(1998) 12, 1281–1287  1998 Stockton Press All rights reserved 0887-6924/98 $12.00 http://www.stockton-press.co.uk/leu Mantle cell : a retrospective study of 121 cases H Samaha1, C Dumontet1, N Ketterer1, I Moullet1, C Thieblemont1, F Bouafia1, E Callet-Bauchu2, P Felman2, F Berger3, G Salles1 and B Coiffier1

1Service d’He´matologie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, and UPRES-JE 1879 ‘He´mopathies Lymphoides malignes’, Universite´ Claude Bernard, Pierre-Be´nite; 2Laboratoire d’He´matologie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Be´nite; and 3Laboratoire d’Anatomie Pathologique, Hoˆpital Edouard-Herriot, Hospices Civils de Lyon, France

Mantle cell lymphoma (MCL) patients represent a difficult prob- phoma usually begins as a disseminated disease with wide- lem, sometimes to establish the diagnosis but mostly because spread involvement of lymph nodes, spleen, bone marrow of their refractoriness to standard lymphoma treatments. Which treatments to apply and to whom is not yet defined. In this and other extranodal sites, specially the gastrointestinal tract study, we attempted to analyze the clinical features, to identify and Waldeyer ring. However, patients usually present a good the major prognostic factors, and to evaluate the outcome of performance status (PS) at diagnosis although adverse prog- 121 MCL patients treated in our institution between 1979 and nostic factors, such as high serum lactic dehydrogenase (LDH) 1997. Clinical data, treatment modalities, and International and ␤2-microglobulin levels, may be present. Initially, these Prognostic Index (IPI) score were evaluated. Median age was 63 patients usually respond to different types of therapy, but years. Patients usually presented with advanced stage disease (87%), disseminated lymph nodes (57%), bone marrow involve- relapses are frequent and rapid. With relapses, the disease ment (79%), but with a good performance status (PS) (81%). becomes more disseminated and gains characteristics of Ͼ4000/␮l and/or peripheral blood involvement aggressiveness and the response to therapy becomes worse or was present in 36% of cases, and gastrointestinal disease in very short. Fatal evolution is ineluctable, with a median over- 18%. The t(11;14)(q13;q32) and/or bcl-1 rearrangement was all survival being the worst compared to other lymphoma cat- detected in 47/57 studied cases. Median overall survival (OS) egories, ranging between 3 and 4 years in all studies.15 was 3.12 years and a longer survival was significantly associa- ted with younger age (Ͻ70 years), good PS (Ͻ2), localized dis- In this study, we attempted to evaluate the clinical features, ease (stage I–II), fewer than two extra-nodal sites, absence of prognostic factors and outcome of the 121 MCL patients spleen or peripheral blood involvement, normal serum LDH and treated in our institution. ␤2-microglobulin levels, and hemoglobin level greater than 12 g/dl. However, the IPI failed to identify patients with longer OS and in a multiparametric analysis, only older age, hemoglo- Patients and methods bin less than 12 g/dl, poor PS, and blood involvement were associated with a poorer outcome. Treatment modalities had no impact on survival with 75% of patients relapsing or pro- Patient population and characteristics gressing. Our data showed that the poor outcome of MCL patients is mainly related to adverse patient characteristics, a Among 1919 consecutive non-Hodgkin’s lymphoma patients highly disseminated tumor, and some unknown parameters treated in our institution between 1979 and 1997, 121 cases associated with the refractoriness to standard therapy. (6.8%) have been diagnosed as MCL. All these cases were Keywords: ; prognostic factors; outcome retrospectively reviewed and complete disease history from initial diagnosis, clinical features, treatment modalities, and follow up information were collected. Introduction Evaluated parameters and initial staging procedures included physical examination, complete blood count with In 1991, Raffeld and Jaffe proposed the term ‘mantle cell lym- differential, serum chemistry panel, serum ␤2-microglobulin phoma’ to the entity