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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. [ABSTRACT FROM AUTHOR]

Background: The hedgehog signaling pathway is normally tightly regulated. Mutations in hedgehog pathway components may lead to abnormal activation. Aberrantly activated hedgehog signaling plays a major role in the development of solid and hematological cancer. In recent years, inhibitors have been developed that attenuate hedgehog signaling; 2 have been approved for use in basal cell carcinoma (BCC), while others are under development or in clinical trials. The aim of this review is to provide an overview of known hedgehog inhibitors (HHIs) and their potential for the treatment of hematological cancers and solid tumors beyond BCC.Design: Published literature was searched to identify articles relating to HHIs in noncutaneous cancer. Both preclinical and clinical research articles were included. In addition, relevant clinical trial results were identified from www.clinicaltrials.gov. Information on the pharmacology of HHIs is also included.Results: HHIs show activity in a variety of solid and hematological cancers. In preclinical studies, HHIs demonstrated efficacy in pancreatic cancer, rhabdomyosarcoma, breast cancer, and acute myeloid leukemia (AML). In clinical studies, HHIs showed activity in medulloblastoma, as well as prostate, pancreatic, and hematological cancers. Current clinical trials testing the efficacy of HHIs are underway for prostate, pancreatic, and breast cancers, as well as multiple myeloma and AML.Conclusions: As clinical trial results become available, it will be possible to discern which additional tumor types are suited to HHI mono- or combination therapy with other anticancer agents. The latter strategy may be useful for delaying or overcoming drug resistance. [ABSTRACT FROM AUTHOR]

Attribution of adverse events (AEs) is critical to oncology drug development and the regulatory process. However, processes for determining the causality of AEs are often sub-optimal, unreliable, and inefficient. Thus, we conducted a toxicity-attribution workshop in Silver Springs MD to develop guidance for improving attribution of AEs in oncology clinical trials. Attribution stakeholder experts from regulatory agencies, sponsors and contract research organizations, clinical trial principal investigators, pre-clinical translational scientists, and research staff involved in capturing attribution information participated. We also included patients treated in oncology clinical trials and academic researchers with expertise in attribution. We identified numerous challenges with AE attribution, including the non-informative nature of and burdens associated with the 5-tier system of attribution, increased complexity of trial logistics, costs and time associated with AE attribution data collection, lack of training in attribution for early-career investigators, insufficient baseline assessments, and lack of consistency in the reporting of treatment-related and treatment-emergent AEs in publications and clinical scientific reports. We developed recommendations to improve attribution: we propose transitioning from the present 5-tier system to a 2-3 tier system for attribution, more complete baseline information on patients' clinical status at trial entry, and mechanisms for more rapid sharing of AE information during trials. Oncology societies should develop recommendations and training in attribution of toxicities. We call for further harmonization and synchronization of recommendations regarding causality safety reporting between FDA, EMA and other regulatory agencies. Finally, we suggest that journals maintain or develop standardized requirements for reporting attribution in oncology clinical trials. [ABSTRACT FROM AUTHOR]

The development of BCR :: ABL1 -targeting tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with chronic myeloid leukemia (CML). Although there are some common class-wide side effects, differences in safety profiles between TKIs allow physicians and patients to personalize treatment plans. Treatment selection depends on several factors, such as age, disease risk, comorbidities, and concomitant medications. In second- and later-line settings, response to previous TKIs and mutation analyses should also be used to guide TKI selection. Several strategies can be used to manage adverse events (AEs) that emerge during treatment, e.g., dose reductions/interruptions, monitoring, treatment of AEs, lifestyle modifications, prophylactic therapy, and other supportive care strategies. This review summarizes the safety profiles of the currently approved TKIs and how they impact treatment selection in the first- and later-line settings of CML, particularly regarding patient comorbidities and concomitant medications. Additionally, strategies to manage AEs of special interest with TKIs are reviewed. [ABSTRACT FROM AUTHOR]

