Pergamon
`
`European Journal of Cancer, Vol. 34, No. 3, pp. 329–336, 1998
`# 1998 Elsevier Science Ltd. All rights reserved
`Printed in Great Britain
`0959-8049/98 $19.00+0.00
`
`PII: S0959-8049(97)10056-9
`
`Original Paper
`
`Mantle Cell Lymphoma: Clinical Features, Treatment and
`Prognosis of 94 Patients
`
`R. Oinonen,1 K. Franssila,2 L. Teerenhovi,3 K. Lappalainen4 and E. Elonen1
`
`1Department of Medicine; 2Department of Pathology, Oncology Hospital; 3Department of Oncology; and
`4Department of Radiology, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290, Helsinki, Finland
`
`Mantle cell lymphoma (MCL) is a subtype of B-cell non-Hodgkin’s lymphoma recently recognised as a
`distinct disease entity. Little is known about the prognostic factors and optimal treatment of MCL.
`The aim of this study was to analyse retrospectively the clinical features and eVect of treatment in 94
`MCL patients diagnosed and treated in one centre between 1980 and 1996, and to find out diVerent
`factors influencing the treatment results and prognosis. The median age of the patients was 66 years,
`and 77% were over 60 years old. Of the patients, 76% had advanced disease, the performance status
`(PS) was WHO 0–1 in 86%, and B symptoms were present in 35% of the cases. Bone marrow infiltra-
`tion was found in 61% and overt leukaemia in 12% of the patients. Of the patients, 47% achieved
`complete remission with first- or second-line therapy. The median duration of remission, time to
`treatment failure (TTF), and survival were 28, 18, and 41 months, respectively. In multivariate analy-
`ses, age, stage and leukaemic disease were significantly associated with TTF, and age, stage, leu-
`kaemic disease and lactate dehydrogenase (LDH) with survival. Long-term prognosis is poor in MCL.
`None of the conventional chemotherapies seems curative. A prospective randomised trial should be
`made to evaluate the benefit of anthracycline-containing regimens in MCL. # 1998 Elsevier Science
`Ltd. All rights reserved.
`
`lymphoma, non-Hodgkin’s lymphoma, diagnosis, treatment, prognosis,
`Key words: mantle cell
`International Prognostic Index
`Eur J Cancer, Vol. 34, No. 3, pp. 329 –336, 1998
`
`INTRODUCTION
`Mantle cell lymphoma (MCL) is a recently well-charac-
`terised subtype of B-cell non-Hodgkin’s lymphoma estimated
`to represent between 2 and 9% of all non-Hodgkin’s lym-
`phomas [1, 2]. Previously defined subtypes, being variously
`termed as intermediate lymphocytic lymphoma, mantle zone
`lymphoma and centrocytic lymphoma, have now been con-
`sidered to comprise a single disease entity and in 1992 the
`unification of all these terms under the name mantle cell
`lymphoma was proposed [3].
`MCL is distinguished from other non-Hodgkin’s lympho-
`mas by morphological, cytochemical, immunohistochemical
`and cytogenetic studies. It is composed of small or inter-
`mediate lymphatic cells with cleaved nuclei. They express B-
`cell associated antigens, surface immunoglobulins IgM and
`IgD, and CD5, but are usually negative for CD10 and CD23
`
`Correspondence to E. Elonen.
`Received 25 Apr. 1997; revised 3 Sep. 1997; accepted 7 Oct. 1997.
`
`antigens [4–6]. The characteristic cytogenetic abnormality is
`a t(11;14)(q13;q32) translocation with re-arrangement of the
`bcl1/CCND1 gene found in 50–70% of MCLs [7, 8]. The
`CCND1 gene encodes for cyclin D1 protein. Its over-
`expression is seen in nearly all cases of MCL, and antibody to
`cyclin D1 is shown to be highly sensitive and specific for
`MCL [9].
`According to the Kiel Classification, MCL (identified as
`centrocytic lymphoma) belongs to low-grade lymphomas.
`However, in spite of its indolent histological features, MCL is
`known to have a poorer prognosis than other small-cell lym-
`phomas. The survival time is short and the survival curves do
`not show any evidence of cure [3, 10, 11]. In the widely used
`Working Formulation classification, MCL is not recognised
`as a distinct disease entity, but has been included in a sub-
`group of diVuse small cleaved cell or diVuse mixed small and
`large cell lymphomas of intermediate grade of malignancy or
`to follicular low-grade lymphomas [12]. In the recently pro-
`posed Revised European–American Lymphoma (REAL)
`
`329
`
`IPR2018-00685
`Celgene Ex. 2049, Page 1
`
`

`

`330
`
`R. Oinonen et al.
`
`including MCL,
`lymphoma entities,
`classification, several
`have a range of morphological grade [5]. Little information is
`available about the prognostic factors and optimal treatment
`of MCL. Whether anthracycline-containing chemotherapy
`improves the prognosis or not is still unclear [13, 14].
