EXHIBIT 2003
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`EXHIBIT 2003
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`The New England Journal of Medicine
`
`FLUDARABINE COMPARED WITH CHLORAMBUCIL AS PRIMARY THERAPY
`FOR CHRONIC LYMPHOCYTIC LEUKEMIA
`
`K
`ANTI
`
` K
`, M.D., J
` R. A
`.D., F
`, P
` L. P
` R. R
`, M.B., B.S., B
`OLITZ
`ONATHAN
`PPELBAUM
`REDERICK
`H
`ETERSON
`AI
`ERCEDIS
`L
` E
`, M.D., L
` S
`, M.D., J
` H
`, M.D., G
` A. T
`, M.D.,
`OHN
`AURENCE
`LIAS
`OIS
`HEPHERD
`INES
`REGORY
`HREATTE
`R
` A. L
`, M.D., B
` D. C
`, M.D.,
` C
` A. S
`, M.D.
`ICHARD
`ARSON
`RUCE
`HESON
`AND
`HARLES
`CHIFFER
`
`, M.D.,
`
`A
`BSTRACT
`Background
`Fludarabine is an effective treatment
`for chronic lymphocytic leukemia that does not re-
`spond to initial treatment with chlorambucil. We com-
`pared the efficacy of fludarabine with that of chloram-
`bucil in the primary treatment of chronic lymphocytic
`leukemia.
`Methods
`Between 1990 and 1994, we randomly as-
`signed 509 previously untreated patients with chronic
`lymphocytic leukemia to one of the following treat-
`ments: fludarabine (25 mg per square meter of body-
`surface area, administered intravenously daily for
`5 days every 28 days), chlorambucil (40 mg per square
`meter, given orally every 28 days), or fludarabine (20
`mg per square meter per day for 5 days every 28
`days) plus chlorambucil (20 mg per square meter
`every 28 days). Patients with an additional response
`at each monthly evaluation continued to receive the
`assigned treatment for a maximum of 12 cycles.
`Results
`Assignment of patients to the fludarabine-
`plus-chlorambucil group was stopped when a planned
`interim analysis revealed excessive toxicity and a re-
`sponse rate that was not better than the rate with flu-
`darabine alone. Among the other two groups, the re-
`sponse rate was significantly higher for fludarabine
`alone than for chlorambucil alone. Among 170 patients
`treated with fludarabine, 20 percent had a complete
`remission, and 43 percent had a partial remission.
`The corresponding values for 181 patients treated with
`chlorambucil were 4 percent and 33 percent (P<
`0.001 for both comparisons). The median duration of
`remission and the median progression-free survival in
`the fludarabine group were 25 months and 20 months,
`respectively, whereas both values were 14 months in
`the chlorambucil group (P<0.001 for both compari-
`sons). The median overall survival among patients
`treated with fludarabine was 66 months, which was
`not significantly different from the overall survival in
`the other two groups (56 months with chlorambucil
`and 55 months with combined treatment). Severe in-
`fections and neutropenia were more frequent with flu-
`darabine than with chlorambucil (P=0.08), although,
`overall, toxic effects were tolerable with the two sin-
`gle-drug regimens.
`Conclusions
`When used as the initial treatment
`for chronic lymphocytic leukemia, fludarabine yields
`higher response rates and a longer duration of remis-
`sion and progression-free survival than chlorambu-
`cil; overall survival is not enhanced. (N Engl J Med
`2000;343:1750-7.)
`©2000, Massachusetts Medical Society.
`
`1750
`
`·
`
`December 14, 2000
`
`C
`
`HLORAMBUCIL has been the standard
`treatment for chronic lymphocytic leukemia
`(CLL) for 40 years, but it has not changed
`the natural history of the disease.
` Fludara-
`1
`bine, a nucleoside analogue, was found to be effec-
`tive in patients who had not had a response to chlor-
`ambucil, and it also showed promise in uncontrolled
`trials as initial therapy for CLL.
`2-8
`In 1990, we began a prospective comparison of
`fludarabine with chlorambucil in previously untreated
`patients with CLL. While this study was in progress,
`the results of two other randomized trials were pub-
` Both studies found that fludarabine was su-
`lished.
`9-11
`perior to chlorambucil in patients with previously
`untreated CLL. We present here the results of our
`study of the efficacy of fludarabine and chlorambucil
`in such patients.
