VOLUME
32
䡠
NUMBER
30
䡠
OCTOBER
20
2014
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Randomized Phase III Trial of Retinoic Acid and Arsenic Trioxide Versus Retinoic Acid and Chemotherapy in Patients With Acute Promyelocytic Leukemia: Health-Related Quality-of-Life Outcomes Fabio Efficace, Franco Mandelli, Francesco Cottone, and Marco Vignetti, Gruppo Italiano Malattie Ematologiche dell’Adulto; Giuseppe Avvisati, Universita` Campus Biomedico; Massimo Breccia, Universita` “La Sapienza,”; Simona Sica, Universita` Cattolica Sacro Cuore; Sergio Amadori and Francesco Lo-Coco, Universita` Tor Vergata; Francesco Lo-Coco, Fondazione Santa Lucia, Roma; Felicetto Ferrara, Ospedale Cardarelli; Olimpia Finizio, Ospedale Cardarelli, Napoli; Eros Di Bona, Ospedale San Bortolo, Vicenza; Giorgina Specchia, Universita` di Bari, Bari; Alessandro Levis, Ospedale SS Antonio e Biagio, Alessandria; Maria Grazia Kropp, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro; Giuseppe Fioritoni, Ospedale Civile, Pescara; Elisa Cerqui, Spedali Civili, Brescia, Italy; Richard F. Schlenk, University of Ulm, Ulm; and Uwe Platzbecker, Universitatsklinikum Carl Gustav Carus, Dresden, Germany. Published online ahead of print at www.jco.org on September 22, 2014. Supported in Italy by the Associazione Italiana contro le Leucemie-linfomi e mieloma and Associazione Italiana per la Ricerca sul Cancro (Grant No. IG 5916 to F.L.-C.); in Germany by the Federal Ministry of Education and Research (Grant No. BMBF FKZ 01KG0903 to U.P.); and in part by Lundbeck (Montreal, Quebec, Canada). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Presented at the 19th Congress of the European Hematology Association, Milan, Italy, June 12-15, 2014. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT00482833. Corresponding author: Fabio Efficace, PhD, Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), GIMEMA Data Center, Via Benevento 6, 00161, Rome, Italy; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology 0732-183X/14/3230w-3406w/$20.00 DOI: 10.1200/JCO.2014.55.3453
3406
Fabio Efficace, Franco Mandelli, Giuseppe Avvisati, Francesco Cottone, Felicetto Ferrara, Eros Di Bona, Giorgina Specchia, Massimo Breccia, Alessandro Levis, Simona Sica, Olimpia Finizio, Maria Grazia Kropp, Giuseppe Fioritoni, Elisa Cerqui, Marco Vignetti, Sergio Amadori, Richard F. Schlenk, Uwe Platzbecker, and Francesco Lo-Coco A
B
S
T
R
A
C
T
Purpose A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results. Patients and Methods HRQOL was a secondary end point of this trial. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 was used to assess HRQOL at end of induction and after consolidation therapy. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. Primary analysis was performed, estimating mean HRQOL score over time and differences between treatment arms using a linear mixed model. Results Overall, 162 patients age 18 to 70 years were enrolled. Of these, 150 and 142 patients were evaluable for HRQOL after induction therapy and third consolidation course, respectively. Overall compliance with HRQOL forms was 80.1%. The largest difference, favoring patients treated with ATRA plus arsenic trioxide, was found for fatigue severity (mean score difference, ⫺9.3; 95% CI, ⫺17.8 to ⫺0.7; P ⫽ .034) at end of induction therapy. This difference was also clinically relevant. HRQOL differences between treatment arms at end of consolidation showed that for several scales, differences between treatment arms were marginal. Conclusion Overall, current HRQOL findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk APL. J Clin Oncol 32:3406-3412. © 2014 by American Society of Clinical Oncology
INTRODUCTION
Acute promyelocytic leukemia (APL) is a special subtype of acute myeloid leukemia (AML) characterized by leukemic bone marrow infiltration by dysplastic promyelocytes, a specific chromosomal translocation [t(15;17)], and life-threatening coagulopathy.1 With the advent of modern treatment with all-trans-retinoic acid (ATRA) and anthracyclinebased chemotherapy, APL has become a highly curable disease, with long-term survival rates exceeding 75% as reported by several large multicenter trials. Thus, ATRA plus chemotherapy has been regarded until recently as the standard therapy for these patients.1,2
On the basis of earlier findings showing that arsenic trioxide, with or without ATRA, was also highly effective in APL and associated with a better safety profile,3-5 we recently carried out a phase III randomized clinical trial (RCT) to compare efficacy and toxicity of standard ATRA plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed APL.6 This RCT, conducted by the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA), the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG), and Study Alliance Leukemia (SAL), showed that ATRA plus arsenic trioxide was at least not inferior to ATRA plus
© 2014 by American Society of Clinical Oncology
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Quality of Life in Patients With Acute Promyelocytic Leukemia
chemotherapy with regard to 2-year event-free survival rate in patients with low- or intermediate-risk APL.6 However, because potential clinical benefits of newer experimental treatments need to be weighed against possible patients’ burden,7 and given the lack of published data on the impact of arsenic trioxide on patients’ symptoms and well being, healthrelated quality-of-life (HRQOL) assessment was included as a secondary end point of this RCT.6 Here, we report HRQOL findings of this study. PATIENTS AND METHODS Study Design and Patients The study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. It was designed to show that the combination of ATRA plus arsenic trioxide was not inferior to ATRA plus chemotherapy with respect to event-free survival rate at 2 years. Eligible patients were adults age 18 to 70 years with newly diagnosed, genetically confirmed low- or intermediate-risk APL (WBC at diagnosis ⱕ 10 ⫻ 109/L). Other inclusion criteria included WHO performance status
ⱕ 2 (where 0 is asymptomatic and higher numbers reflect greater functional compromise), creatinine ⱕ 3.0 mg/dL (ⱕ 260 mol/L), and bilirubin ⱕ 3.0 mg/dL (ⱕ 51 mol/L). Overall, 40 centers from GIMEMA and 27 centers from AMLSG and SAL participated in the study by enrolling at least one patient. Additional details have been reported previously.6 The trial was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of each participating center. All patients provided written informed consent. Procedures for HRQOL Assessment and Data Collection The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30; version 3) was used to assess HRQOL.8 This validated questionnaire consists of five functioning scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea/vomiting, and pain), six single-item scales (dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global QOL scale. However, financial impact was not included in this analysis. Items were scaled and scored using recommended EORTC procedures.9 At time of study design, no leukemiaspecific HRQOL instrument was available. EORTC QLQ-C30 was thus implemented, having being successfully used in previous studies in patients with various types of leukemia including AML.10,11 In addition, this
Random assignment (N = 162)
Assigned to receive ATRA-arsenic trioxide (n = 82) Not eligible Major protocol violation
Assigned to receive ATRA-chemotherapy (n = 80) (n = 3) (n = 2)
Withdrew consent (n = 1)
Received at least one dose of ATRA-arsenic trioxide (n = 77)
Received at least one dose of ATRA-chemotherapy (n = 79)
Discontinued during induction (n = 2) Major protocol violation (n = 1) Withdrawn resulting from (n = 1) a medical decision
Died during induction Differentiation syndrome Ischemic stroke Bronchopneumonia
After induction therapy 1st HRQOL assessment Available for HRQOL analysis (n = 75) Did not have HRQOL form (n = 13)
Discontinued after induction Toxic effect Major protocol violation
Included in consolidation phase (n = 73)
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After induction therapy 1st HRQOL assessment Available for HRQOL analysis (n = 75) Did not have HRQOL form (n = 22)
(n = 2) (n = 1) (n = 1)
Discontinued after induction Toxic effect Lost to follow-up
Fig 1. Trial profile and available healthrelated quality-of-life (HRQOL) data. HRQOL assessments were performed at end of induction therapy and end of third consolidation course (ie, end of consolidation therapy for those randomly assigned to all-trans-retinoic acid [ATRA] plus chemotherapy).
