I m p a c t o f A z a c y t i d i n e o n t h e Q u a l i t y o f L i f e o f P a t i e n t s
`W i t h M y e l o d y s p l a s t i c S y n d r o m e T r e a t e d i n a R a n d o m i z e d
`P h a s e I I I T r i a l : A C a n c e r a n d L e u k e m i a G r o u p B S t u d y
`
`By Alice B. Kornblith, James E. Herndon II, Lewis R. Silverman, Erin P. Demakos, Rosalie Odchimar-Reissig,
`James F. Holland, Bayard L. Powell, Carlos DeCastro, John Ellerton, Richard A. Larson, Charles A. Schiffer,
`and Jimmie C. Holland
`
`Purpose: The impact of azacytidine (Aza C) on the
`quality of life of 191 patients with myelodysplastic
`syndrome was assessed in a phase III Cancer and
`Leukemia Group B trial (9221).
`Patients and Methods: One hundred ninety-one pa-
`tients (mean age, 67.5 years; 69% male) were random-
`ized to receive either Aza C (75 mg/m2 subcutaneous
`for 7 days every 4 weeks) or supportive care, with
`supportive care patients crossing over to Aza C upon
`disease progression. Quality of life was assessed by
`centrally conducted telephone interviews at baseline
`and days 50, 106, and 182. Overall quality of life,
`psychological state, and social functioning were as-
`sessed by the European Organization for Research and
`Treatment of Cancer (EORTC) Quality of Life Question-
`naire C30 and the Mental Health Inventory (MHI).
`Results: Patients on the Aza C arm experienced signif-
`icantly greater improvement in fatigue (EORTC, P ⴝ .001),
`dyspnea (EORTC, P ⴝ .0014), physical functioning (EORTC,
`
`P ⴝ .0002), positive affect (MHI, P ⴝ .0077), and psycho-
`logical distress (MHI, P ⴝ .015) over the course of the
`study period than those in the supportive care arm. Par-
`ticularly striking were improvements in fatigue and psy-
`chological state (MHI) in patients treated with Aza C
`compared with those receiving supportive care for pa-
`tients who remained on study through at least day 106,
`corresponding to four cycles of Aza C. Significant differ-
`ences between the two groups in quality of life were main-
`tained even after controlling for the number of RBC
`transfusions.
`life for patients
`Improved quality of
`Conclusion:
`treated with Aza C coupled with significantly greater
`treatment response and delayed time to transformation
`to acute myeloid leukemia or death compared with pa-
`tients on supportive care (P < .001) establishes Aza C as an
`important treatment option for myelodysplastic syndrome.
`J Clin Oncol 20:2441-2452. © 2002 by American
`Society of Clinical Oncology.
`
`of life.5 It was hypothesized that a response to Aza C would
`result
`in improved quality of life attributable to better
`palliation, with less fatigue resulting in improved physical
`and social functioning and less psychological distress.
`
`THE PROGNOSIS FOR patients with myelodysplastic
`
`syndrome (MDS) is grim, with an overall median
`survival for those with high-risk MDS ranging between 6
`and 12 months.1 Presently, no treatment has been proven
`effective, including antileukemia chemotherapy, hormonal
`therapy, and differentiation-inducing agents.2,3 Allogeneic
`bone marrow transplantation (BMT) has offered the only
`real opportunity for cure, but because of treatment toxicity
`and the older age of the MDS population, it is an option for
`only a few individuals.1,3
`In 1985, a new agent, azacytidine (Aza C) was tested
`for safety and efficacy in two phase II studies in patients
`with poor-risk MDS within the Cancer and Leukemia
`Group B (CALGB).2 There was a demonstrated treatment
`response in 49% of 43 assessable patients (12% in
`complete remission; 25%, partial remission; and 12%,
`improved), with an overall median survival of 13.3
`months. Transfusion requirements were eliminated in
`82% (14 of 17) of patients who responded and had
`previously required RBC transfusions at study entry.2 In
`the second study, Aza C was administered subcutane-
`ously, with comparable results.4
`On the basis of these findings, a phase III randomized
`trial was initiated in the CALGB (CALGB 9221) in 1993 to
`test the clinical efficacy of Aza C and its impact on quality
`
`From the Dana-Farber Cancer Institute, Boston, MA; Cancer and
`Leukemia Group B Statistical Center, Duke University Medical Center,
`Durham, and Wake Forest University School of Medicine, Winston-Salem,
`NC; Mount Sinai School of Medicine and Department of Psychiatry and
`Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New
`York, NY; University Medical Center, South Nevada Community Clinical
`Oncology Program, Las Vegas, NV; University of Chicago Medical
`Center, Chicago, IL; and Barbara Ann Karmanos Cancer Institute, Wayne
`State University School of Medicine, Detroit, MI.
`Submitted April 9, 2001; accepted January 28, 2002.
`Supported by a grant no. 00111401 from the Food and Drug
`Administration,
`in part by grant no. CA31946 from the National
`Cancer Institute to the Cancer and Leukemia Group B, and by grants
`from the T.J. Martell Foundation for Leukemia, Cancer, and AIDS
`Research and the Abdullah Shanfari Memorial Fund.