`
`METHODS
`
`Criteria for Eligibility
`The diagnosis of CLL was based on criteria recommended in
`1988 by the working group on CLL sponsored by the National
` The stage of disease was assessed accord-
`Cancer Institute (NCI).
`12
`ing to the guidelines of the NCI working group
` and the mod-
`12
`ified Rai staging system.
` All patients in the high-risk category
`13,14
`(Rai stage III or IV) were eligible. Intermediate-risk patients (Rai
`stage I or II) were also eligible if they had at least one of the fol-
`lowing: any disease-related symptom such as weight loss, extreme
`fatigue, night sweats, or fever without evidence of infection; massive
`or progressive splenomegaly or lymphadenopathy, or both; or more
`than a 50 percent increase in the number of peripheral-blood lym-
`phocytes over a 2-month period or an anticipated doubling of these
`cells within less than 12 months. Patients who had previously re-
`ceived any cytotoxic therapy were not eligible. Additional eligibility
`requirements were an age of at least 18 years; an Eastern Coop-
`erative Oncology Group performance status of 0, 1, or 2; base-line
`values for liver and kidney function that were no greater than 1.5
`times the upper limits of normal; and a negative direct antiglobulin
`(Coombs’) test. Each patient signed an informed-consent form ap-
`proved by a local institutional review board. Submission of blood
`smears, bone marrow aspirates, and biopsy slides for central patho-
`logical review was required. Central review was also required for
`specimens from patients who had a complete remission.
`
`Randomized Treatment and Crossover
`The Cancer and Leukemia Group B statistical center was re-
`sponsible for the random assignment of patients to one of the fol-
`
`From the Cancer and Leukemia Group B, Chicago (K.R.R., B.L.P.,
`J.K., G.A.T., R.A.L., C.A.S.); the Southwest Oncology Group, San Anto-
`nio, Tex. (F.R.A., L.E.); National Cancer Institute Canada, Clinical Trials
`Group, Kingston, Ont. (L.S.); the Eastern Cooperative Oncology Group,
`Brookline, Mass. (J.H.); and the National Cancer Institute, Rockville, Md.
`(B.D.C.). Address reprint requests to Dr. Rai at the Long Island Jewish
`Medical Center, 270-05 76th Ave., New Hyde Park, NY 11040, or at
`rai@lij.edu.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2003 0001
`
`

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`
`FLUDARABINE COMPARED WITH CHLORAMBUCIL AS PRIMARY THERAPY FOR CHRONIC LYMPHOCY TIC LEUKEMIA
`
`lowing treatments: fludarabine (25 mg per square meter of body-
`surface area, administered intravenously over a period of 10 to 30
`minutes on days 1 through 5 every 28 days), chlorambucil (40 mg
`per square meter given orally once every 28 days), or fludarabine
`(20 mg per square meter given intravenously on days 1 through
`5 every 28 days) plus chlorambucil (20 mg per square meter given
`orally once every 28 days). The treatments were repeated month-
`ly (every 28 days) for a maximum of 12 cycles. They were stopped
`sooner in patients who had disease progression, a complete remis-
`sion, or a response that plateaued over two months of treatment.
`Patients received oral allopurinol (300 mg per day for 9 days) from
`the day before chemotherapy began through day 8 during each
`28-day treatment cycle for the first three cycles, and thereafter ac-
`cording to the judgment of their physicians.
`All patients were evaluated monthly, before the next scheduled
`cycle of treatment, to assess the toxic effects of the drugs and clin-
`ical response. Patients in the fludarabine group or the chlorambucil
`group who did not have a partial remission or who had evidence
`of disease progression were allowed to cross over to the other drug.
`In addition, patients who relapsed within six months after stop-
`ping fludarabine or chlorambucil therapy were started on treatment
`with the other drug. Patients who relapsed more than six months
`after stopping therapy were treated again with the original drug.
`All patients assigned to the fludarabine-plus-chlorambucil group
`who did not have a response or who relapsed within six months
`after stopping therapy were removed from the study and treated
`at the discretion of their physicians.