(n = 2) (n = 1) (n = 1)
Included in consolidation phase (n = 73)
Died Bronchopneumonia + H1N1 infection
After third consolidation course 2nd HRQOL assessment Available for HRQOL analysis Did not have HRQOL form
(n = 4) (n = 2) (n = 1) (n = 1)
(n = 72) (n = 11)
(n = 1) (n = 1)
Died Hemorrhagic shock Pulmonary embolism Bronchopneumonia
After third consolidation course 2nd HRQOL assessment Available for HRQOL analysis Did not have HRQOL form
(n = 3) (n = 1) (n = 1) (n = 1)
(n = 70) (n = 12)
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Efficace et al
is the most frequently used HRQOL measure in the setting of RCTs.12 Unlike other generic cancer measures, this is a heavily symptom-based questionnaire and is thus likely to capture relevant treatment-related adverse effects and overall patient morbidity. As per protocol, two assessments were performed: after induction therapy and at end of third consolidation course, corresponding to end of consolidation therapy for patients randomly assigned to ATRA plus chemotherapy. Acceptable time windows and definition of compliance of HRQOL assessments were a priori specified in the already published protocol.6 Whenever possible, questionnaires were administered at the hospital in a room where the patient would not be disturbed. The protocol specified that a responsible person (eg, nurse, clinician, or data manager) administer the questionnaire to the patient, requesting completion and its return to the GIMEMA Data Center. Patients themselves completed paper questionnaires. Because mode of HRQOL questionnaire administration can have important effects on the accuracy and quality of data obtained,13 guidelines for administering questionnaires were included in the study protocol to ensure a standard approach to data collection by all administrators. The HRQOL results in this trial are presented in accordance with high methodologic quality criteria for documenting patient-reported outcomes in RCTs.14-16 Statistical Methods HRQOL was a secondary outcome in this study. At the time the protocol was written, no studies had provided evidence on possible expected effects of arsenic trioxide on patient-reported outcomes; thus, no specific HRQOL scale of the EORTC QLQ-C30 was identified for primary analysis. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. HRQOL compliance was computed for each time point as percentage of returned valid questionnaires of those expected from patients still on study at that time. Differences in demographic, clinical, and biologic characteristics were assessed between patients who completed the questionnaire after induction and those who did not, using Fisher’s exact or Wilcoxon Mann-Whitney test as appropriate (␣ ⫽ 0.05). Primary analysis was performed estimating mean scores and their differences between treatment arms over time for all EORTC QLQ-C30 scales by a repeated measures linear mixed model with an unrestricted covariance structure. The model included treatment, assessment time, and treatment ⫻ time interaction. For each EORTC QLQ-C30 scale, the null hypothesis was tested that estimated differences between the two treatment arms equal 0 for all time points, by an overall F statistic. If this test was significant (␣ ⫽ 0.05), the estimated differences between treatment arms were tested separately for each single time point by a t test (␣ ⫽ 0.05). Estimated means and standard deviations (SDs) obtained from the model, their differences between treatment arms, and the corresponding 95% CIs are reported for all HRQOL assessments. Because of the exploratory nature of the study, we did not adjust P values for multiple testing. For each scale, clinical relevance of the estimated mean score differences between treatment arms was also interpreted according to recent evidence-based guidelines for EORTC QLQ-C30.17 Missing data were investigated to check their possible impact on results. Relationships between dropout and outcome were investigated, comparing mean observed HRQOL scores after induction between patients who returned the questionnaire after consolidation therapy and those who did not. Logistic regression analysis was used to examine the impact of key sociodemographic, biologic, and clinical characteristics on probability of not completing the HRQOL questionnaire at any time point assessment. Robustness of final results was assessed by the explicit regression model approach,18 identifying a linear regression model to predict a value to be imputed for each missing HRQOL scale. The linear regression model included variables related to the missing data mechanism as well as to the HRQOL values to be imputed. We then applied the previously described linear mixed model to the augmented data set. SAS statistical software (version 9.2; SAS Institute, Cary, NC) was used for all analyses. 3408
© 2014 by American Society of Clinical Oncology
RESULTS
Patient Characteristics Between October 2007 and September 2010, 162 patients were enrolled. Genetic tests excluded a diagnosis of PML-RARA–positive APL in three patients. Three of 159 patients with genetically proven APL did not start allocated treatment. The final HRQOL analysis thus included 156 patients who received at least one dose of the assigned therapy after random assignment. The flowchart of patients included in the final HRQOL analysis is shown in Figure 1. Event-free survival rates at 2 years after diagnosis were 97% and 86% for the ATRA plus arsenic trioxide versus ATRA plus chemotherapy groups, respectively
Table 1. Demographic, Clinical, and Biologic Characteristics of Patients With and Without HRQOL Assessment After Induction Therapy Without HRQOL Assessment (n ⫽ 41) Characteristicⴱ Sex Male Female Age, years Mean SD Median Range WBC count, ⫻ 109/L Mean SD Median Range Platelet count, ⫻ 109/L Mean SD Median Range Risk level‡ Low Intermediate PML-RARA isoform Long Short Missing Hemoglobin count, g/dL Mean SD Median Range Any toxicity§ No Yes
With HRQOL Assessment (n ⫽ 115
No.
%
No.
%
14 27
34.1 65.9
62 53
53.9 46.1
P† .030
.740 45.7 16.5 48 18.7-69.7
44.9 14.0 45 19.1-70.2
2.6 2.6 1.5 0.3-9.6
2.3 2.2 1.5 0.3-10.0
38.3 35.5 28 5.0-193.0
48.5 47.0 31 3.0-236.0
.995
.611
.159 12 29
29.3 70.7
48 67
41.7 58.3
23 17 1
56.1 41.5 2.4
70 43 2
60.9 37.4 1.7
.621
.083 9.0 1.8 8.6 5.6-12.9
9.6 2.0 9.2 4.3-14.6 .774
5 36
12.2 87.8
12 103
10.4 89.6
Abbreviations: HRQOL, health-related quality of life; SD, standard deviation. ⴱ Variables were measured at baseline, except for toxicity, which was measured during induction phase. †Fisher’s exact test used for sex, risk level, PML-RARA isoform, and any toxicity; Wilcoxon Mann-Whitney test used for remaining variables. ‡Low risk level defined as WBC count ⱕ 10 ⫻ 109/L and platelet count ⬎ 40 ⫻ 109/L at presentation; intermediate risk level defined as WBC count ⱕ 10 ⫻ 109/L and platelet count ⱕ 40 ⫻ 109/L at presentation. §Grades 3 to 4 during induction phase.
JOURNAL OF CLINICAL ONCOLOGY
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Quality of Life in Patients With Acute Promyelocytic Leukemia
(difference, 11%; 95% CI, 2% to 22%; noninferiority P ⬍ .001). Detailed clinical efficacy and safety results have been reported elsewhere.6 HRQOL Compliance Rates Of 156 patients analyzed in the primary clinical analysis, 150 were eligible for HRQOL evaluation at end of induction therapy and 142 at end of third consolidation course. Overall compliance with HRQOL forms was 80.1%. After induction, 115 HRQOL forms were received of 150 expected (compliance, 77%), whereas after consolidation phase, 119 forms were received of 142 expected (compliance, 84%). No statistically significant differences were found in compliance rates between treatment arms (data not shown). Patient characteristics by HRQOL compliance at first assessment (ie, end of induction therapy) are listed in Table 1. HRQOL Differences Between Treatment Arms For each EORTC QLQ-C30 scale, Table 2 shows mean estimated scores and corresponding SDs by treatment group and timing of assessment. Estimated mean score differences between treatment arms with corresponding 95% CIs are graphically displayed in Figure 2. Fatigue was the only scale with a statistically significant overall difference between treatment arms (P ⫽ .022; Table 2). When considering single time points, fatigue severity was significantly lower in the group treated with ATRA plus arsenic trioxide (P ⫽ .034) after induction therapy. Mean fatigue scores of patients treated with ATRA plus arsenic trioxide versus those treated with ATRA plus chemotherapy were 29.1 (SD, 25.7) and 38.4 (SD, 28.1), respectively (⌬ ⫽ ⫺9.3; 95% CI, ⫺17.8 to ⫺0.7), reflecting a clinically relevant difference (albeit small; Fig 2). After third consolidation course, however, severity of fatigue was not significantly different between treatment groups (P ⫽ .660).
