EXHIBIT 2005
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`EXHIBIT 2005
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`The New England Journal of Medicine
`
`CHLORAMBUCIL IN INDOLENT CHRONIC LYMPHOCYTIC LEUKEMIA
`
` C
`, M.D., B
` D
`, M.D., P
` M
`.D., K
`, M.D., P
` D
`G
`.D., B
`AZIN
`RUNO
`ESABLENS
`H
`ALOUM
`ARIM
`H
`IGHIERO
`UILLAUME
`ERNARD
` N
`, M.D., R
` L
`, M.D., M
` L
`, M.D., J
` J
`, M.D.,
`M
`ICHEL
`OBERT
`AURICE
`AVARRO
`EBLAY
`EPORRIER
`ÉROME
`AUBERT
` L
`, M.D., B
` D
`, M.D., J
`-L
` B
`, M.D.,
` P
` T
`, M.D.,
`G
`ÉRARD
`EPEU
`RIGITTE
`REYFUS
`ACQUES
`OUIS
`INET
`AND
`HILIPPE
`RAVADE
`
` F
` C
` G
`
` C
` L
` L
`FOR
`THE
`RENCH
`OOPERATIVE
`ROUP
`ON
`HRONIC
`YMPHOCYTIC
`EUKEMIA
`
`, M.D.,
`
`A
`BSTRACT
`Background
`To determine whether chlorambucil
`treatment benefits patients with indolent chronic
`lymphocytic leukemia (CLL), we conducted two ran-
`domized trials in 1535 patients with previously un-
`treated stage A CLL.
`Methods
`In the first trial, 609 patients were ran-
`domly assigned to receive either daily chlorambucil
`or no treatment; in the second trial, 926 patients
`were randomly assigned to receive either intermit-
`tent chlorambucil plus prednisone or no treatment.
`Median follow-up for the first and second trials ex-
`ceeded 11 and 6 years, respectively. The end points
`were overall survival, response to treatment, and
`disease progression.
`Results
`Treatment of indolent CLL did not in-
`crease survival in either trial. In the treated group, as
`compared with the untreated group, the relative risk
`of death was 1.14 (95 percent confidence interval,
`0.92 to 1.41; P=0.23) in the first trial and 0.96 (95 per-
`cent confidence interval, 0.75 to 1.23; P=0.74) in the
`second trial, with 76 percent and 69 percent of pa-
`tients, respectively, having a response to therapy.
`Although chlorambucil slowed disease progression,
`there was no effect on overall survival. In the un-
`treated group in the first trial, 49 percent of patients
`did not have progression to more advanced disease
`and did not need therapy after follow-up of more
`than 11 years; however, 27 percent of patients with
`stage A CLL died of causes related to the disease.
`Conclusions
`Chlorambucil does not prolong sur-
`vival in patients with stage A CLL. Since deferring
`therapy until the disease progresses to stage B or C
`does not compromise survival, treatment of indolent
`CLL is unnecessary. (N Engl J Med 1998;338:1506-14.)
`©1998, Massachusetts Medical Society.
`
`M
`
`ANY patients with chronic lymphocyt-
`ic leukemia (CLL) have long lives and
`die of causes unrelated to the disease.
`1,2
`Rai’s classification
` and Binet’s stag-
`3-5
`ing system
` have improved the identification of the
`6
`indolent form of the disease (Table 1), and both
`ways of staging CLL accurately identify patients
`with a good prognosis. Of all patients with CLL, 31
`percent have Rai stage 0, whereas 63 percent have
`Binet stage A. Among patients with Rai stage 0, 59
`percent are alive 10 years after the diagnosis, and
`among those with Binet’s stage A the 10-year surviv-
`al rate is 51 percent.
`
`1
`
`1506
`
`·
`
`May 21, 1998
`
`There is no evidence that treatment of CLL with
`chlorambucil affects survival, but this alkylating agent
`can relieve symptoms in many patients.
` It is not
`7-14
`clear whether therapy benefits patients with the indo-
`lent form of CLL. An early report from our group
`failed to show differences in survival between patients
`who were treated with chlorambucil immediately af-
`ter the diagnosis of stage A CLL and those who were
`not treated.
` We now report the long-term results of
`14
`the first trial and a second trial in which 926 previ-
`ously untreated patients with stage A CLL were ran-
`domly assigned to either no treatment or a combina-
`tion of chlorambucil and prednisone.
`
`METHODS
`Patients and Treatments
`Both trials included only previously untreated patients with
`stage A CLL. Patients with prolymphocytic leukemia, a second
`neoplasm other than basal-cell carcinoma, a positive Coombs’
`test, or in the second trial, contraindications to prednisone were
`excluded.