`
`Criteria for a Response
`We used the criteria recommended by the NCI-sponsored work-
`ing group on CLL
` to evaluate responses. A complete remission
`12
`was defined as the absence of constitutional symptoms and of lym-
`phadenopathy, splenomegaly, and hepatomegaly on physical ex-
`amination; an absolute neutrophil count of at least 1500 per cubic
`millimeter, a platelet count of at least 100,000 per cubic millimeter,
`a hemoglobin level higher than 11 g per deciliter (without trans-
`fusion), and an absolute lymphocyte count of less than 4000 per
`cubic millimeter; and bone marrow of normal cellularity, with less
`than 30 percent lymphocytes and no lymphoid nodules. (Bone
`marrow biopsy was required two months after clinical evidence of
`a complete remission was present.) A partial remission was defined
`as a reduction of at least 50 percent in the size of the lymph
`nodes, spleen, and liver on physical examination, if they were en-
`larged before therapy; a decrease of at least 50 percent in the num-
`ber of peripheral-blood lymphocytes from the value before treat-
`ment; an absolute neutrophil count of at least 1500 per cubic
`millimeter or an increase of at least 50 percent over the base-line
`value; a platelet count of at least 100,000 per cubic millimeter or
`an increase of at least 50 percent over the base-line value; and a
`hemoglobin level of at least 11 g per deciliter or an increase of at
`least 50 percent over the base-line value (without transfusion).
`Progressive disease was defined as an increase of at least 50 per-
`cent in the size of the lymph nodes, spleen, or liver if they were pre-
`viously enlarged, or the detection of enlargement if they were not
`previously enlarged; an increase of at least 50 percent in the num-
`ber of peripheral-blood lymphocytes; or both. Patients who did not
`meet any of these criteria were considered to have stable disease.
`
`Modifications of Doses
`Guidelines for reductions in the doses of fludarabine and chlor-
`ambucil were based on toxic effects that were assessed with the use
`of the Cancer and Leukemia Group B Expanded Common Tox-
`icity Criteria. The doses of fludarabine and chlorambucil were re-
`duced by 50 percent in patients who had grade 2 pulmonary, renal,
`hepatic, or other toxic effects. In those with toxic effects graded
`3 or higher, treatment was suspended, and decisions about resump-
`tion at a decreased dose were made on a case-by-case basis. Treat-
`ment was suspended during the course of any major infection; af-
`ter recovery, the doses of drugs were set 50 percent lower than
`the original dose.
`
`Statistical Analysis
`This study began in October 1990 and was closed to enrollment
`in December 1994, when 544 patients had been enrolled. We orig-
`inally aimed for a sample of 450 patients, which we calculated would
`provide adequate statistical power for the detection of a difference
`in the rates of complete remission between the chlorambucil group
` A
`and either of the two groups assigned to receive fludarabine.
`15
`planned interim analysis in 1993, in which truncated O’Brien–
`Fleming boundaries
` were used, showed that the response rate in
`15
`the chlorambucil group was significantly lower than the rates in the
`other two groups. The protocol was then modified to make pro-
`gression-free survival the main end point; the target sample size
`remained the same.
`In May 1994, when 450 patients had been enrolled in the trial,
`the fludarabine-plus-chlorambucil group was closed because a sec-
`ond planned interim analysis found excessive rates of life-threaten-
`ing toxic effects with the combined treatment. Further care of pa-
`tients in this group was at the discretion of their physicians, and the
`patients were followed only to assess survival and the occurrence of
`a second cancer. Also in May 1994 (after the interim analysis), we
`found that the overall median progression-free survival in the flu-
`darabine group and the chlorambucil group was longer than we
`had anticipated; for purposes of statistical power, we decided to en-
`roll an additional 94 patients (revised target sample, 544 patients).
`All patients who underwent randomization were included in
`the analysis. The chi-square test was used to compare the response
`rates in the study groups. All time-to-event distributions were cal-
`culated by the Kaplan–Meier method
` and compared with the use
`16
`of the log-rank test, with one or two degrees of freedom.
` The
`17
`duration of response was measured from the time an initial response
`was documented to the time of disease progression or death. Pro-
`gression-free survival was measured from the time of randomiza-
`tion to the time of disease progression or death. Patients who with-
`drew after starting therapy, who were withdrawn because of drug
`toxicity or a complicating disease, or who crossed over to the other
`treatment for reasons other than those defined in the study pro-
`tocol were followed for progression-free survival. Overall survival
`was measured from the time of randomization to the time of death
`from any cause, without adjustment for crossover. All statistical
`tests were two-sided.
