Symposium article
`
`Annals of Oncology 11 (Suppl. 1): SU7-S121. 2000.
`© 2000 Khmer Academic Publishers. Primed in the Netherlands.
`
`Treatment of mantle-cell lymphoma with Rituximab (chimeric monoclonal
`anti-CD20 antibody): Analysis of factors associated with response
`
`J. M. Foran,1 D. Cunningham,2 B. Coiffier,3 P. Solal-Celigny,4 F. Reyes,5 M. Ghielmini,6
`P. W. M. Johnson,7 C. Gisselbrecht,8 M. Bradburn,9 J. Matthews1 & T. A. Lister1
`}ICRFMedical Oncology Unit. St. Bartholomew's Hospital. London; 2 Department of Medicine, Royal Marsden Hospital, Simon, UK;
`3Department of Hematology, Centre Hospitalier Lyon Sud; A Centre Jean Bernard, Le Mans; 5Department of Hematology, Hopilal Henri Mondor,
`Creteil. France, bServizio Oncologico, Ospedale San Giovanni, Bellinzona, Switzerland; 'ICRFCancer Medicine Unit, St. James's Hospital, Leeds,
`UK; 8Department of Hematology, Hopital Si Louis, Paris, France; 9ICRF Medical Statistics Group. Oxford, UK
`* See pages 120-121 for a list of principal in vest iga tors and centres
`
`Summary
`
`Background; A retrospective analysis was performed to delin-
`eate the factors associated with response, and to determine
`the duration of response, in 87 patients with CD20-positive
`mantle-cell lymphoma (MCL) treated with Rituximab (chi-
`meric monoclonal anti-CD20 antibody) in two prior studies.
`Patients and methods: Patients with newly-diagnosed MCL
`(MCL1, n - 37), and previously-treated MCL (MCL2, n = 50),
`received single-agent Rituximab, in the context of two multi-
`centre clinical studies using different schedules and doses,
`conducted in 1996 and 1997. A follow-up analysis was per-
`formed at the end of 1998, including all 81 patients who
`completed therapy. Statistical modeling of factors associated
`with response was performed using ordered logistic regression.
`The duration of complete (CR) and partial response (PR), and
`the time to disease progression (TTP), were also derived.
`Results: The overall response rate (RR) was 34% (30 of 87)
`(81 evaluable patients, RR 37%; CR 14%), and was equivalent
`for MCL1 and MCL2. On univariate analysis, elevated LDH
`
`(P = 0.004); prior therapy with alkylating agents (P = 0.01) or
`fludarabine phosphate (P = 0.04); WHO performance status =
`2 (P = 0.02); MCL2 refractory to last prior therapy (P = 0.04);
`and splenomegaly (P = 0.04), each at the time of treatment
`with Rituximab, were significantly associated with a lower RR.
`On multivariate analysis, only LDH (P = 0.007) and prior
`alkylating agents (P - 0.03) retained statistical significance.
`At a median follow-up of 1.4 years, the median TTP was
`7 months. The median duration of response was one year, and
`was significantly longer for patients achieving CR vs. PR
`(P = 0.04).
`Conclusions- Rituximab is active in MCL, and can induce
`complete responses in a minority of patients. Elevated LDH at
`the time of therapy, and prior therapy with alkylating agents,
`are associated with a significantly lower RR. The duration of
`response of one year is similar to that previously reported in
`follicular lymphoma.
`
`Key words: anti-CD20, chimeric monoclonal antibody, mantle-
`cell lymphoma, R.E.A.L. Classification, Rituximab
`
`Introduction
`
`Mantle-cell lymphoma (MCL) is an uncommon sub-type
`of B-cell non-Hodgkin's lymphoma (NHL), representing
`approximately 6% of new cases [1]. Although frequently
`responsive to cytotoxic chemotherapy, complete remis-
`sion is uncommon, and disease progression is the rule
`[2-4]. The clinical course of MCL is characterised by a
`short median survival (approximately three years), and
`very few long-term survivors [1-4]. MCL is therefore
`considered incurable with present therapy.
`Rituximab, a chimeric monoclonal anti-CD20 anti-
`body [5], has been evaluated primarily in previously-
`treated follicular lymphoma, where it has demonstrated
`significant activity [6, 7]. The median duration of re-
`sponse has been reported to be approximately one year
`[7], However, until recently, little was known about the
`efficacy of Rituximab in MCL, which also expresses
`CD20, or in patients with newly-diagnosed disease.