`The purpose of this study was to analyse the clinical fea-
`tures and eVect of treatment in MCL patients and to find out
`diVerent factors influencing the treatment results and prog-
`nosis. The role of the International Prognostic Index (IPI)
`[15] in predicting the prognosis in MCL was particularly
`evaluated.
`
`PATIENTS AND METHODS
`
`Patients
`A retrospective study of 94 patients with MCL diagnosed
`and treated from November 1980 to April 1996 was under-
`taken. The median follow-up for all patients was 78 months
`(range 6–198 months) and for the surviving patients 51
`months (range 6–129 months). Patients with diVuse cen-
`trocytic lymphoma, according to the Kiel Classification, or
`MCL were collected from a computer database. The pathol-
`ogy specimens were reviewed by one of the authors (K.F.),
`and only the patients with a confirmed diagnosis of MCL
`according to the recently updated criteria (REAL) [5] were
`included. All 94 patients met strict morphological criteria of
`MCL. Immunohistochemistry was performed on frozen tis-
`sue biopsies from 71 patients and on paraYn-embedded
`biopsies from 23 patients. In the frozen tissue sections the
`lymphomas of 71/71 patients were CD20 and/or CD19+,
`64/64 were IgM+, 48/57 were IgD+, 34/71 were kappa+, 37/
`71 were lambda+ and 55/55 were CD2(cid:255). In paraYn-
`embedded sections, all cases were CD20/L26 positive and
`CD3 negative; 70/82 were CD5 positive (52/59 stained in
`frozen tissue sections and 18/23 in paraYn-embedded sec-
`tions). Sixty stained cases were cyclin D1 (NCL-Cyclin D1-
`GM, Novocastra, Newcastle, U.K.) positive in paraYn-
`embedded sections. No diVerence in remission rate, time to
`treatment failure (TTF) or survival were seen in 73 cases with
`positive cyclin D1 and/or CD5+IgD expression or in 21 cases
`without known positive cyclin D1 or CD5+IgD expression.
`The clinical features evaluated for potential prognostic
`importance were age, sex, performance status (PS), Ann
`Arbor stage, B symptoms, IPI, size of the largest tumour, sites
`of lymphomatous involvement and the number of extra nodal
`disease sites. In addition, a number of laboratory findings at
`the time of diagnosis were assembled.
`The stage of the disease was assessed by clinical evaluation
`combined with thorax X-ray examination, thoracic, abdom-
`inal and pelvic computed tomography (CT) scans and bone
`marrow aspirate and biopsy. At the time of diagnosis, a bone
`marrow biopsy was taken in all but 4 patients. In 5 of the
`examined 90 cases, the bone marrow biopsy specimens were
`non-diagnostic for technical reasons. Gastrointestinal tract
`involvement of the symptomatic patients was detected by
`endoscopic examinations or laparotomy. Other known or
`suspected extra nodal disease was investigated by CT or with
`other appropriate imaging techniques. Biopsies were per-
`formed to confirm the involvement of extra nodal sites.
`PS was assessed according to the WHO criteria [16]. The
`Ann Arbor stage was designated according to Lister and
`associates [17]. The largest dimension of the largest site of
`bulky disease was measured and reported as being < 10 cm
`or (cid:21) 10 cm. The number of extra nodal disease sites was
`
`recorded as (cid:20) 1 or > 1. Spleen and Waldeyer’s ring were
`classified as nodal sites. The patients were classified retro-
`spectively to four risk groups according to IPI, a recently
`proposed model to predict the outcome in patients with
`large-cell lymphomas based on patients’ clinical character-
`istics (i.e. age, Ann Arbor stage, PS, number of extra nodal
`sites, serum lactate dehydrogenase (LDH) level) at pres-
`entation [15].
`
`Treatments
`First-line therapy. 5 patients had no treatment for their
`lymphoma. 8 of the 23 patients with stage I or II disease were
`operated on or treated with local radiotherapy only. Chlor-
`ambucil with or without prednisone, or CVP (cyclophos-
`phamide, vincristine, prednisone) was given to 19 patients.
`The other patients received more intensive regimens: 59
`patients received chemotherapy,
`including anthracyclines
`[M-BACOD (high-dose methotrexate, bleomycin, doxo-
`rubicin, cyclophosphamide, vincristine, dexamethasone),
`CHOP (cyclophosphamide, doxorubicin, vincristine, pred-
`nisone with or without bleomycin) or CNOP (mitoxantrone
`instead of doxorubicin)], and 3 patients received ESHAP
`(etoposide, methylprednisolone, cytarabine, cisplatin). 4 of
`the patients with advanced disease were also irradiated or
`operated on in addition to chemotherapy.