previously known as centrocytic lym- and LDH levels, chest radiography, CT scan of the thorax, phoma, lymphocytic lymphoma of intermediate grade of dif- abdomen and pelvis, and bone marrow . Extranodal 1–6 ferentiation, or mantle zone lymphoma. A common sites were biopsied whenever involvement was suspected. biological abnormality for this lymphoma was described with Patients were staged according to the Ann Arbor system, and the identification of the t(11;14) translocation in the majority PS was evaluated according to the Eastern Cooperative of cases. This chromosomal abnormality results in rearrange- Group (ECOG) scale. Patients were assigned to one ment of the bcl-1 gene and deregulation of , which of four prognostic scores according to the International Prog- is a nuclear protein that controls the progression of G1 and nostic Index (IPI) that takes into account the presence or G1/S transition.6–8 The normal counterpart of this lymphoma + − − absence of prognostic factors (serum LDH level, age, stage, is thought to be a population of CD5 CD10 CD23 mantle performance status and number of extranodal sites).16 zone .9 Although clinical and pathological aspects have been well described,5,10,11 controversy still remains about the 12,13 best treatment and the most valuable prognostic factors. Tumor characteristics Although this is a rare lymphoma that represents no more than 14,15 10% (2.5–11%) of all lymphoma subtypes, it recently Diagnosis relied on a typical morphology and/or a typical gained much interest because of its poor outcome which con- immunophenotype. For cases diagnosed before 1992, pathol- stitutes a major disappointing problem for clinicians. This lym- ogy specimens have already been reviewed as part of other studies.15,17 Diagnosis relied on a biopsy in 82 cases, Waldeyer ring tumor biopsy in 12, bone marrow biopsy Correspondence: B Coiffier, Service d’He´matologie, Centre Hospi- talier Lyon-Sud, 69495 Pierre Be´nite Cedex, France; Fax: +33 478 86 in 12, gastrointestinal tract biopsy in eight, splenectomy in 65 66 four, parotid gland, prostate, or skin biopsy in one case each. Received 13 March 1998; accepted 14 May 1998 These patients were divided into two groups for the pattern of Mantle cell lymphoma H Samaha et al 1282 infiltration, diffuse vs nodular (defined only on lymph node death or last contact if the patient did not progress. Disease- specimens), and for the type of lymphoma cells, small to free survival (DFS) was defined for patients who achieved CR medium cells vs large cells (defined as more than 20% large from the date of the beginning of the treatment until relapse, cell in the infiltration). No case with the mantle zone aspect death or last contact. Actuarial survival curves were estimated was individualized. Immunophenotyping varied according to by the Kaplan–Meier method19 and compared by the log-rank the date of biopsy; CD5 immunophenotyping was available test. Chi-square test was used in univariate analysis to deter- in 69 patients, CD10 in 39, CD23 in 55, CD43 in 19, heavy mine whether variables were predictive for response. P values chain immunoglobulin in 52 and light chain in 53 cases. Ͻ0.05 were considered to indicate significant statistical differ- Cytogenetic analysis was performed in 43 cases and the bcl- ences. A multivariate Cox regression analysis was done for 1 rearrangement at the MTC region was studied using the PCR parameters at diagnosis associated with survival.20 Parameters amplification technique in 51 cases. PCR amplification of the entered in the analysis were age, stage, , PS, blood bcl1-JH rearrangement was performed with standard tech- involvement, large spleen, bulky tumor, number of extranodal niques using a consensus JH primer (ACCTGAGGAGACGGT- locations, hemoglobin, LDH, ␤2-microglobulin, and serum GACCAGGGT) and an oligonucleotide for the bcl1-MTC albumin levels. In one analysis the IPI score was not included region (GGGCTTCTCTCACCTACTAATATCG).7 in the analysis and the second analysis was stratified on IPI scores. A logistic regression was realized to determine the parameters associated with a response to therapy.21 Treatment modalities