`This work is solely the responsibility of the authors and does not
`necessarily represent the official views of any of the funding groups.
`Address reprint requests to Alice B. Kornblith, PhD, Women’s Cancers
`Program, Rm D1210, Dana-Farber Cancer Institute, 44 Binney St,
`Boston, MA 02115; email: Alice_Kornblith@dfci.harvard.edu.
`© 2002 by American Society of Clinical Oncology.
`0732-183X/02/2010-2441/$20.00
`CELGENE 2092
`APOTEX v. CELGENE
`IPR2023-00512
`Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
`
`Journal of Clinical Oncology, Vol 20, No 10 (May 15), 2002: pp 2441-2452
`DOI: 10.1200/JCO.2002.04.044
`
`2441
`
`

`

`2442
`
`PATIENTS AND METHODS
`
`Research Procedures
`All participants in the quality-of-life component of the clinical
`trial, CALGB 9221, had a diagnosis of MDS and on informed
`consent had been randomized to either Aza C (75 mg/m2 for 7 days
`subcutaneously every 28 days) or supportive care.5 Treatment arms
`were stratified by histologic subtype using French-American-British
`(FAB) criteria. Patients in both arms continued to receive best
`supportive care with transfusions, antibiotics, and hospitalizations.
`Eligibility requirements for the clinical trial were 16 years of age or
`older, an Eastern Cooperative Oncology Group (ECOG) perfor-
`mance status of 0 to 2,6 and no other serious medical or psychiatric
`illness. After a minimum period of 4 months,
`those on the
`supportive care arm could cross over to the Aza C arm based on
`strict criteria concerning disease progression (see the study by
`Silverman et al in this issue of the Journal of Clinical Oncology for
`an extended description). Patients exited from the supportive care
`arm within the first 4 months only because of leukemic transforma-
`tion or platelets less than 20 ⫻ 109/L.
`the following
`Quality-of-life assessments were scheduled at
`times: study entry, before randomization; day 50 (corresponding to
`completing two cycles of Aza C, and 6 days before a bone marrow
`test
`to assess treatment
`response); day 106 (corresponding to
`completing four cycles of Aza C, and 7 days before re-evaluation of
`treatment response); and day 182, approximately 6 months after
`entry to the study, to capture any sustained quality-of-life benefits at
`the time of maximum treatment response, based on our previous
`experience.2 Patients who crossed over from the supportive care arm
`to Aza C began the series of quality-of-life assessments again at that
`point. Quality-of-life assessment was discontinued when patients
`treated with Aza C either progressed or withdrew from the study.
`Before randomization, patients were given a quality-of-life packet
`of measures on entry onto the clinical
`trial, with a request
`to
`complete it at home within 2 to 3 days. This was followed by a
`telephone interview generally lasting 30 to 40 minutes, conducted
`by two trained nurse research interviewers (E.P.D. and R.O.R). This
`procedure was repeated at all subsequent
`interviews, with the
`quality-of-life questionnaire packet mailed to patients 7 to 10 days
`before the scheduled interview. The use of centralized telephone
`interviews to collect quality-of-life data has been successfully used
`in numerous studies within the CALGB.7
`
`Measures
`The quality-of-life assessment consisted of standardized measures
`assessing patients’ report of their physical symptoms and functioning,
`psychological state, and social functioning. All measures were admin-
`istered at each assessment, except for sociodemographic questions,
`which were asked only at study entry, and the Perception of Improve-
`ment of Condition item, which was administered only to those taking
`Aza C at follow-up assessments.
`European Organization for Research and Treatment of Cancer
`Quality of Life Questionnaire C30. The European Organization for
`Research and Treatment of Cancer
`(EORTC) Quality of Life
`Questionnaire-C30 is a measure of quality of life applicable to
`patients with any cancer diagnosis, consisting of 30 items concern-
`ing general physical symptoms, physical functioning, fatigue and
`malaise, and social and emotional functioning.8,9 All subscale
`scores are transformed to a 0 to 100 scale. Higher scores on
`
`KORNBLITH ET AL
`
`functional scales represented a better level of functioning; higher
`scores on symptom scales represented worsening symptoms.
`Mental Health Inventory. The Mental Health Inventory (MHI),10
`a measure of psychological state, consists of 38 items grouped into
`the following five subscales: anxiety, depression, positive affect,
`emotional ties, and loss of behavioral and emotional control. The
`total score,
`the MHI
`index, and two global subscale scores,
`psychological distress and psychological well-being, are created
`from these subscales. Higher scores on the MHI index and subscales
`measuring positive affect and well-being indicate a better emotional
`state; higher scores on negative psychological states indicate a
`worse emotional state. The MHI has been tested on 5,000 respon-
`dents from six communities, which has served as the basis for the
`norms for the measure.10
`Patients’ perception of improvement in their condition. Patients
`randomized to the Aza C arm and those who later crossed over to
`treatment were asked at each follow-up assessment to rate whether
`they felt their condition was improving as a result of their treatment
`on an 11-point visual analog scale, from 0, “not at all,” to 10,
`“complete improvement.”