`Thirty-one centers participated in the first trial and 46 in the
`second trial, and randomization was performed by telephone at a
`centralized location. The first trial enrolled 609 patients between
`1980 and 1985 and randomly assigned 308 patients to no treat-
`ment and 301 patients to 0.1 mg of chlorambucil per kilogram
`of body weight per day. The second trial enrolled 926 patients
`between 1985 and 1990 and randomly assigned 466 patients to
`no treatment and 460 patients to 0.3 mg of chlorambucil per kil-
`ogram per day for five days every month and 40 mg of prednisone
`per square meter of body-surface area per day for five days every
`
`From the Unité d’Immuno-Hématologie et d’Immunopathologie, Insti-
`tut Pasteur, Paris (G.D.); Département d’Hématologie, Hôpital Pitié-
`Salpêtrière, Paris (K.M., J.-L.B.); Service des Maladies du Sang, Centre
`Hospitalier Régional–Hôpital Sud, Amiens (B. Desablens); Service des
`Maladies du Sang, Hôpital Claude Huriez, Lille (B.C.); Service des Mala-
`dies du Sang, Centre Hospitalier Universitaire–Hôpital Lapeyronie, Mont-
`pellier (M.N.); Service de Médecine G, Centre Hospitalier Régional–Hôpi-
`tal Sud, Rennes (R.L.); Service Hématologie Clinique, Centre Hospitalier
`Universitaire de Caen, Caen (M.L.); Département d’Hématologie, Centre
`Hospitalier Universitaire–Hôpital Nord, Saint-Etienne (J.J.); Onco-Héma-
`tologie, Maladies Infectieuses, Centre Hospitalier Avignon–Hôpital Henri
`Duffaut, Avignon (G.L.); Département d’Hématologie et d’Oncologie
`Virale, Centre Hospitalier Universitaire–Hôpital Jean Bernard, Poitiers
`(B. Dreyfus); and Unité d’Hematologie Clinique, Hôtel-Dieu, Clermont-
`Ferrand (P.T.) — all in France. Address reprint requests to Dr. Dighiero at
`Unité d’Immuno-Hématologie et d’Immunopathologie, Institut Pasteur,
`28 rue du Dr. Roux, F-75724 Paris CEDEX 15, France.
`Other authors were François-Louis Turpin, M.D. (Oncologie Médicale
`et Hématologie, Centre René Huguenin, St. Cloud, France), Gérard Ter-
`tian, M.D. (Laboratoire d’Hématologie, d’Immunologie, et de Cytogéné-
`tique, Hôpital Bicêtre, Le Kremlin Bicêtre, France), and Agnès Bichoffe,
`M.D. (Département de Médecine Interne, Centre Hospitalier Général de
`Montluçon, Montluçon, France).
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 23, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2005 0001
`
`

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`CHLORAMBUCIL IN INDOLENT CHRONIC LYMPHOCYTIC LEUKEMIA
`
`TAGING
`
` U
`
`SED
`
`
`
`FOR
`
` C
`
`HRONIC
`
` L
`
`YMPHOCYTIC
`
` L
`
`EUKEMIA
`
`.*
`
`
`
`
`P
`OF
`ERCENTAGE
`P
`
`ATIENTS
`WITH
`CLL
` S
`IN
`TAGE
`
`S
`URVIVAL
`10-
`MEDIAN
`YEAR
`
`%
`
`59
`
`51
`
`56
`
`38
`
`yr
`
`>10
`
`95
`
`2 2
`
`>10
`
`>10
`
`7
`
`5
`2
`
`31
`35
`26
`
`6 2
`
`63
`
`49
`
`14
`
`30
`7
`
`T
`ABLE
`
` 1.
`
` S
`
` S
`YSTEMS
`
`S
`YSTEM
` R
`AND
`ISK
`
`S
`TAGE
`
`D
`EFINITION
`
`Rai staging system
`Low
`Intermediate
`
`High
`
`0
`I
`II
`
`III
`
`IV
`
`Lymphocytosis only
`Lymphocytosis and lymphadenopathy
`Lymphocytosis and splenomegaly with or without lym-
`phadenopathy or hepatomegaly
`Lymphocytosis and anemia, with or without organo-
`megaly
`Lymphocytosis, anemia, and thrombocytopenia, with or
`without organomegaly
`
`Lymphocytosis, with enlargement of <3 lymphoid
`areas†
`Stage A with lymphocyte count of «30,000/mm
`3
`hemoglobin concentration of »120 g/liter
`, he-
`Stage A with lymphocyte count of >30,000/mm
`3
`moglobin concentration of <120 g/liter, or both
`Lymphocytosis, with enlargement of »3 lymphoid areas
`Lymphocytosis and either anemia or thrombocytopenia,
`or both
`
` and
`
`Binet staging system
`Low
`
`A A
`
`'
`
`Intermediate
`High
`
`A"
`
`B
`C
`
`*Data were obtained from Rai et al.,
`3
`
`kemia.