Skeletal integrity is sustained by osteoblast-osteoclast interactions, controlled by several signaling pathways that include tyrosine kinases. Imatinib is a tyrosine kinase inhibitor with an extended therapeutic range based on its ability to differentially bind to receptor and nonreceptor tyrosine kinases. In this study, we used digital image analysis to assess changes in trabecular bone surface area within bone marrow biopsy specimens of 34 patients with chronic phase chronic myelogenous leukemia treated with single-agent imatinib. These patients were 25 men and 9 women with a median age of 59 years. We selected representative areas of paired bone marrow biopsy specimens obtained at baseline and within the subsequent 48 months. Computer-assisted analysis was performed to calculate trabecular bone area (TBA) within the sample by using the equation TBA% = sum of trabecular area/total biopsy specimen area. Percentage changes were defined as ?TBA% and were arbitrarily subdivided into marked (N50%), moderate (10%-50%), and mild (b10%). During the study interval, TBA% increased in 24 patients (71%) and decreased in 10 patients (29%). Overall, there was a significant increase in TBA% (P = .02). No correlation was found between changes in trabecular bone area and either clinical or cytogenetic response (P = .25). The results show that imatinib therapy can alter trabecular bone in bone marrow biopsy specimens of chronic myelogenous leukemia patients, most often resulting in an increase in TBA%. [ABSTRACT FROM AUTHOR]

Abstract: Representative samples of crude oils from Cusiana, Cupiagua, Apiay, Castilla and Chichimene fields in the Eastern Llanos Basin of Colombia were analyzed to determine its compound-specific stable carbon isotope composition (CSIA) using gas chromatography–isotopic ratio–mass spectrometry (GC–IRMS). GC–IRMS analyses of n-alkanes allowed differentiating between Cretaceous and Cretaceous/Tertiary oil samples. Cretaceous sourced samples have δ 13C-enriched values than Cretaceous/Tertiary sourced samples; the heavier isotope composition of these samples is due to their major terrigenous organic matter input. Their isotope distribution patterns suggest significant algal and/or bacterial contribution (marine origin). The analysis of the n-alkane fractions by GC–IRMS confirms that the organic matter has marine origin in those samples from Cusiana, Cupiagua and Apiay while Castilla and Chichimene have marine origin with terrestrial inputs. The results were confirmed by gas chromatography/FID and gas chromatography/mass spectrometry (GC/MS). Basic geochemical composition show that samples from Cupiagua/Cusiana fields and Apiay/Castilla/Chichimene fields in the Llanos basin, Colombia present different characteristics reflecting a specific for each depositional environment. [Copyright &y& Elsevier]

Abstract: Gain-of-function D816V point mutation within the kinase domain of the transmembrane receptor KIT is found in the great majority of patients with systemic mastocytosis (SM) and is attractive therapeutic target. Twenty patients with SM were enrolled during 2003–2005 in phase II clinical trial with imatinib mesylate (400mg daily), a KIT inhibitor. Median time on therapy was 9 months (range, 0.5–44+). Only one patient, with D816V KIT mutation-negative FIP1L1-PDGFRα-negative SM-HES, achieved complete remission (now lasting for 44 months). Six other patients reported symptomatic improvement, including two with D816V KIT mutation-positive SM (one reported improvement in diarrhea and the other in fatigue). Other patients had no benefit. Imatinib was relatively well tolerated. Our study confirms that imatinib therapy does not result in appreciable clinical activity in patients with D816V mutation-positive SM, but may result in a significant benefit in occasional patient with D816V mutation-negative SM. [Copyright &y& Elsevier]

