Routine management, healthcare resource use and patient and carer-reported outcomes of patients with transfusion-dependent ß-thalassaemia in the United Kingdom: A mixed methods observational study.

Objectives: We evaluated routine healthcare management, clinical status and patient- and carer-reported outcomes in UK paediatric and adult patients with transfusion-dependent ß-thalassaemia (TDT). Methods: A multi-centre, observational mixed-methodology study evaluated 165 patients (50% male; median age 24.1 [interquartile range (IQR)] 11.8-37.2] years) from nine UK centres. Results: Patients had a mean of 13.7 (standard deviation [SD] ±3.2) transfusion episodes/year (mean retrospective observation period 4.7 [±0.7] years). The median (IQR) for iron overload parameters at the last assessment during the observation period were: serum ferritin (n = 165) 1961.0 (1090.0-3003.0) µg/L (38% > 2500 µg/L); R2 liver iron (n = 119) 5.4 (2.9-11.6) mg/g (16% ≥15 mg/g); T2* cardiac iron (n = 132) 30.3 (22.0-37.1) ms (10% < 10 ms). All patients received ≥1 iron chelator during the observation period; 21% received combination therapy. Patients had a mean of 7.8 (±8.1) non-transfusion-related hospital attendances or admissions/year. Adult patients' mean EQ-5D utility score was 0.69 (±0.33; n = 94 [≥16 years]) and mean Transfusion-dependent quality of life score was 58.6 (±18.4; n = 94 [≥18 years]). For Work Productivity and Activity impairment, mean activity impairment for patients ≥18 years (n = 88) was 48% (±32%) and for carers (n = 29) was 28% (±23%). Conclusions: TDT presents significant burden on patients, carers and healthcare resources.

Defining the Optimal Total Number of Chemotherapy Courses in Younger Patients With Acute Myeloid Leukemia: A Comparison of Three Versus Four Courses.

PURPOSE: The optimum number of treatment courses for younger patients with acute myeloid leukemia (AML) is uncertain. The United Kingdom National Cancer Research Institute AML17 trial randomly assigned patients who were not high risk to a total of three versus four courses. PATIENTS AND METHODS: Patients received two induction courses based on daunorubicin and cytarabine (Ara-C), usually with gemtuzumab ozogamicin. Following remission, 1,017 patients were randomly assigned to a third course, MACE (amsacrine, Ara-C, and etoposide), plus a fourth course of MidAc (mitoxantrone and Ara-C) and following an amendment to one or two courses of high-dose Ara-C. Primary end points were cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS). Outcomes were correlated with patient characteristics, mutations, cytogenetics, induction treatments, and measurable residual disease (MRD) postinduction. RESULTS: In logrank analyses, CIR and RFS at 5 years were improved in recipients of four courses (50% v 58%: hazard ratio [HR] 0.81 [0.69-0.97], P = .02 and 43% v 36%: HR 0.83 [0.71-0.98], P = .03, respectively). While OS was not significantly better (63% v 57%: HR 0.84 [0.69-1.03], P = .09), the noninferiority of three courses to four courses was not established. The impact on relapse was only significant when the fourth course was Ara-C. In exploratory analyses, although MRD impacted survival, a fourth course had no effect in either MRD-positive or MRD-negative patients. A fourth course was beneficial in patients who lacked a mutation of FLT3 or NPM1, had < 3 mutations in other genes, or had a presenting WBC of < 10 × 109 L-1. CONCLUSION: Although a fourth course of high-dose Ara-C reduced CIR and improved RFS, it did not result in a significant OS benefit. Subsets including those with favorable cytogenetics, those lacking a mutation of FLT3 or NPM1, or those with < 3 other mutations may derive survival benefit.

Reliability of a Novel Hematological Malignancy Specific Patient-Reported Outcome Measure: HM-PRO.

