Summary Background Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less ...proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Methods In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3–125 mg/m2 in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov , number NCT01261312. Findings Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 41% of 93 patients), pneumonia (27 29% of 93 patients), thrombocytopenia (23 25% of 93 patients), anaemia (23 25% of 93 patients), and sepsis (16 17% of 93 patients). The most common serious adverse events were febrile neutropenia (29 31% of 93 patients), pneumonia (26 28% of 93 patients), and sepsis (16 17% of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m2 daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m2 daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m2 (designated as the biologically effective dose). Interpretation Guadecitabine given subcutaneously at 60 mg/m2 daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m2 daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies. Funding Astex Pharmaceuticals, Stand Up To Cancer.
Summary Background Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more ...potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial. Methods In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov , number NCT01424982. Findings 37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64–90). Grade 3 or more toxic effects included infections during induction (20 54% patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 38% patients), thrombotic events (three 8%), myocardial infarction (three 8%), hypertension (six 16%), skin rash (eight 22%), and pancreatitis (six 16% patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment. Interpretation The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes. Funding ARIAD Pharmaceuticals Inc.
Tyrosine-kinase inhibitors improve overall survival in patients with chronic myeloid leukaemia in chronic phase (CML-CP). Survival compared with the general population by age, response, and type of ...tyrosine-kinase inhibitor is not known. With use of data from trials of tyrosine kinase inhibitors, we compared overall survival in patients with newly diagnosed CML-CP to that of general population.
In this cohort analysis, we included data from patients with CML-CP enrolled in six consecutive or parallel prospective clinical trials of tyrosine-kinase inhibitors at a single institution from July 30, 2000, to Sept 17, 2012. We analysed data for response and survival with the Kaplan-Meier method. For estimated overall survival in the general population, we obtained data from national vital statistics reports and matched to patients with CML-CP by age, sex, ethnicity, and year at diagnosis. We assessed numbers and causes of death within 1 year of beginning treatment by age group and by response to therapy. We then did univariate analysis and multivariate analysis to investigate factors associated with survival probability.
Our analysis included 483 patients, 271 received imatinib, 105 received nilotinib, and 107 received dasatinib. Most patients were younger than 65 years, and no patients were older than 85 years. Median follow-up was 99·4 months (IQR 44·9-121·6), by which time 53 (11%) patients had died. The most common causes of death were progression to advanced disease stage, including complications of stem-cell transplantation (17 4% patients), secondary malignancies (nine 2% patients), and cardiovascular causes (nine 2% patients). 5-year overall survival in patients with CML-CP decreased in older age categories. For the whole population of patients with CML-CP, 5-year survival was only slightly lower than that of the matched general population (relative survival 94·7% 95% 92·1-97·4). Individuals of all ages with a report of complete cytogenetic response to treatment or deeper within 1 year had a 5-year survival similar to that of the general population.
In the era of treatment with tyrosine-kinase inhibitors, patients diagnosed with CML-CP can expect a 5-year survival that is only slightly lower than that of the general population. With access to tyrosine-kinase inhibitors, most patients with chronic myeloid leukaemia could enjoy a near normal life expectancy.
MD Anderson Cancer Center, National Cancer Institute.
Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib ...as first-line treatment for patients with chronic-phase CML.
We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868.
We enrolled 51 patients. Median follow-up was 20·9 months (IQR 14·9–25·2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3–4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib.
Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting.
MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical.
The standard of care for myelodysplastic syndromes is hypomethylating agents such as azacitidine. However, responses to azacitidine are generally temporary, and outcomes after hypomethylating agent ...failure are dismal. Therefore, the development of more effective treatments is crucial to improve outcomes in patients with myelodysplastic syndromes. We aimed to assess azacitidine and lenalidomide in patients with high-risk myelodysplastic syndromes and acute myeloid leukaemia.