`Sociodemographic and medical characteristics. Standard ques-
`tions were used to obtain sociodemographic information at the time of
`interview,11 and age and ethnicity were obtained at the time of patient
`registration. Medical
`information was collected from the medical
`record, including histologic diagnosis (as determined by central pathol-
`ogy review), ECOG performance status rating6 at baseline, treatment
`response, and number of RBCs, platelet transfusions, and infections.
`Statistical Considerations
`Because of patient attrition over the course of the study attribut-
`able to disease progression, illness, and death, a pattern mixture
`model was used to analyze changes in quality of life over the study
`period, which took into account
`the number of quality-of-life
`assessments over time (ie, the pattern).12,13 Patients were therefore
`categorized into four subgroups, based on the time of their last
`quality-of-life assessment, with subgroups generally coinciding
`with the number of assessments, as follows: subgroup 1, patients at
`study entry within 39 days after randomization, including a few
`patients with two assessments within this time interval; subgroup 2,
`mostly consisting of those assessed twice, with the last assessment
`occurring between days 40 and 82; subgroup 3, mostly consisting of
`patients assessed three times, with the last assessment conducted
`between days 83 and 159; and subgroup 4, mostly consisting of
`those assessed four times, with the last assessment conducted
`between days 160 and 259. These subgroups thus formed the
`patterns for the original two-arm design of the study. Within each
`subgroup, or pattern, a form of regression analysis,
`the linear
`random coefficient model, was used to test the effect of treatment
`arm and time on patients’ quality of life. To statistically control for
`covariables to test
`the effect of crossing over to Aza C from
`supportive care on patients’ quality of life, FAB subtypes and time
`elapsed after crossing over from the supportive care arm to Aza C
`were incorporated into the model. Data from subgroup 1 (n ⫽ 31)
`and subgroup 2 (n ⫽ 18) were combined in the analyses because of
`relatively small numbers in these subgroups and the assumption that
`treatment differences would be similar. For patients in the support-
`ive care arm who crossed over to Aza C, subgroup classification was
`determined by the time from study entry to their last quality-of-life
`assessment on Aza C. It should be noted that although the original
`ideal points of assessment were study entry and days 50, 106, and
`182, there was significant variability in the actual time patients were
`
`Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
`
`

`

`MDS PATIENTS’ QUALITY OF LIFE ON AZA C
`
`assessed because of their illness or their being on vacation, delays
`in the mail, and interviewer and patient availability.
`All of the quality-of-life measures were tested for significant
`differences between the treatment groups at baseline. The EORTC role
`functioning subscale was the only variable found to be significantly
`different at baseline between the two treatment arms. There were no
`other statistically significant differences between the two arms of the
`study for any of the remaining scales and subscales.
`MHI scores were compared with norms for each of the subscales and
`total score to identify patients in severe distress with scores 1.5 SD
`above the norm.10 Based on reports by Osoba et al14 and King15 that a
`10-point change on the EORTC was comparable to a clinically
`significant improvement, the percentage of patients was calculated by
`treatment arm whose scores on EORTC subscales and total scores
`improved by 10 points or more at follow-up assessments from study
`entry levels.
`
`Statistical Power Considerations
`With 191 patients in the trial, the study had 80% power to detect
`a medium effect size of 0.57 (comparable with 0.54 of a SD, based
`on standardized means) between treatment arms in three quality-of-
`life measures for the change from baseline to the second follow-up
`assessment at day 106. Because there were three primary end points,
`MHI, EORTC fatigue subscale, and EORTC physical functioning
`subscale, the significance level used for determining the sample size
`was reduced to 0.017 (0.05/3) using Bonferroni’s method.16
`
`RESULTS
`
`Patient Characteristics
`One hundred ninety-one patients were accrued to the
`clinical trial from February 1994 to April 1996, with 99%
`having completed the baseline quality-of-life assessment.
`The mean age of patients was 67.5 years (SD, 10.3
`years), and most were male (69%), white (93%), married
`(61%), and not presently employed (retired, 36%; dis-
`abled or unemployed, 23%) (Table 1). Our sample was
`more heavily represented by men than women than is
`usually indicated in epidemiologic studies.1 There were
`no significant differences between the two treatment
`arms on study entry in any of the sociodemographic or
`medical characteristics.