Most patients received as part of their primary Results treatment: 68 patients received an anthracycline-containing regimen and 43 patients had chemotherapy without anthra- Tumor characteristics cycline (chlorambucil: 22 patients; fludarabine: 12; other mul- tidrug regimens: eight; and anti-CD20 : one patient). All cases were reviewed by at least one expert pathologist. Six patient had no initial treatment; three received exclusive The initial diagnosis made by the local pathologists was modi- radiotherapy; and one patient underwent a splenectomy with fied in 47.5% of cases (n = 58); 15 cases being previously no further treatment. classified as diffuse small cleaved cell lymphoma (subtype E Thirteen patients treated with an anthracycline-containing according to the ), nine cases as chronic regimen received further consolidation by a high-dose mye- lymphocytic leukemia (CLL), and 39 cases were included in loablative radio-chemotherapy and stem cell transplant. These different other histologic categories. Seventy-three percent of patients were selected for high-dose chemotherapy because the cases having a wrong initial diagnosis were cases diag- of first-line treatment failure (refractoriness or relapse), or nosed before 1992. because of two or three unfavorable prognosis parameters. In this study, the architectural pattern of the lymph node The source of stem cells and the conditioning regimen were was diffuse in 54 specimens and nodular in 28. A predomi- quite uniform: only one patient, treated in 1989, was trans- nance of large and/or blastoid cells was observed in 10 planted with bone marrow cells after receiving CBV patients, the other cases having the classical small to medium- (, BCNU, ) as a conditioning regi- sized cell infiltration with 21 of them having some large cells men. All other patients received peripheral blood stem cells but less than 20%. Twenty-four patients showed a transform- (PBSC) combined with bone marrow cells in one case. The ation to a more aggressive histology with predominance of conditioning regimen consisted of cyclophosphamide plus blastoid cells during the course of their disease. Median time etoposide and fractionated in these to transformation (after diagnosis) was 26 months (range 3 to cases.18 54 months). Eighteen responding patients (CR or PR) received mainte- CD5, CD10, CD23 and CD43 immunophenotyping was nance therapy: six with chlorambucil ± and 12 available in 69, 39, 55 and 19 patients, respectively, and were with interferon, seven of them after myeloablative therapy found positive in 64, one, three and 12 cases, respectively. with PBSC transplant. The case with a positive reaction to CD10 antigen presented a double CD10 and CD5 population. This case was reviewed by an expert pathologist and kept as a MCL because of typical Assessment of response morphology. Cytogenetic analysis was done in 43 cases and a typical t(11;14)(q13;q32) was found in 38 of them. The bcl- Complete response (CR) was defined as the complete disap- 1 rearrangement at the MTC region was studied in 51 cases pearance of all physical signs of disease with complete resol- and was found in 25 cases. The t(11;14)(q13;q32) and/or bcl- ution of all previously abnormal investigations including bone 1 rearrangement was detected in 47 of the 57 cases studied marrow biopsy. Partial response (PR) was defined as the by at least one of the two techniques. regression of at least 50% of all measurable disease. Failure was determined as of less than PR, or progressive disease, or death during treatment. Patient characteristics