`
`RESULTS
`The analysis reported here is based on data collect-
`ed through June 1999. We assigned 195 patients to
`receive fludarabine, 200 to receive chlorambucil, and
`149 to receive fludarabine plus chlorambucil. Thirty-
`two patients (15, 7, and 10, respectively, in the three
`groups) were considered ineligible, and 3 patients
`(1 in the fludarabine group and 2 in the fludarabine-
`plus-chlorambucil group) dropped out before begin-
`ning treatment, leaving 509 patients (179, 193, and
`137, respectively) who form the basis of our report.
`Table 1 provides the demographic and clinical char-
`acteristics of these patients. There were no imbalances
`among the three groups with respect to clinical fea-
`tures and risk categories. Survival data were available
`for 507 of the 509 patients; 474 could be evaluated
`for a therapeutic response; 477 could be evaluated for
`drug toxicity; and 172 patients in the fludarabine
`group and 183 patients in the chlorambucil group
`could be evaluated for progression-free survival.
`
`Clinical Response
`As Table 2 shows, the rates of complete remission
`and of complete remission plus partial remission were
`
`Volume 343 Number 24
`
`·
`
`1751
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2003 0002
`
`

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`The New England Journal of Medicine
`
`T
`ABLE
`
` 1.
`
` P
`
` E
`
`
` C
`LIGIBLE
`THE
`OF
`HARACTERISTICS
`RETREATMENT
`A
`
` T
` A
`.
`SSIGNMENT
`CCORDING
`TO
`REATMENT
`
` P
`
`ATIENTS
`
`
`
`F
`LUDARABINE
`(N=179)
`
`C
`HLORAMBUCIL
`(N=193)
`
`F
`
`PLUS
`LUDARABINE
`C
`HLORAMBUCIL
`(N=137)
`
`
`
`71
`29
`
`1
`13
`22
`34
`30
`
`67
`33
`
`3
`13
`24
`38
`22
`
`66
`34
`
`2
`13
`27
`35
`23
`
`64
`33–88
`
`62
`36–89
`
`63
`32–83
`
`87
`12
`<1
`<1
`
`59
`41
`
`63
`33
`4
`
`91
`8
`<1
`<1
`
`61
`39
`
`52
`41
`6
`
`88
`10
`
`11
`
`61
`39
`
`63
`32
`5
`
`81,900
`9000–709,000
`
`80,900
`8000–588,000
`
`78,900
`5000–697,000
`
`155,000
`12,000–451,000
`
`147,000
`10,000–431,000
`
`143,000
`27,000–409,000
`
`12.2
`4.6–16.6
`
`12.2
`5.3–16.7
`
`11.9
`6.3–16.3
`
`C
`HARACTERISTIC
`
`Sex (%)
`Male
`Female
`Age group (%)
`«39 yr
`40–49 yr
`50–59 yr
`60–69 yr
`»70 yr
`Age (yr)
`Median
`Range
`Race or ethnic group (%)
`White
`Black
`Hispanic
`Asian or other
`Rai stage (%)
`I or II (intermediate risk)
`III or IV (high risk)
`ECOG performance status (%)*
`
`012
`
`)
`
`White-cell count (per mm
`3
`Median
`Range
`Platelet count (per mm
`3
`Median
`Range
`Hemoglobin (g/dl)
`Median
`Range
`
`)
`
`*ECOG denotes Eastern Cooperative Oncology Group.
`
`
` R
` C
` 2.
`T
`ESPONSES
`LINICAL
`ABLE
`
` T
` A
`A
`REATMENT
`TO
`CCORDING
`SSIGNMENT
`
`.*
`
`V
`ARIABLE
`
`F
`LUDARABINE
`(N=170)
`
`C
`HLORAMBUCIL
`(N=181)
`
`F
`
`PLUS
`LUDARABINE
`C
`HLORAMBUCIL
`(N=123)
`
`Complete remission
`Partial remission
`Complete or partial
`remission
`Stable or progressive
`disease
`
`number (percent)
`
`34 (20)
`73 (43)
`107 (63)
`
`8 (4)
`59 (33)
`67 (37)
`
`63 (37)
`
`114 (63)
`
`24 (20)
`51 (41)
`75 (61)
`
`48 (39)
`
`*The P values were less than 0.001 for the comparisons of fludarabine
`with chlorambucil and of fludarabine plus chlorambucil with chlorambucil
`alone, in terms of both the rate of complete remission and the overall re-
`sponse rate.
