ABSTRACT
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for chronic myeloid leukaemia (CML), but cardiovascular (CV) risk and exacerbation of underlying risk factors associated with TKIs have become widely debated. Real-world evidence reveals little application of CV risk factor screening or continued monitoring within UK CML management. This consensus paper presents practical recommendations to assist healthcare professionals in conducting CV screening/comorbidity management for patients receiving TKIs. METHODS: We conducted a multidisciplinary panel meeting and two iterative surveys involving 10 CML specialists: five haematologists, two cardio-oncologists, one vascular surgeon, one haemato-oncology pharmacist and one specialist nurse practitioner. RESULTS: The panel recommended that patients commencing second-/third-generation TKIs undergo formal CV risk assessment at baseline, with additional investigations and involvement of cardiologists/vascular surgeons for those with high CV risk. During treatment, patients should undergo CV monitoring, with the nature and frequency of testing dependent on TKI and baseline CV risk. For patients who develop CV adverse events, decision-making around TKI interruption, cessation or change should be multidisciplinary and balance CV and haematological risk. CONCLUSION: The panel anticipates these recommendations will support healthcare professionals in implementing CV risk screening and monitoring, broadly and consistently, and thereby help optimise TKI treatment for CML.
Subject(s)
Antineoplastic Agents , Cardiovascular Diseases , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Humans , Antineoplastic Agents/therapeutic use , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Protein Kinase Inhibitors/adverse effects , Consensus , Risk Factors , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Heart Disease Risk FactorsABSTRACT
The prognosis for younger patients with relapsed acute myeloid leukaemia (AML) is generally dismal. Allogeneic stem cell transplantation is the preferred therapy for these patients. As part of the UK NCRI AML17 trial, daunorubicin/clofarabine (DClo) was compared with fludarabine, cytarabine, granulocyte colony-stimulating factor with idarubicin (FLAG-Ida) in 311 patients designated high-risk following course one of induction therapy, which has previously been reported. We now report the results of the same randomisation in patients who were refractory to two induction courses or subsequently relapsed. A total of 94 relapsed or refractory AML patients, usually less than 60 years of age and with mainly favourable or intermediate-risk cytogenetics, were randomised to receive up to three courses of DClo or FLAG-Ida, with the aim of proceeding to transplant. Complete remission was achieved in 74% of patients with no difference between the arms. Overall, 57% of patients received a transplant with no difference between the arms, likewise overall survival at five years showed no significant difference (21% for DClo vs. 22% for FLAG-Ida). No patient who did not receive a transplant survived beyond 21months. A stratified analysis including the 311 post course 1 high-risk patients who underwent the same randomisation showed a consistent treatment benefit for FLAG-Ida.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Clofarabine , Idarubicin , Leukemia, Myeloid, Acute , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chronic Disease , Clofarabine/therapeutic use , Cytarabine/therapeutic use , Daunorubicin/therapeutic use , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Idarubicin/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , United Kingdom , Vidarabine/adverse effectsABSTRACT
Reduced intensity conditioning (RIC) transplantation is increasingly offered to older patients with acute myeloblastic leukemia. We have previously shown that a RIC allograft, particularly from a sibling donor, is beneficial in intermediate-risk patients aged 35-65 years. We here present analyses from the NCRI AML16 trial extending this experience to older patients aged 60-70 inclusive lacking favorable-risk cytogenetics. Nine hundred thirty-two patients were studied, with RIC transplant in first remission given to 144 (sibling n=52, matched unrelated donor n=92) with a median follow-up for survival from complete remission of 60 months. Comparisons of outcomes of patients transplanted versus those not were carried out using Mantel-Byar analysis. Among the 144 allografted patients, 93 had intermediate-risk cytogenetics, 18 had adverse risk and cytogenetic risk group was unknown for 33. In transplanted patients survival was 37% at 5 years, and while the survival for recipients of grafts from siblings (44%) was better than that for recipients of grafts from matched unrelated donors (34%), this