The main clinical features at diagnosis are illustrated in Table Statistical methods 1. The median age was 63 years (range, 32–84 years). The male to female ratio was 2:1. One hundred patients had stage Overall survival (OS) was calculated from the date of diag- IV disease (83%), five had stage III (4%), eight had stage II nosis until death from any cause or loss to follow-up. Freedom (6.5%), and eight other patients had stage I disease (6.5%). from progression (FFP) survival was calculated from the date Only seventeen patients had B symptoms at presentation. of the beginning of the treatment to the date of progression or Fifty-seven percent of the patients presented with generalized Mantle cell lymphoma H Samaha et al 1283 Table 1 Clinical characteristics of 121 patients with mantle cell in three patients. The isotype of M component matched that lymphoma of the surface Ig in only five (four IgM and one IgG) of the 13 specimens available. Characteristics n % When the international prognostic index (IPI) was applied to the 97 patients with sufficient available data (94 patients Median age at presentation 63 (32–84) had available data for the five parameters of the IPI and three age Ͼ60 years 47 39 age Ͼ70 years 31 25 other patients already presented with four adverse prognostic Sex ratio 2:1 factors without considering the serum LDH level), four sub- PS = 0–1 98 81 groups were identified: low risk subgroup (n = 14; 14%), low– B symptoms 17 14 intermediate risk subgroup (n = 27; 28%), intermediate–high Stage I–II 16 13 risk subgroup (n = 28; 29%) and high risk subgroup (n = 28; Stage III–IV 105 87 29%). Bulk tumor (T у 10 cm) 24 20 Abdominal 9 7 Fourteen patients (12%) had another some time dur- Splenica 10 8 ing their medical history: 10 patients presented cancer before Other 5 4 the diagnosis of lymphoma (median 3 years; range 0.5 to 31 Lymph node involvement years) and four patients after the diagnosis of MCL (median Diffuse 69 57 1.67 years; range 1 to 7 years). The primary site was the skin Localized 36 30 in three cases, colon, prostate, breast, and thyroid in two cases Absent 16 13 Extranodal sites each, and lung, vocal cord, and kidney in one case. Bone marrow 96 79 Spleen 58 47 Peripheral blood 44 36 Treatment and response Gastrointestinal 21 18 Colic 15 13 After the first treatment, 34 patients were in CR, 34 in PR Liver 15 13 Head and neck 14 12 (overall response rate 68%), 49 patients failed to respond, and Pleura 7 6 one patient died of massive pulmonary embolism. Of the 68 Lung 2 2 patients treated with an anthracycline-containing regimen, 20 Skin 3 2 reached a CR, 28 a PR (overall response rate 71%), 16 failed CSFb 11to respond, and one patient died. Details concerning response c Other 65to initial treatment are listed in Table 2. IPId 11414Univariate analysis showed that response to primary treat- 22728ment was strongly associated with a low risk or low–inter- 32829mediate risk IPI (P = 0.0001), Ͻ2 extranodal sites (including 42829spleen, bone marrow and peripheral blood) (P Ͻ 0.0001), nor- Anemia (Hb Ͻ12 g/dl) 38/103d 37 mal ␤2-microglobulin level (P = 0.0003), presence of B symp- d Thrombocytopenia 9/103 9 toms (P = 0.04), localized stage (P = 0.0014), absence of (plts Ͻ100 000/␮l) = Ͼ ␮ d (P 0.01), absence of peripheral blood involve- Lymphocytosis 4000/ l 20/103 19 Ͻ ␮ = Lymphocytosis Ͼ10 000/␮l 11/103d 11 ment, and absolute lymphocyte count 4000/ l(P 0.008), LDH Ͼnormal 38/94d 40 but not with age, gender, PS, presence of anemia, serum albu- Albumin Ͻ35 g/l 13/81d 16 min or LDH levels, nor to the histologic pattern of infiltration, ␤2-microglobulin Ͼ3 mg/l 46/83d 55 the presence of large cells at diagnosis, or to the treatment d Monoclonal component in serum 24/79 30 modality (anthracycline vs non-anthracycline containing IgM 12/24d 50 IgG 8/24d 33 regimen) (Table 3). In a logistic regression analysis, a response IgA 4/24d 17 to treatment, either CR or PR, was associated with no gastro- intestinal location (P Ͻ 0.05), low ␤2-microglobulin level (P Ͻ aSpleen у16 cm; bcerebrospinal fluid; cthyroid (1); pericard (1); 0.05), and with borderline significance absence of B symp- conjunctiva (1); prostate (1); mesenteric (1); peripheral nerves (1); toms and normal serum albumin level. ddata not available for all patients. Twenty-two patients initially treated with chlorambucil and 12 patients treated with fludarabine were compared to the rest of the study population, to the anthracycline-treated patients, lymph node enlargement while 13% (n = 16) had only and to 43 other patients treated with non-anthracycline-con- extranodal disease. Bone marrow involvement was observed taining regimens. No significant difference was found regard- in 79% (n = 96) of the patients and peripheral blood involve- ing the achievement of a complete response. However, ment and/or absolute lymphocyte count Ͼ4000/␮l in 36% (n patients treated with the anthracycline-containing regimen = 44) of them. Only 11 patients had a leukemic picture with achieved significantly more frequently a CR or PR in a logistic absolute lymphocytosis Ͼ10 000/␮l. Twenty-one patients regression analysis. The type of treatment was the most sig- (18%) had gastrointestinal disease and 15 of them presented nificant parameter (P Ͻ 0.001) followed by the level of ␤2- a colonic involvement. Other extranodal sites are illustrated microglobulin level (P = 0.01). in Table 1. Bulk disease (larger than or equal to 10 cm) was present in 19% (n = 24) of cases (abdominal mass in nine cases, splenic in 10, and other in five). Table 1 lists the Evolution and survival patients regarding biological parameters at diagnosis: 40% had high LDH level, 55% high ␤2-microglobulin level, 16% Seventy-five percent of the patients showed a progression of low serum albumin level, and 37% anemia. A monoclonal the disease or a relapse after initial treatment; with a median component was present in 24 cases, but Ͼ1 g/l in serum only FFP survival of 0.94 years (Figure 1). A short FFP survival was Mantle cell lymphoma H Samaha et al 1284 Table 2 Response according to treatment modalities