BACKGROUND: Patients' experience of symptoms often goes undetected during consultation in an outpatient clinic, and the use of a patient-reported outcome measure (PRO) in such a setting could be useful to aid treatment decision-making. A new PRO measure, the HM-PRO (Hematological Malignancy Specific Patient-Reported Outcome Measure) has been recently developed to evaluate hematological malignancy (HM) patients' health-related quality of life (HRQoL) and their symptom experience in daily clinical practice as well as in research. The objectives of the study were to assess: the internal consistency of the scores for Part A (impact) and its four domains (physical behavior; social well-being; emotional behavior; and eating and drinking habits) and Part B (signs and symptoms); and the test-retest reliability of the individual items of the newly developed hematological malignancy specific composite measure, the HM-PRO. METHODS: This was a prospective longitudinal observational study where 150 patients with different HMs and different stage of disease (male n = 98 (65.3%); mean age 64.9 ± 14.4 years, range 17.9-89.2 years; mean time since diagnosis 3.7 ± 4.9 years, range 0.04-25.8 years) completed the HM-PRO at baseline (assessment 1 at t1) and after 7 days (assessment 2 at t2). Data analysis was performed using IBMSPSS 23 statistical software. RESULTS: The Cronbach's alpha estimates of the HM-PRO for both assessment points (t1 and t2) were above 0.9 for Part A, and above 0.8 for Part B, showing strong stability of the measurement. The level of agreement for the reproducibility between the two assessments, using intra-class correlation coefficients (ICC), was very strong with Part A: ICC = 0.93 (95% CI = 0.90-0.95), and Part B: ICC = 0.91 (0.88-0.93). The ICC for the four domains of Part A ranged from 0.85-0.91. The ICC was greater than 0.8 for overall score of Part A and Part B for all the 10 diagnoses, confirming strong reliability. CONCLUSION: This study clearly indicates that the HM-PRO possesses strong test-retest reliability for both Part A and Part B. The Cronbach's alpha confirmed acceptable internal consistency. The extensive reliability testing described in this study supports the generic nature of the HM-PRO for use in hematological malignancies in both routine clinical practice, to aid treatment decisions, as well as in research.

Hematological Malignancy Specific Patient-Reported Outcome Measure (HM-PRO): Construct Validity Study.

BACKGROUND: Validity is the ability of an instrument to measure what it claims to measure. It means the degree to which the empirical evidence supports the trustworthiness of interpretations based on the calculated scores. The hematological malignancy (HM) specific patient reported outcome measure (HM-PRO), is a newly developed instrument for use in daily clinical practice as well as in research. This study, provides the evidence for construct validity of the HM-PRO, specifically focusing on the convergent and divergent validity compared to the other established instruments used in hematology. METHODS: This validation study adopted a prospective cross-sectional design where a heterogeneous group of patients diagnosed with different HMs and different disease state were recruited. A total of 905 patients were recruited from seven secondary care hospitals in the UK and online through five patient organizations. Patients were asked to complete the HM-PRO and other cancer specific PRO's, FACT-G and EORTC QLQ C-30. Data analysis was performed using IBM SPSS 23 statistical software. RESULTS: A total of 486 males (53.7%) and 419 females (46.3%), with a mean age of 64.3 (± 12.4) years and mean time since diagnosis of 4.6 ( ± 5.2) were recruited. The total score of Part A of the HM-PRO highly correlated with the five functional scales of the EORTC QLQ-C30 (Physical = -0.71, Role = -0.72, Emotional = -0.64, Cognitive = -0.58, Social = -0.74-p < 0.001). With respect to correlation with FACT-G, the total score of Part A of the HM-PRO highly correlated with Physical (-0.74), Emotional (-0.57), Functional (-0.66) domains and overall score of FACT-G (-0.74). Similarly, the total score of Part B of the HM-PRO highly correlated with three symptoms scales of EORTC QLQ-C30 (Fatigue scale = -0.74, Nausea and Vomiting = -0.52, Pain = -0.59-p < 0.001) and individual symptom items (Dyspnea = 0.51, Insomnia= 0.43, Appetite loss = 0.54-p < 0.001). CONCLUSION: The construct validity evidence presented in this research is a testimony to the HM-PRO's ability to measure HRQoL issues which it intends to measure. This is of utmost importance when a PRO is used in routine clinical practice so that the interpretation of the scores or response to an individual item is understood by the clinicians/nurses as intended by the patients.

Quality-of-life issues and symptoms reported by patients living with haematological malignancy: a qualitative study.

BACKGROUND: Our aim was to identify health-related quality-of-life (HRQoL) issues and symptoms in patients with haematological malignancies (HMs) and develop a conceptual framework to reflect the inter-relation between them. METHODS: A total of 129 patients with HMs were interviewed in a UK multicentre qualitative study. All interviews were audio recorded, transcribed and analysed using NVivo-11. RESULTS: Overall, 34 issues were reported by patients and were grouped into two parts: quality of life (QoL) and symptoms. The most prevalent HRQoL issues were: eating and drinking habits; social life; physical activity; sleep; and psychological well-being. Furthermore, most prevalent disease-related symptoms were: tiredness; feeling unwell; breathlessness; lack of energy; and back pain. The most prevalent treatment side effects were: tiredness; feeling sick; disturbance in sense of taste; and breathlessness. CONCLUSIONS: Both HMs and their treatments have a significant impact on patients' HRQoL, in particular on issues such as job-role change, body image and impact on finances.

