During cycle 1, there were 78 vs 51 grade 3/4 AEs in the LDAC+lenalidomide and LDAC arms, respectively (P=0.02). This included 5 thrombotic events in the LDAC+lenalidomide arm (4 grade 3 and 1 grade 4) and none in the LDAC arm. In course 1, supportive care requirements were higher in terms of both days of antibiotics (7 vs 3; p=0.001) and hospitalisation days (11 vs 6.5; p=0.005) for the LDAC+lenalidomide arm. There was no difference in transfusion requirements. Conclusions: Despite improving the CR/CRi rate, the combination of lenalidomide+LDAC did not improve OS, relapse-free survival or time in remission in elderly patients with AML. The addition of lenalidomide to LDAC resulted in increased toxicity, including episodes of thrombosis, as well as increased supportive care requirements. Alternative strategies to improve survival for elderly patients with AML remain a significant clinical need. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Celgene for providing drug and additional support for this IIS. Fig 1: OS All patients Figure 1 Figure 1. Disclosures Copland: Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau. OffLabel Disclosure: Off label use of lenalidomide in combination with low dose cytarabine will be discussed in the setting of elderly unfit AML.

Background: Among patients with Acute Myeloid Leukaemia (AML) over the age of 60, a considerable number are not considered suitable for intensive remission-induction chemotherapy. Survival in these patients is poor, whether they are treated using hypomethylating agents or low-dose ara-C (LDAC). The possibility of combination therapy with additional agents represents an attractive option. Arginine metabolism plays a key role in AML pathogenesis (Mussai et al. Blood 2013); BCT-100 is a pegylated recombinant human arginase that leads to a rapid depletion in extracellular and intracellular arginine concentrations resulting in G0/G1 arrest, and subsequent death by necrosis. BCT-100 demonstrates significant activity as single-agent against AML cell lines, AML xenografts and primary AML blasts from newly diagnosed or relapsed patients (Mussai et al. Blood 2015). Importantly BCT-100 is synergistic in combination with cytarabine. Aims: To assess the efficacy of LDAC+BCT100 versus LDAC alone in patients aged 60+ unsuitable for intensive therapy, in a "pick a winner" design. This design allows several treatments to be assessed simultaneously in a randomised fashion, with the aim of doubling 2-year survival from 11% to 22% (HR 0.69), with interim assessments after 50 and 100 patients per arm are recruited. Methods: LDAC was given at 20mg BD SC on days 1-10 of each course. Patients randomised to the combination received LDAC as above with BCT-100 1600U/kg on Days 1, 8, 15 and 22 as a 1-hour intravenous infusion. Courses occurred at 4-6 week intervals. Toxicities were recorded using CTCAE version 3. Pharmacokinetic and biomarker samples were assessed in BCT-100 patients. Results here are based upon median follow-up of 3.8 months (range: 0.1 - 20.6 months) Results: Between September 2018 and December 2020, 83 patients were randomised. The trial was prematurely closed due to the COVID pandemic and did not reach the pre-planned first evaluation. Median age was 76.7 years (range 62-88). Overall, 65% were male; 70% de novo AML, 23% secondary AML, and 6% high risk MDS; 2% favourable, 59% intermediate, 23% adverse and 15% unknown/unreported cytogenetics. Median of 2 courses was delivered in either arm (mean 2 LDAC, 2 LDAC+BCT, range for both: 1-12). BCT-100 leads to a depletion of arginine from baseline in the majority of patients. Overall response (CR/CRi) was achieved in 12/81 patients (15%), (LDAC+BCT-100 15%, LDAC 15%, R 1.03 (0.30, 3.51),P=0.963). Thirty-day mortality was not significantly increased (18% vs 11%, HR 1.71 (0.50, 5.84), P=0.393; and 1-year survival showed no evidence of a difference (31% vs 30%, HR 1.28 (0.72, 2.25). Median overall survival time was 3.8 vs 6.4months; overall survival HR 1.11 (0.64, 1.90), P=0.715. The most common cause of death was resistant/recurrent disease: 12(46%) vs 16(59%). BCT-100 was not associated with any haematological toxicity; although rare grade 3/4 cardiac and hepatic events were reported, these were not significantly increased with BCT-100. Summary: The addition of BCT-100 to LDAC did not improve response rate or survival. BCT-100 was well tolerated with an acceptable toxicity profile. Further clinical evaluation of BCT-100 induced arginase depletion continues in a variety of malignancies. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Bio-Cancer Treatment International for providing drug and additional support for this Investigator Initiated Study. Figure 1. OS All patients Figure 1 Figure 1. Disclosures Knapper: Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. McMullin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Research Funding, Speakers Bureau. Copland: Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding; Astellas: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau.