`
`1752
`
`·
`
`December 14, 2000
`
`significantly higher in both groups treated with flu-
`darabine than in the chlorambucil group (P<0.001
`for both comparisons). There was no significant ad-
`vantage to combination treatment over fludarabine
`alone in terms of the response rates.
`The median duration of response was significantly
`longer (P<0.001) among the 107 patients who had
`either a complete or a partial remission with fludara-
`bine alone (25 months) than among the 67 patients
`with a response who were treated with chlorambu-
`cil alone (14 months) (Fig. 1). There was a signifi-
`cantly longer median time to the progression of dis-
`ease among the patients treated with fludarabine (20
`months) than among those treated with chlorambu-
`cil (14 months, P<0.001) (Fig. 2).
`
`Overall Survival
`There were no significant differences in overall sur-
`vival among the three groups (P=0.21) or between
`the fludarabine group and the chlorambucil group
`(P=0.10) (Fig. 3). The median duration of follow-
`up was 62 months. The results for the fludarabine
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2003 0003
`
`

`
`FLUDARABINE COMPARED WITH CHLORAMBUCIL AS PRIMARY THERAPY FOR CHRONIC LYMPHOCY TIC LEUKEMIA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Fludarabine
`
`100
`
`80
`
`60
`
`40
`
`Patients RemainingE
`
`in Remission (%)
`
`20
`
`Chlorambucil
`
`0
`
`0
`
`1
`
`2
`
`3
`
`I I I
`
`5
`
`6
`
`7
`
`8
`
`4
`Years
`
`NO. AT RISK
`FludarabineE
`Chlorambucil
`
`107E
`167
`
`78E
`34
`
`48E
`13
`
`29E
`14
`
`16E
`11
`
`10E
`10
`
`5E
`0
`
`3E
`0
`
`0E
`0
`
`Figure 1.
` Proportion of Patients with an Initial Response to Fludarabine or Chlorambucil Who Contin-
`ued in Remission.
`Shown are the proportions of the 107 patients assigned to fludarabine and the 67 assigned to chlor-
`ambucil who had a response to treatment and remained in complete or partial remission. In both
`groups combined, 78 percent of patients (135 of 174) had relapses. The median duration of the re-
`sponse was significantly longer in the fludarabine group than in the chlorambucil group (25 vs. 14
`months, P<0.001).
`
`Fludarabine
`
`Chlorambucil
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Patients without DiseaseE
`
`Progression (%)
`
`0
`
`0
`
`1
`
`2
`
`3
`
`5
`
`6
`
`7
`
`8
`
`4
`Years
`
`NO. AT RISK
`FludarabineE
`Chlorambucil
`
`172E
`183
`
`116E
`199
`
`74E
`44
`
`43E
`17
`
`27E
`17
`
`13E
`12
`
`6E
`1
`
`3E
`0
`
`0E
`0
`
`Figure 2.
` Proportion of Patients without Disease Progression, According to Treatment Group.
`Shown are the proportions of the 172 patients assigned to fludarabine and the 183 assigned to chlor-
`ambucil in whom disease progression could be evaluated who did not have progression of disease
`from the time of entry into the study. The disease progressed in 79 percent and 81 percent of the pa-
`tients in the two groups, respectively. The median time to progression was significantly longer in the
`fludarabine group than in the chlorambucil group (20 vs. 14 months, P<0.001).
`
`Volume 343 Number 24
`
`·
`
`1753
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2003 0004
`
`

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`The New England Journal of Medicine
`
`Fludarabine E
`Chlorambucil E
`Fludarabine plusE
`mchlorambucil
`
`
`
`-L ` 2. ` 2.
`
`
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`Li Li
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`100
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`80
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`60
`
`40
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`20
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`Patients Surviving (%)
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`0
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`0
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`1
`
`2
`
`3
`
`5
`
`6
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`7
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`8
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`4
`Years
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`178E
`193E
`136
`
`155E
`172E
`117
`
`140E
`147E
`106
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`124E
`132E
`194
`
`195E
`101E
`170
`
`60E
`52E
`44
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`24E
`21E
`19
`
`9E
`6E
`5
`
`0E
`0E
`0
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`NO. AT RISK
`FludarabineE
`ChlorambucilE
`E
`Fludarabine plusE
`mchlorambucilE
`
`Figure 3.
` Overall Survival According to Treatment Group.
