CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. METHODS: This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete. FINDINGS: Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06-62·98) in the CPX-351 group and 59·93 months (59·73-60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37-11·86) with CPX-351 and 5·95 months (4·99-7·75) with 7+3 (HR 0·70, 95% CI 0·55-0·91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. INTERPRETATION: After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. FUNDING: Jazz Pharmaceuticals.

A clinical transcriptome approach to patient stratification and therapy selection in acute myeloid leukemia.

As more clinically-relevant genomic features of myeloid malignancies are revealed, it has become clear that targeted clinical genetic testing is inadequate for risk stratification. Here, we develop and validate a clinical transcriptome-based assay for stratification of acute myeloid leukemia (AML). Comparison of ribonucleic acid sequencing (RNA-Seq) to whole genome and exome sequencing reveals that a standalone RNA-Seq assay offers the greatest diagnostic return, enabling identification of expressed gene fusions, single nucleotide and short insertion/deletion variants, and whole-transcriptome expression information. Expression data from 154 AML patients are used to develop a novel AML prognostic score, which is strongly associated with patient outcomes across 620 patients from three independent cohorts, and 42 patients from a prospective cohort. When combined with molecular risk guidelines, the risk score allows for the re-stratification of 22.1 to 25.3% of AML patients from three independent cohorts into correct risk groups. Within the adverse-risk subgroup, we identify a subset of patients characterized by dysregulated integrin signaling and RUNX1 or TP53 mutation. We show that these patients may benefit from therapy with inhibitors of focal adhesion kinase, encoded by PTK2, demonstrating additional utility of transcriptome-based testing for therapy selection in myeloid malignancy.

Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.

CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084.

Day 14 Bone Marrow Evaluation During Acute Myeloid Leukemia Induction in a Real-world Canadian Cohort.

INTRODUCTION: The 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as "day 14 [D14] marrow"). Those who do not achieve a hypoplastic marrow, with cellularity < 20% and blasts < 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results. PATIENTS AND METHODS: Patients aged 18 to 70 years undergoing induction therapy with standard "7 + 3" regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS. RESULTS: A total of 486 patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts < 5% were predictive of CR/CR with incomplete count recovery (P < .001). Cytogenetic risk (P < .001), age < 60 years (P = .001), and D14 blasts < 5% (P = .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n = 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P = .004) but no difference in OS. CONCLUSIONS: The results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI.

Quality of life and socioeconomic indicators associated with survival of myeloid leukemias in Canada.

Understanding how patient-reported quality of life (QoL) and socioeconomic status (SES) relate to survival of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may improve prognostic information sharing. This study explores associations among QoL, SES, and survival through administration of the Euro-QoL 5-Dimension, 3-level and Functional Assessment of Cancer Therapy-Leukemia and financial impact questionnaires to 138 adult participants with newly diagnosed AML or MDS in a longitudinal, pan-Canadian study. Cox regression and lasso variable selection models were used to explore associations among QoL, SES, and established predictors of survival. Secondary outcomes were changes in QoL, performance of the QoL instruments, and lost income. We found that higher QoL and SES were positively associated with survival. The Lasso model selected the visual analog scale of the EQ-5D-3L as the most important predictor among all other variables (P = .03; 92% selection). Patients with AML report improved QoL after treatment, despite higher mean out-of-pocket expenditures compared with MDS (up to $599 CDN/month for AML vs $239 for MDS; P = .05), greater loss of productivity-related income (reaching $1786/month for AML vs $709 for MDS; P < .05), and greater caregiver effects (65% vs 35% caregiver productivity losses for AML vs MDS; P < .05). Our results suggest that including patient-reported QoL and socioeconomic indicators can improve the accuracy of survival models.

Consolidation outcomes in CPX-351 versus cytarabine/daunorubicin-treated older patients with high-risk/secondary acute myeloid leukemia.