`7
`†The following lymphoid areas are included: cervical, axillary, and inguinal (whether unilateral or bilateral), spleen, and
`liver.
`
` and the French Cooperative Group on Chronic Lymphocytic Leu-
`
` Binet et al.,
`6
`
`month. In the first trial, chlorambucil was administered until clin-
`ical resistance to the drug was observed. In the second trial, the
`planned duration of treatment was three years.
`In the first trial, patients whose disease progressed from stage
`A to stage B were treated with daily chlorambucil if they were
`previously untreated, or with a combination of cyclophospha-
`mide, vincristine, and prednisone (COP) if they were in the
`chlorambucil group. Patients enrolled in the second trial whose
`disease progressed to stage B were given intermittent chlor-
`ambucil plus prednisone if they were previously untreated or a
`combination of cyclophosphamide, doxorubicin, vincristine, and
`prednisone (CHOP) if they were in the group treated with chlor-
`ambucil plus prednisone. Progression to stage C warranted COP
`for previously untreated patients in the first trial, CHOP for treat-
`ed patients in the first trial and untreated patients in the second
`trial, or CHOP plus methotrexate for patients in the treated
`group in the second trial.
`
`End Points
`The primary end points were overall survival, mortality related
`to CLL, response to treatment, and disease progression. A clinical
`and hematologic response was defined as the absence of lymphad-
`enopathy, a lymphocyte count of less than 4000 per cubic milli-
`meter, a hemoglobin concentration of more than 100 g per liter,
`and a platelet count of more than 100,000 per cubic millimeter.
`Bone marrow biopsy or aspiration was recommended but not re-
`quired for patients who had clinical and hematologic responses.
`A partial response was defined as a reduction of at least 75 per-
`cent in the initial lymphocyte count and at least 50 percent in
`each of the initially enlarged lymph nodes. Resistance to treat-
`ment or treatment failure was defined as the occurrence of any or
`all of the following: progression of disease to stage B or C, the
`lack of a reduction of at least 50 percent in the enlarged lymph
`nodes, or the lack of a reduction of at least 75 percent in the ab-
`solute lymphocyte count.
`
`Causes of death were divided into those related to CLL and
`those unrelated to CLL; the latter category included only deaths
`that were unambiguously unrelated to CLL. Deaths related to
`second neoplasms were recorded separately and considered to be
`related to CLL. Since an increased number of such deaths was
`seen in the chlorambucil-treated group in the initial analysis of
`the first trial, the incidence of cancer was examined in the two
`trials. To evaluate the response, a follow-up examination was
`scheduled during the ninth month in the first trial and the sixth
`month in the second trial. Thereafter, a follow-up examination
`was scheduled every six months.
`
`Statistical Analysis
`Statistical analysis was carried out on an intention-to-treat basis.
`This analysis was based on findings on the reference date of the
`scheduled fifth interim analysis for the first trial (July 1, 1994) and
`the third interim analysis for the second trial (January 1, 1994).
` the log-
`Survival analysis was based on Kaplan–Meier estimates,
`15
`rank test,
` and the Cox regression model.
` All P values are two-
`16
`17
`sided and adjusted for repeated analyses. To account for the five
`planned interim analyses, a threshold alpha level of 0.0158 was
`
`used in order to guarantee an overall type I error of 0.05.
`18
`
`RESULTS
`Characteristics of the Patients
`The median follow-up of survivors was 129
`months (range, 6 to 169) in the first trial and 73
`months (range, 6 to 106) in the second trial. Three
`patients in the first trial and six patients in the sec-
`ond were excluded from the analysis because of the
`lack of information after randomization. There were
`slightly higher blood lymphocyte counts and degrees
`
`Volume 338 Number 21
`
`·
`
`1507
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 23, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2005 0002
`
`

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`
`The New England Journal of Medicine
`
`T
`ABLE
`
` 2.