`Consolidation therapy. 15 of the patients who achieved
`remission following first-line therapy were given further therapy
`for consolidation: radiotherapy (n = 8), radiotherapy and
`chlorambucil (n = 1), radiotherapy and CHOP (n = 1), chlor-
`ambucil (n = 2), M-BACOD (n = 2) or low-dose CHOP
`(n = 1).
`Second-line therapy. An additional therapy given to the
`patients without satisfactory response to first-line therapy was
`defined as second-line therapy. It was divided into three
`groups: (1) local treatment (operation or radiotherapy); (2)
`chlorambucil (with or without radiotherapy, prednisone or
`interferon) or CVP; and (3) more intensive combination
`chemotherapy.
`
`Assessment of response
`total dis-
`Complete response (CR) was defined as
`appearance of all clinical evidence of the disease and nor-
`malisation of the radiographic results and biopsy of the bone
`marrow which had been abnormal before treatment. Regres-
`sion of at least 50% of all measurable disease was defined as a
`partial response (PR). Relapse was defined as the reappear-
`ance of malignant lymphoma in a patient who had previously
`had a complete remission. The duration of remission was
`defined as the time from the documentation of a complete
`remission to relapse. Progression was defined as relapse,
`increase of tumour size or appearance of a new tumour. TTF
`was defined as survival from the date of diagnosis to progres-
`sion of the lymphoma, to the death of any cause, or to the last
`follow-up [18]. The patients without progression were cen-
`sored at the date of the last follow-up. Survival was measured
`as the interval between the date of diagnosis and death or the
`last follow-up evaluation. The patients alive at the time of the
`last follow-up were censored for survival.
`
`Statistical methods
`The analyses were performed on a VAX 6000 computer
`using BMDP statistical software package (BMDP Statistical
`Software, Los Angeles, California, U.S.A.). The univariate
`
`IPR2018-00685
`Celgene Ex. 2049, Page 2
`
`

`

`Mantle Cell Lymphoma
`
`331
`
`association between remission and individual clinical features
`was analysed using the chi-square test and Fisher’s exact test.
`The duration of remission, TTF and overall survival were
`estimated by the method of Kaplan and Meier. The uni-
`variate association between TTF or overall survival and indi-
`vidual clinical features was determined using the Mantel–Cox
`test and generalised Wilcoxon test. To discover the inde-
`pendence of the diVerent prognostic factors, Cox’s propor-
`tional hazards regression model and logistic regression were
`used. The variables chosen for the multivariate analyses
`were age, haemoglobin level, leucocyte count, lymphocyte
`count, erythrocyte sedimentation rate, LDH (as continuous
`variables), sex, stage (I–II versus III–IV), B symptoms
`(absent or present), PS (WHO 0 versus 1–4), bone marrow
`infiltration,
`leukaemic disease,
`involvement of spleen and
`first-line treatment (others versus anthracycline-containing
`regimens and ESHAP). In addition, five IPI variables, as
`defined in the international non-Hodgkin’s lymphoma prog-
`nostic project (age (cid:20) 60 versus > 60 years, stage I–II versus
`III–IV, PS 0–1 versus 2–4, LDH normal versus elevated)
`[15], were analysed together in multivariate analyses. All sig-
`nificance values were calculated from two-sided tests.
`
`RESULTS
`
`Clinical features
`At the time of diagnosis, 72 of the 94 patients (77%) were
`over 60 years old with a median age of 66 years (range 44–87
`years). Fifty-nine per cent of the patients were males. The
`clinical characteristics of the patients are summarised in
`Table 1. The PS of the patients was usually good (WHO 0–1
`in 86%). Most patients had an advanced stage disease (76%
`had Ann Arbor stage III or IV), but only 35% of the patients
`had B symptoms. Bulky tumours were rare and 40% of the
`patients had more than one extra nodal site of disease. Bone
`marrow involvement was found in 61%, but leukaemic dis-
`ease in only 12% of the patients. Spleen, gastrointestinal tract
`and Waldeyer’s ring were the other most common sites of
`lymphomatous involvement. IPI was evaluable in 83 patients
`(88%). In 11 cases, either the LDH value and/or the number
`of extra nodal sites at diagnosis were unknown. The patients
`were almost equally distributed among low,
`low–inter-
`mediate, high–intermediate and high risk groups according to
`IPI.
`
`Outcome of the patients
`Remissions. There were 5 elderly patients who received no
`active treatment for their lymphoma due to their poor con-
`dition at diagnosis. None of
`them showed spontaneous
`recovery. Of the other 89 patients, first-line therapy resulted
`in CR in 34% (30/89) and PR in 44% (39/89). No response
`was seen in 15% (13/89) and progressive disease in 7% (6/89)
`of the patients. 1 patient died during first-line therapy. The
`eVects of diVerent treatments are given in Table 2.