`Shown are the proportions of 178 patients assigned to fludarabine, 193 assigned to chlorambucil, and
`136 assigned to fludarabine plus chlorambucil who were still alive during follow-up. Forty-seven per-
`cent, 57 percent, and 56 percent of the patients in the three groups, respectively, died. There was no
`statistically significant difference in overall survival among the three groups (median, 66 months, 56
`months, and 55 months, respectively; P=0.21).
`
`group and the chlorambucil group include data for
`patients who crossed over and for those who were
`treated again with the originally assigned drug; the
`results thus represent a comparison of the initial
`treatments. The median survival times for the groups
`that received fludarabine, chlorambucil, and fludara-
`bine plus chlorambucil were 66, 56, and 55 months,
`respectively.
`
`Response According to Rai Stage
`Treatment with fludarabine resulted in significantly
`higher rates of complete remission and of complete
`or partial remission than did treatment with chlor-
`ambucil among the intermediate-risk patients (com-
`plete remission, P<0.001; complete or partial remis-
`sion, P=0.002) and among the high-risk patients
`(complete remission, P=0.03; complete or partial re-
`mission, P<0.001) (Table 3). Fludarabine was supe-
`rior to chlorambucil in prolonging the time to disease
`progression both among the intermediate-risk patients
`(median, 23 vs. 16 months; P=0.02) and among the
`high-risk patients (median, 18 vs. 12 months; P=
`0.006).
`
`Crossover
`Of the 79 patients who crossed over from chlor-
`ambucil to fludarabine, 46 percent had a complete
`
`or partial remission. However, of the 29 patients who
`crossed over from fludarabine to chlorambucil, only
`7 percent had a response (P<0.001).
`
`Side Effects
`All side effects were graded on a six-point scale,
`with 0 defined as none, 1 as mild, 2 as moderate, 3 as
`severe, 4 as life-threatening, and 5 as lethal. Most
`side effects in the three groups were of grade 1 or 2.
`Only one treatment-related death was recorded, in a
`patient who had pulmonary and cardiac complications
`after fludarabine treatment. Among all other side ef-
`fects, grade 3 or 4 thrombocytopenia, neutropenia,
`and infections were noteworthy (Table 4). Table 4 also
`lists the overall incidence of grade 3 and grade 4 side
`effects of all types in each of the three treatment
`groups.
`
`DISCUSSION
`Our findings demonstrate that in the initial treat-
`ment of CLL, fludarabine is superior to chlorambu-
`cil. The rate of complete remission and the overall rate
`of response (complete or partial remission), as well as
`the duration of the response and of progression-free
`survival, were significantly better among patients treat-
`ed with fludarabine than among those given chlor-
`ambucil. Treatment with fludarabine plus chloram-
`
`1754
`
`·
`
`December 14, 2000
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2003 0005
`
`

`
`FLUDARABINE COMPARED WITH CHLORAMBUCIL AS PRIMARY THERAPY FOR CHRONIC LYMPHOCY TIC LEUKEMIA
`
`T
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`ABLE
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` 3.
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` C
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`LINICAL
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` R
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`ESPONSES
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` A
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`CCORDING
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`TO
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` R
`
`AI
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` S
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`TAGE
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`AND
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` T
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`REATMENT
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` A
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`SSIGNMENT
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`.
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`T
`YPE
`
`
`
`OF
`
` R
`ESPONSE
`
`S
`TAGE
`
` I
`
`OR
`
`S
`TAGE
`
` III
`
`OR
`
`)
` R
` II (I
`ISK
`NTERMEDIATE
`FLUDARABINE PLUS
`CHLORAMBUCIL
`(N=77)
`
`CHLORAMBUCIL
`(N=111)
`
` RISK)
` IV (H
`IGH
`FLUDARABINE PLUS
`CHLORAMBUCIL
`(N=46)
`
`CHLORAMBUCIL
`(N=70)
`
`FLUDARABINE
`(N=67)
`
`FLUDARABINE
`(N=103)
`
`Complete remission
`Partial remission
`Complete or partial
`remission
`
`26
`41
`67
`
`percent
`
`6
`40
`46
`
`22
`42
`64
`
`10
`46
`57
`
`1
`21
`23
`
`15
`41
`56
`
`TABLE 4. PROPORTION OF PATIENTS WITH SEVERE (GRADE 3) OR LIFE-THREATENING
`(GRADE 4) SIDE EFFECTS.*
`
`SIDE EFFECT
`
`FLUDARABINE
`(N=170)
`
`CHLORAMBUCIL
`(N=178)
`
`FLUDARABINE PLUS
`CHLORAMBUCIL
`(N=129)
`
`P VALUE
`FLUDARABINE VS.
