Short report
`
`Annals of Oncology 8: 701-704, 1997.
`© 1997 Kluwer Academic Publishers. Printed in the Netherlands.
`
`Intensive therapy with peripheral stem cell transplantation in 16 patients with
`mantle cell lymphoma
`
`N. Ketterer, G. Salles, D. Espinouse, C. Dumontet, E. M. Neidhardt-Berard, I. Moullet, F. Bouafia,
`F. Berger, P. Felman & B. Coiffier
`Service d'Hematologie, Centre Hospitaller Lyon-Sud, Hospices Civils de Lyon and UPRES-JE1879
`Claude Bernard, Pierre-Benite, France
`
`'Hemopathies Lymphoides malignes \ Universite
`
`Summary
`
`Background: Despite improved detection of mantle cell lym-
`phoma (MCL), results of its treatment with conventional thera-
`pies remain disappointing and the survival rate poor. The role
`of high-dose chemotherapy has recently been investigated but
`no potential benefit has been clearly established. We report
`here our experience with MCL patients treated with intensive
`chemotherapy and autologous stem cell transplantation (ASCT).
`Patients and methods: Of the 16 MCL patients who received
`high-dose chemotherapy and ASCT beginning in 1989, six
`were treated in first-line and 10 in sensitive relapse. Twelve
`of 16 patients received regimens which included total body
`irradiation. All patients received peripheral blood stem cells
`(PBSC) with the exception of one, who underwent bone mar-
`row transplantation.
`Results: Three patients died of toxic effects of treatment.
`Three months after transplant, seven achieved complete re-
`
`sponses (CR) and two partial responses (PR), two were stable
`and two had progressed. With a median follow-up after trans-
`plant of 22 months, five of the six surviving patients were
`without progression, and three were in CR. The median times
`for event-free survival (EFS) and overall survival (OS) were,
`respectively, 249 and 317 days. The expected three-year EFS
`and OS were 24%. The median survival after diagnosis was
`only 29 months. None of the criteria appeared to be signifi-
`cantly associated with a better outcome, but first-line intensifi-
`cation and a short delay after initial diagnosis may be favor-
`able.
`Conclusion: In this study we were not able to confirm the
`hypothetical benefit of high-dose chemotherapy and PBSC
`transplantation in mantle cell lymphoma, even though this
`approach may be promising in a subgroup of patient.
`
`Key words: autologous transplant, lymphoma, mantle cell,
`peripheral stem cells
`
`Introduction
`
`Mantle cell lymphoma (MCL) is now acknowledged to
`be an entity, including the previously-designated centro-
`cytic or diffuse small cleaved cell lymphomas, with dis-
`tinct immunophenotypic and genetic features [1, 2]. Typ-
`ically, MCL tumor cells show a high expression of IgM,
`IgD and CD20 and a low expression of CD5, while there
`is usually no expression of CD10 and CD23 [3]. The
`most consistent abnormality is a t(ll;14) translocation
`typically found in 70% of cases [4] which results in
`overexpression of the 6c/-1 gene.
`The natural history of MCL shows continuous pro-
`gression toward increased malignancy, even though a
`true histological transformation is a rare event [5]. Prog-
`nosis is poor, with a median survival of three to four
`years [5-8]. Despite further illumination of the disease,
`the therapeutic options remain unclear [9]. The role of
`anthracycline-containing regimens is still controversial
`[7, 10], but an advantage for a CHOP-like aggressive
`chemotherapy has recently been suggested [8]. Other
`studies have demonstrated that the only important pa-
`rameter associated with a longer survival is achievement
`
`of complete remission (CR) [8, 10, 11]. These results
`suggest a role for high-dose therapy with stem cell res-
`cue, and recent reports with a few patients seem encour-
`aging [12, 13]. We report here our experience from 1989
`to 1996 with 16 MCL patients receiving high-dose
`chemotherapy and autologous stem cell rescue.
`
`Patients and methods
`
`Patients
`
`Between August 1989 and February 1996, 16 patients (Table 1) with
`MCL were treated with high-dose chemotherapy and autologous stem
`cell rescue in our department. Histological diagnoses were reviewed
`(FB, PF) in accord with the R.E.A.L. Classification definitions.
`Patients were selected for high-dose chemotherapy because of first
`treatment line failure (refractoriness or relapse), or because of two or
`three unfavorable-prognosis criteria according to the age-adjusted
`International Prognosis Index (IP!) at diagnosis [14], One patient with
`one IPI criteria received high-dose treatment while in partial remission
`(PR) after undergoing the CHOP regimen. All patients had complete
`tumor restaging, including bone marrow (BM) examination, shortly
`before intensive therapy (Table 2). Five patients were in CR, three
`having been treated in first relapse, one in first-line and one in second
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`Table 1 Characteristics of 16 mantle cell lymphoma patients at
`diagnosis.