`Of the 99 patients initially randomized to Aza C, 56% (n ⫽
`56) remained on active treatment by day 182; 16% (n ⫽ 16)
`had died; 22% (n ⫽ 22) had terminated protocol treatment
`because of treatment failure, toxicity, or transformation to
`AML; and 5% (n ⫽ 5) refused to complete the quality-of-life
`questionnaires. Of the 92 patients initially randomized to
`supportive care, 47% (n ⫽ 43) remained on study with
`quality-of-life data collected through day 182, including 13%
`(n ⫽ 12) who remained on supportive care, 34% (n ⫽ 31) who
`remained on Aza C after cross-over, 23% (n ⫽ 21) who had
`died, 26% (n ⫽ 24) who had terminated protocol treatment,
`and 4% (n ⫽ 4) who refused to continue in the quality-of-life
`study. There were 80.4% (n ⫽ 74) and 61.9% (n ⫽ 57) of
`
`2443
`
`Table 1. Patients’ Medical and Sociodemographic Characteristics
`
`Characteristic
`
`Supportive Care
`(n ⫽ 92) (%)
`
`Aza C
`(n ⫽ 99) (%)
`
`Total
`(n ⫽ 191) (%)
`
`Sex
`Male
`Female
`Race
`White
`Black
`Hispanic/Asian
`Age
`30-49
`50-59
`60-69
`70-79
`80⫹
`Mean ⫾ SD, years
`Median, years
`Range, years
`Marital Status
`Married
`Separated/divorced
`Widowed
`Single, never married
`Unknown
`Education
`1-11 grades
`High school graduate
`Some college/junior college
`degree
`Bachelor’s degree or higher
`Unknown
`Present employment
`Part- or full-time
`Homemaker
`Retired
`Disabled/unemployed
`Unknown
`Performance status
`0
`1
`2
`Unknown
`Histology
`RA
`RARS
`RAEB
`RAEB-T
`CMMoL
`Other
`
`65
`35
`
`92
`5
`2
`
`73
`27
`
`94
`3
`3
`
`69
`31
`
`93
`4
`3
`
`6
`7
`5
`12
`10
`13
`39
`37
`40
`32
`36
`27
`12
`9
`14
`67.9 ⫾ 10.3 67.3 ⫾ 10.4 67.5 ⫾ 10.3
`67
`69
`68
`35-88
`31-92
`31-92
`
`65
`5
`12
`3
`14
`
`16
`27
`23
`
`16
`18
`
`24
`3
`36
`21
`16
`
`30
`52
`15
`2
`
`20
`3
`42
`20
`7
`9
`
`58
`6
`11
`4
`21
`
`19
`18
`21
`
`21
`20
`
`17
`3
`35
`24
`20
`
`37
`47
`12
`3
`
`19
`4
`42
`22
`6
`6
`
`61
`6
`12
`4
`18
`
`18
`23
`22
`
`18
`19
`
`20
`3
`36
`23
`18
`
`34
`50
`14
`3
`
`19
`4
`42
`21
`6
`7
`
`Abbreviations: RA, refractory anemia; RARS, refractory anemia with ringed
`sideroblasts; RAEB, refractory anemia with excess blasts; RAEB-T, refractory
`anemia with excess blasts in transformation to leukemia; CMMoL, chronic
`myelomonocytic leukemia.
`
`supportive care patients still on supportive care, completing
`quality-of-life assessments, at days 50 and 106, respectively.
`
`Comparison of Quality of Life of Patients on
`Aza C Arm Versus Supportive Care Arm
`Over time, patients on the Aza C arm experienced
`significantly greater improvement in fatigue (EORTC, P
`
`Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
`
`

`

`2444
`
`⫽ .001), dyspnea (EORTC, P ⫽ .0014), physical func-
`tioning (EORTC, P ⫽ .0002), positive affect (MHI, P ⫽
`.0077), and psychological distress (MHI, P ⫽ .015) than
`those in the supportive care arm (Tables 2, 3, and 4). As
`can be seen in Figs 1 through 4, which illustrate the
`EORTC fatigue, dyspnea, physical functioning, and MHI
`psychological well-being subscales, patients’ quality of
`life for subgroups 3 and 4 was generally stable or
`worsening while on supportive care, compared with an
`improving quality of life for those on the Aza C arm. This
`was statistically demonstrated by the slopes of
`the
`regression lines for subgroups 3 and 4 often being in the
`opposite direction for the Aza C arm compared with the
`supportive care arm for many of the measures (Table 4
`and Figs 1 through 4). Despite the considerable variabil-
`ity in patients’ reporting of symptoms and functioning, as
`seen by the standard errors of the slopes in the regres-
`sions (Table 4), many of the differences between treat-
`ment arms were highly significant.
`The correlations between the baseline measures of
`physical symptoms and functioning (ECOG performance
`status; EORTC subscales) with those of psychological
`state indicated a significant
`interrelationship between
`patients’ physical status and psychosocial state (MHI
`psychological distress, r ⫽ .17 to .46; P ⬍ .05 to
`⬍ .0001; median, r ⫽ .30; P ⬍ .001). These correla-
`tions suggested that physical improvement was the likely
`cause for the psychological
`improvement of patients
`taking Aza C.
`Because RBC transfusions were more frequently ad-
`ministered in the Aza C group compared with the
`supportive care arm (P ⫽ .002) during the first month on
`study, it was possible that these transfusions were respon-
`sible for the significant improvements in patients’ fa-
`tigue, physical
`functioning, and psychological
`state
`rather than Aza C. When RBC transfusions were statis-
`tically controlled for in the linear random coefficient
`model, significant differences between treatment arms
`were still maintained at the adjusted alpha level for the
`EORTC fatigue, dyspnea, physical functioning, and MHI
`psychological well-being subscales. The sole exception
`was the MHI psychological distress subscale, with treat-
`ment arm differences becoming nonsignificant at P ⫽
`.017 (Bonferroni-adjusted alpha level),14 on controlling
`for RBC transfusions (P ⫽ .038).