After induction therapy, there were also small but clinically relevant differences in severity of nausea/vomiting (⌬ ⫽ ⫺5.1; 95% CI, ⫺9.7 to ⫺0.5), appetite loss (⌬ ⫽ ⫺7.1; 95% CI, ⫺14.6 to 0.5), and constipation (⌬ ⫽ ⫺6.1; 95% CI, ⫺16.3 to 4.0), favoring patients treated with ATRA plus arsenic trioxide versus those treated with ATRA plus chemotherapy. With regard to functional aspects, physical (⌬ ⫽ 5.3; 95% CI, ⫺1.9 to 12.4) and cognitive functioning (⌬ ⫽ 5.9; 95% CI, ⫺1.2 to 12.9) also showed clinically relevant (albeit small) differences, favoring patients treated with ATRA plus arsenic trioxide (Fig 2). After third consolidation course, only severity of diarrhea showed a small clinically relevant difference (⌬ ⫽ 5.5; 95% CI, ⫺0.4 to 10.6), favoring patients treated with ATRA plus chemotherapy over those treated with ATRA plus arsenic trioxide. For all other symptoms and functional scales, magnitude of estimated mean score differences between treatment arms was trivial17 (Fig 2). Missing Data Mechanism and Supportive Analysis We compared mean observed HRQOL scores after induction between patients who returned the questionnaire after consolidation therapy and those who did not, and no statistically significant differences were found between groups (data not shown). Univariable logistic regression analysis showed that the missing data mechanism was independent of age, risk level, hemoglobin, time from diagnosis, and toxicity during induction (Table 3). However, sex was significantly associated with higher likelihood of missing data (P ⫽ .044). To assess the robustness of primary analysis results, the explicit regression model approach was used, identifying a linear regression model to predict a value for each missing HRQOL scale. The model was run separately for each arm and included sex, age, and toxicity during induction. Sex was included because it was significantly associated with HRQOL missing data, whereas age and toxicity during induction
Table 2. Estimated EORTC QLQ-C30 Mean Scores and SDs by Treatment Arm and HRQOL Assessment ATRA Plus Arsenic Trioxideⴱ After Third Consolidation Course
After Induction EORTC QLQ-C30 Scale
Mean Score
ATRA Plus Chemotherapyⴱ
SD
Mean Score
Physical functioning Role functioning Emotional functioning Cognitive functioning Social functioning Global health status/QOL
80.9 68.0 81.2 87.2 68.8 67.2
21.5 34.8 21.0 21.1 30.2 21.8
80.6 72.4 74.7 80.8 77.5 72.7
Fatigue Nausea/vomiting Pain Dyspnea Insomnia Appetite loss Constipation Diarrhea
29.1 3.1 16.1 15.8 16.2 5.6 14.5 8.6
25.7 13.9 25.3 24.8 28.7 22.6 30.5 20.6
29.8 5.3 16.9 16.7 21.2 5.3 5.3 7.8
SD
After Third Consolidation Course
After Induction Mean Score
Functional Scales 20.6 75.6 29.7 62.5 24.0 76.8 24.5 81.4 26.5 72.4 22.4 64.7 Symptom Scales 26.4 38.4 13.1 8.3 26.3 11.1 26.6 16.3 30.0 19.4 19.9 12.7 27.6 20.6 15.9 9.5
SD
Mean Score
SD
P†
23.5 38.1 23.0 23.1 33.1 24.1
81.9 75.8 79.6 82.4 78.0 72.9
21.5 31.0 25.1 25.8 27.6 23.4
.147 .280 .088 .089 .778 .761
28.1 15.2 27.8 27.1 31.4 24.8 33.4 22.5
27.9 5.7 17.2 17.5 19.4 8.1 7.7 2.3
27.4 13.5 27.4 27.6 31.2 21.0 28.6 16.3
.022 .095 .467 .978 .614 .183 .489 .106
Abbreviations: ATRA, all-trans-retinoic acid; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30; HRQOL, health-related quality of life; QOL, quality of life; SD, standard deviation. ⴱ Mean scores and corresponding SDs estimated by linear mixed model with unrestricted covariance structure. †For each scale, P value stems from overall F statistic testing null hypothesis that differences between two treatment arms were equal to zero for all time points.
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3409
Efficace et al
A
B DI QoL
CO
SF End of induction End of 3rd consolidation course
End of induction End of 3rd consolidation course
AP
SL
CF
DY EF
PA
RF NV
PF
FA
−15 −10
−5
ATRA-Chemotherapy Better
0
5
10
15
20
ATRA-Arsenic Trioxide Better
−20 −15 −10
DISCUSSION
We report that for patients with low- or intermediate-risk APL treated with ATRA plus arsenic trioxide, the HRQOL profile is at least as good as that for patients treated with ATRA plus chemotherapy. Our findings have important clinical implications, because they support the use of ATRA plus arsenic trioxide as preferred first-line treatment by showing that better clinical outcomes of this newer therapy6 can be obtained without detrimental effects on patients’ HRQOL. Rather, patients treated with ATRA plus arsenic trioxide reported statistically significantly less fatigue at end of induction therapy compared with patients treated with ATRA plus chemotherapy. Importantly, the © 2014 by American Society of Clinical Oncology
−5
ATRA-Arsenic Trioxide Better
were considered based on their importance in possibly influencing HRQOL outcomes. For each scale with a missing score, the value predicted by the linear regression model was imputed (single imputation). The same linear mixed model used for longitudinal analysis was then applied to the augmented data set, showing results similar to those of the primary analysis.
3410
Fig 2. Estimated differences in (A) functional and (B) symptom scales of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 mean scores and 95% CIs between all-trans-retinoic acid (ATRA) plus arsenic trioxide and ATRA plus chemotherapy arms at end of induction therapy and end of third consolidation course. Differences in mean scores (⌬ ⫽ ATRA plus arsenic trioxide ⫺ ATRA plus chemotherapy) and corresponding 95% CIs were estimated by linear mixed model with unrestricted covariance structure. Positive difference in functional scales indicates better outcomes in ATRA plus arsenic trioxide compared with ATRA plus chemotherapy arm; positive difference in symptom scales indicates better outcomes in ATRA plus chemotherapy compared with ATRA plus arsenic trioxide arm. AP, appetite loss; CF, cognitive functioning; CO, constipation; DI, diarrhea; DY, dyspnea; EF, emotional functioning; FA, fatigue; NV, nausea/vomiting; PA, pain; PF, physical functioning; QoL, global health status/quality of life; RF, role functioning; SF, social functioning; SL, insomnia. (*) Small clinically relevant difference (based on Cocks et al17).
0
5
10
15
ATRA-Chemotherapy Better
magnitude of this difference was also clinically relevant (albeit small).17 Fatigue has been shown to be the main factor affecting HRQOL of patients with AML,19 suggesting that our findings of lower fatigue severity after induction therapy might represent a major outcome of arsenic trioxide therapy. After induction, other key symptom and functional scales showed clinically relevant better outcomes for patients treated with ATRA plus arsenic trioxide (Fig 2), providing supporting evidence of the advantages of this newer treatment over standard ATRA plus chemotherapy. Another finding of the this study is that HRQOL differences between treatment arms at end of third consolidation course were substantially reduced, with diarrhea showing a small clinically relevant difference, favoring patients treated with ATRA plus chemotherapy (Fig 2). A possible explanation for this result is that patients randomly assigned to ATRA plus chemotherapy had higher margins for HRQOL recovery after having experienced a more burdensome induction therapy. Conversely, those treated with ATRA plus arsenic trioxide might have already adapted to improved HRQOL outcomes after induction and were thus less likely to experience any additional major improvements.20 Also, progress in supportive care approaches JOURNAL OF CLINICAL ONCOLOGY
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Quality of Life in Patients With Acute Promyelocytic Leukemia
Table 3. Univariable Analysis of Impact of Demographic, Clinical, and Biologic Characteristics on Probability of Missing HRQOL Assessment Variableⴱ
OR
95% CI
P
Sex (referent male) Age, years Risk level (referent low) PML-RARA isoform (referent long) WBC count, ⫻ 109/L Platelet count, ⫻ 109/L Hemoglobin count, g/dL Peripheral blood blasts, % Neutrophils, % Randomization arm (referent ATRA plus arsenic trioxide) Time from diagnosis to CR, days Any toxicity†
2.038 0.998 0.981 1.161 1.054 0.998 0.901 1.004 0.995
1.018 to 4.081 0.975 to 1.021 0.490 to 1.964 0.579 to 2.328 0.914 to 1.215 0.990 to 1.006 0.751 to 1.080 0.992 to 1.016 0.978 to 1.013
.044 .874 .956 .675 .472 .663 .258 .490 .603
1.298 1.023 0.821
0.658 to 2.559 0.984 to 1.062 0.285 to 2.365
.451 .249 .715
Abbreviations: ATRA, all-trans-retinoic acid; CR, complete response; HRQOL, health-related quality of life; OR, odds ratio. ⴱ Variables were measured at baseline, except for toxicity, which was measured during induction phase. †Grades 3 to 4 during induction phase.