CPX-351 is a dual-drug liposomal encapsulation of cytarabine/daunorubicin. In a phase 3 study (ClinicalTrials.gov Identifier: NCT01696084), patients aged 60-75 years with newly diagnosed, high-risk/secondary AML received 1-2 induction cycles with CPX-351 or 7 + 3 chemotherapy; those achieving complete remission (including with incomplete platelet or neutrophil recovery) could receive up to 2 consolidation cycles with CPX-351 or 5 + 2 chemotherapy, respectively. In this exploratory analysis of the subgroup of patients who received consolidation, median overall survival was prolonged among patients receiving CPX-351 induction/consolidation versus 7 + 3/5 + 2 (25.43 vs. 8.53 months; HR = 0.44 [95% CI: 0.25-0.77]). The safety profile of CPX-351 consolidation was consistent with that of the overall study. Outpatient administration of CPX-351 consolidation occurred in 51%-61% of patients and did not diminish overall survival. These findings suggest consolidation with CPX-351 in this patient population contributed to the prolonged overall survival versus 7 + 3/5 + 2, building upon findings from the overall study population, and provide evidence that, with careful monitoring, some patients can successfully receive CPX-351 as outpatients.

Outpatient Autologous Stem Cell Transplants for Multiple Myeloma: Analysis of Safety and Outcomes in a Tertiary Care Center.

BACKGROUND: Autologous stem cell transplant (ASCT) is the preferred consolidation strategy to treat eligible patients with multiple myeloma (MM) and related plasma cell dyscrasias. Given the increasing volume of patients and longer wait time, outpatient ASCT for MM is the standard of care at the Vancouver General Hospital. PATIENTS AND METHODS: Patients with MM, POEMS syndrome, and amyloidosis undergoing ASCT were included in this analysis. We analyzed patient characteristics, the number of patients requiring admission, duration of admission, 30-day and 100-day mortality, and overall survival. RESULTS: Between January 2007 and June 2016, 724 patients underwent 752 ASCTs. Of these, 702 were first ASCTs, 44 were second, and 6 were third. The median age was 60 years (interquartile range [IQR], 54-65 years). Reasons for ASCTs were MM (96.9%) amyloidosis (2.4%), and POEMS syndrome (0.7%). There were 431 (59.5%) males in this group. The median time from diagnosis to transplant was 5 months. Conditioning was melphalan 200 mg/m2 for 89.6% of the patients. Admission to the inpatient ward was required by 245 (32.6%) patients within the first 30 days. The median time to admission was 9 days post-transplant (IQR, 5-13 days). The median duration of admission was 6 days (IQR, 3-9 days). The day 100 all-cause mortality rate was 0.9%, and transplant-related mortality was 0.4%. CONCLUSION: Outpatient ASCT is a safe and feasible treatment strategy with low transplant-related mortality. Overall resource utilization is significantly lower than inpatient ASCT: however, this requires a multidisciplinary approach with close follow-up.

Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy. METHODS: QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0-2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1-10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1-5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 µg/m2 per day or 5 µg/kg per day subcutaneously on days 1-5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2-6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2-6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2-4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after quizartinib could resume quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing. FINDINGS: Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to quizartinib and 122 to chemotherapy. Four patients in the quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4-32·3). Overall survival was longer for quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58-0·98; p=0·02]). Median overall survival was 6·2 months (5·3-7·2) in the quizartinib group and 4·7 months (4·0-5·5) in the chemotherapy group. The most common non-haematological grade 3-5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events). INTERPRETATION: Treatment with quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor. FUNDING: Daiichi Sankyo.

Health state utilities associated with treatment options for acute myeloid leukemia (AML).

Aims: Acute myeloid leukemia (AML) treatment typically involves remission induction chemotherapy followed by consolidation chemotherapy. New treatments for AML have recently been introduced, including a chemotherapy formulation called CPX-351, which is administered via less time-intensive IV infusion than the standard "7 + 3" continuous infusion regimen of cytarabine plus an anthracycline. The purpose of this study was to estimate utilities that could be used in economic modeling of AML treatment. Materials and methods: In time trade-off interviews, participants from the UK general population valued 12 health states drafted based on literature and clinician interviews. To identify disutility associated with chemotherapy, two types of induction and four types of consolidation were added to an otherwise identical health state describing AML. The decrease in utility when adding these chemotherapy regimens represents the disutility of each regimen. Five additional health states were valued to estimate utilities associated with other AML treatments. Results: Two hundred participants completed interviews. Mean (SD) utilities were 0.55 (0.31) for pre-treatment AML and 0.66 (0.29) for AML in temporary remission. Adding any chemotherapy significantly decreased utility (p < 0.0001). Induction had a mean disutility of -0.11 with CPX-351 and -0.15 with 7 + 3. Mean disutility for consolidation ranged from -0.03 with outpatient CPX-351 to -0.11 with inpatient 5 + 2. Utilities are also reported for other AML treatments (e.g. transplant, low-intensity chemotherapy). Limitations: One limitation is that the differences in adverse event profiles between the treatment regimens were based on clinician opinion. Future use of CPX-351 in clinical trials or clinical settings will provide additional information on its adverse event profile. Conclusions: While all chemotherapy regimens were associated with disutility, regimens with shorter hospitalization and less time-intensive infusion were generally perceived as preferable. These utilities may be useful in cost-utility models comparing the value of AML treatments.