`Quality-of-life measures before and after cross-over
`were compared for patients who had at least one quality-
`of-life assessment after cross-over (n ⫽ 38). Before
`cross-over, patients’ quality of life was found to be either
`stable or slowly worsening, varying by quality-of-life
`area. However, subsequent to cross-over to Aza C, there
`
`KORNBLITH ET AL
`
`was a significant improvement in the rates of change in
`several areas, comparable with those observed for the
`entire sample, including EORTC physical functioning,
`fatigue, dyspnea, and overall quality-of-life subscales
`and MHI global psychological distress and well-being
`subscales at the adjusted alpha level (Table 4). Figures 5
`and 6, concerning several EORTC and MHI subscales,
`portray this for the 30 supportive care patients who
`crossed over to Aza C after approximately 4 months on
`supportive care and who were followed for a mean of
`4 months on Aza C therapy. Patients also reported that
`their conditions were improving after cross-over to Aza C
`(P ⫽ .0001).
`FAB histology subtypes were grouped into patients with
`better (refractory anemia [RA], RA with ringed sideroblasts;
`n ⫽ 44) and worse (RA with excess blasts, RA with
`excessive blasts in transformation to leukemia, chronic
`myelomonocytic leukemia; n ⫽ 133) prognoses1 to test
`whether disease prognosis influenced the relationship be-
`tween treatment arm and quality of life. There was no
`evidence of histologic subtypes significantly influencing
`patients’ quality-of-life scores.
`
`Clinical Significance
`The ECOG performance status and MHI psychological
`distress subscale were used to examine whether the statis-
`tically significant differences in psychological status and
`physical functioning between treatment arms were clinically
`meaningful. The translation of the EORTC physical func-
`tioning scores to ECOG ratings at follow-up assessment
`from baseline levels was done by calculating the means of
`the EORTC physical functioning scale scores at baseline for
`the total sample for each of the ECOG ratings (ECOG 0 ⫽
`74.9; 1 ⫽ 62.7; 2 ⫽ 38.3). These scores then served as
`benchmarks for each of the ECOG ratings. The benchmark
`EORTC physical functioning means at baseline for ECOG
`0, 1, and 2 were then subdivided into deciles matched to
`deciles we constructed between ECOG ratings of 0 and 1
`and 1 and 2. The actual EORTC scores for each of the
`subgroups for each treatment arm were then compared with
`these benchmark EORTC decile means related to the decile
`ECOG ratings.
`Using these values as benchmarks for a clinically
`meaningful change, the improvement in physical func-
`tioning in Aza C subgroup 3 patients at day 106 was
`comparable with an improvement in the ECOG score
`from approximately 1.3 to 0.7, whereas patients in the
`supportive care arm worsened from an ECOG status of
`1.1 to 1.5 (see Table 5). Analyses of subgroup 4 were
`somewhat similar, with Aza C patients showing that an
`improved EORTC physical functioning score at day 182
`
`Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
`
`

`

`MDS PATIENTS’ QUALITY OF LIFE ON AZA C
`
`Table 2. Means of Selected EORTC OLQ-C30 and MHI Scales for Each Subgroup for Supportive Care*
`
`QoL Scale
`
`Mean
`
`Baseline
`No.
`
`SD
`
`Mean
`
`F/U 1
`No.
`
`Supportive Care
`
`SD
`
`Mean
`
`F/U 2
`No.
`
`SD
`
`Mean
`
`F/U 3
`No.
`
`52.0
`77.8
`63.5
`70.2
`
`47.8
`42.8
`34.1
`39.5
`
`35.3
`36.7
`27.3
`26.1
`
`28.7
`18.3
`23.0
`23.1
`
`15
`9
`23
`43
`
`15
`9
`22
`43
`
`15
`9
`23
`43
`
`15
`9
`23
`43
`
`29.1
`18.6
`28.7
`24.1
`
`22.5
`18.6
`26.7
`24.3
`
`29.3
`11.0
`21.6
`19.8
`
`30.4
`17.4
`23.2
`25.6
`
`—
`56.0
`62.7