associated with chemotherapy for AML21 might have further decreased the HRQOL differences between treatment arms after consolidation phase. Type of drug administration should also be considered when interpreting study findings, because in our RCT, arsenic trioxide was administered intravenously. Zhu et al22 recently reported that an orally administered formulation of arsenic trioxide was not inferior to intravenous arsenic trioxide in terms of disease-free survival at 2 years in patients with newly diagnosed APL. On the basis of this novel evidence,22 it will be important to investigate in future studies whether oral arsenic trioxide can further increase HRQOL benefits over standard chemotherapy-based approaches. Few leukemia RCTs have included HRQOL as an end point of the study,23 thus limiting evidence-based data on the impact of newer antileukemia drugs over standard therapies in terms of patientreported benefits. To our knowledge, the only RCT evaluating HRQOL in patients with APL was conducted by Burnett et al.24 They evaluated HRQOL over a 2-year period in patients randomly assigned to ATRA plus cytarabine-containing chemotherapy versus those receiving ATRA plus anthracycline-based chemotherapy. Minor differences in HRQOL outcomes were found, and the authors concluded that neither arm seemed to show a disadvantage over the long term.24 However, arsenic trioxide was not part of the treatment schema of this study, and it is therefore difficult to attempt a comparison with our results. Our study has some limitations. A baseline pretreatment HRQOL assessment (before randomization) was not available. Although HRQOL compliance is a major challenge in patients with acute leukemia,23,25,26 this can be particularly challenging in the specific case of APL, a disease representing a medical emergency resulting from frequent life-threatening coagulopathy, where current recommendations suggest starting ATRA therapy even before genetic confirmation of diagnosis.2,27 Thus, considering the poor clinical conditions of patients at disease onset, and a number of additional logistic and administrative factors that typically increase amount of missing data in large multicenter international studwww.jco.org
ies,28 a baseline assessment was not planned a priori in the protocol. Indeed, we expected low baseline compliance, having two main negative consequences in the successful conduct of the HRQOL study: first, limiting the conclusions we could have drawn from this assessment because of the small amount of available questionnaires, and second, negatively influencing attitude and motivation of investigators regarding further participation in HRQOL data collection. In any case, we note that patients were randomly allocated to the two treatment arms, and our supportive analysis did not find an association between HRQOL compliance and several key baseline clinical and biologic factors, thus limiting this aspect as a possible source of bias. Also, we are not able to draw conclusions regarding HRQOL after third consolidation course. We can speculate that long-term HRQOL might be better for patients treated with ATRA plus arsenic trioxide, because such patients only need to undertake another consolidation cycle of therapy.6 Conversely, those randomly assigned to ATRA plus chemotherapy will be receiving maintenance therapy for the successive 2 years.6 Future studies are needed to evaluate long-term HRQOL outcomes in both groups. This study also has strengths. Documenting the impact of newer drugs from the patient perspective is crucial,29 and we report, for the first time to our knowledge, the HRQOL impact of a newer chemotherapy-free treatment approach (ie, ATRA plus arsenic trioxide) in patients with acute leukemia. Also, although implementation of HRQOL assessment in acute leukemia RCTs is highly challenging, because of the possible large amount of missing data,25 our HRQOL compliance was satisfactory. Lastly, the influence of HRQOL missing data on study outcomes was fully investigated, and our additional supportive analysis confirmed robustness of main results. In conclusion, the HRQOL benefits of therapy with ATRA plus arsenic trioxide over standard ATRA plus chemotherapy are mainly relevant at end of induction therapy. Our HRQOL results extend previous clinical findings6 and can help physicians make more informed treatment decisions on first-line therapy for their newly diagnosed patients with APL.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Uwe Platzbecker, TEVA Pharmaceuticals Industries; Francesco Lo-Coco, TEVA Pharmaceuticals Industries, Lundbeck Research Funding: None Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None © 2014 by American Society of Clinical Oncology
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AUTHOR CONTRIBUTIONS Conception and design: Fabio Efficace, Franco Mandelli, Marco Vignetti, Francesco Lo-Coco Financial support: Fabio Efficace, Franco Mandelli Provision of study materials or patients: Felicetto Ferrara, Eros Di Bona, Massimo Breccia, Alessandro Levis, Simona Sica, Olimpia Finizio, Maria Grazia Kropp, Giuseppe Fioritoni, Elisa Cerqui, Richard F. Schlenk, Uwe Platzbecker
REFERENCES 1. Wang ZY, Chen Z: Acute promyelocytic leukemia: From highly fatal to highly curable. Blood 111:2505-2515, 2008 2. Sanz MA, Grimwade D, Tallman MS, et al: Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113:1875-1891, 2009 3. Ghavamzadeh A, Alimoghaddam K, Rostami S, et al: Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol 29:2753-2757, 2011 4. Ravandi F, Estey E, Jones D, et al: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27:504-510, 2009 5. Breccia M, Lo-Coco F: Arsenic trioxide for management of acute promyelocytic leukemia: Current evidence on its role in front-line therapy and recurrent disease. Expert Opin Pharmacother 13: 1031-1043, 2012 6. Lo-Coco F, Avvisati G, Vignetti M, et al: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369:111-121, 2013 7. Basch E: The missing voice of patients in drug-safety reporting. N Engl J Med 362:865-869, 2010 8. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 9. Fayers P, Aaronson N, Bjordal K, et al: EORTC QLQ-C30 Scoring Manual (ed 3). Brussels, Belgium, EORTC Publications, 2001 10. Catovsky D, Richards S, Matutes E, et al: Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): A randomised controlled trial. Lancet 370:230-239, 2007
Collection and assembly of data: Giuseppe Avvisati, Felicetto Ferrara, Eros Di Bona, Giorgina Specchia, Massimo Breccia, Alessandro Levis, Simona Sica, Olimpia Finizio, Maria Grazia Kropp, Giuseppe Fioritoni, Sergio Amadori, Richard F. Schlenk, Uwe Platzbecker, Francesco Lo-Coco Data analysis and interpretation: Fabio Efficace, Franco Mandelli, Francesco Cottone, Elisa Cerqui, Francesco Lo-Coco Manuscript writing: All authors Final approval of manuscript: All authors
11. Redaelli A, Stephens JM, Brandt S, et al: Short- and long-term effects of acute myeloid leukemia on patient health-related quality of life. Cancer Treat Rev 30:103-117, 2004 12. Efficace F, Osoba D, Gotay C, et al: Has the quality of health-related quality of life reporting in cancer clinical trials improved over time? Towards bridging the gap with clinical decision making. Ann Oncol 18:775-781, 2007 13. Bowling A: Mode of questionnaire administration can have serious effects on data quality. J Public Health (Oxf) 27:281-291, 2005 14. Efficace F, Bottomley A, Osoba D, et al: Beyond the development of health-related qualityof-life (HRQOL) measures: A checklist for evaluating HRQOL outcomes in cancer clinical trials—Does HRQOL evaluation in prostate cancer research inform clinical decision making? J Clin Oncol 21:35023511, 2003 15. Calvert M, Blazeby J, Altman DG, et al: Reporting of patient-reported outcomes in randomized trials: The CONSORT PRO extension. JAMA 309: 814-822, 2013 16. Brundage M, Blazeby J, Revicki D, et al: Patient-reported outcomes in randomized clinical trials: Development of ISOQOL reporting standards. Qual Life Res 22:1161-1175, 2013 17. Cocks K, King MT, Velikova G, et al: Evidencebased guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 29:89-96, 2011 18. Fairclough D: Design and Analysis of Quality of Life Studies in Clinical Trials (ed 2). New York, NY, Chapman Hall/CRC, 2010 19. Schumacher A, Wewers D, Heinecke A, et al: Fatigue as an important aspect of quality of life in patients with acute myeloid leukemia. Leuk Res 26:355-362, 2002 20. Hamidou Z, Dabakuyo TS, Bonnetain F: Impact of response shift on longitudinal quality-of-life
assessment in cancer clinical trials. Expert Rev Pharmacoecon Outcomes Res 11:549-559, 2011 21. Derolf AR, Kristinsson SY, Andersson TM, et al: Improved patient survival for acute myeloid leukemia: A population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005. Blood 113:3666-3672, 2009 22. Zhu HH, Wu DP, Jin J, et al: Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: A multicenter randomized controlled trial. J Clin Oncol 31:4215-4221, 2013 23. Efficace F, Kemmler G, Vignetti M, et al: Health-related quality of life assessment and reported outcomes in leukaemia randomised controlled trials: A systematic review to evaluate the added value in supporting clinical decision making. Eur J Cancer 44:1497-1506, 2008 24. Burnett AK, Hills RK, Grimwade D, et al: Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: Results of the MRC AML15 trial. Leukemia 27:843-851, 2013 25. Appelbaum FR, Rosenblum D, Arceci RJ, et al: End points to establish the efficacy of new agents in the treatment of acute leukemia. Blood 109:1810-1816, 2007 26. Uyl-de Groot CA, Lowenberg B, Vellenga E, et al: Cost-effectiveness and quality-of-life assessment of GM-CSF as an adjunct to intensive remission induction chemotherapy in elderly patients with acute myeloid leukemia. Br J Haematol 100:629636, 1998 27. Tallman MS, Altman JK: How I treat acute promyelocytic leukemia. Blood 114:5126-5135, 2009 28. Bernhard J, Cella DF, Coates AS, et al: Missing quality of life data in cancer clinical trials: Serious problems and challenges. Stat Med 17:517-532, 1998 29. Basch E: Toward patient-centered drug development in oncology. N Engl J Med 369:397-400, 2013
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GLOSSARY TERMS
ATRA (all-trans retinoic acid): the molecule that activates retinoic acid receptors.
patient-reported outcomes: questionnaires used in a clinical setting to systemically collect information directly from the patient.
health-related quality of life (HRQoL): a broad multidimensional concept that usually includes self-reported measures of physical and mental health.
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Quality of Life in Patients With Acute Promyelocytic Leukemia
Acknowledgment We thank all patients who participated in this study and all participants and research staff of all centers within the Gruppo Italiano Malattie Ematologiche dell’Adulto, the German-Austrian Acute Myeloid Leukemia Study Group, and Study Alliance Leukemia.