n CR (%) PR (%) SD-PD (%) Death (%) NA (%)

All treatment 121 34 (28) 34 (28) 49 (40) 1 (1) 3 (3) With anthracycline 68 20 (29) 28 (41) 16 (24) 1 (1) 3 (5) Chlorambucil 22 4 (18) 3 (14) 15 (68) 0 (0) 0 (0) 12 3 (25) 1 (8) 08 (67) 0 (0) 0 (0) Other 19 7 (37) 2 (10) 10 (53) 0 (0) 0 (0)

SD, stable disease; PD, progressive disease; NA, not available.

Table 3 Prognostic factors found statistically significant in univariate analysis (P value)

Variables na Achievement of Freedom from Overall CR progression survival survival

Age (р70/Ͼ70) 121 (90/31) NS NS 0.0075 PS (Ͻ2/у2) 118 (98/20) NS NS 0.001 B symptoms (±) 121 (17/104) 0.04 0.01 NS Stage (I–II/III–IV) 121 (16/105) 0.014 NS 0.02 Bulky (T Ͼ 10 cm) 121 (24/97) NS NS NS Spleen involvement 121 (57/64) 0.01 NS 0.04 Gastrointestinal involvement 121 (22/99) NS NS NS Peripheral blood involvement (±)b 121 (51/70) 0.008 0.02 0.0017 Number of extra-nodal sites (Ͻ2/у2) 121 (44/77) Ͻ0.0001 NS 0.00034 Hb (Ͻ12/Ͼ12) 102 (38/64) NS NS 0.014 Albumin (Ͻ35/у35) 81 (13/68) NS NS NS Beta-2-microglobulin (р3/Ͼ3) 83 (37/46) 0.0003 0.03 0.04 LDH (рN/ϾN) 94 (56/38) NS NS 0.009 IPI (р2/Ͼ2) 97 (41/56) Ͻ0.0001 — — Histologic pattern (diffuse/nodular) 82 (54/28) NS NS NS Large cells (±) 118 (31/87) NS NS NS bcl-1 or t(11;14) (±) 57 (47/10) NS NS NS Initial treatment (A+/A−)c 121 (68/53) NS NS NS

aNumber of documented data; bperipheral blood involvement or absolute lymphocytosis у4000/␮l; cwith or without anthracycline-based regimen.

Figure 1 Overall survival (OS), disease-free survival (DFS) and Figure 2 Overall survival according to the presence of peripheral freedom from progression survival (FFP) for the 121 patients. blood involvement (PBI).