`All 5 patients who achieved CR by operation had stage I
`disease. Of the 19 patients treated with chlorambucil or CVP
`only 2 (11%) achieved CR, whereas 21 of the 62 patients
`(34%) treated with anthracycline-containing regimens or
`ESHAP achieved CR (P = 0.048). Of the 59 patients who did
`not achieve CR with the first-line therapy, 14 (24%) achieved
`it with the second-line therapy. Radiotherapy was given to 5
`of them, 8 received chemotherapy (2 chlorambucil, 6 combi-
`nation chemotherapy) and 1 patient achieved CR following
`surgery for local disease.
`
`Table 1. Characteristics of 94 patients with mantle cell lymphoma
`at the time of diagnosis
`
`Parameter
`
`Performance status (WHO)
`0
`1
`2
`3
`4
`
`Ann Arbor stage
`I
`II
`III
`IV
`
`B symptoms
`Absent
`Present
`
`International Prognostic Index (n = 83)
`Low
`Low–intermediate
`High–intermediate
`High
`
`Dimension of the largest tumour
`< 10 cm
`(cid:21) 10 cm
`Extranodal involvement (n = 89)
`(cid:20) 1 site
`> 1 site
`
`Site of disease
`Bone marrow (n = 85)
`Blood
`Spleen
`Gastrointestinal tract
`Conjunctiva/orbita
`Waldeyer’s ring
`
`Lactate dehydrogenase (n = 86)*
`< 450 U/l
`(cid:21) 450 U/l
`Thymidine kinase (n = 46)y
`< 5 U/l
`(cid:21) 5 U/l
`*Normal value < 450 U/l. yNormal value < 5 U/l.
`
`n
`
`38
`43
`9
`2
`2
`
`13
`10
`7
`64
`
`61
`33
`
`19
`24
`22
`18
`
`75
`19
`
`53
`36
`
`52
`11
`29
`18
`6
`16
`
`53
`33
`
`15
`31
`
`%
`
`40
`46
`10
`2
`2
`
`14
`11
`7
`68
`
`65
`35
`
`23
`29
`27
`22
`
`80
`20
`
`60
`40
`
`61
`12
`31
`19
`6
`17
`
`62
`38
`
`33
`67
`
`Table 2. Complete remissions with first-line therapy
`
`Complete remissions
`
`Treatment group
`
`Operation
`Radiotherapy
`Chlorambucil (cid:139) prednisone
`CVP
`M-BACOD
`CHOP/CNOP
`ESHAP
`Total
`
`n
`
`5/5
`2/3
`1/13
`1/6
`11/27
`9/32
`1/3
`30/89
`
`(%)
`
`(100)
`(67)
`(8)
`(17)
`(41)
`(28)
`(33)
`(34)
`
`CVP, cyclophosphamide, vincristine, prednisone; M-BACOD, high-
`dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vin-
`cristine, dexamethasone; CHOP, cyclophosphamide, doxorubicin,
`vincristine, prednisone with or without bleomycin; CNOP, as CHOP
`but with mitoxantrone instead of doxorubicin; ESHAP, etoposide,
`methylprednisolone, cytarabine, cisplatin.
`
`IPR2018-00685
`Celgene Ex. 2049, Page 3
`
`

`

`332
`
`R. Oinonen et al.
`
`CR was achieved by 44 patients (47% of all 94 or 49% of
`those 89 patients whose treatment was evaluable). 23 of the
`44 complete responders (52%) relapsed during follow-up.
`The median duration of remission was 28 months (95%
`confidence interval (CI) 14–57 months) and 44% of the
`patients were in remission at 3 and 25% at 5 years. No pla-
`teau was observed in the curve. The second remission,
`usually short in duration, was achieved in 14 cases (61%), 12
`with chemotherapy and 2 with radiotherapy.
`The clinical findings at presentation and their association
`with the remission rate in the univariate analysis are shown in
`Table 3. A low remission rate was highly associated with poor
`PS (P = 0.002), advanced stage (P < 0.001), B symptoms
`(P < 0.001), high IPI (P = 0.004), bone marrow infiltration
`(P < 0.001), leukaemic disease (P = 0.015), low haemoglobin
`level (P = 0.002), leucocytosis (P = 0.002), low platelet count
`(P = 0.009) and elevated LDH (P = 0.003) and thymidine
`kinase (P = 0.004) levels. The variables with statistically sig-
`nificant impact on the CR rate in the logistic regression analy-
`sis were first-line therapy, haemoglobin level, stage, sex and
`LDH level (Table 4).
`Time to treatment failure (TTF). The median TTF was 18
`months (95% CI 15–25 months). No plateau was observed in
`the curve (Figure 1). In the univariate analysis, the factors
`predicting a shorter TTF were age over 60 years, poor PS,
`advanced stage, B symptoms, high IPI, bone marrow infil-
`tration, leukaemic disease, low haemoglobin level, leucocy-
`tosis and high LDH level (Table 5). The first-line treatment
`with anthracycline-containing regimens and ESHAP, com-
`pared to chlorambucil and CVP, was associated with a longer
`TTF (P = 0.008). In the multivariate analysis, leukaemic dis-
`ease, stage and age were significantly associated with TTF
`(Table 4).