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Randomized Phase III Trial of Retinoic Acid and Arsenic Trioxide Versus Retinoic Acid and Chemotherapy in Patients With Acute Promyelocytic Leukemia: Health-Related Quality-of-Life Outcomes Fabio Efficace, Franco Mandelli, Francesco Cottone, and Marco Vignetti, Gruppo Italiano Malattie Ematologiche dell’Adulto; Giuseppe Avvisati, Universita` Campus Biomedico; Massimo Breccia, Universita` “La Sapienza,”; Simona Sica, Universita` Cattolica Sacro Cuore; Sergio Amadori and Francesco Lo-Coco, Universita` Tor Vergata; Francesco Lo-Coco, Fondazione Santa Lucia, Roma; Felicetto Ferrara, Ospedale Cardarelli; Olimpia Finizio, Ospedale Cardarelli, Napoli; Eros Di Bona, Ospedale San Bortolo, Vicenza; Giorgina Specchia, Universita` di Bari, Bari; Alessandro Levis, Ospedale SS Antonio e Biagio, Alessandria; Maria Grazia Kropp, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro; Giuseppe Fioritoni, Ospedale Civile, Pescara; Elisa Cerqui, Spedali Civili, Brescia, Italy; Richard F. Schlenk, University of Ulm, Ulm; and Uwe Platzbecker, Universitatsklinikum Carl Gustav Carus, Dresden, Germany. Published online ahead of print at www.jco.org on September 22, 2014. Supported in Italy by the Associazione Italiana contro le Leucemie-linfomi e mieloma and Associazione Italiana per la Ricerca sul Cancro (Grant No. IG 5916 to F.L.-C.); in Germany by the Federal Ministry of Education and Research (Grant No. BMBF FKZ 01KG0903 to U.P.); and in part by Lundbeck (Montreal, Quebec, Canada). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Presented at the 19th Congress of the European Hematology Association, Milan, Italy, June 12-15, 2014. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT00482833. Corresponding author: Fabio Efficace, PhD, Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), GIMEMA Data Center, Via Benevento 6, 00161, Rome, Italy; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology 0732-183X/14/3230w-3406w/$20.00 DOI: 10.1200/JCO.2014.55.3453
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Fabio Efficace, Franco Mandelli, Giuseppe Avvisati, Francesco Cottone, Felicetto Ferrara, Eros Di Bona, Giorgina Specchia, Massimo Breccia, Alessandro Levis, Simona Sica, Olimpia Finizio, Maria Grazia Kropp, Giuseppe Fioritoni, Elisa Cerqui, Marco Vignetti, Sergio Amadori, Richard F. Schlenk, Uwe Platzbecker, and Francesco Lo-Coco A
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Purpose A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results. Patients and Methods HRQOL was a secondary end point of this trial. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 was used to assess HRQOL at end of induction and after consolidation therapy. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. Primary analysis was performed, estimating mean HRQOL score over time and differences between treatment arms using a linear mixed model. Results Overall, 162 patients age 18 to 70 years were enrolled. Of these, 150 and 142 patients were evaluable for HRQOL after induction therapy and third consolidation course, respectively. Overall compliance with HRQOL forms was 80.1%. The largest difference, favoring patients treated with ATRA plus arsenic trioxide, was found for fatigue severity (mean score difference, ⫺9.3; 95% CI, ⫺17.8 to ⫺0.7; P ⫽ .034) at end of induction therapy. This difference was also clinically relevant. HRQOL differences between treatment arms at end of consolidation showed that for several scales, differences between treatment arms were marginal. Conclusion Overall, current HRQOL findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk APL. J Clin Oncol 32:3406-3412. © 2014 by American Society of Clinical Oncology
INTRODUCTION
Acute promyelocytic leukemia (APL) is a special subtype of acute myeloid leukemia (AML) characterized by leukemic bone marrow infiltration by dysplastic promyelocytes, a specific chromosomal translocation [t(15;17)], and life-threatening coagulopathy.1 With the advent of modern treatment with all-trans-retinoic acid (ATRA) and anthracyclinebased chemotherapy, APL has become a highly curable disease, with long-term survival rates exceeding 75% as reported by several large multicenter trials. Thus, ATRA plus chemotherapy has been regarded until recently as the standard therapy for these patients.1,2
On the basis of earlier findings showing that arsenic trioxide, with or without ATRA, was also highly effective in APL and associated with a better safety profile,3-5 we recently carried out a phase III randomized clinical trial (RCT) to compare efficacy and toxicity of standard ATRA plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed APL.6 This RCT, conducted by the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA), the German-Austrian Acute Myeloid Leukemia Study Group (AMLSG), and Study Alliance Leukemia (SAL), showed that ATRA plus arsenic trioxide was at least not inferior to ATRA plus
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Quality of Life in Patients With Acute Promyelocytic Leukemia
chemotherapy with regard to 2-year event-free survival rate in patients with low- or intermediate-risk APL.6 However, because potential clinical benefits of newer experimental treatments need to be weighed against possible patients’ burden,7 and given the lack of published data on the impact of arsenic trioxide on patients’ symptoms and well being, healthrelated quality-of-life (HRQOL) assessment was included as a secondary end point of this RCT.6 Here, we report HRQOL findings of this study. PATIENTS AND METHODS Study Design and Patients The study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. It was designed to show that the combination of ATRA plus arsenic trioxide was not inferior to ATRA plus chemotherapy with respect to event-free survival rate at 2 years. Eligible patients were adults age 18 to 70 years with newly diagnosed, genetically confirmed low- or intermediate-risk APL (WBC at diagnosis ⱕ 10 ⫻ 109/L). Other inclusion criteria included WHO performance status
ⱕ 2 (where 0 is asymptomatic and higher numbers reflect greater functional compromise), creatinine ⱕ 3.0 mg/dL (ⱕ 260 mol/L), and bilirubin ⱕ 3.0 mg/dL (ⱕ 51 mol/L). Overall, 40 centers from GIMEMA and 27 centers from AMLSG and SAL participated in the study by enrolling at least one patient. Additional details have been reported previously.6 The trial was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of each participating center. All patients provided written informed consent. Procedures for HRQOL Assessment and Data Collection The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30; version 3) was used to assess HRQOL.8 This validated questionnaire consists of five functioning scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, nausea/vomiting, and pain), six single-item scales (dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global QOL scale. However, financial impact was not included in this analysis. Items were scaled and scored using recommended EORTC procedures.9 At time of study design, no leukemiaspecific HRQOL instrument was available. EORTC QLQ-C30 was thus implemented, having being successfully used in previous studies in patients with various types of leukemia including AML.10,11 In addition, this
Random assignment (N = 162)
Assigned to receive ATRA-arsenic trioxide (n = 82) Not eligible Major protocol violation
Assigned to receive ATRA-chemotherapy (n = 80) (n = 3) (n = 2)
Withdrew consent (n = 1)
Received at least one dose of ATRA-arsenic trioxide (n = 77)
Received at least one dose of ATRA-chemotherapy (n = 79)
Discontinued during induction (n = 2) Major protocol violation (n = 1) Withdrawn resulting from (n = 1) a medical decision
Died during induction Differentiation syndrome Ischemic stroke Bronchopneumonia
After induction therapy 1st HRQOL assessment Available for HRQOL analysis (n = 75) Did not have HRQOL form (n = 13)
Discontinued after induction Toxic effect Major protocol violation
Included in consolidation phase (n = 73)
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After induction therapy 1st HRQOL assessment Available for HRQOL analysis (n = 75) Did not have HRQOL form (n = 22)
(n = 2) (n = 1) (n = 1)
Discontinued after induction Toxic effect Lost to follow-up
Fig 1. Trial profile and available healthrelated quality-of-life (HRQOL) data. HRQOL assessments were performed at end of induction therapy and end of third consolidation course (ie, end of consolidation therapy for those randomly assigned to all-trans-retinoic acid [ATRA] plus chemotherapy).