Outcomes of Intermediate Risk Karyotype Acute Myeloid Leukemia in First Remission Undergoing Autologous Stem Cell Transplantation Compared With Allogeneic Stem Cell Transplantation and Chemotherapy Consolidation: A Retrospective, Propensity-score Adjusted Analysis.

INTRODUCTION: Optimal post-remission therapy (PRT) for intermediate risk acute myeloid leukemia remains an area of ongoing research. We aimed to retrospectively compare outcomes following autologous stem cell transplantation (autoSCT) with allogeneic SCT (alloSCT) and consolidation chemotherapy (CMT) in patients with intermediate-risk karyotype AML in first complete remission. PATIENTS AND METHODS: We compared overall survival (OS) and leukemia-free survival (LFS) using propensity score (PS)-adjusted analysis of patients receiving PRT with autoSCT, matched sibling (MSD) alloSCT, unrelated/mismatch (UD/MM) alloSCT, and CMT. We included patients diagnosed between 1984 and 2003 (period of autoSCT at our center) in CR1 following induction CMT and received at least 2 consolidative cycles. RESULTS: We identified 190 patients (62 MSD-alloSCT, 18 UD/MM-alloSCT, 30 autoSCT, and 80 CMT). Baseline characteristics were used for PS calculation and were well-balanced after weight adjustment. The median follow-up for patients surviving beyond 1 year was 8.7 years. We excluded 55 patients based on PS calculation. Adjusted multivariate hazard ratio (HR), 95% confidence interval (CI) and P-value for OS, considering CMT as reference, were: MSD-alloSCT (HR, 0.4; 95% CI, 0.2-0.8; P = .009), UD/MM-alloSCT (HR, 1.5; 95% CI, 0.6-3.9; P = .363), and autoSCT (HR, 1.2; 95% CI, 0.5-3.1; P = .666), respectively. Adjusted multivariate HR, 95% CI and P-value for LFS were MSD-alloSCT (HR, 0.3; 95% CI, 0.2-0.6; P < .001), UD/MM-alloSCT (HR, 1.1; 95% CI, 0.4-2.7; P = .854), and autoSCT (HR, 0.8; 95% CI, 0.3-2.2; P = .697), respectively. CONCLUSION: Patients with intermediate risk-karyotype acute myeloid leukemia who underwent MSD-alloSCT in first complete remission had the best outcomes. There were no survival differences between autoSCT, UD/MM-alloSCT, and CMT. Further study incorporating molecular changes and minimal residual disease status is warranted to select appropriate patients for autoSCT.

CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia.

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Excellent real-world outcomes of adults with Burkitt lymphoma treated with CODOX-M/IVAC plus or minus rituximab.

Treatment of Burkitt lymphoma (BL) with intensive, multi-agent chemotherapy with aggressive central nervous system (CNS) prophylaxis results in high cure rates, although no regimen is standard of care. We examined population-based survival outcomes of adults with BL treated with a modified combination of cyclophosphamide, vincristine, doxorubicin, prednisone and systemic high-dose methotrexate (MTX) (CODOX-M) with IVAC (ifosfamide, mesna, etoposide, cytarabine and intrathecal MTX) (CODOX-M/IVAC) ± rituximab over a 15-year period in British Columbia. For the 81 patients identified (including 8 with CNS involvement and 18 with human immunodeficiency virus-associated BL), 5-year progression-free survival (PFS) and overall survival (OS) were 75% [95% confidence interval (CI): 63-83%] and 77% (95% CI: 66-85%), respectively, with no treatment-related deaths. Those who completed the regimen per protocol (n = 38) had significantly improved 5-year PFS 86% (P = 0·04) and OS 92% (P = 0·008), as did those under 60 years with 5-year PFS 82% (P = 0·005) and OS 86% (P = 0·002), which remained significant in multivariate analysis [PFS: hazard ratio (HR) 3·36, P = 0·018; OS HR 4·03, P = 0·012]. Incorporation of high-dose systemic methotrexate also significantly affected multivariate survival outcomes (OS HR 0·28, P = 0·025). Stem cell transplant in first remission had no effect on OS or PFS. This large, real-world analysis of BL patients treated with CODOX-M/IVAC ± rituximab demonstrates excellent survival outcomes comparable to clinical trials. These results help to serve as a benchmark when comparing curative therapies for BL patients as novel regimens are incorporated into clinical practice.