`68.6
`
`—
`47.4
`42.5
`37.9
`
`—
`43.0
`25.5
`30.6
`
`—
`33.2
`27.1
`22.0
`
`—
`10
`22
`42
`
`—
`10
`21
`41
`
`—
`10
`22
`42
`
`—
`10
`22
`42
`
`—
`32.4
`32.3
`22.2
`
`—
`22.8
`24.5
`18.3
`
`—
`27.4
`20.2
`19.8
`
`—
`41.5
`26.4
`22.7
`
`—
`—
`49.5
`67.4
`
`—
`—
`47.2
`38.0
`
`—
`—
`33.1
`34.9
`
`—
`—
`28.3
`19.8
`
`—
`—
`61.6
`76.8
`
`—
`—
`21
`35
`
`—
`—
`21
`35
`
`—
`—
`21
`35
`
`—
`—
`21
`35
`
`—
`—
`21
`35
`
`—
`—
`35.0
`21.7
`
`—
`—
`27.4
`17.8
`
`—
`—
`23.5
`19.5
`
`—
`—
`24.1
`21.5
`
`—
`—
`30.3
`23.8
`
`—
`—
`—
`65.0
`
`—
`—
`—
`42.2
`
`—
`—
`—
`30.3
`
`—
`—
`—
`27.5
`
`—
`—
`—
`69.1
`
`—
`—
`—
`12
`
`—
`—
`—
`12
`
`—
`—
`—
`12
`
`—
`—
`—
`12
`
`—
`—
`—
`12
`
`2445
`
`SD
`
`—
`—
`—
`24.3
`
`—
`—
`—
`24.3
`
`—
`—
`—
`26.2
`
`—
`—
`—
`23.7
`
`—
`—
`—
`25.6
`
`EORTC
`Physical functioning†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Fatigue‡
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Dyspnea‡
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Insomnia‡
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Social function†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Overall QoL†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`
`MHI
`MHI index†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Psychological distress‡
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Psychological well-being†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Positive affect†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`
`63.2
`60.8
`70.0
`77.2
`
`46.3
`53.6
`50.8
`56.9
`
`166.5
`170.7
`187.3
`170.2
`
`52.6
`50.2
`39.9
`50.9
`
`53.1
`54.9
`61.2
`54.9
`
`35.4
`37.2
`41.3
`36.9
`
`16
`9
`23
`43
`
`16
`9
`23
`43
`
`16
`9
`23
`43
`
`16
`9
`23
`43
`
`16
`9
`23
`43
`
`16
`9
`23
`43
`
`17.5
`26.5
`31.0
`21.0
`
`14.9
`25.8
`28.3
`20.2
`
`24.4
`34.7
`20.1
`26.0
`
`13.9
`19.9
`9.5
`15.1
`
`11.9
`16.5
`12.6
`12.6
`
`9.1
`12.5
`10.7
`10.3
`
`—
`43.1
`73.2
`79.9
`
`—
`38.3
`54.6
`58.9
`
`—
`160.6
`185.0
`175.6
`
`—
`55.2
`43.1
`46.4
`
`—
`49.8
`62.1
`56.0
`
`—
`33.3
`42.4
`37.9
`
`—
`10
`22
`42
`
`—
`10
`22
`41
`
`—
`10
`22
`42
`
`—
`10
`22
`42
`
`—
`10
`22
`42
`
`—
`10
`22
`42
`
`—
`5.2
`27.2
`25.4
`
`—
`22.7
`28.0
`18.9
`
`—
`36.3
`25.2
`22.7
`
`—
`22.4
`13.3
`12.3
`
`—
`16.3
`13.5
`12.5
`
`—
`13.3
`11.2
`9.8
`
`—
`—
`39.3
`56.6
`
`—
`—
`181.0
`177.6
`
`—
`—
`44.6
`45.3
`
`—
`—
`59.6
`56.7
`
`—
`—
`40.0
`38.0
`
`—
`—
`21
`35
`
`—
`—
`21
`35
`
`—
`—
`21
`35
`
`—
`—
`21
`35
`
`—
`—
`21
`35
`
`—
`—
`26.6
`20.5
`
`—
`—
`29.6
`22.1
`
`—
`—
`17.8
`11.5
`
`—
`—
`14.0
`12.3
`
`—
`—
`11.4
`10.0
`
`—
`—
`—
`51.3
`
`—
`—
`—
`169.4
`
`—
`—
`—
`48.3
`
`—
`—
`—
`51.8
`
`—
`—
`—
`34.3
`
`—
`—
`—
`12
`
`—
`—
`—
`12
`
`—
`—
`—
`12
`
`—
`—
`—
`12
`
`—
`—
`—
`12
`
`—
`—
`—
`21.5
`
`—
`—
`—
`22.8
`
`—
`—
`—
`11.0
`
`—
`—
`—
`12.7
`
`—
`—
`—
`10.1
`
`NOTE. Subgroups generally coincided with the number of follow-up assessments, as follows: subgroup 1, one assessment or baseline assessment only; subgroup
`2, two assessments or baseline ⫹ one follow-up at day 50; subgroup 3, three assessments or baseline through second follow-up at day 106; subgroup 4, four
`assessments or baseline through third follow-up at day 182.
`Abbreviation: F/U, follow-up.
`*Means for supportive care arm are before cross-over.
`†Higher scores indicate better functioning.
`‡Higher scores indicate worse symptoms.
`
`Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
`
`

`

`2446
`
`KORNBLITH ET AL
`
`Table 3. Means of Selected EORTC OLQ-C30 and MHI Scales for Each Subgroup for Aza C*
`
`Aza C
`
`QoL Scale
`
`Mean
`
`No.
`
`SD
`
`Mean
`
`Baseline
`
`F/U 1
`
`No.
`
`SD
`
`Mean
`
`F/U 2
`
`No.
`
`SD
`
`Mean
`
`F/U 3
`
`No.