`
`In two recent studies, significant activity of Rituximab
`was noted in patients with MCL, both newly-diagnosed
`and previously-treated [8, 9]. In order to further charac-
`terise its activity, a retrospective analysis including
`both sets of patients was performed in December 1998,
`to delineate the factors associated with response to
`Rituximab, and with the duration of response. The
`results form the basis of this report.
`
`Patients and methods
`
`Patients
`
`Eighty-seven patients with MCL received single agent Rituximab in
`two multicentre studies evaluating its efficacy in patients with: (i)
`'intermediate-grade' NHL [8] (according to the NCI Working Formu-
`lation) [10]; and (ii) MCL. immunocytoma. and small B-lymphocytic
`lymphoma [9] (Kiel Classification) [11]. The study protocols were
`approved by the local hospital ethics committee for each participating
`
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`n
`
`62
`33-83
`
`66
`21
`
`41
`33
`13
`
`5
`76
`
`74
`
`4 9
`
`37
`24
`22
`
`3 2 1
`
`-9
`
`Table 1. Baseline clinical characteristics (« = 87).
`
`Characteristics
`
`Age (in years)
`Median
`Range
`Sex
`Male
`Female
`WHO performance status
`
`0 1 2
`
`Extent of disease (data available on n =81)
`Limited
`Extensive
`Rituximab dose and schedule
`375 mg/m2/week x 4
`375 mg/m2/week x 8
`500 mg/m2/week x 8
`Disease status at treatment (data available on n = 86)
`Newly-diagnosed
`Relapsed
`Refractory
`"Consolidation of prior response'
`No of previous treatments (n = 50)
`Median
`Range
`
`cline-based regimens (combination chemotherapy including doxo-
`rubicin. most commonly 'CHOP' or "CHVP'); fludarabine phosphate;
`or consolidative high-dose therapy (with autologous haematopoietic
`support).
`Strict response criteria were applied, using the sum of bidimen-
`sional measurements of measurable lesions, and all responses were
`confirmed one month later, in accordance with WHO response crite-
`ria. Briefly, a complete response (CR) was defined as the complete
`resolution of any evidence of MCL, with no residual lymphadenopathy
`> 1 cm2; partial response (PR) was defined as a > 50% decrease in
`measurable lesions as noted above, and a > 50% decrease in 'un-
`measurable' lesions (e.g., bone marrow (BM) infiltration); stable dis-
`ease, a ^50% decrease in MCL, or <25% increase, measured as
`under 'PR'; -and progressive disease. (PD) a >25% increase in disease,
`or the development of any new manifestations of MCL.
`
`Statistical considerations
`
`In order to determine which factors at the time of treatment were
`associated with response (PR and CR). an analysis was performed
`including the factors listed in Table 2. Statistical modeling was per-
`formed by ordered logistic regression [13]. using the four possible
`outcomes to treatment (CR, PR, SD, or PD). Model building was
`performed by first assessing significant univariate factors (P $ 0.05).
`then forming a multivariate model consisting of these, adding or
`subtracting terms as were or were not influential. A (3 coefficient above
`zero is associated with a lower response rate (RR). while a (3 coefficient
`below zero is associated with a higher response rate.
`The duration of response, time to progression (TTP), and survival
`following Rituximab were calculated according to the method of
`Kaplan and Meier [14]. The duration of response was calculated from
`the date of response (CR and PR) to the date of progression. The time
`to progression (TTP) was measured from the start of treatment until
`progression of MCL. including all patients who had a response, and
`those in whom treatment failed (SD and PD). Patients were censored
`in the latter two analyses at the time of further therapy for MCL if
`given prior to disease progression [e.g.. if given as consolidation of
`response following Rituximab (patients achieving CR and PR), or to
`inducea response following failure of the treatment (patients achieving
`
`118
`
`centre, and informed written consent was obtained from each patient
`prior to therapy. All patients were treated between December 1996,
`and December 1997. The participating centres and principle investiga-
`tors are noted in the Appendix.
`Six patients did not complete therapy, and were inevaluable for
`response, the primary outcome of this analysis. They were therefore
`not included in the analysis of response, response duration, and time to
`progression, but have been included in the analysis of overall survival
`from treatment. The reasons for not completing therapy were: Death
`due to splenic rupture following the first infusion of Rituximab (n = 1);
`anaphylaxis (n = 2); atrial fibrillation and congestive cardiac failure
`(/; = 1): and, abnormal liver function tests (n = 1). The remaining
`patient withdrew consent to continue with treatment prior to its
`completion.
