Molecular, clinical and therapeutic determinants of outcome in NPM1 mutated AML.

Although NPM1-mutated acute myeloid leukemia (AML) carries a generally favorable prognosis, many patients still relapse and die. Previous studies identified several molecular and clinical features associated with poor outcome, however only FLT3-ITD mutation and adverse karyotype are currently used for risk stratification due to inconsistent results and uncertainty around how other factors should influence treatment, particularly given the strong prognostic impact of post-induction measurable residual disease (MRD). Here we analyzed a large group of patients with NPM1mut AML enrolled in prospective trials (NCRI AML17 and AML19, n=1357) to delineate the impact of baseline molecular and clinical features, post induction MRD status and treatment intensity on outcome. FLT3-ITD (HR 1.28, 95%CI 1.01-1.63), DNMT3A (HR 1.65, 95%CI 1.32-2.05), WT1 (HR 1.74, 95%CI 1272-2.38) and non-ABD NPM1 mutations (HR 1.64, 95%CI 1.22-2.21) were independently associated with poorer overall survival (OS). These factors were also strongly associated with MRD positivity. For patients achieving MRD negativity, these mutations (except FLT3-ITD) were associated with an increased cumulative incidence of relapse (CIR) and poorer OS. However, apart from the few patients with adverse cytogenetics, we could not identify any group of MRD negative patients with a CIR >40% or with benefit from allograft in first remission. Intensified chemotherapy with the FLAG-Ida regimen was associated with improved outcomes in all subgroups, with greater benefits observed in the highest risk molecular subgroups.

Postinduction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission.

ABSTRACT: Selection of patients with NPM1-mutated acute myeloid leukemia (AML) for allogeneic transplant in first complete remission (CR1-allo) remains controversial because of a lack of robust data. Consequently, some centers consider baseline FLT3-internal tandem duplication (ITD) an indication for transplant, and others rely on measurable residual disease (MRD) status. Using prospective data from the United Kingdom National Cancer Research Institute AML17 and AML19 studies, we examined the impact of CR1-allo according to peripheral blood NPM1 MRD status measured by quantitative reverse transcription polymerase chain reaction after 2 courses of induction chemotherapy. Of 737 patients achieving remission, MRD was positive in 19%. CR1-allo was performed in 46% of MRD+ and 17% of MRD- patients. We observed significant heterogeneity of overall survival (OS) benefit from CR1-allo according to MRD status, with substantial OS advantage for MRD+ patients (3-year OS with CR1-allo vs without: 61% vs 24%; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.24-0.64; P < .001) but no benefit for MRD- patients (3-year OS with CR1-allo vs without: 79% vs 82%; HR, 0.82; 95% CI, 0.50-1.33; P = .4). Restricting analysis to patients with coexisting FLT3-ITD, again CR1-allo only improved OS for MRD+ patients (3-year OS, 45% vs 18%; compared with 83% vs 76% if MRD-); no interaction with FLT3 allelic ratio was observed. Postinduction molecular MRD reliably identifies those patients who benefit from allogeneic transplant in first remission. The AML17 and AML19 trials were registered at www.isrctn.com as #ISRCTN55675535 and #ISRCTN78449203, respectively.

Fludarabine, Cytarabine, Granulocyte Colony-Stimulating Factor, and Idarubicin With Gemtuzumab Ozogamicin Improves Event-Free Survival in Younger Patients With Newly Diagnosed AML and Overall Survival in Patients With NPM1 and FLT3 Mutations.

PURPOSE: To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. PATIENTS AND METHODS: One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). RESULTS: There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. CONCLUSION: Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit.

A randomized comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial.

Liposomal daunorubicin and cytarabine (CPX-351) improved overall survival (OS) compared with 7+3 chemotherapy in older patients with secondary acute myeloid leukemia (AML); to date, there have been no randomized studies in younger patients. The high-risk cohort of the UK NCRI AML19 trial (ISRCTN78449203) compared CPX-351 with FLAG-Ida in younger adults with newly diagnosed adverse cytogenetic AML or high-risk myelodysplastic syndromes (MDS). A total of 189 patients were randomized (median age, 56 years). Per clinical criteria, 49% of patients had de novo AML, 20% had secondary AML, and 30% had high-risk MDS. MDS-related cytogenetics were present in 73% of the patients, with a complex karyotype in 49%. TP53 was the most common mutated gene, in 43%. Myelodysplasia-related gene mutations were present in 75 (44%) patients. The overall response rate (CR + CRi) after course 2 was 64% and 76% for CPX-351 and FLAG-Ida, respectively. There was no difference in OS (13.3 months vs 11.4 months) or event-free survival in multivariable analysis. However, relapse-free survival was significantly longer with CPX-351 (median 22.1 vs 8.35 months). There was no difference between the treatment arms in patients with clinically defined secondary AML or those with MDS-related cytogenetic abnormalities; however, an exploratory subgroup of patients with MDS-related gene mutations had significantly longer OS with CPX-351 (median 38.4 vs 16.3 months). In conclusion, the OS of younger patients with adverse risk AML/MDS was not significantly different between CPX-351 and FLAG-Ida.