Improving Revised International Prognostic Scoring System Pre-Allogeneic Stem Cell Transplantation Does Not Translate Into Better Post-Transplantation Outcomes for Patients with Myelodysplastic Syndromes: A Single-Center Experience.

The natural history of patients with myelodysplastic syndromes (MDS) is variable. The Revised International Prognostic Score (IPSS-R) is commonly used in practice to predict outcomes in patients with MDS at both diagnosis and before hematopoietic stem cell transplantation (HSCT). However, the effect of change in the IPSS-R before allogeneic HSCT with chemotherapy or hypomethylating agents on post-transplantation outcomes is currently unknown. We assessed whether improvement in IPSS-R prognostic score pre-HSCT would result in improvement in clinical outcomes post-HSCT. Secondary goals included studying the effect of prognostic factors on post-transplantation survival. All patients with MDS who underwent allogeneic HSCT at the Leukemia/BMT Program of British Columbia between February 1997 and April 2013 were included. Pertinent information was reviewed from the program database. IPSS-R was calculated based on data from the time of MDS diagnosis and before HSCT. Outcomes of patients who had improved IPSS-R pre-HSCT were compared with those with stable or worse IPSS-R. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method, with P values determined using the log-rank test. Hazard ratios were calculated using multivariable Cox proportional hazards regression models to study the effects of the prognostic variables on OS and EFS. A total of 138 consecutive patients were included. IPSS-R improved in 62 of these patients (45%), worsened in 23 (17%), remained stable in 41 (30%), and was unknown in 12 (9%). OS was not statistically different across the improved, worsened, and stable groups (30% versus 22% versus 40%, respectively; P = .63). The cumulative incidences of relapse and nonrelapse mortality at 5 years were 28.4% (95% confidence interval [CI], 21.1 to 36.1) and 31.6% (95% CI, 23.8 to 39.7), respectively. The rate of relapse was 23% in patients with <5% blasts at the time of HSCT, 69% in those with 5% to 20% blasts, and 66% in those with >20% blasts (P = .0004). In the entire cohort OS was 34% and EFS was 33%. There was no significant difference in outcomes between patients who received myeloablative conditioning and those who received nonmyeloablative conditioning before HSCT (OS, 34% and 39%, respectively; P = .63 and EFS, 34% and 32%, respectively; P = .86). OS was not statistically different among patients with improved, worsened, or stable IPSS-R. On multivariate analysis, only 3 factors were associated with OS: cytogenetic risk group at diagnosis, blast count at transplantation, and the presence or absence of chronic graft-versus-host disease. Improving IPSS-R before HSCT does not translate into better survival outcomes. Blast count pretransplantation was highly predictive of post-transplantation outcomes.

Comparison of a pediatric-inspired treatment protocol versus standard-intensity chemotherapy for young adults with standard-risk BCR-ABL negative acute lymphoblastic leukemia.

We investigated the utility of a pediatric-inspired protocol in adults aged 18-40 years with standard-risk BCR-ABL negative acute lymphoblastic leukemia (ALL). Retrospective outcomes of 25 patients treated with a pediatric protocol between 2008 and 2014 were compared with 22 similarly aged patients treated with an adult protocol between 2003 and 2008. Twenty-five (100%) and 19 (86%) patients achieved complete remission, respectively. At median follow-up of 36.8 months, 3-year event-free survival was increased in patients on the pediatric protocol at 80% versus 45% (p = .019). There was a trend toward improved overall survival at 80% versus 59% (p = .12). Treatment-related toxicity was not increased despite the increased treatment intensity. Patients with BCR and/or ABL copy number variation demonstrated comparatively poorer outcomes in both cohorts. In our experience with this cohort of patients, pediatric-based protocols are safe and effective, justifying their use in younger adults with ALL.