Background Chronic myelomonocytic leukemia (CMML) is a highly heterogeneous myeloid neoplasm with poor prognosis and limited therapeutic options. Tefinostat (CHR-2845) is a cell permeant ester that is converted to an active acid histone deacetylase (HDAC) inhibitor (CHR-2847) by human carboxylesterase 1 (hCE-1), an enzyme predominantly found in cells of monocyte lineage. Pre-clinical studies confirmed selective activity of tefinostat, correlating with hCE-1 expression and acetylation induction, in monocyte derived cell lines, primary CMML and AML (M4/M5) cells (1). A phase 1 study in refractory haematological malignancies showed tefinostat to be well tolerated, with complete remission reported in 1/2 CMML patients (2). Given the compelling rationale for selective activity in monocytoid malignancies, we conducted a phase 2 study to assess safety and efficacy of tefinostat in CMML. Methods MONOCLE was a single arm phase 2 trial conducted to a Bryant and Day 2-stage design with dual primary endpoints of safety and clinical efficacy. CMML-2 patients were included; additionally CMML-1 patients with symptomatic bone marrow failure or proliferative disease, symptomatic splenomegaly, extramedullary involvement, systemic symptoms or CMML-specific Prognostic Score (CPSS) int-2/high. Tefinostat was administered orally in continuous 28-day cycles starting at 360mg once daily, increasing to 480mg after 4 weeks if well tolerated. Concomitant hydroxycarbamide was permitted only with cycles 1-3. Clinical response was assessed according to International Consortium MDS/MPN Response Criteria (3); responding patients at cycle 6 were permitted to continue therapy. Toxicity was assessed according to CTCAE v4.0. Results In stage 1, 21 patients were enrolled at 9 centers (Jan-Sep 2017). 20 patients received tefinostat (median age 75 years [64-88], M/F 14/6) including 16 with CMML-1 (80%) and 4 CMML-2 (20%), 8 (40%) with myelodysplastic and 12 (60%) myeloproliferative CMML; respective proportions in CPSS low/int-1/int-2/high risk groups were 5/50/40/5%. Myeloid NGS analysis confirmed a molecularly relatively high risk population: 70% ASXL1 mutation frequency and median 4 (2-7) mutations per patient; other most commonly observed mutations being TET2 (65%), SRSF2 (50%), EZH2 (35%) and NRAS (35%). Prior therapy included azacitidine (3 patients) and hydroxycarbamide (7). 17/20 patients had high hCE-1 levels, assessed flow cytometrically at trial entry in monocytoid cells (vs bulk myeloid population). Median number of cycles of tefinostat received was 4 (1-15). Of 13 patients completing ≥3 cycles of tefinostat, 1 patient achieved clinical benefit (partial bone marrow response at cycle 6 with red cell transfusion independence sustained over 15 cycles of treatment), 9 had stable disease (of whom 1 had transient clinical benefit [MPN-SAF symptom reduction] which was not sustained to cycle 6) and 3 had progressive disease. Most frequent non-hematologic adverse events of any grade were raised creatinine (55% patients), fatigue (40%) and nausea/vomiting (30%). Grade ≥3 AEs judged potentially related to tefinostat included thrombocytopenia (3 patients), fatigue (2), raised creatinine (2), anorexia, AV block, nausea and neutropenia (1 each). Creatinine rises were in all cases reversible following tefinostat dose reduction/cessation. Induction of intracellular lysine acetylation in monocytes (a marker of HDAC inhibition) was observed in 50% of patients (including clinical responders), peaking between days 15-28 of cycle 1. While no clear relationship between baseline hCE-1 expression and clinical response was evident, reductions in marrow monocyte and myeloid blast fractions were seen in both clinical responders. Conclusion Following failure to achieve a pre-defined minimum number of clinical responses to tefinostat, patient recruitment was not continued into stage 2 of this phase 2 study. Drug tolerability was encouraging although observed renal effects will likely preclude dose escalation in this challenging, often frail patient group. Despite compelling scientific rationale and pre-clinical data favoring this monocyte targeted treatment approach we were unable to demonstrate a clinically significant single agent disease modifying effect in CMML. (1) Zabkiewicz J. Oncotarget 2016; 7: 16650-62 (2) Ossenkoppele G. Br J Haem 2013; 162: 191-201 (3) Savona M. Blood 2015; 125: 1857-65 Disclosures Knapper: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Meeting and travel support; Jazz: Other: Meeting and travel support; Daiichi Sankyo: Other: Meeting and travel support; Chroma Therapeutics: Research Funding. Hills:Daiichi Sankyo: Consultancy, Honoraria. Dillon:Teva Pharmaceuticals UK: Consultancy, Honoraria; AbbVie UK: Consultancy, Honoraria. Pocock:Kent & Canterbury Hospital: Employment. Culligan:Pfizer: Honoraria; Takeda: Honoraria, Other: Support to attend conferences; JAZZ: Honoraria; Merck Sharp & Dohme (MSD): Honoraria; Abbvie: Other: Support to attend conferences; Celgene: Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences.