`The diagnosis of MCL was assigned at the individual centre
`according to the criteria of the proposed R.E.A.L. Classification [12];
`tumour cell expression of CD20 was confirmed in all cases. Both
`newly-diagnosed (MCL1) and previously-treated (MCL2) patients
`were eligible; those with central nervous system involvement. World
`Health Organisation (WHO) performance status (PS) >2, or active
`hepatitis B or C. or HIV infection, were excluded. The characteristics
`of the 87 patients at the time of treatment are noted in Table 1.
`
`Treatment
`
`Rituximab was administered as a single agent by intravenous infusion
`over several hours once weekly for either four or eight weeks, in
`accordance with guidelines issued by Roche Pharmaceuticals (Basel.
`Switzerland). The majority of patients received a four-week course of
`therapy (375 mg/m2 x 4. n = 74), although 13 received an eight-week
`course. The latter 13 patients were randomised to receive either 375
`mg/m2 (n = 4) or 500 mg/m2 (n = 9) [15]. Patients received an anti-
`pyrexic and an anti-histamine as prophylaxis prior to therapy, although
`concomitant administration of corticosteroids was not permitted in
`either study. Restaging studies (CTscanning and bone marrow trephine
`biopsy) were performed one and two months following the completion
`of therapy.
`
`Response and follow-up
`
`Further information on all patients was obtained from the individual
`investigators in December 1998, including details of the clinical and
`biological characteristics of the MCL at the time of treatment with
`Rituximab, and follow-up data. Follow-up data included the dates of
`further treatment and disease progression, and of last follow-up or
`death. The details of previous treatments, and dates of therapy and
`response to Rituximab, were obtained from the pre-existing database
`of the two studies.
`
`Definitions
`
`Abnormal blood test results (e.g., elevated LDH or (3-2 microglobuhn)
`were defined as being above the upper limit of normal at the individual
`centre. Many patients had received previous therapy, and therefore
`the Ann Arbor staging criteria was considered to be inappropriate.
`'Limited extent of disease' was thus defined as 'involvement of one
`or more lymph node regions on the same side of the diaphragm, or
`localised involvement of an extralymphatic organ or site"; all others
`were considered to have extensive disease. Most patients in this
`analysis had extensive disease. Bulk'disease was defined as > 10 cm at
`one or more measurable sites.
`Recurrent disease was defined as that previously responsive to
`treatment (i.e., PR or CR to the last chemotherapy regimen), while
`refractory disease was defined as the failure to respond (i.e.. SD or PD)
`to the last treatment. Three patients received treatment following an
`incomplete response to their last treatment (i.e., in PR), and the
`indication for therapy for these three was considered to be 'consolida-
`tion of prior response'.
`Among the previously-treated patients, the preceding treatments
`were categorised generally as: 'Alkylating agents' (chlorambucil, or
`cyclophosphamide. vincristine and prednisolone-'CVP'); anthracy-
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`Table 2. Factors analysed in relation to response to Ritu.ximab. and
`significance using ordered logistic regression (n =81).
`
`Factor
`
`Univanate
`/•-value
`
`P coeffi-
`cient
`
`SE
`
`Univanate
`Elevated LDH
`Prior alkylating agents
`Performance status = 2
`Refractory disease
`Prior fludarabine phosphate
`Splenomegaly
`Gastrointestinal involvement
`Bulk disease
`Age at treatment
`Elevated 0-2 microglobulin
`Prior high-dose therapy
`Extensive disease
`No. of previous treatments
`Prior anthracycline
`Leukaemic phase
`Dose and schedule
`Blastic histologic variant
`Bone-marrow infiltration
`Multivariate
`Elevated LDH
`Alkylating agents
`
`26
`26
`13
`22
`12
`34
`10
`36
`N/A
`31
`7
`76
`N/A
`31
`24
`N/A
`12
`65
`
`0.004
`0.01
`0.02
`0.04
`0.04
`0.05
`0.06
`0.07
`0.21
`0.23
`0.30
`0.37
`0.47
`0.51
`0.64
`0.85
`0.89
`0.93
`
`0.007
`0.03
`
`1.44
`1.26
`1.53
`1.09
`1.20
`0.89
`1.18
`0.79
`0.03
`0.63
`0.81
`-0.82
`0 48
`0.28
`0.22
`0 13
`0.08
`0.04
`
`1.36
`1.09
`
`0.50
`0.50
`0.65
`0.52
`0.59
`0.45
`0.63
`0.43
`0.02
`0.52
`0.78
`0.91
`0.57
`0.43
`0.46
`0.67
`0.60
`0.45
`
`0.51
`0.50
`
`Abbreviations: SE - standard error of the (5 coefficient; N/A —
`measured as a continuous variable, and therefore 'not applicable'.