Dielectrophoretic Microfluidic Chip Enables Single-Cell Measurements for Multidrug Resistance in Heterogeneous Acute Myeloid Leukemia Patient Samples.

The front-line treatment for adult acute myeloid leukemia (AML) is anthracycline-based combination chemotherapy. However, treatment outcomes remain suboptimal with relapses frequently observed. Among the mechanisms of treatment failure is multidrug resistance (MDR) mediated by the ABCB1, ABCC1, and ABCG2 drug-efflux transporters. Although genetic and phenotypic heterogeneity between leukemic blast cells is a well-recognized phenomenon, there remains minimal data on differences in MDR activity at the individual cell level. Specifically, functional assays that can distinguish the variability in MDR activity between individual leukemic blasts are lacking. Here, we outline a new dielectrophoretic (DEP) chip-based assay. This assay permits measurement of drug accumulation in single cells, termed same-single-cell analysis in the accumulation mode (SASCA-A). Initially, the assay was optimized in pretherapy samples from 20 adults with AML whose leukemic blasts had MDR activity against the anthracyline daunorubicin (DNR) tested using multiple MDR inhibitors. Parameters tested were initial drug accumulation, time to achieve signal saturation, fold-increase of DNR accumulation with MDR inhibition, ease of cell trapping, and ease of maintaining the trapped cells stationary. This enabled categorization into leukemic blast cells with MDR activity (MDR(+)) and leukemic blast cells without MDR activity (MDR(-ve)). Leukemic blasts could also be distinguished from benign white blood cells (notably these also lacked MDR activity). MDR(-ve) blasts were observed to be enriched in samples taken from patients who went on to enter complete remission (CR), whereas MDR(+) blasts were frequently observed in patients who failed to achieve CR following front-line chemotherapy. However, pronounced variability in functional MDR activity between leukemic blasts was observed, with MDR(+) cells not infrequently seen in some patients that went on to achieve CR. Next, we tested MDR activity in two paired AML patient samples. Pretherapy samples taken from patients that achieved CR to front-line chemotherapy were compared with samples taken at time of subsequent relapse. MDR(+) cells were frequently observed in leukemic blast cells in both pretherapy and relapsed samples, consistent with MDR as a mechanism of relapse in these patients. We demonstrate the ability of a new DEP microfluidic chip-based assay to identify heterogeneity in MDR activity in leukemic blasts. The test provides a platform for future studies to characterize the mechanistic basis for heterogeneity in MDR activity at the individual cell level.

Economic impact of genomic diagnostics for intermediate-risk acute myeloid leukaemia.

Acute Myeloid Leukaemia (AML) is a rare but serious group of diseases that require critical decision-making for curative treatment. Over the past decade, scientific discovery has revealed dozens of prognostic gene mutations for AML while sequencing costs have plummeted. In this study, we compared the cost-effectiveness of multigene integrative analysis (genomic analysis) with the standard molecular testing currently used for diagnosis of intermediate-risk AML. We used a decision analytic model with data for costs and outcomes from British Columbia, Canada, to assess the long-term (10-year) economic impacts. Our results suggest that genomic analysis would result in a 26% increase in the use of first-remission allogeneic stem cell transplantation. The resulting treatment decisions and downstream effects would come at an additional cost of $12 556 [2013 Canadian dollars (CAD)] per person and the incremental cost-effectiveness ratio would be $49 493 per quality-adjusted life-year gained. Cost-effectiveness was dependent on quality of life during the long-term (5-10) years of survival, relapse rates following first-remission chemotherapy and the upfront cost of transplantation. Non-relapse mortality rates, short-term quality of life and the cost of genomic sequencing had only minor impacts. Further research on post-remission outcomes can lead to improvements in the cost-effectiveness of curative treatments for AML.

An Integrated Analysis of Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables the Discovery of Predictive Biomarkers.