`Overall survival. Survival was 54 and 28% at 3 and 5
`years, respectively (median 41 months, 95% CI 28–55
`months). No plateau in the survival curve was observed dur-
`ing the follow-up time (Figure 1). As shown in Table 5, age
`(Figure 2a), PS, stage (Figure 2b), B symptoms, bone mar-
`row infiltration, leukaemic disease (Figure 2(c)), haemoglo-
`bin level, leucocytosis, erythrocyte sedimentation rate, LDH
`level (Figure 2d) and IPI (Figure 3) were found to have
`prognostic significance on survival in the univariate analysis.
`In addition, the use of anthracycline-containing regimens and
`ESHAP as the first-line therapy was associated with a longer
`survival (Figure 4). In Cox’s proportional hazards regression
`
`Table 3. Remission rates with the first- and second-line therapy of
`the 89 patients who received active treatment
`
`Parameter
`
`Age(cid:20) 60 years
`
`> 60 years
`
`Sex
`Male
`Female
`
`Performance status
`0
`1–4
`
`Stage
`I–II
`III–IV
`
`B symptoms
`Absent
`Present
`
`International Prognostic
`Index (n = 80)
`Low
`Low-intermediate
`High–intermediate
`High
`
`Site of disease
`Bone marrow (n = 81)
`Yes
`No
`
`Blood
`Yes
`No
`
`Spleen
`Yes
`No
`
`Haemoglobin level (n = 85)
`(cid:20) 125 g/l
`> 125 g/l
`
`Leucocyte count (n = 85)
`(cid:20) 10(cid:2)109/l
`> 10(cid:2)109/l
`Platelet count (n = 83)
`< 140(cid:2)109/l
`(cid:21) 140 (cid:2) 109/l
`Lactate dehydrogenase (n = 82)
`< 450 U/l
`(cid:21) 450 U/l
`Thymidine kinase (n = 43)
`< 5 U/l
`(cid:21) 5 U/l
`
`Remissions
`(CR)
`
`No. of
`patients
`
`n (%)
`
`P
`value
`
`22
`67
`
`52
`37
`
`36
`53
`
`22
`67
`
`56
`33
`
`19
`23
`22
`16
`
`50
`31
`
`10
`79
`
`27
`62
`
`43
`42
`
`70
`15
`
`20
`63
`
`51
`31
`
`12
`31
`
`14 (64)
`30 (45)
`
`21 (40)
`23 (62)
`
`25 (69)
`19 (36)
`
`19 (86)
`25 (37)
`
`36 (64)
`8 (24)
`
`16 (84)
`12 (52)
`9 (41)
`4 (25)
`
`17 (34)
`23 (74)
`
`1 (10)
`43 (54)
`
`6 (22)
`38 (61)
`
`14 (33)
`28 (67)
`
`40 (57)
`2 (13)
`
`5 (25)
`37 (59)
`
`32 (63)
`9 (29)
`
`11 (92)
`14 (45)
`
`0.125
`
`0.043
`
`0.002
`
`< 0.001
`
`< 0.001
`
`0.004
`
`< 0.001
`
`0.015
`
`0.001
`
`0.002
`
`0.002
`
`0.009
`
`0.003
`
`0.004
`
`Figure 1. Time to treatment failure (TTF; median 18 months)
`and overall survival (median 41 months) of 94 patients with
`mantle cell lymphoma.
`
`model, age, leukaemic disease, LDH level and stage were
`found to be statistically significant prognostic factors
`(Table 4).
`IPI. Separately, five IPI variables (as defined in [15])
`were analysed together in the multivariate analyses. Of these,
`stage and LDH were significantly associated with CR rate,
`and age and stage with TTF and with survival.
`
`IPR2018-00685
`Celgene Ex. 2049, Page 4
`
`

`

`Mantle Cell Lymphoma
`
`333
`
`Table 4. Significant variables in logistic regression model and Cox’s proportional hazards regression model
`
`Complete remission rate
`First-line therapy*
`Haemogloblin level
`Stage (I–II versus III–IV)
`Sex
`LDH level
`
`Time to treatment failure
`Leukaemic disease
`Stage (I–II versus III–IV)
`Age
`
`Survival
`Age
`Leukaemic disease
`LDH level
`Stage (I–II versus III–IV)
`
`Odds ratio
`
`95% confidence interval
`
`P value
`
`35.9
`11.1
`0.074
`5.80
`0.995
`
`4.06–318
`2.15–57.0
`0.012–0.471
`1.58–21.4
`0.990–0.999
`
`0.001
`0.004
`0.005
`0.007
`0.018
`
`Relative risk
`
`95% confidence interval
`
`P value
`
`2.537
`2.185
`1.030
`
`1.067
`3.152
`1.001
`2.179
`
`1.228–5.240
`1.118–4.269
`1.002–1.058
`
`1.032–1.103
`1.478–6.723
`1.000–1.002
`1.018–4.666
`
`0.012
`0.022
`0.033
`
`< 0.001
`0.003
`0.015
`0.046
`
`*Others versus anthracycline-containing regimens and ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin). LDH, lactate dehy-
`drogenase.