`
`Table 2. Patient characteristics before high-dose chemotherapy.
`
`Parameters
`
`No. (%)
`
`Parameters
`
`No. (%)
`
`1(6)
`8(50)
`7(44)
`
`1(6)
`3(19)
`1(6)
`5(31)
`6(38)
`9(56)
`
`7(44)
`9(56)
`
`No. of previous treatment
`
`1 2 >
`
`i
`Status at transplant
`First-line in CR
`First relapse in CR
`Second relapse in CR
`First-line in PR
`First relapse in PR
`Persistance of BM infiltration (at harvest)
`Delay between diagnosis and transplant
`< 1 year
`>1 year
`
`* Before conditioning regimen.
`
`progression. Event-free survival (EFS) was defined as the time from
`reinfusion of PBSC to the time of first event, whether progression or
`treatment-related death. Survival distributions were estimated by the
`Kaplan-Meyer product-limit method [15], and observed differences
`were assessed using the log-rank test.
`
`Sex
`Male
`Female
`Age (years)
`<55
`» 55
`Performance status
`0-1
`>2
`Ann arbor stage
`I-II
`III-IV
`B symptoms present
`Lactate dehydrogenase above normal value
`Generalized lymphadenopathy°
`BM involvement
`No. of extranodal site > 1
`Spleen involvement
`GI tract involvement
`Age-adjusted IPI
`0-1
`2-3
`
`7(43)
`9(57)
`
`10(62)
`6(38)
`
`14(87)
`2(12)
`
`1(6)
`15(94)
`2(12)
`6(38)
`12(75)
`12(75)
`8(50)
`5(31)
`3(19)
`
`9(57)
`7(43)
`
`Abbreviations: BM - bone marrow; GI - gastro-intestinal; IPI -
`International Prognostic Index.
`" Generalized lymphadenopathy = disease involving both sides of the
`diaphragm and > 3 lymph nodes area.
`
`Results
`
`Population treated
`
`relapse. Five of the 11 PR patients were intensified in first PR and six
`after responding to salvage regimens.
`
`Treatment
`
`During the seven years of this study, induction chemotherapy varied
`but all patients received at least one anthracydine-containing regimen.
`The source of the stem cells and the conditioning regimen were uni-
`form: the patient treated in 1989 was transplanted with bone marrow,
`while all others received peripheral blood stem cells (PBSC), in one
`case combined with bone marrow. PBSC mobilisation was performed
`with chemotherapy (cyclophosphamide 5,25 g/m2 or 4,5 g/m2 plus
`etoposide 450 mg/m2) followed by growth factors in 11 cases. The
`conditioning regimen consisted of cyclophosphamide plus etoposide
`and fractionated total body irradiation (10 Gy over three days) in 12
`patients, BEAM (BCNU, etoposide, aracytine, melphalan) in three
`patients, while one patient received cyclophosphamide, etoposide and
`BCNU (CBV).
`
`Response
`
`Three months after intensification, the treatment response was eval-
`uated by clinical examination, computerized tomography (CT) scan,
`bone marrow aspirate and biopsy. CR was defined as the disappear-
`ance of disease in all sites, including bone marrow. PR was defined as a
`reduction of more than 50% in the product of the two largest diameters
`of each measurable lesion, or as the persistence of bone marrow
`infiltration as the only residual site of disease.
`
`Statistical methods
`
`OveraU survival (OS) was defined as the time from reinfusion of PBSC
`until death or date of last visit. Freedom from progression (FFP) was
`defined as the time from reinfusion of PBSC to the time of disease
`
`The median number of chemotherapy regimens admin-
`istered before conditioning treatment was 2 (1-4). Six
`patients were intensified at first-line therapy, nine after a
`first relapse and one after the second relapse. The me-
`dian time between diagnosis and transplant was 18
`months (4-36). Disease status before high-dose chemo-
`therapy was CR in five patients and PR in 11, of whom
`nine had persisting marrow infiltration at the time of the
`PBSC collection (Table 2).
`The median number of reinfused MNC was 2.58
`x 108/kg (0.83-11.6). The median count of CFU-GM
`was 4.46 x 104/kg (2.55-298). The amount of CD34+
`cells (six patients) reached a median of 6.0 x 106/kg
`(0.7-44). After bone marrow or PBSC reinfusion (day
`0), the median time to achievement of a PN count
`> 0.5 G/l and > 1 G/l were, respectively, 12 (10-29) and
`13 (10-35) days, but two patients died before neutrophil
`recovery of bleeding complications. The median time to
`attainment of an unsupported platelet count ^ 20 G/l
`for 12 evaluable patients was 10 (7-34) days. The two
`patients who presented toxic death did not reach this
`count, and two further patients remained dependent on
`platelet transfusions for several months.