`FLUDARABINE PLUS
`CHLORAMBUCIL
`
`FLUDARABINE VS.
`CHLORAMBUCIL
`
`Thrombocytopenia
`Neutropenia
`Infection
`Grade 3 or 4 side
`effect of any type
`
`13
`27
`16
`55
`
`percent
`
`14
`19
`9
`44
`
`43
`43
`28
`81
`
`0.81
`0.08
`0.08
`0.05
`
`<0.001
`0.007
`0.01
`<0.001
`
`*Each side effect was recorded at least once.
`
`bucil produced response rates similar to those with
`fludarabine alone, but with greater toxicity.
`Our results are concordant with the findings of
`two large, randomized studies
` conducted at ap-
`9-11
`proximately the same time as our study. These studies
` and the French
`are known as the European study
`9
`study.
` The control group in the European study
`10,11
`received cyclophosphamide, doxorubicin, and pred-
`nisone (CAP), and in the French study there were
`two control groups: one received CAP, and the other
`received cyclophosphamide, doxorubicin, vincristine,
`and prednisone (CHOP). The rate of complete re-
`mission in the French study was higher than the rates
`in other studies, perhaps because the definition of
`complete remission in the French study differed from
`that of the NCI working group and because it did not
`require an examination of the bone marrow. North
`American physicians rarely use CAP for the treat-
`ment of CLL and almost never use CAP or CHOP
`for initial treatment.
`When we analyzed responses according to the stage
`
`of disease, fludarabine was significantly superior to
`chlorambucil among both the intermediate-risk pa-
`tients (with stage I or II disease) and the high-risk
`patients (stage III or IV). We cannot, however, con-
`clude from these results that it is preferable to start
`fludarabine therapy in patients with intermediate-
`risk CLL.
`Although the toxicity of fludarabine plus chloram-
`bucil forced its discontinuation before the comple-
`tion of enrollment in our study, the two single-drug
`regimens were well tolerated, with an acceptable level
`of toxicity. However, the incidence of grade 3 and
`grade 4 neutropenia and infections was greater with
`fludarabine than with chlorambucil, and the com-
`bined incidence of all grade 3 and grade 4 side effects
`was significantly greater with fludarabine than with
`chlorambucil. The toxicity of fludarabine in the French
` was similar to that which we observed.
`study
`10,11
`The incidence of severe infections reported here
`took into account infections that we considered to
`be a consequence of the treatment. A subsequent
`
`Volume 343 Number 24
`
`·
`
`1755
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2003 0006
`
`

`
`The New England Journal of Medicine
`
`retrospective analysis showed a significantly higher in-
`cidence of major infections (those requiring hospi-
`talization or treatment with parenteral antibiotics),
`whether they were related to the disease or to treat-
`ment, among patients who received fludarabine (in-
`cidence of major infections, 29 percent, 17 percent,
`and 45 percent in the fludarabine, chlorambucil, and
`fludarabine-plus-chlorambucil groups, respectively).18
`It is likely that the results of treatment of CLL will
`be improved through small, incremental steps that
`increase the rates of remission. We have come to the
`end of a long period — 40 years — in which therapy
`was limited mainly to chlorambucil. These four dec-
`ades were marked by a lack of progress and persist-
`ently low rates of objectively measured responses.
`Now, a significant increase in the rate of remission
`has been demonstrated with fludarabine. The chal-
`lenge before us is to find other effective agents that,
`when combined with fludarabine, will lead to more
`incremental advances and, ultimately, to increased sur-
`vival among patients with CLL.
`Although intravenous fludarabine therapy is less
`convenient than oral chlorambucil, it offers the pos-
`sibility of a prolonged progression-free interval during
`which no therapy is required. In older patients with
`other medical problems, the ease of administration of
`oral chlorambucil has obvious advantages. Patients
`and their physicians therefore still confront a deci-
`sion about which drug to try first in the case of pre-
`viously untreated, progressive CLL. The information
`from this trial provides a framework for making such
`decisions.