(n = 2) (n = 1) (n = 1)
Included in consolidation phase (n = 73)
Died Bronchopneumonia + H1N1 infection
After third consolidation course 2nd HRQOL assessment Available for HRQOL analysis Did not have HRQOL form
(n = 4) (n = 2) (n = 1) (n = 1)
(n = 72) (n = 11)
(n = 1) (n = 1)
Died Hemorrhagic shock Pulmonary embolism Bronchopneumonia
After third consolidation course 2nd HRQOL assessment Available for HRQOL analysis Did not have HRQOL form
(n = 3) (n = 1) (n = 1) (n = 1)
(n = 70) (n = 12)
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is the most frequently used HRQOL measure in the setting of RCTs.12 Unlike other generic cancer measures, this is a heavily symptom-based questionnaire and is thus likely to capture relevant treatment-related adverse effects and overall patient morbidity. As per protocol, two assessments were performed: after induction therapy and at end of third consolidation course, corresponding to end of consolidation therapy for patients randomly assigned to ATRA plus chemotherapy. Acceptable time windows and definition of compliance of HRQOL assessments were a priori specified in the already published protocol.6 Whenever possible, questionnaires were administered at the hospital in a room where the patient would not be disturbed. The protocol specified that a responsible person (eg, nurse, clinician, or data manager) administer the questionnaire to the patient, requesting completion and its return to the GIMEMA Data Center. Patients themselves completed paper questionnaires. Because mode of HRQOL questionnaire administration can have important effects on the accuracy and quality of data obtained,13 guidelines for administering questionnaires were included in the study protocol to ensure a standard approach to data collection by all administrators. The HRQOL results in this trial are presented in accordance with high methodologic quality criteria for documenting patient-reported outcomes in RCTs.14-16 Statistical Methods HRQOL was a secondary outcome in this study. At the time the protocol was written, no studies had provided evidence on possible expected effects of arsenic trioxide on patient-reported outcomes; thus, no specific HRQOL scale of the EORTC QLQ-C30 was identified for primary analysis. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. HRQOL compliance was computed for each time point as percentage of returned valid questionnaires of those expected from patients still on study at that time. Differences in demographic, clinical, and biologic characteristics were assessed between patients who completed the questionnaire after induction and those who did not, using Fisher’s exact or Wilcoxon Mann-Whitney test as appropriate (␣ ⫽ 0.05). Primary analysis was performed estimating mean scores and their differences between treatment arms over time for all EORTC QLQ-C30 scales by a repeated measures linear mixed model with an unrestricted covariance structure. The model included treatment, assessment time, and treatment ⫻ time interaction. For each EORTC QLQ-C30 scale, the null hypothesis was tested that estimated differences between the two treatment arms equal 0 for all time points, by an overall F statistic. If this test was significant (␣ ⫽ 0.05), the estimated differences between treatment arms were tested separately for each single time point by a t test (␣ ⫽ 0.05). Estimated means and standard deviations (SDs) obtained from the model, their differences between treatment arms, and the corresponding 95% CIs are reported for all HRQOL assessments. Because of the exploratory nature of the study, we did not adjust P values for multiple testing. For each scale, clinical relevance of the estimated mean score differences between treatment arms was also interpreted according to recent evidence-based guidelines for EORTC QLQ-C30.17 Missing data were investigated to check their possible impact on results. Relationships between dropout and outcome were investigated, comparing mean observed HRQOL scores after induction between patients who returned the questionnaire after consolidation therapy and those who did not. Logistic regression analysis was used to examine the impact of key sociodemographic, biologic, and clinical characteristics on probability of not completing the HRQOL questionnaire at any time point assessment. Robustness of final results was assessed by the explicit regression model approach,18 identifying a linear regression model to predict a value to be imputed for each missing HRQOL scale. The linear regression model included variables related to the missing data mechanism as well as to the HRQOL values to be imputed. We then applied the previously described linear mixed model to the augmented data set. SAS statistical software (version 9.2; SAS Institute, Cary, NC) was used for all analyses. 3408
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RESULTS
Patient Characteristics Between October 2007 and September 2010, 162 patients were enrolled. Genetic tests excluded a diagnosis of PML-RARA–positive APL in three patients. Three of 159 patients with genetically proven APL did not start allocated treatment. The final HRQOL analysis thus included 156 patients who received at least one dose of the assigned therapy after random assignment. The flowchart of patients included in the final HRQOL analysis is shown in Figure 1. Event-free survival rates at 2 years after diagnosis were 97% and 86% for the ATRA plus arsenic trioxide versus ATRA plus chemotherapy groups, respectively
Table 1. Demographic, Clinical, and Biologic Characteristics of Patients With and Without HRQOL Assessment After Induction Therapy Without HRQOL Assessment (n ⫽ 41) Characteristicⴱ Sex Male Female Age, years Mean SD Median Range WBC count, ⫻ 109/L Mean SD Median Range Platelet count, ⫻ 109/L Mean SD Median Range Risk level‡ Low Intermediate PML-RARA isoform Long Short Missing Hemoglobin count, g/dL Mean SD Median Range Any toxicity§ No Yes
With HRQOL Assessment (n ⫽ 115
No.
%
No.
%
14 27
34.1 65.9
62 53
53.9 46.1
P† .030
.740 45.7 16.5 48 18.7-69.7
44.9 14.0 45 19.1-70.2
2.6 2.6 1.5 0.3-9.6
2.3 2.2 1.5 0.3-10.0
38.3 35.5 28 5.0-193.0
48.5 47.0 31 3.0-236.0
.995
.611
.159 12 29
29.3 70.7
48 67
41.7 58.3
23 17 1
56.1 41.5 2.4
70 43 2
60.9 37.4 1.7
.621
.083 9.0 1.8 8.6 5.6-12.9
9.6 2.0 9.2 4.3-14.6 .774
5 36
12.2 87.8
12 103
10.4 89.6
Abbreviations: HRQOL, health-related quality of life; SD, standard deviation. ⴱ Variables were measured at baseline, except for toxicity, which was measured during induction phase. †Fisher’s exact test used for sex, risk level, PML-RARA isoform, and any toxicity; Wilcoxon Mann-Whitney test used for remaining variables. ‡Low risk level defined as WBC count ⱕ 10 ⫻ 109/L and platelet count ⬎ 40 ⫻ 109/L at presentation; intermediate risk level defined as WBC count ⱕ 10 ⫻ 109/L and platelet count ⱕ 40 ⫻ 109/L at presentation. §Grades 3 to 4 during induction phase.
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Quality of Life in Patients With Acute Promyelocytic Leukemia
(difference, 11%; 95% CI, 2% to 22%; noninferiority P ⬍ .001). Detailed clinical efficacy and safety results have been reported elsewhere.6 HRQOL Compliance Rates Of 156 patients analyzed in the primary clinical analysis, 150 were eligible for HRQOL evaluation at end of induction therapy and 142 at end of third consolidation course. Overall compliance with HRQOL forms was 80.1%. After induction, 115 HRQOL forms were received of 150 expected (compliance, 77%), whereas after consolidation phase, 119 forms were received of 142 expected (compliance, 84%). No statistically significant differences were found in compliance rates between treatment arms (data not shown). Patient characteristics by HRQOL compliance at first assessment (ie, end of induction therapy) are listed in Table 1. HRQOL Differences Between Treatment Arms For each EORTC QLQ-C30 scale, Table 2 shows mean estimated scores and corresponding SDs by treatment group and timing of assessment. Estimated mean score differences between treatment arms with corresponding 95% CIs are graphically displayed in Figure 2. Fatigue was the only scale with a statistically significant overall difference between treatment arms (P ⫽ .022; Table 2). When considering single time points, fatigue severity was significantly lower in the group treated with ATRA plus arsenic trioxide (P ⫽ .034) after induction therapy. Mean fatigue scores of patients treated with ATRA plus arsenic trioxide versus those treated with ATRA plus chemotherapy were 29.1 (SD, 25.7) and 38.4 (SD, 28.1), respectively (⌬ ⫽ ⫺9.3; 95% CI, ⫺17.8 to ⫺0.7), reflecting a clinically relevant difference (albeit small; Fig 2). After third consolidation course, however, severity of fatigue was not significantly different between treatment groups (P ⫽ .660).