`
`DISCUSSION
`Although MCL usually shows an indolent histology of low-
`grade lymphoma, an aggressive clinical course is common.
`The long-term prognosis is poor and no cure is reached with
`conventional chemotherapy in an advanced disease. No opti-
`
`mal treatment strategies have been defined, and whether the
`anthracycline-containing regimens improve the prognosis or
`not is still unclear [13, 14, 19].
`The clinical characteristics of the present MCL patients
`support those found in previously published smaller series
`
`Figure 2. (a) Overall survival for 22 patients (cid:20) 60 years old compared to 72 patients > 60 years of age (P = 0.014). (b) Overall
`survival for 23 patients with stage I–II disease compared to 71 patients with stage III–IV disease (P = 0.002). (c) Overall survival
`for 83 patients without leukaemic disease compared to 11 patients with leukaemic disease (P < 0.001). (d) Overall survival for 53
`patients with normal serum lactate dehydrogenase (LDH) level (< 450 U/l) compared to 33 patients with elevated serum LDH
`level ((cid:21) 450 U/l) (P = 0.002).
`
`IPR2018-00685
`Celgene Ex. 2049, Page 5
`
`

`

`334
`
`R. Oinonen et al.
`
`Table 5. Time to treatment failure (TTF) and survival of 94 patients with mantle cell lymphoma according to the characteristics in
`univariate analysis
`
`Parameter
`
`Total
`
`Age(cid:20) 60 years
`
`> 60 years
`
`Performance status
`0
`1–4
`
`Ann Arbor stage
`I–II
`III–IV
`
`B symptoms
`Absent
`Present
`
`International Prognostic Index (n = 83)
`Low
`Low–intermediate
`High–intermediate
`High
`
`Site of disease
`Bone marrow (n = 85)
`Yes
`No
`
`Blood
`Yes
`No
`
`Haemoglobin level (n = 90)
`(cid:20) 125 g/l
`> 125 g/l
`
`Leucocyte count (n = 90)
`(cid:20) 10(cid:2)109/l
`> 10(cid:2)109/l
`Sedimentation rate (n = 90)
`< 20 mm/h
`(cid:21) 20 mm/h
`Lactate dehydrogenase (n = 86)
`< 450 U/l
`(cid:21) 450 U/l
`
`n
`
`94
`
`22
`72
`
`38
`56
`
`23
`71
`
`61
`33
`
`19
`24
`22
`18
`
`52
`33
`
`11
`83
`
`45
`45
`
`71
`19
`
`40
`50
`
`53
`33
`
`Median TTF (months)
`
`P value
`
`Median survival (months)
`
`P value
`
`18
`
`27
`17
`
`26
`15
`
`42
`17
`
`21
`13
`
`48
`18
`16
`12
`
`16
`25
`
`6
`21
`
`15
`26
`
`23
`6
`
`24
`15
`
`25
`15
`
`0.042
`
`0.025
`
`0.001
`
`0.007
`
`< 0.001
`
`0.017
`
`< 0.001
`
`0.027
`
`< 0.001
`
`0.144
`
`0.024
`
`41
`
`57
`34
`
`63
`32
`
`70
`32
`
`57
`23
`
`72
`28
`31
`21
`
`32
`67
`
`14
`46
`
`26
`55
`
`54
`8
`
`54
`30
`
`54
`22
`
`0.014
`
`0.026
`
`0.002
`
`< 0.001
`
`0.001
`
`0.011
`
`< 0.001
`
`0.023
`
`< 0.001
`
`0.034
`
`0.002
`
`[14, 20–23]. Most of the patients were over 60 years of age
`with generalised lymphadenopathy and bone marrow infil-
`tration. The involvement of spleen, gastrointestinal tract or
`Waldeyer’s ring were often seen. Although an advanced stage
`disease was very common at the time of diagnosis, PS was
`rarely poorer than WHO 1 and B symptoms were found
`only in 35% of cases. Noticeable was the proportion of the
`aVected females, 41% of the patients in this study, as a great
`preponderance of males (67–94%) has usually been found
`[1, 11, 14, 23].