`
` C
`
`HARACTERISTICS
`
`
`
`OF
`
`
`
`THE
`
` P
`
`ATIENTS
`
`
`
`AT
`
` R
`
`ANDOMIZATION
`
`.*
`
`C
`HARACTERISTIC
`
`F
`IRST
`
` T
`RIAL
`
`NO
`
`
`TREATMENT
`(
`=308)
`N
`
`
`DAILY
`CHLORAMBUCIL
`(
`=301)
`N
`
`NO
`
`
`TREATMENT
`(
`=466)
`N
`
`S
`ECOND
`
` T
`RIAL
`CHLORAMBUCIL
`
`PLUS
`PREDNISONE
`(
`=460)
`N
`
`Age — yr
`Male sex — no. (%)
`Lymphoid area involved —
`no. (%)
`Cervical
`Axillary
`Inguinal
`Splenomegaly — no. (%)
`Hepatomegaly — no. (%)
`Degree of bone marrow infiltra-
`tion — %
`Lymphocyte count —
`/mm
`¬10
`¡3
`3
`Hemoglobin — g/liter
`Platelet count — ¬10
`/mm
`¡3
`3
`Binet stage — no. (%)
`A'
`A"
`
`66±9
`187 (61)
`
`65±9
`179 (59)
`
`64±9
`283 (61)
`
`64±9
`278 (60)
`
`75 (24)
`96 (31)
`27 (9)
`40 (13)
`12 (4)
`55±20
`
`65 (22)
`64 (21)
`22 (7)
`31 (10)
`8 (3)
`57±19
`
`108 (23)
`96 (21)
`20 (4)
`51 (11)
`7 (2)
`56±20
`
`98 (21)
`100 (22)
`28 (6)
`49 (11)
`8 (2)
`55±19
`
`20±17
`
`24±20
`
`26±27
`
`24±21
`
`141±14
`226±74
`
`246 (80)
`62 (20)
`
`143±14
`231±80
`
`226 (75)
`75 (25)
`
`141±14
`238±70
`
`327 (70)
`139 (30)
`
`141±14
`238±74
`
`325 (71)
`135 (29)
`
`*Plus–minus values are means ±SD.
`
`of bone marrow infiltration in the daily-chlorambucil
`group in the first trial. There were no significant dif-
`ferences between the groups in either trial at the
`time of randomization (Table 2).
`
`Survival
`
`The First Trial
`In the first trial, 344 deaths were reported (Fig.
`1), 169 in the untreated group (5-year survival, 80
`percent; 10-year survival, 54 percent) and 175 in the
`treated group (5-year survival, 76 percent; 10-year
`survival, 47 percent) (relative risk of death, 1.14 in
`the treated group as compared with the untreated
`group; 95 percent confidence interval, 0.92 to 1.41;
`P=0.23 by the log-rank test). In the untreated group,
`54 of the 169 deaths were unrelated to CLL, 22
`were caused by a second neoplasm, and no cause
`was found in 9. Death was considered to be related
`to CLL in 84 patients (due to disease progression in
`41, infection in 36, iatrogenic causes in 2, thrombo-
`cytopenia in 1, and other causes in 4). In the treated
`group, 47 of the 175 deaths were unrelated to CLL,
`28 were the consequence of a second cancer, and no
`cause was found in 6. Death was related to CLL in
`94 patients (due to disease progression in 45, infec-
`tion in 41, iatrogenic complications in 6, and auto-
`immune hemolytic anemia in 2). The distribution of
`deaths related to CLL was similar in the two groups
`(P=0.11 by the log-rank test) (Fig. 2).
`Table 3 shows the incidence of second neoplasms
`in the two groups. Forty-eight cancers were observed
`
`1508
`
`·
`
`May 21, 1998
`
`in the untreated group (median interval between en-
`try into the trial and the occurrence of the second
`cancer, 67 months; range, 6 to 165), as compared
`with 66 in the treated group (median interval, 72
`months; range, 2 to 141) (P=0.045 by the chi-
`square test). Skin, mammary, and colon cancers and
`acute leukemia predominated in the treated group.
`Five of the six cases of leukemia in the two groups
`were of myeloid origin. The two cases of acute leu-
`kemia in the untreated group occurred in patients
`who were switched to chlorambucil five and nine
`years before the diagnosis of acute leukemia. The
`same phenomenon was observed in six of the nine
`patients with skin cancer in the untreated group.
`
`The Second Trial
`In the second trial, 247 deaths were recorded
`(Fig. 3), 126 in the untreated group (five-year sur-
`vival, 81 percent; seven-year survival, 69 percent)
`and 121 in the treated group (five-year survival, 81
`percent; seven-year survival, 69 percent; relative risk
`of death, 0.96; 95 percent confidence interval, 0.75
`to 1.23; P=0.74 by the log-rank test).