Terms of Use.\udJournal of Clinical Oncology\udLog In\udassignment_turned_inSubmit\udmail_outlineE-Alerts\udadd_shopping_cartSubscribe\ud\udOpenAthens/Shibboleth »\udAdvanced Search\ud\ud Newest Articles\ud Issues\ud Special Content\ud Authors\ud Subscribers\ud About\ud ASCO Publications\ud Career Center\ud COVID-19\ud\ud\ud\ud\ud\ud\ud\ud\ud\ud\ud\ud\ud\ud Journal of Clinical Oncology > List of Issues > Volume 36, Issue 15 > \ud\udORIGINAL REPORTS Hematologic Malignancy\udArticle Tools\udOPTIONS & TOOLS\udExport Citation \udTrack Citation \udAdd To Favorites \udPurchase\ud\ud Rights & Permissions \ud\udArticle has an altmetric score of 27\udCOMPANION ARTICLES\ud\ud Minimal Residual Disease Testing After Induction Chemotherapy for Acute Myeloid Leukemia: Moving Beyond Prognostication?. April 06, 2018\ud\udARTICLE CITATION\ud\udDOI: 10.1200/JCO.2017.76.3425 Journal of Clinical Oncology - published online before print March 30, 2018\ud\udPMID: 29601212\udMeasurable Residual Disease at Induction Redefines Partial Response in Acute Myeloid Leukemia and Stratifies Outcomes in Patients at Standard Risk Without NPM1 Mutations\udSylvie D. Freeman, Robert K. Hills, Paul Virgo, Naeem Khan, Steve Couzens, Richard Dillon, ...\udShow More\ud\udS.D.F. and R.K. H. contributed equally to this work.\ud\ud Abstract\ud Full Text\ud PDF\ud Figures and Tables\ud Supplements\ud\udPurpose\ud\udWe investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria.\udMethods\ud\udAs part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/μL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD−. Patients without high-risk factors, including Flt3 internal tandem duplication wt/−NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors.\udResults\ud\udSurvival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival [OS], 27% RD v 46% PR v 51% MRD+ v 70% MRD−; P < .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio [HR], 1.88 [95% CI, 1.50 to 2.36], P < .001; survival: HR, 1.77 [95% CI, 1.41 to 2.22], P < .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD−, P = .003; relapse incidence, 89% when MRD+ ≥ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD− (HR, 1.68 [95% CI, 0.75 to 3.85]; P = .16 for interaction).\udConclusion\ud\udMFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.