`The most important factors related to inferior outcome in
`the univariate analyses were poor PS, advanced stage, B
`symptoms, high IPI, bone marrow infiltration,
`leukaemic
`disease, low haemoglobin level, leucocytosis, lymphocytosis
`and LDH level above normal. Advanced age (> 60 years) had
`no influence on the CR rate but was related to shorter TTF
`and survival. Neither the number of extra nodal sites nor
`large tumours had any influence on the outcome. In the
`
`(others versus
`multivariate analyses, first-line treatment
`anthracycline-containing regimens and ESHAP), haemoglo-
`bin level, stage, sex and LDH level were significantly asso-
`ciated with CR rate, leukaemic disease, stage and age with
`TTF, and age, leukaemic disease, LDH level and stage with
`survival, respectively.
`One of the purposes of this study was to clarify the role
`the International Prognostic Index (IPI), a proposed
`of
`model for predicting the outcome in diVuse large-cell lym-
`phomas,
`in the prediction of
`the outcome in MCL
`[15, 24]. In the univariate analysis, a good prognostic value
`for IPI was detected, but
`the results in the low–inter-
`mediate and high–intermediate groups were very similar. A
`similar result was seen in the study of 65 MCL patients by
`Zucca and co-workers
`[14] where the overall
`survival
`curves were almost equal
`in these groups. Velders and
`associates [23] studied 41 patients with MCL and found,
`according to IPI, only a small group of low risk patients
`
`IPR2018-00685
`Celgene Ex. 2049, Page 6
`
`

`

`Mantle Cell Lymphoma
`
`335
`
`Figure 3. Overall survival according to the International
`Prognostic Index. Low-risk group, 19 patients; intermediate-
`risk group (including low–intermediate and high–intermediate
`groups), 46 patients; high-risk group, 18 patients (P = 0.001).
`
`with a significantly longer survival compared to patients in
`other groups.
`the
`In the univariate analyses, all IPI factors, except
`number of extra nodal disease sites, showed prognostic sig-
`nificance on TTF and survival. However, when all IPI
`covariates were analysed together in Cox’s proportional
`hazards regression model, only age and stage contributed
`significantly to TTF or survival. According to this study, IPI
`might not be an optimal prognostic index in MCL. However,
`there were a small proportion of patients who had low per-
`formance status or multiple extra nodal sites and we cannot
`be confident of the impact of these factors with the small
`number of patients involved. A large collaborative study is
`needed to determine the relevant and generally acceptable
`prognostic factors in MCL.
`It is still unclear whether anthracycline-containing regi-
`mens improve the prognosis in MCL or not. The limita-
`tions of our
`retrospective study where patients with
`diVerent kinds of prognosis may have received diVerent
`treatments have to be taken into consideration. However, it
`cannot be overlooked that an obvious improvement in the
`outcome of MCL patients is seen in the univariate analyses
`when anthracycline-containing regimens and ESHAP were
`used. In the logistic regression analysis a benefit of anthra-
`cyclines and ESHAP to the remission rate was seen. Our
`finding is supported by Zucca and associates [14] who, in
`a retrospective study of 65 patients with MCL,
`found
`benefit for anthracycline-containing regimens. Also, Teo-
`dorovic and associates [25] reported CR in 15 out of 29
`MCL patients (52%) treated with aggressive chemotherapy
`and suggested improved survival with the use of CHOP-
`like aggressive chemotherapy. In a prospective randomised
`trial of advanced low-grade non-Hodgkin’s lymphomas by
`the German Low-Grade Lymphoma Study Group, the CR
`rate was 26% (5/19) in MCL patients treated with pred-
`nimustine and mitoxantrone, compared to 5% (1/19)
`treated with COP, although no diVerences in the overall
`response rates were found [26]. In contrast, a prospective
`randomised therapeutic trial of advanced centrocytic lym-
`phoma showed no significant diVerence in prognosis
`between 37 patients treated with COP and 27 treated with
`CHOP [13]. All
`these studies have included relatively
`small numbers of patients and it
`is evident
`that
`larger
`
`Figure 4. EVect of intensity of chemotherapy on survival. The
`intensive chemotherapy group included 59 patients treated
`with anthracycline-containing chemotherapy and 3 patients
`treated with ESHAP (etoposide, methylprednisolone, cyta-
`rabine, cisplatin). The non-intensive chemotherapy group
`included 19 patients treated with chlorambucil or CVP
`(cyclophosphamide, vincristine, prednisone) (P = 0.003).
`
`prospective studies are needed to find out if anthracylines
`have a benefit in MCL. Even so, none of the conventional
`chemotherapies seems to be curative and, to improve the
`poor prognosis in MCL, a more accurate and eYcient
`therapy should be found. Although not yet properly eval-
`uated, the possibility of autologous stem cell transplanta-
`tion
`for
`younger
`patients
`has
`been
`discussed
`[14, 19, 22, 27, 28]. Another interesting candidate might be
`immunotherapy by anti-CD20 antibody with or without a
`radioactive label [29].