`
`53.3
`68.9
`55.8
`64.3
`
`47.7
`37.9
`44.1
`39.4
`
`39.6
`29.3
`41.8
`36.0
`
`33.0
`22.1
`24.3
`33.7
`
`15
`9
`19
`56
`
`15
`9
`19
`56
`
`15
`9
`19
`56
`
`15
`9
`19
`56
`
`22.3
`20.3
`20.6
`28.0
`
`21.5
`18.3
`24.5
`24.2
`
`22.3
`11.0
`31.1
`24.6
`
`27.9
`33.3
`21.6
`33.2
`
`—
`58.9
`53.3
`65.0
`
`—
`42.8
`39.2
`37.0
`
`—
`29.3
`42.2
`33.0
`
`—
`33.0
`22.0
`25.8
`
`—
`9
`18
`55
`
`—
`9
`18
`55
`
`—
`9
`18
`55
`
`—
`9
`18
`55
`
`—
`28.5
`23.8
`26.7
`
`—
`16.0
`17.9
`20.0
`
`—
`19.8
`22.2
`21.1
`
`—
`23.3
`25.3
`28.3
`
`—
`—
`66.3
`70.3
`
`—
`—
`38.8
`31.2
`
`—
`—
`33.0
`28.6
`
`—
`—
`27.8
`17.1
`
`—
`—
`19
`54
`
`—
`—
`19
`54
`
`—
`—
`19
`53
`
`—
`—
`19
`54
`
`—
`—
`28.3
`26.0
`
`—
`—
`19.3
`18.4
`
`—
`—
`22.0
`23.4
`
`—
`—
`31.8
`22.0
`
`—
`—
`23.7
`22.6
`
`—
`—
`—
`77.1
`
`—
`—
`—
`26.2
`
`—
`—
`—
`22.0
`
`—
`—
`—
`16.2
`
`—
`—
`—
`77.3
`
`—
`—
`—
`55
`
`—
`—
`—
`55
`
`—
`—
`—
`55
`
`—
`—
`—
`55
`
`—
`—
`—
`55
`
`SD
`
`—
`—
`—
`4.5
`
`—
`—
`—
`21.2
`
`—
`—
`—
`23.0
`
`—
`—
`—
`23.7
`
`—
`—
`—
`22.4
`
`EORTC
`Physical functioning†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Fatigue‡
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Dyspnea‡
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Insomnia‡
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Social function†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Overall QoL†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`
`MHI
`MHI index†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Psychological distress‡
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Psychological well-being†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`Positive affect†
`Subgroup 1
`Subgroup 2
`Subgroup 3
`Subgroup 4
`
`61.8
`75.7
`80.4
`69.6
`
`47.1
`59.1
`52.6
`54.0
`
`167.6
`172.2
`169.9
`175.3
`
`50.9
`49.8
`52.3
`48.6
`
`52.1
`56.0
`56.2
`57.7
`
`34.3
`37.8
`37.2
`38.9
`
`15
`9
`19
`56
`
`15
`9
`19
`56
`
`15
`9
`18
`56
`
`15
`9
`18
`56
`
`15
`9
`18
`56
`
`15
`9
`18
`56
`
`25.6
`30.3
`15.2
`26.6
`
`14.4
`18.8
`24.9
`22.9
`
`29.2
`30.9
`26.0
`30.7
`
`16.5
`17.3
`15.9
`17.8
`
`14.7
`15.6
`11.9
`14.5
`
`11.6
`12.1
`10.1
`11.2
`
`—
`53.4
`68.2
`68.2
`
`—
`49.9
`54.1
`56.9
`
`—
`163.4
`172.2
`179.7
`
`—
`52.6
`51.0
`45.7
`
`—
`50.0
`57.2
`59.4
`
`—
`33.1
`38.4
`40.2
`
`—
`9
`18
`55
`
`—
`9
`18
`55
`
`—
`9
`18
`55
`
`—
`9
`18
`55
`
`—
`9
`18
`55
`
`—
`9
`18
`55
`
`—
`36.1
`26.9
`25.9
`
`—
`17.2
`19.1
`21.2
`
`—
`27.5
`25.5
`29.2
`
`—
`14.7
`15.2
`17.7
`
`—
`14.1
`11.6
`13.3
`
`—
`11.4
`9.8
`10.3
`
`—
`—
`71.6
`71.9
`
`—
`—
`63.3
`65.9
`
`—
`—
`176.9
`184.7
`
`—
`—
`47.8
`43.2
`
`—
`—
`58.6
`61.9
`
`—
`—
`39.6
`42.3
`
`—
`—
`19
`54
`
`—
`—
`19
`54
`
`—
`—
`19
`54
`
`—
`—
`19
`54
`
`—
`—
`19
`54
`
`—
`—
`19
`54
`
`—
`—
`20.1
`18.4
`
`—
`—
`22.0
`25.3
`
`—
`—
`14.0
`14.4
`
`—
`—
`9.9
`12.4
`
`—
`—
`8.4
`9.8
`
`—
`—
`—
`73.3
`
`—
`—
`—
`192.7
`
`—
`—
`—
`38.8
`
`—
`—
`—
`65.5
`
`—
`—
`—
`45.4
`
`—
`—
`—
`55
`
`—
`—
`—
`54
`
`—
`—
`—
`54
`
`—
`—
`—
`55
`
`—
`—
`—
`55
`
`—
`—
`—
`20.1
`
`—
`—
`—
`24.8
`
`—
`—
`—
`14.3
`
`—
`—
`—
`11.5
`
`—
`—
`—
`9.0
`
`NOTE. Subgroups generally coincided with the number of follow-up assessments, as follows: subgroup 1, one assessment or baseline assessment only; subgroup
`2, two assessments or baseline ⫹ one follow-up at day 50; subgroup 3, three assessments or baseline through second follow-up at day 106; subgroup 4, four
`assessments or baseline through third follow-up at day 182.