difference was not statistically significant (P=0.2). When comparing RIC versus chemotherapy, survival of patients treated with the former was significantly improved (37% versus 20%, hazard ratio = 0.67 [0.53-0.84]; P<0.001). When stratified by Wheatley risk group into good, standard and poor risk there was consistent benefit for RIC across risk groups. When stratified by minimal residual disease status after course 1, there was consistent benefit for allografting. The benefit for RIC was seen in patients with a FLT3 ITD or NPM1 mutation with no evidence of a differential effect by genotype. We conclude that RIC transplantation is an attractive option for older patients with acute myeloblastic leukemia lacking favorable-risk cytogenetics and, in this study, we could not find a group that did not benefit.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Adult , Aged , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Retrospective Studies , Survival Analysis , Transplantation Conditioning/methodsABSTRACT
OBJECTIVES: To describe the real-world effectiveness and safety of bosutinib in patients with chronic myeloid leukemia (CML). METHODS: This was a multi-center, retrospective, non-interventional chart review study conducted in 10 hospitals in the United Kingdom and the Netherlands. RESULTS: Eighty-seven patients were included. Bosutinib was the third-line tyrosine kinase inhibitor (TKI) in 33 (38%) and fourth-line in 44 (51%) patients. Median treatment duration was 15.6 months. Among 84 patients in chronic phase (CP) at baseline, 26 (31%) switched to bosutinib due to resistance and 57 (68%) due to intolerance to prior TKIs. Cumulative complete cytogenetic and major molecular response rates in CP patients were 67% and 55%, respectively. After a median follow-up of 21.5 months, nine (11%) patients in CP died; estimated overall survival rates at 1 and 2 years postbosutinib initiation were 95% and 91%, respectively. Overall, 33/87 (38%) patients discontinued bosutinib due to either lack of efficacy/disease progression (17%), adverse events (14%), death (2%), or other reasons (5%). Eighty-two (94%) patients experienced ≥1 adverse event possibly related to bosutinib, most commonly diarrhea (52%). CONCLUSIONS: Bosutinib used in routine clinical practice in heavily pretreated patients with CML is an effective treatment for patients in CP and is generally tolerable.
Subject(s)
Antineoplastic Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Quinolines , Aniline Compounds , Antineoplastic Agents/adverse effects , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Netherlands/epidemiology , Nitriles , Protein Kinase Inhibitors/adverse effects , Quinolines/adverse effects , Retrospective StudiesABSTRACT
Older patients with acute myeloid leukaemia (AML) account for nearly half of those with the disease. Because they are perceived to be unfit for, unwilling to receive, or unlikely to benefit from conventional chemotherapy they represent an important unmet need. Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy. We report the only randomised study of low-dose cytosine arabinoside (LDAC) combined with tosedostat (LDAC-T) versus LDAC in untreated older patients not suitable for intensive treatment. A total of 243 patients were randomised 1:1 as part of the 'Pick-a-Winner' LI-1 trial. There was a statistically non-significant increase in the complete remission (CR) rate with the addition of tosedostat, LDAC-T 19% versus LDAC 12% [odds ratio (OR) 0·61, 95% confidence interval (CI) 0·30-1·23; P = 0·17]. For overall response (CR+CR with incomplete recovery of counts), there was little evidence of a benefit to the addition of tosedostat (25% vs. 18%; OR 0·68, 95% CI 0·37-1·27; P = 0·22). However, overall survival (OS) showed no difference (2-year OS 16% vs. 12%, hazard ratio 0·97, 95% CI 0·73-1·28; P = 0·8). Exploratory analyses failed to identify any subgroup benefitting from tosedostat. Despite promising pre-clinical, early non-randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML. International Standard Randomised Controlled Trial Number: ISRCTN40571019.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Cytarabine/therapeutic use , Enzyme Inhibitors/therapeutic use , Glycine/analogs & derivatives , Hydroxamic Acids/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Age Factors , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytarabine/administration & dosage , Cytarabine/adverse effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Female , Glycine/administration & dosage , Glycine/adverse effects , Glycine/therapeutic use , Humans , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/adverse effects , Leukemia, Myeloid, Acute/epidemiology , Male , Middle Aged , Survival AnalysisABSTRACT
Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML.