Development of a Novel Hematological Malignancy Specific Patient-Reported Outcome Measure (HM-PRO): Content Validity.

BACKGROUND: The quality of life of patients at all stages of hematological malignancy is greatly affected by the disease and its treatment. There is a wide range of health-related quality of life (HRQoL) issues important to these patients. Any new instrument developed to measure HRQoL of such patients should be content valid, i.e., the items should be comprehensively relevant to the patients and their health condition. The aim of the present study was to examine content validity of a hematological malignancy specific patient reported outcome measure (HM-PRO) developed for use in routine clinical practice. METHODS: Following literature review and semi-structured interviews, the generated themes and sub-themes were discussed to develop the prototype version of the HM-PRO. A 4-step approach was used for content validation: initial testing and cognitive interviewing; item rating; content validity panel meeting; final field testing and cognitive interviewing. Additional questions related to patients' perception of recall period and preferred sentence structure (i.e., question or statement) of the items were also asked during cognitive interviews. RESULTS: The content analysis of 129 transcribed semi-structured interviews resulted in the prototype version of the instrument consisting of 58 items grouped into two parts: Part A (impact/HRQoL - 34 items) and Part B (signs and symptoms - 24 items). The initial testing showed intra-class correlation coefficient (ICC) of >0.8 for both Part A and Part B. Item rating for language clarity, completeness, relevance, and response scale by experts and patients showed content validity index for scales average >0.8 for both Part A and Part B, except 0.64 for relevance for Part A by the patient panel. The final testing of the revised version of the instrument showed the Cronbach's alpha value of 0.91 for Part A and 0.76 for Part B, suggesting high internal consistency, and ICC of 0.91 for Part A and 0.76 for Part B. The recall period of "today" for Part-A and "last 3 days" for Part-B were the patients' preferred "recall period." Furthermore, the patients expressed preference to the HM-PRO items as statements. CONCLUSION: The findings of this study confirm that the HM-PRO possesses a strong content validity, includes all the issues important to patients and is easy to read, understand and respond to spontaneously.

Paper and electronic versions of HM-PRO, a novel patient-reported outcome measure for hematology: an equivalence study.

Aim: To determine measurement equivalence of paper and electronic application of the hematological malignancy-patient-reported outcome (HM-PRO), a specific measure for the evaluation of patient-reported outcomes in HMs. Patients & methods: Following International Society of Pharmacoeconomics and Outcomes Research ePRO Good Research Practice Task Force guidelines, a total of 193 adult patients with different HMs were recruited into a multicenter prospective study. The paper and the electronic version of the instrument were completed in the outpatient clinics in a randomized crossover design with a 30 min time interval to minimize the learning effect. Those who completed the paper version first, completed the electronic version after 30 min and vice versa. Instrument version and order effects were tested on total score of the two parts of the HM-PRO (Part A: quality of life and Part B: signs & symptoms) in a two-way ANOVA with patients as random effects. Intraclass correlation coefficients (95% CI) and Spearman's rank correlation coefficients were used to evaluate test-retest reliability and reproducibility. The effects of instrument version and order were tested on total score of the two parts of HM-PRO. Results: The questionnaire version and administration order effects were not significant at the 5% level. There were no interactions found between these two factors for HM-PRO (Part A [quality of life]; p = 0.95); and (part B [signs and symptoms]; p = 0.72]. Spearman's rank correlation coefficients were greater than 0.9, and intraclass correlation coefficients ranged from 0.94 to 0.98; furthermore, the scores were not statistically different between the two versions, showing acceptable reliability indexes. Noteworthy, the difference between the completion time for both paper (mean = 6:38 min) and electronic version (mean = 7:29 min) was not statistically significant (n = 100; p = 0.11). Patients did not report any difficulty in completing the electronic version during cognitive interviews and were able to understand and respond spontaneously. Conclusion: Measurement equivalence has been demonstrated for the paper and electronic application of the HM-PRO.

Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia.