`Abbreviation: F/U, follow-up.
`*Means for supportive care arm are before cross-over.
`†Higher scores indicate better functioning.
`‡Higher scores indicate worse symptoms.
`
`Copyright © 2002 American Society of Clinical Oncology. All rights reserved.
`
`

`

`MDS PATIENTS’ QUALITY OF LIFE ON AZA C
`
`2447
`
`Table 4. QoL of Patients Treated With Aza C Versus Supportive Care: Summary of Significant Findings From Linear Regression Analyses
`
`QoL Scale
`
`No.
`
`Supportive Care
`Slope
`
`SE
`
`No.
`
`EORTC
`Physical functioning*
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`Fatigue¶
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`Dyspnea¶
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`Insomnia¶
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`Social functioning*
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`Overall QoL*
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`
`MHI
`MHI index*
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`Psychological distress¶
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`Psychological well-being*
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`Positive affect*
`Subgroup 1/2
`Subgroup 3
`Subgroup 4
`After cross-over
`
`26
`23
`43
`
`26
`23
`43
`
`26
`23
`43
`
`26
`23
`43
`
`26
`23
`43
`
`26
`23
`43
`
`26
`23
`43
`
`26
`23
`43
`
`26
`23
`43
`
`26
`23
`43
`
`⫺0.12
`⫺0.13
`⫺0.025
`0.12
`
`0.11
`0.12
`0.02
`⫺0.14
`
`0.18
`0.05
`0.04
`⫺0.16
`
`0.28
`0.03
`0.004
`⫺0.10
`
`⫺0.38
`⫺0.10
`⫺0.04
`0.06
`
`⫺0.28
`⫺0.11
`⫺0.02
`0.15
`
`⫺0.20
`⫺0.07
`0.02
`0.08
`
`0.095
`0.045
`⫺0.02
`⫺0.04
`
`⫺0.10
`⫺0.03
`0.003
`⫺0.04
`
`⫺0.07
`⫺0.02
`0.02
`0.03
`
`0.19
`0.05†
`0.02
`0.05
`
`0.12
`0.05†
`0.02
`0.04
`
`0.13
`0.06
`0.03
`0.04
`
`0.20
`0.06
`0.03
`0.04
`
`0.20
`0.05
`0.02
`0.04
`
`0.11#
`0.05†
`0.02
`0.04
`
`0.14
`0.045
`0.02
`0.04
`
`0.08
`0.03
`0.01
`0.02
`
`0.06
`0.02
`0.01
`0.02
`
`0.05
`0.02
`0.008
`0.01
`
`24
`19
`56
`
`24
`19
`56
`
`24
`19
`56
`
`24
`19
`56
`
`24
`19
`56
`
`24
`19
`56
`
`24
`19
`56
`
`24
`19
`56
`
`24
`19
`56
`
`24
`19
`56
`
`Aza C
`Slope
`
`⫺0.041
`0.11
`0.07
`
`0.04
`⫺0.055
`⫺0.07
`
`⫺0.02
`⫺0.08
`⫺0.07
`
`0.14
`0.02
`⫺0.089
`
`⫺0.34
`⫺0.07
`0.04
`
`⫺0.10
`0.10
`0.10
`
`⫺0.01
`0.05
`0.08
`
`0.04
`⫺0.04
`⫺0.045
`
`⫺0.10
`0.01
`0.04
`
`⫺0.075
`0.01
`0.03
`
`SE
`
`P
`
`0.19
`0.06†
`0.02§
`
`0.11
`0.05
`0.015§
`
`0.01
`0.06
`0.02§
`
`0.19
`0.065
`0.02§
`
`0.20
`0.055
`0.02†
`
`0.10
`0.05†
`0.02§
`
`0.13
`0.05
`0.015§
`
`0.08
`0.03
`0.01§
`
`0.06
`0.02
`0.007§
`
`0.05
`0.02
`0.006§
`
`.0002‡
`
`.0040㛳
`
`.0010‡
`
`.0001㛳
`
`.0014‡
`
`.0002㛳
`
`.035‡
`
`.025㛳
`
`.041‡
`
`.156㛳
`
`.0001‡
`
`.0001㛳
`
`.025‡
`
`.037㛳
`
`.015‡
`
`.016㛳
`
`.025‡
`
`.016㛳
`
`.0077‡
`
`.019㛳
`
`*Because higher scores in this measure indicate better functioning, negative slopes indicate worsening status/functioning over time and positive slopes indicate
`improved status/functioning over time.
`†Because higher scores in this measure indicate worse functioning, negative slopes indicate improved status/functioning over time and positive slopes indicate
`worsening status/functioning over time.
`‡Slope for the supportive care and Aza C arms is significantly different from zero at the .05 level of significance.
`§Slope for supportive care and Aza C arms is significantly different from zero at the .01 level of significance.
`¶Slope for supportive care and Aza C arms is significantly different from zero at the .001 level of significance.
`㛳The first P value in right column represents a test of whether the slopes of the Aza C and supportive care arms are equal before patients crossed over from the
`supportive care into the Aza C arm.
`#Second P value in right column represents a test of whether the change in scores after cross-over is significant.
`
`Copyright ©