We did this single-arm phase 1/2 study at the University of Texas MD Anderson Cancer Center, TX, USA. Patients of any age were eligible for phase 1 and 2a if they had relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome with bone marrow blasts more than 10%. For phase 2b, eligible participants were previously untreated with myelodysplastic syndrome with an International Prognostic Scoring System (IPSS) score of intermediate-1 or higher with up to 30% blasts. All participants received 75 mg/m(2) azacitidine once a day for days 1-5 for each 28 day cycle. We gave patients oral lenalidomide for 5 or 10 days starting on day 6. We assessed seven lenalidomide doses in a 3 + 3 phase 1 design (n=28). The primary endpoint in phase 1 was the maximum tolerated dose, and the primary endpoint in phase 2 was overall survival. Outcome analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01038635.
Between Dec 30, 2009, and June, 17, 2013, we enrolled 88 patients (28 in phase 1 and 60 in phase 2). One patient unexpectedly died in the phase 1 study at the highest dose level, six more patients were recruited with no further serious adverse events. We recorded no dose-limiting toxic effects, and the maximum tolerated dose of lenalidomide in combination with azacitidine in patients with acute myeloid leukaemia and myelodysplastic syndrome was initially established at 50 mg per day for 10 days. In the first 20 patients in phase 2, we noted a high rate of myelosuppression and myelosuppression-related toxic effects; therefore, we amended the lenalidomide dose to 25 mg per day for 5 days. We also adjusted the inclusion criteria to include patients with less than 30% blasts to focus mainly on patients with myelodysplastic syndromes. Median overall survival was 75 weeks (IQR 25-not reached) for the 40 patients in phase 2b. The most common grade 3-4 adverse events overall were neutropenic fever (n=27) and pneumonia (n=18).
We have identified a safe and active sequential treatment combination of azacitidine and lenalidomide for patient with myelodysplastic syndrome and have preliminary evidence that this dose is also safe for patients with acute myeloid leukaemia.
MD Anderson Cancer Center and Celgene.
Abstract
Background
The majority of studies that provide insights into the influence of the microbiome on the health of hematologic malignancy patients have concentrated on the transplant setting. ...Here, we sought to assess the predictive capacity of the gastrointestinal microbiome and its relationship to infectious outcomes in patients with acute myeloid leukemia (AML).
Methods
16s rRNA-based analysis was performed on oral swabs and stool samples obtained biweekly from baseline until neutrophil recovery following induction chemotherapy (IC) in 97 AML patients. Microbiome characteristics were correlated with clinical outcomes both during and after IC completion.
Results
At the start of IC, higher stool Shannon diversity (hazard ratio HR, 0.36; 95% confidence interval CI, .18–.74) and higher relative abundance of Porphyromonadaceae (HR, 0.36; 95% CI, .18–.73) were associated with increased probability of remaining infection-free during neutropenia. A baseline stool Shannon diversity cutoff of <2 had optimal operating characteristics for predicting infectious complications during neutropenia. Although 56 patients received therapy >72 hours with a carbapenem, none of the patients had an infection with an extended spectrum β-lactamase–producing organism. Patients who received carbapenems for >72 hours had significantly lower α-diversity at neutrophil recovery (P = .001) and were approximately 4 times more likely to have infection in the 90 days following neutrophil recovery (HR, 4.55; 95% CI, 1.73–11.93).
Conclusions
Our results suggest that gut microbiome evaluation could assist with infectious risk stratification and that improved targeting of antibiotic administration during IC could decrease subsequent infectious complications in AML patients.
Baseline microbiome diversity is a strong independent predictor of infection during acute myeloid leukemia induction chemotherapy (IC) among clinical and microbiome covariates. Higher baseline levels of Porphyromonadaceae appear protective against infection, while carbapenem use is associated with consequences to the microbiome and infection susceptibility post-IC.
Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Our ...aim was to evaluate the response rate, toxicities, and outcome of adults with newly diagnosed ALL who received liposomal vincristine, rather than regular vincristine in combination with intensive chemotherapy (Hyper‐CMAD). In a single‐center, phase 2 study, patients ≥18 years with newly‐diagnosed B‐cell ALL were eligible to receive hyper‐CMAD alternating with high‐dose methotrexate and cytarabine. Rituximab was administered in CD20 positive ALL. Tyrosine kinase inhibitors (imatinib or dasatinib) were added in Philadelphia chromosome‐positive (Ph‐positive) ALL. Thirty‐one patients were enrolled, median follow‐up of 59 months (0.3‐70). Thirteen patients (42%) had CD20 positive ALL, and 21 (68%) had Ph‐positive ALL. Thirty (97%) achieved complete remission (CR). All 26 patients with abnormal karyotype achieved complete cytogenetic response (CCyR), and 27/30 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable Ph‐positive ALL patients, major molecular response (MMR) was achieved in 19 patients (95%); complete molecular response (CMR) in 14 (70%). Grade 3/4 peripheral neuropathy was observed in five (16%) with all grade peripheral neuropathy in 21 (68%). With a median follow‐up of 59 months, 21 (68%) patients are alive. The 5‐year CR duration and survival rates were 73% and 61%, respectively. Ten (32%) patients died: one, sepsis on C1D10; four, unknown; one, post‐transplant complications; four, relapse. Hyper‐CMAD with liposomal vincristine is safe and demonstrated high response and survival rates in newly diagnosed ALL.
Background: Ponatinib, a third-generation pan-tyrosine kinase inhibitor (TKI), was found to be effective in heavily pretreated patients (pts) with chronic myeloid leukemia (CML). With the ...availability of multiple TKI, these agents are used in different sequences, and there is limited information on the value of various TKI in different lines of therapy. Since ponatinib has been effective in 3rd and subsequent lines of therapy, we performed an analysis of a cohort of pts with CML who received ponatinib as a different line of treatment.
Method: A total of 80 pts with chronic phase of CML and received ponatinib from 2009 to 2018 were analyzed. Only pts who received ponatinib as a second or subsequent line of therapy of CML were included. Major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), molecular response (MR) 4, and MR 4.5 were assessed. Event-free (EFS), transformation-free (TFS), failure-free (FFS) and overall survival (OS) were also analyzed.
Results: Nine pts (11%) received ponatinib as a 2nd line therapy (prior TKI imatinib in 6, dasatinib in 1, and nilotinib in 2 pts); 21 (26%) as a 3rd line, 26 (33%) as a 4th line, and 24 (30%) as a 5th and above line. The median age was over 50 years (Y) in all the groups except for pts who received ponatinib as a 3rd line 38 Y (23-76). Among pts who received ponatinib as 2nd line, 9 (100%) achieved CCyR and MR 4.5; the median time to achieve CCyR and MR 4.5 was 3 and 6.8 months (mo), respectively (Table 1). In pts treated in 3rd line CCyR and MR 4.5 were 67% and 57%, respectively and the median time to response was 4.8 and 19.3 mo, respectively. Of the 26 pts treated in 4th line, 13 (50%) achieved CCyR (median time to CCyR 3 mo) and 7 (27%) achieved MR 4.5 (median time 11.6 mo). In 5th line and above 14 (58%) achieved CCyR (median time 6.4 mo) and 8 (33%) achieved MR 4.5 (median time 12.3 mo) (Figure 1). After a median follow-up of 59.8 months (range, 4.7 to 114.3) for all pts, the median OS was not reached in pts treated in 2nd to 4th line and 81.4 mo in ≥5th line. The median FFS was not reached in 2nd line, and was 45.6, 20.2, and 17.8 mo in 3rd, 4th, and ≥5th line, respectively. The median EFS and TFS was not reached in any line of treatment. The TFS was significantly better in pts who received ponatinib as a 2nd-4th line therapy as compared to ≥5th p=0.0026, HR-55.97 (4.076-768.7) (Figure 2).
Conclusion: Our results suggest that CCyR and MR 4.5 were higher when ponatinib was used in up to 4th line of therapy for resistant CML, and it was particularly effective in 2nd or 3rd line where high rates of MR4.5 can be achieved. These results underscore the efficacy of ponatinib in these settings.
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Sasaki:Otsuka Pharmaceutical: Honoraria. Ravandi:Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau. Kadia:Takeda: Consultancy; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; BMS: Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. DiNardo:Agios: Consultancy; Bayer: Honoraria; Medimmune: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Konopleva:Stemline Therapeutics: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Immunogen: Research Funding. Pemmaraju:stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; samus: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; abbvie: Research Funding. Daver:ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Consultancy; Incyte: Research Funding; Karyopharm: Research Funding; Kiromic: Research Funding; Pfizer: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding; Alexion: Consultancy; ImmunoGen: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding.
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