`In the untreated group, 25 of the 126 deaths were
`unrelated to CLL, 19 were caused by a second neo-
`plasm, and no cause was identified in 17. Death was
`related to CLL in 65 patients (due to disease pro-
`gression in 37, infection in 23, iatrogenic causes in
`2, and thrombocytopenia in 3). In the treated group,
`39 of the 121 deaths were unrelated to CLL, 18
`were related to cancer, no cause was identified in 17,
`and 47 were related to CLL (due to disease progres-
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 23, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2005 0003
`
`

`
`CHLORAMBUCIL IN INDOLENT CHRONIC LYMPHOCYTIC LEUKEMIA
`
`
`
`
`
`
`
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`
`
`
`
`
`No treatmentG
`(169 deaths)
`
`ChlorambucilG
`(175 deaths)
`
`P=0.23
`
`0
`
`2
`
`4
`
`6
`
`8
`Year
`
`10
`
`12
`
`14
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Overall Survival (%)
`
`NO. AT RISK
`ChlorambucilG
`No treatment
`
`301G
`308
`
`296G
`291
`
`283G
`284
`
`277G
`266
`
`264G
`247
`
`246G
`230
`
`230G
`213
`
`205G
`196
`
`191G
`179
`
`179G
`159
`
`132G
`114
`
`86G
`70
`
`54G
`39
`
`26G
`17
`
`2G
`7
`
`Figure 1.
` Overall Survival in the First Trial.
`The log-rank test was used to calculate the P value.
`
`No treatmentG
`(115 deaths)
`
`ChlorambucilG
`(128 deaths)
`
`P=0.11
`
`0
`
`2
`
`4
`
`6
`
`8
`Year
`
`10
`
`12
`
`14
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Survival (%)
`
`NO. AT RISK
`ChlorambucilG
`No treatment
`
`301G
`308
`
`296G
`291
`
`284G
`283
`
`277G
`266
`
`264G
`247
`
`246G
`230
`
`230G
`213
`
`205G
`196
`
`191G
`179
`
`179G
`159
`
`132G
`114
`
`86G
`70
`
`54G
`39
`
`26G
`17
`
`2G
`7
`
`Figure 2.
` Kaplan–Meier Estimates of Mortality Due to CLL-Related Causes, Second
`Cancers, and Unknown Causes in the First Trial.
`The log-rank test was used to calculate the P value.
`
`Volume 338 Number 21
`
`·
`
`1509
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 23, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2005 0004
`
`

`
`The New England Journal of Medicine
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TABLE 3. INCIDENCE OF SECOND CANCERS IN THE TWO TRIALS
`ACCORDING TO TREATMENT ASSIGNMENT.
`
`SITE OR TYPE
`OF CANCER
`
`FIRST TRIAL
`
`NO
`TREATMENT
`
`DAILY
`CHLORAMBUCIL
`
`SECOND TRIAL
`CHLORAMBUCIL
`PLUS
`PREDNISONE
`
`NO
`TREATMENT
`
`no. of cases
`
`Skin
`Mammary
`Colon
`Acute leukemia*
`Lung
`Prostate
`Bladder
`Oral
`Pharynx and larynx
`Pancreas
`Kidney
`Disseminated
`Other
`Unknown
`Total
`
`9
`1
`3
`2
`4
`8
`2
`2
`1
`2
`2
`2
`3
`7
`48
`
`17
`7
`7
`4
`4
`5
`3
`1
`4
`0
`1
`1
`8
`4
`66
`
`13
`3
`2
`0
`7
`7
`2
`1
`0
`2
`2
`1
`8
`2
`50
`
`4
`4
`6
`1
`5
`7
`0
`1
`0
`0
`1
`0
`11
`2
`42
`
`*There were three cases of acute myeloblastic leukemia type 2, one case
`each of type 3 and type 5, one case of type 2 following myelodysplasia,
`and one case of acute plasmacytic leukemia.
`
`sion in 20, infection in 24, and thrombocytopenia
`in 3). There was no significant difference in overall
`survival after the exclusion of deaths unrelated to
`CLL (P=0.16 by the log-rank test) (Fig. 4).
`The median follow-up was five years less than that
`of the first trial. As shown in Table 3, there were 50
`second neoplasms in the untreated group (median
`interval from entry into the trial to the occurrence
`of a second cancer, 42 months; range, 1 to 104), as
`compared with 42 in the treated group (median in-
`terval, 30 months; range, 1 to 100) (P=0.42 by the
`chi-square test).