Introduction Relapse remains the most common cause of treatment failure for patients with acute myeloid leukaemia (AML) who undergo allogeneic stem cell transplantation (SCT) and carries a grave prognosis. Multiple studies have identified the presence of minimal residual disease (MRD) prior to SCT assessed by flow cytometry (FCM) as a strong predictor of relapse: however, little is known about the impact of molecular MRD pre-SCT. Molecular techniques can provide 100-1000 fold greater sensitivity than FCM in NPM1 mutated AML allowing identification of patients with very low level MRD prior to SCT. Peri-transplant management decisions for patients with positive molecular MRD are highly challenging due to the absence of robust outcome data. Methods Between 2009-14 the NCRI AML17 study enrolled 3215 adult non-APML patients aged 16-77 eligible for intensive chemotherapy. Central screening for NPM1 mutations was positive in 861/2949 (29%); 530 patients provided serial samples for MRD monitoring. Paired blood (PB) and bone marrow aspirates (BM) were requested after each chemotherapy cycle and then quarterly; additional samples were requested pre- and post-SCT. Samples were analysed by RT-qPCR using a suite of 27 mutation-specific reverse primers. Results were only fed back to clinicians after June 2012 when patients could be treated for confirmed re-emergent or persistent molecular positivity. Post-remission treatment was determined according to the validated NCRI risk score, with poor-risk patients recommended for SCT during first complete remission (CR1). Survival analysis was performed using the logrank test. Results In total 108/530 patients received SCT (CR1 57 (52%), after molecular relapse or progression (MR) 30 (28%), CR2 21 (19%)). Five-year survival post-SCT (5y-OS) was 65% in CR1, and 54% in MR/CR2 (p=0.3). After MR 26/30 patients received chemotherapy prior to SCT. Evaluable pre-SCT PB and BM samples taken within 60 days of SCT were available for 104 and 78 patients (both available n=74). Considering PB samples, 5y-OS was 73% (median OS (mOS) not reached (NR)) for MRD-ve patients (n=74) vs. 30% (mOS 8.1 m) for any PB positivity (n=30) (p Of the 47 patients who received additional chemotherapy for morphologic or molecular relapse or progression, 26 (55%) converted to MRD negativity accounting for 44% of 59 patients who were MRD negative pre-SCT. Ninety-three per cent of 59 pre SCT-MRD negative patients had been MRD negative in the PB after the second cycle of induction (a previously identified marker of favourable outcome). A threshold of 200 mutant NPM1 transcripts/105 ABL copies in the pre-SCT PB sample split patients into 3 groups with 2y-OS of 81% (negative, n=74), 54% (low, n=13) and 9% (high, n=17; p Thirty four patients were positive for FLT3-ITD at diagnosis (5y-OS 55%) and 74 were negative (5y-OS 62%; p=0.3). For patients without FLT3 ITD, negative, low and high levels of MRD in the pre-SCT PB sample were associated with 2y-OS of 79% (n=53), 88% (n=8) and 0% (n=9) (p We assigned 80 patients to high and low risk groups based on FLT3 ITD status and pre-SCT MRD level in PB and BM. High-risk patients (FLT3 ITD and any detectable level of MRD in the PB or BM, or FLT3 ITD negative with > 200 copies in the PB or > 1000 copies in the BM) had 3y-OS of 14% (n=27, mOS 6.5 months) compared with 80% for low-risk patients (n=53, p Conclusions Patients who test negative for NPM1 mutant transcripts immediately before SCT have a favourable outcome which is also observed in FLT3 ITD negative patients who are MRD positive at levels which do not exceed 200 copies in the PB or 1000 copies in the BM. FLT3 ITD mutated patients with any level of MRD prior to SCT, and FLT3 ITD negative patients with transcript levels above these thresholds, have a very high risk of relapse and may benefit from further chemotherapy or FLT3 inhibition prior to or after SCT; studies to investigate this are urgently needed. Disclosures Hills: Daiichi Sankyo: Consultancy, Honoraria. Cavenagh:Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Russell:Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau.

The late Nobel laureate Seamus Heaney used a geological analogy of igneous and sedimentary rock formation to describe modes of poetic composition.1 Igneous rocks, derived from solidified magma, imply an eruptive, pre-emptory form of composition. Sedimentary rock formation in contrast is by accrual. It strikes us that such analogy fits equally well for the evolution of clinical research ideas: sometimes rapid or unlooked for, more often driven by observation and recognition of patterns over time. Today for most of us, in reality, the analogy sadly all too often evokes the weather-beaten image of the wearing down rather than the building up. Anyone familiar with the drama of transforming a research project from idea to fruition may be forgiven for feeling that the Atlantic ocean has indeed washed over them more than once. Papers continue to appear in the palliative care literature documenting the many challenges, with familiar themes over time.2 ,3 Common among these are excessive bureaucracy and lack of clinician time, funding and institutional capacity.4 ,5 Progress has been made, with focused efforts to improve funding and infrastructure, patient recruitment,6 and to address methodological challenges.7 A recent Lancet editorial has …