Many promising new cancer drugs proceed through preclinical testing and early-phase trials only to fail in late-stage clinical testing. Thus, improved models that better predict survival outcomes and enable the development of biomarkers are needed to identify patients most likely to respond to and benefit from therapy. Here, we describe a comprehensive approach in which we incorporated biobanking, xenografting, and multiplexed phospho-flow (PF) cytometric profiling to study drug response and identify predictive biomarkers in acute myeloid leukemia (AML) patients. To test the efficacy of our approach, we evaluated the investigational JAK2 inhibitor fedratinib (FED) in 64 patient samples. FED robustly reduced leukemia in mouse xenograft models in 59% of cases and was also effective in limiting the protumorigenic activity of leukemia stem cells as shown by serial transplantation assays. In parallel, PF profiling identified FED-mediated reduction in phospho-STAT5 (pSTAT5) levels as a predictive biomarker of in vivo drug response with high specificity (92%) and strong positive predictive value (93%). Unexpectedly, another JAK inhibitor, ruxolitinib (RUX), was ineffective in 8 of 10 FED-responsive samples. Notably, this outcome could be predicted by the status of pSTAT5 signaling, which was unaffected by RUX treatment. Consistent with this observed discrepancy, PF analysis revealed that FED exerted its effects through multiple JAK2-independent mechanisms. Collectively, this work establishes an integrated approach for testing novel anticancer agents that captures the inherent variability of response caused by disease heterogeneity and in parallel, facilitates the identification of predictive biomarkers that can help stratify patients into appropriate clinical trials.

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.

BACKGROUND: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. METHODS: This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. FINDINGS: Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). INTERPRETATION: Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. FUNDING: Sunesis Pharmaceuticals.

MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia.

A precise understanding of the role of miR-223 in human hematopoiesis and in the pathogenesis of acute myeloid leukemia (AML) is still lacking. By measuring miR-223 expression in blasts from 115 AML patients, we found significantly higher miR-223 levels in patients with favorable prognosis, whereas patients with low miR-223 expression levels were associated with worse outcome. Furthermore, miR-223 was hierarchically expressed in AML subpopulations, with lower expression in leukemic stem cell-containing fractions. Genetic depletion of miR-223 decreased the leukemia initiating cell (LIC) frequency in a myelomonocytic AML mouse model, but it was not mandatory for rapid-onset AML. To relate these observations to physiologic myeloid differentiation, we knocked down or ectopically expressed miR-223 in cord-blood CD34⁺ cells using lentiviral vectors. Although miR-223 knockdown delayed myeloerythroid precursor differentiation in vitro, it increased myeloid progenitors in vivo following serial xenotransplantation. Ectopic miR-223 expression increased erythropoiesis, T lymphopoiesis, and early B lymphopoiesis in vivo. These findings broaden the role of miR-223 as a regulator of the expansion/differentiation equilibrium in hematopoietic stem and progenitor cells where its impact is dose- and differentiation-stage-dependent. This also explains the complex yet minor role of miR-223 in AML, a heterogeneous disease with variable degree of myeloid differentiation.

Identification of prognostic subgroups among acute myeloid leukemia patients with intermediate risk cytogenetics using a flow-cytometry-based assessment of ABC-transporter function.

BACKGROUND: A median fluorescence intensity ratio (MFIR) which measures the efflux of mitoxantrone (an ATP Binding Cassette (ABC) transporter substrate) with and without ABC transporter inhibition correlates with expression of MDR1 and BCRP in acute myeloid leukemia (AML) blasts. METHODS: This study evaluates the impacts of the MFIR on AML outcomes and its interaction with detection of the FLT3 ITD. RESULTS: Among 200 newly diagnosed AML patients, an MFIR of ≥ 1.9 (MFIR+) was detected in 60 (30%) leukemic blast samples. In multivariate analysis, MFIR was an independent prognostic factor for response to induction chemotherapy (OR=7.2, P<0.00001), DFS (HR=2.3, P=0.004) and OS (HR=2.2, P=0.0005) with the main effect being in the 141 patients with intermediate risk cytogenetics. Among intermediate risk cytogenetics patients: MFIR+ outcomes were similar to unfavorable cytogenetic risk (CR, 53% vs. 52%, P=1.0; OS, 11 vs. 9 months, P=0.79). MFIR status can further stratify the prognostic risk for patients with or without FLT3 ITD mutation. CONCLUSIONS: MFIR has value in predicting outcomes including DFS and OS as well as induction failure. This is particularly true for patients with intermediate risk cytogenetics and when combined with assessment for the FLT3-ITD mutation.