`In conclusion, MCL is seen in elderly patients with
`advanced stage at the time of diagnosis. Long-term prognosis
`is poor, and none of the conventional chemotherapies seems
`to be curative. A benefit of anthracyclines was seen in this
`study, but a prospective randomised trial should be made to
`evaluate their value.
`
`1. Shivdasani RA, Hess JL, Skarin AT, Pinkus GS. Intermediate
`lymphocytic lymphoma: clinical and pathologic features of a
`recently characterized subtype of non-Hodgkin’s lymphoma. J
`Clin Oncol 1993, 11, 802–811.
`2. Zucca E, Stein H, CoiYer B. European Lymphoma Task Force
`(ELTF): report of the workshop on mantle cell
`lymphoma
`(MCL). Ann Oncol 1994, 5, 507–511.
`3. Banks PM, Chan J, Cleary ML, et al. Mantle cell lymphoma. A
`proposal
`for unification of morphologic,
`immunologic, and
`molecular data. Am J Surg Pathol 1992, 16, 637–640.
`4. Zuckerberg LR, Medeiros JL, Ferry JA, Harris NL. DiVuse low-
`grade B-cell
`lymphomas. Four clinically distinct
`subtypes
`defined by a combination of morphologic and immunopheno-
`typic features. Am J Clin Pathol 1993, 100, 373–385.
`5. Harris NL, JaVe ES, Stein H, et al. A Revised European–Ameri-
`can Classification of lymphoid neoplasms: a proposal from the
`International Lymphoma Study Group. Blood 1994, 84, 1361–
`1392.
`6. Molot RJ, Meeker TC, Wittwer CT, et al. Antigen expression
`and polymerase chain reaction amplification of mantle cell lym-
`phomas. Blood 1994, 83, 1626–1631.
`7. Rimokh R, Berger F, Cornillet P, et al. Break in the BCL-1 locus
`is closely associated with intermediate lymphocytic lymphoma
`subtype. Genes Chromosomes Cancer 1990, 2, 223–226.
`8. Williams ME, Meeker TC, Swederlow SH. Re-arrangement of
`the chromosome 11 bcl-1 locus in centrocytic lymphoma: analy-
`sis with multiple breakpoints probes. Blood 1991, 78, 493–498.
`9. De Boer CJ, Schuuring E, Dreef E, et al. Cyclin D1 protein
`analysis in the diagnosis of mantle cell lymphoma. Blood 1995,
`86, 2715–2723.
`
`IPR2018-00685
`Celgene Ex. 2049, Page 7
`
`

`

`336
`
`R. Oinonen et al.
`
`10. De Wolf-Peeters C, Pittaluga S. Mantle-cell lymphoma. Ann
`Oncol 1994, 5(Suppl. 1), S35–S37.
`11. Fisher RI, Dahlberg S, Nathwani BN, Banks PM, Miller TP,
`Grogan TM. A clinical analysis of two indolent lymphoma
`entites: mantle cell
`lymphoma and marginal zone lymphoma
`(including the mucosa-associated lymphoid tissue and mono-
`cytoid B-cell subcategories): a Southwest Oncology Group
`study. Blood 1995, 85, 1075–1082.
`12. Pittaluga S, Bijnens L, Teodorovic I, et al. Clinical analysis of
`670 cases in two trials of the European Organization for the
`Research and Treatment of Cancer Lymphoma Cooperative
`Group subtyped according to the Revised European–American
`Classification of lymphoid neoplasms: a comparison with the
`Working Formulation. Blood 1996, 87, 4358–4367.
`13. Meusers P, Engelhard M, Bartels H, et al. Multicentre random-
`ized therapeutic trial
`for advanced centrocytic lymphoma:
`anthracycline does not improve the prognosis. Hemat Oncol
`1989, 7, 365–380.
`14. Zucca E, Roggero G, Pinotti G, et al. Patterns of survival in
`mantle cell lymphoma. Ann Oncol 1995, 6, 257–262.
`15. The International Non-Hodgkin’s Lymphoma Prognostic Proj-
`ect. A predictive model for aggressive non-Hodgkin’s lymphoma.
`N Engl J Med 1993, 329, 987–994.
`16. WHO Handbook for Reporting Results of Cancer Treatment.
`OVset publication No. 48, World Health Organization, Geneva,
`1979.
`17. Lister TA, Crowther D, SutccliVe SB, et al. Report of committee
`convened to discuss the evaluation and staging of patients with
`Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 1989, 7,
`1630–1636.
`18. Anderson JR, Propert KJ, Harrington DP. Guidelines for
`reporting outcomes of lymphoma trials. J Clin Oncol 1988, 6,
`559–560.
`19. CoiYer B, Hiddemann W, Stein H. Mantle cell lymphoma: a
`therapeutic di