Subject(s)
Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Disease Management , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Middle Aged , Retrospective Studies , Treatment Outcome , United Kingdom/epidemiologyABSTRACT
Over the past 60 years, haematologists and scientists from the United Kingdom, notably John Goldman and Tessa Holyoake, have punched above their weight in changing chronic myeloid leukaemia (CML) from an incurable and invariably fatal disease for all, to a chronic condition where over 90% have normal life expectancy. As a result, it is now difficult to power a worthwhile phase 3 study for newly diagnosed patients. Nevertheless, important clinical questions remain.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , History, 20th Century , History, 21st Century , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/history , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , United Kingdom/epidemiologyABSTRACT
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an adverse biomarker across many malignancies. Using K562 cells engineered to have high or low CIP2A expression, we show that high CIP2A levels significantly bias cellular energy production towards oxidative phosphorylation (OXPHOS) rather than glycolysis. Mass spectrometric analysis of CIP2A interactors and isobaric tagging for relative and absolute protein quantitation (ITRAQ) experiments identified many associated proteins, several of which co-vary with CIP2A level. Many of these CIP2A associating and co-varying proteins are involved in energy metabolism including OXPHOS, or in 5' AMP-activated protein kinase (AMPK) signalling, and manipulating AMPK activity mimics the effects of low/high CIP2A on OXPHOS. These effects are dependent on the availability of nutrients, driven by metabolic changes caused by CIP2A. CIP2A level did not affect starvation-induced AMPK phosphorylation of Unc-51 autophagy activating kinase 1 (ULK-1) at Ser555, but autophagy activity correlated with an increase in AMPK activity, to suggest that some AMPK processes are uncoupled by CIP2A, likely via its inhibition of protein phosphatase 2A (PP2A). The data demonstrate that AMPK mediates this novel CIP2A effect on energy generation in malignant cells.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Autoantigens/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Neoplasm Proteins/metabolism , Neoplasms/drug therapy , Oxidative Phosphorylation , Signal Transduction/drug effects , AMP-Activated Protein Kinases/genetics , Animals , Autoantigens/genetics , Autophagy-Related Protein-1 Homolog/genetics , Autophagy-Related Protein-1 Homolog/metabolism , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/genetics , K562 Cells , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/pathology , SmegmamorphaABSTRACT
Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.
Subject(s)
Blast Crisis/mortality , Leukemia, Myeloid, Accelerated Phase/mortality , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Blast Crisis/blood , Blast Crisis/diagnosis , Blast Crisis/genetics , Bone Marrow/pathology , Cell Count , Chromosome Aberrations , Europe/epidemiology , Female , Follow-Up Studies , Hemoglobins/analysis , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Accelerated Phase/blood , Leukemia, Myeloid, Accelerated Phase/diagnosis , Leukemia, Myeloid, Accelerated Phase/genetics , Male , Middle Aged , Neoplasm Staging/methods , Neoplastic Stem Cells , Prognosis , Proportional Hazards Models , Registries , Young AdultABSTRACT
As part of the UK NCRI AML17 trial, adult patients with acute myeloid leukemia in remission could be randomized to receive the mammalian target of rapamycin inhibitor everolimus, sequentially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maximum of 84 days between chemotherapy courses. The primary endpoint was relapse-free survival. At 5 years there was no difference in relapse-free survival [29% versus 40%; odds ratio 1.19 (0.9-1.59) P=0.2], cumulative incidence of relapse [60% versus 54%: odds ratio 1.12 (0.82-1.52): P=0.5] or overall survival [45% versus 58%: odds ratio 1.3 (0.94-1.81): P=0.11]. The independent Data Monitoring Committee advised study termination after randomization of 339 of the intended 600 patients because of excess mortality in the everolimus arm without any evidence of beneficial disease control. The delivery of the everolimus dose was variable, but there was no evidence of clinical benefit in patients with adequate dose delivery compared with no treatment. This study suggests that the addition of mammalian target of rapamycin inhibition to chemotherapy provides no benefit.