`
`SD)]. Differences in the duration of response and TTP between groups
`were analysed for statistical significance using the log-rank test. Sur-
`vival was calculated from the start of treatment until death, including
`all 87 patients. Patients were censored at last follow-up in each of the
`analyses if the event (I e., PD or death, respectively) had not yet
`occurred.
`
`Results
`
`Response
`
`119
`
`were not associated with a higher RR. It must be noted
`that the number of patients treated with a higher dose or
`longer course of therapy was relatively small.
`On multivariate analysis, only elevated LDH (P =
`0.007) and previous alkylating agents (P = 0.03) retained
`statistical significance.
`
`Duration of response
`
`Seven of thirty patients were censored in this analysis at
`the time of further treatment given to consolidate the
`response achieved with Rituximab, (i.e., prior to MCL
`progression). At a median follow-up of 1.4 years, 12
`patients have developed progressive MCL. The median
`duration of response was one year.
`The duration of response was significantly longer for
`patients achieving CR vs. PR (P = 0.04) (Figure 1), but
`not for patients with MCL1 vs. MCL2 (not shown). The
`median duration of CR has not yet been reached, and
`the median duration of PR was almost seven months.
`
`Time to progression following Rituximab
`
`Twenty of eighty-one patients were censored in this
`analysis, at the time of further therapy for MCL prior
`to documentation of progressive MCL. At a median
`follow-up from therapy of 1.4 years, 48 patients have
`developed PD. The median TTP from the start of treat-
`ment was seven months (Figure 2). There was no differ-
`ence between patients with MCL1 vs. MCL2, or for
`patients with relapsed vs. refractory disease.
`
`Survival
`
`The median survival of patients with MCL2 was 1.7
`years, and for those with MCL1 has not yet been
`reached (not shown).
`
`A response was achieved in 30 patients (CR, n = 11;
`PR, n - 19). Six patients did not complete therapy, and
`treatment failed in the remaining 51 (SD, n = 33; PD,
`n - 18). The overall RR was therefore 34% (30 of 87).
`Considering only evaluable patients (n - 81), the RR
`was 37%, and was the same for patients with both MCL1
`and MCL2. The CR rate was 14%.
`
`Analysis of factors associated with response
`
`On univariate analysis, several factors at the time of
`treatment were associated with a significantly lower RR
`(Table 2), including: Elevated LDH (P - 0.004); refrac-
`tory disease (P = 0.04); PS of two (P - 0.04); and
`splenomegaly (P - 0.05). Previous therapy with either
`alkylating agents, or with fludarabine phosphate, were
`also associated with a lower RR {P - 0.01 and P - 0.04,
`respectively). Gastrointestinal tract involvement (P = 0.07)
`and bulky disease (P = 0.07), had borderline significance.
`Importantly, MCL1, and Rituximab dose and schedule
`(500 mg/m2 vs. 375 mg/m2, and eight vs. four weeks),
`
`Discussion
`
`Anti-CD20 monoclonal antibody-based therapy with
`Rituximab can induce a remission in over one-third of
`patients with MCL, both newly-diagnosed and previ-
`ously-treated. Importantly, some (albeit few) patients
`achieve CR, which in many instances appears to be
`durable. The treatment of MCL has been unsatisfactory;
`more intensive anthracycline-based chemotherapy regi-
`mens have not been shown to improve survival [4, 15],
`and high-dose therapy does not appear to offer long-
`term remission to most patients [16]. New treatments for
`MCL are needed, and Rituximab is therefore a welcome
`and important addition.
`The CR rate of 14% in this study compares favorably
`with the experience of Rituximab in follicular
`lym-
`phoma (CR rate 6%), although the overall RR in MCL
`was somewhat lower (approximately 50% in follicular
`lymphoma) [7]. The finding that the RR was similar for
`both MCL1 and MCL2 was unexpected. This suggests
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`120
`
`DURATION OF REMISSION
`
`TIME TO PROGRESSION
`
`, CRN" 11
`
`PRN=19
`
`N=81
`
`TIME (years)
`
`Figure 1 The duration of response for patients achieving CR vs. PR
`(P = 0.04).
`
`TIME (years)
`
`Figure 2. Time to progression from the start of treatment (/! = 81)
`
`that the activity of Rituximab is not affected by prior
`exposure to cytotoxic chemotherapy, and that resistance
`to Rituximab is therefore mediated by some other
`(unique) mechanism.