Treatment responses to imatinib vary among patients with chronic myeloid leukemia (CML), and definitions of treatment failure and suboptimal response have been published. This article discusses monitoring and treatment of patients with CML after failure of or suboptimal response to imatinib therapy. We reviewed articles listed on PubMed from January 1, 2002, to July 31, 2008, and abstracts from the 2007 Annual Meeting of the American Society of Hematology. Search terms used were chronic myeloid/myelogenous leukemia, imatinib, and BCR-ABL. To enable early recognition of suboptimal responses, patients should be frequently monitored according to published guidelines, including cytogenetic analysis every 6 months until a complete response is achieved and molecular monitoring every 3 months from the start of therapy or monthly if an increasing BCR-ABL1 transcript level is detected. Mutational analysis of BCR-ABL1 may assist with treatment selection. A recent survey suggests that a notable proportion of physicians do not follow treatment guidelines and that broader communication is required. Recent recommendations state that, in patients whose response to Imatinib at 400 mg/d is suboptimal, the dose should be increased, whereas alternative therapies, such as dasatinib, nilotinib, and aliogeneic stem cell transplant (in eligible patients), and imatinib dose escalation should be considered after imatinib failure. However, clinical data are lacking to confirm this sequence of treatments, and introducing alternative therapies at an earlier stage of treatment, for example, after a suboptimal response, may produce better long-term outcomes in a higher proportion of patients. Patient and disease characteristics should be carefully considered to optimize treatment strategy for CML. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) has become a model in research and management among malignant disorders. Since the discovery of the presence of a unique and constant chromosomal abnormality slightly more than 40 years ago, substantial progress has been made in the understanding of the biology of the disease. This progress has translated into significant improvement in the long-term prognosis of patients with this disease. This change came first with the use of stem cell transplantation and interferon alfa, but recently it has opened the era of molecularly targeted therapies. Imatinib, a potent and selective tyrosine kinase inhibitor, may be the best example of our attempts to identify molecular abnormalities and develop drugs directed specifically at them. Furthermore, the understanding of at least some of the mechanisms of resistance to imatinib has led to rapid development of new agents that may overcome this resistance. The outlook today for patients with CML is much brighter than just a few years ago. It is our hope that this fascinating journey in CML can be replicated in other malignancies. In this article, we review our current understanding of this disease. [ABSTRACT FROM AUTHOR]

As fludarabine, topotecan and cytarabine (ara-C) are effective in acute myeloid leukemia (AML), a pilot study of these three agents combined (FTA) was conducted. FTA consisted of topotecan 1.25 mg/m2 by CIV days 1–5, fludarabine 15 mg/m2 and ara-C 0.5 g/m2 IV, BID, on days 2–6. Seventeen patients (6 primary resistant, 11 relapsed) with AML received 33 courses of FTA. Six patients (35%) achieved complete remission. Seven patients (41%) developed grade 3 or 4 diarrhea. FTA was effective and warrants further study in patients with refractory AML. [Copyright &y& Elsevier]

Cancer patients are at increased risk for pulmonary arterial hypertension (PAH) due to the disease itself, chemo- or radiation therapy, pulmonary embolism, or comorbidities. Several tyrosine kinase inhibitors (TKIs), which are increasingly used in the treatment of various cancers, have been linked with PAH. We aimed to describe the incidence of PAH triggered or worsened by tyrosine kinase inhibitors (TKIs) in patients with chronic myelogenous leukemia (CML). In this retrospective study, the medical records of all patients with CML who received first line treatment with imatinib, dasatinib, or nilotinib for ≥3 months at a large tertiary cancer center from 2000 to 2017 were reviewed. PAH was defined as a right ventricular systolic pressure >30 mmHg on transthoracic echocardiogram. Patients with PAH were categorized in 3 groups based on the TKI agent used. Descriptive statistics were used for analysis. We identified 632 patients who were treated with TKIs for ≥3 months at our institution: 241 (38.1%) dasatinib, 105 (16.6%) nilotinib, 286 (45.3%) imatinib. New or worsened PAH was identified in 83 (13.1%) cases. In the dasatinib PAH group (n=75, 90.4% of all PAH), mean age was 54.95 years and there were 45 (60%) women. In the nilotinib PAH group (n=3, 6% of all PAH), mean age was 69 years and there was 1 (33%) woman. In the imatinib PAH group (n=5, 3.6% of all PAH), mean age was 49.6 years and there were 3 (60%) women. Patients treated with TKIs, especially dasatinib, may develop PAH while the incidence of PAH with nilotinib and imatinib appears to be low. Further research is warranted to cover the gap of screening guidelines, which challenges the detection of CML patients treated with TKIs who develop PAH. As comparable outcomes are reported with first line therapy, in patients at risk for PAH, clinicians can opt for the therapy with decreased association with the syndrome. [ABSTRACT FROM AUTHOR]