`
`Response to Treatment and Disease Progression
`
`The First Trial
`In the first trial, the response to treatment could
`be evaluated in 278 of the 293 patients in the treat-
`ed group who were alive at nine months. Of these
`278 patients, 125 had complete responses (45 per-
`cent), 86 (31 percent) had partial responses, and 67
`(24 percent) had no response to treatment. Among
`patients with complete responses and partial re-
`sponses, the respective seven-year survival rates were
`78 percent and 69 percent, as compared with a rate
`of 50 percent for patients with no response to ther-
`apy. Rai stage 0, Binet stage A',
`and fewer areas
`19
`with enlarged lymph nodes were selected by a Cox
`model (data not shown) as predictive of a therapeu-
`tic response.
`
`1510
`
`·
`
`May 21, 1998
`
`The Second Trial
`In the second trial, the response to treatment
`could be evaluated in 437 of the 453 patients in the
`treated group who were alive at six months. Of these
`437 patients, 124 (28 percent) had complete re-
`sponses, 179 (41 percent) had partial responses, and
`134 patients (31 percent) had no response to treat-
`ment. Among patients with complete responses and
`partial responses, the respective seven-year survival
`rates were 84 percent and 77 percent, as compared
`with a rate of 58 percent for patients who had no
`response to therapy. Rai stage 0, Binet stage A', low-
`er initial lymphocyte count, and fewer areas with en-
`larged lymph nodes were selected by a Cox model
`(data not shown) as predictive of a therapeutic re-
`sponse.
`
`Both Trials
`Figure 5 shows that in both trials disease progres-
`sion occurred in significantly more patients in the
`untreated group than in the treated group. Progres-
`sion to stage B occurred in 67 and 85 patients, re-
`spectively, in the untreated groups of the first and
`second trials, as compared with 38 and 41 patients
`in the treated groups of the two protocols. The sur-
`vival of the untreated patients after progression to
`stage B (five-year survival, 56 percent in the first trial
`and 52 percent in the second trial) was similar to the
`survival of patients with stage B at presentation who
`received the same therapy in portions of the two tri-
`als devoted to the study of patients with stage B
`CLL.20,21 With respect to the proportion of patients
`with progression to stage C, there were no major
`differences between the untreated and treated groups
`in either trial. A minority of the untreated patients
`with progression to stage B (22 of 67 in the first tri-
`al and 22 of 85 in the second trial) were crossed over
`to therapy, whereas most of the untreated patients
`with progression to stage C (64 of 81 in the first tri-
`al and 67 of 84 in the second trial) were crossed over
`to therapy, and in some of these patients, CLL had
`previously evolved to stage B. Thus, the absence of
`a difference in the rate of progression to stage C
`might reflect resistance to chemotherapy in these pa-
`tients.
`
`Modifications of the Therapeutic Schedule
`
`The First Trial
`Among the 308 patients who were assigned to re-
`ceive no treatment in the first trial (Table 4), 158
`ultimately received treatment (110 received daily
`chlorambucil, 13 intermittent chlorambucil plus pred-
`nisone, 15 COP, 4 CHOP, 8 other combinations of
`chemotherapy, 6 corticosteroids, and 1 splenic irra-
`diation, and 1 underwent splenectomy). Of these
`158 patients, 97 were treated despite remaining in
`stage A, 44 because of progression to stage B, and
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 23, 2015. For personal use only. No other uses without permission.
`
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`

`
`CHLORAMBUCIL IN INDOLENT CHRONIC LYMPHOCYTIC LEUKEMIA
`
`Chlorambucil plus prednisoneG
`(121 deaths)
`
`No treatmentG
`(126 deaths)
`
`P=0.74
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`Year
`
`6
`
`7
`
`8
`
`9
`
`10
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Overall Survival (%)
`
`NO. AT RISK
`ChlorambucilG
`plus prednisone
`No treatment
`
`460
`
`446
`
`434
`
`415
`
`376
`
`294
`
`208
`
`110
`
`466
`
`455
`
`444
`
`420
`
`81
`
`299
`
`202
`
`104
`
`38
`
`33
`
`Figure 3. Overall Survival in the Second Trial.
`The log-rank test was used to calculate the P value.
`
`..-. ,L
`
`"i....•••,,
`
`Chlorambucil plus prednisoneG
`(82 deaths)
`
`No treatmentG
`(101 deaths)
`
`P=0.16
`
`1
`
`2
`
`3
`
`4
`
`5
`Year
`
`6
`
`7
`
`8
`
`9
`
`10
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`_
`-
`-
`
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`0
`
`Survival (%)
`
`NO. AT RISK
`ChlorambucilG
`plus prednisone
`No treatment
`
`460
`
`446
`
`434
`
`415
`
`376
`
`294
`
`208
`
`110
`
`466
`
`455
`
`444
`
`420
`
`381
`
`299
`
`202
`
`104
`
`38
`
`33
`
`Figure 4. Kaplan–Meier Estimates of Mortality Due to CLL-Related Causes, Second
`Cancers, and Unknown Causes in the Second Trial.