Subject(s)
Consolidation Chemotherapy , Everolimus/administration & dosage , Leukemia, Myeloid, Acute , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adolescent , Adult , Aged , Disease-Free Survival , Everolimus/adverse effects , Female , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Survival RateSubject(s)
Drug Monitoring/methods , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Molecular Diagnostic Techniques , Protein Kinase Inhibitors/administration & dosage , Clinical Trials as Topic/methods , Dose-Response Relationship, Drug , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Prognosis , Progression-Free Survival , Protein Kinase Inhibitors/adverse effects , Recurrence , Remission Induction , Withholding TreatmentABSTRACT
Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45 mg/m(2), and has been recommended as a standard of care. However, 60 mg/m(2) is widely used and has never been directly compared with 90 mg/m(2). As part of the UK National Cancer Research Institute (NCRI) AML17 trial, 1206 adults with untreated AML or high-risk myelodysplastic syndrome, mostly younger than 60 years of age, were randomized to a first-induction course of chemotherapy, which delivered either 90 mg/m(2) or 60 mg/m(2) on days 1, 3, and 5 combined with cytosine arabinoside. All patients then received a second course that included daunorubicin 50 mg/m(2) on days 1, 3, and 5. There was no overall difference in complete remission rate (73% vs 75%; odds ratio, 1.07 [0.83-1.39]; P = .6) or in any recognized subgroup. The 60-day mortality was increased in the 90 mg/m(2) arm (10% vs 5% (hazard ratio [HR] 1.98 [1.30-3.02]; P = .001), which resulted in no difference in overall 2-year survival (59% vs 60%; HR, 1.16 [0.95-1.43]; P = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Daunorubicin/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Adolescent , Adult , Aged , Antibiotics, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cytarabine/administration & dosage , Cytarabine/adverse effects , Daunorubicin/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Induction Chemotherapy/methods , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Young AdultABSTRACT
The development of new treatments for older patients with acute myeloid leukemia is an active area, but has met with limited success. Vosaroxin, a quinolone-derived intercalating agent has several properties that could prove beneficial. Initial clinical studies showed it to be well-tolerated in older patients with relapsed/refractory disease. In vitro data suggested synergy with cytarabine (Ara-C). To evaluate vosaroxin, we performed 2 randomized comparisons within the "Pick a Winner" program. A total of 104 patients were randomized to vosaroxin vs low-dose Ara-C (LDAC) and 104 to vosaroxin + LDAC vs LDAC. When comparing vosaroxin with LDAC, neither response rate (complete recovery [CR]/complete recovery with incomplete count recovery [CRi], 26% vs 30%; odds ratio [OR], 1.16 (0.49-2.72); P = .7) nor 12-month survival (12% vs 31%; hazard ratio [HR], 1.94 [1.26-3.00]; P = .003) showed benefit for vosaroxin. Likewise, in the vosaroxin + LDAC vs LDAC comparison, neither response rate (CR/CRi, 38% vs 34%; OR, 0.83 [0.37-1.84]; P = .6) nor survival (33% vs 37%; HR, 1.30 [0.81-2.07]; P = .3) was improved. A major reason for this lack of benefit was excess early mortality in the vosaroxin + LDAC arm, most obviously in the second month following randomization. At its first interim analysis, the Data Monitoring and Ethics Committee recommended closure of the vosaroxin-containing trial arms because a clinically relevant benefit was unlikely.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Neoplasm Recurrence, Local/drug therapy , Aged , Aged, 80 and over , Cytarabine/administration & dosage , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Naphthyridines/administration & dosage , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Prospective Studies , Remission Induction , Survival Rate , Thiazoles/administration & dosageABSTRACT
BACKGROUND: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia. METHODS: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805. FINDINGS: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib. INTERPRETATION: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established. FUNDING: ARIAD Pharmaceuticals.
Subject(s)
Drug-Related Side Effects and Adverse Reactions/pathology , Imatinib Mesylate/administration & dosage , Imidazoles/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Pyridazines/administration & dosage , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Drug-Related Side Effects and Adverse Reactions/classification , Female , Fusion Proteins, bcr-abl/genetics , Humans , Imatinib Mesylate/adverse effects , Imidazoles/adverse effects , Kaplan-Meier Estimate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Philadelphia Chromosome/drug effects , Pyridazines/adverse effects , Treatment OutcomeABSTRACT
Up to 30% of adults with acute myeloid leukemia fail to achieve a complete remission after induction chemotherapy - termed primary refractory acute myeloid leukemia. There is no universally agreed definition of primary refractory disease, nor have the optimal treatment modalities been defined. We studied 8907 patients with newly diagnosed acute myeloid leukemia, and examined outcomes in patients with refractory disease defined using differing criteria which have previously been proposed. These included failure to achieve complete remission after one cycle of induction chemotherapy (RES), less than a 50% reduction in blast numbers with >15% residual blasts after one cycle of induction chemotherapy (REF1) and failure to achieve complete remission after two courses of induction chemotherapy (REF2). 5-year overall survival was decreased in patients fulfilling any criteria for refractory disease, compared with patients achieving a complete remission after one cycle of induction chemotherapy: 9% and 8% in patients with REF1 and REF2 versus 40% (P<0.0001). Allogeneic stem cell transplantation improved survival in the REF1 (HR 0.58 (0.46-0.74), P=0.00001) and REF2 (HR 0.55 (0.41-0.74), P=0.0001) cohorts. The utilization of REF1 criteria permits the early identification of patients whose outcome after one course of induction chemotherapy is very poor, and informs a novel definition of primary refractory acute myeloid leukemia. Furthermore, these data demonstrate that allogeneic stem cell transplantation represents an effective therapeutic modality in selected patients with primary refractory acute myeloid leukemia.