After induction therapy, there were also small but clinically relevant differences in severity of nausea/vomiting (⌬ ⫽ ⫺5.1; 95% CI, ⫺9.7 to ⫺0.5), appetite loss (⌬ ⫽ ⫺7.1; 95% CI, ⫺14.6 to 0.5), and constipation (⌬ ⫽ ⫺6.1; 95% CI, ⫺16.3 to 4.0), favoring patients treated with ATRA plus arsenic trioxide versus those treated with ATRA plus chemotherapy. With regard to functional aspects, physical (⌬ ⫽ 5.3; 95% CI, ⫺1.9 to 12.4) and cognitive functioning (⌬ ⫽ 5.9; 95% CI, ⫺1.2 to 12.9) also showed clinically relevant (albeit small) differences, favoring patients treated with ATRA plus arsenic trioxide (Fig 2). After third consolidation course, only severity of diarrhea showed a small clinically relevant difference (⌬ ⫽ 5.5; 95% CI, ⫺0.4 to 10.6), favoring patients treated with ATRA plus chemotherapy over those treated with ATRA plus arsenic trioxide. For all other symptoms and functional scales, magnitude of estimated mean score differences between treatment arms was trivial17 (Fig 2). Missing Data Mechanism and Supportive Analysis We compared mean observed HRQOL scores after induction between patients who returned the questionnaire after consolidation therapy and those who did not, and no statistically significant differences were found between groups (data not shown). Univariable logistic regression analysis showed that the missing data mechanism was independent of age, risk level, hemoglobin, time from diagnosis, and toxicity during induction (Table 3). However, sex was significantly associated with higher likelihood of missing data (P ⫽ .044). To assess the robustness of primary analysis results, the explicit regression model approach was used, identifying a linear regression model to predict a value for each missing HRQOL scale. The model was run separately for each arm and included sex, age, and toxicity during induction. Sex was included because it was significantly associated with HRQOL missing data, whereas age and toxicity during induction
Table 2. Estimated EORTC QLQ-C30 Mean Scores and SDs by Treatment Arm and HRQOL Assessment ATRA Plus Arsenic Trioxideⴱ After Third Consolidation Course
After Induction EORTC QLQ-C30 Scale
Mean Score
ATRA Plus Chemotherapyⴱ
SD
Mean Score
Physical functioning Role functioning Emotional functioning Cognitive functioning Social functioning Global health status/QOL
80.9 68.0 81.2 87.2 68.8 67.2
21.5 34.8 21.0 21.1 30.2 21.8
80.6 72.4 74.7 80.8 77.5 72.7
Fatigue Nausea/vomiting Pain Dyspnea Insomnia Appetite loss Constipation Diarrhea
29.1 3.1 16.1 15.8 16.2 5.6 14.5 8.6
25.7 13.9 25.3 24.8 28.7 22.6 30.5 20.6
29.8 5.3 16.9 16.7 21.2 5.3 5.3 7.8
SD
After Third Consolidation Course
After Induction Mean Score
Functional Scales 20.6 75.6 29.7 62.5 24.0 76.8 24.5 81.4 26.5 72.4 22.4 64.7 Symptom Scales 26.4 38.4 13.1 8.3 26.3 11.1 26.6 16.3 30.0 19.4 19.9 12.7 27.6 20.6 15.9 9.5
SD
Mean Score
SD
P†
23.5 38.1 23.0 23.1 33.1 24.1
81.9 75.8 79.6 82.4 78.0 72.9
21.5 31.0 25.1 25.8 27.6 23.4
.147 .280 .088 .089 .778 .761
28.1 15.2 27.8 27.1 31.4 24.8 33.4 22.5
27.9 5.7 17.2 17.5 19.4 8.1 7.7 2.3
27.4 13.5 27.4 27.6 31.2 21.0 28.6 16.3
.022 .095 .467 .978 .614 .183 .489 .106
Abbreviations: ATRA, all-trans-retinoic acid; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30; HRQOL, health-related quality of life; QOL, quality of life; SD, standard deviation. ⴱ Mean scores and corresponding SDs estimated by linear mixed model with unrestricted covariance structure. †For each scale, P value stems from overall F statistic testing null hypothesis that differences between two treatment arms were equal to zero for all time points.
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A
B DI QoL
CO
SF End of induction End of 3rd consolidation course
End of induction End of 3rd consolidation course
AP
SL
CF
DY EF
PA
RF NV
PF
FA
−15 −10
−5
ATRA-Chemotherapy Better
0
5
10
15
20
ATRA-Arsenic Trioxide Better
−20 −15 −10
DISCUSSION
We report that for patients with low- or intermediate-risk APL treated with ATRA plus arsenic trioxide, the HRQOL profile is at least as good as that for patients treated with ATRA plus chemotherapy. Our findings have important clinical implications, because they support the use of ATRA plus arsenic trioxide as preferred first-line treatment by showing that better clinical outcomes of this newer therapy6 can be obtained without detrimental effects on patients’ HRQOL. Rather, patients treated with ATRA plus arsenic trioxide reported statistically significantly less fatigue at end of induction therapy compared with patients treated with ATRA plus chemotherapy. Importantly, the © 2014 by American Society of Clinical Oncology
−5
ATRA-Arsenic Trioxide Better
were considered based on their importance in possibly influencing HRQOL outcomes. For each scale with a missing score, the value predicted by the linear regression model was imputed (single imputation). The same linear mixed model used for longitudinal analysis was then applied to the augmented data set, showing results similar to those of the primary analysis.
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Fig 2. Estimated differences in (A) functional and (B) symptom scales of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 mean scores and 95% CIs between all-trans-retinoic acid (ATRA) plus arsenic trioxide and ATRA plus chemotherapy arms at end of induction therapy and end of third consolidation course. Differences in mean scores (⌬ ⫽ ATRA plus arsenic trioxide ⫺ ATRA plus chemotherapy) and corresponding 95% CIs were estimated by linear mixed model with unrestricted covariance structure. Positive difference in functional scales indicates better outcomes in ATRA plus arsenic trioxide compared with ATRA plus chemotherapy arm; positive difference in symptom scales indicates better outcomes in ATRA plus chemotherapy compared with ATRA plus arsenic trioxide arm. AP, appetite loss; CF, cognitive functioning; CO, constipation; DI, diarrhea; DY, dyspnea; EF, emotional functioning; FA, fatigue; NV, nausea/vomiting; PA, pain; PF, physical functioning; QoL, global health status/quality of life; RF, role functioning; SF, social functioning; SL, insomnia. (*) Small clinically relevant difference (based on Cocks et al17).
0
5
10
15
ATRA-Chemotherapy Better
magnitude of this difference was also clinically relevant (albeit small).17 Fatigue has been shown to be the main factor affecting HRQOL of patients with AML,19 suggesting that our findings of lower fatigue severity after induction therapy might represent a major outcome of arsenic trioxide therapy. After induction, other key symptom and functional scales showed clinically relevant better outcomes for patients treated with ATRA plus arsenic trioxide (Fig 2), providing supporting evidence of the advantages of this newer treatment over standard ATRA plus chemotherapy. Another finding of the this study is that HRQOL differences between treatment arms at end of third consolidation course were substantially reduced, with diarrhea showing a small clinically relevant difference, favoring patients treated with ATRA plus chemotherapy (Fig 2). A possible explanation for this result is that patients randomly assigned to ATRA plus chemotherapy had higher margins for HRQOL recovery after having experienced a more burdensome induction therapy. Conversely, those treated with ATRA plus arsenic trioxide might have already adapted to improved HRQOL outcomes after induction and were thus less likely to experience any additional major improvements.20 Also, progress in supportive care approaches JOURNAL OF CLINICAL ONCOLOGY
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Quality of Life in Patients With Acute Promyelocytic Leukemia
Table 3. Univariable Analysis of Impact of Demographic, Clinical, and Biologic Characteristics on Probability of Missing HRQOL Assessment Variableⴱ
OR
95% CI
P
Sex (referent male) Age, years Risk level (referent low) PML-RARA isoform (referent long) WBC count, ⫻ 109/L Platelet count, ⫻ 109/L Hemoglobin count, g/dL Peripheral blood blasts, % Neutrophils, % Randomization arm (referent ATRA plus arsenic trioxide) Time from diagnosis to CR, days Any toxicity†
2.038 0.998 0.981 1.161 1.054 0.998 0.901 1.004 0.995
1.018 to 4.081 0.975 to 1.021 0.490 to 1.964 0.579 to 2.328 0.914 to 1.215 0.990 to 1.006 0.751 to 1.080 0.992 to 1.016 0.978 to 1.013
.044 .874 .956 .675 .472 .663 .258 .490 .603
1.298 1.023 0.821
0.658 to 2.559 0.984 to 1.062 0.285 to 2.365
.451 .249 .715
Abbreviations: ATRA, all-trans-retinoic acid; CR, complete response; HRQOL, health-related quality of life; OR, odds ratio. ⴱ Variables were measured at baseline, except for toxicity, which was measured during induction phase. †Grades 3 to 4 during induction phase.