`The log-rank test was used to calculate the P value.
`
`Volume 338 Number 21
`
`· 1511
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 23, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2005 0006
`
`

`
`The New England Journal of Medicine
`
`of chemotherapy, 6 to corticosteroids, 1 to splenec-
`tomy, and 1 to splenic irradiation). Treatment was
`changed in 53 patients even though they remained
`in stage A, in 18 because of progression to stage B,
`and in 26 because of progression to stage C. In both
`trials, the intention-to-treat analysis included all pa-
`tients who were treated even though they remained
`in stage A.
`
`DISCUSSION
`A major issue in the management of indolent CLL
`(stage A) is whether deferring treatment is a reason-
`able alternative to immediate therapy. Our two trials,
`with more than 11 and 6 years of follow-up on 1535
`patients, addressed this question. We found that dai-
`ly chlorambucil alone or intermittent treatment with
`chlorambucil and prednisone did not prolong sur-
`vival in patients with indolent CLL. Since deferring
`therapy until the disease progressed to stage B or
`stage C did not compromise survival, initial therapy
`could have been appropriately postponed.
`Given daily or intermittently, alone or combined
`with corticosteroids, chlorambucil is the most com-
`monly used drug in CLL.8-11,22 Although one study
`reported12 that high doses of chlorambucil (15 mg
`per day until there was complete remission) were ef-
`ficacious in advanced CLL, our results and previous
`reports from our group concerning stage A7 and
`stage B20 CLL, together with the results of Shustik
`et al.10 and Catovsky et al.,9 demonstrate that the
`early use of chlorambucil does not influence survival
`in CLL.
`In the absence of curative therapy, there are ad-
`vantages to deferring treatment for patients with
`stage A CLL (63 percent of all patients with CLL
`have stage A disease). Postponing treatment avoids
`the side effects of cytotoxic therapy, including the
`infectious complications related to myelosuppression
`and the need for stringent follow-up. However,
`some patients who are concerned about their disease
`may want treatment, even in the absence of disease
`progression.
`Although chlorambucil has been reported to in-
`duce secondary acute leukemia in patients treated
`for polycythemia vera23 and when used as an immu-
`nosuppressive agent,24-27 this complication has not
`been reported in patients with CLL. In our series
`there were six cases of acute leukemia among the
`422 patients who received daily chlorambucil as ini-
`tial or secondary treatment, as compared with no
`cases among the 145 patients who never received
`therapy (Table 3).
`An unexpected finding that emerged from the ear-
`ly results of the first trial was the relatively high fre-
`quency of epithelial neoplasms in the group treated
`with chlorambucil. This was subsequently found in
`three successive interim analyses (33, 50, and 66 can-
`cers in the treated group at the third, fourth, and fifth
`
`ChlorambucilG
`(102 with progression)
`
`No treatmentG
`(127 with progression)
`
`P=0.03
`
`2
`
`4
`
`6
`
`8
`Year
`
`10
`
`12
`
`14
`
`Chlorambucil plus prednisoneG
`(108 with progression)
`
`'I-
`'I^
`No treatmentG
`(142 with progression)
`
`P<0.001
`
`1
`
`2
`
`3
`
`4
`
`5
`Year
`
`6
`
`7
`
`8
`
`9
`
`10
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`-
`-
`-
`-
`-
`-
`
`- -
`
`- -
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`0
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`- (cid:9)
`
`- -
`
`
`
`- -
`
`
`- -
`-
`
`- -
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`0
`
`Patients without ProgressionG
`
`to Stage B or C (%)
`
`A
`
`Patients without ProgressionG
`
`to Stage B or C (%)
`
`B
`
`Figure 5. Patients without Progression to Stage B or C in the
`First Trial (Panel A) and the Second Trial (Panel B).
`The log-rank test was used to calculate the P value.
`
`17 because of progression to stage C. In the group
`assigned to daily chlorambucil, 83 of the 301 pa-
`tients were changed to another therapy (13 received
`chlorambucil plus prednisone, 24 COP, 20 CHOP,
`22 other combinations of chemotherapy, and 4 cor-
`ticosteroids). Treatment was changed in 28 patients
`even though they remained in stage A, in 14 because
`of progression to stage B, and in 41 because of pro-
`gression to stage C.