`
`Toxicity and results of treatments
`
`Two patients treated in 1991 died early, on days 19 and
`40, of toxic effects, one of diffuse and irreversible intra-
`alveolary haemorrhage during undocumented infection,
`and the other of uncontrolled intravesical bleeding. A
`third patient who still required platelet transfusions three
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`overall survival
`
`|
`
`'
`
`event-free survival
`
`703
`
`Upfront intensification (1st line) 16 pts)
`Intensification at progression (10 pts)
`
`12
`
`18
`
`21
`
`30
`
`36
`
`42
`
`48
`
`54
`
`72
`
`78
`
`84
`
`9C
`
`Figure 1. Overall and event-free survival after transplant.
`
`12
`
`18 24 30
`
`54 60
`36 42 48
`Overall survival in ""o-1**
`
`72
`
`78
`
`84
`
`90
`
`Figure 2. Comparison of overall survival in six patients who received
`upfront intensification (1st line), with 10 patients intensified at relapse
`
`months after transplant died on day 97 of intracerebral
`bleeding. These three patients in first relapse had been
`heavily pretreated at the time of the conditioning regi-
`men. Except for the two early deaths, the median time
`of hospitalisation after transplant was 18 days (12-41).
`Other relevant toxicities were grade 3 infection in five
`patients and grade 3 hepatic toxicity in one patient.
`Grade 3-4 digestive toxicity and mucositis occurred,
`respectively, in two and five patients.
`Three months after transplant, seven patients were in
`CR and two in PR, two were stable and two had pro-
`gressed. Of the seven patients who achieved CR, four
`relapsed at 11, 13, 15 and 17 months after intensive
`therapy, and three have died. The two patients in PR
`because of persisting BM infiltration were treated with
`interferon-a and remained in continuous PR 9+ and 6+
`months after transplant. With a median follow-up of 22
`months (12-90), only five patients are now alive without
`progression, three of them in CR. The median times of
`event-free survival (EFS) and overall survival (OS) were,
`respectively, 249 and 317 days (Figure 1). Excluding
`the three treatment-related deaths, the median time of
`freedom-from-progression (FFP) was 288 days. The
`expected three-year OS and EFS were, respectively,
`24% ± 13% and 24% ± 12%. The median OS after diag-
`nosis was 29 months. Considering different parameters
`before high-dose chemotherapy, neither disease status at
`transplant (PR versus CR), number of previous treat-
`ment before intensification, nor persistence of BM infil-
`tration at harvest could be identified as having signifi-
`cantly influenced outcome after transplant. A longer but
`not statistically significantly different survival was ob-
`served in patients intensified in first PR or CR (Figure 2)
`and in those intensified during the first year after diag-
`nosis than in patients intensified after progression or
`after more than one year of follow-up (P = 0.14 and 0.24,
`respectively).
`
`Discussion
`
`The results of this study analyzing 16 MCL-intensified
`patients are disappointing and fail to compare favorably
`
`with the outcome observed with standard chemotherapy
`[7-9].
`Few studies had explored the existence of a dose-
`response relationship and the possible benefit of high-
`dose chemotherapy in MCL. Stewart et al. reported the
`intensification of nine MCL patients, and suggested that
`high-dose treatment could yield benefit if delivered early
`in the disease [12]. Recently, Haas et al. reported 13
`patients who show a very favorable outcome, with a
`disease-free survival of 76% and an overall survival of
`92% [13].
`In the present study, we were not able to confirm
`those good results. One of the reasons may be that nine
`of 13 patients (69%) in the Haas study were in first
`remission as compared to six of 16 (38%) in our series.
`The importance of this point is suggested in Figure 2,
`which shows a better outcome for patients intensified in
`first remission. Secondly, the median time from diag-
`nosis to intensive treatment in the Haas study was 12
`months compared to 18 months in our trial. The patients
`in our study who were intensified less than one year after
`initial diagnosis tend to have better outcomes. However,
`this apparent benefit of early intensification may only
`reflect the natural history of the disease.