A feasibility study to inform the design of a randomised controlled trial to identify the most clinically effective and cost-effective length of Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT).

BACKGROUND: Venous thromboembolism is common in cancer patients and requires anticoagulation with low-molecular-weight heparin (LMWH). Current data recommend LMWH for anticoagulation as far as 6 months, yet guidelines recommend LMWH beyond 6 months in patients who have ongoing or active cancer. This recommendation, based on expert consensus, has not been evaluated in a clinical study. OBJECTIVES: (1) To identify the most clinically and cost-effective length of anticoagulation with LMWH in the treatment of cancer-associated thrombosis (CAT); (2) to identify practicalities of conducting a full randomised controlled trial (RCT) with regard to recruitment, retention and outcome measurement; and (3) to explore the barriers for progressing to a full RCT. DESIGN: The Anticoagulation with Low-molecular-weight heparin In the treatment of Cancer-Associated Thrombosis (ALICAT) trial is a randomised, multicentre, feasibility mixed-methods study with three components: (1) a RCT comparing ongoing LMWH treatment for CAT with cessation of LMWH at 6 months' treatment (current licensed practice) in patients with locally advanced or metastatic cancer, consulted in three clinical settings (haematology outpatients, oncology outpatients and primary care); (2) a nested qualitative study, including focus groups with clinicians to investigate attitudes for recruiting to the study and identify the challenges of progressing to a full RCT, and semistructured interviews with patients and relatives to explore their attitudes towards participating in the study, and potential barriers and concerns to participation; and (3) a UK-wide survey exercise to develop a classification and enumeration system for the CAT models and pathways of care. SETTING: A haematology outpatients department, an oncology outpatients department and primary care. PARTICIPANTS: Patients with ongoing active or metastatic cancer who have received 6 months of LMWH for CAT. INTERVENTIONS: Ongoing LMWH treatment for CAT versus cessation of LMWH at 6 months' treatment in patients with locally advanced or metastatic cancer. MAIN OUTCOME MEASURES: (i) The number of eligible patients over 12 months; (ii) the number of recruited patients over 12 months (target recruitment rate of 30% of eligible patients); and (iii) the proportion of randomised participants with recurrent venous thromboembolisms (VTEs) during follow-up. RESULTS: Following several delays in setting up the RCT component of the study, 5 out of 32 eligible patients consented to be randomised to the RCT suggesting progression to a full RCT was not feasible. Reasons for non-consenting were primarily based on a fixed preference for continuing or discontinuing treatment after 6 months of anticoagulation, and a fear of randomisation to their non-preferred option. Views were largely influenced by patients' initial experience of CAT. Focus groups with clinicians revealed that they would be reticent to recruit to such a study as they had fixed views of best management despite the lack of evidence. Patient pathway modelling suggested that there is a broad heterogeneity of practice with respect to CAT management and co-ordination, with no consensus on which specialty should best manage such cases. CONCLUSIONS: The results of the RCT reflect recruitment from the oncology site only and provide no recruitment data from haematology centres. However, it is unlikely that these other sites would have access to more eligible patients. The management of cancer-associated thrombosis beyond 6 months will remain a clinical challenge. As it is unlikely that a prospective study will successfully recruit, other strategies to accrue relevant data are necessary. Currently the LONGHEVA (Long-term treatment for cancer patients with deep-venous thrombosis or pulmonary embolism) registry is in development to prospectively evaluate this important and common clinical scenario. STUDY REGISTRATION: This study is registered as clinical trials.gov number NCT01817257 and International Standard Randomised Controlled Trial Number (ISRCTN) 37913976. FUNDING DETAILS: Funding for the ALICAT trial was provided by the Health Technology Assessment programme (10/145/01) in response to a themed funding call. The study was designed in accordance with the initial funding brief and feedback from the review process.