strongly associated with the presence of B symptoms (P = 0.0075), good PS (P = 0.001), localized disease stage (P = 0.01), high ␤2-microglobulin level (P = 0.03), and the pres- 0.02), no enlarged spleen, no peripheral blood involvement ence of peripheral blood involvement (P = 0.02). (Figure 2) or absolute lymphocyte count Ͻ4000/␮l(P = 0.04 Median overall survival was 3.12 years (Figure 1). The prog- and P = 0.0017, respectively), low number of extranodal sites nostic impact of clinical and biologic parameters at diagnosis (P = 0.00034) (Figure 3), normal serum LDH and ␤2- is presented in Table 3. Longer survival appeared to be sig- microglobulin levels (P = 0.009 and P = 0.04, respectively), nificantly associated with younger age (Ͻ70 years) (P = absence of anemia (P = 0.014), good IPI score (P = 0.00003). Mantle cell lymphoma H Samaha et al 1285 tumor (P = 0.01). When the IPI was included in the analysis, the results did not change. The last analysis was stratified on IPI scores and determined that the parameters associated with a short survival were bulky tumor (P Ͻ 0.002), anemia (P Ͻ 0.01), blood involvement (P Ͻ 0.01), and older age (P Ͻ 0.02). Although it was not a randomized study, responding patients (CR or PR) were evaluated in order to assess the impact of maintenance therapy on overall survival and FFP survival. We did not find a significant difference between patients receiving maintenance therapy and other responding patients. We did not find a significant difference either, when we compared patients receiving chlorambucil and those receiving interferon as maintenance therapy. At the time of the analysis, 77 patients (64%) had died with a median survival of 3.12 years (range of survival for deceased patients: 0.22 to 11.34 years). The cause of death was pro- Figure 3 Overall survival according to extranodal sites number gression of the disease in 45 cases (58%), treatment related (ENS). (severe infections or hemorrhage) in 23 cases (30%), and death unrelated to the lymphoma or its treatment in nine other Median overall survival for the 14 low risk patients, the 27 cases (12%); four patients were lost to follow-up (three had low–intermediate risk, the 28 intermediate–high risk, and the progressive disease and the other CR at the date of the last 28 high risk patients was respectively 2.97, 2.36, 2.08 and contact). 1.24 years (Figure 4). A response to first-line treatment, either CR or PR, was associated with a longer survival (P = 0.02). Gender, presence of B symptoms, another associated pri- Discussion mary cancer, bulky tumor, gastrointestinal involvement, serum albumin level, presence of monoclonal component, Although increasing numbers of recent publications have histologic growth pattern, percentage of large cells at diag- described the characteristics, natural history, and prognostic nosis, blastoid transformation, detection of the t(11;14) or the factors of mantle cell lymphoma patients, confusion remains bcl-1 rearrangement, as well as the use of an anthracycline- about the latter, and many questions are still unresolved, containing regimen were not associated with a longer sur- especially those concerning the most adequate treatment. In vival. Overall survival of patients receiving intensive therapy this analysis of 121 MCL patients, the largest retrospective ser- and peripheral blood stem cell transplant after first-line treat- ies published to date, we attempted to find answers to these ment was not significantly superior to the overall survival of questions. The clinical features were comparable with those the rest of the population.18 Twenty-four patients showed a previously described:22–31 a median age of 63 years, male pre- histologic transformation and median survival after transform- dominance, good PS with few patients presenting B symptoms ation was 0.58 years. at diagnosis, advanced disease stage, widespread lymph node A multivariate analysis was run to determine the initial para- involvement with more than one extranodal site, the bone meters associated with shorter survival. In the first run, IPI was marrow being the most frequently infiltrated (79%), followed not included in the analysis and the parameters found to be by the spleen (47%), the peripheral blood (36%), the gastro- significantly associated with short survival were age older than intestinal tract (18%), the liver (13%), and the Waldeyer ring 70 (P Ͻ 0.0005), poor PS (P = 0.001), blood involvement (P (12%). = 0.001), hemoglobin level Ͻ12 g/dl (P Ͻ 0.05), and bulky One of the most striking findings in our study was that a relatively high number of cases (30%) had a circulating mono- clonal component, even if it was often at very low level. This could be explained by an immunoglobulin secretion by lym- phoma cells, as in some cases proposed by Preudhomme et al.32 Another explanation could be the one suggested by Hiro- kawa et al33 that a clonal Ig production may have been driven by autoreactive T cells, presumably against the neoplastic B cells. Several authors attempted to determine which clinical and pathological factors were of prognostic value. In particular, younger age at diagnosis, limited stage of disease, normal serum LDH level, good IPI, and achievement of a CR after initial treatment were found to be associated with a longer survival,24–26,28,30,31 but not in all retrospective series.28,30 In this study, we confirm that a longer survival was significantly associated with younger age (Ͻ70 years) and