Subject(s)
Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/therapy , Patient Selection , Salvage Therapy/methods , Stem Cell Transplantation/methods , Adult , Age Factors , Aged , Allografts , Combined Modality Therapy , Female , Humans , Karyotyping , Leukemia, Myeloid, Acute/drug therapy , Male , Middle Aged , Remission Induction , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony-stimulating factor, G-CSF). Seventy (71.4%) plerixafor-mobilised patients achieved the composite primary endpoint of ≥4 × 10(6) CD34+ cells kg(-1) in ≤2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P < 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient-level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was £12,679 compared with £11,694 for historical controls. However, plerixafor produces an average saving of £3,828 per lymphoma patient but average cost increase by £5,245 per myeloma patient. The present data demonstrate cost-effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434-442, 2016. © 2015 Wiley Periodicals, Inc.
Subject(s)
Hematopoietic Stem Cell Mobilization/methods , Heterocyclic Compounds/therapeutic use , Benzylamines , Cost-Benefit Analysis , Costs and Cost Analysis , Cyclams , Granulocyte Colony-Stimulating Factor/economics , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Mobilization/economics , Heterocyclic Compounds/economics , Historically Controlled Study , Humans , Lymphoma/economics , Lymphoma/therapy , Multiple Myeloma/economics , Multiple Myeloma/therapyABSTRACT
BACKGROUND: Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia. METHODS: In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10â×â10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535. FINDINGS: Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group. INTERPRETATION: ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenicals/therapeutic use , Idarubicin/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Tretinoin/therapeutic use , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Arsenic Trioxide , Arsenicals/adverse effects , Biomarkers, Tumor/genetics , Denmark , Female , Humans , Idarubicin/adverse effects , Intention to Treat Analysis , Kaplan-Meier Estimate , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/mortality , Leukocyte Count , Male , Middle Aged , New Zealand , Oncogene Proteins, Fusion/genetics , Oxides/adverse effects , Quality of Life , Real-Time Polymerase Chain Reaction , Time Factors , Treatment Outcome , Tretinoin/adverse effects , United Kingdom , Young AdultABSTRACT
Myelofibrosis is characterized by splenomegaly and debilitating constitutional symptoms that negatively impact patients' quality of life. ROBUST, a UK, open-label, phase II study, evaluated the safety and efficacy of ruxolitinib in patients with myelofibrosis (N = 48), including intermediate-1 risk patients. The primary composite endpoint was the proportion of patients achieving treatment success [≥ 50% reduction in palpable spleen length and/or a ≥ 50% decrease in Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF TSS)] at 48 weeks. This was the first time that efficacy of ruxolitinib in myelofibrosis has been evaluated based on these criteria and the first time the MF-SAF was used in a population of patients solely from the United Kingdom. Overall, 50% of patients and 57% of intermediate-1 risk patients, achieved treatment success; reductions in spleen length and symptoms were observed in all risk groups. The majority of patients (66.7%) experienced ≥ 50% reductions from baseline in spleen length at any time. Improvements in MF-SAF TSS were seen in 80.0%, 72.7%, and 72.2% of intermediate-1, intermediate-2, and high-risk patients, respectively. Consistent with other studies of ruxolitinib, the most common haematological adverse events were anaemia and thrombocytopenia. Results indicate that most patients with myelofibrosis, including intermediate-1 risk patients, may benefit from ruxolitinib treatment.