Despite advances in understanding the complexities of acute myeloid leukaemia (AML), the treatment of refractory or relapsed AML (rrAML) remains a daunting clinical challenge. Numerous clinical trials have failed to identify new treatments or combinations of existing therapies that substantially improve outcomes and survival. This may be due, at least in part, to heterogeneity among study patients with respect to multiple inter-related factors that have been shown to affect treatment outcomes for patients with rrAML; such factors include age, cytogenetics, immunophenotypic changes, and (in the case of relapsed AML) duration of first complete remission, or if the patient has had a previous blood and marrow transplant (BMT). A clear understanding of disease characteristics and patient-related factors that influence treatment response, as well as expected outcomes with existing and emerging therapies, can aid clinicians in helping their patients navigate through this complex disease state.

The addition of gemtuzumab ozogamicin to chemotherapy in adult patients with acute myeloid leukemia.

The treatment of acute myeloid leukaemia has remained largely unchanged for the last 30 years since the advent of combination chemotherapy with cytarabine arabinoside and daunorubicin with remission rates around 70% but with long term survival still only around 40% in young adults. Doses of chemotherapy have been pushed to the limit of toxicity. Gemtuzumab ozogamicin allows additional chemotherapy to be delivered to the leukaemic cells without significantly adding to toxicity since the active agent is coupled to a monoclonal anti-CD33 antibody. It was approved by the FDA in 2000 for the treatment of elderly patients with relapsed CD33 positive AML at a dose of 9mg/m(2) on two days two weeks apart. Almost at once, questions were raised about its safety, with a particular liver signal, and it was voluntarily withdrawn from practice in 2010. Many groups have been examining the role of gemtuzumab ozogamicin in combination with chemotherapy, usually at lower doses than originally recommended, with varying degrees of success and toxicity and gemtuzumab ozogamicin is now entering a period of rehabilitation. Currently it is only commercially available in Japan although it is currently also available in the UK Bloodwise AML18 study.

Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial.

Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m(2) or 6 mg/m(2) In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m(2) or 6 mg/m(2) with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m(2) [82% vs 76%; odds ratio 1.46 (1.04-2.06); P=0.03], but this was balanced by a higher rate of complete remission with incomplete peripheral blood count recovery in the 6 mg/m(2) treatment (10% vs 7%) resulting in similar overall response rate [89% vs 86%; hazard ratio 1.34 (0.88-2.04); P=0.17]. There was no overall difference in relapse or survival at four years between the arms: 46% vs 54%; hazard ratio 1.17 (0.94-1.45), P=0.5, and 50% versus 47%; hazard ratio 1.10 (0.90-1.34), P=0.3, respectively. The 30- and 60-day mortality was significantly higher in the 6 mg/m(2) recipients: 7% versus 3%; hazard ratio 2.07 (1.11-3.87), P=0.02, and 9% versus 5%; hazard ratio 1.99 (1.17-3.39), P=0.01, respectively, which in addition was associated with a higher rate of veno-occlusive disease (5.6% vs 0.5%; P<0.0001). Our conclusion from this trial is that there is no advantage in using a single dose of 6 mg/m(2) of gemtuzumab ozogamicin in combination with induction chemotherapy when compared with a 3 mg/m(2) dose, with respect to response, disease-free and overall survival, either overall, or in any disease subgroup. (AML17 was registered as ISRCTN55675535).

Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial.

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 >10 × 10(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.

A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients.

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.

Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia.

PURPOSE: There has been little survival improvement in older patients with acute myeloid leukemia (AML) in the last two decades. Improving induction treatment may improve the rate and quality of remission and consequently survival. In our previous trial, in younger patients, we showed improved survival for the majority of patients when adding gemtuzumab ozogamicin (GO) to induction chemotherapy. PATIENTS AND METHODS: Untreated patients with AML or high-risk myelodysplastic syndrome (median age, 67 years; range, 51 to 84 years) were randomly assigned to receive induction chemotherapy with either daunorubicin/ara-C or daunorubicin/clofarabine, with (n = 559) or without (n = 556) GO 3 mg/m(2) on day 1 of course one of therapy. The primary end point was overall survival (OS). RESULTS: The overall response rate was 69% (complete remission [CR], 60%; CR with incomplete recovery [CRi], 9%), with no difference between GO (70%) and no GO (68%) arms. There was no difference in 30- or 60-day mortality and no major increase in toxicity with GO. With median follow-up of 30 months (range, 5.5 to 54.6 months), 3-year cumulative incidence of relapse was significantly lower with GO (68% v 76%; hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .007), and 3-year survival was significantly better (25% v 20%; HR, 0.87; 95% CI, 0.76 to 1.00; P = .05). The benefit was apparent across subgroups. There was no interaction with other treatment interventions. A meta-analysis of 2,228 patients in two United Kingdom National Cancer Research Institute trials showed significant improvements in relapse (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002) and OS (HR, 0.88; 95% CI, 0.79 to 0.98; P = .02). CONCLUSION: Adding GO (3 mg/m(2)) to induction chemotherapy reduces relapse risk and improves survival with little increase in toxicity.