`Moreover, CR before high-dose therapy has been ob-
`tained in only five (31%) cases in the present trial,
`compared with eight (62%) in the Haas study. Intensifi-
`cation has made possible the achievement of two further
`CR in our group of patients. Of the six patients who
`were not in CR after transplant, five had persisting BM
`infiltration as the only site of disease. However, we must
`note that two of the three patients alive in CR showed
`minimal but persistent BM infiltration before under-
`going the high-dose conditioning regimen. Achievement
`of CR in the bone marrow is certainly an important
`factor in longer survival, and indicates that a small
`infiltration does not preclude intensification.
`Finally, we cannot rule out that the dose of the TBI
`administered (14.4 Gy in the Haas study compared with
`10 Gy in our study) could also be a reason for the differ-
`ence observed between the results of these two trials.
`We were not able to establish, on the basis of this
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`704
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`trial, a benefit for intensive chemotherapy for MCL
`patients. However, in view of these results and others,
`this approach could be beneficial for some patients. In
`this hypothesis, it is possible that intensification in first-
`line and a short delay between lymphoma diagnosis and
`transplant, could represent important criteria, whereas
`intensification is probably not beneficial after relapse.
`
`References
`
`1. Banks PM, Chan J, Clearly ML et al. Mantle cell lymphoma. A
`proposal for unification of morphologic, immunology, and mo-
`lecular data. Am J Surg Pathol 1992; 16: 637^40.
`2. Harris NL, Jaffe ES, Stein H et al. A revised European-American
`Classification of lymphoid neoplasms. A proposal from the Inter-
`national Lymphomas Study Group. Blood 1994; 84: 1361-92.
`3. Zucca E, Stein H, CoifBer B. European Lymphoma Task Force
`(ELTF): Report of the workshop on Mantle Cell Lymphoma
`(MCL). Ann Oncol 1994; 5: 507-11.
`4. Rosenberg CL.Wong E, Petty EM et al. PRAD 1, a candidate bcl-\
`oncogene: Mapping and expression in centrocytic lymphoma.
`Proc Natl Acad Sci USA 1991; 88: 9638-42.
`5. Berger F, Felman P, Sonet A et al. Nonfollicular small B-cell
`lymphomas: A heterogeneous group of patients with distinct clin-
`ical features and outcome. Blood 1994,83 (10): 2829-35.
`6. Velders GA, KJuin-Nelemans JC, De Boer CJ et al. Mantle-Cell
`Lymphoma: A population-based clinical study. J Clin Oncol 1996;
`14: 1269-74.
`7. Zucca E, Roggero E, Pinotti G et al. Patterns of survival in
`mantle cell lymphoma. Ann Oncol 1995; 6: 257-62.
`8. Teodorovic I, Pittaluga S, KJuin-Nelemans JC et al. For the
`European Organization for the Research and Treatment of Can-
`
`cer Lymphoma Cooperative Group. Efficacy of four different
`regimens in 64 mantle-cell lymphoma cases: Climcopathologic
`comparison with 498 other non-Hodgkin's lymphoma subtypes. J
`Clin Oncol 1995; 13: 2819-26.
`9. Coiffier B, Hiddemann W, Stein H. Mantle Cell Lymphoma: A
`therapeutic dilemma. Ann Oncol 1995; 6: 208-10.
`10. Meusers P, Engelhard M, Bartels H et al. Multicentre randomized
`therapeutic trial for advanced centrocytic lymphoma: Anthracy-
`cline does not improve the prognosis. Hematol Oncol 1989; 7:
`365-80.
`11. Bookman MA, Lardelli P, Jaffe ES et al. Lymphocytic lymphoma
`of intermediate differentiation: Morphologic, immunopheno-
`typic, and prognostic factors. J Natl Cancer Inst 1990; 82: 742-8.
`12. Stewart DA, Vose JM, Weisenburger DD et al. The role of high-
`dose therapy and autologous hematopoietic stem cell transplanta-
`tion for mantle cell lymphoma. Ann Oncol 1995; 6: 263-6.
`13. Haas R, Brittinger G, Meusers P et al. Myeloablative therapy
`with blood stem cell transplantation is effective in mantle cell
`lymphoma. Leukemia 1996; 10: 1975-9.
`14. Shipp MA et al. A predictive model for aggressive non-Hodgkin's
`lymphoma. (The International Non-Hodgkin's Lymphoma Prog-
`nostic Factors Project). N Engl J Med 1993, 329: 987-94.
`15. Kaplan EL, Meier P. Nonparametric estimation from incomplete
`observations. J Am Stat Assoc 1958; 53: 157.
`
`Received 7 March 1997; accepted 14 May 1997.
`
`Correspondence to:
`Prof. G. Salles
`Service d'Hematologie
`Centre Hospitalier Lyon-Sud
`69495 Pierre-Benite Cedex
`France
`
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