associated with chemotherapy for AML21 might have further decreased the HRQOL differences between treatment arms after consolidation phase. Type of drug administration should also be considered when interpreting study findings, because in our RCT, arsenic trioxide was administered intravenously. Zhu et al22 recently reported that an orally administered formulation of arsenic trioxide was not inferior to intravenous arsenic trioxide in terms of disease-free survival at 2 years in patients with newly diagnosed APL. On the basis of this novel evidence,22 it will be important to investigate in future studies whether oral arsenic trioxide can further increase HRQOL benefits over standard chemotherapy-based approaches. Few leukemia RCTs have included HRQOL as an end point of the study,23 thus limiting evidence-based data on the impact of newer antileukemia drugs over standard therapies in terms of patientreported benefits. To our knowledge, the only RCT evaluating HRQOL in patients with APL was conducted by Burnett et al.24 They evaluated HRQOL over a 2-year period in patients randomly assigned to ATRA plus cytarabine-containing chemotherapy versus those receiving ATRA plus anthracycline-based chemotherapy. Minor differences in HRQOL outcomes were found, and the authors concluded that neither arm seemed to show a disadvantage over the long term.24 However, arsenic trioxide was not part of the treatment schema of this study, and it is therefore difficult to attempt a comparison with our results. Our study has some limitations. A baseline pretreatment HRQOL assessment (before randomization) was not available. Although HRQOL compliance is a major challenge in patients with acute leukemia,23,25,26 this can be particularly challenging in the specific case of APL, a disease representing a medical emergency resulting from frequent life-threatening coagulopathy, where current recommendations suggest starting ATRA therapy even before genetic confirmation of diagnosis.2,27 Thus, considering the poor clinical conditions of patients at disease onset, and a number of additional logistic and administrative factors that typically increase amount of missing data in large multicenter international studwww.jco.org
ies,28 a baseline assessment was not planned a priori in the protocol. Indeed, we expected low baseline compliance, having two main negative consequences in the successful conduct of the HRQOL study: first, limiting the conclusions we could have drawn from this assessment because of the small amount of available questionnaires, and second, negatively influencing attitude and motivation of investigators regarding further participation in HRQOL data collection. In any case, we note that patients were randomly allocated to the two treatment arms, and our supportive analysis did not find an association between HRQOL compliance and several key baseline clinical and biologic factors, thus limiting this aspect as a possible source of bias. Also, we are not able to draw conclusions regarding HRQOL after third consolidation course. We can speculate that long-term HRQOL might be better for patients treated with ATRA plus arsenic trioxide, because such patients only need to undertake another consolidation cycle of therapy.6 Conversely, those randomly assigned to ATRA plus chemotherapy will be receiving maintenance therapy for the successive 2 years.6 Future studies are needed to evaluate long-term HRQOL outcomes in both groups. This study also has strengths. Documenting the impact of newer drugs from the patient perspective is crucial,29 and we report, for the first time to our knowledge, the HRQOL impact of a newer chemotherapy-free treatment approach (ie, ATRA plus arsenic trioxide) in patients with acute leukemia. Also, although implementation of HRQOL assessment in acute leukemia RCTs is highly challenging, because of the possible large amount of missing data,25 our HRQOL compliance was satisfactory. Lastly, the influence of HRQOL missing data on study outcomes was fully investigated, and our additional supportive analysis confirmed robustness of main results. In conclusion, the HRQOL benefits of therapy with ATRA plus arsenic trioxide over standard ATRA plus chemotherapy are mainly relevant at end of induction therapy. Our HRQOL results extend previous clinical findings6 and can help physicians make more informed treatment decisions on first-line therapy for their newly diagnosed patients with APL.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Uwe Platzbecker, TEVA Pharmaceuticals Industries; Francesco Lo-Coco, TEVA Pharmaceuticals Industries, Lundbeck Research Funding: None Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None © 2014 by American Society of Clinical Oncology
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AUTHOR CONTRIBUTIONS Conception and design: Fabio Efficace, Franco Mandelli, Marco Vignetti, Francesco Lo-Coco Financial support: Fabio Efficace, Franco Mandelli Provision of study materials or patients: Felicetto Ferrara, Eros Di Bona, Massimo Breccia, Alessandro Levis, Simona Sica, Olimpia Finizio, Maria Grazia Kropp, Giuseppe Fioritoni, Elisa Cerqui, Richard F. Schlenk, Uwe Platzbecker
REFERENCES 1. Wang ZY, Chen Z: Acute promyelocytic leukemia: From highly fatal to highly curable. Blood 111:2505-2515, 2008 2. Sanz MA, Grimwade D, Tallman MS, et al: Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113:1875-1891, 2009 3. Ghavamzadeh A, Alimoghaddam K, Rostami S, et al: Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol 29:2753-2757, 2011 4. Ravandi F, Estey E, Jones D, et al: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27:504-510, 2009 5. Breccia M, Lo-Coco F: Arsenic trioxide for management of acute promyelocytic leukemia: Current evidence on its role in front-line therapy and recurrent disease. Expert Opin Pharmacother 13: 1031-1043, 2012 6. Lo-Coco F, Avvisati G, Vignetti M, et al: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369:111-121, 2013 7. Basch E: The missing voice of patients in drug-safety reporting. N Engl J Med 362:865-869, 2010 8. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 9. Fayers P, Aaronson N, Bjordal K, et al: EORTC QLQ-C30 Scoring Manual (ed 3). Brussels, Belgium, EORTC Publications, 2001 10. Catovsky D, Richards S, Matutes E, et al: Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): A randomised controlled trial. Lancet 370:230-239, 2007
Collection and assembly of data: Giuseppe Avvisati, Felicetto Ferrara, Eros Di Bona, Giorgina Specchia, Massimo Breccia, Alessandro Levis, Simona Sica, Olimpia Finizio, Maria Grazia Kropp, Giuseppe Fioritoni, Sergio Amadori, Richard F. Schlenk, Uwe Platzbecker, Francesco Lo-Coco Data analysis and interpretation: Fabio Efficace, Franco Mandelli, Francesco Cottone, Elisa Cerqui, Francesco Lo-Coco Manuscript writing: All authors Final approval of manuscript: All authors
11. Redaelli A, Stephens JM, Brandt S, et al: Short- and long-term effects of acute myeloid leukemia on patient health-related quality of life. Cancer Treat Rev 30:103-117, 2004 12. Efficace F, Osoba D, Gotay C, et al: Has the quality of health-related quality of life reporting in cancer clinical trials improved over time? Towards bridging the gap with clinical decision making. Ann Oncol 18:775-781, 2007 13. Bowling A: Mode of questionnaire administration can have serious effects on data quality. J Public Health (Oxf) 27:281-291, 2005 14. Efficace F, Bottomley A, Osoba D, et al: Beyond the development of health-related qualityof-life (HRQOL) measures: A checklist for evaluating HRQOL outcomes in cancer clinical trials—Does HRQOL evaluation in prostate cancer research inform clinical decision making? J Clin Oncol 21:35023511, 2003 15. Calvert M, Blazeby J, Altman DG, et al: Reporting of patient-reported outcomes in randomized trials: The CONSORT PRO extension. JAMA 309: 814-822, 2013 16. Brundage M, Blazeby J, Revicki D, et al: Patient-reported outcomes in randomized clinical trials: Development of ISOQOL reporting standards. Qual Life Res 22:1161-1175, 2013 17. Cocks K, King MT, Velikova G, et al: Evidencebased guidelines for determination of sample size and interpretation of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. J Clin Oncol 29:89-96, 2011 18. Fairclough D: Design and Analysis of Quality of Life Studies in Clinical Trials (ed 2). New York, NY, Chapman Hall/CRC, 2010 19. Schumacher A, Wewers D, Heinecke A, et al: Fatigue as an important aspect of quality of life in patients with acute myeloid leukemia. Leuk Res 26:355-362, 2002 20. Hamidou Z, Dabakuyo TS, Bonnetain F: Impact of response shift on longitudinal quality-of-life
assessment in cancer clinical trials. Expert Rev Pharmacoecon Outcomes Res 11:549-559, 2011 21. Derolf AR, Kristinsson SY, Andersson TM, et al: Improved patient survival for acute myeloid leukemia: A population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005. Blood 113:3666-3672, 2009 22. Zhu HH, Wu DP, Jin J, et al: Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: A multicenter randomized controlled trial. J Clin Oncol 31:4215-4221, 2013 23. Efficace F, Kemmler G, Vignetti M, et al: Health-related quality of life assessment and reported outcomes in leukaemia randomised controlled trials: A systematic review to evaluate the added value in supporting clinical decision making. Eur J Cancer 44:1497-1506, 2008 24. Burnett AK, Hills RK, Grimwade D, et al: Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: Results of the MRC AML15 trial. Leukemia 27:843-851, 2013 25. Appelbaum FR, Rosenblum D, Arceci RJ, et al: End points to establish the efficacy of new agents in the treatment of acute leukemia. Blood 109:1810-1816, 2007 26. Uyl-de Groot CA, Lowenberg B, Vellenga E, et al: Cost-effectiveness and quality-of-life assessment of GM-CSF as an adjunct to intensive remission induction chemotherapy in elderly patients with acute myeloid leukemia. Br J Haematol 100:629636, 1998 27. Tallman MS, Altman JK: How I treat acute promyelocytic leukemia. Blood 114:5126-5135, 2009 28. Bernhard J, Cella DF, Coates AS, et al: Missing quality of life data in cancer clinical trials: Serious problems and challenges. Stat Med 17:517-532, 1998 29. Basch E: Toward patient-centered drug development in oncology. N Engl J Med 369:397-400, 2013
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GLOSSARY TERMS
ATRA (all-trans retinoic acid): the molecule that activates retinoic acid receptors.
patient-reported outcomes: questionnaires used in a clinical setting to systemically collect information directly from the patient.
health-related quality of life (HRQoL): a broad multidimensional concept that usually includes self-reported measures of physical and mental health.
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Quality of Life in Patients With Acute Promyelocytic Leukemia
Acknowledgment We thank all patients who participated in this study and all participants and research staff of all centers within the Gruppo Italiano Malattie Ematologiche dell’Adulto, the German-Austrian Acute Myeloid Leukemia Study Group, and Study Alliance Leukemia.
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