good PS. How- ever, we associated these parameters with the absence of per- ipheral blood involvement and absence of anemia. The most Figure 4 Overall survival according to the International Prognostic significant prognostic parameter in our series was the pres- Factor (IPI). (1, low risk group; 2, low–intermediate risk group; 3, inter- ence of peripheral blood involvement, a parameter already mediate–high risk group; and 4, high risk group.) identified in several other studies.25,28,31,34,35 The IPI per se Mantle cell lymphoma H Samaha et al 1286 could only individualize the high risk subgroup as being 4 The Non-Hodgkin’s Lymphoma Pathologic Classification Project. worse than the other but was not able to discriminate between National Cancer Institute sponsored study of classifications of non- the three other risk groups (Figure 4). In fact, the so-called Hodgkin’s . Summary and description of a Working Formulation for Clinical Usage. Cancer 1982; 49: 2112–2135. standard prognostic parameters such as IPI score, stage, PS, ␤ 5 Banks PM, Chan J, Cleary ML et al. Mantle cell lymphoma. A number of extranodal sites, LDH and 2-microglobulin levels proposal for unification of morphologic, immunologic, and mol- were not the most important parameters in our study. It may ecular data. Am J Surg Pathol 1992; 16: 637–640. suggest that MCL are different from other lymphomas. 6 Raffeld M, Jaffe ES. bcl-1, t(11;14), and mantle cell-derived lym- The two histologic subgroups did not differ significantly phomas. Blood 1991; 78: 259–263. regarding the response to therapy, FFP survival, or overall sur- 7 Rimokh R, Berger F, Delsol G et al. Detection of the chromosomal translocation t(11;14) by polymerase chain reaction in mantle cell vival. This is in agreement with other reports suggesting that 25,29 lymphomas. Blood 1994; 83: 1871–1875. growth pattern has no impact on outcome. However, our 8 Rosenberg CL, Wong E, Petty EM et al. PRAD1, a candidate BCL1 number of patients is too low to formerly refute the con- oncogene: mapping and expression in centrocytic lymphoma. clusions from other authors regarding the poor outcome Proc Natl Acad Sci USA 1991; 88: 9638–9642. associated with presence of blastoid cells at diag- 9 Vandenberghe E, van den Oord J, Mecucci C, van den Berghe H, nosis22,25,28,30,31,34,36 or the indolent course of patients having De Wolf-Peeters C. B-cell non-Hodgkin’s lymphomas of follicle a mantle zone pattern.27 In contrast with other authors’ find- mantle lineage: part of a biological spectrum. Leukemia 1991; 5: 25 829–831. ing, histologic transformation during the course of the dis- 10 Zucca E, Stein H, Coiffier B. European Lymphoma Task Force ease was not associated with a shorter survival, but our num- (ELTF): report of the workshop on Mantle Cell Lymphoma (MCL). ber of patients is low and the definition of the transformation Ann Oncol 1994; 5: 507–511. is not yet standardized. 11 Weisenburger DD, Armitage JO. Mantle cell lymphoma. An entity Because this lymphoma type is rare and only recently indi- comes of age. Blood 1996; 87: 4483–4494. vidualized, very few prospective studies evaluated the efficacy 12 Coiffier B, Hiddemann W, Stein H. Mantle cell lymphoma: a therapeutic dilemma. Ann Oncol 1995; 6: 208–210. of a particular treatment modality. In some retrospective stud- 13 Coiffier B. Which treatment for mantle-cell lymphoma patients in ies, an anthracycline-containing chemotherapy was found to 1998. J Clin Oncol 1998; 16: 3–5. be associated with a prolonged overall survival,23 especially 14 Pittaluga S, Bijnens L, Teodorovic I et al. Clinical analysis of 670 for the patients with favorable IPI scores (low and intermediate cases in two trials of the European Organization for the Research risk disease).24 This finding was not demonstrated in other ser- and Treatment of Cancer Lymphoma Cooperative Group subtyped ies25,31 but it seems to be confirmed by the regression logistic according to the Revised European–American Classification of analysis in our patients. Preliminary results of an ongoing trial lymphoid . A comparison with the Working Formu- lation. Blood 1996; 87: 4358–4367. suggest that maintenance therapy with interferon alpha could 15 The Non-Hodgkin’s Lymphoma Classification Project. A clinical 37,38 be associated with a prolonged DFS but this benefit was trial of the International Lymphoma Study Group classification of not observed by Teodorovic et al23 and we did not find any non-Hodgkin’s lymphoma. Blood 1997; 89: 3909–3918. advantage for a maintenance therapy either with chlorambucil 16 The International Non-Hodgkin’s Lymphoma Prognostic Factors or with interferon alpha, probably because of the small num- Project. A predictive model for aggressive non-Hodgkin’s lym- ber of patients in our study. phoma. New Engl J Med 1993; 329: 987–994. 17 Berger F, Felman P, Sonet A et al. Nonfollicular small B-cell lym- A more aggressive therapy, myeloablative chemotherapy phomas: a heterogenous group of patients with distinct clinical with peripheral stem cells transplant, was recently pro- features and outcome. Blood 1994; 83: 2829–2835. posed18,39,40 but did not result in better long-term outcome 18 Ketterer N, Salles G, Espinouse D et al. Intensive therapy with except in one report,40 even with the ex vivo purge of the peripheral stem cell transplantation in 16 patients with mantle cell harvest.41,42 lymphoma. Ann Oncol 1997; 8: 701–704. 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