Introduction CPX-351 (Vyxeos®), a dual-drug liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved by the FDA and EMA for adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study, CPX-351 significantly improved median overall survival (OS; 9.56 vs 5.95 mo; HR = 0.69 [95% CI: 0.52-0.90]; 1-sided P = 0.003) and event-free survival (EFS; 2.53 vs 1.31 mo; HR = 0.74 [95% CI: 0.58-0.96]; 2-sided P = 0.021), and produced a higher rate of complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CR+CRi; 47.7% vs 33.3%; 2-sided P = 0.016) vs 7+3 in patients (pts) aged 60-75 y with newly diagnosed high-risk/sAML. The higher CR+CRi rate may contribute to a higher rate of HCT, which is a potentially curative therapy that can impact long-term survival. Objective This exploratory analysis used a time-dependent proportional hazards model to assess the impact of CPX-351 vs 7+3 on survival independent of HCT status. Methods Pts could receive up to 2 induction cycles of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving CR or CRi could receive up to 2 consolidation cycles with CPX-351 (65 units/m2 [C 65 mg/m2 + D 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). HCT was performed at the physician's discretion. Results Baseline characteristics were balanced between arms. The HCT rate was 34.0% (n = 52) with CPX-351 and 25.0% (n = 39) with 7+3. Median time to HCT was 114.5 d with CPX-351 and 113.0 d with 7+3. Median OS landmarked from the time of HCT was significantly improved with CPX-351 vs 7+3 (not reached vs 10.25 mo; HR = 0.46 [95% CI: 0.24-0.89]). When HCT was treated as a time-dependent covariate, the HRs favored CPX-351 vs 7+3 for OS and EFS (Table), suggesting CPX-351 may be associated with prolonged OS and EFS independent of HCT. The safety profile of CPX-351 was generally consistent with that of 7+3. Early mortality rates with CPX-351 and 7+3, respectively, were 5.9% and 10.6% at Day 30 and 13.7% and 21.2% at Day 60. Conclusions CPX-351 was associated with significantly longer median OS and EFS and higher rates of CR+CRi and HCT vs 7+3 in older pts with newly diagnosed high-risk/sAML. Exploratory analyses suggest CPX-351 prolonged OS and EFS independent of HCT. [ABSTRACT FROM AUTHOR]