`
`Supported by funding from the Chemotherapy Foundation and the
`United Leukemia Fund (to Dr. Rai) and by grants from the National Can-
`cer Institute to the Cancer and Leukemia Group B (CA31946; R.L. Schil-
`sky, chairman), the Southwest Oncology Group (CA32102; C. Coltman,
`chairman) and the Eastern Cooperative Oncology Group (CA21115; R.L.
`Comis, chairman). The work of Cancer and Leukemia Group B was also
`supported by a grant from Berlex Laboratories.
`Presented in part at the plenary session of the 38th Annual Meet-
`ing of the American Society of Hematology, Orlando, Fla., December
`6–10, 1996.
`The contents of this report are solely the responsibility of the authors
`and do not necessarily represent the official views of the National Cancer
`Institute.
`
`We are indebted to Audrey McKinnon for assistance with data
`management; to the participating physicians and nurses for their
`collaboration; to Dr. John Byrd for reviewing the manuscript; to
`Sandy Nissel-Horowitz, R.P.A., and Susan Mrwik for their assist-
`ance; and to all the patients for their participation.
`
`APPENDIX
`The following institutions and investigators participated in this study
`(National Cancer Institute grant numbers are shown in parentheses). Can-
`cer and Leukemia Group B: Statistical office: S. George (CA33601);
`Christiana Care Health Services Community Clinical Oncology Program
`(CCOP): I.M. Berkowitz (CA45418); Community Hospital–Syracuse
`CCOP: J. Kirshner (CA45389); Dana–Farber Cancer Institute: G.P.
`Canellos (CA32291); Dartmouth Medical School–Norris Cotton Cancer
`Center: L.H. Maurer (CA04326); Duke University Medical Center: J.
`Crawford (CA47577); Kaiser Permanente CCOP: J.A. Polikoff (CA45374);
`Long Island Jewish Medical Center: M. Citron (CA11028); Massachusetts
`General Hospital: M.L. Grossbard (CA12449); McGill Department of On-
`
`1756 · December 14, 2000
`
`cology: B. Leyland-Jones (CA31809); Milwaukee CCOP: R. Hart
`(CA45400); Mount Sinai Medical Center CCOP: E. Davila (CA45564);
`Mount Sinai School of Medicine: J.F. Holland (CA04457); North Shore
`University Hospital: D.R. Budman (CA35279); Rhode Island Hospital:
`L.A. Leone (CA08025); Roswell Park Cancer Institute: E. Levine
`(CA02599); South New Jersey CCOP: J. Goldberg (CA54697); Southeast
`Cancer Control Consortium CCOP: J.N. Atkins (CA45808); Southern
`Nevada Cancer Research Foundation CCOP: J. Ellerton (CA35421); St.
`Michael’s Medical Center Tri-County CCOP: A.D. Rubin (CA60247);
`SUNY Upstate Medical University: S.L. Graziano (CA21060); University
`of Alabama, Birmingham: R. Diasio (CA47545); University of California
`at San Diego: S.L. Seagren (CA11789); University of Chicago Medical
`Center: G. Fleming (CA41287); University of Iowa Hospitals: G.H. Cla-
`mon (CA47642); University of Maryland Cancer Center: D. Van Echo
`(CA31983); University of Massachusetts Medical Center: M. Stewart
`(CA37135); University of Minnesota: B.A. Peterson (CA16450); Univer-
`sity of Missouri–Ellis Fischel Cancer Center: M.C. Perry (CA12046); Uni-
`versity of North Carolina at Chapel Hill: T.C. Shea (CA47559); University
`of Tennessee, Memphis: H.B. Niell (CA47555); Virginia Commonwealth
`University CCOP: J.D. Roberts (CA52784); Wake Forest University
`School of Medicine: D.D. Hurd (CA03927); Walter Reed Army Medical
`Center: J.C. Byrd (CA26806); Washington University School of Medicine:
`N.L. Bartlett (CA77440); Weill Medical College of Cornell University: T.P.
`Szatrowski (CA07968); Southwest Oncology Group: Atlanta Regional
`CCOP: T.E. Seay (CA45450); Brooke Army Medical Center and Wilford
`Hall Medical Center: D.L. Ornstein (CA76447); Boston Medical Center:
`D.V. Faller (CA76448); California Health Care System CCOP: P.D. Eisen-
`berg (CA52420); Central Illinois CCOP: J.L. Wade (CA45807); Cleveland
`Clinic: G.T. Budd (CA04919); Columbus CCOP: P.J. Kuebler (CA35261);
`Dayton CCOP: H.M. Gro