`Patients previously-treated with alkylating agents had
`a lower RR (24%). While the import of this is not clear,
`it must be stressed that this represents a statistical
`association (and not causation), and that the reasons
`for prescribing alkylating agents for specific patients
`with MCL may play a large role in confounding inter-
`pretation of this finding. In this study, those treated with
`alkylating agents were more likely to have refractory
`disease, to be older, and to have had a greater number
`of previous treatments. Obviously, then, other factors
`may be at play, and this result should be treated with
`caution.
`In contrast, it is not surprising that LDH at the time
`of treatment was closely associated with response. Ele-
`vated LDH is an important adverse prognostic factor in
`both aggressive and indolent NHL [17, 18].
`Most patients in this study had extensive disease, and
`many had other adverse risk factors (e.g., refractory
`disease, extranodal involvement, elevated (3-2 micro-
`globulin, etc.). While adverse prognostic factors are
`common in MCL [1-4], it is possible that patients with
`a more favorable prognostic profile (e.g., limited stage
`disease, normal LDH, etc.) may have a higher RR to
`Rituximab. It was beyond the scope of this study to
`determine whether other histological, immunopheno-
`typic, or molecular biological factors (e.g., presence of
`t(ll;14)) had an impact on the response to Rituximab.
`The duration of response (median 1 year) was encour-
`aging, and was similar to that seen in follicular lympho-
`ma. However, the TTP gives a more accurate description
`of the expectations of treatment for the larger group of
`evaluable patients. The median TTP of only seven
`months for both MCL1 and MCL2 was disappointing.
`The fact that all of the patients with PD following
`therapy are included in the analysis of TTP, while 20
`patients (including seven who achieved a response) were
`censored at the time of further therapy, suggests that this
`
`is maybe a conservative estimate. However, the relent-
`less pattern of progression (Figure 2), and the persistent
`decline in survival evident following treatment, suggests
`that Rituximab will not significantly alter the clinical
`course of the disease. Single agent Rituximab does not
`therefore represent a cure for MCL, but instead may
`offer significant benefit in the palliative setting.
`The activity of Rituximab, and in particular the
`ability to induce a complete response in some patients,
`suggests a future role for its use in the treatment of
`MCL. Studies of Rituximab in combination with cyto-
`toxic chemotherapy in other subtypes of NHL have
`demonstrated high complete response rates with (gener-
`ally) acceptable toxicity [19, 20]. Combination studies in
`MCL to test that hypothesis are now appropriate.
`
`Acknowledgements
`
`The authors gratefully acknowledge the help of Radiol-
`ogists, diagnostic Haematologists, and Pathologists at
`the participating centres, and the medical and nursing
`staff who helped care for the patients. In particular, we
`acknowledge the patients who participated in these early
`phase II studies.
`
`* Appendix
`
`List of principal investigators and centres
`
`T. A. Lister (St. Bartholomew's Hospital, London, UK); D. Cunning-
`ham (Royal Marsden Hospital. Sutton. UK): B. Coiffier (Centre
`Hospitalier Lyon Sud. France): P. Solal-Celigny (Centre Victor Hugo.
`Le Mans, France): F. Reyes (Hopital Henri Mondor. Creteil, France);
`F. Cavalli (Ospedali San Giovanni, Bellinzona, Switzerland); P.
`Johnson (St. James' Hospital, Leeds, UK): C. Gisselbrecht (Hopital
`St. Louis, Paris, France): G. Nedellec (Hopital destructions des
`Armees de Percy, Clamart. France): J. F. Rossi (Hopital Lapeyronie.
`Montpellier. France); A. Delmer (Hotel Dieu, Paris. France): B. Varet
`(Hopital Necker, Paris, France): E. Bessell (Nottingham City Hospital.
`Nottingham. UK); N. Milpied (Hotel Dieu, Nantes. France): J. A.
`Radford (Christie Hospital. Manchester. UK); J. Sweetenham (Royal
`
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`South Hants. Hospital. Southampton. UK.): H. Tilly (Centre Henri
`Becquerel. Rouen. France): P. Colombat (Hopital Bretonneau, Tours,
`France): D. Ma (Royal North Shore Hospital, St. Leonards. NSW.
`Australia); R. Pettengell (St. George's Hospital. London. UK).
`
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`
`Correspondence to.
`J. M. Foran, MD
`Imperial Cancer Research Fund Medical Oncology Unit
`Department of Medical Oncology
`St. Bartholomew's Hospital
`45 Little Britain
`London EC1A 7BE
`UK
`E-mail: foran@icrf.icnet.uk
`
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