The addition of the farnesyl transferase inhibitor, tipifarnib, to low dose cytarabine does not improve outcome for older patients with AML.

The AML16 trial evaluated the combination of the farnesyltransferase inhibitor, tipifarnib, and low dose cytarabine (LDAC) in older acute myeloid leukaemia (AML) patients in a 'Pick a Winner' design. The aim was to double remission rates compared to LDAC, with initial evaluation after 100 patients. Failure to improve remission would result in discontinuation. A total of 65 patients, median age 74 years (range 62-86), were randomized. After reviewing the first 45 patients, the Data Monitoring Committee concluded that the overall aspirations would not be met and recommended closure. The addition of tipifarnib had no effect on response, toxicity or survival.

Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial.

PURPOSE: Antibody-directed chemotherapy for acute myeloid leukemia (AML) may permit more treatment to be administered without escalating toxicity. Gemtuzumab ozogamicin (GO) is an immunoconjugate between CD33 and calicheamicin that is internalized when binding to the epitope. We previously established that it is feasible to combine GO with conventional chemotherapy. We now report a large randomized trial testing the addition of GO to induction and/or consolidation chemotherapy in untreated younger patients. PATIENTS AND METHODS: In this open-label trial, 1,113 patients, predominantly younger than age 60 years, were randomly assigned to receive a single dose of GO (3 mg/m(2)) on day 1 of induction course 1 with one of the following three induction schedules: daunorubicin and cytarabine; cytarabine, daunorubicin, and etoposide; or fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin. In remission, 948 patients were randomly assigned to GO in course 3 in combination with amsacrine, cytarabine, and etoposide or high-dose cytarabine. The primary end points were response rate and survival. RESULTS: The addition of GO was well tolerated with no significant increase in toxicity. There was no overall difference in response or survival in either induction of consolidation. However, a predefined analysis by cytogenetics showed highly significant interaction with induction GO (P = .001), with significant survival benefit for patients with favorable cytogenetics, no benefit for patients with poor-risk disease, and a trend for benefit in intermediate-risk patients. An internally validated prognostic index identified approximately 70% of patients with a predicted benefit of 10% in 5-year survival. CONCLUSION: A substantial proportion of younger patients with AML have improved survival with the addition of GO to induction chemotherapy with little additional toxicity.

European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy.

PURPOSE: Treatment options for older patients with acute myeloid leukemia (AML) who are not considered suitable for intensive chemotherapy are limited. We assessed the second-generation purine nucleoside analog, clofarabine, in two similar phase II studies in this group of patients. PATIENTS AND METHODS: Two consecutive studies, UWCM-001 and BIOV-121, recruited untreated older patients with AML to receive up to four or six 5-day courses of clofarabine. Patients in UWCM-001 were either older than 70 years or 60 to 69 years of age with poor performance status (WHO > 2) or with cardiac comorbidity. Patients in BIOV-121 were >or= 65 years of age and deemed unsuitable for intensive chemotherapy. RESULTS: A total of 106 patients were treated in the two monotherapy studies. Median age was 71 years (range, 60 to 84 years), 30% had adverse-risk cytogenetics, and 36% had a WHO performance score >or= 2. Forty-eight percent had a complete response (32% complete remission, 16% complete remission with incomplete peripheral blood count recovery), and 18% died within 30 days. Interestingly, response and overall survival were not inferior in the adverse cytogenetic risk group. The safety profile of clofarabine in these elderly patients with AML who were unsuitable for intensive chemotherapy was manageable and typical of a cytotoxic agent in patients with acute leukemia. Patients had similar prognostic characteristics to matched patients treated with low-dose cytarabine in the United Kingdom AML14 trial, but had significantly superior response and overall survival. CONCLUSION: Clofarabine is active and generally well tolerated in this patient group. It is worthy of further evaluation in comparative trials and might be of particular use in patients with adverse cytogenetics.