`
`The Second Trial
`Among the 466 patients assigned to receive no
`therapy in the second trial, 187 received treatment
`(137 received chlorambucil plus prednisone, 20
`CHOP, 14 daily chlorambucil, 14 other combina-
`tions of chemotherapy, 1 corticosteroids, and 1 total
`irradiation). Of these, 107 were given treatment de-
`spite remaining in stage A, 63 because they had pro-
`gression to stage B, and 17 because they had pro-
`gression to stage C. Among the treated patients, 97
`were changed to another treatment (37 to CHOP,
`28 to daily chlorambucil, 24 to other combinations
`
`1512 · May 21, 1998
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on July 23, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2005 0007
`
`

`
`CHLORAMBUCIL IN INDOLENT CHRONIC LYMPHOCYTIC LEUKEMIA
`
`TABLE 4. ADDITIONAL TREATMENT GIVEN AND STAGE AT THE TIME OF THE CHANGE
`IN TREATMENT, ACCORDING TO TREATMENT ASSIGNMENT IN THE FIRST TRIAL.
`
`VARIABLE
`
`NO TREATMENT (N=158)
`PROGRESSION
`PROGRESSION
`TO STAGE B
`TO STAGE C
`
`STAGE A
`
`DAILY CHLORAMBUCIL (N=83)
`PROGRESSION
`PROGRESSION
`TO STAGE B
`TO STAGE C
`
`STAGE A
`
`No. of patients
`No. of deaths
`Interval between study
`entry and change
`in treatment (mo)
`Median
`Range
`Survival 9 yr after
`randomization (%)
`
`97*
`52
`
`44
`31
`
`17
`10
`
`28†
`19
`
`14
`13
`
`41
`35
`
`32
`5–148
`61
`
`22
`5–134
`54
`
`36
`3–108
`33
`
`62
`9–146
`45
`
`44
`14–127
`21
`
`66
`3–142
`27
`
`*Treatment was started because of increased lymphocytosis or lymphadenopathy in 61 patients and
`causes unrelated to disease progression in 36 patients.
`†Treatment was changed because of increased lymphocytosis or lymphadenopathy in 20 patients
`and causes unrelated to disease progression in 8 patients.
`
`interim analyses, respectively, as compared with 19,
`25, and 48 cancers in the untreated group). However,
`these differences are not significant (P=0.045), and
`they were not confirmed in the second trial. Nev-
`ertheless, we cannot rule out an oncogenic potential
`of chlorambucil because the total dose of chloram-
`bucil differed in the two trials (3 mg per kilogram per
`month vs. 1.5 mg per kilogram when given intermit-
`tently), as did the duration of treatment (long-term
`continuous therapy vs. three years of therapy) and the
`timing of therapy (daily vs. intermittent).
`Our results indicate that chlorambucil can delay
`disease progression, even though it does not affect
`survival. We cannot rule out the possibility that pa-
`tients in the treated groups with progression to stage
`B had a poorer initial prognosis. However, the dif-
`ferences in survival nine years after randomization
`(Table 4) between untreated patients with progres-
`sion to stage B and treated patients with progression
`to stage B (54 percent vs. 21 percent) suggest that
`early exposure to the drug selects for resistant clones,
`which are the cause of the poor prognosis of patients
`who have no response to early therapy.
`Of the 308 patients in the first trial who were not
`treated, 49 percent remained in stage A and needed
`no therapy after follow-up of more than 11 years.
`However, 27 percent of the untreated patients in
`stage A died of causes related to the disease, and
`more than half began therapy because the disease
`began to progress.
`Our results emphasize the need for both a better
`definition of stage A CLL and curative treatment for
`indolent CLL, particularly in young patients. There
`is evidence that purine analogues, particularly flu-
`darabine, are the most effective agents for this disor-
`der.28-30 Since these drugs have not been shown to
`
`improve overall survival, it is premature to recom-
`mend them for patients with stage A CLL, particu-
`larly in stage A', since survival in patients with stage
`A' disease is close to that of a sex-matched and age-
`matched normal population. However, young pa-
`tients with stage A" CLL, whose five-year survival
`rate is 62 percent,7 may be candidates for treatment
`with these drugs.
`
`We are indebted to Professor Jacques Benichou (Centre Hospitalier
`Universitaire de Rouen) for his invaluable help in revising the
`manuscript.
`
`APPENDIX
`
`The following institutions (all in France unless otherwise specified) and
`members of the French Cooperative Group on Chronic Lymphocytic
`Leukemia were involved in the two trials: Centre Hospitalier Régional,
`Lille: P. Fenaux