In QuANTUM-R, the once-daily, oral, highly potent and selective FLT3 inhibitor Q improved clinical benefit vs SC (median overall survival [mOS], 6.2 vs 4.7 mo [HR, 0.76 (95% CI, 0.58-0.98); P =.02]) in R/R FLT3 -ITD AML (NCT02039726). Before randomization, 25% (Q) and 23% (SC) of pts had 1 prior HSCT. To describe post hoc analyses in pts who underwent subsequent HSCT during QuANTUM-R. Pts with FLT3 -ITD R/R AML received Q (60 mg [30-mg lead-in]) or SC. Pts in the Q arm could resume Q 30-100 d after HSCT. Decisions to proceed to HSCT and resume Q after HSCT were made per investigator discretion/institutional policy. Of 367 randomized pts, 85 in the Q arm underwent any subsequent HSCT (allogeneic HSCT [allo-HSCT], 84 [6 with and 78 w/o additional AML therapy]; autologous HSCT, 1), and 19 in the SC arm underwent any HSCT (5 with and 14 w/o additional AML therapy]). Q + SC pooled data showed a longer mOS (95% CI) in 104 pts with any HSCT vs 263 w/o (12.2 [10.0-24.1] vs 4.4 [4.1-4.9] mo; P <.0001; Fig 1); 1-year OS rates were 50% vs 13%. Among pts preselected for low-intensity therapy, 13/57 in the Q arm and 0/29 in the SC arm underwent any HSCT. Q + SC pooled data also showed a longer mOS (95% CI) in pts with a composite complete remission (CRc) as last recorded response before allo-HSCT vs pts w/o CRc (20.1 [11.7-NA] vs 8.8 [7.0-11.4] mo). Regardless of treatment, mOS was longer with any HSCT vs w/o (Q, 11.9 [10.2-25.1] vs 4.5 [4.1-5.4] mo; SC, 12.7 [6.1-NA] vs 4.0 [2.7-5.0] mo); respective 1-year OS rates were 50% vs 13% and 51% vs 12%. In the Q arm, mOS (95% CI) was longer in pts with a best response of CRc who resumed Q after allo-HSCT (27.1 [18.2-NA] mo) vs pts not resuming Q (5.4 [4.7-11.4] mo; Fig 2). In 48 pts (62%) in the Q arm resuming Q after allo-HSCT, median time from allo-HSCT to Q resumption was 65 d (range, 30-106 d). Four pts (5%) in the Q arm died < 30 d after allo-HSCT. As of 2/22/2018, 46/78 pts in the Q arm (59%) and 9/14 pts in the SC arm (64%) with allo-HSCT w/o additional AML therapy died, mostly due to AML progression (Q, 31 [40%]; SC, 7 [50%]). The frequency of treatment-emergent adverse events (TEAEs) and TEAEs of interest was similar in pts resuming Q after allo-HSCT and in the overall Q population. Independent of HSCT, Q improved survival vs SC in pts with FLT3 -ITD R/R AML in QuANTUM-R. Q + SC pooled analyses showed longer survival in pts with HSCT vs pts w/o and in pts with CRc before allo-HSCT. Survival in transplanted pts was similar in both arms, indicating that HSCT-eligible pts received transplants appropriately, and the higher HSCT rate in the Q arm was beneficial. In pts preselected for low-intensity SC at study entry, 13 were able to undergo HSCT after Q treatment. Q resumption after HSCT was associated with better survival outcomes and was tolerable. These data illustrate the value of using Q to target the FLT3 -ITD mutation as a part of the overall treatment sequence in pts with FLT3 -ITD R/R AML. [ABSTRACT FROM AUTHOR]

Background FLT3-ITD mutations occur in about 25% of patients (pts) with acute myeloid leukemia (AML) and are associated with poor outcomes. Pts with relapsed/refractory (R/R) FLT3-ITD AML have worse prognosis and high unmet medical need. Quizartinib (Q) is a potent and selective FLT3i with promising activity and a manageable safety profile. QuANTUM-R was a global, phase 3, randomized trial of Q vs chemotherapy (SC) in pts with R/R FLT3-ITD AML (NCT02039726). Methods Pts with R/R FLT3-ITD AML w/wo hematopoietic stem cell transplant (HSCT) were randomized to receive Q or a preselected investigator choice SC: low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and G-CSF with idarubicin (FLAG-IDA). Prior midostaurin was allowed. Pts receiving HSCT after Q could resume Q after HSCT. Primary and secondary endpoints were overall survival (OS) and event-free survival (EFS), respectively. Exploratory endpoints included response rate, time to and duration of response, and transplant rate. Results 367 pts were randomized; 245 to Q and 122 to SC. Median follow-up was 23.5 mo. OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; P=.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; P=.1071); median EFS was 1.4 (95% CI, 0.0-1.9) vs 0.9 (95% CI, 0.4-1.3) mo, respectively. Sensitivity analyses and OS subgroup analyses supported Q vs SC. Composite complete response (CRc) was 48% and 27% in Q and SC arms, respectively. Transplant rate was 32% (Q) and 12% (SC). Median time to first CRc was 4.9 wk for Q. The most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Conclusion OS benefit was observed with single-agent Q vs SC in pts with R/R FLT3-ITD AML with a favorable Q safety profile, providing evidence of meaningful clinical benefit in pts with limited treatment options. [ABSTRACT FROM AUTHOR]